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WO2019084075A1 - Antagonistes sélectifs du récepteur de la dopamine et leurs procédés d'utilisation - Google Patents

Antagonistes sélectifs du récepteur de la dopamine et leurs procédés d'utilisation

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Publication number
WO2019084075A1
WO2019084075A1 PCT/US2018/057201 US2018057201W WO2019084075A1 WO 2019084075 A1 WO2019084075 A1 WO 2019084075A1 US 2018057201 W US2018057201 W US 2018057201W WO 2019084075 A1 WO2019084075 A1 WO 2019084075A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
pharmaceutically acceptable
heteroaryl
Prior art date
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PCT/US2018/057201
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English (en)
Inventor
Robert H. Mach
Sean W. REILLY
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University of Pennsylvania Penn
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University of Pennsylvania Penn
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Classifications

    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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

Definitions

  • the disclosure is directed to spirocyclic, selective dopamine receptor antagonists and methods of their use in treating, for example, dopamine D 3 receptor-mediated diseases and disorders.
  • the dopamine D 3 receptor (D 3 R) has been associated with various neurological and neuropsychiatric disorders including, for example, schizophrenia, Parkinson's disease, dementia, anxiety, and depression.
  • the D 3 R has a high density of expression within the mesolimbic pathway of the CNS, the region of the brain that is responsible for the reward and motivational mechanisms associated with, for example, addiction.
  • D 3 R is an attractive target for pharmacological therapy and imaging
  • development of a specific D 3 R agent has been challenging due to the high sequence identity and homology shared between the dopamine D 2 receptor (D 2 R) and D 3 R.
  • potent and selective D 3 R agents are needed.
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • X is S, O, or H
  • Y is a 5-membered unsubstituted heteroaryl or 5- membered substituted heteroaryl
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • k is 1, 2, 3, 4, 5, or 6
  • t is 1 or 2
  • u is 1 or 2
  • v is 0, 1, or 2
  • w is 1, 2, or 3; or isotopic variants thereof; or enantiomers thereof, or diastereomers thereof, or mixtures thereof.
  • each is a single or double bond, provided that one of :
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • Y is a 5-membered unsubstituted heteroaryl or 5-membered substituted heteroaryl;
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k is 1, 2, 3, 4, 5, or 6;
  • t is 1 or 2;
  • v is 0, 1, or 2; or isotopic variants thereof; or enantiomers thereof, or diastereomers thereof, or mixtures thereof.
  • compositions are also described, as well as methods of making the compounds of the disclosure. Also described are methods of using the compounds of the disclosure in therapeutic treatments and in imaging.
  • Figure 1 depicts a competition curve of compounds of the disclosure at the 5-HTIAR.
  • Figure 2 depicts the efficacy of compounds of the disclosure to inhibit forskolin- dependent stimulation of adenylyl cyclase and ⁇ -arrestin binding.
  • Each test compound was used at a concentration equal to lOx the Ki value.
  • the bar graph represents the mean percent efficacy ⁇ SEM relative to the full agonist Quinpirole. Mean ⁇ SEM values were determined by at least three experiments. Haloperidol was included as a prototypical antagonist.
  • Figures 3 A and 3B are line graphs depicting the influence of compounds of the disclosure and congeners thereof compared to dopamine, on ?-arrestin 2 accumulation at the D 3 R. Data is normalized to the fraction of maximum dopamine response at increasing
  • Figures 4A-4D are line graphs depicting the functional activity of dopamine at the D 3 R with or without presence of increasing concentrations of synthons of the disclosure in a ⁇ - arrestin 2 recruitment assay. Data is normalized to the fraction of maximum dopamine response at increasing concentrations of the neuroreceptor. Data points represent the mean ⁇ SEM obtained from eight replicates.
  • Figure 5 is a line graph depicting the functional activity of dopamine at the D 3 R in the presence of 300 ⁇ of synthons described herein, with and without varying concentrations of compound FF in a ?-arrestin 2 recruitment assay. Data is normalized to the fraction of maximum dopamine response at increasing concentrations of the neuroreceptor. Data points represent the mean ⁇ SEM obtained from eight replicates.
  • Figure 6A is a line graph depicting functional activity of dopamine at the D3R with or without the presence of increasing concentrations of a compound of the disclosure in a ?-arrestin 2 recruitment assay.
  • Figure 6B is a Schild plot generated from the concentration-response (CR) curves of Figure 6A.
  • Figure 6C is a line graph depicting functional activity of dopamine at the D3R with or without the presence of increasing concentrations of SB269,652 in a ?-arrestin 2 recruitment assay.
  • Figure 6D is a Schild plot generated from the concentration-response (CR) curves outlined in Figure 6C. Data in Figures 6 A and 6C is normalized to the maximum dopamine-induced luminescence response. Data points represent the mean ⁇ SEM obtained from seven to sixteen replicates.
  • an exemplary embodiment includes from the one particular value and/or to the other particular value. All ranges are inclusive and
  • alkyl when used alone or as part of a substituent group, refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms (“Ci-12”), preferably 1 to 6 carbons atoms (“Ci-6”), in the chain.
  • alkyl groups include methyl (Me, Cialkyl) ethyl (Et, C 2 alkyl), n-propyl (C 3 alkyl), isopropyl (C 3 alkyl), butyl (C 4 alkyl), isobutyl (C 4 alkyl), sec-butyl (C 4 alkyl), tert-butyl (C 4 alkyl), pentyl (Csalkyl), isopentyl (Csalkyl), tert-pentyl (Csalkyl), hexyl (C 6 alkyl), isohexyl (C 6 alkyl), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • Ci-6 when a range of carbon atoms is used herein, for example, Ci-6, all ranges, as well as individual numbers of carbon atoms are encompassed.
  • Ci- 3 includes Ci- 3 , C1-2,
  • alkoxy refers to an alkyl moiety that is attached to a compound of the disclosure through an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, tert- pentoxy, hexoxy, isohexoxy, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • aryl refers to carbocyclic aromatic groups having from 6 to 10 carbon atoms (“C6-10”) such as phenyl, naphthyl, and the like.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents chloro, fluoro, bromo, or iodo.
  • haloalkyl refers to an alkyl moiety wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms.
  • One exemplary substituent is fluoro.
  • Preferred haloalkyl groups of the disclosure include trihalogenated alkyl groups such as trifluoromethyl groups.
  • heteroaryl refers to a mono- or bicyclic aromatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms ("Cs-io").
  • heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizidinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
  • cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms ("C3-10"), preferably from 3 to 6 carbon atoms ("C 3 -6").
  • Examples of cycloalkyl groups include, for example, cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C5), cyclohexyl (C 6 ), 1-methylcyclopropyl (C 4 ), 2-methylcyclopentyl (C 4 ), adamantanyl (Cio), and the like.
  • pharmaceutically acceptable indicates that the designated entity such as, for example, a pharmaceutically acceptable excipient, is generally chemically and/or physically compatible with other ingredients in a composition, and/or is generally physiologically compatible with the recipient thereof.
  • composition refers to a composition prepared by combining any of the formulations including suspensions, or dispersions described herein with one or more pharmaceutically acceptable excipients.
