Substituted heteroaryl analogs and uses thereof for the treatment of HIV-associated neurocognitive disorders

Abstract

The present disclosure is concerned with compounds, compositions, and methods of using same to treat HIV-1 -associated neurocognitive disorders (e.g., asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

SUBSTITUTED HETEROARYL ANALOGS AND USES THEREOF FOR THE TREATMENT OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No. 63 / 612,181, filed on December 19, 2023, the contents of which are incorporated herein by reference in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grants number 1R01DA047924-01A1, awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] An estimated thirty-eight million people worldwide are living with Human Immunodeficiency Virus (HIV). More than 50% of HIV-1 positive individuals suffer from neurological complications collectively referred to as HIV- 1 -associated neurocognitive disorders (HANDs) (Heaton et al. (2010) Neurology 75: 2087-2096). HAND is a spectrum of disorders that is generally divided into three main groups: asymptomatic neurocognitive impairment (ANI; 33%), mild neurocognitive disorders (MND, 20-30%), and the more severe, albeit rare, HIV-associated dementia (HAD; 2-8%) (Heaton et al. (2010) Neurology 75: 2087-2096; McArthur et al. (2010) Ann. Neurol. 67:699-714). Despite the widespread use of various combinations of antiretroviral therapies (cART) to control peripheral HIV infection, milder forms of neurocognitive impairments continue to persist, affecting between 30% and 70% of HIV-1 seropositive individuals (Soontomniyomkij et al. (2016) J Neuroimmune Pharmacol 11: 495-510; Heaton et al. 2010).

[0004] The majority of HAND patients experience deficits in memory, concentration, and decision-making. HAND patients present neuropathological conditions that emerge from the continued exposure of the central nervous system (CNS) tissues to HIV-1, viral proteins, immune inflammation, and cART (King et al. (2006) Microbes and inf ection / Insti tut Pasteur 8: 1347-1357; Clifford and Ances (2013) The Lancet infectious diseases 13: 976-986). The current therapeutics are insufficient for treating HIV-infected individuals with HAND.Considering the progressive and neurodegenerative nature of HAND, establishing an early intervention strategy would be beneficial to the preservation of neurocognitive function in HIV-infected individuals.

[0005] Converging lines of clinical observation, supported by imaging (Wang et al. (2004)Brain 127: 2452-2458; Chang et al. (2008) Neuroimage 42: 869-878), neuropsychological performance testing (Meade et al. (2011) Psychiatry Res.192: 167-175; Kumar et al. (2011)J. Neurovirol. 17: 26-40), and post-mortem examinations (Gelman et al. (2012) J.Neuroimmune Pharmacol.7: 686-700), have implicated dopamine (DA) dysregulation with the abnormal neurocognitive function observed in HAND (Berger et al. (2000) Journal of psychopharmacology 14: 214-221; Purohit et al. (2011) Molecular neurobiology 44: 102- 110). DA-rich brain regions (basal ganglia and related structures) are highly susceptible to the effects of both HIV infection and substance use. In the early stage of HIV infection, increased levels of DA and decreased DA turnover are found in the cerebrospinal fluid of therapy-naïve HIV patients with asymptomatic infection (Scheller et al. (2010) J. Neural. Transm.117: 699-705), which may contribute to decreased levels of DA in DA-rich brain regions (Kumar et al. (2011) J. Neurovirol.17: 26-40; Sardar et al. (1996) Neuroreport 7: 910-912; Kumar et al. (2009) J. Neurovirol.15: 257-274) in the advanced stages of HIV infection. Importantly, HIV-induced elevated levels of extracellular DA in the CNS can stimulate viral replication in human macrophages within DA-rich brain regions (Gaskill et al. (2009) Am. J. Pathol.175: 1148-1159; Gaskill et al. (2014) PLoS One 9: e108232; Gaskill et al. (2013) J. Neuroimmune Pharmacol.8: 621-642), resulting in viral protein release. It is commonly accepted that viral replication and proteins within the CNS are correlated with the persistence of HIV-related neuropathology and subsequent neurocognitive deficits (Brack-Werner, R. (1999) AIDS 13: 1-22; Frankel and Young (1998) Annu. Rev. Biochem.67: 1-25; Johnston et al. (2001) Ann. Neurol.49: 230-241; Power et al. (1998) J. Virol.72: 9045-9053). Importantly, long-term HIV-1 viral protein exposure leads to persistent DA deficits and neurocognitive impairments (Frankel and Young, 1998; Power et al., 1998; Brack-Werner, 1999; Johnston et al., 2001), which is independent of treatment with cART.

[0006] Among the viral proteins, HIV-1 trans-activator of transcription (Tat) is a majorpathogenic factor for HAND. Tat protein is secreted from HIV-infected microglia and astrocytes and taken up by neurons, leading to neuronal damages (Frankel and Pabo, 1988; Bagasra et al., 1996; Brack-Werner, 1999; Liu et al., 2000; Wallet et al., 2019; Marino et al., 2020). The presynaptic DA transporter (DAT) is essential for DA homeostasis and maintaining stable synaptic dopaminergic tone involved in attention, learning, memory, andmotivation. HIV-1 Tat protein and cocaine synergistically increase synaptic DA levels by directly inhibiting DAT activity, ultimately leading to dopaminergic neuron damage. Published work has demonstrated that Tat-induced inhibition of DAT is mediated by binding to allosteric binding site(s) on DAT, not by interacting with the DA uptake site (Zhu et aL, 2009; Zhu et al., 2011; Yuan et al., 2015). Accordingly, attenuating Tat binding to DAT would be expected to have only minimal influence on physiological DA transport. Notably, through integrated computational modeling prediction and experimental validation, key residues in human DAT (hDAT) were identified with which Tat interacts, which are critical for Tat-induced inhibition of DAT and transporter conformational transitions (Midde et al., 2013; Midde et al., 2015; Yuan et al., 2015; Quizon et al.. 2016). These initial findings demonstrate that small molecule allosteric modulators can decrease cocaine affinity for inhibition of DA uptake and attenuate Tat-induced inhibition of cocaine binding and DA reuptake by DAT (Zhu et al., 2022; Neuropharmacology).

[0007] Despite the established correlation between abnormal dopaminergic transmission and HAND, there are currently no drugs approved by the U.S. Food and Drug Administration (FDA) for neuroHIV therapy. Thus, there remains a need for compounds and compositions to treat HAND and methods of making and using same.SUMMARY

[0008] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds, compositions, and methods of using same to treat HAND (e.g.. asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV).

[0009] Disclosed are compounds having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, Cl- C4 haloalkoxy. C1-C4 alkoxy. C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C 1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl; and or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cy anoalkyL C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C 1- C4)(C 1 -C4) dialkylamino, and C 1 -C4 aminoalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eis hydrogen, provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl, R2is hydrogen, and at least one of R3a, R3b, R3c, R3d, and R3eis a non-hydrogen group.

[0010] Also disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:; wherein * denotes; wherein ** denotes a bond connected; wherein R10is selected from hydrogenan - alkyl; wherein R11is selected from ‒NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, ‒CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cy anoalkyL C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C 1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

[0011] Also disclosed are methods of modifying dopaminergic signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2. C1-C4 alkyl, C 1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH. -NO2, C1-C4 alkyl. C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, Cl- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1. 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl. C2-C4 alkenyl,C1-C4 haloalky l, C1-C4 cyanoalkyl, C1-C4 hydroxyalky l, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

[0012] Also disclosed are methods of modifying dopaminergic signaling in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2. C1-C4 alkyl, C 1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH. -NO2, C1-C4 alkyl. C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, Cl- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1. 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl. C2-C4 alkenyl,C1-C4 haloalky l, C1-C4 cyanoalkyl, C1-C4 hydroxyalky l, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl,- or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

[0013] Also disclosed are methods of treating HAND in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl: wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0. 1, 2, or 3 groups independently selected from halogen, -CN, -NH2. -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl; and or apharmaceutically acceptable salt thereof, provided that when Z is -CH-, then R2is hydrogen, provided that when Q is a structure represented by a formula:then n is 0, and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen.

[0014] Also disclosed are kits comprising a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:and wherein * denotes a bond connected towherein ** denotes a bond connected towherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NHy C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2. -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C 1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyd; and or a pharmaceutically acceptable salt thereof, provided that when Z is -CH-, then R2is hy drogen, provided that when Q is a structure represented by a formula:then n is 0. and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and one or more selected from: (a) an agent associated with the treatment of a HAND; (b) instructions foradministering the compound in connection with treating a condition associated with dysregulated dopaminergic signaling; and (c) instructions for treating a condition associated with dysregulated dopaminergic signaling.

[0015] Also disclosed are compounds having a structure represented by a formula selected from:wherein n is 0 or 1; wherein Q is a structure represented by a formula selected from:and wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1 -C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 haloalkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen. -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl. C1-C4 haloalkoxy. C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd, -CO2H, and -CO2(C1-C4 alky l); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise anunsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2- C10 heteroaryl, and is substituted with 0, 1, 2. or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C 1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0. then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0016] Also disclosed are compounds having a structure represented by a formula selected from:wherein n is 0 or 1; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl: wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, and C1-C4 alkyl: wherein R2is selected from hydrogen, halogen, -CN. -NH2, C1-C4 alkyl, C1-C4 haloalkyl. -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C 1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis hydrogen, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4- C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0017] Also disclosed are compounds selected from:or a pharmaceutically acceptable salt thereof.

[0018] Also disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0019] Also disclosed are methods of modifying dopaminergic signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0020] Also disclosed are methods of modifying dopaminergic signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0021] Also disclosed are methods of treating a HAND in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0022] Also disclosed are kits comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of a HAND; (b)instructions for administering the compound in connection withtreating a condition associated with dysregulated dopaminergic signaling; (c) instructions for treating a condition associated with dysregulated dopaminergic signaling.

[0023] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.DETAILED DESCRIPTION

[0024] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0025] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0026] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art w ill understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-expressbasis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0027] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.A. DEFINITIONS

[0028] As used in the specification and the appended claims, the singular forms ‘'a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0029] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of’ and “consisting essentially of.”

[0030] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0031] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It isgenerally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off. measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0032] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0033] A weight percent (wt. %) of a component, unless specifically stated to the contrary', is based on the total weight of the formulation or composition in which the component is included.

[0034] As used herein, “EC50,” is intended to refer to the concentration of a substance (e g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein.

[0035] As used herein, ‘TC50,” is intended to refer to the half maximal inhibitory concentration (IC50) values for compounds inhibiting a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.

[0036] As used herein. “Emax,” is intended to refer to the maximum attributable drug effect of a substance (e g, a compound or a drug).

[0037] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0038] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0039] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g, a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i. e. , arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g, cats, dogs, etc.), livestock (e.g, cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g, mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0040] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0041] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0042] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically: that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0043] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0044] As used herein, “dosage form’" means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxy ethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488. carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0045] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0046] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc ), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form,which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0047] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics. antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and otherbiologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0048] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, z.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0049] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, and amides, salts of esters or amides, and N-oxides of a parent compound.

[0050] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0051] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution7’ or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (z.e., further substituted or unsubstituted).

[0052] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0053] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight chain (z.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphaticgroups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0054] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobuty l, s- butyl, / -butyl, w-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyd, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a Cl alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl. C1-C8 alkyl, C1-C9 alkyl, Cl -CIO alkyl, and the like up to and including a C1-C24 alkyl.

[0055] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyd groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyd group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyd” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyd” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalky 1” specifically refers to an alkyd group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyd” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyd” does not also refer to specific terms such as “hydroxyalkyd” and the like.

[0056] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, thesubstituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl. ” Similarly, a substituted alkoxy can be specifically referred to as, e.g, a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0057] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, and the like. The term “heterocycloalkyl” is a non-aromatic carbon-based ring type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalky l group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0058] The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula — (CH2)a— , where “a” is an integer of from 2 to 500.

[0059] The terms “alkoxy” and “alkoxy!” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a poly ether such as — OA1— OA2or — OA1— (OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0060] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0061] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, z.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbomenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to. alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0062] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0063] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to. alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0064] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized n electrons above and below the plane of the molecule, where the n clouds contain (4n+2) it electrons. A further discussion of aromaticity is found in Morrisonand Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity ,’' pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0065] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to. alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NEE, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0066] The term “aldehyde” as used herein is represented by the formula — C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0067] The terms “amine” or “amino” as used herein are represented by the formula — NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl. aryl, or heteroaryl group as described herein. A specific example of amino is — NFE.

[0068] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl )amino group, hexylamino group, and the like.

[0069] The term “dialkylamino” as used herein is represented by the formula — N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to. dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di (sec-butyl )amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group. N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propyl amino group and the like.

[0070] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0071] The term “ester” as used herein is represented by the formula — OC(O)A1or — C(O)OA', where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A1O(O)C-A2-C(O)O)a— or — (A1O(O)C-A2-OC(O))a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0072] The term “ether” as used herein is represented by the formula AXOA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A1O-A2O)a— , where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0073] The terms “halo,” “halogen,” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0074] The terms “pseudohalide,” “pseudohalogen.” or “pseudohalo.” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyd, and perfluoroalkoxy groups.

[0075] The term “heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0076] The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy,nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, A-methyl pyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[t7| oxazolyl, benzo [<7|thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazolyl, and pyrido[2.3-b]pyrazinyl.

[0077] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2, 5 -thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1.2.3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl. oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group that has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0078] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1. 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1. 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[l ,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, lH-pyrazolo[4,3-c]pyridin-3-yl; lH-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.

[0079] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazoliny 1, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0080] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0081] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0082] The term “azide” or “azido” as used herein is represented by the formula — N3.

[0083] The term “nitro” as used herein is represented by the formula — NO2.

[0084] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0085] The term “silyl” as used herein is represented by the formula — SiA3A2A3, where A1. A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, ary l, or heteroary l group as described herein.

[0086] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)AX, — S(O)2A1. — OS(O)2A1, or — OS(O)2OA1. where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alky nyl, cycloalkynyl, aryl, or heteroaryl group as described herein.Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A'SfOhA2. where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, ary 1. or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalky nyl, ary l, or heteroaryl group as described herein.

[0087] The term “thiol” as used herein is represented by the formula — SH.

[0088] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (z'.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyd group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0089] As described herein, compounds of the invention may' contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any' given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (z.e., further substituted or unsubstituted).

[0090] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0091] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted’" group are independently halogen; -(CH2)o-4R0: -(CH2)O^IOR0; -0(CH2)o-4R°, - 0-(CH2)o UC(O)OR°; -(CH2)O4CH(ORO)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o 40(CH2)o i -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o4N(RO)2; -(CH2)o-4N(R0)C(0)R°; -N(R°)C(S)R°; - (CH2)O 4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(0)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)O4C(O)R°; -C(S)R°; -(CH2)O-4C(O)ORO; -(CH2)O 4C(O)SRO; -(CH2)O 4C(O)OSIR°3; -(CH2)O4OC(O)RO; -OC(0)(CH2)O4SR- SC(S)SR°; -(CH2)O4SC(O)RO; -(CH2)O 4C(O)NRO2; -C(S)NRO2; -C(S)SR°; -(CH2)O4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)O4SSRO; -(CH2)O 4S(O)2RO; -(CH2)O 4S(O)2ORO; (CH2)O 4OS(O)2RO; -S(O)2NRO2; -(CH2)O4S(O)R°; -N(RO)S(O)2NR°2; -N(R°)S(O)2RO; -N(OR°)R°; -C(NH)NRO2; -P(O)2RO;-P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; — (C i-4straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic. -CH2Ph, -0(CH2)o-iPh, - CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0092] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen. - (CH2)O 2R*, -(haloR*), -(CH2)0 2OH, -(CH2)o2OR*, -(CH2)0 2CH(OR’)2; -O(haloR’), -CN, -N3, -(CH2)O 2C(O)R", -(CH2)O 2C(O)OH, -(CH2)O 2C(O)OR", -(CH2)O 2SR*, -(CH2)O2SH, -(CH2)O 2NH2, -(CH2)O2NHR*, -(CH2)O2NR-2, -NO2, -SiR*3. -OSiR*3, -C(O)SR* -(Ci4straight or branched alkylene)C(O)OR*. or -SSR* wherein each R" is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci^ aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0093] Suitable divalent substituents on a saturated carbon atom of an ‘'optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =N0R*, -O(C(R*2))2-3O- or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0094] Suitable substituents on the aliphatic group of R* include halogen, -R*. -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0095] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R;. -NRt2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each R;is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R1', taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0096] Suitable substituents on the aliphatic group of R1' are independently halogen, -R*, -(haloR*), -OH, -OR’, -O(haloR*). -CN. -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently CH aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0097] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing abi li ty that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0098] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, <?.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see. for example. “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0099] The term “organic residue” defines a carbon-containing residue, i. e. , a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyds, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms. 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0100] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure:

[0101] regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e.. substituted alkyl) by having bonded thereto one or more “substituent radicals.” The numberof atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0102] ’‘Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms. 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen. phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl. alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0103] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0104] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures usedto prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0105] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0106] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press. 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzy matic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciatedthat where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0107] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%. greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the ”R ' forms of the compounds can be substantially free from the “S” forms of the compounds and are. thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of R ' forms of the compounds and are, thus, in enantiomeric excess of the “R?’ forms.

[0108] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S) / (R.R) and (R,S) / (S,R)). The pairs of enantiomers (e.g., (S,S) / (R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[0109] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0110] “Derivatives’' of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, and solvates. Examples of radioactively labeled forms include compounds labeled with tritium, phosphorous-32, iodine- 129, carbon-11, fluorine-18. and the like.

[0111] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically labeled or isotopically substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2El,3H,13C,14C.15N,18O,170,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e..3H. and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2FI, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0112] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0113] The term “co-crystal” means a physical association of two or more molecules that owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Cry stal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O.. et. al., The Royal Society of Chemistry. 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[0114] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.keto form enol form amide form imidic acid form

[0115] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, .V’-unsubstituted. 3-A3and M-unsubstituted. 5-A3as shown below.

[0116] Unless stated to the contrary, the invention includes all such possible tautomers.

[0117] It is known that chemical substances form solids that are present in different states of order that are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0118] In some aspects, a structure of a compound can be represented by a formula:

[0119] which is understood to be equivalent to a formula:

[0120] wherein n is typically an integer. That is. R” is understood to represent five independent substituents, R”(a), R”(b). R"(c). R"(d). R"(c’. By "‘independent substituents / ’ it is meant that each R substituent can be independently defined. For example, if in one instance R"(a)is halogen, then R"(b)is not necessarily halogen in that instance.

[0121] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh. Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions. Volumes 1-40 (John Wiley and Sons. 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0122] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived fromgrammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0123] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F. B-D. B-E, B-F, C-D, C-E. and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0124] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.B. COMPOUNDS

[0125] In one aspect, the invention relates to compounds useful in treating HAND (e.g., asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV).

[0126] In one aspect, the disclosed compounds exhibit antiretroviral activity7.

[0127] In one aspect, the compounds of the invention are useful in modulating dopaminergic signaling in a mammal. In a further aspect, the compounds of the invention are useful in modulating dopaminergic signaling in at least one cell.

[0128] In one aspect, the compounds of the invention are useful in the treatment of HAND, as further described herein.

[0129] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.1. STRUCTURE

[0130] In one aspect, disclosed are compounds having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NHz, C1-C4 alkyl. C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, Cl- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1 -C4 alkylamino, (C1 -C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl; and or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R12a. R12b, R12c, R12d, and R12eis hydrogen, provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl, R2is hydrogen, and at least one of R3a, R3b, R3c, R3d, and R3eis a non-hydrogen group.

[0131] In one aspect, disclosed are compounds having a structure represented by a formula selected from:wherein n is 0 or 1; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl: wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 haloalkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen. -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy. C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C 1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alky l); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2- C10 heteroaryl, and is substituted with 0, 1. 2. or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalky l, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0. then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0132] In one aspect, disclosed are compounds having a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen. -CN. -NH2, -OH. -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd. -CO2H, and -CC>2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis hydrogen, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4- C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1 -C4 alky lamino, (C1 -C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0133] In one aspect, disclosed are compounds selected from:or a pharmaceutically acceptable salt thereof.

[0134] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0135] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0136] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0137] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0138] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0139] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0140] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0141] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0142] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0143] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0144] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0145] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0146] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0147] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0148] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0149] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0150] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0151] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0152] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0153] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0154] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0155] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0156] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0157] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0158] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0159] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0160] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0161] In one aspect, n is 0 or 1. In a further aspect, n is 0. In a still further aspect, n is 1. a. Q GROUPS

[0162] In one aspect. Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected to

[0163] In one aspect. Q is a structure represented by a formula selected from:wherein * denotes a bond connected to -(CR4aR4b)n-;wherein ** denotes a bond connected to -(CR4aR4b)n-

[0164] In various aspects, Q is a structure:

[0165] In various aspects, Q is a structure:In a further aspect, Z is -N-. In a still further aspect, Z is -CH-.

[0166] In various aspects, Q is a structure represented by a formula:In a further aspect, R10is hydrogen. In a still further aspect, R11is C1-C4 alkyl and R12is hydrogen. b. Z GROUPS

[0167] In one aspect, Z is selected from -N- and -CH-. In a further aspect, Z is -N-. In a still further aspect, Z is -CH-. c. R1GROUPS

[0168] In one aspect. R1is selected from hydrogen, -CN, and C1-C4 alkyl. In a further aspect, R1is selected from hydrogen, -CN, methyl, ethyl, n-propyl. and isopropyl. In a still further aspect, R1is selected from hydrogen, -CN, methyl, and ethyl. In yet a further aspect, R1is selected from hydrogen, -CN, and methyl.

