WO2019050988A1 - ANTAGONISTS OF THE VASOPRESSIN RECEPTOR, PRODUCTS AND RELATED METHODS - Google Patents

ANTAGONISTS OF THE VASOPRESSIN RECEPTOR, PRODUCTS AND RELATED METHODS Download PDF

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Publication number
WO2019050988A1
WO2019050988A1 PCT/US2018/049607 US2018049607W WO2019050988A1 WO 2019050988 A1 WO2019050988 A1 WO 2019050988A1 US 2018049607 W US2018049607 W US 2018049607W WO 2019050988 A1 WO2019050988 A1 WO 2019050988A1
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Prior art keywords
independently
halo
haloalkyl
alkoxy
lower alkyl
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PCT/US2018/049607
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English (en)
French (fr)
Inventor
Robert M. Jones
Mariangela URBANO
Gary Brandt
Mark Chambers
David Hardick
Jason Tierney
Chris KNIGHT
Chris Lock
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Neumora Therapeutics Inc
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Blackthorn Therapeutics Inc
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Priority to ES18779495T priority Critical patent/ES2951874T3/es
Priority to EP18779495.3A priority patent/EP3679043B9/en
Priority to CN201880057828.7A priority patent/CN111212842B/zh
Priority to JP2020534818A priority patent/JP7368357B2/ja
Priority to CA3072766A priority patent/CA3072766A1/en
Priority to SG11202001498QA priority patent/SG11202001498QA/en
Priority to KR1020207009443A priority patent/KR102765806B1/ko
Priority to MX2020002436A priority patent/MX2020002436A/es
Application filed by Blackthorn Therapeutics Inc filed Critical Blackthorn Therapeutics Inc
Priority to AU2018330423A priority patent/AU2018330423B2/en
Priority to NZ762031A priority patent/NZ762031B2/en
Publication of WO2019050988A1 publication Critical patent/WO2019050988A1/en
Priority to IL272563A priority patent/IL272563B2/en
Priority to ZA2020/01027A priority patent/ZA202001027B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • Vasopressin functions as a neurochemical signal in the brain to affect social behavior.
  • the Via receptor is extensively expressed in the brain and particularly in limbic areas like the amygdala, lateral septum and hippocampus which are known to have an important role in the regulation of majority of the known effects of AVP, including anxiety, memory and learning, social cognition, aggressive behavior, affiliation, depression and the like.
  • the Via receptor is implicated in other neuropsychological disorders such as autistic spectrum disorders, schizophrenia, aggression, aggressive behavior and obsessive-compulsive disorders.
  • the Via receptor also mediates the cardiovascular effects of vasopressin in the brain by centrally regulating blood pressure and heart rate in the solitary tract nucleus and peripherally by inducing the contraction of vascular smooth muscles.
  • vasopressin receptor antagonists particularly Via receptor antagonists
  • Via receptor antagonists provide significant promise for the treatment of a variety of disorders which may benefit from antagonism of the Via receptor.
  • a number of Via antagonists have been taken forward for clinical use and/or development.
  • the present invention is directed to compounds that antagonize vasopressin receptors, particularly the Via receptor, to compositions containing the same, and to methods of their preparation and use for treatment of a malcondition wherein antagonism of the Via receptor is medically indicated or beneficial.
  • compounds are provided having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • a pharmaceutical composition comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent, or excipient.
  • a method for antagonizing the Via receptor comprising contacting the receptor with an effective amount of a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition comprising the same.
  • a pharmaceutical composition comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a method of synthesis is provided for a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • q 0, 1, or 2;
  • t 0, 1, or 2;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • Halo or halogen refers to fluorine, chlorine, bromine, and iodine.
  • “Lower haloalkyl” refers to a lower alkyl as defined above with one or more hydrogen atoms replaced with halogen.
  • Examples of lower haloalkyl groups include, but are not limited to, -CF 3 , -C3 ⁇ 4CF 3 , and the like.
  • “Lower alkoxy” refers to a lower alkyl as defined above joined by w r ay of an oxygen atom (i.e., -0-(lower alkyl).
  • Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, H-propoxy, ra-butoxy, isopropoxy, see-butoxy, fer/-butoxy, and the like.
  • Lower haloalkoxy refers to a lower haloalkyl as defined above joined by way of an oxygen atom (i.e., -0-(lower haloalkyl).
  • Examples of lower haloalkoxy groups include, but are not limited to, -OCF3, -OCH 2 CF3, and the like.
  • Cycloalkylalkyl are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Heterocyclyl groups also include fused ring species including those having fused aromatic and non-aromatic groups.
  • a heterocyclyl group also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl, and also includes heterocyclyl groups that have substituents, including but not limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxv groups, bonded to one of the ring members.
  • a heterocyclyl group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl,
  • Heteroaryl refers to aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridin
  • Racemic is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the invention.
  • racemate and “racemic mixture” refer to an equal mixture of two enantiomers.
  • a racemate is labeled “( ⁇ )” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).
  • All compounds with an asterisk (*) adjacent to a tertiary or quarternary carbon are optically active isomers, which may be purified from the respective racemate and/or synthesized by appropriate chiral synthesis.
  • a “hydrate” is a compound that exists in combination with water molecules.
  • the combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is similar to a hydrate except that a solvent other that w r ater is present.
  • a solvent other that w r ater is present.
  • methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric.
  • a “solvate” refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.
  • Isotope refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein one or more atoms are replaced by an isotope of that atom.
  • carbon 12 the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons.
  • Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 19 is longest-lived.
  • an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon- 13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine- 19.
  • Pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,A ibenzylethylenediamine, chloroprocaine, choline, diethanolamine-, ethylenediamine, meglumine (Nmethylglucamine-), and procaine.
  • Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,
  • salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of compounds having the structure of Formula I, for example in their purification by recrystallization.
  • compounds are provided having the structure of Formula (II), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) a O(CR x R y ) q - -(CR x R y ) n S(0) t (CR x R y ) q - -(CR x R y ) n N(R x )(CR x R y ) q - or -(CR x R y ) n -
  • R is, at each occurrence, independently H, lower alkyl, lower haloaikyi, halo, or R 6 ;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • R 3 is H, cycloalkyl, lower alkyl, lower haloaikyi, lower alkoxy, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • n 0, 1, or 2;
  • q 0, 1, or 2;
  • t 0, 1, or 2;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Il-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • n 0, 1, 2, 3, 4, 5, or 6; and p is 0, 1, or 2.
  • compounds are provided having the structure of Formula (Il-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, lower haloaikyi, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • Q is aryl or heteroaryl
  • n 0, 1, 2, 3, 4, 5, or 6;
  • compounds are provided having the structure of Formula (II-c), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloaikyi, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloaikyi, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1 , 2, 3, 4, 5, or 6;
  • Q is aryl or heteroaryl
  • R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (Il-e), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (Il-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • R 3 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • p 0, 1, or 2.
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • R 3 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • compounds are provided having the structure of Formula (Il-h), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, low r er haloaikyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloaikyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyl, or low r er alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • R 5 is H, cycloalkyl, lower alkyl, lower haloaikyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Il-i), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • R 3 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R is, at each occurrence, independently H, lower alkyl, low r er haloaikyl, or halo:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloaikyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyl, or low r er alkoxy;
  • R z is H or CH 3
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Il-k), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • R 3 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or -O-heterocyclyl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • compounds are provided having the structure of Formula ( ⁇ ), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) n O(CR x R y ) q - -(CR x R y ) admirS(0) t (CR x R y ) q - -(CR x R y ) n N(R x )(CR x R y ) q - or -(CR x R y ) n - R is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • Q is aryl or heteroaryl
  • q 0, 1, or 2;
  • t 0, l, or 2;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • compounds are provided having the structure of Formula (IH-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1 , 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (III-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, low r er haloaikyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyl, lower alkoxy, cyano, or halo;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (III-c), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, low r er haloaikyl, or halo;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1, 2, 3, 4, 5, or 6;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or C3 ⁇ 4
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Ill-e), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1 , 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Ill-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isoto e, or salt thereof:
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R" a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1 , or 2.
