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WO2025064325A1 - Gpr35 modulators - Google Patents

Gpr35 modulators Download PDF

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Publication number
WO2025064325A1
WO2025064325A1 PCT/US2024/046835 US2024046835W WO2025064325A1 WO 2025064325 A1 WO2025064325 A1 WO 2025064325A1 US 2024046835 W US2024046835 W US 2024046835W WO 2025064325 A1 WO2025064325 A1 WO 2025064325A1
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compound
solvate
pharmaceutically acceptable
acceptable salt
formula
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French (fr)
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Robert I. Higuchi
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Prometheus Biosciences Inc
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Prometheus Biosciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • IBD inflammatory bowel disease
  • CD Crohn’s disease
  • UC ulcerative colitis
  • ⁇ is a single or double bond;
  • ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; , ynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 4 , -SR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , -
  • C2-6alkynyl, Cs- ecycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; each R 8 is independently selected from -CN, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cs- ecycloalkyl, C2-9heterocycloalkyl. Ce-ioaryl, Ci-9heteroaryl. -SR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , - OC(O)N(R 4 )(R 5 ).
  • each R 9 is independently selected from halogen, -CN, Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, C2-9heterocycloalkyl, Ce-ioary l, and Ci gheteroaryl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof.
  • Formula (lb) is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof
  • ring A is phenyl.
  • ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
  • ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
  • ring A is oxazolyl or thiazolyl.
  • ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • ring A is a compound of Formula (I), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein the compound has the structure of Formula (laa), or a pharmaceutically acceptable salt or solvate thereof:
  • Formula (IIcc) is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ildd), or a pharmaceutically acceptable salt or solvate thereof:
  • In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb).
  • p is 1.
  • each R 2 is independently selected from halogen, Ci-salkyl, and -OR 4 .
  • each R 4 is independently selected from H and unsubstituted Ci-ealkyl.
  • n 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + (Idd)
  • laa 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1
  • n 0.
  • composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd). or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • a method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb). (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc). or (Ildd). or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb). (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is selected from Crohn’s disease, ulcerative colitis, and perianal Crohn’s disease.
  • a method of modulating GPR35 activity comprising contacting GPR35, or portion thereof, with a compound of Formula (I), (la). (Ib), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie). (lid), (Ilaa), (Ilbb), (lice), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof.
  • Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.
  • Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e g., electroporation, lipofection).
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • Cl-Cx includes C1-C2, C1-C3 . . . Cl-Cx.
  • Cl-Cx refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
  • An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl groups may or may not include units of unsaturation.
  • the alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon-carbon double bond or a carboncarbon triple bond).
  • the alkyl group may also be an “unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation.
  • the alkyl moiety, whether saturated or unsaturated may be branched, straight chain, or cyclic.
  • the “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyd” where no numerical range is designated).
  • the alkyd group of the compounds described herein may be designated as "Ci-Cealkyl" or similar designations.
  • Ci- Cealkyl indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.
  • Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
  • alkoxy refers to a “-O-alkyl” group, where alkyl is as defined herein.
  • alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a “cycloalkenyl” group).
  • Alkenyl groups may have 2 to 6 carbons.
  • Alkenyl groups can be substituted or unsubstituted.
  • an alkenyl group can be a monoradical or a diradical (i.e.. an alkenylene group).
  • the “R” portion of the alkynyl moiety’ may be branched, straight chain, or cyclic.
  • An alkynyl group can have 2 to 6 carbons.
  • Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
  • Amino refers to a -NH2 group.
  • “Dialkylamino” refers to a -N(alkyl)2 group, where alkyl is as defined herein.
  • aromatic refers to a planar ring having a delocalized Ti-electron system containing 4n+2 it electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups (e.g., phenyl, naphthal enyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
  • Aryl rings can be formed by five, six. seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • Carboxy refers to -CO2H.
  • carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhi bi Is similar physical and/or chemical properties as a carboxylic acid moiety.
  • a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
  • a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound.
  • a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
  • bioisosteres of a carboxylic acid include, but are not limited to,
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • heteroaryl or. alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • An A-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyL pyrazolyl, triazolyl, pyrazinyL tetrazolyl, fund, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline. 1,8-naphthyridine. and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, both rings of a bicyclic heterocycle are aromatic. In some embodiments, bicyclic heteroaryl is a Ce-Csiheteroaryl.
  • heterocycloalkyl group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur.
  • the radicals may be fused with an ary l or heteroaryl.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring.
  • the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • halo or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.
  • fluoroalkyl and fluoroalkoxy include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms.
  • fluoroalkyls include -CF3, -CHF2, -CH2F. -CH2CF3, -CF2CF3, -CF2CF2CF3. -CF(CH3)3, and the like.
  • fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, - OCF2CF2CF3, -OCF(CH3)2, and the like.
  • heteroalkyl refers to an alkyd radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3.
  • heteroalkyl may have from 1 to 6 carbon atoms.
  • bond or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
  • "Optional” or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
  • the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
  • a “therapeutically effective amount” as used herein refers to the amount of a compound of Formula (I) that, when administered to a mammal in need, is effective to at least partially treat the conditions described herein.
  • modulate encompasses either a decrease or an increase in activity depending on the target molecule.
  • activator is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically.
  • the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.
  • patient refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal.
  • a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /Mol uenesul Tonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates
  • Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • pharmaceutically acceptable base addition salts are formed wi th metals or amines, such as alkali and alkaline earth metals or organic amines.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A.A-dibenzylethylenediamine.
  • treatment or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
  • the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
  • GPR35 G Protein-Coupled Receptor 35
  • the compounds of Formula (I) described herein are GPR35 modulators. In some embodiments, compounds of Formula (I) described herein are GPR35 antagonists. In some embodiments, compounds of Formula (I) described herein are GPR35 agonists. In some embodiments, compounds of Formula (I) described herein are GPR35 inverse agonists. The compounds of Formula (I) described herein, and compositions comprising these compounds, are useful for the treatment of an inflammatory bowel disease.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein: is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; , ynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein the compound has the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein the compound has the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein the compound has the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein the compound has the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof: .
  • ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • ring B is pyridinyl.
  • ring B is triazinyl.
  • ring B is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is triazinyl.
  • ring B is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherei nd ring B is a 5- membered heteroaryl ring selected from oxazolyl, thiazoly rrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
  • nts is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is .
  • nts is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is independently selected from -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from -CN, C 1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from -CN and C1- 6 alkyl optionally substituted with one, two, or three R 9 .
  • R 3 is C2- 8 alkynyl.
  • ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
  • ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • ring A is pyridinyl.
  • [0084] is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CO 2 H.
  • R 1 is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is .
  • [0086] in some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , me ly acceptable salt or solvate thereof, wherein R 1
  • R 1 is a compound of Formula (I), acceptable salt or solvate thereof, wherein R 1 is .
  • R 1 is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 i .
  • R 1 is a compound of Formula (I), (Ia), (Ib), (Ic), or ( maceutically acceptable salt or solvate thereof, wherein R 1 .
  • In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pha y acceptable salt or solvate thereof, wherein R 1 i .
  • R 1 i is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1
  • ents is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a y acceptable salt or solvate thereof, wherein .
  • ents is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • n is 2.
  • n is 1 or 2.
  • each R 2 is independently selected from halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C1-9heteroaryl, -OR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , -C(O)R 7 , -C(O)N(R 4 )(R 5 ), -S(O)2R 7 , and - S(O) 2 N(R 4 )(R 5 )-, wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloal
  • each R 2 is independently selected from halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 4 , and -N(R 4 )(R 5 ), wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, -CN, C 1-6 alkyl, -OR 4 , and -N(R 4 )(R 5 ), wherein C 1-6 alkyl is optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, C1-6alkyl, and -OR 4 , and wherein each R 4 is independently selected from H and unsubstituted C1-6alkyl.
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof: , ynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , -SR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , - OC(O)N(R 4 )(R 5 ), -N(R 6 )C(O)N(R 4 )(R 5 ), -N(R 6 )C(O)OR 7 , -N(R 6 )S(O) 2 R 7 , -C(O)R 7 , -S(O)R 7 , - OC(O)R 7 , -C(O)N(R 4 )(R 5 ), -C(O)C(
  • a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof is , ynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , -SR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , - OC(O)N(R 4 )(R 5 ), -N(R 6 )C(O)N(R 4 )(R 5 ), -N(R 6 )C(O)OR 7 , -N(R 6 )S(O) 2 R 7 , -C(O)R 7 , -S(O)R 7 , - OC(O)R 7 , -C(O)N(R 4 )(R 5 ), -C(O)C(O)N(R 4 )(R 5 ), -C(O)C(O)
  • each R 8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from -CN, C 1-6 alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from -CN and C 1- 6alkyl optionally substituted with one, two, or three R 9 .
  • [0096] is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CO2H.
  • R 1 is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is .
  • [0098] is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 i , me lly acceptable salt or solvate thereof, wherein R 1
  • R 1 is a compound of Formula (Iaa), cceptable salt or solvate thereof, wherein R 1 is .
  • R 1 is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 i .
  • ents is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), o ly acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or y acceptable salt or solvate thereof, wherein . [0099] ents is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • n is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
  • n is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
  • n is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2.
  • each R 2 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , -C(O)R 7 , -C(O)N(R 4 )(R 5 ), -S(O)2R 7 , and - S(O)2N(R 4 )(R 5 )-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, wherein C
  • each R 2 is independently selected from halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , and -N(R 4 )(R 5 ), wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, -CN, C1-6alkyl, -OR 4 , and -N(R 4 )(R 5 ), wherein C1-6alkyl is optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, C 1-6 alkyl, and -OR 4 , and wherein each R 4 is independently selected from H and unsubstituted C1-6alkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 3 is ; ring B is pyridinyl; R 8 is C 1-6 alkyl; n is 0; p is 1; and q is solvate thereof, wherein: ; ring B is pyridinyl; R 8 is C1-6alkyl; n is 0; p is 1; and q is 1.
  • R 1 is -CO2H; R 3 is C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-8 alkyl; n is 0; and q is 1.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 3 is C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-8 alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 3 is C 1-8 alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein: 1 3 C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 3 is C 1-8 alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 3 is C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • R 1 is -CO2H
  • R 2 is -OR 4
  • R 3 is C1-8alkyl
  • R 4 is H
  • n is 1
  • q is 1.
  • a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 3 is C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-6alkyl; n is 0; and p is 1.
  • a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is halogen; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof wherein: is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • [0137] s a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is -CO 2 H; R 2 is C 1-6 alkyl; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • R 1 is -CO 2 H
  • R 2 is C 1-6 alkyl
  • R 8 is C 1-6 alkyl
  • n is 1
  • p is 1.
  • a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 4 is H; R 8 is C1-6alkyl; n is 1; and p is 1.
  • ula (Iaa), or a pharmaceutically acceptable salt or solvate t ereo , w ere n R 1 is ; R 8 is unsubstituted C6-10aryl; n is 0; and p is 1.
  • Pr rein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is -CO 2 H; R 8 is C 1-6 alkyl; n is 0; and p is 0.
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 0; and p is 0.
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 8 is C1-6alkyl; n is 0; and p is 1.
  • R 1 is -CO2H
  • R 8 is C1-6alkyl
  • n is 0
  • p is 1.
  • Ibb is halogen
  • R 8 is C1-6alkyl
  • n is 1
  • p is 1.
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof wherein: is halogen; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • R 1 is -CO2H; R 2 is C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof wherein: 1 2 C 1-6 alkyl; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 4 is H; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 is -CO2H
  • R 2 is -OR 4
  • R 4 is H
  • R 8 is C1-6alkyl
  • n is 1
  • p is 1.
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 1; and p is 1.
  • ula (Ibb), or a pharmaceutically acceptable salt or solvate thereof wherein: ; R 8 is unsubstituted C 6-10 aryl; n is 0; and p is 1.
  • a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 0; and p is 1.
  • a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof wherein: 1 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • [0159] s a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is -CO2H; R 2 is C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 is -CO2H
  • R 2 is C1-6alkyl
  • R 8 is C1-6alkyl
  • n is 1
  • p is 1.
  • a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 4 is H; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • R 1 is -CO 2 H
  • R 2 is -OR 4
  • R 4 is H
  • R 8 is C 1-6 alkyl
  • n is 1
  • p is 1.
  • ula (Icc), or a pharmaceutically acceptable salt or solvate thereof wherein: ; R 8 is unsubstituted C6-10aryl; n is 0; and p is 1.
  • rein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is -CO 2 H; R 8 is C 1-6 alkyl; n is 0; and p is 0.
  • a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate t ereo , w ere n R 1 is -CO2H; R 8 is C1-6alkyl; n is 0; and p is 1.
  • a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof wherein: 1.
  • Idd), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof wherein: is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • s a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is -CO2H; R 2 is C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 4 is H; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • R 1 is -CO 2 H
  • R 2 is -OR 4
  • R 4 is H
  • R 8 is C 1-6 alkyl
  • n is 1
  • p is 1.
  • Provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1.
  • R 1 is ; R 8 is unsubstituted C 6-10 aryl; n is 0; and p is 1.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein: is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; , l, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , -
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein the compound has the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: [0177] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof: [0178] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof: [0179] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof: [0180] In some embodiments is a compound of Formula (II), (IIa),
  • In some embodiments is a compound of Formula (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (II), (IIa), (IIb), ( ically acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (II), (IIa), (IIb), (I cally acceptable salt or solvate thereof, wherein In some embodiments is a compound of Formula (II), (IIa), (IIb) eutically acceptable salt or solvate thereof, wherein 2.
  • R 3 is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R is and ring B is a 5- membered heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
  • ring B is triazolyl.
  • ring B is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is tetrazolyl.
  • ring B is isoxazolyl.
  • a compound of Formula (II) is a compound of Formula (II).
  • ring B is isothiazolyl.
  • In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R and p is 0. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is and p is 1. In some embodiments is a compound of Formula (II), (IIa), (IIb), (I harmaceutically acceptable salt or solvate thereof, wherein R 3 is and p is 2.
  • each R 8 is independently selected from -CN, halogen, -OR 4 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from -CN, halogen, -OR 4 , C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from halogen, -OR 4 , and C 1-6 alkyl optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from halogen, -OH, -OCH3, and unsubstituted C 1-6 alkyl.
  • ring A is phenyl.
  • ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
  • ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
  • ring A is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl.
  • [0188] in some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 .
  • ents is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • n is 1 or 2.
  • a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof wherein n is 1 or 2.
  • each R 2 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C 1-9 heteroaryl, -OR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , -C(O)R 7 , -C(O)N(R 4 )(R 5 ), -S(O) 2 R 7 , and - S(O)
  • each R 2 is independently selected from halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , and -N(R 4 )(R 5 ), wherein C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, -CN, C1-6alkyl, -OR 4 , and -N(R 4 )(R 5 ), wherein C1-6alkyl is optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, C1-6alkyl, and -OR 4 , and wherein each R 4 is independently selected from H and unsubstituted C 1-6 alkyl.
  • In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2.
  • a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof is , l, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , -SR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , - OC(O)N(R 4 )(R 5 ), -N(R 6 )C(O)N(R 4 )(R 5 ), -N(R 6 )C(O)OR 7 , -N(R 6 )S(O) 2 R 7 , -C(O)R 7 , -S(O)R 7 , - OC(O)R 7 , -C(O)N(R 4 )(R 5 ), -C(O)C(O)N(R 4 )(R 5 ),
  • a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof is , l, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , -SR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , - OC(O)N(R 4 )(R 5 ), -N(R 6 )C(O)N(R 4 )(R 5 ), -N(R 6 )C(O)OR 7 , -N(R 6 )S(O) 2 R 7 , -C(O)R 7 , -S(O)R 7 , - OC(O)R 7 , -C(O)N(R 4 )(R 5 ), -C(O)C(O)N(R 4 )(R 5 ),
  • a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof is , l, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR 4 , -SR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , - OC(O)N(R 4 )(R 5 ), -N(R 6 )C(O)N(R 4 )(R 5 ), -N(R 6 )C(O)OR 7 , -N(R 6 )S(O) 2 R 7 , -C(O)R 7 , -S(O)R 7 , - OC(O)R 7 , -C(O)N(R 4 )(R 5 ), -C(O)C(O)N(R 4 )(R 5 ),
  • each R 8 is independently selected from -CN, halogen, -OR 4 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from -CN, halogen, -OR 4 , C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from halogen, -OR 4 , and C1-6alkyl optionally substituted with one, two, or three R 9 .
  • each R 8 is independently selected from halogen, -OH, -OCH 3 , and unsubstituted C1-6alkyl.
  • [0199] in some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is .
  • R 1 is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , me tically acceptable salt or solvate thereof, wherein R 1
  • a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof where In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd cally acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd) ally acceptable salt or solvate thereof, wherein .
  • nts is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • n is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
  • n is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
  • n 1 or 2.
  • n 1 or 2.
  • each R 2 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C 1-9 heteroaryl, -OR 4 , -N(R 4 )(R 5 ), -C(O)OR 4 , -C(O)R 7 , -C(O)N(R 4 )(R 5 ), -S(O) 2 R 7 , and - S(O)
  • each R 2 is independently selected from halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl, -OR 4 , and -N(R 4 )(R 5 ), wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, -CN, C 1-6 alkyl, -OR 4 , and -N(R 4 )(R 5 ), wherein C 1-6 alkyl is optionally substituted with one, two, or three R 9 .
  • each R 2 is independently selected from halogen, C1-6alkyl, and -OR 4 , and wherein each R 4 is independently selected from H and unsubstituted C 1-6 alkyl.
  • each R 2 is independently selected from halogen, C1- 6alkyl, -OH, and -OCH3.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 3 i ; ring B is pyridinyl; R 8 is C1-6alkyl; n is 0; p is 1; and q is 1.
  • R 1 is -CO2H; R 3 i ; ring B is pyridinyl; R 8 is C1-6alkyl; n is 0; p is 1; and q is 1.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 3 is C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate t ereo , w ere n R 1 is -CO2H; R 2 is -OR 4 ; R 3 is C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-8 alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 3 is C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-8 alkyl; n is 0; and q is 1.
  • a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 3 is C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • R 1 is -CO 2 H; R 3 is ; ring B is pyridinyl; R 8 is C 1-6 alkyl; n is 0; p is 1; and q is or solvate thereof, wherein: d q t or solvate thereof, wherein: R 1 is -CO 2 H; R 3 is C 1-8 alkyl; n is 0; and q is 1.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-8 alkyl; n is 0; and q is 1.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 3 is C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-8 alkyl; R 4 is H; n is 1; and q is 1.
  • Prov ded ere n s a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is -CO 2 H; R 3 is C 1-8 alkyl; n is 0; and q is 1.
  • R 1 is -CO 2 H
  • R 3 is C 1-8 alkyl
  • n is 0
  • q is 1.