  • “Pharmaceutically acceptable excipient” refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered.
  • a “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients are enumerated in, for example, Remington' s Pharmaceutical Sciences, 17 ed., Mack Publishing Co. (1985).
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • hydrochloride hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • subject(s), As used herein, whether by themselves or in conjunction with another term or terms, “subject(s),” “individual(s),” and “patient(s)”, refer to mammals, including humans.
  • human(s) refers to and includes, a human child, adolescent, or adult.
  • treats As used herein, whether by themselves or in conjunction with another term or terms, “treats,” “treating,” “treated,” and “treatment,” refer to and include ameliorative, palliative, and/or curative uses and results, or any combination thereof. In other embodiments, the methods described herein can be used prophylactically.
  • prophylaxis or a prophylactic use or result do not refer to nor require absolute or total prevention (i.e., a 100% preventative or protective use or result).
  • prophylaxis or a prophylactic use or result refers to uses and results in which administration of a compound or composition diminishes or reduces the severity of a particular condition, symptom, disorder, or disease described herein; diminishes or reduces the likelihood of experiencing a particular condition, symptom, disorder, or disease described herein; or delays the onset or relapse (reoccurrence) of a particular condition, symptom, disorder, or disease described herein; or any combination of the foregoing.
  • terapéutica refers to an amount of a compound or composition that (a) treats a particular condition, symptom, disorder, or disease described herein; (b) attenuates, ameliorates, or eliminates one or more symptoms of a particular condition, disorder, or disease described herein; (c) delays the onset or relapse (reoccurrence) of a particular condition, symptom, disorder, or disease described herein.
  • therapeutic and “therapeutically effective” encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the others (a)-(c).
  • Compounds of the disclosure may be chiral and as a result, can exist as a single enantiomer or mixture of enantiomers. Some compounds of the disclosure may include more than one chiral center will can, therefore, exist as a single diastereomer or mixture of
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • X is S, O, or H;
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k is 1, 2, 3, 4, 5, or 6;
  • t 1 or 2;
  • u 1 or 2;
  • v 0, 1, or 2;
  • w is 1, 2, or 3.
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • Y is a 5-membered unsubstituted heteroaryl or 5-membered substituted heteroaryl;
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k 1, 2, 3, 4, 5, or 6, t is 1 or 2;
  • Isotopic variants of the compounds of Formula I, II, III, and IV are also within the scope of the disclosure.
  • “Isotopic variant” refers to a compound that contains proportions of isotopes at one or more of the atoms that is greater than natural abundance.
  • an isotopic variant of a compound can be radiolabeled, that is, contain one or more non-radioactive isotopies, such as, for example, deuterium ( 2 H or D), carbon- 13 ( 13 C), carbon-11 ( U C), nitrogen-15 ( 15 N), nitrogen 13 ( 13 N), oxygen-15 ( 15 0), fluorine-18 ( 18 F), or the like.
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • X is S, O, or H;
  • Y is a 5-membered unsubstituted heteroaryl or 5-membered substituted heteroaryl
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k is 1, 2, 3, 4, 5, or 6;
  • v 0, 1, or 2;
  • w is 1, 2, or 3.
  • A is substituted aryl, for example, substituted phenyl or substituted naphthyl. In preferred aspects, A is substituted phenyl. In some embodiments, A is substituted with one substituent (R 1 ). In other embodiments, A is substituted with two substituents (two R 1 ) that may be the same or different. In yet other embodiments, A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred aryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF 3 , CHCF2, CH2CF 3 ), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF 3 , OCHCF2, OCH 2 CF 3 ), CN, aryl, heteroaryl, - H(Ci- 6 alkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci- 6 alkyl) 2 (e.g., -N(CH 3 ) 2 ), and NH 2 .
  • Ci-6alkyl e.g., methyl, ethyl, propyl, is
  • A is substituted aryl wherein the aryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci- 6 alkyl) 2 , or NH 2 .
  • A is unsubstituted heteroaryl, for example, unsubstituted pyridyl, unsubstituted pyrimidine, unsubstituted pyrazine, unsubstituted pyridazine,
  • unsubstituted pyrrolyl unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula I through any available carbon of the heteroaryl ring.
  • A is unsubstituted pyridyl.
  • A is unsubstituted pyrimidine.
  • A is unsubstituted pyrazine.
  • A is unsubstituted pyridazine. In some embodiments, A is unsubstituted pyrrolyl. In some embodiments, A is unsubstituted imidazolyl. In some embodiments, A is unsubstituted triazolyl. In some embodiments, A is unsubstituted oxazolyl. In some embodiments, A is unsubstituted isoxazolyl. In some embodiments, A is unsubstituted oxadiazolyl. In some embodiments, A is unsubstituted thiazolyl.
  • A is substituted heteroaryl, for example, substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula I through any available carbon of the heteroaryl ring.
  • A is substituted with one substituent (R 1 ).
  • A is substituted with two substituents (two R 1 ) that may be the same or different.
  • A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci-6alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, NH(Ci- 6 alkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g
  • A is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci- 6 alkyl)2, or NFh.
  • A is substituted pyridyl.
  • A is substituted pyrimidine.
  • A is substituted pyrazine.
  • A is substituted pyridazine.
  • A is substituted pyrrolyl.
  • A is substituted imidazolyl. In some embodiments, A is substituted triazolyl. In some embodiments, A is substituted oxazolyl. In some embodiments, A is substituted isoxazolyl. In some embodiments, A is substituted oxadiazolyl. In some embodiments, A is substituted thiazolyl.
  • X is S. In other aspects, X is O. In yet other aspects, X is NH.
  • Y is a 5-membered unsubstituted heteroaryl, for example, Y is unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the 5-membered unsubstituted heteroaryl can be attached to the rest of the compound of Formula I through any available carbon of the heteroaryl ring.
  • Y is unsubstituted pyrrolyl.
  • Y is unsubstituted imidazolyl. In some aspects, Y is unsubstituted triazolyl. In some aspects, Y is unsubstituted oxazolyl. In some aspects, Y is unsubstituted isoxazolyl. In some aspects, Y is unsubstituted oxadiazolyl. In some aspects, Y is unsubstituted thiazolyl.
  • Y is a 5-membered substituted heteroaryl, for example, Y is substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the 5-membered substituted heteroaryl can be attached to the rest of the compound of Formula I through any available carbon of the heteroaryl ring.
  • Y is substituted imidazolyl. In some aspects, Y is substituted triazolyl. In some aspects, Y is substituted oxazolyl. In some aspects, Y is substituted isoxazolyl. In some aspects, Y is substituted oxadiazolyl. In some aspects, Y is substituted thiazolyl. In particularly preferred aspects, Y is triazolyl substituted with one Ci- 6 alkyl.
  • Z is unsubstituted C 3 -6cycloalkyl.
  • Z is unsubstituted cyclopropyl.
  • Z is
  • Z is unsubstituted cyclobutyl. In other aspects, Z is unsubstituted cyclopentyl. In other aspects, Z is unsubstituted cyclohexyl.
  • Z is substituted C 3 -6cycloalkyl.
  • Z is substituted with one substituent (R).