  • R l . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • Q is aryl or heteroaryl
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1 , 2, 3, 4, 5, or 6;
  • p 0, 1 , or 2.
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1, 2, 3, 4, 5, or 6;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula ( ⁇ -j), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • R z is H or CH 3
  • Q is aryl or heteroaryl
  • n 0, 1 , 2, 3, 4, 5, or 6;
  • compounds are provided having the structure of Formula (III-k), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • Q is aryl or heteroaryl
  • n 0, 1, 2, 3, 4, 5, or 6;
  • compounds are provided having the structure of Formula (IV), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • R z is H or CH 3
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR ;
  • n 0, 1, or 2;
  • q 0, 1, or 2;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R z is H or CH
  • J 1 , J 2 , , and F are each, independently, N, O, CH, or CR 4 ;
  • compounds are provided having the structure of Formula (IV-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo:
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R "A and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1 , or 2.
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R z is H or CH 3
  • J 1 , J 2 , , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IV-d), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J ' , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • R z is H or CH 3
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IV-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R z is H or CH 3
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IV-g), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloaikyi, lower alkoxy, cyano, or halo;
  • R z is H or CH 3
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (IV-h), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, low r er haloaikyi, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • R z is H or CH 3
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • J 1 , f, f, and J 4 are each, independently, N, O, CH, or CR 4 ;
  • compounds are provided having the structure of Formula (IV-j), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • p 0, 1, or 2.
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • R z is H or CH 3
  • J 1 , J 2 , , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • compounds are provided having the structure of Formula (V), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloaikyi, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • n 0, 1 , or 2;
  • t 0, l , or 2;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl. or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxv;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-c), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-d), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano,
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR ;
  • p 0, 1, or 2.
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • J 1 , J 2 , J ' , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p is 0, 1 , or 2.
  • compounds are provided having the structure of Formula (V-g), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-h), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-i), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (V-j), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo:
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (V-k), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR ;
  • compounds are provided having the structure of Formula (VI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) n O(CR x R y ) q - -(CR x R y ) n S(0) t (CR x R y ) q - -(CR x R y ) n N(R x )(CR x R y ) q - or -(CR x R y ) n -
  • R x is, at each occurrence, independently H, lower alkyl, lower haloaikyi, or halo;
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • n 0, 1 , or 2;
  • t 0, L or 2;
  • R l , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vl-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (VI-c), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, low r er haloalkyl, or halo:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vl-d), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vl-e), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R le are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (VI-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vl-h), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p is 0, 1 , or 2.
  • compounds are provided having the structure of Formula (VI-i), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (VI-j), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vl-k), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • compounds are provided having the structure of Formula (VII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) n O(CR x R y ) q - -(CR x R y ) n S(0) t (CR x R y ), -(CR x R y ) sanctionN(R x )(CR x R y ) q -, or -(CR x R y ) n -
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • n 0, 1, or 2;
  • q 0, 1 , or 2;
  • t 0, 1, or 2;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vll-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vll-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (VII-c), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, low r er haloaikyl, or halo:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyl, or low r er alkoxy;
  • p 0, 1, or 2.
  • compounds having the structure of Formula (Vll-d), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vll-e), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vll-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vll-h), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p is 0, 1 , or 2.
  • compounds are provided having the structure of Formula (VII-i), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (VH-j), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R is, at each occurrence, independently H, lower alkyl, low r er haloaikyl, or halo:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyl, or low r er alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vll-k), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vll-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein p is zero.
  • compounds are provided having the structure of Formula (Vll-a) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ib is halo ;
  • R ia and R lc are each, independently, H, lower alkyl, lower alkoxy;
  • R 2a and R 2b are each, independently, H, lower alkyl, or lower alkoxy.
  • compounds are provided having the structure of Formula (VIII), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) n O(CR x R y ) q - -(CR x R y ) n S(O) t (CR x R y ) q - -(CR x R y ) n N(R x )(CR x R y ) q - or -(CR x R y ) n - R x is, at each occurrence, independently H, lower alkyl, lower haloaikyi, or halo:
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo:
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • n 0, 1, or 2;
  • q 0, 1, or 2;
  • t 0, 1 , or 2;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (Vlll-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo:
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (VHI-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1 , or 2.