  • Provided herein is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 3 is C 1-8 alkyl; R 4 is H; n is 1; and q is 1.
  • R 1 is -CO 2 H
  • R 2 is -OR 4
  • R 3 is C 1-8 alkyl
  • R 4 is H
  • n is 1
  • q is 1.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein: 1 3 C1-8alkyl; n is 0; and q is 1.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 3 is C 1-8 alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-8alkyl; R 4 is H; n is 1; and q is 1.
  • a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 0; and p is 1.
  • a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 i R 2 is halogen
  • R 8 is C 1-6 alkyl
  • n is 1
  • p is 1.
  • Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 4 is H; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 is -CO2H
  • R 2 is -OR 4
  • R 4 is H
  • R 8 is C1-6alkyl
  • n is 1
  • p is 1.
  • a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-6alkyl; n is 1; and p is 1.
  • ula (IIaa), or a pharmaceutically acceptable salt or solvate thereof wherein: ; R 8 is unsubstituted C 6-10 aryl; n is 0; and p is 1.
  • [0244] rein is a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R 8 is -OR 4 ; n is 0; and p is 1.
  • Provided herein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 i R 8 i C 1-6 alkyl; n is 0; and p is 0.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate t ereo , w ere n R 1 is -CO2H; R 8 is C1-6alkyl; n is 0; and p is 1.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 0; and p is 1.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof wherein: is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 is -CO2H; R 2 is C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 2 is C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 4 is H; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • R 1 is -CO 2 H
  • R 2 is -OR 4
  • R 4 is H
  • R 8 is C 1-6 alkyl
  • n is 1
  • p is 1.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is ; R 8 is unsubstituted C 6-10 aryl; n is 0; and p is 1.
  • Pr rein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R 8 is -OR 4 ; n is 0; and p is 1.
  • a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 8 is C 1-6 alkyl; n is 0; and p is 0.
  • a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 0; and p is 0.
  • a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 8 is C1-6alkyl; n is 0; and p is 1.
  • a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 0; and p is 1.
  • a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 is -CO2H; R 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 is -CO2H; R 2 is C1-6alkyl; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is -OR 4 ; R 4 is H; R 8 is C1-6alkyl; n is 1; and p is 1.
  • R 1 is -CO2H
  • R 2 is -OR 4
  • R 4 is H
  • R 8 is C1-6alkyl
  • n is 1
  • p is 1.
  • ula (IIcc), or a pharmaceutically acceptable salt or solvate thereof wherein: ; R 8 is unsubstituted C6-10aryl; n is 0; and p is 1.
  • [0268] rein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C 1-6 alkyl; R 8 is -OR 4 ; n is 0; and p is 1.
  • Provided herein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: C 1-6 alkyl; n is 0; and p is 0.
  • a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 8 is C1-6alkyl; n is 0; and p is 1.
  • R 1 is -CO2H
  • R 8 is C1-6alkyl
  • n is 0
  • p is 1.
  • a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: 1 C1-6alkyl; n is 0; and p is 1.
  • a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO2H; R 2 is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: is halogen; R 8 is C1-6alkyl; n is 1; and p is 1.
  • s a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 is -CO 2 H; R 2 is C 1-6 alkyl; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: C1-6alkyl; n is 1; and p is 1.
  • Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is -CO 2 H; R 2 is -OR 4 ; R 4 is H; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • R 1 is -CO 2 H; R 2 is -OR 4 ; R 4 is H; R 8 is C 1-6 alkyl; n is 1; and p is 1.
  • a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: C 1-6 alkyl; n is 1; and p is 1.
  • mula (IIdd), or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 is ; R 8 is unsubstituted C 6-10 aryl; n is 0; and p is 1.
  • Pro erein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate there of, wherein: 1 i 4 i C1-6alkyl; R 8 is -OR 4 ; n is 0; and p is 1.
  • nts is a compound selected from: , , , , f. ted herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
  • the therapeutic agent(s) e.g. compound of Formula (I)
  • any compound described above is suitable for any method or composition described herein.
  • the compounds described herein exist as geometric isomers.
  • the compounds described herein possess one or more double bonds.
  • the compounds presented herein include all cis, trans, syn, anti,
  • E
  • Z
  • the compounds described herein include all possible tautomers within the formulas described herein.
  • the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein.
  • the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers.
  • dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
  • Labeled compounds [0285] In some embodiments, the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H, 3 H, 13 C, 14 C, l5 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Pharmaceutically acceptable salts [0287] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Solvates [0289]
  • the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Synthesis of Compounds [0291] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary. [0292] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.
  • the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4 th Ed., Vols.
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. [0295] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
  • Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pd 0 -catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from: H 3 C H 3 C C H C (H C) C C H3 creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure).
  • Methods of Treatment and Prevention [0300] is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is selected from Crohn’s disease, ulcerative colitis, and perianal Crohn’s disease.
  • a method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is Crohn’s disease.
  • a method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is ulcerative colitis.
  • a method of treating an inflammatory bowel disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is perianal Crohn’s disease.
  • Pharmaceutical compositions and methods of administration [0301] In certain embodiments, the compounds described herein are administered as a pure chemical.
  • the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers.
  • the carrier(s) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof.
  • Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutically acceptable carrier consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), or a pharmaceutically acceptable salt or solvate thereof.
  • the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
  • formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration.
  • Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as
  • compositions comprise buffering agents.
  • solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • tablets, and other solid dosage forms such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.
  • compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
  • inert diluents such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl be
  • suspensions in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension is used.
  • sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Topical administration may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution.
  • a semi-solid composition is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company.
  • Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide an absorption enhancer such as DMSO to increase the absorption of the compounds.
  • Patches can include those that control the rate of drug delivery to the skin.
  • Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and talc, or mixtures thereof.
  • Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals.
  • such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice.
  • Sprays can additionally contain customary propellants, such a chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the dose of the composition comprising at least one compound described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.
  • Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented).
  • an appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration.
  • an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity).
  • Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.
  • Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. [0323] Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used. [0324] It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the compound of Formula (I) and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Exact dosages are determined in conjunction with standard dose-response studies.
  • Toxicity and therapeutic efficacy of a compound of Formula (I) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Step 2 Into a 500-mL round-bottom flask, was placed potassium 2,4-dioxo-1,3- thiazolidin-3-ide (17.0 g, 109.5 mmol, 1.00 equiv), DMF (170 mL), and ethyl 4-bromobutanoate (25.0 g, 128 mmol, 1.17 equiv). The resulting solution was stirred for 2 hr at 80 °C in an oil bath. The reaction was then quenched by the addition of 700 mL of water/ice. The resulting solution was extracted with 3 x 200 mL of ethyl acetate and the organic layers were concentrated under vacuum.
  • Step 3 Into a 100-mL round-bottom flask, was placed ethyl 4-(2,4-dioxo-1,3-thiazolidin- 3-yl)butanoate (3.00 g, 13.0 mmol, 1.00 equiv), concentrated HCl (15.0 mL), and AcOH (15.0 mL). The resulting solution was stirred for 1 overnight at 100 °C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 2.6 g (99%) of 4-(2,4-dioxo-1,3-thiazolidin-3- yl)butanoic acid as an off-white solid.
  • LCMS (ESI) 204.0 [M + H] + .
  • Step 4 Into a 100-mL round-bottom flask, was placed 4-(2,4-dioxo-1,3-thiazolidin-3- yl)butanoic acid (2.60 g, 12.8 mmol, 1.00 equiv), 4-ethylbenzaldehyde (1.89 g, 14.1 mmol, 1.10 equiv), pyrrolidine (1.80 g, 25.3 mmol, 1.98 equiv), MeOH (20 mL), and H 2 O (4.0 mL). The resulting solution was stirred for 3 hr at 25 °C, then the resulting mixture was concentrated under vacuum.
  • Step 5 To a stirred solution of (Z)-4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanoic acid (50.0 mg, 0.157 mmol, 1.00 equiv) and TEA (63.4 mg, 0.626 mmol, 4.00 equiv) in DCM (1.0 mL) was added 2,2-dimethylpropanoyl chloride (22.6 mg, 0.188 mmol, 1.20 equiv) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred for 30 min at 0 °C.
  • Example 4 Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 104) [0335] Into a 50-m 3 mmol, 1.00 equiv), toluene (10 mL), triethylamine hydrochloride (1.45 g, 10.5 mmol, 2.49 equiv), and NaN 3 (690 mg, 10.6 mmol, 2.51 equiv). The resulting solution was heated overnight at 100 °C. The reaction mixture was cooled to 25 °C.
  • Example 10 Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-nitrobenzoic acid (Compound 110) [0342] in-3- yl)butanoic acid (50.0 mg, 0.157 mmol, 1.00 equiv), DCM (1.00 mL), TEA (50.0 mg, 0.494 mmol, 3.16 equiv). To the above mixture was added 2,2-dimethylpropanoyl chloride (21.0 mg, 0.174 mmol, 1.11 equiv) dropwise over at 0 °C. The resulting mixture was stirred for 30 min at 0 °C.
  • Example 11 Synthesis of (Z)-2-amino-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 111) [0343 - dioxothiazolidin-3-yl)butanamido)-2-nitrobenzoic acid (450 mg, 0.931 mmol, 1.00 equiv), Fe (261 mg, 4.67 mmol, 5.02 equiv), NH 4 Cl (247 mg, 4.62 mmol, 4.96 equiv), EtOH (10 mL), and H 2 O (2.0 mL). The resulting mixture was stirred for 2 h at 70 °C.
  • Example 14 Synthesis of (Z)-2-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)oxazole-4-carboxylic acid (Compound 114) [0346] I din-3- yl)butanoic acid (50.0 mg, 0.157 mmol, 1.00 equiv), TEA (47.0 mg, 0.464 mmol, 2.97 equiv), and DMF (1.0 mL). To the above mixture was added BOP (69.0 mg, 0.156 mmol, 1.00 equiv) at 0 °C and the resulting mixture was stirred for 30 min at rt.
  • BOP 69.0 mg, 0.156 mmol, 1.00 equiv
  • Example 15 Synthesis of (Z)-4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)-N-(3- hydroxy-4-(1H-tetrazol-5-yl)phenyl)butanamide (Compound 115) [0347] Ste nzonitrile (4.20 g, 25.6 mmol, 1.00 equiv), toluene (30 mL), triethylamine hydrochloride (5.00 g, 36.3 mmol, 1.42 equiv), and NaN3 (2.40 g, 36.9 mmol, 1.44 equiv). The resulting solution was heated overnight at 100 °C.
  • Example 16 Synthesis of (Z)-5-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-[1,1'-biphenyl]-2-carboxylic acid (Compound 116) [0350] Ste 4.06 mmol, 1.00 equiv), phenyl boronic acid (0.99 g, 8.12 mmol, 2.00 equiv), K2CO3 (1.69 g, 12.2 mmol, 3.01 equiv) and Pd(dppf)Cl2 (0.30 g, 0.406 mmol, 0.10 equiv) in dioxane (10 mL) and H2O (1.0 mL) at rt.
  • Step 2 Into a 100 mL round-bottom flask was added 5-nitro-[1,1’-biphenyl]-2-carboxylic acid (260 mg, 1.07 mmol, 1.00 equiv), MeOH (10 mL) and Pd/C (26.0 mg, 0.1 equiv) at rt. The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred 1 h at rt under an atmosphere of hydrogen (balloon). The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 30 mL).
  • Example 17 Synthesis of (Z)-2-acetamido-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 117) [0353] Step mg, 2.74 mmol, 1.00 equiv), TEA (833 mg, 8.23 mmol, 3.00 equiv) and DCM (5 mL) at rt. Acetyl chloride (215 mg, 2.74 mmol, 1.00 equiv) was added dropwise at 0-5 °C (ice/water bath). The mixture was stirred for 1 h at rt, then concentrated under reduced pressure.
  • Example 21 Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- fluorobenzoic acid (Compound 121) [ - dioxothiazolidin-3-yl)butanoic acid (500 mg, 1.57 mmol, 1.00 equiv), EtOH (10 mL), Pd/C (50.0 mg, 0.470 mmol, 0.30 equiv). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred 2 h at rt under an atmosphere of hydrogen (balloon). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure.
  • Compound 121 [ - dioxothiazolidin-3-yl)butanoic acid (500 mg, 1.57 mmol, 1.00 equiv), EtOH (10 mL), Pd/C (50.0 mg, 0.470 mmol,
  • Example 26 Synthesis of the single enantiomers of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4- ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 126A and Compound 126B) [03 yl)butanamide (60 mg) was separated into the single enantiomers by chiral preparative HPLC using a CHIRALCEL OJ-3 column, 4.6*50mm, 3um. Mobile phase A: n-Hexane and B: Ethanol (with 0.1% TFA) (eluted with 40% B).
  • Example 31 Synthesis of 2-amino-4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 131) [0370] 2- nitrobenzoic acid (50.0 mg, 0.103 mmol, 1.00 equiv) in MeOH (5 mL) was added 10% Pd/C (11.0 mg, 0.010 mmol, 0.10 equiv) under nitrogen atmosphere. The mixture was stirred at rt for 4 h under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure.
  • Step 2 To a solution of tert-butyl (E)-but-2-enoate (2.00 g, 14.1 mmol, 1.00 equiv) and NBS (2.50 g, 14.1 mmol, 1.00 equiv) in CCl4 (20 mL) was added AIBN (0.23 g, 1.41 mmol, 0.10 equiv). The resulting mixture was stirred for 4 h at 80 °C. The mixture was allowed to cool to rt.
  • Step 3 Into a 8 mL vial was added (Z)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione (200 mg, 0.857 mmol, 1.00 equiv), tert-butyl (E)-but-2-enoate (228 mg, 1.03 mmol, 1.20 equiv) and K2CO3 (355 mg, 2.57 mmol, 3.00 equiv) in MeCN (2 mL) at rt. The mixture was stirred for 1 h at 80 °C.
  • Step 4 Into a 8 mL vial was added tert-butyl (E)-4-(5-((Z)-4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)but-2-enoate (280 mg, 0.750 mmol, 1.00 equiv), TFA (1.50 mL) in DCM (3.0 mL) at rt. The mixture was stirred for 1 h at rt, then the resulting mixture was concentrated under reduced pressure.
  • Step 5 Into a 8 mL vial were added (E)-4-(5-((Z)-4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)but-2-enoic acid (50.0 mg, 0.158 mmol, 1.00 equiv), DIEA (22.0 mg, 0.170 mmol, 1.09 equiv) and DCE (1.00 mL) at rt. To the above mixture was added 2, 2- dimethylpropanoyl chloride (21.0 mg, 0.174 mmol, 1.12 equiv) dropwise at 0-5 °C with ice/water bath. The resulting mixture was stirred for 1 h at rt.
  • Example 40 Synthesis of (E)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((Z)-4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)but-2-enamide (Compound 140) [0383 din-3- yl)but- 2-enoic acid (50.0 mg, 0.158 mmol, 1.00 equiv), pyridine (25.0 mg, 0.316 mmol, 2.01 equiv), 4-(1H-tetrazol-5-yl)aniline (31.0 mg, 0.192 mmol, 1.22 equiv) in DCM (1 mL) at rt.
  • Example 41 Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethoxybenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 141) [ , , 1.3 mmol, 1.00 equiv), KOH (1.30 g, 23.2 mmol, 1.09 equiv) and EtOH (50 mL). The resulting mixture was stirred for 1 h at 70 °C, then was allowed to cool down to rt.
  • Step 2 Into a 50 mL round-bottom flask was added potassium 2,4-dioxo-1,3-thiazolidin- 3-ide (2.80 g, 18.0 mmol, 1.00 equiv), ethyl 4-bromobutanoate (3.50 g, 17.9 mmol, 0.99 equiv), DMF (30 mL). The resulting mixture was stirred for 2 h at 80 °C. The mixture was allowed to cool down to rt.
  • Step 4 Into a 80 mL vial was added 4-(2,4-dioxo-1,3-thiazolidin-3-yl)butanoic acid (500 mg, 2.46 mmol, 1.00 equiv), 4-(1H-tetrazol-5-yl)aniline (475 mg, 2.95 mmol, 1.20 equiv), HATU (1.12 g, 2.95 mmol, 1.20 equiv), DIEA (953 mg, 7.37 mmol, 3.00 equiv), DMF (5.00 mL). The resulting mixture was stirred for 2 h at rt. The mixture was acidified to pH 3 with HCl (aq.). The precipitated solids were collected by filtration.
  • 4-(2,4-dioxo-1,3-thiazolidin-3-yl)butanoic acid 500 mg, 2.46 mmol, 1.00 equiv
  • 4-(1H-tetrazol-5-yl)aniline 475 mg, 2.
  • Step 5 Into a 8 mL vial was added N-(4-(1H-tetrazol-5-yl)phenyl)-4-(2,4- dioxothiazolidin-3-yl)butanamide (50.0 mg, 0.144 mmol, 1.00 equiv), 4-ethoxybenzaldehyde (43.0 mg, 0.286 mmol, 1.98 equiv), pyrrolidine (21.0 mg, 0.295 mmol, 2.05 equiv), MeOH (1.00 mL), H2O (0.20 mL). The resulting mixture was stirred for 2 h at rt.
  • Example 47 Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- hydroxybenzoic acid (Compound 147) [0394] 2,4- dioxothiazolidin-3-yl)butanamido)-2-hydroxybenzoic acid (10.0 mg, 0.022 mmol, 1.00 equiv), EtOH (5.0 mL), and Pd/C (2.0 mg, 0.019 mmol, 0.85 equiv). The flask was placed under a hydrogen atmosphere. The resulting mixture was stirred for 5 h at rt. The mixture was filtered and concentrated under reduced pressure.
  • Example 54 Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((5-ethylpyridin-2- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 154) [0401] Into a 40 mL vial de (500 mg, 2.69 mmol, 1.00 equiv), ethyl boronic acid, ( 1000 mg, 13.5 mmol, 5.03 equiv), Pd(PPh 3 ) 4 (50.0 mg, 0.043 mmol, 0.02 equiv), Na2CO3 (795 mg, 7.50 mmol, 2.79 equiv), toluene (5.0 mL), and H2O (0.5 mL).
  • Example 60 Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6-ethylpyridin-3- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 160) [0408] (Z)-N-(4-(1H-Tetrazo in-3-yl)methylene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 54. 464.2 [M + H] + .
  • Example 62 Synthesis of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6-ethylpyridin-3-yl)methyl)- 2,4-dioxothiazolidin-3-yl)butanamide (Compound 162) [0410] lpyridin-3- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (50.0 mg, 0.108 mmol, 1.00 equiv), AcOH (1 ml) and zinc (35.3 mg, 0.539 mmol, 5.0 equiv). The resulting mixture was stirred for 3 hr at 100 °C.
  • Example 71 Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(3-methoxy-4- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 171) [0419] (Z)-N-(4-(1H-Tetrazol -methylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide.