  • Z is substituted with two substituents (two R) that may be the same or different.
  • Z is substituted with three substituents (three R) that may be the same or different.
  • Preferred Z substituents include, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF 3 , CHCF 2 , CH 2 CF 3 ), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF 3 , OCHCF 2 , OCH 2 CF 3 ), CN, aryl, heteroaryl, - H(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci- 6 alkyl) 2 (e.g., -N(CH 3 ) 2 ), and H 2 .
  • Ci- 6 alkyl e.g., methyl, ethy
  • Z is substituted C3-6cycloalkyl wherein the C3-6cycloalkyl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci- 6 alkyl)2, or H2.
  • Z is substituted cyclopropyl.
  • Z is substituted cyclobutyl.
  • Z is substituted cyclopentyl.
  • Z is substituted cyclohexyl.
  • Z is unsubstituted aryl.
  • Z is unsubstituted phenyl or unsubstituted naphthyl.
  • Z is unsubstituted phenyl.
  • Z is substituted aryl.
  • Z is substituted phenyl or substituted naphthyl, preferably substituted phenyl.
  • Z is substituted with one substituent (R).
  • Z is substituted with two substituents (two R) that may be the same or different.
  • Z is substituted with three substituents (three R) that may be the same or different.
  • Preferred Z substituents include, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., -NH(CH 3 ), -NH(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 ) 2 ), and NH 2 .
  • Ci- 6 alkyl e.g., methyl, ethyl, propyl, isopropyl,
  • Z is substituted aryl wherein the aryl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci-6alkyl) 2 , or NH2.
  • Z is unsubstituted heteroaryl.
  • Z is unsubstituted pyridyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted pyridazinyl, unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula I through any available carbon of the heteroaryl ring.
  • Z is unsubstituted pyridyl.
  • Z is unsubstituted pyrimidinyl.
  • Z is unsubstituted pyrazinyl.
  • Z is unsubstituted pyridazinyl.
  • Z is unsubstituted pyrrolyl.
  • Z is unsubstituted imidazolyl.
  • Z is unsubstituted triazolyl.
  • Z is unsubstituted oxazolyl. In some embodiments, Z is unsubstituted isoxazolyl. In some embodiments, Z is unsubstituted oxadiazolyl. In some embodiments, Z is unsubstituted thiazolyl.
  • Z is substituted heteroaryl.
  • Z is substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula I through any available carbon of the heteroaryl ring.
  • Z is substituted with one substituent (R).
  • Z is substituted with two
  • heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 )
  • Ci-6alkyl e.g., methyl, ethyl, propyl, isopropyl, or butyl
  • Z is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, or NFh.
  • Z is substituted pyridyl.
  • Z is substituted pyrimidine.
  • Z is substituted pyrazine.
  • Z is substituted pyridazine.
  • Z is substituted pyrrolyl. In some embodiments, Z is substituted imidazolyl. In some embodiments, Z is substituted triazolyl. In some embodiments, Z is substituted oxazolyl. In some embodiments, Z is substituted isoxazolyl. In some embodiments, Z is substituted oxadiazolyl. In some embodiments, Z is substituted thiazolyl.
  • k is 1, 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, 4, or 5. In some embodiments, k is 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, or 4. In some embodiments, k is 3, 4, 5, or 6. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5. In some embodiments, k is 6. [00059] According to the disclosure, in compounds of Formula I, t is 1 or 2. In some aspects, t is 1. In other aspects, t is 2.
  • u is 1 or 2. In some aspects, u is 1. In other aspects, u is 2.
  • v is 0, 1, or 2. In some aspects, v is 0. In some aspects, v is 1. In other aspects, v is 2.
  • w is 1, 2, or 3. In some aspects, w is 1. In other aspects, w is 2. In other aspects, w is 3.
  • t is 2 and u is 2. In other aspects, t is 2 and u is 1. In other aspects, t is 1 and u is 1.
  • v is 2 and 2 is 2. In other aspects, v is 2 and w is 1. In other aspects, v is 1 and w is 2. In other aspects, v is 1 and w is 1. In other aspects, v is 0 and w is 2.
  • A is substituted aryl
  • Y is a 5-membered unsubstituted heteroaryl or a 5-membered substituted heteroaryl
  • Z is
  • A is substituted phenyl
  • Y is unsubstituted triazole or substituted triazole
  • Z is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • k is 1, 2, 3, 4, 5, or 6.
  • Particularly preferred compounds of Formula I of the disclosure include:
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • X is S, O, or H;
  • Y is a 5-membered unsubstituted heteroaryl or 5-membered substituted heteroaryl
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k 1, 2, 3, 4, 5, or 6 t is 1 or 2;
  • u 1 or 2;
  • v 0, 1, or 2;
  • w is 1, 2, or 3.
  • A is unsubstituted aryl, for example, unsubstituted phenyl or naphthyl. In preferred aspects, A is unsubstituted phenyl.
  • A is substituted aryl, for example, substituted phenyl or substituted naphthyl. In preferred aspects, A is substituted phenyl. In some embodiments, A is substituted with one substituent (R 1 ). In other embodiments, A is substituted with two substituents (two R 1 ) that may be the same or different. In yet other embodiments, A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred aryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF 3 , CHCF2, CH2CF 3 ), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF 3 , OCHCF2, OCH 2 CF 3 ), CN, aryl, heteroaryl, - H(Ci- 6 alkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci- 6 alkyl) 2 (e.g., -N(CH 3 ) 2 ), and NH 2 .
  • Ci-6alkyl e.g., methyl, ethyl, propyl, is
  • A is substituted aryl wherein the aryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci- 6 alkyl) 2 , or NH 2 .
  • A is unsubstituted heteroaryl, for example, unsubstituted pyridyl, unsubstituted pyrimidine, unsubstituted pyrazine, unsubstituted pyridazine,
  • unsubstituted pyrrolyl unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula II through any available carbon of the heteroaryl ring.
  • A is unsubstituted pyridyl.
  • A is unsubstituted pyrimidine.
  • A is unsubstituted pyrazine.
  • A is unsubstituted pyridazine. In some embodiments, A is unsubstituted pyrrolyl. In some embodiments, A is unsubstituted imidazolyl. In some embodiments, A is unsubstituted triazolyl. In some embodiments, A is unsubstituted oxazolyl. In some embodiments, A is unsubstituted isoxazolyl. In some embodiments, A is unsubstituted oxadiazolyl. In some embodiments, A is unsubstituted thiazolyl.
  • A is substituted heteroaryl, for example, substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula II through any available carbon of the heteroaryl ring.
  • A is substituted with one substituent (R 1 ).
  • A is substituted with two substituents (two R 1 ) that may be the same or different.
  • A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci-6alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF 3 , CHCF2, CH 2 CF 3 ), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF 3 , OCHCF2, OCH 2 CF 3 ), CN, aryl, heteroaryl, - H(Ci- 6 alkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-
  • A is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci-6alkyl) 2 , or NH 2 .
  • A is substituted pyridyl.
  • A is substituted pyrimidine.
  • A is substituted pyrazine.
  • A is substituted pyridazine.