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vlll-d), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vlll-e), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (Vlll-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vlll-g), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Vlll-h), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (Vlll-j), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1 , or 2.
  • compounds having the structure of Formula (VHI-k), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p is 0, 1 , or 2.
  • compounds are provided having the structure of Formula (IX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) n O(CR s R y ) q - -(CR x R y ) n S(0) t (CR x R y ) q - -(CR x R y ) n N(R x )(CR x R y ) q - or -(CR x R y ) n -
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and are each, independently, H, lower alkyl, lower haloalkyl, or low r er alkoxy;
  • n 0, 1, or 2;
  • q 0, 1, or 2;
  • t 0, 1, or 2;
  • p is 0, 1 , or 2.
  • compounds are provided having the structure of Formula (IX-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IX-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein p is zero.
  • compounds are provided having the structure of Formula (IX-a) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R !b is halo ;
  • R ia and R lc are each, independently, H, lower alkyl, lower alkoxy;
  • R 2a and R 2b are each, independently, H, lower alkyl, or lower alkoxy.
  • compounds are provided having the structure of Formula (IX-a) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R lb is halo; R la and R 5c are each, independently, H, lower alkyl, lower alkoxy or halo; and R 2a and R 2b are each, independently, H, lower alkyl, or lower alkoxy.
  • compounds are provided having the structure of Formula (IX-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo:
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or low r er alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IX-c), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R "A and R ib are each, independently, H, lower alkyl, lower haloalkyl, or low r er alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IX-d), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IX-e), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • compounds are provided having the structure of Formula (IX-g), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo:
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (IX-h), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (IX-j), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • compounds are provided having the structure of Formula (IX-k), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p is 0, 1 , or 2.
  • compounds are provided having the structure of Formula (X), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) n O(CR s R y ) q - -(CR x R y ) n S(0) t (CR x R y ) q - -(CR x R y ) n N(R x )(CR x R y ) q - or -(CR x R y ) n -
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R "A and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR ;
  • q 0, 1 , or 2;
  • t 0, 1, or 2;
  • p is 0, 1, or 2.
  • compounds are provided having the structure of Formula (X-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (X-b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R "A and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Xc-), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • compounds are provided having the structure of Formula (Xd-), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR ;
  • p 0, 1, or 2.
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • compounds are provided having the structure of Formula (X-f), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, low r er haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J ' , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • compounds are provided having the structure of Formula (Xh-), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloaikyi, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • R ia and R ib are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy:
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (X-i), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1, or 2.
  • compounds are provided having the structure of Formula (Xj-), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R l , R l , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • J 1 , f, f, and J 4 are each, independently, N, O, CH, or CR 4 ;
  • p 0, 1 , or 2.
  • compounds are provided having the structure of Formula (Xk-), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R le are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR ;
  • compounds are provided having the structure of Formula (XI), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • X is -(CR x R y ) n O(CR x R y ) q - -(CR x R y ) n S(0) t (CR x R y ) q - -(CR x R y ) n N(R x )(CR x R y ) q - or -(CR x R y ) n -
  • R x is, at each occurrence, independently H, lower alkyl, lower haloaikyi, or halo;
  • R lb . and R lc are each, independently, H, lower alkyl, lower haloaikyi, lower alkoxy, cyano, or halo;
  • R 2a and R 2b are each, independently, H, lower alkyl, lower haloaikyi, or lower alkoxy;
  • n 0, 1 , or 2;
  • q 0, 1 , or 2;
  • t 0, 1, or 2;
  • p is 0, 1, or 2.
  • compounds are provided having the structure of Formula (Xl-a), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R ⁇ a and R ⁇ b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0 or 1.
  • compounds are provided having the structure of Formula ( ⁇ -b), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
  • R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
  • R y is, at each occurrence, independently H, -OH, lower alkyl, lower alkoxy, or halo;
  • R la , R lb , and R lc are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
  • R 2a and R 2 are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
  • p 0, 1, or 2.

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