  • LCMS (ESI) 479.1 [M + H] + .
  • Example 79 Synthesis of 4-(5-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)pentanamido)-2- hydroxybenzoic acid (Compound 179) .
  • 4-(5-(5-(4-Ethylbenzyl anamido)-2-hydroxybenzoic acid was prepared using similar methods as described in Examples 1-77 except methyl 5- bromopentanoate was used as the starting material.
  • LCMS (ESI) 471.2 [M + H] + .
  • Example 82 Beta-Arrestin Antagonist Assay
  • Human GPR35 expressing JumpIn (Thermo Fisher) 294R Tango U2OS cells were plated in 384-well format in clear bottom plates at a cell density of 10,000 cells / well and allowed to grow overnight. The next day, cells were treated with serially diluted test compounds for 5 hours. LiveBLAzer-FRET B/G (CCF4-AM) detection reagents were then added and cells were allowed to incubate for 2 hours before reading plates on a BioTek Cytation 5 plate reader. Zaprinast was used as a positive control for dose-response curves. In order to determine IC 50 values, data were fit to a four-parameter dose-response curves.
  • IC50 values are shown in Table 1.
  • the examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

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Abstract

Described herein are GPR35 modulators and methods of using these compounds in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Description

GPR35 MODULATORS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/584,061, filed September 20, 2023.
BACKGROUND OF THE INVENTION
[0002] Millions of people are affected by inflammatory disease or conditions. A prominent inflammatory disease is inflammatory bowel disease (IBD). IBD has two common forms, Crohn’s disease (CD) and ulcerative colitis (UC), which are chronic, relapsing inflammatory disorders of the gastrointestinal tract. Each of these forms has various sub-conditions that are present in subpopulations of CD and UC patients. Some CD and UC patients experience a rapid onset of subconditions, while others experience a relative delay.
[0003] Few treatment options are available to patients that suffer from IBD. Further, selecting a therapy that is appropriate for any individual patient at any given stage of their disease is complicated by the unpredictability of each individual’s prognosis. Current therapeutic regimens include one or more of anti -infl ammatory medication (e g., corticosteroids) and immunomodulatory therapy (e.g., anti-TNF therapy). However, nearly half of all patients treated with an anti-TNF therapy do not respond to the induction of the therapy, or experience a loss of response to the treatment after a period of time, during which, disease severity has progressed significantly.
Therefore, there remains a significant need for targeted and effective treatment options that respond to the underlying immunopathogenesis of IBD.
SUMMARY OF THE INVENTION
[0004] In one aspect, provided herein are compounds of Formula (I):
Figure imgf000002_0001
Formula (I); wherein:
~ is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; , ynyl,
Figure imgf000003_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; R3 is C1-8alkyl, C2-8alkenyl, C2-8alkynyl s a 5-membered heteroaryl ring selected from oxa
Figure imgf000003_0002
imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, or ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from Ci-ealkyl, C2-ealkenyl, C2-6alkynyl, Cs-ecycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, and Ci-9heteroaryl, wherein Ci-ealkyl, C2-6alkenyl. C2-6alkynyl, Cs- ecycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from -CN, Ci-ealkyl, C2-ealkenyl, C2-ealkynyl, Cs- ecycloalkyl, C2-9heterocycloalkyl. Ce-ioaryl, Ci-9heteroaryl. -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5). -N(R6)C(O)N(R4)(R5). -N(R6)C(O)OR7. -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein Ci-ealkyl. C2-ealkenyl, Cs-ealkynyl. Cs-ecycloalkyl, C2- 9heterocycloalkyl. Ce-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two. or three R9; each R9 is independently selected from halogen, -CN, Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, C2-9heterocycloalkyl, Ce-ioary l, and Ci gheteroaryl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof.
[0005] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (la), or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000004_0001
Formula (la).
[0006] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000004_0002
Formula (lb). [0007] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000005_0001
Formula (Ic).
[0008] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000005_0002
Formula (Id).
[0009] In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic). or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl or thiazolyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl. In some embodiments is a compound of Formula (I), (la), (lb),
(Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000005_0003
some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (Id), wherein R3 is ( B 4-(R8)P
. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (I). (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.
[0010] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (laa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000006_0001
[0011] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof
Figure imgf000006_0002
Formula (Ibb).
[0012] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000006_0003
[0013] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0001
Formula (Idd).
[0014] In some embodiments is a compound of Formula (I), (la). (Ib), (Ic), (Id), (laa). (Ibb). (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CO2H. In some embodiments is a compound of Formula (I), (la), (Ib), (Ic), (Id), (laa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Figure imgf000007_0002
In some embodiments is a compound of Formula (I), (la), (Ib), (Ic), (Id), (laa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Figure imgf000007_0003
Figure imgf000007_0004
some embodiments is a compound of
Formula (I), (la), (Ib), (Ic), (Id), (laa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -CN, and Ci-ealkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula
(I), (la), (Ib), (Ic). (Id), (laa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted Ci-6alkyl.
[0015] In another aspect, provided herein are compounds of Formula (II):
Figure imgf000007_0005
Formula (II); wherein: is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; , l,
Figure imgf000008_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; R3 is C1-8alkyl, C2-8alkenyl, C2-8alkynyl s a 5-membered heteroaryl ring selected from oxa
Figure imgf000008_0002
imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, or ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof. [0016] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0001
[0017] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0002
. [0018] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (lie), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0001
Formula (lie).
[0019] In some embodiments is a compound of Formula (II). or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (lid), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0002
Formula (lid).
[0020] In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl or thiazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000010_0003
some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), wherein R is
Figure imgf000011_0001
. In some embodiments is a compound of Formula (II), (Ila),
(lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a 6- membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.
[0021] In some embodiments is a compound of Formula (II). or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ilaa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0002
[0022] In some embodiments is a compound of Formula (II). or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ilbb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0003
Formula (Ilbb).
[0023] In some embodiments is a compound of Formula (II). or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0004
Formula (IIcc). [0024] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ildd), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000012_0001
Formula (Ildd).
[0025] In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb).
. H
X-N (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is X "N "N . in some embodiments is a compound of Formula (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or
O
(Ildd). or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Figure imgf000012_0002
Figure imgf000012_0003
embodiments is a compound of Formula (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OR4, and Ci-ealkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II). (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb). (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from unsubstituted Ci-ealkyl and -OR4. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (II). (Ila). (lib). (lie). (lid). (Ilaa), (Ilbb). (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from H and unsubstituted Ci-salkyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted Ci-salkyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Ice). (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc). or (Ildd). or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa). (Ilbb), (IIcc). or (Ildd). or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, Ci-salkyl, and -OR4. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd). or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from H and unsubstituted Ci-ealkyl. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (II d), (Ilaa), (Ilbb), (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[0026] In another aspect described herein is a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc), or (Ildd). or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
[0027] In another aspect described herein is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb). (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb), (IIcc). or (Ildd). or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie), (lid), (Ilaa), (Ilbb). (IIcc), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is selected from Crohn’s disease, ulcerative colitis, and perianal Crohn’s disease.
[0028] In another aspect described herein is a method of modulating GPR35 activity comprising contacting GPR35, or portion thereof, with a compound of Formula (I), (la). (Ib), (Ic), (Id), (laa), (Ibb), (Icc), (Idd), (II), (Ila), (lib), (lie). (lid), (Ilaa), (Ilbb), (lice), or (Ildd), or a pharmaceutically acceptable salt or solvate thereof.
INCORPORATION BY REFERENCE
[0029] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0030] In the context of this disclosure, a number of terms shall be utilized.
[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g, sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.
[0032] It is to be understood that the foregoing general description and the following detailed description are exemplary' and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, 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. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.
[0033] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[0034] Definition of standard chemistry' terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press. New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.
[0035] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.
[0036] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. 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 limit the scope of the methods, compounds, compositions described herein.
[0037] As used herein, Cl-Cx includes C1-C2, C1-C3 . . . Cl-Cx. Cl-Cx refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents). [0038] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl groups may or may not include units of unsaturation. The alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon-carbon double bond or a carboncarbon triple bond). The alkyl group may also be an “unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
[0039] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyd” where no numerical range is designated). The alkyd group of the compounds described herein may be designated as "Ci-Cealkyl" or similar designations. By way of example only, “Ci- Cealkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
[0040] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein.
[0041] The term “alkenyl” refers to a type of alkyd group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms -C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. Non-limiting examples of an alkenyl group include -CH=CH2, - C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2 and -C(CH3)=CHCH3. The alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a “cycloalkenyl” group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e.. an alkenylene group).
[0042] The term “alkynyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms -C=C-R, wherein R refers to the remaining portions of the alkynyl group. Non-limiting examples of an alkynyl group include -C=CH, -C=CCH3, -C=CCH2CH3 and -C=CCH2CH2CH3. The “R” portion of the alkynyl moiety’ may be branched, straight chain, or cyclic. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
[0043] “Amino” refers to a -NH2 group.
[0044] The term “alkylamine” or “alkylamino” refers to the -N(alkyl)xHy group, where alkyl is as defined herein and x and y are selected from the group x=l, y=l and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl)2 group, where alkyl is as defined herein. [0045] The term “aromatic” refers to a planar ring having a delocalized Ti-electron system containing 4n+2 it electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthal enyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl). [0046] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six. seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
[0047] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhi bi Is similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,
Figure imgf000017_0001
[0048] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.
[0049] The terms “heteroaryl” or. alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An A-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyL pyrazolyl, triazolyl, pyrazinyL tetrazolyl, fund, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline. 1,8-naphthyridine. and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, both rings of a bicyclic heterocycle are aromatic. In some embodiments, bicyclic heteroaryl is a Ce-Csiheteroaryl.
[0050] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an ary l or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
[0051] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.
[0052] The term “haloalkyl” refers to an alky l group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH2CI, -CF3, -CHF2, -CH2CF3. -CF2CF3, and the like.
[0053] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2F. -CH2CF3, -CF2CF3, -CF2CF2CF3. -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, - OCF2CF2CF3, -OCF(CH3)2, and the like.
[0054] The term “heteroalkyl” refers to an alkyd radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3. - CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S- CH2-CH3, -CH2-CH2-S(O)-CHS, -CH2-CH2-S(O)2-CHS, -CH2-NH-OCH3, CH2-O-Si(CH3)3, -CH2- CH=N-OCH3. and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms. [0055] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. [0056] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [0057] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl. [0058] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. [0059] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. –NH2, -NHR, -N(R)2), and the protected derivatives thereof. By way of example, an optional substituents may be LsRs, wherein each Ls is independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, - NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(C1-C6alkyl)-, or -(C2-C6alkenyl)-; and each Rs is independently selected from among H, (C1-C6alkyl), (C3-C8cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above. [0060] As used herein, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range. [0061] The term a “therapeutically effective amount” as used herein refers to the amount of a compound of Formula (I) that, when administered to a mammal in need, is effective to at least partially treat the conditions described herein. [0062] The term “modulate” encompasses either a decrease or an increase in activity depending on the target molecule. [0063] The term "activator" is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically. Thus, the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.
[0064] The term “patient’' or “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
[0065] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.
[0066] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, /Mol uenesul Tonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt. [0067] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed wi th metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A.A-dibenzylethylenediamine. chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, /V-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.
[0068] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
G Protein-Coupled Receptor 35 (GPR35)
[0069] G Protein-Coupled Receptor 35 (GPR35) is a receptor for kynurenic acid, an intermediate in the try ptophan metabolic pathway. GPR35 mediates calcium mobilization and inositol phosphate production. GPR35. and nucleic acids encoding GPR35, are characterized by NCBI Entrez Gene ID 2859. Studies show that GPR35 is linked to inflammatory regulation, either by the presence of the receptor at the surface of immune specific cells, or by ligand-mediated modulation leading to changes in immune response. Accordingly, it is hypothesized that GPR35, and nucleic acids encoding GPR35, play a role is inflammatory disease pathology making GPR35 an attractive therapeutic target to treat inflammatory diseases or conditions. [0070] The compounds of Formula (I) described herein are GPR35 modulators. In some embodiments, compounds of Formula (I) described herein are GPR35 antagonists. In some embodiments, compounds of Formula (I) described herein are GPR35 agonists. In some embodiments, compounds of Formula (I) described herein are GPR35 inverse agonists. The compounds of Formula (I) described herein, and compositions comprising these compounds, are useful for the treatment of an inflammatory bowel disease. [0071] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000022_0001
wherein: is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; ,
Figure imgf000022_0002
ynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; R3 is C1-8alkyl is a 5-membered heteroar imidazolyl, triazolyl, t
Figure imgf000023_0001
etrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, or ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 1 or 2. [0072] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000024_0001
[0073] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000024_0002
[0074] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000024_0003
[0075] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000024_0004
. [0076] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherei . [0077] In some embodiments is a compound of Formula ), or (Id), or a
Figure imgf000025_0001
pharmaceutically acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic) y
Figure imgf000025_0002
acceptable salt or solvate thereof, wherei . In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), ly acceptable salt or solvate
Figure imgf000025_0003
thereof, wherein In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), o cceptable salt or solvate thereof, wherein R3 is
Figure imgf000025_0004
2. ments is a compound of Formula (I), (Ia), (Ib), (Ic) 3
Figure imgf000025_0005
, or (Id), wherein R is . In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrimidinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrazinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridazinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is triazinyl. [0079] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherei nd ring B is a 5- membered heteroaryl ring selected from oxazolyl, thiazoly rrolyl,
Figure imgf000026_0001
imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is oxazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is thiazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is thienyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrrolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is imidazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is triazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is tetrazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is isoxazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is isothiazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is oxadiazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is thiadiazolyl. [0080] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein and p is 0. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), o
Figure imgf000026_0002
r , or a p armaceutically acceptable salt or solvate thereof, wherein R3 is and p is 1. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), maceutically acceptable salt or solvate
Figure imgf000027_0001
thereof, wherein R3 is and p is 2. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is . nts is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a
Figure imgf000027_0002
pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN and C1- 6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted C1-6alkyl. [0082] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-8alkyl, C2-8alkenyl, or C2- 8alkynyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-8alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-8alkenyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2- 8alkynyl. [0083] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl or thiazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is thiazolyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl. [0084] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CO2H. [0085] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is . [0086] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 ,
Figure imgf000028_0001
me
Figure imgf000028_0002
ly acceptable salt or solvate thereof, wherein R1
Figure imgf000028_0003
In some embodiments is a compound of Formula (I),
Figure imgf000028_0004
acceptable salt or solvate thereof, wherein R1 is . In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a
Figure imgf000029_0001
pharmaceutically acceptable salt or solvate thereof, wherein R1 i . In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or ( maceutically
Figure imgf000029_0002
acceptable salt or solvate thereof, wherein R1 . In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pha y acceptable salt or solvate thereof,
Figure imgf000029_0003
wherein R1 i . In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or
Figure imgf000029_0004
(Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a p ly
Figure imgf000029_0005
acceptable salt or solvate thereof, wherein . In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a
Figure imgf000029_0006
y acceptable salt or solvate thereof, wherein . [0087]
Figure imgf000029_0007
ents is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2. [0088] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -N(R4)(R5), -C(O)OR4, -C(O)R7, -C(O)N(R4)(R5), -S(O)2R7, and - S(O)2N(R4)(R5)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, and -N(R4)(R5), wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, -OR4, and -N(R4)(R5), wherein C1-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4, and wherein each R4 is independently selected from H and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, -OH, and -OCH3. [0089] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. [0090] In some embodiments, provided herein is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000030_0001
wherein: , ynyl,
Figure imgf000031_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR , -SR , -N(R )(R ), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0091] In some embodiments, provided herein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof: , ynyl,
Figure imgf000032_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0092] In some embodiments, provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof: ,
Figure imgf000033_0001
ynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0093] In some embodiments, provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000034_0001
wherein: , ynyl,
Figure imgf000035_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR , -SR , -N(R )(R ), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0094] In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. [0095] In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN and C1- 6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted C1-6alkyl. [0096] In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CO2H. [0097] In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is . [0098] In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 i ,
Figure imgf000037_0001
me lly
Figure imgf000037_0002
acceptable salt or solvate thereof, wherein R1
Figure imgf000037_0003
In some embodiments is a compound of Formula (Iaa), cceptable salt or solvate thereof, wherein R1 is
Figure imgf000037_0004
. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a
Figure imgf000037_0005
pharmaceutically acceptable salt or solvate thereof, wherein R1 i . In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (I
Figure imgf000037_0006
armaceutically acceptable salt or solvate thereof, wherein R1 . In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a ph
Figure imgf000037_0007
lly acceptable salt or solvate thereof, wherein R1 i . In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or
Figure imgf000037_0008
(Idd), or a pharmaceutically acceptable salt or solvate thereof, where In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), o
Figure imgf000037_0009
ly acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or y acceptable salt or solvate thereof,
Figure imgf000038_0001
wherein . [0099] ents is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a
Figure imgf000038_0002
pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2. [0100] In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -N(R4)(R5), -C(O)OR4, -C(O)R7, -C(O)N(R4)(R5), -S(O)2R7, and - S(O)2N(R4)(R5)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, and -N(R4)(R5), wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, -OR4, and -N(R4)(R5), wherein C1-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4, and wherein each R4 is independently selected from H and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Iaa), (Ibb), (Icc), or (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, -OH, and -OCH3. [0101] Provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is
Figure imgf000039_0004
solvate thereof, wherein: ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000039_0001
[0103] Provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0104] Provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1. [0105]
Figure imgf000039_0002
a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0106] Provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0107]
Figure imgf000039_0003
of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein: q is
Figure imgf000039_0005
[0108] Provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 3 ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1. [0109]
Figure imgf000040_0001
Provded ere n s a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0110] Provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1. [0111] a compound of Formula (Ia), or a pharmaceutically acceptable salt or
Figure imgf000040_0002
solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0112] Provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0113]
Figure imgf000040_0003
of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein: q is
Figure imgf000040_0005
or solvate thereof, wherein: ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000040_0004
[0115] Provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0116] Provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 3 C1-8alkyl; n is 0; and q is 1. [0117] a compound of Formula (Ib), or a pharmaceutically acceptable salt or
Figure imgf000041_0001
solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0118] Provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0119] of Formula (Ic), or a pharmaceutically acceptable salt or
Figure imgf000041_0002
solvate thereof, wherein: 1 3 8 q is
Figure imgf000041_0004
or solvate thereof, wherein: d q
Figure imgf000041_0005
or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0122] Provided herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1. [0123]
Figure imgf000041_0003
a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0124] Provided herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 2 4 3 C1-8alkyl; R4 is H; n is 1; and q is 1. [0125] of Formula (Id), or a pharmaceutically acceptable salt or solvate
Figure imgf000042_0001
thereof, wherein: R1 is -CO2H R3 is rin B is ridin l R8 is C16alk l n is 0 is 1 and q is or
Figure imgf000042_0005
solvate thereof, wherein: ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000042_0002
[0127] Provided herein is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0128] Provided herein is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1. [0129]
Figure imgf000042_0003
a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0130] Provided herein is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0131]
Figure imgf000042_0004
of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0132] Provided herein is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 8 C1-6alkyl; n is 0; and p is 0. [0133] a compound of Formula (Iaa), or a pharmaceutically acceptable salt or
Figure imgf000043_0001
solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0134] Provided herein is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 1. [0135] a compound of Formula (Iaa), or a pharmaceutically acceptable salt or
Figure imgf000043_0002
solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0136] Provided herein is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0137]
Figure imgf000043_0003
s a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0138] Provided herein is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0139]
Figure imgf000043_0004
a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0140] Provided herein is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 i R2 i R4 R4 i H R8 i C1-6alkyl; n is 1; and p is 1. [0141] ula (Iaa), or a pharmaceutically acceptable salt or solvate
Figure imgf000044_0001
t ereo , w ere n: R1 is ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0142] Pr rein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or
Figure imgf000044_0002
solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0143] Provided herein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 0. [0144] a compound of Formula (Ibb), or a pharmaceutically acceptable salt or
Figure imgf000044_0003
solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0145] Provided herein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1. [0146]
Figure imgf000044_0004
Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0147] Provided herein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0148]
Figure imgf000044_0005
is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0149] Provided herein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 2 C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0150] a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate
Figure imgf000045_0001
thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0151] Provided herein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1. [0152] ula (Ibb), or a pharmaceutically acceptable salt or
Figure imgf000045_0002
solvate thereof, wherein: ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0153] rein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or
Figure imgf000045_0003
solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0154] Provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 0. [0155]
Figure imgf000045_0004
a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0156] Provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 1.