  • A is substituted pyrrolyl. In some embodiments, A is substituted imidazolyl. In some embodiments, A is substituted triazolyl. In some embodiments, A is substituted oxazolyl. In some embodiments, A is substituted isoxazolyl. In some embodiments, A is substituted oxadiazolyl. In some embodiments, A is substituted thiazolyl.
  • Z is unsubstituted C 3 -6cycloalkyl.
  • Z is unsubstituted cyclopropyl.
  • Z is
  • Z is substituted C3-6cycloalkyl. In some embodiments, Z is substituted with one substituent (R). In other embodiments, Z is substituted with two substituents (two R) that may be the same or different. In yet other embodiments, Z is substituted with three substituents (three R) that may be the same or different.
  • Preferred Z substituents include, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 ) 2 ), and H 2 .
  • Ci- 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, or
  • Z is substituted C3-6cycloalkyl wherein the C3-6cycloalkyl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci- 6 alkyl)2, or NH2.
  • Z is substituted cyclopropyl.
  • Z is substituted cyclobutyl.
  • Z is substituted cyclopentyl.
  • Z is substituted cyclohexyl.
  • Z is unsubstituted aryl.
  • Z is unsubstituted phenyl or unsubstituted naphthyl.
  • Z is unsubstituted phenyl.
  • Z is substituted aryl.
  • Z is substituted phenyl or substituted naphthyl, preferably substituted phenyl.
  • Z is substituted with one substituent (R).
  • Z is substituted with two substituents (two R) that may be the same or different.
  • Z is substituted with three substituents (three R) that may be the same or different.
  • Preferred Z substituents include, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., -NH(CH 3 ), -NH(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 ) 2 ), and NH 2 .
  • Ci- 6 alkyl e.g., methyl, ethyl, propyl, isopropyl,
  • Z is substituted aryl wherein the aryl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci-6alkyl) 2 , or NH2.
  • Z is unsubstituted heteroaryl.
  • Z is unsubstituted pyridyl, unsubstituted pyrimidine, unsubstituted pyrazine, unsubstituted pyridazine, unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula II through any available carbon of the heteroaryl ring.
  • Z is unsubstituted pyridyl.
  • Z is unsubstituted pyrimidine.
  • Z is unsubstituted pyrazine.
  • Z is unsubstituted pyridazine.
  • Z is unsubstituted pyrrolyl.
  • Z is unsubstituted imidazolyl.
  • Z is unsubstituted triazolyl.
  • Z is substituted heteroaryl.
  • Z is substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula II through any available carbon of the heteroaryl ring.
  • Z is substituted with one substituent (R).
  • Z is substituted with two
  • heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci-6alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 ) 2 ),
  • Ci-6alkyl e.g., methyl, ethyl, propyl, isopropyl, or butyl
  • Ci-6alkoxy
  • Z is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, or NFh.
  • Z is substituted pyridyl.
  • Z is substituted pyrimidine.
  • Z is substituted pyrazine.
  • Z is substituted pyridazine.
  • Z is substituted pyrrolyl. In some embodiments, Z is substituted imidazolyl. In some embodiments, Z is substituted triazolyl. In some embodiments, Z is substituted oxazolyl. In some embodiments, Z is substituted isoxazolyl. In some embodiments, Z is substituted oxadiazolyl. In some embodiments, Z is substituted thiazolyl.
  • k is 1, 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, 4, or 5. In some embodiments, k is 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, or 4. In some embodiments, k is 3, 4, 5, or 6. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5. In some embodiments, k is 6.
  • t is 1 or 2. In some aspects, t is 1. In other aspects, t is 2.
  • u is 1 or 2. In some aspects, u is 1. In other aspects, u is 2.
  • v is 0, 1, or 2. In some aspects, v is 0. In some aspects, v is 1. In other aspects, v is 2.
  • w is 1, 2, or 3. In some aspects, w is 1. In other aspects, w is 2. In other aspects, w is 3.
  • t is 2 and u is 2. In other aspects, t is 2 and u is 1. In other aspects, t is 1 and u is 1.
  • v is 2 and 2 is 2. In other aspects, v is 2 and w is 1. In other aspects, v is 1 and w is 2. In other aspects, v is 1 and w is 1. In other aspects, v is 0 and w is 2.
  • A is substituted aryl, n is 1, 2, or 3, k is 1, 2, 3, 4, 5, or 6, and each R is independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci-ehaloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci-ealkyl)2, or NFb.
  • Particularly preferred compounds of Formula II of the disclosure include:
  • each is a single or double bond, provided that one of is a double bond;
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • Y is a 5-membered unsubstituted heteroaryl or 5-membered substituted heteroaryl;
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k is 1, 2, 3, 4, 5, or 6;
  • v 0, 1, or 2.
  • one is a single bond and the other is a double bond.
  • A is unsubstituted aryl, for example, unsubstituted phenyl or naphthyl. In preferred aspects, A is unsubstituted phenyl. [00096] In other embodiments, A is substituted aryl, for example, substituted phenyl or substituted naphthyl. In preferred aspects, A is substituted phenyl. In some embodiments, A is substituted with one substituent (R 1 ). In other embodiments, A is substituted with two substituents (two R 1 ) that may be the same or different. In yet other embodiments, A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred aryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, - H(Ci- 6 alkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 ) 2 ), and NH 2 .
  • Ci-6alkyl e.g., methyl, ethyl, propyl, isopropyl, or buty
  • A is substituted aryl wherein the aryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci-6alkyl) 2 , or NH2.
  • A is unsubstituted heteroaryl, for example, unsubstituted pyridyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted pyridazinyl, unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula III through any available carbon of the heteroaryl ring.
  • A is unsubstituted pyridyl.
  • A is unsubstituted pyrimidinyl.
  • A is unsubstituted pyrazinyl.
  • A is unsubstituted pyridazinyl.
  • A is unsubstituted pyrrolyl.
  • A is unsubstituted imidazolyl.
  • A is unsubstituted triazolyl.
  • A is unsubstituted oxazolyl. In some embodiments, A is unsubstituted isoxazolyl. In some embodiments, A is unsubstituted oxadiazolyl. In some embodiments, A is unsubstituted thiazolyl.
  • A is substituted heteroaryl, for example, substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula III through any available carbon of the heteroaryl ring.
  • A is substituted with one substituent (R 1 ).
  • A is substituted with two substituents (two R 1 ) that may be the same or different.
  • A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci-6alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF 3 , CHCF2, CH 2 CF 3 ), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF 3 , OCHCF2, OCH 2 CF 3 ), CN, aryl, heteroaryl, H(Ci- 6 alkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci- 6 alkyl) (e.
  • A is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci-6alkyl) 2 , or NH 2 .
  • A is substituted pyridyl.
  • A is substituted pyrimidine.
  • A is substituted pyrazine.
  • A is substituted pyridazine.
  • A is substituted pyrrolyl. In some embodiments, A is substituted imidazolyl. In some embodiments, A is substituted triazolyl. In some embodiments, A is substituted oxazolyl. In some embodiments, A is substituted isoxazolyl. In some embodiments, A is substituted oxadiazolyl. In some embodiments, A is substituted thiazolyl.