[0169] In one aspect. R1is selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 haloalkyl. In a further aspect, R1is selected from hydrogen. -CN, -F, -Cl, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2C1, -CH2CH2F, -CH2CH2CL - CH2CH2CH2F, -CH2CH2CH2CL -CH(CH3)CH2F, and -CH(CH3)CH2C1. In a still further aspect, R1is selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, - CH2C1. -CH2CH2F, and -CH2CH2C1. In yet a further aspect, R1is selected from hydrogen, -F. -Cl, -CN, methyl, -CH2F. -CHF2, -CF3, and -CH2C1.

[0170] In various aspects, R1is selected from hydrogen, halogen, -CN, and C1-C4 alkyl. In a further aspect, R1is selected from hydrogen, -CN, -F, -Cl, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R1is selected from hydrogen, -F, -Cl, -CN, methyl, and ethyl. In yet a further aspect, R1is selected from hydrogen, -F, -Cl, -CN. and methyl.

[0171] In various aspects, R1is selected from hydrogen and -CN. In a further aspect, R1is -CN.

[0172] In various aspects, R1is selected from hydrogen and halogen. In a further aspect, R1is selected from hydrogen, -F, -Cl. and -Br. In a still further aspect, R1is selected from hydrogen, -F, and -Cl. In yet a further aspect, R1is selected from hydrogen and -Cl. In an even further aspect, R1is selected from hydrogen and -F.

[0173] In various aspects, R1is selected from -CN and C1-C4 alkyl. In a further aspect, R1is selected from -CN. methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R1is selected from -CN, methyl, and ethyl. In yet a further aspect, R1is selected from -CN and methyl.

[0174] In various aspects, R1is selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a further aspect, R1is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2. -CF3, -CH2C1. -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F. - CH2CH2CH2C1, -CH(CH3)CH2F, and -CH(CH3)CH2C1. In a still further aspect, R1is selected from hydrogen, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2C1, -CH2CH2F, and - CH2CH2C1. In yet a further aspect, R1is selected from hy drogen methyl, -CH2F, -CHF2, - CF3, and -CH2C1.

[0175] In various aspects, R1is selected from hydrogen and C1-C4 alkyl. In a further aspect, R1is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R1is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R1is selected from hydrogen and methyl.

[0176] In various aspects, R1is C1-C4 alkyl. In a further aspect, R1is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R1is selected from methyl and ethyl. In yet a further aspect, R1is methy l.

[0177] In various aspects, R1is selected from hydrogen and C1-C4 haloalkyl. In a further aspect, R1is selected from hydrogen, -CH2F, -CHF2, -CF3. -CH2CL -CH2CH2F, - CH2CH2C1, -CH2CH2CH2F, -CH2CH2CH2C1, -CH(CH3)CH2F, and -CH(CH3)CH2C1. In a still further aspect, R1is selected from hydrogen, -CH2F, -CHF2, -CF3, -CH2C1, -CH2CH2F, and -CH2CH2C1. In yet a further aspect, R1is selected from hydrogen, -CH2F, -CHF2, -CF3, and -CH2C1.

[0178] In various aspects, R1is C1-C4 haloalkyl. In a further aspect, R1is selected from -CH2F. -CHF2, -CF3, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F, - CH2CH2CH2C1, -CH(CH3)CH2F, and -CH(CH3)CH2C1. In a still further aspect, R1is selected from -CH2F, -CHF2, -CF3, -CH2C1, -CH2CH2F, -CH2CH2C1. In yet a further aspect, R1is selected from -CH2F, -CHF2, -CF3, and -CH2C1.

[0179] In various aspects, R1is hydrogen. d. R2GROUPS

[0180] In one aspect. R2is selected from hydrogen, halogen, and C1-C4 alkyl. In a further aspect, R2is selected from hydrogen. -F, -Cl, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R2is selected from hydrogen, -F, -Cl, methyl, and ethyl. In yet a further aspect, R2is selected from hydrogen, -F, -Cl, and methyl.

[0181] In one aspect. R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2. -C(O)NH(C1-C4 alkyl), and Cy2. In a further aspect, R2is selected from hydrogen, -F, -Cl, -CN, -NH2, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F -CH2CH2CH2F, -CH(CHS)CH2F, -CH2CI, -CHCI2, -CC13, -CH2CH2C1, -CH2CH2CH2C1, -CH(CH3)CH2C1, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, -C(O)NHCH2CH2CH3, -C(O)NHCH(CH3)2, and Cy2. In a still further aspect, R2is selected from hydrogen, -F, -Cl, -CN, -NH2, methyl, ethyl, -CH2F, -CHF2, -CFs, -CH2CH2F -CH2CL -CHC12, -CC13, -CH2CH2C1,-CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, and Cy2. In yet a further aspect, R2is selected from hydrogen, -F, -Cl, -CN. -NH2, methyl, -CH2F. -CHF2, -CF3, -CH2C1, -CHC12. -CC13, -CO2H, -C(O)NH2, -C(O)NHCH3. and Cy2.

[0182] In various aspects, R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, and Cy2. In a further aspect, R2is selected from hydrogen, -F, -Cl, -CN, -NH2, methyl, ethyl, n-propyl. isopropyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CH2CH2F, -CH(CH3)CH2F, -CH2CI, -CHCI2, -CC13. -CH2CH2C1.-CH2CH2CH2C1. -CH(CH3)CH2C1, and Cy2. In a still further aspect, R2is selected from hydrogen, -F, -Cl, -CN, -NH2, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F. -CH2C1, -CHC12, -CC13, -CH2CH2C1, and Cy2. In yet a further aspect, R2is selected from hydrogen, -F, -Cl, -CN, -NH2, methyl, -CH2F. -CHF2, -CF3, -CH2C1, -CHC12. -CC13, and Cy2.

[0183] In various aspects, R2is selected from hydrogen, halogen, C 1-C4 haloalkyl, and Cy2. In a further aspect, R2is selected from hydrogen, -F, -Cl, -CH2F, -CHF2, -CF3,-CH2CH2F -CH2CH2CH2F, -CH(CH3)CH2F, -CH2CI, -CHC12, -CCh, -CH2CH2CI. -CH2CH2CH2CL -CH(CH3)CH2C1, and Cy2. In a still further aspect. R2is selected from hydrogen, -F, -Cl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CI, -CHCk,

[0184] -CCls, -CH2CH2CI, and Cy2. In yet a further aspect, R2is selected from hydrogen, -F, -Cl, -CH2F, -CHF2, -CF3, -CH2C1, -CHCk, -CCI3, and Cy2.

[0185] In various aspects, R2is selected from hydrogen, -CN, -NH2, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2. In a further aspect, R2is selected from hydrogen, -CN, -NH2, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, -C(O)NHCH2CH2CH3, -C(O)NHCH(CH3)2, and Cy2. In a still further aspect, R2is selected from hydrogen, -CN, -NH2, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, and Cy2. In yet a further aspect, R2is selected from hydrogen, -CN, -NH2, -CO2H, -C(O)NH2, -C(O)NHCH3, and Cy2.

[0186] In various aspects, R2is selected from -CN, C1-C4 alky l, -CChNFB, and Cy2. In a further aspect, R2is selected from -CN, methyl, ethyl, n-propyl, isopropyl, -CO2NH2, and Cy2. In a still further aspect, R2is selected from -CN, methyl, ethyl, -CO2NH2, and Cy2. In yet a further aspect. R2is selected from -CN. methyl, -CO2NH2. and Cy2.

[0187] In various aspects, R2is selected from hydrogen and Cy2. In a further aspect, R2is Cy2.

[0188] In various aspects, R2is selected from hy drogen and halogen. In a further aspect, R2is selected from hydrogen, -F, -Cl, and -Br. In a still further aspect, R2is selected from hydrogen, -F, and -Cl. In yet a further aspect, R2is selected from hydrogen and -Cl. In an even further aspect, R2is selected from hydrogen and -F.

[0189] In various aspects, R2is halogen. In a further aspect, R2is selected from -F, -Cl, and -Br. In a still further aspect, R2is selected from -F and -Cl. In yet a further aspect, R2is -Cl. In an even further aspect, R2is -F.

[0190] In various aspects, R2is selected from hydrogen and C1-C4 alkyl. In a further aspect, R2is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R2is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R2is selected from hydrogen, and methyl.

[0191] In various aspects, R2is C 1 -C4 alkyl. In a further aspect, R2is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R2is selected from methyl, and ethyl. In yet a further aspect, R2is methyl.

[0192] In various aspects, R2is hydrogen.e. R3A, R3B, R3C, R3D, AND R3EGROUPS

[0193] In one aspect each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C 1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd. -CO2H, and -CO2(C1-C4 alkyl). In a further aspect, each of R3a, R3b, R3c. R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, methyl, ethyl, w-propyl, z-propyl, ethenyl, n-propenyl, z-propenyl, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, - CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN -CH2CH2CN, -CH2CH2CH2CN, - CH(CH3)CH2CN, -CH2OH -CH2CH2OH. -CH2CH2CH2OH. -CH(CH3)CH2OH, -OCH2F, - OCHF2, -OCF3, -OCH2CI, -OCHCh, -OCC13, -OCH2CH2F, -OCH2CH2C1, - OCH2CH2CH2F, -OCH2CH2CH2CI, -OCH(CH3)CH2F, -OCH(CH3)CH2C1, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3. -NHCH2CH2CH3, - NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2. - N(CH3)(CH2CH3), -CO2H, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, and -CO2CH(CH3)2. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH2F, - CH2CI. -CH2CH2F, -CH2CH2C1, -CH(CH3)CH2C1. -CH2CN -CH2CH2CN, -CH2OH, - CH2CH2OH. -OCH3, -OCH2CH3. -0CH2F, -0CHF2, -OCF3, -OCH2C1, -OCHCh. -OCC13. -OCH2CH2F, -OCH2CH2C1, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3), -CO2H, -CO2CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen. -F. -Cl, -NH2, -CN, - OH, -NO2. methyl, -CH2F, -CH2C1, -CH2CN, -CH2OH. -OCH?, -OCH2F, -OCHF2, - OCF3, -OCH2C1, -OCHCh, -OCC13, -NHCH3, -N(CH3)2, -CO2H, and -CO2CH3.

[0194] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C 1-C4 cyanoalkyl, -CO2H, and -CO2(C1-C4 alkyl). In a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, - OH, -NO2, methyl, ethyl, zz-propyl, z-propyl, ethenyl, w-propenyl, z-propenyl, -CH2F, - CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, - CH(CH3)CH2C1, -CH2CN -CH2CH2CN, -CH2CH2CH2CN, -CH(CH3)CH2CN, -CO2H, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3. and -CO2CH(CH3)2. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2C1, - CH(CH3)CH2C1, -CH2CN, -CH2CH2CN, -CO2H, -CO2CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, - F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2F, -CH2CI, -CH2CN, -CO2H, and -CO2CH3.

[0195] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN. C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R3a, R3b, R3c. R3d, and R3eis independently selected from hydrogen, -F, -Cl, -CH2F. -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, - CH(CH3)CH2C1, -CH2CN -CH2CH2CN, -CH2CH2CH2CN, and -CH(CH3)CH2CN. In a still further aspect, each of R3a, R3b, R3c, R3d. and R3eis independently selected from hydrogen, - F, -Cl, -CH2F. -CH2CI, -CH2CH2F, -CH2CH2CI, -CH(CH3)CH2C1, -CH2CN. and - CH2CH2CN. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -CH2F, -CH2CI, and -CH2CN.

[0196] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen. -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -CO2H. and -CO2(C1-C4 alkyl). In a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, - F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, n-propyl, / -propyl, -CH2OH,-CH2CH2OH, - CH2CH2CH2OH. -CH(CH3)CH2OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -0CH2F. -0CHF2, -OCF3, -0CH2CI. -OCHCh. -OCC13, -OCH2CH2F. -OCH2CH2CL - OCH2CH2CH2F, -OCH2CH2CH2CI, -OCH(CH3)CH2F, -OCH(CH3)CH2C1, -CO2H, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, and -CO2CH(CH3)2. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, - CN, -OH, -NO2. methyl, ethyl, ethenyl. -CH2OH, -CH2CH2OH. -OCH3, -OCH2CH3. - OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, -OCCh, -OCH2CH2F, -OCH2CH2CL -CO2H, -CO3CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, - CH2OH, -OCH3. -0CH2F, -0CHF2, -OCF3, -0CH2CI, -OCHCh. -OCCh, -CO2H, and -CO2CH3.

[0197] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -OH, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R3a, R3b, R3c, R3d. and R3eis independently selected from hydrogen, - OH, -CH2OH -CH2CH2OH. -CH2CH2CH2OH. -CH(CH3)CH2OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -0CH2F, -0CHF2, -OCF3, -0CH2CI, -OCHCh, -OCC13,-OCH2CH2F, -OCH2CH2CI, -OCH2CH2CH2F, -OCH2CH2CH2CI, -OCH(CH3)CH2F, and - OCH(CH3)CH2C1. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -OH, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, - OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCI2, -OCCh, -OCH2CH2F, and -OCH2CH2CI. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -OH, -CH2OH, -OCH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCI2, and - OCCh.

[0198] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C 1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd, -CO2H, and -CO2(C1-C4 alkyl). In a further aspect, each of R3a, R3b, R3c. R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, w-propyl, z-propyl, ethenyl, n- propenyl, z-propenyl, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, - N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, -N(CH3)(CH2CH3), -CO2H, -CO2CH3. -CO2CH2CH3. -CO2CH2CH2CH3, and -CO2CH(CH3)2. In a still further aspect, each of R3a, R3b, R3c. R3d, and R3eis independently selected from hydrogen. -F. -Cl, - NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -NHCH3, -NHCH2CH3, -N(CH3)2, - N(CH2CH3)2, -N(CH3)(CH2CH3), -CO2H, -CO2CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen. -F. -Cl, - NH2. -CN. -OH. -NO2, methyl. -NHCH3, -N(CH3)2. -CO2H, and -CO2CH3.

[0199] In various aspects, ach of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -NH2, -NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R3a. R3b, R3c, R3d, and R3eis independently selected from hydrogen, -NH2, -NO2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -NH2, -NO2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3). In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -NH2, -NO2. -NHCH3, and -N(CH3)2.

[0200] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, -CO2H, and -CO2(C1-C4 alkyl). In a further aspect, each of R3a, R3b, R3c. R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2. -CN. -OH. methyl, ethyl, zr-propyl, z-propyl, ethenyl, / z-propenyl. z-propenyl, -CO2H, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, and-CO2CH(CH3)2. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH. -NO2, methyl, ethyl, ethenyl, -CO2H. -CO2CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CO2H, and -CO2CH3.

[0201] In various aspects, each of R3a, R3b, R3c, R3d. and R3eis independently selected from hydrogen, halogen. C1-C4 alkyl. C2-C4 alkenyl, -CO2H, and -CO2(C1-C4 alkyl). In a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, - F, -Cl, methyl, ethyl, zz-propyl, z-propyl, ethenyl, w-propenyl. / -propenyl, -CO2H, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3. and -CO2CH(CH3)2. In a still further aspect, each of R3a. R3b, R3c, R3d. and R3eis independently selected from hydrogen, -F, -Cl, methyl, ethyl, ethenyl, -CO2H, -CO2CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, methyl, -CO2H, and -CO2CH3.

[0202] In various aspects, each of R3a. R3b, R3c, R3d. and R3eis independently selected from hydrogen, -CO2H, and -CO2(C1-C4 alkyl). In a further aspect, each of R3a, R3b. R3c. R3d, and R3eis independently selected from hydrogen, -CO2H, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, and -CO2CH(CH3)2. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -CO2H, -CO2CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d. and R3eis independently selected from hydrogen, -CO2H, and -CO2CH3.

[0203] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R3a, R3b, R3c. R3d, and R3cis independently selected from hydrogen, methyl, ethyl, zz-propyl, z-propyl, ethenyl, zz-propenyl, and z-propenyl. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen and methyl.

[0204] In various aspects, each of R3a. R3b, R3c, R3d. and R3eis independently selected from hydrogen and halogen. In a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, and -Br. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, and -Cl. In yet a further aspect, each of R3a, R3b, R3c. R3d, and R3eis independently selected from hydrogen and -Cl.In an even further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen and -F.

[0205] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, C1-C4 alkyl, -CO2H, and -CC>2(C1-C4 alkyl). In a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, methyl, ethyl, / / -propyl, / -propyl. -CO2H, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, and -CO2CH(CH3)2. In a still further aspect, each of R3a, R3b. R3c, R3d, and R3eis independently selected from hydrogen, -F, -CL methyl, ethyl, -CO2H, -CO2CH3, and -CO2CH2CH3. In yet a further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, - F, -Cl, methyl, -CO2H, and -CO2CH3.

[0206] In various aspects, each of R3a. R3b, R3c, R3d. and R3eis independently selected from hydrogen and -CO2H.

[0207] In various aspects, at least one of R3a, R3b, R3c, R3d, and R3eis a non-hydrogen group. In a further aspect, at least two of R3a, R3b, R3c, R3d, and R3eis a non-hydrogen group. In a still further aspect, at least three of R3a, R3b. R3c, R3d, and R3eis a non-hydrogen group. In an even further aspect, each of R3a. R3b. R3c, R3d. and R3eis a non-hydrogen group.

[0208] In various aspects, each of R3a, R3b, R3c, R3d, and R3eis hydrogen. f. R4AAND R4BGROUPS

[0209] In one aspect, R4ais C1-C4 alkyl and R4bis selected from hydrogen and Cl- C4 alkyl, or each of R4aand R4btogether comprise an unsubstituted cyclopropyl.

[0210] In various aspects, R4ais C1-C4 alkyl and R4bis hydrogen, or each of R4aand R4btogether comprise an unsubstituted cyclopropyl.

[0211] In various aspects, R4ais C 1-C4 alkyl and R4bis hydrogen and C1-C4 alkyl.In a further aspect, R4ais selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl, and R4bis selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R4ais selected from methyl and ethyl, and R4bis selected from hydrogen, methyl and ethyl. In yet a further aspect, R4ais methyl and R4bis selected from hydrogen and methyl.

[0212] In various aspects, R4ais C1-C4 alkyl and R4bis C1-C4 alky l. In a further aspect, R4ais selected from methyl, ethyl, n-propyl, and isopropyl, and R4bis selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R4ais selected from methyl and ethyl, and R4bis selected from methyl and ethyl. In yet a further aspect, R4ais methyl and R4bis methyl.

[0213] In various aspects, R4ais C1-C4 alkyl and R4bis hydrogen. In a further aspect, R4ais selected from methyl, ethyl, n-propyl, and isopropyl, and R4bis hydrogen. In a still further aspect, R4ais selected from methyl and ethyl, and R4bis hydrogen. In yet a further aspect, R4ais methyl and R4bis hydrogen.

[0214] In various aspects, each of R4aand R4btogether comprise an unsubstituted cyclopropyl. g. R10GROUPS

[0215] In one aspect. R10is selected from hydrogen and C1-C4 alkyd. In a further aspect. R10is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R10is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R10is selected from hydrogen and ethyl. In an even further aspect, R10is selected from hydrogen and methyl.

[0216] In various aspects, R10is C1-C4 alkyl. In a further aspect. R10is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R10is selected from methyl and ethyl. In yet a further aspect, R10is ethyl. In an even further aspect, R10is methyl.

[0217] In various aspects, R10is hydrogen. h. R11GROUPS

[0218] In one aspect. R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, R11is selected from -NH2, methyl, ethyl, n-propyl, isopropyl, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, - N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, R11is selected from -NH2, methyl, ethyl, -NHCH3, -NHCH2CH3, - N(CH3)2. and -N(CH2CH3)2. In yet a further aspect, R11is selected from -NH2, methyl, - NHCH3, and -N(CH3)2.

[0219] In various aspects, R11is selected from -NH2, C1-C4 alkylamino, and (Cl- C4)(C1-C4) dialkylamino. In a further aspect, R11is selected from -NH2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2. and -N(CH3)(CH2CH3). In a still further aspect, R11is selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -N(CH2CH3)2. In yet a further aspect, R11is selected from -NH2, -NHCHs, and -N(CHs)2.

[0220] In various aspects, Rnis selected from C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In a further aspect. R11is selected from -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, — N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, and -N(CH3)(CH2CHs). In a still further aspect, R11is selected from - NHCH3, -NHCH2CH3, -N(CHS)2, and -N(CH2CH3)2. In yet a further aspect, R11is selected from -NHCH3 and -N(CHs)2.

[0221] In various aspects, R11is C1-C4 alkyl. In a further aspect. R11is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R11is selected from methyl and ethyl. In yet a further aspect, R11is methyl.

[0222] In various aspects, R11is -NH2. i. R12GROUPS

[0223] In one aspect. R12is selected from hydrogen and methyl. In a further aspect, R12is methyl. In a still further aspect. R12is hydrogen. j. R12A, R12B, R12C, R12D, AND R12EGROUPS

[0224] In one aspect, each of R12a. R12b. R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C 1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R12a. R12b, R12c, R12d, and R12eis hydrogen. In a further aspect, each of R12a. R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, methyl, ethyl, w-propyl. z-propyl, ethenyl, w-propenyl, z-propenyl, -CH2F, -CH2CI, -CH2CH2F, - CH2CH2C1, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN,- CH2CH2CN, -CH2CH2CH2CN, -CH(CH3)CH2CN, -CH2OH.-CH2CH2OH, - CH2CH2CH2OH. -CH(CH3)CH2OH, -0CH2F, -OCHF2, -0CF3. -0CH2CI, -OCHC12, - OCC13, -OCH2CH2F, -OCH2CH2CL -OCH2CH2CH2F, -OCH2CH2CH2CI, - OCH(CH3)CH2F, -OCH(CH3)CH2C1, -0CH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)CH3, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, - N(CH2CH?)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH2F, -CH2CI, - CH2CH2F, -CH2CH2CI, -CH(CH3)CH2C1, -CH2CN -CH2CH2CN, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -0CF3, -OCH2CI, -0CHC12, -OCCh, -OCH2CH2F, -OCH2CH2CI, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, and -N(CH3)(CH2CH3). In yet a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2F, -CH2CI, -CH2CN, -CH2OH, - OCH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, -OCCh, -NHCH3, and -N(CH3)2.