Figure imgf000045_0005
[0157] Provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0158] Provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0159] s a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate
Figure imgf000046_0001
thereof, wherein: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0160] Provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0161] a compound of Formula (Icc), or a pharmaceutically acceptable salt or
Figure imgf000046_0002
solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0162] Provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1. [0163]
Figure imgf000046_0003
ula (Icc), or a pharmaceutically acceptable salt or solvate thereof, wherein: ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0164]
Figure imgf000046_0004
rein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0165] Provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 i R8 i C1-6alkyl; n is 0; and p is 0. [0166] a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate
Figure imgf000047_0001
t ereo , w ere n: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0167] Provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1. [0168] Idd), or a pharmaceutically acceptable salt or
Figure imgf000047_0002
solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0169] Provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0170]
Figure imgf000047_0003
s a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0171] Provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0172]
Figure imgf000047_0004
a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0173] Provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1.
Figure imgf000047_0005
[0174] Provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0175] In bodiments, provided herein is a compound of Formula (II), or a
Figure imgf000048_0001
pharmaceutically acceptable salt or solvate thereof:
Figure imgf000048_0002
wherein: is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; ,
Figure imgf000048_0003
l, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; R3 is C1-8alkyl, C2-8alkenyl, C2-8alkynyl , wherein ring B is a 5-membered heteroaryl ring selected from oxa ienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isot
Figure imgf000049_0001
azo y , oxa azo y, an thiadiazolyl, or ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof. [0176] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000050_0001
[0177] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000050_0002
[0178] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000050_0003
[0179] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000050_0004
[0180] In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherei . [0181] In some embodiments is a compound of Formula (IIc), or (IId), or a
Figure imgf000051_0001
pharmaceutically acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (II), (IIa), (IIb), ( ically
Figure imgf000051_0002
acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (II), (IIa), (IIb), (I cally acceptable salt or
Figure imgf000051_0003
solvate thereof, wherein In some embodiments is a compound of Formula (II), (IIa), (IIb) eutically acceptable salt or solvate thereof,
Figure imgf000051_0004
wherein 2. [0182]
Figure imgf000051_0005
mpound of Formula (II), (IIa), (IIb), (IIc), or (IId), wherein R3 is . In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrimidinyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrazinyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridazinyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is triazinyl.
[0183] In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R is
Figure imgf000052_0001
and ring B is a 5- membered heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is oxazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is thiazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is thienyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyrrolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is imidazolyl. In some embodiments is a compound of Formula (II). (Ila). (lib). (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is triazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is tetrazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is isoxazolyl. In some embodiments is a compound of Formula (II). (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is isothiazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is oxadiazolyl. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is thiadiazolyl.
[0184] In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R
Figure imgf000052_0002
and p is 0. In some embodiments is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is and p is 1. In some embodiments is a compound of Formula (II), (IIa), (IIb), (I harmaceutically acceptable salt or
Figure imgf000053_0001
solvate thereof, wherein R3 is and p is 2. In some embodiments is a compound of Formula (II), (IIa), (IIb), a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000053_0002
wherein R3 is and p is 1 or 2. [0185] und of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmac
Figure imgf000053_0003
eutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, halogen, -OR4, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, halogen, -OR4, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OR4, and C1-6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OH, - OCH3, and C1-6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OH, -OCH3, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted C1- 6alkyl. [0186] In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-8alkyl, C2-8alkenyl, or C2- 8alkynyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C1-8alkyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-8alkenyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2- 8alkynyl. [0187] In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl or thiazolyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is thiazolyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl. [0188] In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 . [0189] In some embodiments is a compound of Formula (II),
Figure imgf000054_0001
b), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 ,
Figure imgf000054_0002
me
Figure imgf000054_0003
ically acceptable salt or solvate thereof, wherein R1
Figure imgf000054_0004
In some embodiments is a compound of Formula (II), ally acceptable salt or solvate thereof, wherein R1 is
Figure imgf000055_0001
. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a
Figure imgf000055_0002
pharmaceutically acceptable salt or solvate thereof, wherein R1 is . In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), pharmaceutically
Figure imgf000055_0003
acceptable salt or solvate thereof, wherein R1 . In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a ically acceptable salt or solvate thereof,
Figure imgf000055_0004
wherein R1 i . In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or
Figure imgf000055_0005
(IId), or a pharmaceutically acceptable salt or solvate thereof, where In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (II
Figure imgf000055_0006
ically acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId)
Figure imgf000055_0007
ally acceptable salt or solvate thereof, wherein . [0190]
Figure imgf000055_0008
ents is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2. [0191] In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -N(R4)(R5), -C(O)OR4, -C(O)R7, -C(O)N(R4)(R5), -S(O)2R7, and - S(O)2N(R4)(R5)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, and -N(R4)(R5), wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, -OR4, and -N(R4)(R5), wherein C1-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4, and wherein each R4 is independently selected from H and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1- 6alkyl, -OH, and -OCH3. [0192] In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (II), (IIa), (IIb), (IIc), or (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. [0193] In some embodiments, provided herein is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof: , l,
Figure imgf000057_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0194] In some embodiments, provided herein is a compound of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof: ,
Figure imgf000058_0001
l, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0195] In some embodiments, provided herein is a compound of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000059_0001
wherein: , l,
Figure imgf000060_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR , -SR , -N(R )(R ), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0196] In some embodiments, provided herein is a compound of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof: , l,
Figure imgf000061_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4. [0197] In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. [0198] In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, halogen, -OR4, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN, halogen, -OR4, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OR4, and C1-6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OH, - OCH3, and C1-6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OH, -OCH3, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted C1- 6alkyl. [0199] In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is . [0200] In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 ,
Figure imgf000063_0001
me
Figure imgf000063_0002
tically acceptable salt or solvate thereof, wherein R1
Figure imgf000063_0003
In some embodiments is a compound of Formula (IIaa),
Figure imgf000063_0004
y acceptable salt or solvate thereof, wherein R1 is . In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a
Figure imgf000063_0005
pharmaceutically acceptable salt or solvate thereof, wherein R1 is . In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), o pharmaceutically
Figure imgf000064_0001
acceptable salt or solvate thereof, wherein R1 i . In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a ically acceptable salt or solvate thereof,
Figure imgf000064_0002
wherein R1 i . In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or
Figure imgf000064_0003
(IIdd), or a pharmaceutically acceptable salt or solvate thereof, where In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd cally
Figure imgf000064_0004
acceptable salt or solvate thereof, wherei In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd)
Figure imgf000064_0005
ally acceptable salt or solvate thereof, wherein . [0201]
Figure imgf000064_0006
nts is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2. [0202] In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -N(R4)(R5), -C(O)OR4, -C(O)R7, -C(O)N(R4)(R5), -S(O)2R7, and - S(O)2N(R4)(R5)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, and -N(R4)(R5), wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, -CN, C1-6alkyl, -OR4, and -N(R4)(R5), wherein C1-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4, and wherein each R4 is independently selected from H and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1- 6alkyl, -OH, and -OCH3. [0203] Provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 i ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000065_0001
[0204] Provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000065_0002
[0205] Provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0206] Provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 i R3 i C1-8alkyl; n is 0; and q is 1. [0207] a compound of Formula (II), or a pharmaceutically acceptable salt or solvate
Figure imgf000066_0001
t ereo , w ere n: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0208] Provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0209] of Formula (IIa), or a pharmaceutically acceptable salt or
Figure imgf000066_0002
solvate thereof, wherein: R1 is -CO2H; R3 i ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000066_0003
[0210] Provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein: ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000066_0004
[0211] Provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0212] Provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1. [0213]
Figure imgf000066_0005
a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0214] Provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 i R2 i R4 R3 i C1-8alkyl; R4 is H; n is 1; and q is 1. [0215] of Formula (IIb), or a pharmaceutically acceptable salt or solvate
Figure imgf000067_0001
t ereo , w ere n: R1 is -CO2H; R3 is ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is or
Figure imgf000067_0005
solvate thereof, wherein: d q t or
Figure imgf000067_0006
solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0218] Provided herein is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1. [0219]
Figure imgf000067_0002
a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0220] Provided herein is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0221]
Figure imgf000067_0003
of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein: ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000067_0004
[0222] Provided herein is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 3 ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1. [0223]
Figure imgf000068_0001
Prov ded ere n s a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0224] Provided herein is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; n is 0; and q is 1. [0225] a compound of Formula (IIc), or a pharmaceutically acceptable salt or
Figure imgf000068_0002
solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0226] Provided herein is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0227]
Figure imgf000068_0003
of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein: q is
Figure imgf000068_0005
or solvate thereof, wherein: ; ring B is pyridinyl; R8 is C1-6alkyl; n is 0; p is 1; and q is 1.
Figure imgf000068_0004
[0229] Provided herein is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R3 is C1-8alkyl; n is 0; and q is 1. [0230] Provided herein is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 3 C1-8alkyl; n is 0; and q is 1. [0231] a compound of Formula (IId), or a pharmaceutically acceptable salt or
Figure imgf000069_0001
solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R3 is C1-8alkyl; R4 is H; n is 1; and q is 1. [0232] Provided herein is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-8alkyl; R4 is H; n is 1; and q is 1. [0233] of Formula (IIaa), or a pharmaceutically acceptable salt or
Figure imgf000069_0002
solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0234] Provided herein is a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 0. [0235]
Figure imgf000069_0003
a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0236] Provided herein is a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 1. [0237]
Figure imgf000069_0004
a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0238] Provided herein is a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 i R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0239] s a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate
Figure imgf000070_0001
t ereo , w ere n: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0240] Provided herein is a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1. [0241] Formula (IIaa), or a pharmaceutically acceptable salt or
Figure imgf000070_0002
solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0242] Provided herein is a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1. [0243]
Figure imgf000070_0003
ula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0244]
Figure imgf000070_0004
rein is a compound of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R8 is -OR4; n is 0; and p is 1. [0245]
Figure imgf000070_0005
a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0246] Provided herein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 i R8 i C1-6alkyl; n is 0; and p is 0. [0247] a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate
Figure imgf000071_0001
t ereo , w ere n: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0248] Provided herein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 1. [0249] a compound of Formula (IIbb), or a pharmaceutically acceptable salt or
Figure imgf000071_0002
solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0250] Provided herein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0251]
Figure imgf000071_0003
is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0252] Provided herein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0253]
Figure imgf000071_0004
a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0254] Provided herein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1.
Figure imgf000071_0005
[0255] Provided herein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0256] Pr rein is a compound of Formula (IIbb), or a pharmaceutically acceptable salt or
Figure imgf000072_0001
solvate thereof, wherein: C1-6alkyl; R8 is -OR4; n is 0; and p is 1. [0257] a compound of Formula (IIcc), or a pharmaceutically acceptable salt or
Figure imgf000072_0002
solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0258] Provided herein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 0. [0259]
Figure imgf000072_0003
a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0260] Provided herein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 1. [0261]
Figure imgf000072_0004
a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0262] Provided herein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: s halogen; R8 is C1-6alkyl; n is 1; and p is 1.
Figure imgf000072_0005
[0263] Provided herein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0264] Provided herein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 2 C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0265] a compound of Formula (IIcc), or a pharmaceutically acceptable salt or
Figure imgf000073_0001
solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0266] Provided herein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1. [0267] ula (IIcc), or a pharmaceutically acceptable salt or
Figure imgf000073_0002
solvate thereof, wherein: ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0268]
Figure imgf000073_0003
rein is a compound of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; R8 is -OR4; n is 0; and p is 1. [0269]
Figure imgf000073_0004
a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 0. [0270] Provided herein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 0; and p is 0.