  • X is S. In other aspects, X is O. In yet other aspects, X is NH.
  • Y is a 5-membered unsubstituted heteroaryl, for example, Y is unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the 5-membered unsubstituted heteroaryl can be attached to the rest of the compound of Formula III through any available carbon of the heteroaryl ring.
  • Y is unsubstituted pyrrolyl.
  • Y is unsubstituted imidazolyl. In some aspects, Y is unsubstituted triazolyl. In some aspects, Y is unsubstituted oxazolyl. In some aspects, Y is unsubstituted isoxazolyl. In some aspects, Y is unsubstituted oxadiazolyl. In some aspects, Y is unsubstituted thiazolyl.
  • Y is a 5-membered substituted heteroaryl, for example, Y is substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the 5-membered substituted heteroaryl can be attached to the rest of the compound of Formula III through any available carbon of the heteroaryl ring.
  • Y is substituted with one substituent (R 2 ). In other embodiments, Y is substituted with two substituents (two R 2 ) that may be the same or different.
  • Preferred heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), H(Ci- 6 alkyl) (e.g., -NH(CH 3 ), - H(CH 2 CH 3 )), -N(Ci- 6 alkyl) 2 (e.g., -N(CH 3 ) 2 ), and H 2 .
  • Y is substituted pyrrolyl.
  • Y is substituted imidazolyl.
  • Y is substituted triazolyl.
  • Y is substituted oxazolyl.
  • Y is substituted isoxazolyl. In some aspects, Y is substituted oxadiazolyl. In some aspects, Y is substituted thiazolyl. In particularly preferred aspects, Y is triazolyl substituted with one Ci- 6 alkyl.
  • Z is unsubstituted cyclobutyl. In other aspects, Z is unsubstituted cyclopentyl. In other aspects, Z is unsubstituted cyclohexyl.
  • Z is substituted C 3 -6cycloalkyl.
  • Z is substituted with one substituent (R).
  • Z is substituted with two substituents (two R) that may be the same or different.
  • Z is substituted with three substituents (three R) that may be the same or different.
  • Z is substituted C 3 -6cycloalkyl wherein the C 3 -6cycloalkyl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci- 6 alkyl) 2 , or NH 2 .
  • Z is substituted cyclopropyl.
  • Z is substituted cyclobutyl.
  • Z is substituted cyclopentyl.
  • Z is substituted cyclohexyl.
  • Z is unsubstituted aryl.
  • Z is unsubstituted phenyl or unsubstituted naphthyl.
  • Z is unsubstituted phenyl.
  • Z is substituted aryl.
  • Z is substituted phenyl or substituted naphthyl, preferably substituted phenyl.
  • Z is substituted with one substituent (R).
  • Z is substituted with two substituents (two R) that may be the same or different.
  • Z is substituted with three substituents (three R) that may be the same or different.
  • Z is unsubstituted heteroaryl.
  • Z is unsubstituted pyridyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted pyridazinyl, unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula III through any available carbon of the heteroaryl ring.
  • Z is unsubstituted pyridyl.
  • Z is unsubstituted pyrimidinyl.
  • Z is unsubstituted pyrazinyl.
  • Z is unsubstituted pyridazinyl.
  • Z is unsubstituted pyrrolyl.
  • Z is unsubstituted imidazolyl.
  • Z is unsubstituted triazolyl.
  • Z is unsubstituted oxazolyl. In some embodiments, Z is unsubstituted isoxazolyl. In some embodiments, Z is unsubstituted oxadiazolyl. In some embodiments, Z is unsubstituted thiazolyl.
  • Z is substituted heteroaryl.
  • Z is substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula III through any available carbon of the heteroaryl ring.
  • Z is substituted with one substituent (R).
  • Z is substituted with two
  • heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 )
  • Ci-6alkyl e.g., methyl, ethyl, propyl, isopropyl, or butyl
  • Z is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci-6alkyl)2, or NFh.
  • Z is substituted pyridyl.
  • Z is substituted pyrimidine.
  • Z is substituted pyrazine.
  • Z is substituted pyridazine.
  • Z is substituted pyrrolyl. In some embodiments, Z is substituted imidazolyl. In some embodiments, Z is substituted triazolyl. In some embodiments, Z is substituted oxazolyl. In some embodiments, Z is substituted isoxazolyl. In some embodiments, Z is substituted oxadiazolyl. In some embodiments, Z is substituted thiazolyl.
  • k is 1, 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, 4, or 5. In some embodiments, k is 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, or 4. In some embodiments, k is 3, 4, 5, or 6. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5. In some embodiments, k is 6.
  • t is 1 or 2. In some aspects, t is 1. In other aspects, t is 2.
  • v is 0, 1, or 2. In some aspects, v is 0. In some aspects, v is 1. In other aspects, v is 2. [000111] In preferred aspects of compounds of Formula III, t is 2 and v is 2. In other aspects, t is 2 and v is 1. In other aspects, t is 1 and v is 1.
  • A is substituted aryl
  • Y is a 5-membered unsubstituted heteroaryl or a 5-membered substituted heteroaryl
  • Z is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • k is 1, 2, 3, 4, 5, or 6.
  • A is substituted phenyl
  • Y is unsubstituted triazole or substituted triazole
  • Z is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • k is 1, 2, 3, 4, 5, or 6.
  • a particularly preferred compound of Formula III of the disclosure includes:
  • each is a single or double bond, provided that one of is a double bond;
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k is 1, 2, 3, 4, 5, or 6;
  • t 1 or 2;
  • v 0, 1, or 2.
  • one is a single bond and the other is a double bond.
  • each is a double bond.
  • A is unsubstituted aryl, for example, unsubstituted phenyl or naphthyl. In preferred aspects, A is unsubstituted phenyl.
  • A is substituted aryl, for example, substituted phenyl or substituted naphthyl. In preferred aspects, A is substituted phenyl. In some embodiments, A is substituted with one substituent (R 1 ). In other embodiments, A is substituted with two substituents (two R 1 ) that may be the same or different. In yet other embodiments, A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred aryl substituents include, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF 3 , CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF 3 , OCHCF2, OCH 2 CF 3 ), CN, aryl, heteroaryl, - H(Ci- 6 alkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci- 6 alkyl) 2 (e.g., -N(CH 3 ) 2 ), and NH 2 .
  • Ci- 6 alkyl e.g., methyl, ethyl, propy
  • A is substituted aryl wherein the aryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci-6alkyl, Ci-6alkoxy, Ci-6haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, - H(Ci- 6 alkyl), -N(Ci-6alkyl) 2 , or H 2 .
  • A is unsubstituted heteroaryl, for example, unsubstituted pyridyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted pyridazinyl, unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula IV through any available carbon of the heteroaryl ring.
  • A is unsubstituted pyridyl.
  • A is unsubstituted pyrimidinyl.
  • A is unsubstituted pyrazinyl.
  • A is unsubstituted pyridazinyl.
  • A is unsubstituted pyrrolyl.
  • A is unsubstituted imidazolyl.
  • A is unsubstituted triazolyl.