[0225] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl. Cl- C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, n-propyl, z-propyl, ethenyl, zz-propenyl. / -propenyl, -CH2F. -CH2CI, -CH2CH2F, - CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI. -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN,- CH2CH2CN, -CH2CH2CH2CN, and -CH(CH3)CH2CN. In a still further aspect, each of R12a, R12b, R12C, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, - OH, -NO2, methyl, ethyl, ethenyl, -CH2F. -CH2C1, -CH2CH2F, -CH2CH2C1, - CH(CH3)CH2C1, -CH2CN, and -CH2CH2CN. In yet a further aspect, each of R12a. R12b, R12c, R12d, and R12eis independently selected from hydrogen. -F. -Cl, -NH2. -CN, -OH, -NO2. methyl, -CH2F, -CH2CL and -CH2CN.

[0226] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R12a, R12b, R12e, R12d. and R12eis independently selected from hydrogen, -F, - Cl, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, - CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN -CH2CH2CN, -CH2CH2CH2CN, and - CH(CH3)CH2CN. In a still further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, - CH(CH3)CH2C1, -CH2CN, and -CH2CH2CN. In yet a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -CH2F, -CH2CI, and - CH2CN.

[0227] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl. Cl- C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R12a, R12b, R12C, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, - OH, -NO2, methyl, ethyl, / 7-propyl, z-propyl, -CH2OH,-CH2CH2OH. -CH2CH2CH2OH, - CH(CH3)CH2OH, -OCH3. -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3. -OCH2F. -OCH2CH2CH2F, -OCH2CH2CH2CI, -OCH(CH3)CH2F, and -OCH(CH3)CH2C1. In a still further aspect, each of R12a, R12b, R12c. R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, -OCC13, - OCH2CH2F, and -OCH2CH2CI. In yet a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl. -NH2, -CN, -OH, -NO2, methyl, - CH2OH, -OCH3. -0CH2F, -0CHF2, -OCF3, -0CH2CI, -OCHCh. and -OCC13.

[0228] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -OH, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R12a, R12b, R12c, R12d. and R12eis independently selected from hydrogen, -OH, -CH2OH.-CH2CH2OH, -CH2CH2CH2OH. -CH(CH3)CH2OH, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CL - OCHCh, -OCC13, -OCH2CH2F, -OCH2CH2CI, -OCH2CH2CH2F, -OCH2CH2CH2CI, - OCH(CH3)CH2F, and -OCH(CH3)CH2C1. In a still further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen. -OH. -CH2OH, -CH2CH2OH, - OCH3. -OCH2CH3, -0CH2F, -0CHF2, -OCF3. -0CH2CI, -OCHCh, -OCC13. -OCH2CH2F, and -OCH2CH2CI. In yet a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -OH, -CH2OH, -OCH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, and -OCCh

[0229] In various aspects, each of R12a, R12b, R12c. R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl- C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R12a, R12b, R12c, R12d. and R12eis independently selected from hydrogen, -F, -Cl, - NH2, -CN. -OH. -NO2, methyl, ethyl, w-propyl. / -propyl, ethenyl, w-propenyl, / -propenyl, - NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CHS)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, - CN, -OH, -NO2. methyl, ethyl, ethenyl. -NHCH3, -NHCH2CH3. -N(CH3)2, -N(CH2CH3)2, and -N(CH3)(CH2CH3). In yet a further aspect, each of R12a. R12b, R12c, R12d. and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -NHCH3, and -N(CH3)2.

[0230] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -NH2, -NO2. C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R12a, R12b, R12c, R12d, and R12eisindependently selected from hydrogen, -NH2, -NO2, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3. -NHCH(CH3)CH3, -N(CH3)2. -N(CH2CH3)2. -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -NH2, -NO2, -NHCH3, - NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3). In yet a further aspect, each of R12a, R12b, R12c, R12d. and R12eis independently selected from hydrogen, -NH2, -NO2, - NHCH3, and -N(CH3)2.

[0231] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R12a, R12b, R12c, R12d. and R12eis independently selected from hydrogen, -F, -Cl. -NH2, -CN, -OH, methyl, ethyl, w-propyl. / -propyl, ethenyl, / 7-propenyl. and / -propenyl. In a still further aspect, each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, and ethenyl. In yet a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, and methyl.

[0232] In various aspects, each of R12a, R12b, R12c. R12d. and R12eis independently selected from hydrogen, halogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, methyl, ethyl, n-propyl, / -propyl, ethenyl, / / -propenyl, and / -propenyl. In a still further aspect, each of R12a, R12b, R12e, R12d. and R12eis independently selected from hydrogen, -F, -Cl, methyl, ethyl, and ethenyl. In yet a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, and methyl.

[0233] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R12a, Ri2b, R12c, R12d, and R12eis independently selected from hydrogen, methyl, ethyl, w-propyl, / - propyl, ethenyl, / / -propenyl, and / -propenyl. In a still further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, each of R12a, R12b, R12c. R12d, and R12eis independently selected from hydrogen and methyl.

[0234] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen and halogen. In a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, and -Br. In a still further aspect, each of R12a. R12b. R12c, R12d, and R12eis independently selected from hydrogen, -F, and -Cl. In yet a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected fromhydrogen and -Cl. In an even further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen and -F.

[0235] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, methyl, ethyl, n-propyl, and / -propyl. In a still further aspect, each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, methyl, and ethyl. In yet a further aspect, each of R12a. R12b, R12c, R12d, and R12eis independently selected from hydrogen, -F, -Cl, methyl.

[0236] In various aspects, at least one of R12a, R12b, R12c, R12d, and R12eis a non- hydrogen group. In a further aspect, at least two of R12a, R12b, R12c, R12d, and R12eis a non- hydrogen group. In a still further aspect, at least three of R12a, R12b, R12c. R12d, and R12eis a non-hydrogen group. In an even further aspect, each of R12a, R12b, R12c, R12d, and R12eis a non-hydrogen group.

[0237] In various aspects, each of R12a, R12b, R12c, R12d, and R12eis hy drogen. k. R13A, R13B, R13c, AND R13DGROUPS

[0238] In one aspect, each of R13a, R13b, R13c, and R,3dis independently selected from hydrogen, halogen, -CN, -NH2, -OH. -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cy anoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R13a, R13b, R13c, and R13dis hy drogen. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl. -NH2, -CN, -OH, methyl, ethyl, w-propyl, / -propyl, ethenyl, / / -propenyl, / -propenyl, -CH2F, -CH2CI, -CH2CH2F. -CH2CH2CI. - CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN -CH2CH2CN,CH2CH2CH2CN, CH(CH3)CH2CN, CH2OH, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, -OCH2F, -OCHF2, -OCF3. -OCH2CI, -OCHCh, -OCC13, -OCH2CH2F, - OCH2CH2CI, -OCH2CH2CH2F, -OCH2CH2CH2CI. -OCH(CH3)CH2F. -OCH(CH3)CH2C1, - OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -NHCH3, -NHCH2CH3, - NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, - N(CH(CH3)CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R13a. R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2CI, -CH(CH3)CH2C1, -CH2CN ,- CH2CH2CN, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, -OCC13, -OCH2CH2F, -OCH2CH2CI, -NHCH3, -NHCH2CH3, - N(CHS)2. -N(CH2CH3)2. and -N(CH3)(CH2CH3). In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2F, -CH2CL -CH2CN, -CH2OH, -OCHs, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, -OCCI3, -NHCH3, and -N(CH3)2.

[0239] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen. -CN. -NH2, -OH. -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, and C1 -C4 cyanoalkyl. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, n- propyl, z-propyl, ethenyl, n-propenyl, z-propenyl, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH3)CH2F, -CH(CH3)CH2C1, -CH2CN,- CH2CH2CN, -CH2CH2CH2CN, and -CH(CH3)CH2CN. In a still further aspect, each of R13a, Ri3b, R13C, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH2F, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH(CH3)CH2C1, - CH2CN, and -CH2CH2CN. In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -CL -NH2, -CN, -OH. -NO2, methyl, -CH2F. - CH2CI, and -CH2CN.

[0240] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen, -CN. C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each of R13a, R13b, R13e, and R13dis independently selected from hydrogen, -F, -Cl, -CH2F, - CH2CI, -CH2CH2F, -CH2CH2CL -CH2CH2CH2F, -CH2CH2CH2CL -CH(CH3)CH2F, - CH(CH3)CH2C1, -CH2CN -CH2CH2CN, -CH2CH2CH2CN, and -CH(CH3)CH2CN. In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -CH2F, -CH2CL -CH2CH2F, -CH2CH2CI, -CH(CH3)CH2C1, -CH2CN, and - CH2CH2CN. In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -CH2F, -CH2CL and -CH2CN.

[0241] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen. -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R13a. R13b. R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, / z-propyl, z-propyl, CH2OH, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -OCH2F. - OCHF2, -OCF3, -OCH2CI, -OCHCh. -OCCI3, -OCH2CH2F. -OCH2CH2CL - OCH2CH2CH2F, -OCH2CH2CH2CI, -OCH(CH3)CH2F, and -OCH(CH3)CH2C1. In a stillfurther aspect, each of Rl3a, R13b, R13c, and R,3dis independently selected from hydrogen, -F, -Cl, -NH2, -CN. -OH, -NO2, methyl, ethyl, ethenyl, -CH2OH. -CH2CH2OH, -OCH3, - OCH2CH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, -OCCh, -OCH2CH2F, and - OCH2CH2CI. In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2OH, -OCH3, - OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, and -OCCh.

[0242] In various aspects, each of R13a, R13b, R13c. and R13dis independently selected from hydrogen, -OH, Cl -C4 hydroxyalkyl, C 1 -C4 haloalkoxy, and Cl -C4 alkoxy. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, - OH, -CH2OH -CH2CH2OH, -CH2CH2CH2OH, -CH(CH3)CH2OH, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)CH3, -0CH2F, -0CHF2, -0CF3. -0CH2CI, -OCHCh, -OCCh, -OCH2CH2F, -OCH2CH2CL -OCH2CH2CH2F, -OCH2CH2CH2CI, -OCH(CH3)CH2F, and - OCH(CH3)CH2C1. In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -OH, -CH2OH, -CH2CH2OH, -OCH3, -OCH2CH3, -OCH2F, - OCHF2, -OCF3, -OCH2CI, -OCHCh. -OCCh, -OCH2CH2F. and -OCH2CH2CI. In yet a further aspect, each of R13a, R13b, R13c. and R13dis independently selected from hydrogen, - OH, -CH2OH, -OCH3, -OCH2F, -OCHF2, -OCF3, -OCH2CI, -OCHCh, and -OCCh.

[0243] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen, -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, - OH, -NO2, methyl, ethyl, n-propyl, z-propyl, ethenyl, w-propenyl, z-propenyl, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH2CH2CH3)2, -N(CH(CH3)CH3)2. and -N(CH3)(CH2CH3). In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, - OH, -NO2, methyl, ethyl, ethenyl, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, and - N(CH3)(CH2CH3). In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NHz, -CN, -OH. -NO2, methyl, -NHCH3, and -N(CH3)2.

[0244] In various aspects, each of R13a, R13b, R13c. and R13dis independently selected from hydrogen, -NH2, -NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyd. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -NH2, -NO2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)CH3)2, and -N(CH3)(CH2CH3). In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected fromhydrogen, -NH2, -NO2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3). In yet a further aspect, each of R13a. R13b, R13c, and R13dis independently selected from hydrogen, -NH2, -NO2, -NHCH3, and -N(CH?)2.

[0245] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2. -CN. -OH, methyl, ethyl, zz-propyl, z-propyl, ethenyl, zz-propenyl, and z-propenyl. In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, and ethenyl. In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, - NH2, -CN. -OH. -NO2, and methyl.

[0246] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen, C 1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, methyl, ethyl, n- propyl, z-propyl, ethenyl, / z-propenyl. and z-propenyl. In a still further aspect, each of R13a, Ri3b, R13c, and R13dis independently selected from hydrogen. -F. -Cl, methyl, ethyl, and ethenyl. In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, and methyl.

[0247] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R13a. R13b, R13c, and R13dis independently selected from hydrogen, methyl, ethyl, n-propyl, z-propyl, ethenyl, / z-propenyl. and z-propenyl. In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen and methyl.

[0248] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen and halogen. In a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, and -Br. In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, and -Cl. In yet a further aspect, each of R13a, R13b, R13c. and R13dis independently selected from hydrogen and -Cl. In an even further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen and -F.

[0249] In various aspects, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen, and C1-C4 alkyl. In a further aspect, each of R13a, R13b, R13c. and R13dis independently selected from hydrogen, -F, -Cl, methyl, ethyl, zz-propyl, and z-propyl.In a still further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, methyl, and ethyl. In yet a further aspect, each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, -F, -Cl, methyl.

[0250] In various aspects, at least one of R13a, R13b, R13c, and R13dis a non-hydrogen group. In a further aspect, at least two of R13a, R13b, R13c, and R13dis a non-hydrogen group. In a still further aspect, at least three of R13a, R13b, R13c, and R13dis a non-hydrogen group. In an even further aspect, each of R13a, R13b, R13e, and R13dis a non-hydrogen group.

[0251] In various aspects, each of R13a, R13b, R13c, and R13dis hydrogen.1. CY1GROUPS

[0252] In one aspect, Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In a further aspect, Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen. -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkyl amino, (C1-C4)(C1-C4) dialkylamino, C 1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In a still further aspect, Cy1is selected from a C4-C7 heterocy cle and a C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy. C 1-C4 alkoxy. C1-C4 alkylamino, (C 1-C4)(C1-C4) dialkylamino, C 1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In yet a further aspect, Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In an even further aspect, Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is unsubstituted.

[0253] In various aspects, Cy1is a C4-C7 heterocycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. Examples of C4-C7 heterocycles include, but are not limited to, thietane, azetidine, oxetane, pyrrolidine, imidazolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, piperazine, thiane, morpholine, and azaindole. In a further aspect, Cy1is a C4-C7 heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl. C2-C4 alkenyl. C1-C4 haloalkyl, Cl- C4 cyanoalkyl, C1 -C4 hydroxyalkyl, C1-C4 haloalkoxy, C1 -C4 alkoxy, C1 -C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd, and an unsubstituted C3-C6 cycloalkyl. In a still further aspect, Cy1is a C4-C7 heterocycle substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd, and an unsubstituted C3-C6 cycloalkyl. In yet a further aspect, Cy1is a C4-C7 heterocycle monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl. C1-C4 haloalkyl, Cl- C4 cyanoalkyl. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In an even further aspect, Cy1is an unsubstituted C4-C7 heterocycle.

[0254] In various aspects, Cy1is an imidazopyridine substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyd, C1-C4 haloalkoxy, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkydamino, C1-C4 aminoalkyd, and an unsubstituted C3-C6 cycloalky l. In a further aspect, Cy1is an imidazopyridine substituted with 0, 1. or 2 groups independently selected from halogen. -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalky l, C 1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkydamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalky l. In a still further aspect, Cy1is an imidazopyridine substituted with 0 or 1 group selected from halogen, -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl. C1-C4 cyanoalkyd. C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalky l. In yet a further aspect, Cy1is an imidazopyridine substituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In an even further aspect, Cy1is an unsubstituted imidacopyridine.

[0255] In various aspects, Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eis hydrogen.

[0256] In various aspects, Cy1is a compound having a structure represented by a formula:

[0257] In various aspects, Cy1is selected from an imidazopyridine and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In a further aspect, Cy1is selected from an imidazopyridine and a C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In a still further aspect, Cy1is selected from an imidazopyridine and a C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In yet a further aspect, Cy1is selected from an imidazopyridine and a C2-C10heteroaryl, and is monosubstituted with a group selected from halogen, -CN, -Nth, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In an even further aspect, Cy1is selected from an imidazopyridine and a C2-C10 heteroaryl, and is unsubstituted.

[0258] In various aspects, Cy1is a C2-C10 heteroaryl substituted with 0, 1. 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C 1 -C4 alkyl, C2-C4 alkenyl, C1-C4 haloalky l, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyd, C1-C4 haloalkoxy, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialky lamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyd. Examples of C2-C10 heteroaryls include, but are not limited to, thiophene, furan, pyrrole, oxazole, isoxazole, isothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, indole, azaindole, purine, benzofuran, quinolone, isoquinoline, and quinoxaline. In a further aspect, Cy1is a C2-C10 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyd. C 1-C4 haloalkoxy. Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd, and an unsubstituted C3-C6 cycloalkyd. In a still further aspect, Cy1is a C2-C10 heteroaryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C 1-C4 aminoalkyd, and an unsubstituted C3-C6 cycloalkyd. In yet a further aspect, Cy1is a C2-C10 heteroaryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyd, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, Cl- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In an even further aspect, Cy1is an unsubstituted C2-C10 heteroaryl.

[0259] In various aspects, Cy1is a pyridinyl substituted with 0, 1. 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkydamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In a further aspect, Cy1is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In a still further aspect, Cy1is a pyridinyl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C 1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl. In yet a further aspect, Cy1is a pyridinyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl. C2-C4 alkenyl. C1-C4 haloalkyl, Cl- C4 cyanoalkyl, C1 -C4 hydroxyalkyl, C1-C4 haloalkoxy, C1 -C4 alkoxy, C1 -C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd, and an unsubstituted C3-C6 cycloalkyl. In an even further aspect, Cy1is an unsubstituted pyridinyl.

[0260] In various aspects, Cy1is a compound having a structure represented by a formula:wherein each of R13a, R13b, R13c, and R13dis independently selected from hydrogen, halogen, -CN. -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R13a, R13b, R13c, and R13dis hydrogen.

[0261] In various aspects, Cy1is a compound having a structure represented by a formula:m. CY2GROUPS

[0262] In one aspect, Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group. In a further aspect, Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is monosubstituted witha C1-C4 alkyl group. In a still further aspect, Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is unsubstituted.

[0263] In various aspects, Cy2is a C3-C6 cycloalkyl substituted with 0 or 1 C1-C4 alkyl group. Examples of C3-C6 cycloalkyls include, but are not limited to, cyclopropyl and cyclobutyl. In a further aspect, Cy2is a C3-C6 cycloalkyl monosubstituted with a C1-C4 alkyl group. In a still further aspect. Cy2is an unsubstituted C3-C6 cycloalkyl.

[0264] In various aspects, Cy2is a C3-C6 heterocycloalkyl substituted with 0 or 1 Cl- C4 alkyl group. Examples of C3-C6 heterocycloalkyls include, but are not limited to, thietane, azetidine, oxetane, pyrrolidine, imidazolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, piperazine, thiane, morpholine, and azaindole. In a further aspect, Cy2is a C3-C6 heterocycloalkyl monosubstituted with a C1-C4 alkyl group. In a still further aspect, Cy2is an unsubstituted C3-C6 heterocycloalkyl.2. EXAMPLE COMPOUNDS

[0265] In one aspect, a compound can be present as one or more of the following structures:or a pharmaceutically acceptable salt thereof.

[0266] In one aspect, a compound can be present as one or more of the following structures:or a pharmaceutically acceptable salt thereof.

[0267] In one aspect, a compound can be present as one or more of the following structures:or a pharmaceutically acceptable salt thereof.

[0268] In one aspect, a compound can be present as one or more of the following structures:or a pharmaceutically acceptable salt thereof.3. PROPHETIC COMPOUND EXAMPLES

[0001] The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be active as inhibitors of a viral infection, and such activity can be determined using the assay methods described herein below.

[0002] In one aspect, a compound can be selected from:or a pharmaceutically acceptable salt thereof.

[0003] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0004] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0005] It is understood that pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses. The pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.C. PHARMACEUTICAL COMPOSITIONS

[0269] In one aspect disclosed are pharmaceutical compositions comprising a disclosed compound, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and CH ; wherein R10is selected from hydrogen and C 1-C4 alkyl; wherein R11is selected from-Nth, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, Cl -C4 alky l, and Cl -C4 haloalkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group: wherein each of R3a. R3b, R3c, R3d. and R3cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise anunsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2- C10 heteroaryl, and is substituted with 0, 1, 2. or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C 1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0. then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0270] In various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl: wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, and C1-C4 alkyl: wherein R2is selected from hydrogen, halogen, -CN. -NH2, C1-C4 alkyl, C1-C4 haloalkyl. -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C 1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis hydrogen, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4- C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0271] In various further aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0272] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, Cl- C4 haloalkoxy. C1-C4 alkoxy. C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C 1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyL C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C 1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

[0273] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0274] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0275] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0276] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g, administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.

[0277] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory7compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory- compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example. Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0278] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity- of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0279] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0280] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid earners are sugar syrup,peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0281] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0282] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0283] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0284] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0285] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability7. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0286] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouthwashes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0287] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0288] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0289] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[0290] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0291] In a further aspect, the pharmaceutical composition is used to treat HAND (e.g., asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV).

[0292] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.D. METHODS OF MAKING A COMPOUND

[0293] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0294] Reactions used to generate the compounds of this invention are prepared byemploying reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-III, as described and exemplified below . The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.1. ROUTE 1

[0295] In one aspect, substituted heteroaryl compounds can be prepared as shown below.SCHEME 1A.

[0296] Compounds are represented in generic form, wherein each of X1and X2is independently a halogen, wherein each of R and R’ is independently selected from hydrogen and C1-C4 alkyl, wherein Ar is a 6-membered heteroaryl containing one or more nitrogen atoms (as further described herein) and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME IB.