Figure imgf000073_0005
[0271] Provided herein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R8 is C1-6alkyl; n is 0; and p is 1. [0272] Provided herein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: 1 C1-6alkyl; n is 0; and p is 1. [0273] a compound of Formula (IIdd), or a pharmaceutically acceptable salt or
Figure imgf000074_0001
solvate thereof, wherein: R1 is -CO2H; R2 is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0274] Provided herein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: is halogen; R8 is C1-6alkyl; n is 1; and p is 1. [0275] s a compound of Formula (IIdd), or a pharmaceutically acceptable salt or
Figure imgf000074_0002
solvate thereof, wherein: R1 is -CO2H; R2 is C1-6alkyl; R8 is C1-6alkyl; n is 1; and p is 1. [0276] Provided herein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1. [0277]
Figure imgf000074_0003
Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is -CO2H; R2 is -OR4; R4 is H; R8 is C1-6alkyl; n is 1; and p is 1. [0278] Provided herein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: C1-6alkyl; n is 1; and p is 1. [0279]
Figure imgf000074_0004
mula (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is ; R8 is unsubstituted C6-10aryl; n is 0; and p is 1. [0280] Pro erein is a compound of Formula (IIdd), or a pharmaceutically acceptable salt or solvate there
Figure imgf000075_0001
of, wherein: 1 i 4 i C1-6alkyl; R8 is -OR4; n is 0; and p is 1. [0281] nts is a compound selected from:
Figure imgf000075_0002
, , ,
Figure imgf000075_0003
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
, f. ted
Figure imgf000079_0001
herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds. [0283] In some embodiments, the therapeutic agent(s) (e.g. compound of Formula (I)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any compound described above is suitable for any method or composition described herein. Further Forms of Compounds Disclosed Herein Isomers [0284] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. Labeled compounds [0285] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H, 3H, 13C, 14C, l5N, 17O, 18O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method. [0286] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [0287] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [0288] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. Solvates [0289] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions. [0290] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Synthesis of Compounds [0291] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary. [0292] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics. [0293] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized. Use of Protecting Groups [0294] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. [0295] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. [0296] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates. [0297] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd0-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. [0298] Typically blocking/protecting groups may be selected from: H3C H3C C H C (H C) C CH3
Figure imgf000083_0001
creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure). Methods of Treatment and Prevention [0300] In some embodiments is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is selected from Crohn’s disease, ulcerative colitis, and perianal Crohn’s disease. In some embodiments is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is Crohn’s disease. In some embodiments is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is ulcerative colitis. In some embodiments is a method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory bowel disease is perianal Crohn’s disease. Pharmaceutical compositions and methods of administration [0301] In certain embodiments, the compounds described herein are administered as a pure chemical. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [0302] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition. [0303] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof. [0304] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Iaa), (Ibb), (Icc), (Idd), (II), (IIa), (IIb), (IIc), (IId), (IIaa), (IIbb), (IIcc), or (IIdd), or a pharmaceutically acceptable salt or solvate thereof. [0305] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method. [0306] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration. [0307] Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [0308] In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [0309] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [0310] In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings. [0311] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [0312] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [0313] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof. [0314] In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0315] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [0316] Compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. [0317] In some embodiments, compositions and compounds described herein are administered to subjects in a biologically compatible form suitable for topical administration. Topical administration may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. By the term “a semi-solid composition” is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company. [0318] Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide an absorption enhancer such as DMSO to increase the absorption of the compounds. Patches can include those that control the rate of drug delivery to the skin. [0319] Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and talc, or mixtures thereof. Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals. In general, such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can additionally contain customary propellants, such a chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [0320] The dose of the composition comprising at least one compound described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors. [0321] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient. [0322] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. [0323] Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used. [0324] It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the compound of Formula (I) and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Exact dosages are determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration. [0325] Toxicity and therapeutic efficacy of a compound of Formula (I) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 /ED50. EXAMPLES [0326] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. [0327] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile AcOH acetic acid AlMe3 trimethylaluminum Bn benzyl BOC or Boc t-butyl carbamate BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate CDI 1,1'-carbonyldiimidazole Cy3P BF4 tricyclohexylphosphonium tetrafluoroborate DCE dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIPEA or DIEA diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF dimethylformamide DMA N,N-dimethylacetamide DMSO dimethylsulfoxide equiv equivalent(s) Et ethyl EtOH ethanol EA or EtOAc ethyl acetate FA formic acid h hour HPLC high performance liquid chromatography LAH lithium aluminum hydride Me methyl MeOH methanol MS mass spectroscopy NMM N-methylmorpholine NMR nuclear magnetic resonance Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(DTBPF)Cl2 [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2 palladium(II) acetate PMB para-methoxybenzyl rt room temperature TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Example 1: Synthesis of (Z)-5-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-hydroxybenzoic acid (Compound 101) [0328
Figure imgf000091_0001
0 g, 171 mmol, 1.00 equiv), EtOH (200 mL), and KOH (9.60 g, 171 mmol, 1.00 equiv). The resulting solution was stirred for 1 hr at 70 °C in an oil bath. After cooling, the solids were collected by filtration. This resulted in 23 g (87%) of potassium 2,4-dioxo-1,3-thiazolidin-3-ide as a light brown solid. LCMS (ESI) = 155.9 [M + H]+. [0329] Step 2: Into a 500-mL round-bottom flask, was placed potassium 2,4-dioxo-1,3- thiazolidin-3-ide (17.0 g, 109.5 mmol, 1.00 equiv), DMF (170 mL), and ethyl 4-bromobutanoate (25.0 g, 128 mmol, 1.17 equiv). The resulting solution was stirred for 2 hr at 80 °C in an oil bath. The reaction was then quenched by the addition of 700 mL of water/ice. The resulting solution was extracted with 3 x 200 mL of ethyl acetate and the organic layers were concentrated under vacuum. The residue was purified on a silica gel column to afford 23.8 g (94%) of ethyl 4-(2,4-dioxo-1,3- thiazolidin-3-yl)butanoate as a light brown oil. LCMS (ESI) = 232.1 [M + H]+; 1H NMR (300 MHz, CDCl3) δ 4.14 (qd, J = 7.1, 4.8 Hz, 2H), 3.96 (s, 2H), 3.71 (t, J = 6.9 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.96 (p, J = 7.1 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). [0330] Step 3: Into a 100-mL round-bottom flask, was placed ethyl 4-(2,4-dioxo-1,3-thiazolidin- 3-yl)butanoate (3.00 g, 13.0 mmol, 1.00 equiv), concentrated HCl (15.0 mL), and AcOH (15.0 mL). The resulting solution was stirred for 1 overnight at 100 °C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 2.6 g (99%) of 4-(2,4-dioxo-1,3-thiazolidin-3- yl)butanoic acid as an off-white solid. LCMS (ESI) = 204.0 [M + H]+. [0331] Step 4: Into a 100-mL round-bottom flask, was placed 4-(2,4-dioxo-1,3-thiazolidin-3- yl)butanoic acid (2.60 g, 12.8 mmol, 1.00 equiv), 4-ethylbenzaldehyde (1.89 g, 14.1 mmol, 1.10 equiv), pyrrolidine (1.80 g, 25.3 mmol, 1.98 equiv), MeOH (20 mL), and H2O (4.0 mL). The resulting solution was stirred for 3 hr at 25 °C, then the resulting mixture was concentrated under vacuum. The residue was applied onto a C18 silica gel column with H2O (with FA additive)/ACN (75/25). This resulted in 700 mg (17%) of (Z)-4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanoic acid as a white solid. LCMS (ESI) = 320.1 [M + H]+. [0332] Step 5: To a stirred solution of (Z)-4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanoic acid (50.0 mg, 0.157 mmol, 1.00 equiv) and TEA (63.4 mg, 0.626 mmol, 4.00 equiv) in DCM (1.0 mL) was added 2,2-dimethylpropanoyl chloride (22.6 mg, 0.188 mmol, 1.20 equiv) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added mesalazine (36.0 mg, 0.235 mmol, 1.50 equiv) at 0 °C. The resulting mixture was stirred for additional 2 h at rt, then the resulting mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC to afford (Z)-5-(4-(5-(4- ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamido)-2-hydroxybenzoic acid (17.1 mg, 24%) as a white solid. LCMS (ESI) = 455.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.86 (s, 1H), 7.61 (dd, J = 8.9, 2.7 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.9 Hz, 1H), 3.73 (t, J = 6.7 Hz, 2H), 2.67 (q, J = 7.5 Hz, 2H), 2.33 (t, J = 7.3 Hz, 2H), 1.92 (t, J = 7.0 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 2: Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-fluorobenzoic acid (Compound 102) O H N F OH [0333] (Z)-4-(4-(5-(4-Ethylbe
Figure imgf000092_0001
, 3-yl)butanamido)-2-fluorobenzoic acid was prepared using the procedures in Example 1. LCMS (ESI) = 457.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.86 (s, 1H), 7.75 (t, J = 8.6 Hz, 1H), 7.61 (d, J = 14.5 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.34 – 7.25 (m, 1H), 3.74 (t, J = 6.6 Hz, 2H), 2.67 (q, J = 7.5 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 1.94 (t, J = 6.9 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 3: Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-methylbenzoic acid (Compound 103) [0334] (Z)-4-(4-(5-(4-Ethylbe 3-yl)butanamido)-2-methylbenzoic
Figure imgf000093_0001
acid was prepared using the procedures in Example 1. LCMS (ESI) = 453.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.57 – 7.32 (m, 6H), 3.73 (t, J = 6.8 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.41 (d, J = 12.9 Hz, 4H), 1.94 (t, J = 7.0 Hz, 2H), 1.31 – 1.14 (m, 5H). Example 4: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 104) [0335] Into a 50-m
Figure imgf000093_0002
3 mmol, 1.00 equiv), toluene (10 mL), triethylamine hydrochloride (1.45 g, 10.5 mmol, 2.49 equiv), and NaN3 (690 mg, 10.6 mmol, 2.51 equiv). The resulting solution was heated overnight at 100 °C. The reaction mixture was cooled to 25 °C. The reaction was then quenched by the addition of 25 mL of water. The pH of the solution was adjusted to 5-6 with HCl. The solids were collected by filtration, washed with 30 ml water, filter cake baking. This resulted in 520 mg (74%) of 4-(1H-tetrazol-5- yl)aniline as a light brown solid. [0336] (Z)-N-(4-(1H-Tetrazol-5-yl)phenyl)-4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamide was prepared using the procedures in Example 1. LCMS (ESI) = 463.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) 10.19 (s, 1H), 7.95 – 7.86 (d, J = 8.7 Hz , 2H), 7.84 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.75 (t, J = 6.7 Hz, 2H), 2.63 (q, J = 7.6 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 1.98 (q, J = 7.0 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). Example 5: Synthesis of (Z)-N-(3-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 105) [0337] (Z)-N-(3-(1H-Tetraz idene)-2,4-dioxothiazolidin-3- yl)butanamide was prepared us
Figure imgf000094_0001
ing the procedures in Example 1. LCMS (ESI) = 463.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 7.87 (s, 1H), 7.74 – 7.60 (m, 2H), 7.49 (m, 3H), 7.36 (d, J = 8.1 Hz, 2H), 3.75 (t, J = 6.7 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 1.97 (q, J = 7.0 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 6: Synthesis of (Z)-3-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 106) [0338] (Z)-3-(4-(5-(4-Ethylb -yl)butanamido)benzoic acid was
Figure imgf000094_0002
prepared using the procedures in Example 1. LCMS (ESI) = 439.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.84 – 7.74 (m, 1H), 7.55 (dd, J = 11.8, 7.8 Hz, 3H), 7.44 – 7.30 (m, 3H), 3.72 (q, J = 6.4 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.38 (t, J = 7.3 Hz, 2H), 1.94 (t, J = 7.1 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 7: Synthesis of (Z)-5-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-fluorobenzoic acid (Compound 107) [0339] (Z)-5-(4-(5-(4-Ethylb
Figure imgf000094_0003
-3-yl)butanamido)-2-fluorobenzoic acid was prepared using the procedures in Example 1. LCMS (ESI) = 457.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.20 (s, 1H), 10.07 (s, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.86 (s, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.17 (t, J = 9.7 Hz, 1H), 3.73 (t, J = 6.7 Hz, 2H), 2.67 (q, J = 7.5 Hz, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1.94 (t, J = 6.9 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 8: Synthesis of (Z)-5-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-methylbenzoic acid (Compound 108) [0340] (Z)-5-(4-(5-(4-Ethylb -yl)butanamido)-2-methylbenzoic acid was prepared using the pr
Figure imgf000095_0001
oce ures n xamp e . C S ( SI) = 453.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.85 (s, 1H), 7.65 (dd, J = 8.2, 2.4 Hz, 1H), 7.56 – 7.47 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.3 Hz, 1H), 3.73 (t, J = 6.7 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.41 (s, 3H), 2.36 (t, J = 7.3 Hz, 2H), 1.93 (p, J = 7.1 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 9: Synthesis of (Z)-2-bromo-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 109) [0341] (Z)-2-Bromo-4-(4-(5- azolidin-3-yl)butanamido)benzoic
Figure imgf000095_0002
acid was prepared using the procedures in Example 1. LCMS (ESI) = 519.1 [M + H]+. Example 10: Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-nitrobenzoic acid (Compound 110) [0342]
Figure imgf000095_0003
in-3- yl)butanoic acid (50.0 mg, 0.157 mmol, 1.00 equiv), DCM (1.00 mL), TEA (50.0 mg, 0.494 mmol, 3.16 equiv). To the above mixture was added 2,2-dimethylpropanoyl chloride (21.0 mg, 0.174 mmol, 1.11 equiv) dropwise over at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added 4-amino-2-nitrobenzoic acid (31.0 mg, 0.170 mmol, 1.09 equiv). The resulting mixture was stirred for additional 16 h at 50 °C, then concentrated under vacuum. The crude product was purified by preparative HPLC to afford (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamido)-2-nitrobenzoic acid (36 mg, 48%) as an off-white solid. LCMS (ESI) = 484.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.85 (s, 1H), 7.81 – 7.69 (m, 2H), 7.57 – 7.43 (m, 2H), 7.38 (d, J = 8.2 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 2.44 (t, J = 7.1 Hz, 2H), 1.96 (q, J = 6.9 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 11: Synthesis of (Z)-2-amino-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 111) [0343 -
Figure imgf000096_0001
dioxothiazolidin-3-yl)butanamido)-2-nitrobenzoic acid (450 mg, 0.931 mmol, 1.00 equiv), Fe (261 mg, 4.67 mmol, 5.02 equiv), NH4Cl (247 mg, 4.62 mmol, 4.96 equiv), EtOH (10 mL), and H2O (2.0 mL). The resulting mixture was stirred for 2 h at 70 ℃. The resulting mixture was diluted with water (100 mL), and the precipitated solids were collected by filtration and washed with water to afford (600 mg) of a brown solid. A portion (30 mg) was purified by preparative HPLC to afford (Z)-2-amino-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamido)benzoic acid (15.5 mg) as an off-white solid. LCMS (ESI) = 454.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.90 (s, 1H), 7.63 – 7.51 (m, 3H), 7.40 (d, J = 8.1 Hz, 2H), 7.02 (s, 1H), 6.55 (d, J = 8.9 Hz, 1H), 6.08 (s, 2H), 3.72 (t, J = 7.0 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 1.95 – 1.84 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 12: Synthesis of (Z)-5-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)picolinic acid (Compound 112) [0344] (Z)-5-(4-(5-(4-Ethylbe
Figure imgf000096_0002
-yl)butanamido)picolinic acid was prepared using the procedures in Examples 1 and 10. LCMS (ESI) = 440.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.78 (s, 1H), 8.25 – 8.11 (m, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.86 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 3.75 (t, J = 6.6 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.44 (d, J = 7.1 Hz, 2H), 1.96 (t, J = 6.9 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 13: Synthesis of (Z)-2-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)thiazole-5-carboxylic acid (Compound 113)
Figure imgf000096_0003
[0345] (Z)-2-(4-(5-(4-Ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamido)thiazole-5- carboxylic acid was prepared using the procedures in Examples 1 and 10. LCMS (ESI) = 446.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.40 (s, 1H), 7.96 (s, 1H), 7.86 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 3.72 (t, J = 6.6 Hz, 2H), 2.67 (q, J = 7.5 Hz, 2H), 2.54 (d, J = 7.2 Hz, 2H), 2.01 – 1.90 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H). Example 14: Synthesis of (Z)-2-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)oxazole-4-carboxylic acid (Compound 114) [0346] I din-3-
Figure imgf000097_0001
yl)butanoic acid (50.0 mg, 0.157 mmol, 1.00 equiv), TEA (47.0 mg, 0.464 mmol, 2.97 equiv), and DMF (1.0 mL). To the above mixture was added BOP (69.0 mg, 0.156 mmol, 1.00 equiv) at 0 °C and the resulting mixture was stirred for 30 min at rt. To the above mixture was added 2-amino-1,3- oxazole-4-carboxylic acid (34.0 mg, 0.265 mmol, 1.70 equiv) and was stirred for additional 16 h at rt. The crude product was purified by preparative HPLC to afford (Z)-2-(4-(5-(4-ethylbenzylidene)- 2,4-dioxothiazolidin-3-yl)butanamido)oxazole-4-carboxylic acid (16.9 mg, 25%) as an off-white solid. LCMS (ESI) = 430.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 11.39 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 3.71 (t, J = 6.8 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.45 (m, 2H), 1.95 – 1.85 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 15: Synthesis of (Z)-4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)-N-(3- hydroxy-4-(1H-tetrazol-5-yl)phenyl)butanamide (Compound 115) [0347] Ste