  • A is unsubstituted oxazolyl. In some embodiments, A is unsubstituted isoxazolyl. In some embodiments, A is unsubstituted oxadiazolyl. In some embodiments, A is unsubstituted thiazolyl.
  • A is substituted heteroaryl, for example, substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula IV through any available carbon of the heteroaryl ring.
  • A is substituted with one substituent (R 1 ).
  • A is substituted with two substituents (two R 1 ) that may be the same or different.
  • A is substituted with three substituents (three R 1 ) that may be the same or different.
  • Preferred heteroaryl substituents include, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF 3 , CHCF 2 , CH 2 CF 3 ), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF 3 , OCHCF 2 , OCH 2 CF 3 ), CN, aryl, heteroaryl, NH(Ci- 6 alkyl) (e.g., -NH(CH 3 ), -NH(CH 2 CH 3 )),
  • A is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R 1 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci- 6 alkyl) 2 , or H2.
  • A is substituted pyridyl.
  • A is substituted pyrimidine.
  • A is substituted pyrazine.
  • A is substituted pyridazine.
  • A is substituted pyrrolyl.
  • A is substituted imidazolyl. In some embodiments, A is substituted triazolyl. In some embodiments, A is substituted oxazolyl. In some embodiments, A is substituted isoxazolyl. In some embodiments, A is substituted oxadiazolyl. In some embodiments, A is substituted thiazolyl.
  • Z is unsubstituted C3-6cycloalkyl.
  • Z is unsubstituted cyclopropyl.
  • Z is
  • Z is unsubstituted cyclobutyl. In other aspects, Z is unsubstituted cyclopentyl. In other aspects, Z is unsubstituted cyclohexyl.
  • Z is substituted C3-6cycloalkyl. In some embodiments, Z is substituted with one substituent (R). In other embodiments, Z is substituted with two substituents (two R) that may be the same or different. In yet other embodiments, Z is substituted with three substituents (three R) that may be the same or different.
  • Preferred Z substituents include, for example, Ci- 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 ) 2 ), and H 2 .
  • Ci- 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, or
  • Z is substituted C3-6cycloalkyl wherein the C3-6cycloalkyl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci-6alkyl), -N(Ci- 6 alkyl)2, or NH2.
  • Z is substituted cyclopropyl.
  • Z is substituted cyclobutyl.
  • Z is substituted cyclopentyl.
  • Z is substituted cyclohexyl.
  • Z is unsubstituted aryl.
  • Z is unsubstituted phenyl or unsubstituted naphthyl.
  • Z is unsubstituted phenyl.
  • Z is substituted aryl.
  • Z is substituted phenyl or substituted naphthyl, preferably substituted phenyl.
  • Z is substituted with one substituent (R).
  • Z is substituted with two substituents (two R) that may be the same or different.
  • Z is substituted with three substituents (three R) that may be the same or different.
  • Preferred Z substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci-6alkoxy (e.g., methoxy, ethoxy), Ci-6haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 ) 2 ), and H 2 .
  • Ci-6alkyl e.g., methyl, ethyl, propyl, isopropyl, or butyl
  • Z is substituted aryl wherein the aryl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci-6alkyl) 2 , or NH2.
  • Z is unsubstituted heteroaryl.
  • Z is unsubstituted pyridyl, unsubstituted pyrimidinyl, unsubstituted pyrazinyl, unsubstituted pyridazinyl, unsubstituted pyrrolyl, unsubstituted imidazolyl, unsubstituted triazolyl, unsubstituted oxazolyl, unsubstituted isoxazolyl, unsubstituted oxadiazolyl, or unsubstituted thiazolyl.
  • the unsubstituted heteroaryl can be attached to the rest of the compound of Formula IV through any available carbon of the heteroaryl ring.
  • Z is unsubstituted pyridyl.
  • Z is unsubstituted pyrimidinyl.
  • Z is unsubstituted pyrazinyl.
  • Z is unsubstituted pyridazinyl.
  • Z is unsubstituted pyrrolyl.
  • Z is unsubstituted imidazolyl.
  • Z is unsubstituted triazolyl.
  • Z is unsubstituted oxazolyl. In some embodiments, Z is unsubstituted isoxazolyl. In some embodiments, Z is unsubstituted oxadiazolyl. In some embodiments, Z is unsubstituted thiazolyl.
  • Z is substituted heteroaryl.
  • Z is substituted pyridyl, substituted pyrimidine, substituted pyrazine, substituted pyridazine, substituted pyrrolyl, substituted imidazolyl, substituted triazolyl, substituted oxazolyl, substituted isoxazolyl, substituted oxadiazolyl, or substituted thiazolyl.
  • the substituted heteroaryl can be attached to the rest of the compound of Formula IV through any available carbon of the heteroaryl ring.
  • Z is substituted with one substituent (R).
  • Z is substituted with two
  • heteroaryl substituents include, for example, Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, or butyl), Ci- 6 alkoxy (e.g., methoxy, ethoxy), Ci- 6 haloalkyl (e.g., CF3, CHCF2, CH2CF3), halo (e.g., F, CI, Br), Ci-ehaloalkoxy (e.g., OCF3, OCHCF2, OCH2CF3), CN, aryl, heteroaryl, -NH(Ci- ealkyl) (e.g., - H(CH 3 ), - H(CH 2 CH 3 )), -N(Ci-6alkyl) 2 (e.g., -N(CH 3 )
  • Ci-6alkyl e.g., methyl, ethyl, propyl, isopropyl, or butyl
  • Z is substituted heteroaryl wherein the heteroaryl is substituted with 1, 2, or 3 R substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, CN, aryl, heteroaryl, -NH(Ci- 6 alkyl), -N(Ci-6alkyl)2, or NH2.
  • Z is substituted pyridyl.
  • Z is substituted pyrimidine.
  • Z is substituted pyrazine.
  • Z is substituted pyridazine.
  • Z is substituted pyrrolyl. In some embodiments, Z is substituted imidazolyl. In some embodiments, Z is substituted triazolyl. In some embodiments, Z is substituted oxazolyl. In some embodiments, Z is substituted isoxazolyl. In some embodiments, Z is substituted oxadiazolyl. In some embodiments, Z is substituted thiazolyl.
  • k is 1, 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, 4, or 5. In some embodiments, k is 2, 3, 4, 5, or 6. In some embodiments, k is 1, 2, 3, or 4. In some embodiments, k is 3, 4, 5, or 6. In some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, k is 3. In some embodiments, k is 4. In some embodiments, k is 5. In some embodiments, k is 6.
  • t is 1 or 2. In some aspects, t is 1. In other aspects, t is 2.
  • v is 0, 1, or 2. In some aspects, v is 0. In some aspects, v is 1. In other aspects, v is 2.
  • t is 2 and v is 2. In other aspects, t is 2 and v is 1. In other aspects, t is 1 and v is 1.
  • A is substituted aryl
  • Z is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • k is 1 , 2, 3, 4, 5, or 6.
  • A is substituted phenyl
  • Z is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl
  • k is 1,
  • Compounds of the disclosure are useful as, for example, dopamine D 3 receptor modulators, in particular, dopamine D 3 receptor antagonists.
  • the compounds of the disclosure demonstrate selectivity for the D 3 receptor over other dopamine receptors, for example, the D 2 receptor.