[0297] In one aspect, compounds of type 1.10, and similar compounds, can be prepared according to reaction Scheme IB above. Thus, compounds of type 1.8 can be prepared by a coupling reaction between an appropriate heteroaryl halide, e.g., 1.6 as shown above, and an appropriate amine, e.g., 1.7 as shown above. Appropriate heteroaryl halides and appropriate amines are commercially available or prepared by methods known to a person of ordinary skill in the art. The coupling reaction can be carried out in the presence of an appropriate base, e.g., diisopropylethylamine (DIPEA), in an appropriate solvent, e.g., acetonitrile (MeCN), at a suitable temperature, e.g., 80 °C, for an appropriate amount of time, e.g., 5 hours. Compounds of type 1.10 can be prepared by a coupling reaction (e.g. , a Suzukicoupling reaction) between an appropriate organohalide, e.g., 1.8 as shown above, and an appropriate boronic acid, e.g., 1.9 as shown above. Appropriate boronic acids are commercially available or prepared by methods known to person of ordinary skill in the art. The coupling reaction can be carried out in the presence of an appropriate catalyst, e.g., palladium-tetrakis(triphenylphosphine), and an appropriate base, e.g., potassium carbonate, in an appropriate solvent system (e g, 1,4-dioxane and water), at an appropriate temperature, e.g., 120 °C, for an appropriate amount of time, e.g, 48 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1, 1.2, 1.3, and 1.4), can be substituted in the reaction to provide substituted heteroaryl analogs similar to Formula 1.5.2. ROUTE 2

[0298] In one aspect, substituted heteroaryl compounds can be prepared as shown below.SCHEME 2A.

[0299] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.2.4 2.5

[0300] In one aspect compounds of type 2.6, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.5 can be prepared by converting an appropriate carboxylic acid, e.g., 2.4 as shown above, to an appropriate amide, e.g., 2.5 as shown above. Appropriate carboxylic acids are commercially available or prepared by methods known to a person of ordinary skill in the art. The reaction can be carried out in the presence of an appropriate amine, e.g., ammonium hydroxide, an appropriate activating agent, e.g., l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and an appropriate coupling agent, e.g., hydroxybenzotriazole (HOBt), in an appropriate solvent, e.g., dimethylformamide (DMF), at an appropriate temperature, e.g.. 0 °C to room temperature, for an appropriate amount of time, e.g., 16 hours. Compounds of type 2.6 can be prepared by reduction of an appropriate amide, e.g. , 2.5 as shown above. The reduction can be carried out in the presence of an appropriate reducing agent, e.g., borane dimethylsulfide (BMS), in an appropriate solvent, e.g., tetrahydrofuran (THF), at an appropriate temperature, e.g., 0 °C to room temperature, for an appropriate amount of time, e.g., 16 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1 and 2.2), can be substituted in the reaction to provide substituted heteroaryl analogs similar to Formula 2.3.3. ROUTE 3

[0301] In one aspect, substituted heteroaryl compounds can be prepared as shown below.SCHEME 3 A.

[0302] Compounds are represented in generic form, wherein PG is an amine protecting group (e.g, carbobenzyloxy. p-methoxybenzyl carbonyl, t-butyloxy carbonyl, 9- fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzy l, carbamate, p-melhoxy benzyl. 3,4- dimethoxybenzyl, p-methoxyphenyl. tosyl, 4-nitrobenzenesulfonyl) and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below.SCHEME 3B.3.8

[0303] In one aspect, compounds of type 3.8, and similar compounds, can be prepared according to reaction Scheme 3B above. Thus compounds of type 3.7 can be prepared by an alkylation reaction between an appropriate amine, e.g., 3.5 as shown above, and an appropriate alkyl halide, e.g, 3.6 as shown above. Appropriate amines and appropriate alkyl halides are commercially available or prepared by methods known to a person of ordinary skill in the art. The alkylation reaction is carried out in the presence of an appropriate base, e.g., DIPEA, in an appropriate solvent, e.g, acetonitrile, at an appropriate temperature, e.g., 125 °C, for an appropriate period of time, e.g, 3 days. Compounds of type 3.8 can be prepared by deprotection of an appropriate protected amine, e.g, 3.7 as shown above. Thedeprotection can be carried out in the presence of an appropriate acid, e.g., 4-hydroxybenzoic acid, hydrobromic acid, and acetic acid, at an appropriate temperature, e.g, room temperature, for an appropriate period of time, e.g., 4 days. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1, 3.2, and 3.3), can be substituted in the reaction to provide substituted heteroaryl analogs similar to Formula 3.4.E. METHODS OF USING THE COMPOUNDS

[0304] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with dysregulated dopaminergic signaling. To treat or control the disorder, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of HAND (e.g., asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV).

[0305] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of HAND, such as asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV.

[0306] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.1. TREATMENT METHODS

[0307] The compounds disclosed herein are useful for treating or controlling disorders associated with HAND. Thus, provided is a method comprising administering a therapeutically effective amount of a disclosed compound to a subject. In a further aspect, the method can be a method for treating HAND (e.g., asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV). a. TREATING HAND

[0308] In one aspect, disclosed are methods of treating HAND in a subject in need thereof, the method comprising the step of administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof. Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and CH ; wherein R10is selected from hydrogen and C 1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, and C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen. -CN. Cl -C4 alky l, Cl -C4 haloalkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, and C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group: wherein each of R3a. R3b, R3c, R3d. and R3cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2- C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyd. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or apharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0309] In various aspects, the compound has compounds having a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl: wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, and C1-C4 alkyl: wherein R2is selected from hydrogen, halogen, -CN. -NH2, C1-C4 alkyl, C1-C4 haloalkyl. -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C 1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis hydrogen, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4- C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0310] In various further aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0311] In one aspect, disclosed are methods of treating HAND in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:and wherein * denotes a bond connected towherein ** denotes a bond connected towherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NHy C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2. -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C 1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyd; and or a pharmaceutically acceptable salt thereof, provided that when Z is -CH-, then R2is hydrogen, provided that when Q is a structure represented by a formula:then n is 0. and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen.

[0312] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0313] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0314] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0315] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0316] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0317] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0318] In various aspects, the compound has a structure represented by a formula:or a pharmaceutically acceptable salt thereof.

[0319] Examples of HANDs include, but are not limited to, asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV. In a further aspect, the HAND is neuroHIV.

[0320] In a further aspect, the subject has been diagnosed with a need for treatment of HAND prior to the administering step. In a still further aspect, the subject is at risk for developing HAND prior to the administering step.

[0321] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.

[0322] In a further aspect, the method further comprises the step of identifying a subject in need of treatment of HAND.

[0323] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[0324] In a further aspect, the method further comprises the step of administering a therapeutically effective amount of at least one the agent is an antiretroviral agent. In a still further aspect, the antiretroviral agent is a nucleoside / nucleotide reverse transcriptase inhibitor. In yet a further aspect, the nucleoside / nucleotide reverse transcriptase inhibitor is abacavir. emtricitabine, or tenofovir.

[0325] In a further aspect, the at least one compound and the at least one agent are administered sequentially. In a still further aspect, the at least one compound and the at least one agent are administered simultaneously.

[0326] In a further aspect, the at least one compound and the at least one agent are co- formulated. In a still further aspect, the at least one compound and the at least one agent are co-packaged.2. METHODS OF MODIFYING DOPAMINERGIC SIGNALING IN A CELL

[0327] In one aspect, disclosed are methods of modifying dopaminergic signaling in a cell, the method comprising the step of contacting the cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof. Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl: wherein R11is selected from -NH2, C1-C4 alkyl, and C1-C4 alkylamino, and (C1-C4)(C 1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, C1-C4 alkyl, C1-C4 haloalkyl; wherein R2is selected from hydrogen, halogen, -CN. -NH2, C1-C4 alkyl, and C1-C4 haloalkyl, -CO2H, -C(O)NH2. -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen. -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy. C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C 1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2<C1-C4 alky l); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2- C10 heteroaryl, and is substituted with 0, 1. 2. or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalky l, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0. then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0328] Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen. -CN. -NH2, -OH. -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd. -CO2H, and -CC>2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis hydrogen, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4- C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1 -C4 alky lamino, (C1 -C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0329] In various further aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0330] In one aspect, disclosed are methods of modifying dopaminergic signaling in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, Cl- C4 haloalkoxy. C1-C4 alkoxy. C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C 1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C 1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

[0331] In a further aspect, modifying is decreasing. In a still further aspect, modifying is inhibiting.

[0332] In a further aspect, the cell is mammalian. In a still further aspect, the cell is human.

[0333] In a further aspect, the cell has been isolated from a human prior to the administering step.

[0334] In a further aspect, contacting is via administration to a subject. In a still further aspect, the subject has been diagnosed with a need for modification of dopaminergic signaling prior to the administering step. In yet a further aspect, the subject has beendiagnosed with a need for treatment of a disease associated with dysregulated dopaminergic signaling prior to the administering step.3. METHODS OF MODIFYING DOPAMINERGIC SIGNALING IN A SUBJECT

[0335] In one aspect, disclosed are methods of modifying dopaminergic signaling in a subject, the method comprising the step of administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof. Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -Nth, C1-C4 alkyl, and C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkydamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, C1-C4 alky l. C1-C4 haloalkyl; wherein R2is selected from hydrogen, halogen. -CN. -Nth, C1-C4 alky l, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalky l and a C3-C6 heterocycloalky l, and is substituted with 0 or 1 C1-C4 alkyl group: wherein each of R3a, R3b, R3c, R3d. and R3eis independently selected from hydrogen, halogen. -CN, -Nth, -OH. -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy.C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CC>2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2- C10 hcteroaryl. and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino. (Cl- C4)(C1 -C4) dialkylamino, C1 -C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0336] Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and CH ; wherein R10is selected from hydrogen and C 1-C4 alkyl; wherein R11is selected from-NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, and Cl -C4 alkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C 1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3cis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd, -CO2H, and -CO2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis hydrogen, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4- C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalky l. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0,then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0337] In various further aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0338] In one aspect, disclosed are methods of modifying dopaminergic signaling in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:wherein * denotes a bond connected towherein ** denotes a bond connected towherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl. C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, Cl- C4 haloalkoxy. C1-C4 alkoxy. C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C 1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula:then Cy1is a structure represented by a formula:wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2. C1-C4 alkyl. C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C 1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

[0339] In a further aspect, modifying is decreasing. In a still further aspect, modifying is inhibiting.

[0340] In a further aspect, the subject is a mammal. In a still further aspect, the subject is a human.

[0341] In a further aspect, the subject has been diagnosed with a disease associated with dysregulated dopaminergic signaling. In a still further aspect, the disease is a human immunodeficiency virus- (HIV-) associated neurocognitive disorder (HAND). In yet a further aspect, the HAND is selected from asymptomatic neurocognitive impairment (ANI),minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV. In an even further aspect, the HAND is neuroHIV.

[0342] In a further aspect, the subject has been diagnosed with a need for modification of dopaminergic signaling prior to the administering step. In a still further aspect, the subject has been diagnosed with a need for treatment of a disease associated with dysregulated dopaminergic signaling prior to the administering step. In yet a further aspect, the method further comprises the step of identifying a subject in need of treatment of a disease associated with dysregulated dopaminergic signaling.4. USE OF COMPOUNDS

[0343] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of HAND in a subject.

[0344] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0345] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[0346] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0347] In various aspects, the use relates to a treatment of HAND in a subject. Also disclosed is the use of a compound for antagonism or inhibition of HAND. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that HAND is neuroHIV.

[0348] In a further aspect, the use relates to the manufacture of a medicament for the treatment of HAND in a subject.

[0349] In a further aspect, the use relates to modification of dopaminergic signaling in a subject. In a further aspect, the use relates to modification of dopaminergic signaling in a cell. In yet a further aspect, the subject is a human.

[0350] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of HAND in a mammal. In a further aspect, the HAND is selected from asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV.5. MANUFACTURE OF A MEDICAMENT

[0351] In one aspect, the invention relates to a method for the manufacture of a medicament for treating HAND in a subject in need thereof, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[0352] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of HAND. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time- frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[0353] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg / kg and about 1000 mg / kg of body weight for mice, and between about 100 mg / kg and about 500 mg / kg of body weight, and more preferably between 200 mg / kg and about 400 mg / kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[0354] The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desiredphysiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[0355] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.6. KITS

[0356] In one aspect, disclosed are kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of HAND; (b) instructions for administering the compound in connection with treating a condition associated with dysregulated dopaminergic signaling; and (c) instructions for treating a condition associated with dysregulated dopaminergic signaling. Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from-NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 haloalkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group: wherein each of R3a. R3b, R3c, R3d. and R3eis independently selected from hydrogen, halogen. -CN, -NH2, -OH. -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C 1 -C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CO2H, and -CO2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2- C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (Cl- C4)(C1-C4) dialkylamino. C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0. and provided that the compound is not:

[0357] Thus, in various aspects, the compound has a structure represented by a formula selected from:wherein n is 0 or 1 ; wherein Q is a structure represented by a formula selected from:wherein ** denotes a bond connected to -(CR4aR4b)n-; wherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, -CN, -NH2, C1-C4 alkyl, C1-C4 haloalkyl, -CO2H, -C(O)NH2, -C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen. -CN. -NH2, -OH. -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxy alkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyd. -CO2H, and -CC>2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis hydrogen, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4- C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl. C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1 -C4 alky lamino, (C1 -C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula:then n is 0, and provided that the compound is not:

[0358] In various further aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0359] In one aspect, kits comprising a compound having a structure represented by a formula:wherein Q is a structure represented by a formula selected from:and wherein * denotes a bond connected towherein ** denotes a bond connected towherein Z is selected from -N- and -CH-; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from -NHy C1-C4 alkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, -CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2. -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C 1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyd; and or a pharmaceutically acceptable salt thereof, provided that when Z is -CH-, then R2is hydrogen, provided that when Q is a structure represented by a formula:then n is 0. and provided that when Q is a structure represented by a formula:then R1is selected from -CN and C1-C4 alkyl and R2is hydrogen, and one or more selected from: (a) an agent associated with the treatment of a HAND; (b) instructions for administering the compound in connection with treating a condition associated wi th dysregulated dopaminergic signaling; and (c) instructions for treating a condition associated with dysregulated dopaminergic signaling.

[0360] In a further aspect, the HAND is selected from asymptomatic neurocognitive impairment (ANI). minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV. In a still further aspect, the HAND is neuroHIV.

[0361] In a further aspect, the agent is an antiretroviral agent. In a still further aspect, the antiretroviral agent is a nucleoside / nucleotide reverse transcriptase inhibitor. In yet a further aspect, the nucleoside / nucleotide reverse transcriptase inhibitor is abacavir. emtricitabine, or tenofovir.

[0362] In a further aspect, the at least one compound and the at least one agent are co- formulated. In a further aspect, the at least one compound and the at least one agent are co- packaged.

[0363] The kits can also comprise compounds and / or products co-packaged, co- formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery' to a patient.

[0364] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.

[0365] The foregoing description illustrates and describes the disclosure.Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in theart to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0366] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls.F. EXAMPLES

[0367] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g, amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0368] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way.1. CHEMISTRY EXPERIMENTALS a. GENERAL EXPERIMENTAL METHODS

[0369] The reactions were performed under argon atmosphere and reaction temperatures were measured externally. Anhydrous solvents were obtained from Aldrich and used as received. Microwave (MW) reactions were performed in an Initiator+ equipped with Robot Eight microwave system. The reactions were monitored by thin-layer chromatography (TLC) on pre-coated silica gel (6OF254) glass plates from E. Merck and visualized using UV light (254 nm). Purification of compounds was carried out by flash chromatography using Combiflash® Rf with Teledyne ISCO Rf columns, or Biotage columns. Pure samples were dried overnight under high vacuum before analyses. The high-resolution electrospray ionization mass spectral data (HRMS) were obtained on an Agilent LC-MS TOF. 'HNMR spectra were recorded at 400 MHz on Agilent / Varian MR-400 spectrometer in CDCh or DMSO-Je, as solvents. The chemical shifts (5) are in ppm downfield from standard tetramethylsilane (TMS), referenced to 0.00 pm (5). All final compounds with reported biological data had purity > 95%, which was determined by analytical HPLC performed on an Agilent 1100 LC equipped with a diode array UV detector and monitored at 254 nm. b. PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 4A-Ei. SYNTHESIS OF 7-METHYL-6-(4-METHYL-6-(4-PHENYLPIPERIDIN- l-YL)PYRIMIDIN-2-YLIMIDAZO [1,2-A] PYRIDINE (4 A)

[0370] Preparation of 2-Chl-phenylpiperidin-1-yl)pyrimidine (3a).To a mixture of 2,4-dichloro-6-methyl-pyrimidine 1 (500 mg, 3.1 mmol, 1 eq) and 4- Phenylpiperidine 2 (494.6 mg, 3.1 mmol, 1 eq) in acetonitrile (15 mL) was added N, N- diisopropylethylamine (DIPEA, 1.6 mL, 9.3 mmol, 3 eq). The reaction was stirred at 100 °C for 18 h, then concentrated in vacuo to afford a crude residue, which was purified by flash chromatography (10 g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 3 (655 mg, 74.2% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 7.34 – 7.21 (m, 4H), 7.24 – 7.14 (m, 1H), 6.78 (s, 1H), 4.48 (s, 2H), 3.00 (t, J = 12.8 Hz, 2H), 2.85 (tt, J = 12.0, 3.6 Hz, 1H), 2.24 (s, 3H), 1.91 – 1.80 (m, 2H), 1.57 (qd, J = 12.6, 4.0 Hz, 2H).

[0371] Preparation of Compound 4a. 2-Chloro-4-methyl-6-(4-phenyl-1-piperidyl)pyrimidine 3 (100 mg, 0.35 mmol, 1 eq), potassium carbonate (K2CO3, 144 mg, 1.04 mmol, 3 eq), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 80.3 mg, 0.07 mmol, 0.2 eq), commercially available 7-methylimidazo[1,2-a]pyridine-6-boronic acid (122.3 mg, 0.69 mmol, 2 eq) were added to a pressure vial and purged with argon. The reactants were dissolved in 1,4-dioxane (0.9 mL) and water (0.9 mL), and the mixture was stirred at 120 °C for 18 h. On completion, the reaction was diluted with EtOAc (5 mL) and filtered through a pad of silica gel. The filtrate was concentrated in vacuo and the resulting crude residue was purified by flash chromatography (24 g silica column, 0-5% methanol in dichloromethane) to provide 4a (18.8 mg, 13.4% yield) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 7.99 (s, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.34 – 7.23 (m, 4H), 7.23 – 7.15 (m, 1H), 6.76 (s, 1H), 4.63 (d, J = 13.1 Hz, 2H), 3.08 – 2.97 (m, 2H), 2.87 (td, J = 10.3, 8.6, 5.9 Hz, 1H), 2.61 – 2.56 (m, 3H), 2.35 (s, 3H), 1.88 (d, J = 12.6 Hz, 2H), 1.61 (qd, J = 12.5, 4.0 Hz, 2H). HRMS m / z calc for C24H25N5.H 384.2188, found 384.2190. HPLC purity: 95.7% at 254 nm. ii. SYNTHESIS OF 5-(4-METHYL-6-(4-PHENYLPIPERIDIN-1-YL)PYRIMIDIN-2-YL)PYRIDIN-2-AMINE (4B)F3

[0372] Compound 4b washloro-4-methyl-6-(4-phenyl-1-piperidyl)pyrimidine 3 (150 mg, 0.52 mmol), commercially available 2- trifluoromethylpyridine-5-boronic acid (119.4 mg, 0.63 mmol), K2CO3 (216 mg, 1.56 mmol) and Pd(PPh3)4(120.4 mg, 0.1 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) according to the procedure described for the preparation of 4a to afford a crude residue, which was purified by flash chromatography (10g silica column, 0-10% ethyl acetate in hexanes, gradient elution) to provide 4b (196.8 mg, 93.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.59 (d, J = 2.1 Hz, 1H), 8.86 (dd, J = 8.2, 2.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.35 – 7.23 (m, 4H), 7.23 – 7.14 (m, 1H), 6.85 (s, 1H), 4.71 (s, 2H), 3.05 (td, J = 13.0, 2.6 Hz, 2H), 2.88 (tt, J = 12.2, 3.6 Hz, 1H), 2.39 (s, 3H), 1.95 – 1.85 (m, 2H), 1.63 (qd, J = 12.6, 4.0 Hz, 2H).19F NMR (376 MHz, DMSO- d6) δ -73.51 (s, 3F). HRMS m / z calc forC22H21F3N4.H 399.1797, found 399.1798. HPLC purity: 98.8% @ 254 nm.c. PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 11A AND 11B[003anoicacid 5 (5 g, 30.4 mmol, 1 eq) in DMF (15 mL) was added 1-Hydroxybenzotriazole (HOBT) (4.9 g, 36.5 mmol, 1.1 eq) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.6 g, 39.6 mmol, 1.2 eq) under argon. The mixture was cooled to 0 °C and 28% aqueous ammonium hydroxide (50.8 mL, 365.4 mmol, 110 eq) was added. The reaction was warmed to room temperature and stirred for 16 h. After completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 100 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude residue, which was purified by flash chromatography (40g silica column, 0-50% ethyl acetate in hexanes, gradient elution) to provide 6 (2.45 g, 49.3% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.37 – 7.24 (m, 5H), 5.47 (d, J = 75.8 Hz, 2H), 3.28 (dd, J = 8.2, 7.0 Hz, 1H), 2.23 – 2.11 (m, 1H), 1.80 (ddq, J = 13.7, 8.3, 7.4 Hz, 1H), 0.89 (t, J = 7.4 Hz, 3H).