Figure imgf000097_0002
nzonitrile (4.20 g, 25.6 mmol, 1.00 equiv), toluene (30 mL), triethylamine hydrochloride (5.00 g, 36.3 mmol, 1.42 equiv), and NaN3 (2.40 g, 36.9 mmol, 1.44 equiv). The resulting solution was heated overnight at 100 °C. The reaction was allowed to cool to rt and was extracted with 4 x 30 mL of H2O and the aqueous layers were combined. The pH value of the solution was adjusted to pH 5 with 4M HCl. The resultant solids were collected by filtration to afford 3.5 g (66%) of 5-nitro-2-(1H-tetrazol-5- yl)phenol as a light brown solid which was carried on without further purification. LCMS (ESI) = 206.0 [M - H]-. [0348] Step 2: To a solution of 5-nitro-2-(1H-1,2,3,4-tetrazol-5-yl)phenol (3.50 g, 16.9 mmol, 1.00 equiv) in 200 mL MeOH was added Pd/C (1.80 g, 10%) under nitrogen. The mixture was then placed under a hydrogen atmosphere at rt for 4 h using a hydrogen balloon. The mixture was filtered through a Celite pad and concentrated under reduced pressure to afford 5-amino-2-(1H- 1,2,3,4-tetrazol-5-yl)phenol (2.9 g, 97%) as a brown solid. LCMS (ESI) = 178.1 [M + H]+. [0349] (Z)-4-(5-(4-Ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)-N-(3-hydroxy-4-(1H-tetrazol-5- yl)phenyl)butanamide was prepared using the procedures in Example 1. LCMS (ESI) = 479.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.88 - 7.78 (m, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.08 (dd, J = 8.6, 2.0 Hz, 1H), 3.74 (t, J = 6.7 Hz, 2H), 2.63 (d, J = 7.6 Hz, 2H), 2.40 (s, 2H), 1.94 (s, 2H), 1.18 (t, J = 7.6 Hz, 3H). Example 16: Synthesis of (Z)-5-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-[1,1'-biphenyl]-2-carboxylic acid (Compound 116) [0350] Ste
Figure imgf000098_0001
4.06 mmol, 1.00 equiv), phenyl boronic acid (0.99 g, 8.12 mmol, 2.00 equiv), K2CO3 (1.69 g, 12.2 mmol, 3.01 equiv) and Pd(dppf)Cl2 (0.30 g, 0.406 mmol, 0.10 equiv) in dioxane (10 mL) and H2O (1.0 mL) at rt. The resulting mixture was stirred for 4 h at 100 °C under nitrogen atmosphere. The resulting mixture was acidified to pH 4-5 with conc. HCl (12 M). The organic layer was concentrated and was purified by C18 reverse-phase flash to afford 5-nitro-[1,1-biphenyl]-2-carboxylic acid (260 mg, 24%) as an off-white solid. LCMS (ESI) = 242.1 [M + H]+. [0351] Step 2: Into a 100 mL round-bottom flask was added 5-nitro-[1,1’-biphenyl]-2-carboxylic acid (260 mg, 1.07 mmol, 1.00 equiv), MeOH (10 mL) and Pd/C (26.0 mg, 0.1 equiv) at rt. The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred 1 h at rt under an atmosphere of hydrogen (balloon). The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 30 mL). The filtrate was concentrated under reduced pressure to afford 5-amino-[1,1’-biphenyl]-2-carboxylic acid (270 mg, 92%) as a light-yellow oil. [0352] (Z)-5-(4-(5-(4-Ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamido)-[1,1'-biphenyl]- 2-carboxylic acid was prepared using the procedures in Example 1. LCMS (ESI) = 515.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.16 (s, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.3 Hz,2H), 7.51 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 15.8, 7.6 Hz, 5H), 7.22 (dd, J = 7.3, 2.1 Hz, 2H), 3.73 (t, J = 6.6 Hz, 2H), 2.67 (q, J = 7.5 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.02 – 1.84 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 17: Synthesis of (Z)-2-acetamido-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 117) [0353] Step
Figure imgf000099_0001
mg, 2.74 mmol, 1.00 equiv), TEA (833 mg, 8.23 mmol, 3.00 equiv) and DCM (5 mL) at rt. Acetyl chloride (215 mg, 2.74 mmol, 1.00 equiv) was added dropwise at 0-5 °C (ice/water bath). The mixture was stirred for 1 h at rt, then concentrated under reduced pressure. The reaction was quenched with water at rt and acidified to pH 3-4 with conc. HCl. The precipitated solids were collected by filtration and washed with water. The resulting solid was dried under a heat lamp to afford 2-acetamido-4- nitrobenzoic acid (360 mg, 53%) as a yellow solid. LCMS (ESI) = 225.0 [M + H]+. [0354] Step 2: Into a 100 mL round-bottom flask was added 2-acetamido-4-nitrobenzoic acid (360 mg, 1.61 mmol, 1.00 equiv), MeOH (10 mL) and Pd/C (36.0 mg,) at rt. The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred for 1 h at rt under an atmosphere of hydrogen (balloon). The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 30 mL). The filtrate was concentrated under reduced pressure to afford 4-amino-2-acetamidobenzoic acid (300 mg, 77%) as an off-white solid. LCMS (ESI) = 195.1 [M + H]+. [0355] (Z)-2-Acetamido-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid was prepared using the procedures in Example 1. LCMS (ESI) = 496.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 11.31 (s, 1H), 10.24 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.84 (t, J = 4.4 Hz, 2H), 7.58 (dd, J = 8.8, 2.1 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 3.73 (t, J = 6.8 Hz, 2H), 2.66 (q, J = 7.6 Hz, 3H), 2.40 (t, J = 7.2 Hz, 2H), 2.11 (s, 3H), 1.99 – 1.87 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 18: Synthesis of (Z)-2-benzamido-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin- 3-yl)butanamido)benzoic acid (Compound 118) [0356] (Z)-2-Benzamido-4-( othiazolidin-3-
Figure imgf000100_0001
yl)butanamido)benzoic acid was prepared from benzoyl chloride using the procedures in Example 17. LCMS (ESI) = 558.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.46 (s, 1H), 12.41 (s, 1H), 10.32 (s, 1H), 8.89 (d, J = 1.9 Hz, 1H), 7.93 (t, J = 7.2 Hz, 3H), 7.84 (s, 1H), 7.70 – 7.54 (m, 4H), 7.48 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.75 (t, J = 6.5 Hz, 2H), 2.64 (q, J = 7.6 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 2.03 – 1.90 (m, 2H), 1.19 (t, J = 7.6 Hz, 3H). Example 19: Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-((methoxycarbonyl)amino)benzoic acid (Compound 119) [0357] (Z)-4-(4-(5-(4-Ethylb
Figure imgf000100_0002
-yl)butanamido)-2- ((methoxycarbonyl)amino)benzoic acid was prepared from methyl chloroformate using the procedures in Example 17. LCMS (ESI) = 512.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.31 (s, 1H), 10.82 (s, 1H), 10.27 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.84 (t, J = 4.4 Hz, 2H), 7.55 – 7.42 (m, 3H), 7.37 (d, J = 8.2 Hz, 2H), 3.80 – 3.65 (m, 5H), 2.66 (q, J = 7.5 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.01 – 1.87 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 20: Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-(methylsulfonamido)benzoic acid (Compound 120) [0358] (Z)-4-(4-(5-(4-Ethylbe 3-yl)butanamido)-2- (methylsulfonamido)benzoic ac
Figure imgf000101_0001
d was prepared n a manner s milar to Example 17 except the nitro group reduction was performed using the method in Example 11. LCMS (ESI) = 532.2 [M + H]+. Example 21: Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- fluorobenzoic acid (Compound 121) [
Figure imgf000101_0002
- dioxothiazolidin-3-yl)butanoic acid (500 mg, 1.57 mmol, 1.00 equiv), EtOH (10 mL), Pd/C (50.0 mg, 0.470 mmol, 0.30 equiv). The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred 2 h at rt under an atmosphere of hydrogen (balloon). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. This resulted in 4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanoic acid (280 mg, 56%) as an off-white solid. LCMS (ESI) = 320.2 [M + H]+. [0360] Step 2: Into a 4-mL vial was placed 4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3- yl)butanoic acid (50.0 mg, 0.156 mmol, 1.00 equiv), DCM (1.0 mL), and TEA (47.0 mg, 0.464 mmol, 2.99 equiv). This was followed by the addition of 2,2-dimethylpropanoyl chloride (21.0 mg, 0.174 mmol, 1.12 equiv) dropwise at 0 °C. The solution was stirred for 30 min at 0 °C in a water/ice bath. To this was added 2-fluoro-4-aminobenzoic acid (27.0 mg, 0.174 mmol, 1.12 equiv). The solution was stirred overnight at 25 °C. The resulting mixture was concentrated under vacuum and purified by preparative HPLC to afford 9.7 mg (14%) of 4-(4-(5-(4-ethylbenzyl)-2,4- dioxothiazolidin-3-yl)butanamido)-2-fluorobenzoic acid as a white solid. LCMS (ESI) = 459.1 [M + H]+. 12.95 (s, 1H), 10.36 (s, 1H), 7.82 (t, J = 8.6 Hz, 1H), 7.66 (dd, J = 13.7, 1.9 Hz, 1H), 7.34 (dd, J = 8.7, 2.0 Hz, 1H), 7.12 (s, 4H), 4.87 (dd, J = 8.9, 4.3 Hz, 1H), 3.65 - 3.44 (m, 2H), 3.36 (dd, J = 14.1, 4.3 Hz, 1H), 3.12 (d, J = 9.0 Hz, 1H), 2.54 (d, J = 4.4 Hz, 1H), 2.53 (s, 1H), 2.37 - 2.17 (m, 2H), 1.75 (t, J = 7.1 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). Example 22: Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- methylbenzoic acid (Compound 122) [0361] 4-(4-(5-(4-Ethylbenzy amido)-2-methylbenzoic acid was
Figure imgf000102_0001
prepared using the procedures in Example 21. LCMS (ESI) = 455.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.06 (s, 1H), 7.81 (d, J = 9.1 Hz, 1H), 7.62 - 7.43 (m, 2H), 7.12 (s, 4H), 4.87 (dd, J = 9.1, 4.3 Hz, 1H), 3.61 - 3.46 (m, 2H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.09 (dd, J = 14.1, 9.1 Hz, 1H), 2.55 (d, J = 7.6 Hz, 1H), 2.51 (s, 3H), 2.49 (s, 1H), 2.27 (td, J = 7.4, 3.5 Hz, 2H), 1.76 (q, J = 7.0 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H). Example 23: Synthesis of N-(3-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethylbenzyl)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 123) [0362] N-(3-(1H-Tetrazol-5-
Figure imgf000102_0002
-dioxothiazolidin-3- yl)butanamide was prepared using the procedures in Example 21. LCMS (ESI) = 465.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.42 (t, J = 1.9 Hz, 1H), 7.82 - 7.60 (m, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.11 (s, 4H), 4.88 (dd, J = 9.0, 4.3 Hz, 1H), 3.63 - 3.47 (m, 2H), 3.47 - 3.18 (m, 1H), 3.09 (dd, J = 14.1, 9.1 Hz, 1H), 2.54 (d, J = 7.6 Hz, 1H), 2.48 (s, 1H), 2.29 (td, J = 7.5, 3.0 Hz, 2H), 1.79 (q, J = 7.1 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). Example 24: Synthesis of 3-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 124) [0363] 3-(4-(5-(4-Ethylbenzy
Figure imgf000102_0003
, amido)benzoic acid was prepared using the procedures in Example 21. LCMS (ESI) = 441.1 [M + H]+. 1H NMR (300 MHz, DMSO- d6) δ 12.93 (s, 1H), 10.05 (s, 1H), 8.22 (t, J = 1.9 Hz, 1H), 7.85 - 7.75 (m, 1H), 7.60 (dt, J = 7.6, 1.4 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.11 (s, 4H), 4.87 (dd, J = 9.0, 4.3 Hz, 1H), 3.52 (dt, J = 6.9, 3.7 Hz, 2H), 3.36 (dd, J = 14.1, 4.3 Hz, 1H), 3.08 (dd, J = 14.1, 9.0 Hz, 1H), 2.54 (d, J = 7.6 Hz, 1H), 2.48 (d, J = 2.2 Hz, 1H), 2.25 (td, J = 7.4, 3.0 Hz, 2H), 1.75 (p, J = 7.1 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). Example 25: Synthesis of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethylbenzyl)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 125) [0364] N-(4-(1H-Tetrazol-5 -dioxothiazolidin-3-
Figure imgf000103_0001
yl)butanamide was prepared using the procedures in Example 21. LCMS (ESI) = 465.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.7 Hz, 2H), 7.11 (s, 4H), 4.87 (dd, J = 9.0, 4.3 Hz, 1H), 3.62 - 3.47 (m, 2H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.10 (dd, J = 14.1, 9.1 Hz, 1H), 2.54 (d, J = 7.7 Hz, 1H), 2.47 (s, 1H), 2.36 - 2.22 (m, 2H), 1.78 (q, J = 7.1 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H). Example 26: Synthesis of the single enantiomers of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4- ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 126A and Compound 126B) [03
Figure imgf000103_0002
yl)butanamide (60 mg) was separated into the single enantiomers by chiral preparative HPLC using a CHIRALCEL OJ-3 column, 4.6*50mm, 3um. Mobile phase A: n-Hexane and B: Ethanol (with 0.1% TFA) (eluted with 40% B). This resulted in 17 mg (28%) of N-(4-(1H-tetrazol-5-yl)phenyl)- 4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamide (Peak 1, Compound 126A). tR = 1.54 min (n-Hexane/EtOH(0.1%TFA)) as off-white solid and 15 mg (25%) of N-(4-(1H-tetrazol-5- yl)phenyl)-4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamide (Peak 2, Compound 126B), tR = 2.75 min (n-Hexane/EtOH (with 0.1%TFA)) as off-white solid. Example 27: Synthesis of 5-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- hydroxybenzoic acid (Compound 127) O H O N N OH S O [0366] 5-(4-(5-(4-Ethylbenz amido)-2-hydroxybenzoic acid was prepared using the proced
Figure imgf000104_0001
ures in Example 21. LCMS (ESI) = 457.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.64 (dd, J = 8.9, 2.7 Hz, 1H), 7.12 (s, 4H), 6.90 (d, J = 8.9 Hz, 1H), 4.87 (dd, J = 9.0, 4.3 Hz, 1H), 3.60 - 3.47 (m, 2H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.09 (dd, J = 14.1, 9.1 Hz, 1H), 2.56 (d, J = 7.6 Hz, 2H), 2.21 (d, J = 2.5 Hz, 2H), 1.76 (q, J = 7.1 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H). Example 28: Synthesis of 5-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- fluorobenzoic acid (Compound 128) [0367] 5-(4-(5-(4-Ethylbenzy amido)-2-fluorobenzoic acid was
Figure imgf000104_0002
prepared using the procedures in Example 21. LCMS (ESI) = 459.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.24 (s, 1H), 10.07 (s, 1H), 8.13 (dd, J = 6.7, 2.8 Hz, 1H), 7.78 (ddd, J = 9.0, 4.2, 2.9 Hz, 1H), 7.24 (dd, J = 10.6, 9.0 Hz, 1H), 7.12 (s, 4H), 4.88 (dd, J = 9.0, 4.2 Hz, 1H), 3.64 - 3.45 (m, 2H), 3.41 - 3.21 (m, 1H), 3.09 (dd, J = 14.1, 9.0 Hz, 1H), 2.54 (s, 2H), 2.24 (td, J = 7.6, 3.3 Hz, 2H), 1.77 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H). Example 29: Synthesis of 5-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- methylbenzoic acid (Compound 129) [0368] 5-(4-(5-(4-Ethylbenzy
Figure imgf000104_0003
amido)-2-methylbenzoic acid was prepared using the procedures in Example 21. LCMS (ESI) = 455.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 9.94 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 8.3, 2.4 Hz, 1H), 7.25 - 7.06 (m, 1H), 7.12 (s, 4H), 4.87 (dd, J = 9.1, 4.3 Hz, 1H), 3.58 - 3.45 (m, 2H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.09 (dd, J = 14.1, 9.1 Hz, 1H), 2.56 (d, J = 7.6 Hz, 2H), 2.45 (s, 3H), 2.24 (td, J = 7.4, 2.5 Hz, 2H), 1.75 (p, J = 7.0 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H). Example 30: Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- nitrobenzoic acid (Compound 130) [0369] 4-(4-(5-(4-Ethylben mido)-2-nitrobenzoic acid was prepared using the procedures
Figure imgf000105_0001
in Example 21. LCMS (ESI) = 486.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.64 (s, 1H), 10.56 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.12 (s, 4H), 4.88 (dd, J = 9.0, 4.3 Hz, 1H), 3.60 - 3.45 (m, 2H), 3.37 (dd, J = 14.2, 4.4 Hz, 1H), 3.09 (dd, J = 14.1, 9.0 Hz, 1H), 2.54 (d, J = 7.9 Hz, 2H), 2.37 - 2.14 (m, 2H), 1.86 - 1.65 (m, 2H), 1.11 (t, J = 7.6 Hz, 3H). Example 31: Synthesis of 2-amino-4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 131) [0370] 2-
Figure imgf000105_0002
nitrobenzoic acid (50.0 mg, 0.103 mmol, 1.00 equiv) in MeOH (5 mL) was added 10% Pd/C (11.0 mg, 0.010 mmol, 0.10 equiv) under nitrogen atmosphere. The mixture was stirred at rt for 4 h under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 2-amino-4- (4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)benzoic acid (18.2 mg, 39%) as a white solid. LCMS (ESI) = 456.2 [M + H]+.1H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.12 (s, 4H), 6.62 (dd, J = 8.8, 2.0 Hz, 1H), 4.88 (dd, J = 9.0, 4.3 Hz, 1H), 3.59 - 3.47 (m, 2H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.10 (dd, J = 14.1, 9.1 Hz, 1H), 2.55 (s, 2H), 2.25 (td, J = 7.5, 2.7 Hz, 2H), 1.83 - 1.67 (m, 2H), 1.12 (t, J = 7.6 Hz, 3H). Example 32: Synthesis of 2-acetamido-4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 132)
Figure imgf000105_0003
[0371] 2-Acetamido-4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)benzoic acid was prepared using the procedures in Examples 17 and 21. LCMS (ESI) = 498.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.29 (s, 1H), 11.51 (s, 1H), 10.23 (s, 1H), 8.63 (d, J = 2.1 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.1 Hz, 1H), 7.12 (s, 4H), 4.88 (dd, J = 9.1, 4.3 Hz, 1H), 3.59 - 3.45 (m, 2H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.10 (dd, J = 14.1, 9.1 Hz, 1H), 2.55 (d, J = 7.6 Hz, 2H), 2.28 (td, J = 7.4, 3.0 Hz, 2H), 2.13 (s, 3H), 1.76 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H). Example 33: Synthesis of 2-benzamido-4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 133) [0372] 2-Benzamido-4-(4-( n-3-yl)butanamido)benzoic acid
Figure imgf000106_0001
was prepared using the procedures in Examples 18 and 21. LCMS (ESI) = 560.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.04 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.58 (dt, J = 14.3, 7.0 Hz, 4H), 7.11 (d, J = 2.2 Hz, 4H), 4.69 (dd, J = 8.9, 3.9 Hz, 1H), 3.67 (d, J = 1.7 Hz, 2H), 3.42 (dd, J = 14.1, 4.0 Hz, 1H), 3.16 (dd, J = 14.1, 8.9 Hz, 1H), 2.56 (q, J = 7.6 Hz, 2H), 2.36 (td, J = 7.3, 4.1 Hz, 2H), 1.93 (p, J = 6.9 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). Example 34: Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- ((methoxycarbonyl)amino)benzoic acid (Compound 134) [0373] 4-(4-(5-(4-Ethylben
Figure imgf000106_0002
mido)-2- ((methoxycarbonyl)amino)benzoic acid was prepared using the procedures in Examples 19 and 21. LCMS (ESI) = 514.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 11.07 (s, 1H), 10.24 (s, 1H), 8.51 (d, J = 2.1 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.46 (dd, J = 8.8, 2.1 Hz, 1H), 7.12 (s, 4H), 4.88 (dd, J = 9.0, 4.3 Hz, 1H), 3.70 (s, 3H), 3.57 - 3.46 (m, 2H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.10 (dd, J = 14.1, 9.1 Hz, 1H), 2.55 (d, J = 7.5 Hz, 2H), 2.35 - 2.20 (m, 2H), 1.75 (t, J = 7.1 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H). Example 35: Synthesis of 5-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-[1,1'- biphenyl]-2-carboxylic acid (Compound 135) [0374] 5-(4-(5-(4-Ethylben mido)-[1,1'-biphenyl]-2- carboxylic acid was prepared
Figure imgf000107_0001
us ng t e procedures n Examp es 16 and 21. LCMS (ESI) = 517.2 [M + H]+. Example 36: Synthesis of 4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)-N-(3-hydroxy-4-(1H- tetrazol-5-yl)phenyl)butanamide (Compound 136) [0375] 4-(5-(4-Ethylbenzyl) roxy-4-(1H-tetrazol-5-
Figure imgf000107_0002
yl)phenyl)butanamide was prepared using the procedures in Examples 15 and 21. LCMS (ESI) = 481.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.12 (s, 5H), 4.88 (dd, J = 9.0, 4.3 Hz, 1H), 3.53 (t, J = 7.1 Hz, 2H), 3.10 (dd, J = 14.1, 9.1 Hz, 1H), 2.56 (s, 2H), 2.27 (td, J = 7.6, 3.5 Hz, 2H), 1.76 (t, J = 7.1 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H). Example 37: Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- (methylsulfonamido)benzoic acid (Compound 137) [0376] 4-(4-(5-(4-Ethylbenz
Figure imgf000107_0003
amido)-2- (methylsulfonamido)benzoic acid was prepared using the procedures in Examples 20 and 21. LCMS (ESI) = 534.2 [M + H]+. Example 38: Synthesis of 4-((E)-4-(5-((Z)-4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)but-2- enamido)-2-hydroxybenzoic acid (Compound 138)
Figure imgf000107_0004
Figure imgf000108_0001