  • Compounds of the disclosure are, therefore, useful in treating subjects in need of treatment for a dopamine D 3 receptor-mediated disease or disorder.
  • Dopamine D 3 receptor-mediated diseases and disorders include, for example, substance abuse, addiction, schizophrenia, Parkinson's disease, dementia, anxiety, and depression.
  • a subject in need of treatment for a dopamine D 3 receptor-mediated disease or disorder can be administered a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • substance abuse is the harmful or hazardous use of psychoactive substances, for example, alcohol, nicotine, and illicit drugs such as opioids, stimulants, and the like.
  • addiction is a disorder wherein a subject ingests a substance (for example, an opioid, a stimulant, food, alcohol, nicotine) or engages in a behavior (for example, gambling, sex, shopping) that can be pleasurable but the continuation of which becomes compulsive and interferes with work, relationships, or health.
  • a substance addiction for example, an opioid, a stimulant, food, alcohol, nicotine
  • a behavior for example, gambling, sex, shopping
  • the subject is treated for a substance addiction.
  • the subject is treated for a behavioral addiction.
  • the subject is treated for a gambling addiction.
  • the subject is treated for schizophrenia.
  • the subject is treated for Parkinson's disease.
  • the subject is treated for dementia.
  • the subject is treated for anxiety.
  • the subject is treated for depression.
  • Compounds of the disclosure that are isotopic variants are also useful as functional imaging agents, for example as positron emission tomography ("PET") imaging agents.
  • PET positron emission tomography
  • a compound of the disclosure is prepared to include one or more radioisotopes, for example, one or more atoms of U C, 13 N, 15 0, or 18 F, using the methods described herein in combination with methods known to those of ordinary skill in the art. The resulting
  • radioisotopic compound can be formulated into a pharmaceutical composition by combination with a pharmaceutically acceptable excipient.
  • compositions comprising these can be administered using techniques known to those of ordinary skill in the art.
  • a subject will be
  • an isotopic variant of the disclosure in an amount sufficient to bind to the subject' s D3R receptor(s).
  • Functional imaging for example, PET imaging, using a radioisotopic compound of the disclosure can be achieved using methods known in the art.
  • the isotopic variant compound of the disclosure is selective for D3R over D2R.
  • the D3R/D2R ratio of a compound of the disclosure is at least 10.
  • the D3R/D2R ratio of a compound of the disclosure is between about 10 and 10,000.
  • the D3R/D2R ratio of a compound of the disclosure is between about 100 and about 10,000.
  • the D3R/D2R ratio of a compound of the disclosure is between about 1000 and about 10,000.
  • the D3R/D2R ratio of a compound of the disclosure is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, or about 10,000.
  • compositions comprising: (a) an effective amount of at least one compound in accordance with the disclosure; and (b) a pharmaceutically acceptable excipient.
  • compositions can be prepared by, for example, combining a compound of the disclosure, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable excipient.
  • the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • the compositions are formulated for intravenous infusion, topical administration, or oral administration.
  • the compounds of the disclosure are provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
  • a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.
  • Oral tablets may include a compound according to the disclosure mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • compounds of the disclosure are mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the compound of the disclosure with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, optionally, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water
  • compositions can be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the disclosure can be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms are presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses may range from about 1 to 1000 ⁇ g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the compounds of the disclosure may utilize a patch formulation to affect transdermal delivery.
  • Compounds of the disclosure may alternatively be administered in methods of this disclosure by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • Arylated synthons (I) and 6 were prepared following procedures previously reported. See, e.g., Reilly, S. W.; Bryan, N. W.; Mach, R. H. Pd-Catalyzed Arylation of Linear and Angular Spirodiamine Salts Under Aerobic Conditions. Tetrahedron Lett. 2017, 58, 466-469. Reilly, S. W.; Mach, R. H. Pd-Catalyzed Synthesis of Piperazine Scaffolds Under Aerobic and Solvent-Free Conditions. Org. Lett. 2016, 18, 5272-5275.
  • the catalytic protocol can be conducted under aerobic conditions, eliminating the needs for an inert atmosphere or anhydrous solvents.
  • Boc refers to the nitrogen protecting group, "tert-butoxycarbonyl.”
  • Alternative nitrogen protecting groups that are known in the art can also be used in the methods of the disclosure.
  • ⁇ Reagents and conditions (a) l-bromo-3-chloropropane, K2CO3, acetone, RT, 20 h; (b) CS2CO3, ACN, 70 °C, 12 h; (c) l-bromo-3-chloropropane, K2CO3, acetone, RT, 20 h; (d) TEA, EtOH, 75 °C, 12 h.
  • Compound 4 a Miydride elimination side-product, may be prepared as described in Scheme 4. Room temperature N- and S-alkylation in acetone afforded desired synthons 5 and 6a, respectively. Formation of 1,2,4-triazole fragments 6c-d and 6f were readily accessed by reacting 7 with the desired amine.
  • ⁇ Reagents and conditions (i) Pd 2 (dba) 3 , RuPhos, aryl halide, diazaspiro reagent, NaO-t-Bu, dioxane, 100 °C, 20 min; (ii) TFA, DCM, rt, 3 h; (iii) 1-bromobutane, K 2 C0 3 , acetone, rt, 12 h; (iv) alkylating reagent, K 2 C0 3 , acetone, rt, 12 h; (v) amine, Cs 2 C0 3 , ACN, 70 °C, 8h.
  • Aryl amide scaffolds 35-36 may be prepared by reacting FF with 2-(4- bromobutyl)isoindoline-l,3-dione, to afford precursor GG. GG was then treated with hydrazine in refluxing EtOH to afford free-amine intermediate HH. Finally, benzamide compounds 35-36 were synthesized by coupling HH with the respective benzoic acid in the presence of 1- hydroxybenzotriazole (HOBt) hydrate and l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDC) in dichloromethane at room temperature. All final compounds were converted to the corresponding hydrochloric acid salt for pharmacological evaluation.
  • Scheme 5 fl
  • ⁇ Reagents and conditions (i) CC, TFA, DCM, rt, 3 h; (ii) alkylating reagent, K2CO3, acetone, rt, 12 h; (iii) DD, EE, TEA, EtOH, 75 °C, 12 h; (iv) FF, 2-(4-bromobutyl)isoindoline-l,3-dione, KI and CS2CO3, ACN, 75 °C for 3 h; (v) GG, hydrazine, EtOH, 75 °C for 2 h; (vi) HH, benzoic acid, HOBt, EDC, CH2CI2, rt, 2 h.
  • Aspect 1 A compound of Formula I or II, or a pharmaceutically acceptable salt thereof:
  • A is unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • X is S, O, or H;
  • Y is a 5-membered unsubstituted heteroaryl or 5-membered substituted heteroaryl
  • Z is unsubstituted C3-6cycloalkyl, substituted C3-6cycloalkyl, unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, or substituted heteroaryl;
  • k is 1, 2, 3, 4, 5, or 6;
  • t 1 or 2;
  • u 1 or 2;
  • v 0, 1, or 2;
  • w is 1, 2, or 3;
  • Aspect 2 The compound of Aspects 1, or a pharmaceutically acceptable salt thereof, wherein A is substituted phenyl.