[0374] Preparation of 2-Phenylbutan-1-amine (7). To a stirred solution of 2-phenylbutanamide 6 (2.5 g, 15.01 mmol, 1 eq) in anhydrous THF (35 mL) under argon was added borane dimethylsulfide (16.5 mL, 33 mmol, 2.2 eq) dropwise for 15 min at 0 °C, then warmed to room temperature, stirred for 15 min, and refluxed for 20 h. On completion, the reaction was cooled to 0 °C, quenched with cold MeOH (5 mL), and the pH was adjusted to ~2 using 1N HCl. The solvent was removed in vacuo. The pH of the residue was basified using saturated NaHCO3 solution and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 2-phenylbutan-1-amine (2 g, 89.3% yield) as a colorless oil. The crude material was used without purification for the next step.1H NMR (400 MHz, DMSO-d6) δ 7.32 – 7.27 (m, 2H), 7.21 – 7.15 (m, 3H), 2.77 – 2.65 (m, 2H), 2.43 (dtd, J = 9.5, 6.9, 4.9 Hz, 1H), 1.74 (dqd, J = 13.5, 7.4, 5.0 Hz, 1H), 1.45 (ddq, J = 13.4, 9.6, 7.4 Hz, 1H), 0.71 (t, J = 7.4 Hz, 3H). i. SYNTHESIS OF 2-(7-METHYLIMIDAZO[1,2-A]PYRIDIN-6-YL)-N-(2-PHENYLBUTYL)PYRIMIDIN-4-AMINE (11A)

[0375] Preparation of 2-o o- - -p eny u y )pyrimidin-4-amine (9a). A mixtureof 2,4-dichloropyrimidine 8a (0.5 g, 3.4 mmol), 2-phenylbutan-1-amine 7 (551 mg, 3.7 mmol), and DIPEA (0.6 mL, 3.7 mmol) was taken in anhydrous acetonitrile (3 mL) and stirred at room temperature under argon for 18 h. The reaction mixture was evaporated to afford a crude residue, which was purified by flash chromatography (12g silica column, 0- 50% ethyl acetate in hexanes, gradient elution) to provide 9a (0.51 g, 58% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.40 – 7.03 (m, 5H), 6.13 (s, 1H), 3.38 (s, 2H), 2.74 (tt, J = 9.6, 5.4 Hz, 1H), 1.86 – 1.57 (m, 3H), 0.85 (t, J = 7.4 Hz, 3H).

[0376] Preparation of Compound 11a. Compound 11a was prepared from 2-chloro-N-(2-phenylbutyl)pyrimidin-4-amine 9a (100 mg, 0.38 mmol), 7-methylimidazo[1,2- a]pyridine-6-boronic acid 10 (134.4 mg, 0.76 mmol), K2CO3 (158 mg, 1.15 mmol), Pd(PPh3)4 (44.1 mg, 0.04 mmol) according to the procedure described for the preparation of 4a to afford a crude residue, which was purified on preparative HPLC (C18 column, 0-100% MeCN + 0.1% TFA in H2O + 0.1% TFA, gradient elution). The desired fractions were collected and acetonitrile was removed in vacuo. The aqueous layer was neutralized with saturated aqueous NaHCO3and extracted with EtOAc (3 × 25 mL). The combined organic layers were further washed with saturated aqueous NaHCO3 and brine, then dried over anhydrous MgSO4, filtered and concentrated to provide 11a (27.3 mg, 19.8% yield) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.61 – 7.35 (m, 3H), 7.35 – 7.14 (m, 5H), 6.41 (d, J = 6.0 Hz, 1H), 3.58 (d, J = 33.0 Hz, 2H), 2.89 – 2.75 (m, 1H), 2.59 (s, 3H), 1.80 (ddd, J = 12.8, 7.5, 5.1 Hz, 1H), 1.57 (ddq, J = 14.4, 9.8, 7.3 Hz, 1H), 0.74 (t, J = 7.3 Hz, 3H). HRMS m / z calcd for C22H23N5.H 358.2026, found 358.2023. HPLC purity: 99.1% @ 254 nm. ii. SYNTHESIS OF 6-METHYL-2-(7-METHYLIMIDAZO[1,2-A]PYRIDIN-6-YL)-N-(2-PHENYLBUTYL)PYRIMIDIN-4-AMINE (11B)

[0377] Preparation of 2-Chloro-6-methyl-N-(2-phenylbutyl)pyrimidin-4-amine (9b).Intermediate 9b was prepared from 2,4-dichloro-6-methyl-pyrimidine 1 (0.5 g, 3.1 mmol), 2- phenylbutan-1-amine 7 (503.5 mg, 3.4 mmol) and DIPEA (0.59 mL, 3.4 mmol) in anhydrous acetonitrile (3 mL) according to the procedure described for the preparation of 9a to afford a crude residue, which was purified by flash column chromatography (12g silica column, 0- 50% ethyl acetate in hexanes, gradient elution) to provide 9b (0.4 g, 1.5 mmol, 48.5% yield) as a yellow oil. LCMS m / z 275.9 [M]+

[0378] Preparation of Compound 11b. Compound 11b was prepared from 2-chloro-6-methyl-N-(2-phenylbutyl)pyrimidin-4-amine 9b (100 mg, 0.36 mmol), 7- methylimidazo[1,2-a]pyridine-6-boronic acid 10 (127.6 mg, 0.73 mmol), K2CO3 (150.3 mg, 1.1 mmol) and Pd(PPh3)4(83.8 mg, 0.07 mmol) in 1,4-dioxane (4 mL) and water (1 mL) according to the procedure described for the preparation of 4a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-5% methanol indichloromethane) to provide 11b (40.5 mg, 29.6% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ 8.91 (s, 1H), 7.97 (s, 1H), 7.52 (d, J = 1.2 Hz, 1H), 7.44 – 7.06 (m, 7H), 6.25 (s, 1H), 3.56 (d, J = 33.4 Hz, 1H), 2.81 (dq, J = 11.9, 7.0 Hz, 1H), 2.58 (s, 3H), 2.25 (s, 3H), 1.79 (ddd, J = 12.9, 7.6, 5.2 Hz, 1H), 1.56 (ddt, J = 17.1, 14.6, 7.5 Hz, 1H), 0.73 (t, J = 7.3 Hz, 3H). HRMS m / z calc for C23H25N5.H 372.2178, found 372.2180. HPLC purity: 98.6% @ 254 nm. d. PROCEDURE FOR THE SYNTHESIS OF COMPOUND 14

[003] reparat on of -( - oro- -met y pyr m n- -y )- , - met y -2-phenylpropane-1,2-diamine (13). Intermediate 13 was prepared from 2,4-dichloro-6-methyl- pyrimidine 1 (163 mg, 1 mmol), commercially available N2, N2-dimethyl-2-phenyl-propane- 1,2-diamine 12 (196 mg, 1.1 mmol), and DIPEA (0.38 mL, 2.2 mmol) in anhydrous acetonitrile (5 mL) according to the procedure described for the preparation of 9a to afford a crude residue, which was purified by flash column chromatography (12 g silica column, 0- 50% ethyl acetate in hexanes, gradient elution) to provide 13 (159 mg, 52.2% yield) as a light yellow sticky oil.1H NMR (400 MHz, DMSO-d6) δ 7.50 – 7.47 (m, 2H), 7.27 (dd, J = 8.4, 6.9 Hz, 2H), 7.22 (d, J = 5.5 Hz, 1H), 7.20 – 7.15 (m, 1H), 6.42 (s, 1H), 3.68 – 3.57 (m, 1H), 3.52 (d, J = 13.2 Hz, 1H), 2.12 (s, 6H), 2.10 (s, 3H), 1.34 (s, 3H).

[0380] Preparation of N2,N2-Dimethyl-N1-(6-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)-2-phenylpropane-1,2-diamine (14). Compound 14 was prepared from N1-(2-chloro-6-methyl-pyrimidin-4-yl)-N2,N2-dimethyl-2-phenyl-propane-1,2-diamine 13 (61 mg, 0.2 mmol), 2-trifluoromethylpyridine-5-boronic acid (76.4 mg, 0.4 mmol), Pd(PPh3)4(46.4 mg, 0.04 mmol) and K2CO3 (82.9 mg, 0.6 mmol) in 1,4-Dioxane (2 mL) and water (0.5 mL) at 110 °C for 48 h according to the procedure described for the preparation of 4a to afford a crude residue, which was purified first by flash chromatography (4 g silica column, 0-30% ethyl acetate in dichloromethane, gradient elution), then by preparative TLC (silica, 10:1 DCM:EtOAc, isocratic, 2 elutions) to provide 14 (20 mg, 23.8% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.47 (d, J = 1.9 Hz, 1H), 8.74 (d, J = 8.3 Hz, 1H), 7.99 (dd, J = 8.2, 0.9 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 1H), 7.03 (s, 1H), 6.46 (s, 1H), 3.91 (s, 1H), 3.69 (s, 1H), 2.24 (s, 3H), 2.17 (s, 6H), 1.38 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -66.34 (s, 3F). HRMS m / z calc for C22H24F3N5.H 416.2062, found 416.2064. HPLC purity: 98.7% @ 254 nm e. PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 17A-Ei. SYNTHESIS OF 7-METHYL-6-(4-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRIMIDIN-2-YL)IMIDAZO[1,2- A]PYRIDINE (17A)N

[0381] Preparation of 2-C1-phenylethyl)piperazin-1-yl]pyrimidine (16a). 2,4-dichloro-6-methyl-pyrimidine 1 (500 mg, 3.06 mmol, 1 eq), 1-[1- phenylethyl]piperazine (642.1 mg, 3.37 mmol, 1.1 eq), DIPEA (1.6 mL, 9.20 mmol, 3 eq) in anhydrous THF (10 mL) were refluxed together under argon for 5 h, then stirred at room temperature for 12 h. On completion, the reaction mixture was concentrated under reduced pressure to afford a crude residue, which was purified by flash chromatography (24 g gold silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 16a (0.59 g, 60% yield) as a colorless syrup.1H NMR (400 MHz, CDCl3) δ 7.63 – 6.70 (m, 5H), 6.18 (s, 1H), 3.62 (s, 4H), 3.43 (s, 1H), 2.46-2.54 (d, 4H), 2.30 (s, 1H), 1.40 (m, 3H). LCMS m / z 317.10 (M + H)+.

[0382] Preparation of Compound 17a. To a microwave vial, 2-chloro-4-methyl-6-(4-(1-phenylethyl)piperazin-1-yl)pyrimidine 16a (320 mg, 1.01 mmol, 1 eq), 7- methylimidazo[1,2-a]pyridine-6-boronic acid (444.3 mg, 2.52 mmol, 2.5 eq), Pd(PPh3)4 (233.4 mg, 0.20 mmol, 0.2 eq) and K2CO3(418.8 mg, 3.03 mmol, 3 eq) were added under argon followed by 1,4-dioxane (8.1 mL) and water (2.0 mL). The tube was degassed and filled with argon for 3 cycles. The vial was sealed and the reaction mixture was stirred at 120 °C for 48 h under microwave conditions. The reaction mixture was then filtered through a Celite pad, washed with 40% methanol in dichloromethane solution (4 × 15 mL), and the filtrate was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford a crude residue, which was purified by flash chromatography (24 g gold silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 17a (96 mg, 22% yield) as an off-white solid.1H NMR (400 MHz, DMSO- d6) δ 8.96 (d, J = 3.1 Hz, 1H), 7.97 (d, J = 3.1 Hz, 1H), 7.55 – 7.41 (m, 1H), 7.36 – 7.30 (m, 6H), 7.25 (s, 1H), 3.64 (s, 4H), 3.47 (d, J = 7.3 Hz, 1H), 2.54 (d, J = 3.1 Hz, 3H), 2.49 (s, 2H), 2.39 (s, 2H), 2.33 (d, J = 3.2 Hz, 3H), 1.33 (d, J = 6.4 Hz, 3H). LCMS m / z 413.2 (M + H)+. HRMS m / z calc for C25H28N6.H, 413.2454, found, 413.2457; HPLC purity: 99.6 % at 254 nm.ii. SYNTHESIS OF 6-(4-(4-(1-(3-METHOXYPHENYL)ETHYL)PIPERAZIN-1-YL)-6- METHYLPYRIMIDIN-2-YL)-7-METHYLIMIDAZO[1,2-A]PYRIDINE (17B) OMe N

[0383] Preparation of 2-Coxyphenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine (16b). Intermediate 16b was prepared from 2,4-dichloro-6-methyl- pyrimidine 1 (165 mg, 1.01 mmol), 1-[1-(3-methoxyphenyl)ethyl]piperazine (245.3 mg, 1.11 mmol), DIPEA (0.53 mL, 3.04 mmol) in anhydrous acetonitrile (2 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g gold silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 16b (0.209 g, 59% yield) as a colorless syrup.1H NMR (400 MHz, DMSO-d6) δ 7.24 (t, J = 7.8 Hz, 1H), 6.91 – 6.84 (m, 2H), 6.81 (dd, J = 8.1, 2.6 Hz, 1H), 6.67 (s, 1H), 3.74 (s, 3H), 3.57 (s, 4H), 3.42 (q, J = 6.7 Hz, 1H), 2.44 (dt, J = 10.8, 5.1 Hz, 2H), 2.35 (dt, J = 11.0, 5.0 Hz, 2H), 2.21 (s, 3H), 1.30 (d, J = 6.7 Hz, 3H). LCMS m / z 347.0 (M + H)+.

[0384] Preparation of Compound 17b. Compound 17b was prepared from 2-chloro-4-[4-[1-(3-methoxyphenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine 1.2 (200 mg, 0.58 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid (202.9 mg, 1.15 mmol), Pd(PPh3)4 (266.5 mg, 0.23 mmol) and K2CO3(398.5 mg, 2.88 mmol) in 1, 4-dioxane (4.6 mL) and water (1.2 mL) according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0-5% methanol indichloromethane, gradient elution) to provide 17b (17.5 mg, 6.6 % yield) as an off-whitesolid.1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.98 (t, J = 1.0 Hz, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.40 (q, J = 0.9 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 6.93 – 6.87 (m, 2H), 6.82 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.65 (s, 1H), 3.75 (s, 3H), 3.65 (s, 4H), 3.43 (t, J = 6.7 Hz, 1H), 2.55 (d, J = 1.1 Hz, 3H), 2.49 (d, J = 7.8 Hz, 2H), 2.40 (dt, J = 11.0, 5.1 Hz, 2H), 2.34 (s, 3H), 1.32 (d, J = 6.7 Hz, 3H). LCMS m / z 442.90 (M + H)+. HRMS m / z calc for C26H30N60.H, 443.2559, found, 443.2556; HPLC purity: 97.4 % at 254 nm. iii. SYNTHESIS OF 6-[4-[4-[1-(4-FLUOROPHENYL)ETHYL]PIPERAZIN-1-YL]-6-METHYL-PYRIMIDIN-2-YL]-7-METHYL-IMIDAZO[1,2- A]PYRIDINE (17C) F N

[0385] Preparation of 2-Chloro-4-[4-[1-(4-fluorophenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine (16c). Intermediate 16c was prepared from 2,4-dichloro-6-methyl- pyrimidine 1 (313 mg, 1.92 mmol), 1-[1-(4-fluorophenyl)ethyl]piperazine (440 mg, 2.11 mmol), DIPEA (1.0 mL, 5.76 mmol) in anhydrous acetonitrile (5 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 16c (0.18 g, 27% yield) as a colorless syrup.1H NMR (400 MHz, DMSO- d6) δ 7.39 – 7.31 (m, 2H), 7.15 (t, J = 8.7 Hz, 2H), 6.67 (s, 1H), 3.63 – 3.45 (m, 5H), 2.46 – 2.38 (m, 2H), 2.33 (q, J = 6.1, 5.6 Hz, 2H), 2.21 (s, 3H), 1.30 (d, J = 6.7 Hz, 3H);19F NMR (376 MHz, DMSO- d6) δ -116.04 (s, 1F). LCMS m / z 335.10 (M + H)+.

[0386] Preparation of Compound 17c. Compound 17c was prepared from 2-chloro-4-[4-[1-(4-fluorophenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine 16c (180 mg, 0.54 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid (189.2 mg, 1.08 mmol), Pd(PPh3)4 (124.2 mg, 0.11 mmol) and K2CO3(222.9 mg, 1.61 mmol) in 1,4-dioxane (4.3 mL) and water (1.0 mL) according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (24 g gold silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 17c (65 mg, 27 % yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.96 (s, 1H), 7.51 (s, 1H), 7.37 (dd, J =13.0, 5.8 Hz, 3H), 7.15 (t, J = 8.7 Hz, 2H), 6.64 (s, 1H), 3.63 (s, 4H), 3.50 (d, J =6.7 Hz, 1H), 2.54 (s, 3H), 2.46 (d, J = 6.4 Hz, 2H), 2.37 (d, J = 10.2 Hz, 2H), 2.33 (s, 3H), 1.31 (d, J = 6.6 Hz, 3H);19F NMR (376 MHz, DMSO- d6) δ -116.06 (s, 1F). LCMS m / z 431.9 (M + H)+. HRMS m / z calc for C25H27FN6.H, 431.2359, found, 431.2357; HPLC purity: 97.4 % at 254 nm. iv. SYNTHESIS OF 4-(1-(4-(6-METHYL-2-(7-METHYLIMIDAZO[1,2-A]PYRIDIN-6-YL)PYRIMIDIN-4-YL)PIPERAZIN-1- YL)ETHYL)BENZONITRILE (17D) NC N

[0387] Preparation of 4-[1-[4-(2-Chloro-6-methyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]benzonitrile (16d). Intermediate 16d was prepared from 2,4-dichloro-6-methyl- pyrimidine 1 (172 mg, 1.05 mmol), 4-[1-(piperazin-1-yl)ethyl]benzonitrile (249.9 mg, 1.16 mmol), DIPEA (0.55 mL, 3.16 mmol) in anhydrous acetonitrile (2 mL) according to the procedure escribed for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 16d (0.225 g, 62% yield) as a colorless syrup.1H NMR (400 MHz, DMSO-d6) δ 7.84 – 7.77 (m, 2H), 7.57 – 7.51 (m, 2H), 6.68 (s, 1H), 3.58 (q, J = 5.3, 4.0 Hz, 5H), 2.47 (d, J = 19.5 Hz, 2H), 2.32 (dd, J = 11.2, 5.4 Hz, 2H), 2.22 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H). LCMS m / z 342.10 (M + H)+.

[0388] Preparation of Compound 17d. Compound 17d was prepared from 4-[1-[4-(2-chloro-6-methyl-pyrimidin-4-yl)piperazin-1-yl]ethyl]benzonitrile 16d (220 mg, 0.64 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid (226.5 mg, 1.28 mmol), Pd(PPh3)4 (297.4 mg, 0.26 mmol) and K2CO3(444.7 mg, 3.22 mmol) in 1,4-dioxane (5.2 mL) and water (1.2 mL) according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (24 g gold silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 17d (10.5 mg, 3.6% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.97 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 1.2 Hz, 1H), 7.40 (s, 1H), 6.66 (s, 1H), 3.62 (d, J = 22.2 Hz, 5H), 2.56 – 2.53 (m, 3H), 2.42 – 2.35 (m, 1H), 2.33 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). LCMS m / z 438.0 (M + H)+. HRMS m / z calc for C26H27N7.H, 438.2406, found, 438.2398; HPLC purity: 97.4 % at 254 nm. v. SYNTHESIS OF 6-(4-(4-(1-(2,4-DIFLUOROPHENYL)ETHYL)PIPERAZIN-1-YL)-6- METHYLPYRIMIDIN-2-YL)-7-METHYLIMIDAZO[1,2-A]PYRIDINE (17E)F F N

[0389] Preparation of 2orophenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine (16e). Intermediate 16e was prepared from 2,4-dichloro-6-methyl- pyrimidine 1 (161 mg, 1.01 mmol), 1-[1-(2,4-difluorophenyl)ethyl]piperazine (245.8 mg, 1.1 mmol), DIPEA (0.52 mL, 3.04mmol) in anhydrous acetonitrile (2 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 16e (0.215 g, 61% yield) as a colorless syrup.1H NMR (400 MHz, DMSO-d6) δ 7.49 (td, J = 8.5, 6.8 Hz, 1H), 7.19 (ddd, J = 10.9, 9.4, 2.6 Hz, 1H), 7.08 (td, J = 8.6, 2.6 Hz, 1H), 6.68 (d, J = 1.0 Hz, 1H), 3.84 (q, J = 6.9 Hz, 1H), 3.57 (s, 4H), 2.40 (dtd, J = 16.6, 11.2, 5.1 Hz, 4H), 2.22 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H). LCMS m / z 353.0 (M + H)+.