ethylbenzaldehyde (2.75 g, 20.5 mmol, 1.20 equiv) in AcOH (20 mL) was added AcONa (2.10 g, 25.6 mmol, 1.50 equiv) at rt. The resulting mixture was stirred overnight at 100 °C. The mixture was allowed to cool down to rt. The mixture was diluted with water (80 mL). The precipitated solids were collected by filtration and washed with water (3 x 30 mL) and petroleum ether (3 x 30 mL). The solid was dried under a heat lamp to afford (Z)-5-(4-ethylbenzylidene)thiazolidine-2,4- dione (2 g, 50%) as a white solid. [0378] Step 2: To a solution of tert-butyl (E)-but-2-enoate (2.00 g, 14.1 mmol, 1.00 equiv) and NBS (2.50 g, 14.1 mmol, 1.00 equiv) in CCl4 (20 mL) was added AIBN (0.23 g, 1.41 mmol, 0.10 equiv). The resulting mixture was stirred for 4 h at 80 °C. The mixture was allowed to cool to rt. The mixture was washed sequentially with 3 x 20 mL of water and 20 mL of brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl (E)-4-bromobut-2-enoate (2.5 g, crude) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 6.92 (dt, J = 15.1, 7.5 Hz, 1H), 5.97 (dt, J = 15.3, 1.3 Hz, 1H), 4.01 (dd, J = 7.4, 1.3 Hz, 2H), 1.51 (d, J = 6.4 Hz, 9H). [0379] Step 3: Into a 8 mL vial was added (Z)-5-(4-ethylbenzylidene)thiazolidine-2,4-dione (200 mg, 0.857 mmol, 1.00 equiv), tert-butyl (E)-but-2-enoate (228 mg, 1.03 mmol, 1.20 equiv) and K2CO3 (355 mg, 2.57 mmol, 3.00 equiv) in MeCN (2 mL) at rt. The mixture was stirred for 1 h at 80 °C. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford tert-butyl (E)-4-(5-((Z)-4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)but-2-enoate (280 mg, 79%) as a light yellow oil. LCMS (ESI) = 374.2 [M + H]+. [0380] Step 4: Into a 8 mL vial was added tert-butyl (E)-4-(5-((Z)-4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)but-2-enoate (280 mg, 0.750 mmol, 1.00 equiv), TFA (1.50 mL) in DCM (3.0 mL) at rt. The mixture was stirred for 1 h at rt, then the resulting mixture was concentrated under reduced pressure. This resulted in (E)-4-(5-((Z)-4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)but- 2-enoic acid (200 mg, 76%) as an off-white solid. LCMS (ESI) = 318.1 [M + H]+. [0381] Step 5: Into a 8 mL vial were added (E)-4-(5-((Z)-4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)but-2-enoic acid (50.0 mg, 0.158 mmol, 1.00 equiv), DIEA (22.0 mg, 0.170 mmol, 1.09 equiv) and DCE (1.00 mL) at rt. To the above mixture was added 2, 2- dimethylpropanoyl chloride (21.0 mg, 0.174 mmol, 1.12 equiv) dropwise at 0-5 °C with ice/water bath. The resulting mixture was stirred for 1 h at rt. To the above mixture was added aminosalicylic acid (24.0 mg, 0.157 mmol, 0.99 equiv) at rt. To the above mixture was stirred for additional 16 h at 50 °C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 4-((E)-4-(5-((Z)-4-ethylbenzylidene)-2,4-dioxothiazolidin- 3-yl)but-2-enamido)-2-hydroxybenzoic acid (13.3 mg,18%) as an off-white solid. LCMS (ESI) = 453.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.99 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.36 (s, 1H), 7.10 – 6.99 (m, 1H), 6.85 (dt, J = 15.5, 4.4 Hz, 1H), 6.12 (d, J = 15.5 Hz, 1H), 4.48 (d, J = 3.2 Hz, 2H), 2.68 (dd, J = 15.1, 7.6 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H). Example 39: Synthesis of (E)-N-(3-(1H-tetrazol-5-yl)phenyl)-4-(5-((Z)-4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)but-2-enamide (Compound 139) [0382] (E)-N-(3-(1H-Tetr
Figure imgf000109_0001
azol-5-yl)phenyl)-4-(5-((Z)-4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)but-2-enamide was prepared using the procedures in Example 38. LCMS (ESI) = 461.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.41 (s, 1H), 7.99 (s, 1H), 7.74 (dd, J = 21.1, 7.9 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 6.86 (dt, J = 15.4, 4.6 Hz, 1H), 6.15 (d, J = 15.5 Hz, 1H), 4.50 (d, J = 3.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). Example 40: Synthesis of (E)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((Z)-4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)but-2-enamide (Compound 140) [0383 din-3- yl)but-
Figure imgf000110_0001
2-enoic acid (50.0 mg, 0.158 mmol, 1.00 equiv), pyridine (25.0 mg, 0.316 mmol, 2.01 equiv), 4-(1H-tetrazol-5-yl)aniline (31.0 mg, 0.192 mmol, 1.22 equiv) in DCM (1 mL) at rt. To the above solution was added T3P (100 mg, 0.314 mmol, 1.99 equiv) dropwise at 0-5 ℃. The resulting mixture was stirred for 1 h at rt, then the resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford (E)-N-(4-(1H-tetrazol-5- yl)phenyl)-4-(5-((Z)-4-ethylbenzylidene)-2,4-dioxothiazolidin-3-yl)but-2-enamide (12.3 mg, 16%) as an off-white solid. LCMS (ESI) = 461.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.99 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.84 (dt, J = 15.5, 4.7 Hz, 1H), 6.15 (d, J = 15.5 Hz, 1H), 4.49 (d, J = 3.1 Hz, 2H), 2.69 (q, J = 7.7 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). Example 41: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethoxybenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 141) [
Figure imgf000110_0002
, , 1.3 mmol, 1.00 equiv), KOH (1.30 g, 23.2 mmol, 1.09 equiv) and EtOH (50 mL). The resulting mixture was stirred for 1 h at 70 °C, then was allowed to cool down to rt. The precipitated solids were collected by filtration to afford potassium 2,4-dioxo-1,3-thiazolidin-3-ide (2.8 g, 84.5%) as an off-white solid. [0385] Step 2: Into a 50 mL round-bottom flask was added potassium 2,4-dioxo-1,3-thiazolidin- 3-ide (2.80 g, 18.0 mmol, 1.00 equiv), ethyl 4-bromobutanoate (3.50 g, 17.9 mmol, 0.99 equiv), DMF (30 mL). The resulting mixture was stirred for 2 h at 80 °C. The mixture was allowed to cool down to rt. The resulting mixture was diluted with water (200 mL) and the resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 4-(2,4-dioxo-1,3-thiazolidin-3- yl)butanoate (3.3 g, 79%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.14 (qd, J = 7.1, 4.8 Hz, 2H), 3.96 (s, 2H), 3.71 (t, J = 6.9 Hz, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.96 (p, J = 7.1 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). [0386] Step 3: Into a 100 mL round-bottom flask were added ethyl 4-(2,4-dioxo-1,3-thiazolidin- 3-yl)butanoate (1.50 g, 6.49 mmol, 1.00 equiv), AcOH (20 mL), HCl (20 mL). The mixture was stirred for 16 h at 80 °C then was concentrated under vacuum. This resulted in 4-(2,4-dioxo-1,3- thiazolidin-3-yl)butanoic acid (1.3 g, 98.63%) as an off-white solid. LCMS (ESI) = 202.0 [M + H]+. [0387] Step 4: Into a 80 mL vial was added 4-(2,4-dioxo-1,3-thiazolidin-3-yl)butanoic acid (500 mg, 2.46 mmol, 1.00 equiv), 4-(1H-tetrazol-5-yl)aniline (475 mg, 2.95 mmol, 1.20 equiv), HATU (1.12 g, 2.95 mmol, 1.20 equiv), DIEA (953 mg, 7.37 mmol, 3.00 equiv), DMF (5.00 mL). The resulting mixture was stirred for 2 h at rt. The mixture was acidified to pH 3 with HCl (aq.). The precipitated solids were collected by filtration. This resulted in N-(4-(1H-tetrazol-5-yl)phenyl)-4- (2,4-dioxothiazolidin-3-yl)butanamide (800 mg, 94%) as an off-white solid. LCMS (ESI) = 347.1 [M + H]+. [0388] Step 5: Into a 8 mL vial was added N-(4-(1H-tetrazol-5-yl)phenyl)-4-(2,4- dioxothiazolidin-3-yl)butanamide (50.0 mg, 0.144 mmol, 1.00 equiv), 4-ethoxybenzaldehyde (43.0 mg, 0.286 mmol, 1.98 equiv), pyrrolidine (21.0 mg, 0.295 mmol, 2.05 equiv), MeOH (1.00 mL), H2O (0.20 mL). The resulting mixture was stirred for 2 h at rt. The crude product was purified by preparative HPLC to afford (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-ethoxybenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide (17 mg, 25%) as an off-white solid. LCMS (ESI) = 479.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.83 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.75 (t, J = 6.6 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.04 – 1.90 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H). Example 42: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(2,4-dioxo-5-(4- propoxybenzylidene)thiazolidin-3-yl)butanamide (Compound 142) [0389] (Z)-N-(4-(1H-Tetraz opoxybenzylidene)thiazolidin-3- yl)butanamide was prepared u
Figure imgf000112_0001
sing the procedures in Example 41. LCMS (ESI) = 493.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.94 – 7.85 (m, 2H), 7.83 (s, 1H), 7.78 – 7.68 (m, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.10 – 7.01 (m, 2H), 3.99 (t, J = 6.5 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.95 (t, J = 6.9 Hz, 2H), 1.75 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). Example 43: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-benzylidene-2,4- dioxothiazolidin-3-yl)butanamide (Compound 143) [0390] (Z)-N-(4-(1H-Tetrazol- 2,4-dioxothiazolidin-3-
Figure imgf000112_0002
yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 435.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.96 – 7.86 (m, 3H), 7.81 – 7.72 (m, 2H), 7.64 – 7.41 (m, 5H), 3.76 (t, J = 6.7 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.96 (p, J = 7.0 Hz, 2H). Example 44: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-([1,1'-biphenyl]-4- ylmethylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 144) [0391] (Z)-N-(4-(1H-Tetraz
Figure imgf000112_0003
-4-ylmethylene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 511.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 7.96 – 7.79 (m, 5H), 7.78 – 7.65 (m, 4H), 7.57 (d, J = 8.4 Hz, 2H), 7.54 – 7.46 (m, 2H), 7.46 – 7.35 (m, 1H), 3.75 (t, J = 6.7 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 1.94 (t, J = 7.0 Hz, 1H). Example 45: Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)benzoic acid (Compound 145) [0392] (Z)-4-(4-(5-(4-Ethylb 3-yl)butanamido)benzoic acid was prepared using the procedures i
Figure imgf000113_0001
n Exampe 41. LCMS (ESI) = 439.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.90 – 7.79 (m, 3H), 7.72 – 7.61 (m, 2H), 7.56 – 7.48 (m, 2H), 7.43 – 7.33 (m, 2H), 3.74 (t, J = 6.7 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 1.94 (p, J = 7.0 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 46: Synthesis of (Z)-4-(4-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)butanamido)-2-hydroxybenzoic acid (Compound 146) [0393] (Z)-4-(4-(5-(4-Ethylbe 3-yl)butanamido)-2-
Figure imgf000113_0002
hydroxybenzoic acid was prepared using the procedures in Example 41. LCMS (ESI) = 455.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.88 (s, 1H), 7.55 (m, 3H), 7.45 – 7.33 (m, 2H), 7.11 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.5, 2.0 Hz, 1H), 3.72 (t, J = 6.8 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 2.36 (t, J = 7.3 Hz, 2H), 1.91 (p, J = 7.2 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 47: Synthesis of 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2- hydroxybenzoic acid (Compound 147) [0394]
Figure imgf000113_0003
2,4- dioxothiazolidin-3-yl)butanamido)-2-hydroxybenzoic acid (10.0 mg, 0.022 mmol, 1.00 equiv), EtOH (5.0 mL), and Pd/C (2.0 mg, 0.019 mmol, 0.85 equiv). The flask was placed under a hydrogen atmosphere. The resulting mixture was stirred for 5 h at rt. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 4-(4-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)butanamido)-2-hydroxybenzoic acid (2.8 mg, 28%) as an off-white solid. LCMS (ESI) = 457.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.13 (s, 5H), 6.88 (d, J = 8.6 Hz, 1H), 4.88 (dd, J = 9.1, 4.2 Hz, 1H), 3.52 (t, J = 6.9 Hz, 2H), 3.37 (dd, J = 14.0, 4.2 Hz, 1H), 3.10 (dd, J = 14.0, 9.1 Hz, 1H), 2.56 (d, J = 7.6 Hz, 1H), 2.28 – 2.19 (m, 1H), 1.75 (q, J = 7.4 Hz, 2H), 1.18 – 1.01 (m, 3H). Example 48: Synthesis of (Z)-N-(3-hydroxy-4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 148) [0395] (Z)-N-(3-Hydroxy-4-( methylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamid
Figure imgf000114_0001
e was prepared from 5-amino-2-(1H-tetrazol-5-yl)phenol using the procedures in Example 41. LCMS (ESI) = 465.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.84 (t, J = 4.3 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.08 (dd, J = 8.6, 2.0 Hz, 1H), 3.74 (t, J = 6.7 Hz, 2H), 2.36 (d, J = 18.7 Hz, 5H), 1.94 (s, 2H). Example 49: Synthesis of N-(3-hydroxy-4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-methylbenzyl)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 149) [0396] N-(3-Hydroxy-4-(1H-t hylbenzyl)-2,4-dioxothiazolidin-3-
Figure imgf000114_0002
yl)butanamide was prepared was prepared using the procedures in Example 47. LCMS (ESI) = 467.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 1.9 Hz, 1H), 7.09 (s, 5H), 4.88 (dd, J = 8.9, 4.3 Hz, 1H), 3.53 (t, J = 6.9 Hz, 2H), 3.39 (d, J = 4.3 Hz, 1H), 3.13 (d, J = 8.9 Hz, 1H), 2.32 - 2.24 (m, 2H), 2.24 (s, 3H), 1.84 - 1.68 (m, 2H). Example 50: Synthesis of (Z)-N-(3-hydroxy-4-(1H-tetrazol-5-yl)phenyl)-4-(5-(3- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 150) [0397] (Z)-N-(3-Hydroxy-4-(
Figure imgf000114_0003
3-methylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 465.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.91 - 7.80 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.45 - 7.34 (m, 3H), 7.28 (t, J = 4.3 Hz, 1H), 7.08 (dd, J = 8.6, 2.0 Hz, 1H), 3.74 (t, J = 6.7 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.95 (t, J = 7.0 Hz, 2H). Example 51: Synthesis of N-(3-hydroxy-4-(1H-tetrazol-5-yl)phenyl)-4-(5-(3-methylbenzyl)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 151) [0398] N-(3-Hydroxy-4-(1H-t hylbenzyl)-2,4-dioxothiazolidin-3- yl)butanamide was prepared usin
Figure imgf000115_0001
g t e procedures n Examp e 47. LCMS (ESI) = 467.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.09 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.21 - 7.07 (m, 2H), 7.06 - 6.97 (m, 3H), 4.88 (dd, J = 9.2, 4.3 Hz, 1H), 3.54 (t, J = 6.7 Hz, 2H), 3.42 - 3.34 (m, 1H), 3.08 (dd, J = 14.1, 9.2 Hz, 1H), 2.35 - 2.26 (m, 2H), 2.23 (s, 3H), 1.78 (d, J = 6.9 Hz, 2H). Example 52: Synthesis of (Z)-N-(3-hydroxy-4-(1H-tetrazol-5-yl)phenyl)-4-(5-(2- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 152) [0399] (Z)-N-(3-Hydroxy-4-(1 -methylbenzylidene)-2,4-
Figure imgf000115_0002
dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 465.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.98 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.48 - 7.24 (m, 3H), 7.09 (dd, J = 8.6, 2.0 Hz, 1H), 3.75 (t, J = 6.7 Hz, 2H), 2.39 (d, J = 9.8 Hz, 5H), 1.95 (t, J = 7.0 Hz, 2H). Example 53: Synthesis of N-(3-hydroxy-4-(1H-tetrazol-5-yl)phenyl)-4-(5-(2-methylbenzyl)-2,4- dioxothiazolidin-3-yl)butanamide (Compound 153) [0400] N-(3-Hydroxy-4-(1H-t
Figure imgf000115_0003
thylbenzyl)-2,4-dioxothiazolidin-3- yl)butanamide was prepared using the procedures in Example 47. LCMS (ESI) = 467.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.27 - 7.01 (m, 5H), 4.88 (dd, J = 10.5, 4.2 Hz, 1H), 3.68 - 3.47 (m, 3H), 3.09 (dd, J = 14.4, 10.5 Hz, 1H), 2.36 (t, J = 7.3 Hz, 2H), 2.30 (s, 3H), 1.85 (s, 2H). Example 54: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((5-ethylpyridin-2- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 154) [0401] Into a 40 mL vial de (500 mg, 2.69 mmol, 1.00 equiv), ethyl boronic acid, (
Figure imgf000116_0001
1000 mg, 13.5 mmol, 5.03 equiv), Pd(PPh3)4 (50.0 mg, 0.043 mmol, 0.02 equiv), Na2CO3 (795 mg, 7.50 mmol, 2.79 equiv), toluene (5.0 mL), and H2O (0.5 mL). The resulting mixture was heated for 16 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool to rt. The residue was purified by silica gel column chromatography to afford 5- ethylpyridine-2-carbaldehyde (120 mg, 33%) as a brown oil. LCMS (ESI) = 136.2 [M + H]+. [0402] (Z)-N-(4-(1H-Tetrazol-5-yl)phenyl)-4-(5-((5-ethylpyridin-2-yl)methylene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 464.4 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.62 (s, 1H), 7.94 – 7.83 (m, 3H), 7.79 – 7.70 (m, 4H), 3.73 (t, J = 6.8 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.95 (t, J = 7.0 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Example 55: Synthesis of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((5-ethylpyridin-2-yl)methyl)- 2,4-dioxothiazolidin-3-yl)butanamide (Compound 155) [0403] N-(4-(1H-Tetrazol-5-
Figure imgf000116_0002
yl)methyl)-2,4-dioxothiazolidin- 3-yl)butanamide was prepared using the procedures in Example 47. LCMS (ESI) = 466.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.02 – 7.93 (m, 2H), 7.87 – 7.77 (m, 2H), 7.60 (dd, J = 8.0, 2.3 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.91 (dd, J = 8.9, 4.2 Hz, 1H), 3.67 – 3.54 (m, 2H), 3.43 (m, 2H), 2.63 – 2.52 (m, 2H), 2.48 – 2.38 (m, 2H), 1.91 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H). Example 56: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((5-butylpyridin-2- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 156)
Figure imgf000116_0003
[0404] (Z)-N-(4-(1H-Tetrazol-5-yl)phenyl)-4-(5-((5-butylpyridin-2-yl)methylene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 54. LCMS (ESI) = 492.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 7.94 – 7.83 (m, 3H), 7.80 – 7.68 (m, 4H), 3.73 (t, J = 6.7 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 1.95 (t, J = 6.9 Hz, 2H), 1.57 (p, J = 7.4 Hz, 2H), 1.29 (dt, J = 14.6, 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). Example 57: Synthesis of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((5-butylpyridin-2-yl)methyl)- 2,4-dioxothiazolidin-3-yl)butanamide (Compound 157) [0405] N-(4-(1H-Tetrazol-5- -yl)methyl)-2,4-dioxothiazolidin-
Figure imgf000117_0001
3-yl)butanamide was prepared using the procedures in Example 47. LCMS (ESI) = 494.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.56 (dd, J = 8.0, 2.3 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.91 (dd, J = 8.8, 4.2 Hz, 1H), 3.67 – 3.53 (m, 2H), 3.41 (dd, J = 16.1, 8.8 Hz, 1H), 2.55 (m, 1H), 2.46 – 2.35 (m, 2H), 1.91 (q, J = 7.1 Hz, 2H), 1.51 (p, J = 7.6 Hz, 2H), 1.25 (dq, J = 14.6, 7.2 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H). Example 58: Synthesis of (Z)-4-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(3-hydroxy-4-(1H- tetrazol-5-yl)phenyl)butanamide (Compound 158) [0406] (Z)-4-(5-Benzylidene-
Figure imgf000117_0002
hydroxy-4-(1H-tetrazol-5- yl)phenyl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 451.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.98 - 7.78 (m, 2H), 7.59 (dq, J = 4.8, 2.7, 2.3 Hz, 3H), 7.56 - 7.41 (m, 3H), 7.08 (dd, J = 8.6, 2.0 Hz, 1H), 3.75 (t, J = 6.7 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 1.95 (t, J = 7.0 Hz, 2H). Example 59: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6-bromopyridin-3- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 159)
Figure imgf000117_0003
[0407] (Z)-N-(4-(1H-Tetrazol-5-yl)phenyl)-4-(5-((6-bromopyridin-3-yl)methylene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 516.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.61 (d, J = 2.5 Hz, 1H), 7.94 – 7.81 (m, 4H), 7.75 (dd, J = 8.5, 4.6 Hz, 3H), 3.76 (t, J = 6.7 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 1.98 (q, J = 6.9 Hz, 2H). Example 60: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6-ethylpyridin-3- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 160) [0408] (Z)-N-(4-(1H-Tetrazo in-3-yl)methylene)-2,4-
Figure imgf000118_0001
dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 54. 464.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 2H), 8.72 (d, J = 2.3 Hz, 2H), 8.14 (s, 1H), 7.92 – 7.80 (m, 8H), 7.69 (d, J = 8.4 Hz, 5H), 7.40 (d, J = 8.2 Hz, 2H), 3.76 (t, J = 6.6 Hz, 4H), 2.84 – 2.73 (m, 3H), 2.40 (d, J = 6.9 Hz, 3H), 1.96 (t, J = 7.0 Hz, 3H), 1.22 (t, J = 7.6 Hz, 6H). Example 61: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6-butylpyridin-3- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 161) [0409] (Z)-N-(4-(1H-Tetra
Figure imgf000118_0002