  • Aspect 3 The compound of Aspect 2, or a pharmaceutically acceptable salt thereof, wherein A is phenyl substituted with 1 or 2 substituents that are independently Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 haloalkyl, halo, Ci- 6 haloalkoxy, or CN.
  • Aspect 4 The compound of Aspect 1, or a pharmaceutically acceptable salt thereof, wherein A is unsubstituted or substituted heteroaryl, preferably pyridyl or substituted pyridyl.
  • Aspect 5 The compound of any one of the preceding Aspects, or a pharmaceutically acceptable salt thereof, wherein X is S.
  • Aspect 6 The compound of any one of the preceding Aspects, or a pharmaceutically acceptable salt thereof, wherein Y is substituted triazolyl.
  • Aspect 7 The compound of any one of the preceding Aspects, or a pharmaceutically acceptable salt thereof, wherein Z is substituted aryl or substituted heteroaryl.
  • Aspect 8 The compound of any one of the preceding Aspects, or a pharmaceutically acceptable salt thereof, wherein k is 2, 3, or 4.
  • Aspect 9 The compound of any one of the preceding Aspects, or a pharmaceutically acceptable salt thereof, wherein t is 2 and u is 2.
  • Aspect 10 The compound of any one of Aspects 1 to 8, or a pharmaceutically acceptable salt thereof, wherein t is 2 and u is 1.
  • Aspect 11 The compound of any one of Aspects 1 to 8, or a pharmaceutically acceptable salt thereof, wherein t is 1 and u is 1.
  • Aspect 12 The compound of any one of the preceding Aspects, or a pharmaceutically acceptable salt thereof, wherein v is 2 and w is 2.
  • Aspect 13 The compound of any one of Aspects 1 to 11, or a pharmaceutically acceptable salt thereof, wherein v is 2 and w is 1.
  • Aspect 14 The compound of any one of Aspects 1 to 11, or a pharmaceutically acceptable salt thereof, wherein v is 1 and w is 2.
  • Aspect 15 The compound of any one of Aspects 1 to 11, or a pharmaceutically acceptable salt thereof, wherein v is 1 and w is 1.
  • Aspect 16 The compound of any one of Aspects 1 to 11, or a pharmaceutically acceptable salt thereof, wherein v is 0 and w is 2.
  • Aspect 23 The method of Aspect 21, wherein the dopamine D 3 receptor-mediated disease or disorder is substance abuse, addiction, schizophrenia, Parkinson's disease, dementia, anxiety, or depression.
  • Aspect 24 A method of analyzing D 3 R receptors in a subject comprising
  • SB269,652 refers to lH-indole-2-carboxylic acid ⁇ 4-[2-(cyano-3,4-dihydro-lH-isoquinolin-2-yl)-ethyl]-cyclohexyl ⁇ -amide, (see, Silvano, "The Tetrahydroisoquinoline Derivative SB269,652 Is an Allosteric Antagonist at Dopamine D3 and D2 Receptors," Mol. Pharmacol., 2010, 78, 925-934).
  • Compounds DD, FF, and congener 37 may be prepared using the general procedures herein. NMR spectra were taken on a Bruker DMX 500 MHz.
  • ⁇ -arrestin 2 recruitment to D3R was assayed using the Discoverx Pathhunter kit according to the manufacturer's instructions, with some minor modifications.
  • CHO-Kl cells expressing human ⁇ -arrestin 2 tagged with a ⁇ -galactosidase enzyme lacking part of the catalytic domain, and human D3R C-terminally tagged with a complementary fragment of ⁇ - galactosidase were grown in culture medium (Discoverx) supplemented with G418 and hygromycin.
  • Binding was terminated by the addition of ice cold wash buffer (D2/3R; 10 mM Tris-HCl, 150 mM NaCl, pH 7.5, 5-HTIAR; 10 mM TrisHCl, pH 7.4) and filtration over a glass-fiber filter (D3/2R; Schleicher and Schuell No. 32, 5-HTIAR; Whatman grade 934-AH, GE Healthcare Bio-Sciences,
  • Fragmentation Studies Compound 15a was fragmented in order to identify synthons acting as primary or secondary pharmacophores. Fragments were evaluated in radioligand binding assays using [ IJIABN in HEK 293 cells stably expressing human D3R and D 2 L. See,
  • each compound was assessed in a chemiluminescent assay allowing measurement of?-arrestin 2 recruitment induced by activation of the D 3 R expressed in a CHO-K1 parent cell line. See, Figures 3 A and 3B.
  • compound 37 stimulates ?-arrestin 2 recruitment in a contrasting fashion than what is observed with piperazine derivative 15a.
  • compound 15a acts as an inverse agonist at the D 3 R, while 37 behaves as a neutral antagonist.

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Abstract

L'invention concerne des antagonistes spirocycliques sélectifs du récepteur de la dopamine et leurs procédés d'utilisation dans le traitement, par exemple, de maladies et de troubles médiés par le récepteur D3 de la dopamine.
PCT/US2018/057201 2017-10-24 2018-10-24 Antagonistes sélectifs du récepteur de la dopamine et leurs procédés d'utilisation Ceased WO2019084075A1 (fr)

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US20080214591A1 (en) * 2002-07-05 2008-09-04 Bhatti Balwinder S N-Aryl Diazaspirocyclic Compounds and Methods of Preparation and Use Thereof
US20090156575A1 (en) * 2005-09-06 2009-06-18 Lena Borjesson Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
WO2017021920A1 (fr) * 2015-08-05 2017-02-09 Indivior Uk Limited Antagonistes du récepteur d3 de la dopamine ayant un fragment bicyclo
US20170260185A1 (en) * 2014-09-16 2017-09-14 Shire International Gmbh 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decan-10-one derivatives and related compounds as inhibitors of the human dopamine-active-transporter (dat) protein for the treatment of e.g. attention deficit disorder (add)

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US20080214591A1 (en) * 2002-07-05 2008-09-04 Bhatti Balwinder S N-Aryl Diazaspirocyclic Compounds and Methods of Preparation and Use Thereof
US20090156575A1 (en) * 2005-09-06 2009-06-18 Lena Borjesson Novel diazaspiroalkanes and their use for treatment of ccr8 mediated diseases
US20170260185A1 (en) * 2014-09-16 2017-09-14 Shire International Gmbh 2-[bis(4-fluorophenyl)methyl]-2,7-diazaspiro[4.5]decan-10-one derivatives and related compounds as inhibitors of the human dopamine-active-transporter (dat) protein for the treatment of e.g. attention deficit disorder (add)
WO2017021920A1 (fr) * 2015-08-05 2017-02-09 Indivior Uk Limited Antagonistes du récepteur d3 de la dopamine ayant un fragment bicyclo

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REILLY, SW ET AL.: "Highly Selective Dopamine D3 Receptor Antagonists with Arylated Diazaspiro Alkane Cores", JOURNAL OF MEDICINAL CHEMISTRY, vol. 60, no. 23, 2017, pages 9905 - 9910, XP055595471, DOI: 10.1021/acs.jmedchem.7b01248 *

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