[0390] Preparation of Compound 17e. Compound 17e was prepared from 2-chloro-4-[4-[1-( 2,4-difluorophenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine 16e (215 mg, 0.61 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid (214.5 mg, 1.22 mmol), Pd(PPh3)4 (281.6 mg, 0.24 mmol) and K2CO3(421.1 mg, 3.05 mmol) in 1,4-dioxane (4.8 mL) and water (1.2 mL) according to the procedure described for the preparation of 17a to afford a crude residue which was purified by flash chromatography (24 g silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 17e (15 mg, 5.3% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.96 (t, J = 1.0 Hz, 1H), 7.50 (dd, J = 8.0, 1.5 Hz, 2H), 7.39 (q, J = 1.0 Hz, 1H), 7.19 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.08 (td, J = 8.3, 2.4 Hz, 1H), 6.64 (s, 1H), 3.84 (q, J = 6.8 Hz, 1H), 3.64 (s, 4H), 2.53 (d, J = 1.1 Hz, 3H), 2.49 – 2.36 (m, 4H), 2.32 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). LCMS m / z 448.90 (M + H)+. HRMS m / z calc for C25H26F2N6.H, 443.2559, found, 443.2556; HPLC purity: 97.9 % at 254 nm. vi. SYNTHESIS OF 7-METHYL-6-(4-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRIMIDIN-2-YL)IMIDAZO[1,2-A]PYRIDINE (17F)N

[0391] Preparation of 2-Cthyl)piperazin-1-yl)pyrimidine (16f).Intermediate 16f was prepared from 2,4-dichloropyrimidine 8a (148.9 mg, 1.0 mmol), commercially available 1-(1-phenyl)ethyl)piperazine dihydrochloride 15a (289.5 mg, 1.1 mmol), DIPEA (0.7 mL, 4 mmol) in anhydrous acetonitrile (5 mL) at room temperature for 18 h according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 16f (190 mg, 62.7% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 6.2 Hz, 1H), 7.30 (d, J = 19.3 Hz, 5H), 6.33 (d, J = 6.2 Hz, 1H), 3.63 (s, 4H), 3.43 (s, 1H), 2.54 (s, 4H), 1.40 (s, 3H).

[0392] Preparation of Compound 17f. Compound 17f was prepared from 2-chloro-4-(4-(1-phenylethyl)piperazin-1-yl)pyrimidine 16f (75.7 mg, 0.25 mmol), 7- methylimidazo[1,2-a]pyridine-6-boronic acid 10 (74.8 mg, 0.42 mmol), Pd(PPh3)4(57.9 mg, 0.05 mmol) and K2CO3 (103.6 mg, 0.75 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) at 120 °C for 5 h under microwave conditions according to the procedure described for the preparation of 17a to afford a crude residue which was purified by flash chromatography (4 g silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 17f (16 mg, 15.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 0.8 Hz, 1H), 8.30 (d, J = 6.2 Hz, 1H), 7.98 (dd, J = 1.3, 0.8 Hz, 1H), 7.57 (d, J = 1.3 Hz, 1H), 7.43 (d, J = 1.0 Hz, 1H), 7.34 (d, J = 4.4 Hz, 4H), 7.26 (dt, J = 8.7, 4.1 Hz, 1H), 6.77 (d, J = 6.2 Hz, 1H), 3.67 (s, 4H), 3.53 (s, 1H), 2.56 (d, J = 1.1 Hz, 5H), 2.44 (s, 2H), 1.35 (d, J = 6.7 Hz, 3H). HRMS m / z calcd for C24H26N6.H 399.2292, found 399.2294. HPLC purity: 99.4% @ 254 nm. vii. SYNTHESIS OF 7-METHYL-6-[4-[4-(1-PHENYLETHYL)PIPERAZIN-1-YL]-6-(TRIFLUOROMETHYL)PYRIMIDIN-2-YL]IMIDAZO[1,2- A]PYRIDINE (17G)

[0393] Preparation of 2-chthyl)piperazin-1-yl]-6-(trifluoromethyl)pyrimidine 16g. Intermediate 16g was prepared from 1-(1- phenylethyl)piperazine 15a (578.78 mg, 3.04 mmol), 2,4-Dichloro-6- (trifluoromethyl)pyrimidine 8c (0.37 mL, 2.77 mmol) and N, N-Diisopropylethylamine (1.45 mL, 8.3 mmol) in anhydrous acetonitrile (5mL) refluxing at 80 °C for 5 h to afford a crude residue, which was purified by flash chromatography (24 g gold silica column, 0-20% ethyl acetate in hexanes, gradient elution) to provide 16g (0.52 g, 51% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 6.56 – 6.38 (m, 6H), 2.88 (d, J = 40.9 Hz, 4H), 2.67 (q, J = 6.7 Hz, 1H), 1.64 (s, 2H), 1.56 (dt, J = 11.0, 5.1 Hz, 2H), 0.50 (d, J = 6.8 Hz, 3H). LCMS m / z 371.8 (M + H)+.

[0394] Preparation of 17g. Compound 17g was prepared from 16g (350 mg, 0.94mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid 10 (332.22 mg, 1.89 mmol), Pd(PPh3)4(436.29 mg, 0.38 mmol) and K2CO3(652.28 mg, 4.72 mmol) in 1, 4-dioxane (7.9 mL) and water (1.6 mL) stirring at 120 °C for 7 h according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (40 g silica column, 0-10% methanol in dichloromethane, gradient elution) to provide 17g(52 mg, 12 % yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.02 (s,1H), 7.54 (d, J = 1.3 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 4.4 Hz, 4H), 7.26 (h, J = 4.1 Hz, 1H), 7.20 (s, 1H), 3.79 (s, 4H), 3.50 (q, J = 6.6 Hz, 1H), 2.58 – 2.50 (m, 5H), 2.41 (dt, J = 11.0, 5.1 Hz, 2H), 1.34 (d, J = 6.7 Hz, 3H). LCMS m / z 467.5 (M + H)+. HRMS m / z calc for C25H25F3N6.H, 467.2171, found, 467.2188; HPLC purity: 100 % at 254 nm.f. PROCEDURE FOR THE SYNTHESIS OF COMPOUND 23A-C

[0395] Preparation of Intermediate 1-(1-(4-Chlorophenyl)ethyl)-4-tosylpiperazine(20a). Commercially available 1-(4-Chlorophenyl) ethanamine 18a (0.28 mL, 1.93 mmol, 1 eq), N, N-Bis(2-chloroethyl)-p-toluenesulfonamide 19 (628.1 mg, 2.12 mmol, 1.1 eq) were taken together in neat DIPEA (1.0 mL, 5.78 mmol, 3 eq) and stirred for 48 h at 125 °C until completion. The reaction mixture was then concentrated under reduced pressure, diluted with DCM, washed with 1N HCl (1 × 5 mL), water (5 mL) and saturated NaHCO3(2 × 5 mL). The organic layer was then dried with anhydrous Na2SO4, filtered, and concentrated to afford a crude residue, which was purified by flash chromatography (24 g silica column, 5-60% ethyl acetate in hexanes, gradient elution) to provide 1-[1-(4-chlorophenyl)ethyl]-4-(p- tolylsulfonyl)piperazine 20a (441.8 mg,1, 60.5% yield) as a colorless syrup.1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 3.43 (d, J = 6.7 Hz, 1H), 2.82 (s, 4H), 2.42 (s, 5H), 2.34 (d, J = 5.8 Hz, 2H), 1.20 (d, J = 6.6 Hz, 3H).

[0396] Preparation of 1-(1-(4-Chlorophenyl)ethyl)piperazine (21a). 1-[1-(4-chlorophenyl)ethyl]-4-(p-tolylsulfonyl)piperazine 20a (235 mg, 0.62 mmol, 1 eq) and 4- hydroxybenzoic acid (256.9 mg, 1.86 mmol, 3 eq) were added to hydrogen bromide (2.6 mL, 45.6 mmol, 33% in CH3COOH) at room temperature under argon. The mixture was stirred for 2 days at rt. Water (20 mL) was then added slowly to the reaction mixture, after which it was continuously stirred for another 2 h. A white precipitate formed and was removed by filtration. The filter cake was washed with water (2 × 20 mL). The combined acidic aqueous washes were washed with toluene (40 mL). The aqueous phase was then cooled to 0 °C, basified with KOH pellets portion wise until pH > 10, and extracted with toluene (40 mL) and EtOAc (2 × 40 mL). The combined organic phases were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The compound was carried forward to the next step without further purification. Crude1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 3.64 (d, J = 1.3 Hz, 1H), 2.65 (t, J = 4.9 Hz, 4H), 2.29 (s, 2H), 2.24 – 2.15 (m, 2H), 1.24 (d, J = 6.6 Hz, 4H).

[0397] Preparation of 2-Chloro-4-(4-(1-(4-chlorophenyl)ethyl)piperazin-1-yl)-6-methylpyrimidine (22a). Intermediate 22a was prepared from 2,4-dichloro-6-methyl- pyrimidine 1 (245 mg, 1.5 mmol), 1-[1-(4-chlorophenyl)ethyl]piperazine 21a (371.6 mg, 1.65 mmol) and DIPEA (0.24 mL, 1.37 mmol) in anhydrous acetonitrile (2 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 5-50% ethyl acetate in hexanes, gradient elution) to provide 22a (270 mg, 51% yield) as a colorless syrup.1H NMR (400MHz, DMSO-d6) δ 7.42 – 7.27 (m, 4H), 6.67 (s, 1H), 3.56 (s, 4H), 3.49 (q, J = 6.8 Hz, 1H), 2.43 (dt, J = 10.8, 5.1 Hz, 2H), 2.33 (dt, J = 10.9, 5.1 Hz, 2H), 2.21 (s, 3H), 1.29 (d, J = 6.7 Hz, 3H).

[0398] Preparation of Compound 23a. Compound 23a was prepared from 2-chloro-4-[4-[1-(4-chlorophenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine 22a (250 mg, 0.71 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid 10 (250.5 mg, 1.42 mmol), Pd(PPh3)4 (328.9 mg, 0.28 mmol) and K2CO3 (491.8 mg, 3.56 mmol) in in 1,4-dioxane (4.8 mL) and water (1.2 mL) according to the procedure described for the preparation of 17a to afford a crude residue which was purified by flash chromatography (24 g silica column, 0- 10% methanol in dichloromethane, slow gradient elution) to provide 23a (32.5 mg, 9.7% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.97 (t, J = 1.0 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.41 – 7.32 (m, 5H), 6.65 (s, 1H), 3.64 (s, 4H), 3.50 (q, J = 6.6 Hz, 1H), 2.54 (d, J = 1.1 Hz, 3H), 2.46 (d, J = 4.9 Hz, 2H), 2.38 (q, J = 5.9, 5.5 Hz, 2H), 2.33 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H). HRMS m / z calcd. for C25H27ClN6.H 447.2064, found 447.2061. HPLC purity: 95.5% @ 254 nm.

[0399] ii. SYNTHESIS OF 7-METHYL-6-(4-METHYL-6-(4-(1-(4-(TRIFLUOROMETHYL)PHENYL)ETHYL)PIPERAZIN-1- YL)PYRIMIDIN-2-YL)IMIDAZO[1,2-A]PYRIDINE (23B)

[0400] Preparation of Intermediate 1-(p-tolylsulfonyl)-4-[1-[4-(trifluoromethyl)phenyl]ethyl]piperazine (20b). Commercially available 1-(4- Trifluoromethylphenyl)ethylamine 18b (0.42 mL, 2.64 mmol, 1 eq), N, N-Bis(2-chloroethyl)- p-toluenesulfonamide 19 (861.6 mg, 2.91 mmol, 1.1 eq) were taken together in neat DIPEA (1.38 mL, 7.93 mmol, 3 eq) and stirred for 22 h at 125 °C until completion according to the procedure described for the preparation of 20a to afford a crude residue, which was purifiedby flash chromatography (24 g silica column, 0-30% ethyl acetate (containing 5% dichloromethane) in hexanes, gradient elution) to provide 20b (752 mg, 69% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.62 (dd, J = 18.9, 8.2 Hz, 4H), 7.46 (dd, J = 8.4, 2.4 Hz, 4H), 3.53 (q, J = 6.7 Hz, 1H), 2.83 (s, 4H), 2.47 (d, J = 5.7 Hz, 2H), 2.42 (s, 3H), 2.34 (dt, J = 10.7, 4.9 Hz, 2H), 1.23 (d, J = 6.7 Hz, 3H). LCMS m / z 413.47 (M + H)+.

[0401] Preparation of 1-[1-[4-(trifluoromethyl)phenyl]ethyl]piperazine (21b).Intermediate 21b was prepared by heating a mixture of 1-(p-tolylsulfonyl)-4-[1-[4- (trifluoromethyl)phenyl]ethyl]piperazine 20b (732 mg, 1.77 mmol), trifluoroacetic acid (1.37 mL, 17.8 mmol) and sulfuric acid (0.67 mL, 12.4 mmol) at 75 °C for 6h. After completion, the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), carefully washed with 2M Na2CO3 till pH is 8-9 and then brine. The aqueous layer was extracted with ethyl acetate (2x200 mL). The organic layer was separated, dried with anhydrous Na2SO4and concentrated in vacuo to afford crude residue 21b as an off white foamy solid, which was used for next reaction without purification.1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 3.65 (q, J = 6.7 Hz, 1H), 3.03 (t, J = 5.1 Hz, 4H), 2.56 (dt, J = 10.5, 4.9 Hz, 2H), 2.50 – 2.41 (m, 4H), 2.29 (s, 0H), 1.32 (d, J = 6.8 Hz, 3H). LCMS m / z 260.1 (M + H)+.

[0402] Preparation of 2-chloro-4-methyl-6-[4-[1-[4-(trifluoromethyl)phenyl]ethyl]piperazin-1-yl]pyrimidine (22b). Intermediate 22b was prepared from 2,4-dichloro-6-methyl-pyrimidine 1 (228 mg, 1.4 mmol), 21b (397.4 mg, 1.53 mmol) and DIPEA (0.24 mL, 1.3 mmol) in anhydrous acetonitrile (5 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0-50% ethyl acetate in hexanes, gradient elution) to provide 22b (370 mg, 38% yield) as off white solid.1H NMR (400 MHz, DMSO- d6) δ 7.70 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 6.67 (s, 1H), 3.59 (d, J = 7.7 Hz, 4H), 2.49 – 2.42 (m, 4H), 2.35 (d, J = 5.5 Hz, 1H), 2.22 (s, 3H), 1.32 (d, J = 6.7 Hz, 3H). LCMS m / z 385.83 (M + H)+.

[0403] Preparation of Compound 23b. Compound 23b was prepared from 2-chloro-4-methyl-6-[4-[1-[4-(trifluoromethyl)phenyl]ethyl]piperazin-1-yl]pyrimidine 22b (350 mg, 0.90 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid 10 (320 mg, 1.81 mmol), Pd(PPh3)4 (420.4 mg, 0.36 mmol) and K2CO3 (628.5 mg, 4.54 mmol) in in 1,4-dioxane (7.7 mL) and water (1.3 mL) refluxing at 120 °C for 7h according to the procedure described for the preparation of 17a to afford a crude residue which was purified by flash chromatography (40 g silica column, 0-10% methanol in dichloromethane, slow gradient elution) to provide23b (45 mg, 10 % yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.97 (s, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H), 7.39 (s, 1H), 6.65 (s, 1H), 3.65 (s, 4H), 3.59 (t, J = 6.6 Hz, 1H), 2.56 – 2.50 (m, 5H), 2.38 (dt, J = 10.6, 4.8 Hz, 2H), 2.33 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H). LCMS m / z 481.53 (M + H)+.HRMS m / z calcd. for C26H27F3N6.H 481.2327, found 481.2325. HPLC purity: 98.5% @ 254 nm. iii. SYNTHESIS OF 7-METHYL-6-(4-METHYL-6-(4-(2-PHENYLPROPAN-2-YL)PIPERAZIN-1-YL)PYRIMIDIN-2- YL)IMIDAZO[1,2-A]PYRIDINE 23C N

[0404] Preparation of Inte1-phenyl-ethyl)-4-(p-tolylsulfonyl)piperazine (20c). Commercially available 2-Phenylpropan-2-amine 18c (1 g, 7.4 mmol, 1 eq), N, N-Bis(2-chloroethyl)-p-toluenesulfonamide 19 (2.4 g, 8.14 mmol, 1.1 eq) were taken together in neat DIPEA (3.86 mL, 22.18 mmol, 3 eq) and stirred for 18 h at 125 °C until completion according to the procedure described for the preparation of 20a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0- 30% ethyl acetate in hexanes, gradient elution) to provide 20c (2.25 g, 85% yield) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.49 – 7.44 (m, 2H), 7.40 – 7.33 (m, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.19 – 7.13 (m, 1H), 3.71 (t, J = 6.9 Hz, 1H), 3.44 (t, J = 6.9 Hz, 2H), 2.81 (s, 4H), 2.45 (d, J = 4.7 Hz, 3H), 1.24 (s, 6H). LCMS m / z 359.5 (M + H)+.

[0405] Preparation of 1-(1-methyl-1-phenyl-ethyl)piperazine (21c). Intermediate 21cwas prepared by stirring a mixture of 1-(1-methyl-1-phenyl-ethyl)-4-(p- tolylsulfonyl)piperazine 20c (1 g, 2.79 mmol), 4-hydroxybenzoic acid (1.1g , 8.37 mmol) and Hydrogen Bromide (33% in Acetic Acid, 11.67 mL) for 3 days according to the procedure described for the preparation of 21a to afford a crude residue 21c (480 mg, 84% yield). The compound was carried forward to the next step without further purification. Crude1H NMR(400 MHz, DMSO-d6). δ 7.52 – 7.44 (m, 2H), 7.30 (td, J = 7.8, 2.6 Hz, 2H), 7.23 – 7.14 (m, 1H), 2.79 – 2.70 (m, 4H), 2.37 (q, J = 6.8, 5.0 Hz, 5H), 1.27 (s, 6H). LCMS m / z 205.3 (M + H)+.

[0406] Preparation of 2-chloro-4-methyl-6-[4-(1-methyl-1-phenyl-ethyl)piperazin-1-yl]pyrimidine (22c). Intermediate 22c was prepared from 2,4-dichloro-6-methyl-pyrimidine 1 (345 mg, 2.1 mmol), 1-(1-methyl-1-phenyl-ethyl)piperazine 21c (475.6 mg, 2.32 mmol) and DIPEA (0.37 mL, 2.1 mmol) in anhydrous acetonitrile (5 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0-50% ethyl acetate in hexanes, gradient elution) to provide 22c (378 mg, 54% yield) as an off white solid.1H NMR (400 MHz, DMSO-d6) δ 7.56 – 7.49 (m, 2H), 7.32 (dd, J = 8.4, 7.0 Hz, 2H), 7.25 – 7.17 (m, 1H), 6.66 (d, J = 0.8 Hz, 1H), 3.55 (s, 4H), 2.44 (d, J = 5.1 Hz, 4H), 2.21 (s, 3H), 1.30 (s, 6H). LCMS m / z 331.86 (M + H)+.

[0407] Preparation of Compound 23c. Compound 23c was prepared from 2-chloro-4-methyl-6-[4-(1-methyl-1-phenyl-ethyl)piperazin-1-yl]pyrimidine 22c (325 mg, 0.98 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid 10 (345.7 mg, 1.86 mmol), Pd(PPh3)4 (454.04 mg, 0.39 mmol) and K2CO3 (578.81 mg, 4.91 mmol) in in 1,4-dioxane (7.9 mL) and water (1.8 mL) refluxing at 120 °C for 10 h according to the procedure described for the preparation of 17a to afford a crude residue which was purified by flash chromatography (40 g silica column, 0-10% methanol in dichloromethane, slow gradient elution) to provide 23c (35 mg, 8.3 % yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 2.54 (d, J = 1.1 Hz, 3H), 7.96 (t, J = 1.0 Hz, 1H), 2.48 (d, J = 4.5 Hz, 4H), 7.57 – 7.48 (m, 3H), 7.38 (q, J = 0.9 Hz, 1H), 7.32 (dd, J = 8.4, 7.0 Hz, 2H), 7.25 – 7.18 (m, 1H), 6.63 (s, 1H), 3.62 (s, 4H), 2.32 (s, 3H), 1.32 (s, 6H). LCMS m / z 427.56 (M + H)+.HRMS m / z calcd. for C26H30N6.H 427.2610, found 427.2610. HPLC purity: 100% @ 254 nm.g. PROCEDURE FOR THE SYNTHESIS OF COMPOUND 29

[0408] Preparation of tert-Butyl 4-[1-(2,4-dichlorophenyl)ethyl]piperazine-1-carboxylate (26). 1-Boc-piperazine 25 (0.81 g, 4.33 mmol, 1.1 eq) and K2CO3(1.63 g, 11.84 mmol, 3 eq) were added to a solution of 1-(1-bromoethyl)-2,4-dichloro-benzene 24 (1 g, 3.94 mmol, 1 eq) in anhydrous DMF (10 mL) and the resulting mixture was stirred under argon for 13h at rt. After that, the mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 50 ml). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-50% ethyl acetate in hexanes, gradient elution) to provide 26a (1.2 g, 85% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 7.60 – 7.53 (m, 2H), 7.43 (dd, J = 8.4, 2.2 Hz, 1H), 3.79 (t, J = 6.7 Hz, 1H), 3.28 (s, 4H), 2.39 (s, 2H), 2.28 – 2.17 (m, 2H), 1.38 (s, 9H), 1.23 (d, J = 6.6 Hz, 3H).

[0409] Preparation of 1-[1-(2,4-Dichlorophenyl)ethyl]piperazine (27).Trifluoroacetic acid (2.14 mL, 27.83 mmol) was added to a solution of tert-butyl 4-[1-(2,4- dichlorophenyl)ethyl]piperazine-1-carboxylate 26 (1 g, 2.78 mmol) in anhydrous DCM (5 mL). The reaction mixture was stirred for 30 minutes under argon at room temperature. The volatiles were then removed under reduced pressure to provide 27 (0.72 g, 99% crude yield) as a foam. The material was carried forward without further purification.1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.00 (s, 1H), 3.09 (s, 4H), 2.72 (s, 2H), 2.57 (s, 2H), 1.39 (s, 1H), 1.29 (d, J= 6.6 Hz, 3H). LCMS m / z 258.8 (M + H)+.