-3-yl)methylene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 54. LCMS (ESI) = 492.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J = 2.3 Hz, 1H), 7.88 – 7.75 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.2 Hz, 1H), 4.01 (d, J = 6.1 Hz, 13H), 3.72 (t, J = 6.6 Hz, 2H), 2.69 (d, J = 7.6 Hz, 1H), 2.36 (t, J = 7.2 Hz, 2H), 1.98 – 1.88 (m, 2H), 1.58 (p, J = 7.7 Hz, 2H), 1.23 (dt, J = 14.5, 7.2 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H). Example 62: Synthesis of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6-ethylpyridin-3-yl)methyl)- 2,4-dioxothiazolidin-3-yl)butanamide (Compound 162) [0410]
Figure imgf000118_0003
lpyridin-3- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (50.0 mg, 0.108 mmol, 1.00 equiv), AcOH (1 ml) and zinc (35.3 mg, 0.539 mmol, 5.0 equiv). The resulting mixture was stirred for 3 hr at 100 °C. The mixture was diluted with 4 mL of DMSO and the solids were filtered. The filtrate was purified by preparative HPLC to afford 26.4 mg (53%) of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6- ethylpyridin-3-yl)methyl)-2,4-dioxothiazolidin-3-yl)butanamide as a white solid. LCMS (ESI) = 466.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.01 – 7.91 (m, 2H), 7.83 – 7.74 (m, 2H), 7.55 (dd, J = 8.0, 2.4 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 4.94 (dd, J = 8.3, 4.6 Hz, 1H), 3.53 (td, J = 6.8, 1.8 Hz, 2H), 3.44 – 3.34 (m, 2H), 3.19 (dd, J = 14.2, 8.3 Hz, 1H), 2.67 (q, J = 7.6 Hz, 2H), 2.32 – 2.22 (m, 1H), 1.76 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.6 Hz, 3H). Example 63: Synthesis of N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((6-butylpyridin-3-yl)methyl)- 2,4-dioxothiazolidin-3-yl)butanamide (Compound 163) [0411] N-(4-(1H-Tetrazol- l)methyl)-2,4-dioxothiazolidin-
Figure imgf000119_0001
3-yl)butanamide was prepared using the procedures in Example 62. LCMS (ESI) = 494.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.00 – 7.90 (m, 2H), 7.81 – 7.72 (m, 2H), 7.53 (dd, J = 8.0, 2.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.93 (dd, J = 8.0, 4.6 Hz, 1H), 3.60 – 3.47 (m, 2H), 3.43 – 3.30 (m, 2H), 3.19 (dd, J = 14.2, 8.1 Hz, 1H), 2.69 – 2.58 (m, 2H), 2.35 – 2.15 (m, 2H), 1.74 (q, J = 7.2 Hz, 2H), 1.57 (tt, J = 7.8, 6.4 Hz, 2H), 1.23 (h, J = 7.3 Hz, 2H), 0.83 (t, J = 7.3 Hz, 3H). Example 64: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-((5-bromopyridin-2- yl)methylene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 164) [0412] (Z)-N-(4-(1H-Tetrazo
Figure imgf000119_0002
din-2-yl)methylene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 516.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.21 – 8.11 (m, 1H), 7.93 – 7.78 (m, 4H), 7.73 (d, J = 8.3 Hz, 2H), 3.74 (t, J = 6.7 Hz, 2H), 2.41 (m, 2H), 1.95 (t, J = 7.0 Hz, 2H). Example 65: Synthesis of (Z)-4-(5-hexylidene-2,4-dioxothiazolidin-3-yl)-N-(3-hydroxy-4-(1H- tetrazol-5-yl)phenyl)butanamide (Compound 165) [0413] (Z)-4-(5-Hexylidene-2 droxy-4-(1H-tetrazol-5- yl)phenyl)butanamide was prep
Figure imgf000120_0001
ared us ng t e procedures n Example 41. LCMS (ESI) = 455.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J = 23.6 Hz, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 3.93 (t, J = 6.5 Hz, 2H), 2.64 (t, J = 7.3 Hz, 2H), 2.30 (q, J = 7.5 Hz, 2H), 2.24 - 2.05 (m, 2H), 1.57 (t, J = 7.3 Hz, 2H), 1.31 (dt, J = 7.2, 3.5 Hz, 4H), 0.99 - 0.71 (m, 3H). Example 66: Synthesis of 4-(5-hexyl-2,4-dioxothiazolidin-3-yl)-N-(3-hydroxy-4-(1H-tetrazol-5- yl)phenyl)butanamide (Compound 166) [0414] 4-(5-Hexyl-2,4-dioxoth -(1H-tetrazol-5-
Figure imgf000120_0002
yl)phenyl)butanamide was prepared using the procedures in Example 47. LCMS (ESI) = 447.2 [M + H]+. 1H NMR (300 MHz, CF3COOD-d1) δ 8.02 (t, J = 4.4 Hz, 2H), 7.16 (d, J = 8.6 Hz, 1H), 4.43 (dd, J = 9.6, 3.8 Hz, 1H), 3.84 (t, J = 6.7 Hz, 2H), 2.62 (t, J = 7.4 Hz, 2H), 2.17 (dt, J = 27.5, 6.6 Hz, 3H), 1.88 (dt, J = 14.3, 9.8 Hz, 1H), 1.57 - 1.18 (m, 8H), 0.93 - 0.73 (m, 3H). Example 67: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(2,4-dioxo-5-(4- (trifluoromethyl)benzylidene)thiazolidin-3-yl)butanamide (Compound 167) [0415] (Z)-N-(4-(1H-Tetrazo
Figure imgf000120_0003
(trifluoromethyl)benzylidene)thiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 503.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.95 – 7.72 (m, 9H), 3.77 (t, J = 6.7 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 1.98 (t, J = 6.9 Hz, 2H). Example 68: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(3,4-dimethylbenzylidene)- 2,4-dioxothiazolidin-3-yl)butanamide (Compound 168)
Figure imgf000120_0004
[0416] (Z)-N-(4-(1H-Tetrazol-5-yl)phenyl)-4-(5-(3,4-dimethylbenzylidene)-2,4-dioxothiazolidin- 3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 463.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.85 (d, J = 9.3 Hz, 3H), 7.58 (d, J = 8.4 Hz, 2H), 7.41 – 7.26 (m, 3H), 3.74 (t, J = 6.8 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 2.27 (s, 6H), 1.94 (p, J = 7.1 Hz, 2H). Example 69: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(2-hydroxy-4- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 169) [0417] (Z)-N-(4-(1H-Tetrazol -methylbenzylidene)-2,4-
Figure imgf000121_0001
dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 465.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H), 10.15 (s, 1H), 8.09 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 6.6 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.25 (s, 3H), 1.94 (t, J = 7.0 Hz, 2H). Example 70: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(2,4-dioxo-5-(3- (trifluoromethyl)benzylidene)thiazolidin-3-yl)butanamide (Compound 170) [0418] (Z)-N-(4-(1H-Tetraz
Figure imgf000121_0002
(trifluoromethyl)benzylidene)thiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 503.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.98 (d, J = 12.9 Hz, 2H), 7.92 – 7.67 (m, 7H), 3.76 (t, J = 6.7 Hz, 2H), 2.41 (d, J = 7.2 Hz, 2H), 1.97 (t, J = 7.0 Hz, 2H). Example 71: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(3-methoxy-4- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 171) [0419] (Z)-N-(4-(1H-Tetrazol
Figure imgf000121_0003
-methylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide. LCMS (ESI) = 479.1 [M + H]+. 1H NMR (300 MHz, DMSO- d6) δ 10.19 (s, 1H), 7.94 – 7.88 (m, 2H), 7.85 (s, 1H), 7.82 – 7.71 (m, 2H), 7.27 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 7.06 (dd, J = 7.6, 1.7 Hz, 1H), 3.83 (s, 3H), 3.76 (t, J = 6.7 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 2.17 (s, 3H), 1.98 (q, J = 6.9 Hz, 2H). Example 72: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-hydroxy-3,5- dimethylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 172) [0420] (Z)-N-(4-(1H-Tetrazo 5-dimethylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanam
Figure imgf000122_0001
ide was prepared using the procedures in Example 41. LCMS (ESI) = 479.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.88 – 7.85 (m, 2H), 7.74 (s, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.21 (s, 2H), 3.73 (t, J = 6.8 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 2.20 (s, 5H), 1.93 (t, J = 7.0 Hz, 2H). Example 73: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-methoxy-3- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 173) [0421] (Z)-N-(4-(1H-Tetrazo methylbenzylidene)-2,4-
Figure imgf000122_0002
dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 479.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.94 – 7.86 (m, 2H), 7.81 – 7.71 (m, 3H), 7.47 – 7.38 (m, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 3.85 (s, 3H), 3.75 (t, J = 6.6 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.97 (t, J = 6.8 Hz, 2H). Example 74: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(2-hydroxy-3- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 174) [0422] (Z)-N-(4-(1H-Tetrazo
Figure imgf000122_0003
methylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 465.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.21 (s, 1H), 7.89– 7.86 (m, 2H), 7.64 – 7.61 (m, 2H), 7.22 (t, J = 6.6 Hz, 2H), 6.91 (t, J = 7.5 Hz, 1H), 3.75 (t, J = 6.6 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.23 (s, 4H), 1.94 (t, J = 7.2 Hz, 2H). Example 75: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(2-methoxy-4- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 175) [0423] (Z)-N-(4-(1H-Tetrazol 4-methylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamid
Figure imgf000123_0001
e was prepared using the procedures in Example 41. LCMS (ESI) = 479.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.01 (s, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.8 Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 3.87 (s, 3H), 3.74 (t, J = 7.5 Hz, 2H), 2.40 (d, J = 7.5 Hz, 2H), 2.33 (s, 3H), 1.96 (t, J = 6.8 Hz, 2H). Example 76: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(3-hydroxy-4- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 176) [0424] (Z)-N-(4-(1H-Tetrazo methylbenzylidene)-2,4-
Figure imgf000123_0002
dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 465.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.77 (s, 1H), 7.96 – 7.87 (m, 2H), 7.82 – 7.71 (m, 3H), 7.19 (d, J = 7.8 Hz, 1H), 7.03 – 6.91 (m, 2H), 3.74 (t, J = 6.6 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 2.15 (s, 3H), 1.96 (q, J = 7.0 Hz, 2H). Example 77: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-4-(5-(4-hydroxy-3- methylbenzylidene)-2,4-dioxothiazolidin-3-yl)butanamide (Compound 177) [0425] (Z)-N-(4-(1H-Tetrazo
Figure imgf000123_0003
methylbenzylidene)-2,4- dioxothiazolidin-3-yl)butanamide was prepared using the procedures in Example 41. LCMS (ESI) = 465.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (d, J = 18.5 Hz, 2H), 7.97 – 7.87 (m, 2H), 7.81 – 7.71 (m, 3H), 7.35 – 7.24 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 3.73 (t, J = 6.7 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.13 (s, 3H), 2.08 (s, 1H), 1.95 (t, J = 7.0 Hz, 2H). Example 78: Synthesis of (Z)-4-(5-(5-(4-ethylbenzylidene)-2,4-dioxothiazolidin-3- yl)pentanamido)-2-hydroxybenzoic acid (Compound 178) [0426] (Z)-4-(5-(5-(4-Ethylben -3-yl)pentanamido)-2- hydroxybenzoic acid was prepare
Figure imgf000124_0001
d using similar methods as described in Examples 1-77 except methyl 5-bromopentanoate was used as the starting material. LCMS (ESI) = 469.1 [M + H]+. Example 79: Synthesis of 4-(5-(5-(4-ethylbenzyl)-2,4-dioxothiazolidin-3-yl)pentanamido)-2- hydroxybenzoic acid (Compound 179) . [0427] 4-(5-(5-(4-Ethylbenzyl anamido)-2-hydroxybenzoic acid
Figure imgf000124_0002
was prepared using similar methods as described in Examples 1-77 except methyl 5- bromopentanoate was used as the starting material. LCMS (ESI) = 471.2 [M + H]+. Example 80: Synthesis of (Z)-N-(4-(1H-tetrazol-5-yl)phenyl)-5-(5-(4-ethylbenzylidene)-2,4- dioxothiazolidin-3-yl)pentanamide (Compound 180) [0428] (Z)-N-(4-(1H-Tetrazol-
Figure imgf000124_0003
ylidene)-2,4-dioxothiazolidin-3- yl)pentanamide was prepared using similar methods as described in Examples 1-77 except methyl 5-bromopentanoate was used as the starting material. LCMS (ESI) = 475.2 [M - H]-. Example 81: Synthesis of N-(4-(1H-tetrazol-5-yl)phenyl)-5-(5-(4-ethylbenzyl)-2,4- dioxothiazolidin-3-yl)pentanamide (Compound 181) [0429] N-(4-(1H-Tetrazol-5-yl)
Figure imgf000124_0004
2,4-dioxothiazolidin-3- yl)pentanamide was prepared using similar methods as described in Examples 1-77 except methyl 5-bromopentanoate was used as the starting material LCMS (ESI) = 479.2 [M + H]+. Example 82: Beta-Arrestin Antagonist Assay [0430] Human GPR35 expressing JumpIn (Thermo Fisher) 294R Tango U2OS cells were plated in 384-well format in clear bottom plates at a cell density of 10,000 cells / well and allowed to grow overnight. The next day, cells were treated with serially diluted test compounds for 5 hours. LiveBLAzer-FRET B/G (CCF4-AM) detection reagents were then added and cells were allowed to incubate for 2 hours before reading plates on a BioTek Cytation 5 plate reader. Zaprinast was used as a positive control for dose-response curves. In order to determine IC50 values, data were fit to a four-parameter dose-response curves. IC50 values are shown in Table 1. Table 1 Compound IC50 Compound IC50 Compound IC50 101 A 105 A 109 A
Figure imgf000125_0001
134 B 157 A 180 A 135 C 158 A 181 A
Figure imgf000126_0001
A < 0.5 ^M; 0.5 ^M < B < 2.0 ^M; 2.0 ^M < C < 10.0 ^M; NT = not tested [0431] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

Claims

CLAIMS 1. A compound having the structure of Formula (I):
Figure imgf000127_0001
wherein: is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; ,
Figure imgf000127_0002
ynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; R3 is C1-8alkyl, C2-8alkenyl, C2-8alkynyl is a 5-membered heteroaryl ring selected from oxa
Figure imgf000127_0003
, , , , , imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, or ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; p is 0, 1,
2,
3, or 4; and q is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof. 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000129_0001
3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000129_0002
4. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000129_0003
5. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000129_0004
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl.
7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl or thiazolyl.
9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
10. The compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein .
Figure imgf000130_0001
12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 i .
Figure imgf000130_0002
13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
14. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.
16. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000131_0001
17. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Ibb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000131_0002
18. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Icc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000131_0003
19. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (Idd), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000131_0004
.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CO2H.
21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or 1 .
Figure imgf000132_0001
22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein ,
Figure imgf000132_0002
.
Figure imgf000132_0003
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from -CN and C1-6alkyl optionally substituted with one, two, or three R9.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted C1-6alkyl.
25. A compound having the structure of Formula (II):
Figure imgf000132_0004
wherein: is a single or double bond; ring A is phenyl; or ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; or ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; , l,
Figure imgf000133_0001
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; R3 is C1-8alkyl, C2-8alkenyl, C2-8alkynyl s a 5-membered heteroaryl ring selected from oxa
Figure imgf000133_0002
imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, or ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl; each R4 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R9; each R6 is independently selected from H, C1-6alkyl, and C1-6haloalkyl; each R7 is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R8 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR4, -SR4, -N(R4)(R5), -C(O)OR4, - OC(O)N(R4)(R5), -N(R6)C(O)N(R4)(R5), -N(R6)C(O)OR7, -N(R6)S(O)2R7, -C(O)R7, -S(O)R7, - OC(O)R7, -C(O)N(R4)(R5), -C(O)C(O)N(R4)(R5), -N(R6)C(O)R7, -S(O)2R7, -S(O)2N(R4)(R5)-, S(=O)(=NH)N(R4)(R5), -CH2C(O)N(R4)(R5), -CH2N(R6)C(O)R7, -CH2S(O)2R7, and - CH2S(O)2N(R4)(R5), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 1 or 2; or a pharmaceutically acceptable salt or solvate thereof.
26. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000134_0001
27. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000134_0002
Formula (IIb).
28. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000135_0001
29. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000135_0002
30. The compound of any one of claims 25-29, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is phenyl.
31. The compound of any one of claims 25-29, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5-membered heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
32. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is oxazolyl or thiazolyl.
33. The compound of any one of claims 25-29, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is pyridinyl.
35. The compound of any one of claims 25-34, or a pharmaceutically acceptable salt or solvate thereof, wherein .
Figure imgf000136_0001
36. The compound of any one of claims 25-34, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is .
Figure imgf000136_0002
37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is a 6-membered heteroaryl ring selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
38. The compound of claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein ring B is pyridinyl.
39. The compound of any one of claims 25-38, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.
40. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIaa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000136_0003
41. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIbb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000137_0001
42. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIcc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000137_0002
43. The compound of claim 25, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of Formula (IIdd), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000137_0003
44. The compound of any one of claims 25-43, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 i .
Figure imgf000137_0004
45. The compound of any one of claims 25-43, or a pharmaceutically acceptable salt or solvate thereof, wherein ,
Figure imgf000138_0001
.
Figure imgf000138_0002
46. The compound of any one of claims 25-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from halogen, -OR4, and C1-6alkyl optionally substituted with one, two, or three R9.
47. The compound of any one of claims 25-46, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is independently selected from unsubstituted C1-6alkyl and -OR4.
48. The compound of claim 46 or 47, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from H and unsubstituted C1-6alkyl.
49. The compound of any one of claims 25-46, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8 is unsubstituted C1-6alkyl.
50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2.
51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
52. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.
53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, C1-6alkyl, and -OR4.
54. The compound of claim 53, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from H and unsubstituted C1-6alkyl.
55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
56. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
57. A compound selected from: , , ,
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
,
Figure imgf000143_0001
58. A pharmaceutical composition comprising a compound of any one of claims 1-57, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 59. A method of treating an inflammatory bowel disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-57, or a pharmaceutically acceptable salt or solvate thereof. 60. The method of claim 59, wherein the inflammatory bowel disease is selected from Crohn’s disease, ulcerative colitis, and perianal Crohn’s disease. 61. A method of modulating GPR35 activity comprising contacting GPR35, or portion thereof, with a compound of any one of claims 1-57, or a pharmaceutically acceptable salt or solvate thereof.
PCT/US2024/046835 2023-09-20 2024-09-16 Gpr35 modulators Pending WO2025064325A1 (en)

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