[0410] Preparation of 2-Chloro-4-[4-[1-(2,4-dichlorophenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine (28). Intermediate 28 was prepared from 2,4-dichloro-6-methyl- pyrimidine 1 (0.54 mL, 2.45 mmol), DIPEA (0.43 mL, 2.45 mmol) and 1-[1-(2,4- dichlorophenyl)ethyl]piperazine 27 (0.7 g, 2.70 mmol) in anhydrous acetonitrile (5 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 28 (0.5 g, 53% yield) as a colorless syrup.1H NMR (400 MHz, DMSO-d6) δ 7.64 – 7.55 (m, 2H), 7.44 (dd, J = 8.5, 2.2 Hz, 1H), 6.62 (s, 1H), 4.09 (q, J = 5.2 Hz, 1H), 3.81 (q, J = 6.6 Hz, 1H), 3.68 (t, J = 5.1 Hz, 4H), 3.16 (d, J = 5.0 Hz, 3H), 2.34 (dt, J = 11.3, 5.2 Hz, 2H), 2.25 (s, 3H), 1.25 (d, J = 6.6 Hz, 3H). LCMS m / z 384.80 (M + H)+.

[0411] Preparation of Compound 29. Compound 29 was prepared from 2-chloro-4-[4-[1-(2,4-dichlorophenyl)ethyl]piperazin-1-yl]-6-methyl-pyrimidine 28 (250 mg, 0.65 mmol), 7-methylimidazo[1,2-a]pyridine-6-boronic acid 10 (228.11 mg, 1.3 mmol), Pd(PPh3)4 (299.6 mg, 0.26 mmol) and K2CO3(447.9 mg, 3.24 mmol) in 1,4-dioxane (5.2 mL) and water (1.3 mL) according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 29 (17 mg, 5.4% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.97 (s, 1H), 7.66 – 7.57 (m, 2H), 7.52 (d, J = 1.2 Hz, 1H), 7.45 (dd, J = 8.4, 2.2 Hz, 1H), 7.40 (s, 1H), 6.66 (s, 1H), 3.85 (d, J = 6.6 Hz, 1H), 3.65 (s, 4H), 2.55 (s, 5H), 2.44 – 2.36 (m, 2H), 2.34 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). LCMS m / z 480.80 (M + H)+. HRMS m / z calc for C25H26Cl2N6.H, 481.1674, found, 481.1671; HPLC purity: 99.3 % at 254 nm. h. PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 30A-G(1-[00412phenylethyl)piperazin-1-yl]pyrimidine 16a (141 mg, 0.45 mmol), (6-methyl-3- pyridyl)boronic acid (73.1 mg, 0.53 mmol), Pd(PPh3)4 (102.8 mg, 0.09 mmol) and K2CO3 (184.5 mg, 1.3 mmol) in 1, 4-dioxane (2 mL) and water (0.5 mL) at 120 °C for 18 h according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash column chromatography (12g silica column, 0-10% methanol in dichloromethane, gradient elution, then 12g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 30a (43 mg, 24.8% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.29 (dd, J = 2.2, 0.9 Hz, 1H), 8.45 (dd, J = 8.0, 2.2 Hz, 1H), 7.39 – 7.27 (m, 5H), 7.25 (ddd, J = 8.7, 5.0, 3.6 Hz, 1H), 6.63 (s, 1H), 3.67 (s, 4H), 3.47 (q, J = 6.7 Hz, 1H), 2.51 (s, 3H), 2.38 (dt, J = 11.0, 5.1 Hz, 2H), 2.33 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). HRMS m / z calc. for C23H27N5.H 374.2345, found 374.2354. HPLC purity: 96.4% @ 254 nm ii. SYNTHESIS OF 5-(4-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRIMIDIN-2-YL)PICOLINONITRILE(30B)CN

[0413] Compound 30b waoro-4-methyl-6-[4-(1-phenylethyl)piperazin-1-yl]pyrimidine 16a (120 mg, 0.38 mmol), (6-cyano-3-pyridyl)boronic acid (112.0 mg, 0.76 mmol), Pd(PPh3)4 (87.5 mg, 0.08 mmol) and K2CO3 (157.0 mg, 1.14 mmol), in 1,4-dioxane (1.5 ml) and water (0.38 ml) at 120 °C for 18 h according to the procedure described for the preparation of 30a to afford a crude residue, which was purified by flash column chromatography twice (10g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 30b (20.3 mg, 13.7% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.53 (dd, J = 2.1, 0.9 Hz, 1H), 8.77 (dd, J = 8.1, 2.1 Hz, 1H), 8.11 (dd, J = 8.1, 0.9 Hz, 1H), 7.33 (d, J = 4.8 Hz, 4H), 7.30 – 7.19 (m, 1H), 6.73 (d, J = 0.7 Hz, 1H), 3.70 (s, 4H), 3.48 (q, J = 6.7 Hz, 1H), 3.31 (d, J = 1.8 Hz, 2H), 2.47 (d, J = 5.2 Hz, 1H), 2.44 – 2.32 (m, 5H), 1.34 (d, J = 6.7 Hz, 3H). HRMS m / z calc. for C23H24N6.H 385.2135, found 381.2139. HPLC purity: 98.4% @ 254 nm. iii. SYNTHESIS OF 2-(6-FLUOROPYRIDIN-3-YL)-4-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRIMIDINE(30C) F

[0414] Compound 30c was prepared from 2-chloro-4-methyl-6-[4-(1-phenylethyl)piperazin-1-yl]pyrimidine 1 (120 mg, 0.38 mmol), (6-fluoro-3-pyridyl)boronic acid (64.0 mg, 0.45 mmol), Pd(PPh3)4 (87.5 mg, 0.08 mmol) and K2CO3 (157.0 mg, 1.14 mmol) in 1, 4-dioxane (2 mL) and water (0.5 mL) at 120 °C for 18 h according to the procedure described for the preparation of 30a to afford a crude residue, which was purified by flash chromatography (10g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 30c (99.3 mg, 68% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.06 (dt, J = 2.5, 0.8 Hz, 1H), 8.74 (td, J = 8.3, 2.4 Hz, 1H), 7.33 (d, J = 4.8 Hz, 4H), 7.29 – 7.19 (m, 2H), 6.69 – 6.63 (m, 1H), 3.68 (s, 4H), 3.47 (q, J = 6.7 Hz, 1H), 3.31 (d, J = 1.8 Hz, 2H), 2.51 – 2.35 (m, 3H), 2.33 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). HRMS m / z calc for C22H24FN5.H 378.2089, found 378.2094. HPLC purity: 98% @ 254 nm. iv. SYNTHESIS OF 2-(6-CYCLOPROPYLPYRIDIN-3-YL)-4-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRIMIDINE (30D)

[0415] Compound 30d was prepared from 2-chloro-4-methyl-6-[4-(1-phenylethyl)piperazin-1-yl]pyrimidine 1 (67 mg, 0.21 mmol), (6-Cyclopropylpyridin-3- yl)boronic acid (41.3 mg, 0.25 mmol), Pd(PPh3)4 (48.9 mg, 0.04 mmol) and K2CO3 (87.7 mg, 0.63 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) according to the procedure described for the preparation of 30a to afford a crude residue, which was purified by flash column chromatography (10g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 30d (52.3 mg, 61.3% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 2.2 Hz, 1H), 8.41 (dd, J = 8.1, 2.2 Hz, 1H), 7.38 – 7.29 (m, 5H), 7.25 (q, J = 4.5 Hz, 1H), 6.61 (s, 1H), 3.66 (s, 4H), 3.47 (q, J = 6.5 Hz, 1H), 2.47 (d, J = 5.1 Hz, 2H), 2.42 – 2.34 (m, 2H), 2.32 (s, 3H), 2.15 (tt, J = 7.8, 5.1 Hz, 1H), 1.33 (d, J = 6.7 Hz, 3H), 0.98 (ddt, J = 7.8, 4.4, 2.6 Hz, 4H). HRMS m / z calc for C25H29N5.H 400.2501, found 400.2497. HPLC purity: 99.7% @ 254 nm. v. SYNTHESIS OF 2-(6-METHOXYPYRIDIN-3-YL)-4-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRIMIDINE (30E) Me

[0416] Compound 30e was prepared from 2-chloro-4-methyl-6-[4-(1-phenylethyl)piperazin-1-yl]pyrimidine 1 (120 mg, 0.38 mmol), 2-methyoxypyridine-5- boronic acid (115.8 mg, 0.76 mmol), Pd(PPh3)4 (87.5 mg, 0.08 mmol) and K2CO3 (157.0 mg, 1.14 mmol) in 1,4-dioxane (1.5 mL) and water (0.4 mL) according to the procedure described for the preparation of 30a to afford a crude residue, which was purified by flash chromatography (10g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 30e (98 mg, 65.8% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 2.3 Hz, 1H), 8.49 (dd, J = 8.7, 2.4 Hz, 1H), 7.33 (d, J = 4.4 Hz, 4H), 7.25 (q, J = 4.5 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.59 (s, 1H), 3.90 (s, 3H), 3.66 (s, 4H), 3.46 (q, J = 6.6 Hz, 1H), 2.51 – 2.44 (m, 2H), 2.42 – 2.34 (m, 2H), 2.31 (s, 3H), 1.33 (d, J = 6.6 Hz, 3H). HRMS m / z calcd. for C23H27N5O.H 390.2288, found 390.2285. HPLC purity: 99.2% @ 254 nm. vi. SYNTHESIS OF 4-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)-2-(6-(TRIFLUOROMETHYL)PYRIDIN-3-YL)PYRIMIDINE (30F) F3

[0417] Compound 30f was prepared from 2-chloro-4-methyl-6-[4-(1-phenylethyl)piperazin-1-yl]pyrimidine 1 (120 mg, 0.38 mmol), 2-trifluoromethylpyridine-5- boronic acid (144.6 mg, 0.76 mmol), Pd(PPh3)4 (87.5 mg, 0.08 mmol) and K2CO3 (157.0 mg, 1.14 mmol) in 1,4-dioxane (1.5 mL), water (0.4 mL) according to the procedure described for the preparation of 30a to afford a crude residue, which was purified by flash chromatography (10g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 30f (140 mg, 86.3% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J = 2.0 Hz, 1H), 8.83 (ddd, J = 8.2, 2.0, 0.8 Hz, 1H), 7.99 (dd, J = 8.2, 0.9 Hz, 1H), 7.33 (d, J = 4.4 Hz, 4H), 7.26 (dt, J = 8.9, 4.3 Hz, 1H), 6.74 (s, 1H), 3.71 (s, 4H), 3.48 (q, J = 6.7 Hz, 1H), 2.44 – 2.38 (m, 4H), 2.36 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H). HRMS m / z calcd. for C23H24F3N5.H 428.2057, found 428.2053. HPLC purity: >99% @ 254 nm. vii. SYNTHESIS OF 2-(3,5-DIMETHYL-1H-PYRAZOL-4-YL)-4-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRIMIDINE (30G)Attorney

[0418] Compound 30g was prepared from 2-chloro-4-methyl-6-[4-(1-phenylethyl)piperazin-1-yl]pyrimidine 1 (120 mg, 0.38 mmol), 3,5-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (168.2 mg, 0.76 mmol), Pd(PPh3)4 (43.8 mg, 0.04 mmol) and K2CO3(78.5 mg, 0.57 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) according to the procedure described for the preparation of 30a to afford a crude residue, which was purified by flash chromatography (25g silica column, 0-10% methanol in dichloromethane, then 4g silica column, 0-10% methanol in dichloromethane, gradient elution) to provide 30g (38.3 mg, 24.7% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 7.31 (d, J = 3.8 Hz, 4H), 7.26 – 7.20 (m, 1H), 6.38 (s, 1H), 3.57 (s, 4H), 3.43 (q, J = 6.7 Hz, 1H), 2.42 (s, 6H), 2.46 – 2.30 (m, 4H), 2.23 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H). HRMS m / z calcd. for C22H28N6.H 377.2454, found 377.2460. HPLC purity: 92.4% @ 254 nm. i. PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 33A-CCl R1NIN-

[0419] Preparation of 2-Chloro-6-[4-(1-phenylethyl)piperazin-1-yl]pyrazine (32a).Intermediate 32a was prepared from commercially available 2,6-dichloro-pyrazine 31a (1.25 g, 8.41 mmol), 1-(1-phenylethyl)piperazine 15a (1 g, 5.26 mmol) and DIPEA (2.75 mL, 15.77 mmol) in anhydrous acetonitrile (5 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 32a (0.99 g, 62% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.83 (s, 1H), 7.34 (d, J = 5.4 Hz, 4H), 7.30 – 7.21 (m, 1H), 3.55 (t, J = 5.1 Hz, 4H), 3.47 (q, J = 6.7 Hz, 1H), 2.51 – 2.45 (m, 2H), 2.39 (dt, J = 11.1, 5.1 Hz, 2H), 1.33 (d, J = 6.7 Hz, 3H). LCMS m / z 303.10 (M + H)+.

[0420] Preparation of Compound 33a. Compound 33a was prepared from 2-chloro-6-[4-(1-phenylethyl)piperazin-1-yl]pyrazine 32a (335 mg, 1.11 mmol), 7-methylimidazo[1,2- a]pyridine-6-boronic acid 10 (389.4 mg, 2.21 mmol), Pd(PPh3)4 (255.7 mg, 0.22 mmol) and K2CO3(458.7 mg, 3.32 mmol) in 1,4-dioxane (4 mL) and water (1 mL) using the procedure described for preparation of 17a to afford a crude residue, which was purified by flash chromatography (40 g silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 33a (28 mg, 6.2% yield) as an off-white powder.1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J = 4.4 Hz, 4H), 7.25 (q, J = 4.3 Hz, 1H), 3.59 (t, J = 5.2 Hz, 4H), 3.46 (d, J = 6.7 Hz, 1H), 2.41 (dd, J = 11.1, 5.3 Hz, 2H), 2.36 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). LCMS m / z 399.2 (M + H)+. HRMS m / z calc for C24H26N6.H, 399.2297, found, 399.2299; HPLC purity: 96.4 % at 254 nm. ii. SYNTHESIS OF 7-METHYL-6-[5-METHYL-6-[4-(1-PHENYLETHYL)PIPERAZIN-1-YL]PYRAZIN-2-YL]IMIDAZO[1,2- A]PYRIDINE (33B) N

[0421] Preparation of 5-Chloro-2-methyl-3-[4-(1-phenylethyl)piperazin-1-yl]pyrazine (32b). Intermediate 32b was prepared from 3,5-dichloro-2-methylpyrazine 31b (0.69 g, 4.20 mmol),1-(1-phenylethyl)piperazine 15a (0.5 g, 2.62 mmol), DIPEA (1.4 mL, 7.88 mmol) in anhydrous acetonitrile (5 mL) at 80 °C for 15 h according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 32b (385 mg, 46% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.33 (d, J = 3.8 Hz, 4H), 7.29 – 7.20 (m, 1H), 3.46 (q, J = 6.7 Hz, 1H), 3.19 (t, J = 5.0 Hz, 4H), 2.55 (dt, J = 10.0, 4.8 Hz, 2H), 2.44 (dt, J = 10.7, 5.0 Hz, 2H), 2.39 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). LCMS m / z 317.1 (M + H)+.

[0422] Preparation of Compound 33b. Compound 33b was prepared from 5-chloro-2-methyl-3-[4-(1-phenylethyl)piperazin-1-yl]pyrazine 32b (215 mg, 0.68 mmol), 7- methylimidazo[1,2-a]pyridine-6-boronic acid 10 (238.8 mg, 1.36 mmol), Pd(PPh3)4 (156.83 mg, 0.14 mmol) and K2CO3(281.4 mg, 2.04 mmol) in 1,4-dioxane (5.6 mL) and water (1.3 mL) according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (40 g silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 33b (37 mg, 12.6% yield) as an off-white powder.1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.54 (s, 1H), 7.47 (s, 1H), 7.33 (d, J = 4.4 Hz, 4H), 7.25 (q, J = 4.4 Hz, 1H), 3.47 (q, J = 6.7 Hz, 1H), 3.19 (d, J = 5.2 Hz, 4H), 2.63 – 2.56 (m, 2H), 2.47 (s, 5H), 2.38 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H). LCMS m / z 413.2 (M + H)+. HRMS m / z calc for C25H28N6.H, 413.2454, found, 413.2458; HPLC purity: 97.1% at 254 nm. iii. SYNTHESIS OF 7-METHYL-6-(3-METHYL-6-(4-(1-PHENYLETHYL)PIPERAZIN-1-YL)PYRAZIN-2-YL)IMIDAZO[1,2- A]PYRIDINE (33C) N

[0423] Preparation of 3-Chloro-2-methyl-5-(4-(1-phenylethyl)piperazin-1-yl)pyrazine(32c). Intermediate 32c was prepared from 3,5-dichloro-2-methylpyrazine 31b (0.69 g, 4.20 mmol),1-(1-phenylethyl)piperazine 15a (0.5 g, 2.62 mmol), DIPEA (1.4 mL, 7.88 mmol) in anhydrous acetonitrile (5 mL) at 80 °C for 15 h according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (24 g silica column, 0-30% ethyl acetate in hexanes, gradient elution) to provide 32c (105 mg, 12.6% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.33 (d, J = 5.5 Hz, 4H), 7.25 (td, J=5.5, 3.1 Hz, 1H), 3.46 (q, J = 7.4, 6.2 Hz, 5H), 2.48 (dd, J = 9.1, 3.9 Hz, 2H), 2.38 (d, J = 9.4 Hz, 5H), 1.32 (d, J = 6.7 Hz, 3H).

[0424] Preparation of Compound 33c. Compound 33c was prepared from 3-chloro-2-methyl-5-(4-(1-phenylethyl)piperazin-1-yl)pyrazine 32b (135 mg, 0.43 mmol), 7- methylimidazo[1,2-a]pyridine-6-boronic acid 10 (150 mg, 0.85 mmol), Pd(PPh3)4(196.9 mg, 0.17 mmol) and K2CO3 (294.4 mg, 2.13 mmol) in 1,4-dioxane (3.5 mL) and water (0.8 mL) according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (40 g silica column, 0-5% methanol in dichloromethane, gradient elution) to provide 33c (27 mg, 14.8% yield) as an off-white powder.1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.48 (s, 1H), 7.32 (d, J = 5.0 Hz, 4H), 7.24 (ddd, J = 8.8, 5.6, 3.3 Hz, 1H), 3.49 (t, J = 5.2 Hz, 4H), 3.46 – 3.42 (m, 1H), 2.49 (s, 2H), 2.39 (dt, J = 11.1, 5.0 Hz, 2H), 2.21 (s, 3H), 2.07 (d, J = 1.1 Hz, 3H), 1.31 (d, J = 6.7 Hz, 3H). HRMS m / z calc for C25H28N6.H 413.2454, found 413.2464. HPLC purity: 97.5% @ 254 nm. j. PROCEDURE FOR THE SYNTHESIS OF 4-METHYL-6-(4-((6-METHYLPYRIDIN-3-YL)OXY)PIPERIDIN-1-YL)-2-(6- (TRIFLUOROMETHYL)PYRIDIN-3-YL)PYRIMIDINE(36)

[0425] Preparation of 2-Chloro-4-methyl-6-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)pyrimidine (35). Intermediate 35 was prepared from 2,4-dichloro-6-methylpyrimidine 1 (163 mg, 1 mmol), 2-methyl-5-(piperidin-4-yloxy)pyridine 342(211.5 mg, 1.1 mmol) and DIPEA (0.4 mL, 2.2 mmol) in anhydrous acetonitrile (5 mL) at room temperature for 18 h according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (12 g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 35 (247 mg, 77.5% yield) as a sticky oil.1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 2.9 Hz, 1H), 7.16 (dd, J = 8.4, 2.9 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.29 (s, 1H), 4.57 (dt, J = 6.6, 3.2 Hz, 1H), 3.85 (t, J = 11.8 Hz, 2H), 3.67 (s, 2H), 2.51 (s, 3H), 2.34 (s, 3H), 2.00 (ddd, J = 12.8, 8.2, 4.0 Hz, 2H), 1.88 (dtd, J = 13.3, 6.7, 3.8 Hz, 2H). LCMS m / z 319 (M + H)+.

[0426] Preparation of Compound 36. Compound 36 was prepared from 2-chloro-4-methyl-6-(4-((6-methylpyridin-3-yl)oxy)piperidin-1-yl)pyrimidine 35 (127.5 mg, 0.4 mmol), 2-trifluoromethylpyridine-5-boronic acid (152.7 mg, 0.8 mmol), Pd(PPh3)4(92.8 mg, 0.08 mmol) and K2CO3 (165.8 mg, 1.2 mmol) in 1,4-dioxane (3 mL) and water (0.75 mL) at 110 °C for 18 h according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (4g silica column, 0-65% ethyl acetate in hexanes, then 12g silica column, 0-25% ethyl acetate in dichloromethane, gradient elution) to provide 36 (65 mg, 37.5% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.58 (dt, J = 2.0, 0.7 Hz, 1H), 8.85 (ddd, J = 8.2, 2.0, 0.7 Hz, 1H), 8.20 (dd, J = 3.0, 0.7 Hz, 1H), 8.00 (dd, J = 8.2, 0.8 Hz, 1H), 7.39 (dd, J = 8.5, 3.0 Hz, 1H), 7.19 (dt, J = 8.5, 0.6 Hz, 1H), 6.86 (d, J = 0.7 Hz, 1H), 4.71 (dq, J = 7.8, 3.9 Hz, 1H), 4.14 (s, 2H), 3.57 (t, J = 10.8 Hz, 2H), 2.41 – 2.37 (m, 6H), 2.08 – 1.98 (m, 2H), 1.66 (dtd, J = 12.6, 8.4, 3.8 Hz, 2H).19F NMR (376 MHz, DMSO- d6) δ -66.37 (s, 3F). HRMS m / z calc for C22H22F3N5O.H, 430.1855, found, 430.1858; HPLC purity: > 99% purity at 254 nm. k. PROCEDURE FOR THE SYNTHESIS OF COMPOUND 39

[0427] Preparation of N-(1-(2-Chloro-6-methylpyrimidin-4-yl)piperidin-4-yl)-4-fluorobenzamide (38). Intermediate 38 was prepared from 2,4-dichloro-6-methylpyrimidine 1 (586.3 mg, 3.6 mmol), 4-fluoro-N-(piperidin-4-yl)benzamide 373(799.5 mg, 3.6 mmol) and DIPEA (1.88 mL, 10.8 mmol) in anhydrous acetonitrile (18 mL) at 100 °C for 18 h according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (10 g silica column, 0-100% ethyl acetate in hexanes, gradient elution) to provide 38 (839 mg, 66.9% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 7.8 Hz, 1H), 7.96 – 7.83 (m, 2H), 7.27 (t, J = 8.8 Hz, 2H), 6.77 (s, 1H), 4.29 (s, 2H), 4.09 (dtt, J = 11.3, 8.1, 4.3 Hz, 1H), 3.07 (t, J = 13.0 Hz, 2H), 2.23 (s, 3H), 1.87 (dd, J = 11.9, 3.9 Hz, 2H), 1.46 (qd, J = 12.2, 4.2 Hz, 2H).

[0428] Preparation of 4-Fluoro-N-(1-(6-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yl)piperidin-4-yl)benzamide (39). Compound 39 was prepared from N-(1-(2- chloro-6-methylpyrimidin-4-yl)piperidin-4-yl)-4-fluorobenzamide 38 (150 mg, 0.43 mmol), 2-trifluoromethylpyridine-5-boronic acid (98.5 mg, 0.52 mmol), Pd(PPh3)4 (99.4 mg, 0.09 mmol) and K2CO3(178.3 mg, 1.29 mmol) in 1,4-dioxane (1.7 mL) and water (0.4 mL) according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (10 g silica column, 0-35% ethyl acetate in hexanes, gradient elution) to provide 39 (14.5 mg, 7.1% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.57 (d, J = 2.0 Hz, 1H), 8.85 (dd, J = 8.2, 2.0 Hz, 1H), 8.30 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.89 (ddd, J = 8.5, 5.3, 2.4 Hz, 2H), 7.32 – 7.22 (m, 2H), 6.85 (s, 1H), 4.53 (s, 2H), 4.21 – 4.04 (m, 1H), 3.13 (t, J = 12.7 Hz, 2H), 2.38 (s, 3H), 1.91 (d, J = 12.7 Hz, 2H), 1.59 – 1.45 (m, 2H).19F NMR (376 MHz, DMSO- d6) δ -110.0 (s, 1F), - 74.0 (s, 3F), HRMS m / z calc for C23H21F4N5O.H, 460.1760, found, 460.1770; HPLC purity: 97.3% at 254 nm. l. PROCEDURE FOR THE SYNTHESIS OF COMPOUNDS 43A-Fepaa on o - oo- - -sopopyppea n- -y - -me ypy m ne(42a). Intermediate 42a was prepared from 2,4-dichloro-6-methyl-pyrimidine 1 (933.6 mg, 5.73 mmol), commercially available 1-(1-methylethyl)-piperazine 41a (612 mg, 4.77 mmol) and DIPEA (2.5 mL, 14.3 mmol) in anhydrous acetonitrile (24 mL) at 120 °C for 18 h according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (40g silica column, 0-40% ethyl acetate in hexanes, gradient elution) to provide 42a (1.02 g, 84.2% yield).1H NMR (400 MHz, CDCl3) δ 11.45 (s, 1H), 8.31 (t, J = 4.8 Hz, 4H), 7.42 (h, J = 6.6 Hz, 1H), 7.28 – 7.17 (m, 4H), 6.98 (s, 3H), 5.72 (d, J = 6.6 Hz, 6H).

[0430] Preparation of Compound 43a. Compound 43a was prepared from 2-chloro-4-(4-isopropylpiperazin-1-yl)-6-methylpyrimidine 42a (300 mg, 1.18 mmol), 7- methylimidazo[1,2-a]pyridine-6-boronic acid 10 (248.7 mg, 1.41 mmol), Pd(PPh3)4 (272.1 mg, 0.24 mmol) and K2CO3(488.2 mg, 3.53 mmol) in 1,4-dioxane (4.7 mL) and water (1.2 mL) at 120 °C for 18 h according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (10g silica column, 0- 10% methanol in dichloromethane) to provide 43a (88.2 mg, 21.4% yield) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 7.98 (s, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.40 (s, 1H), 6.68 (s, 1H), 3.78 – 3.52 (m, 4H), 2.76 – 2.64 (m, 1H), 2.56 (s, 3H), 2.51 (d, J = 1.9 Hz, 9H), 2.34 (s, 3H), 0.99 (d, J = 6.5 Hz, 6H). HRMS m / z calc for C20H26N6.H, 351.1760, found, 351.1770. ii. SYNTHESIS OF 7-METHYL-6-(4-METHYL-6-(4-PHENYLPIPERAZIN-1-YL)PYRIMIDIN-2-YL)IMIDAZO[1,2- A]PYRIDINE (43B)

[0431] Preparation of 2-Choro- -me y - - -phenylpiperazin-1-yl)pyrimidine(42b). Intermediate 42b was prepared from 2,4-dichloro-6-methylpyrimidine 1 (1 g, 6.1 mmol), 1-phenylpiperazine 41b (1.1 g, 6.75 mmol) and DIPEA (2.1 mL, 12.3 mmol) in anhydrous acetonitrile (25 mL) at room temperature for 4 h according to the procedure described for the preparation of 16a to afford a crude residue which was purified by flash chromatography (40g silica column, 0-50% ethyl acetate in hexanes, gradient elution) to provide 42b (1.45 g, 81.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.29 – 7.14 (m, 2H), 7.02 – 6.89 (m, 2H), 6.85 – 6.72 (m, 2H), 3.74 (t, J = 5.2 Hz, 4H), 3.19 (dd, J = 6.3, 4.1 Hz, 4H), 2.24 (s, 3H).

[0432] Preparation of Compound 43b. Compound 43b was prepared from 2-chloro-4-methyl-6-(4-phenylpiperazin-1-yl)pyrimidine 42b (250 mg, 0.87 mmol), 7- methylimidazo[1,2-a]pyridine-6-boronic acid 10 (335.2 mg, 1.90 mmol), Pd(PPh3)4 (200.1 mg, 0.17 mmol), K2CO3(382.9 mg, 2.77 mmol) in 1,4-dioxane (7 mL) and water (1.7 mL) at 110 °C for 48 h according to the procedure described for the preparation of 17a to afford a crude residue, which was purified by flash chromatography (40g silica column, 0-5% methanol in dichloromethane) to provide 43b (87.3 mg, 25.6% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 7.99 (t, J = 1.0 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.28 – 7.19 (m, 2H), 7.03 – 6.97 (m, 2H), 6.81 (t, J = 7.3 Hz, 1H), 6.78 (s, 1H), 3.83 (t, J = 5.1 Hz, 4H), 3.25 (t, J = 5.3 Hz, 4H), 2.59 (d, J = 1.2 Hz, 3H), 2.37 (s, 3H). HRMS m / z calc for C23H24N6.H, 385.2141, found, 385.2139; HPLC > 97.6% purity at 254 nm. iii. SYNTHESIS OF 6-(4-(4-(4-FLUOROPHENYL)PIPERAZIN-1-YL)-6-METHYLPYRIMIDIN-2-YL)-7-METHYLIMIDAZO[1,2-A]PYRIDINE (43C) F N

[0433] Preparation of 2-Choro-4-[4-(4-f uorophenyl)piperazin-1-yl]-6-methylpyrimidine (42c). Intermediate 42c was prepared from 2,4-dichloro-6- methylpyrimidine 1 (1.0 g, 6.135 mmol), para-fluorophenylpiperazine 41c (1.11 g, 6.13 mmol) and DIPEA (1.59 g, 12.270 mmol) in anhydrous acetonitrile (10 mL) at 80 °C for 2 h according to the procedure described for the preparation of 16a.On completion, a solid precipitated which was collected by filtration and washed with MeCN (3 x 2 mL). The residue was purified by flash chromatography (silica gel, 1:5 ethyl acetate: pet. ether, isocratic) to provide 42c (1.13 g, 60.0%) as a white solid. LCMS (ESI) m / z (M + H)+= 307.

[0434] Preparation of Compound 43c. Compound 43c was prepared from 2-chloro-4-[4-(4-fluorophenyl)piperazin-1-yl]-6-methylpyrimidine 42c (100 mg, 0.33 mmol), 7- methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)imidazo[1,2-a]pyridine (84.1 mg, 0.33 mmol), Pd(PPh3)4(37.7 mg, 0.033 mmol) and K2CO3(135.1 mg, 0.978 mmol) at 100 °C for 2 h according to the procedure described for the preparation of 17a. On completion, the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10 / 1), then re-purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A:water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 38% B to 62% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 8) to provide 43c (14.6 mg, 11.0%) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 8.98 (s, 1H), 7.99 (t, J = 1.0 Hz, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.11 – 7.00 (m, 4H), 6.79 (s, 1H), 3.83 (t, J = 4.9 Hz, 4H), 3.19 (t, J = 5.2 Hz, 4H), 2.58 (d, J = 1.1 Hz, 3H), 2.37 (s, 3H). LCMS m / z (M + H)+403.25. HPLC purity: 99.06% @ 254 nm. iv. SYNTHESIS OF 7-METHYL-6-(4-METHYL-6-(4-(4-(TRIFLUOROMETHYL)PHENYL)PIPERAZIN-1-YL)PYRIMIDIN-2- YL)IMIDAZO[1,2-A]PYRIDINE (43D) CF3N

[0435] Preparation of 2-Chloro-4-methyl-6-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidine (42d). Intermediate 42d was prepared from 2,4-dichloro-6-methylpyrimidine 1 (1.0 g, 6.13 mmol), 1-[4-(trifluoromethyl)phenyl]piperazine 41d (1.41 g, 6.13 mmol) and DIPEA (1.59 g, 12.27 mmol) in anhydrous acetonitrile (10 mL) according to the procedure described for the preparation of 16a to afford a crude residue, which was purified by flash chromatography (silica gel, 3:7 ethyl acetate: dichloromethane, isocratic) to provide 42d (1.5g, 68.5% yield) as a light yellow solid. LCMS (ESI) m / z (M + H)+= 357.

[0436] Preparation of Compound 43d. Compound 43d was prepared from 2-chloro-4-methyl-6-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}pyrimidine 42d (200 mg, 0.56 mmol), 7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (144.7 mg, 0.56 mmol), Pd(PPh3)4 (64.7 mg, 0.05 mmol) and K2CO3 (232.4 mg, 1.68 mmol) in 1,4-dioxane (4 mL) and water (1 mL) according to the procedure described for the preparation of 43c to afford a crude residue, which was purified by flash chromatography (silica gel column, eluted with CH2Cl2: MeOH (10 : 1), isocratic) then re-purified by Prep- HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30 * 150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 20% B in 9 min; Wave Length: 254nm / 220nm; RT(min): 8.5) to provide 43d (20.4 mg, 8.0%) as a pink solid..1H NMR (300 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.00 (s, 1H), 7.59 – 7.50 (m, 3H), 7.43 (s, 1H7.12 (d, J = 8.7 Hz, 2H), 6.78 (s, 1H), 3.86 (t, J = 5.3 Hz, 4H), 3.45 (t, J = 5.3 Hz, 4H), 2.60 (s, 3H), 2.38 (s, 3H). LCMS (ESI): (M + H)+= 453. HPLC purity: 99.5% @ 254 nm. v. SYNTHESIS OF 6-(4-ISOPROPYL-6-(4-PHENYLPIPERAZIN-1-YL)PYRIMIDIN-2-YL)-7-METHYLIMIDAZO[1,2-A]PYRIDINE (43E)

[0437] Preparation of 4-Chloro-6-isopropyl-2-(4-phenylpiperazin-1-yl)pyrimidine(42e). Intermediate 42e was prepared from 2,4-dichloro-6-isopropylpyrimidine 40a (500 mg, 2.62 mmol), 1-phenylpiperazine 41b (424.6 mg, 2.62 mmol) and DIPEA (676.5 mg, 5.23 mmol) in anhydrous acetonitrile (5 mL) according to the procedure described for the preparation of 42a to afford a crude residue, which was purified by flash chromatography (silica gel, 6:1 pet ether: ethyl acetate, isocratic) to provide 42e (1.180 mg) as a white solid. LCMS (ESI) m / z (M + H)+= 317.

[0438] Preparation of Compound 43e. Compound 43e was prepared from 2-chloro-4-isopropyl-6-(4-phenylpiperazin-1-yl)pyrimidine 42e (300 mg, 0.947 mmol), 7-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin...

Claims

CLAIMS What is claimed is:

1. A compound having a structure represented by a formula:, wherein Q is a structure represented by a ormu a selected from: ;wherein * denotes a bond connected to ;wherein ** denotes a bond connected to ;wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from ‒NH2,C1-C4 alkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino;wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, ‒CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl; and or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula: en 1Cy is a structure represented by a formula: ,wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eis hydrogen, provided that when Q is a structure represented by a formula: ,then R1is selected from ‒CN and C1-C4 alkyl, R2is hydrogen, and at least one of R3a, R3b, R3c, R3d, and R3eis a non-hydrogen group.

2. The compound of claim 1, wherein Q is a structure:.

3. The compound of claim 1, wherein Q is a structure represented by a formula:.

4. The compound of claim 3, wherein R10 is hydrogen.

5. The compound of claim 3 or claim 4, wherein R11 is C1-C4 alkyl and R12 is hydrogen.

6. The compound of any one of claims 1 to 5, wherein R1 is selected from hydrogen andC1-C4 alkyl.

7. The compound of any one of claims 1 to 5, wherein R1 is selected from hydrogen andmethyl.

8. The compound of any one of claims 1 to 7, wherein R2 is hydrogen.

9. The compound of any one of claims 1 to 8, wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, C1-C4 alkyl, ‒CO2H, and ‒CO2(C1-C4 alkyl).

10. The compound of any one of claims 1 to 8, wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen and ‒CO2H.

11. The compound of any one of claims 1 to 8, wherein each of R3a, R3b, R3c, R3d, and R3eis hydrogen.

12. The compound of any one of claims 1 to 11, wherein Cy1 is selected from animidazopyridine and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl.

13. The compound of any one of claims 1 to 11, wherein Cy1 is an imidazopyridinesubstituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl.

14. The compound of claim 13, wherein Cy1 is a compound having a structurerepresented by a formula: .

15. The compound of claim 14, wherein Cy1 is a compound having a structurerepresented by a formula:.

16. The compound of any one of c, wherein Cy1 is a pyridinyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl.

17. The compound of claim 16, wherein Cy1 is a compound having a structurerepresented by a formula: , 13a 13bwherein each of R , R , R13c, and R13dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R13a, R13b, R13c, and R13dis hydrogen.

18. The compound of claim 16, wherein Cy1 is a compound having a structurerepresented by a formula: .

19. The compound of claim 1, wherein the compound has a structure represented by aformula:, or a pharmaceutically accepa e sa ereo .

20. The compound of claim 1, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound has a structure represented by aformula: R3cR3bR3d3ey1, or a pharmaceutically acceptable sa t t ereo .

23. The compound of claim 1, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound has a structure represented by aformula:, or a pharmaceutically accepa e sa ereo .

25. The compound of claim 1, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound is selected from:,, or a pharmaceutically acceptable27. A pharmaceutical composition comprising an effective amount of a compound havinga structure represented by a formula: ,wherein Q is a structure represented by a formula selected from: ;wherein * denotes a bond connected to ;wherein ** denotes a bond connected to; wherein R10is selected frod C1-C4 alkyl; wherein R11is selected from ‒NH2,C1-C4 alkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, ‒CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula: ,then Cy1is a structure represented by a formula:, wherein each of R12a, R, , , R12eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula: ,then R1is selected from ‒CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, wherein the compound has a structurerepresented by a formula: ,or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition of claim 27, wherein the compound is selected from:, , or a py p .

30. A method of modifying dopaminergic signaling in a subject in need thereof, themethod comprising administering to the subject an effective amount of a compound having a structure represented by a formula: ,wherein Q is a structure represented by a formula selected from: ; wherein; wherein ** denotes a bond; wherein R10is selected fromhydrogen and C1-C4 alkyl; wherein R11is selected from ‒NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, ‒CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH,‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula: ,then Cy1is a structure represented by a formula: , wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula: ,then R1is selected from ‒CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

31. The method of claim 30, wherein modifying is decreasing.

32. The method of claim 30, wherein modifying is inhibiting.

33. The method of any one of claims 30 to 32, wherein the subject has been diagnosedwith a disease associated with dysregulated dopaminergic signaling.

34. The method of claim 33, wherein the disease is a human immunodeficiency virus-(HIV-) associated neurocognitive disorder (HAND).

35. The method of claim 34, wherein the HAND is selected from asymptomaticneurocognitive impairment (ANI), minor neurocognitive disorder (MND), HIV-associated dementia (HAD), and neuroHIV.

36. The method of claim 34, wherein the HAND is neuroHIV.

37. The method of any one of claims 30 to 36, wherein the subject has been diagnosedwith a need for modification of dopaminergic signaling prior to the administering step.

38. The method of any one of claims 30 to 37, wherein the subject has been diagnosedwith a need for treatment of a disease associated with dysregulated dopaminergic signaling prior to the administering step.

39. The method of any one of claims 30 to 38, further comprising the step of identifying asubject in need of treatment of a disease associated with dysregulated dopaminergic signaling.

40. A method of modifying dopaminergic signaling in a cell, the method comprisingcontacting the cell with an effective amount of a compound having a structure represented by a formula: ,wherein Q is a structure represented by a formula selected from:; whereindenotes a bond connected to ; wherein ** denotes a bond; wherein R10is selected fromy rogen and C1-C4 alkyl; wherein R11is selected from ‒NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, ‒CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒CO2(C1-C4 alkyl); and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when Q is a structure represented by a formula: ,then Cy1is a structure represented by a formula: , wherein each of R12a, R12b, R12c, R12d, and R12eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, provided that at least two of R12a, R12b, R12c, R12d, and R12eare hydrogen, and provided that when Q is a structure represented by a formula: ,then R1is selected from ‒CN and C1-C4 alkyl and R2is hydrogen, and a pharmaceutically acceptable carrier.

41. The method of claim 40, wherein modifying is decreasing.

42. The method of claim 40, wherein modifying is inhibiting.

43. The method of any one of claims 30 to 42, wherein the cell is mammalian.

44. The method of any one of claims 30 to 42, wherein the cell is human.

45. The method of any one of claims 30 to 44, wherein the cell has been isolated from ahuman prior to the administering step.

46. The method of any one of claims 30 to 44, wherein contacting is via administration toa subject.

47. The method of any one of claims 30 to 46, wherein the subject has been diagnosedwith a need for modification of dopaminergic signaling prior to the administering step.

48. The method of any one of claims 30 to 47, wherein the subject has been diagnosedwith a need for treatment of a disease associated with dysregulated dopaminergic signaling prior to the administering step.

49. A method of treating a HAND in a subject in need thereof, the method comprisingadministering to the subject an effective amount of a compound having a structure represented by a formula: ,wherein Q is a structure represented by a formula selected from:; wherein; wherein ** denotes a bondconnecte to ;wherein Z is selected from ‒N‒ and ‒CH‒; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from ‒NH2,C1-C4 alkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, ‒CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl; wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl; and or a pharmaceutically acceptable salt thereof,provided that when Z is ‒CH‒, then R2is hydrogen, provided that when Q is a structure represented by a formula: , thenthen n is 0, and provided that when Q is a structure represented by a formula: ,then R1is selected from ‒CN and C1-C4 alkyl and R2is hydrogen.

50. The method of claim 49, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

51. The method of claim 49, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable.

52. The method of claim 49, wherein the compound has a structure represented by aformula: R3cR3bR3d3ey1,or a pharmaceutically acceptable salt thereof.

53. The method of claim 49, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

54. The method of claim 49, wherein the compound has a structure represented by aformula: , or a pharmaceutically acceptable sa t t ereo .

55. The method of claim 49, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

56. The method of claim 49, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptabe sa t t ereo .

57. The method of any one of claims 49 to 56, wherein the effective amount is atherapeutically effective amount.

58. The method of any one of claims 49 to 56, wherein the effective amount is aprophylactically effective amount.

59. The method of any one of claims 49 to 58, wherein the subject is a mammal.

60. The method of claim 59, wherein the mammal is a human.

61. The method of any one of claims 49 to 60, wherein the subject has been diagnosedwith a need for treatment of HAND prior to the administering step.

62. The method of any one of claims 49 to 61, wherein the subject is at risk fordeveloping HAND prior to the administering step.

63. The method of any one of claims 49 to 62, further comprising the step of identifying asubject in need of treatment of HAND.

64. A kit comprising a compound having a structure represented by a formula:, wherein Q is a structure represeny selected from: ; wherein;wherein ** denotes a bond connected to ;wherein Z is selected from ‒N‒ and ‒CH‒; wherein R10is selected from hydrogen and C1-C4 alkyl; wherein R11is selected from ‒NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, ‒CN, and C1-C4 alkyl; wherein R2is selected from hydrogen, halogen, and C1-C4 alkyl;wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl; and or a pharmaceutically acceptable salt thereof, provided that when Z is ‒CH‒, then R2is hydrogen, provided that when Q is a structure represented by a formula: ,then n is 0, and provided that when Q is a structure represented by a formula: ,then R1is selected from ‒CN and C1-C4 alkyl and R2is hydrogen, and one or more selected from: (a) an agent associated with the treatment of a HAND;(b) instructions for administering the compound in connection with treating acondition associated with dysregulated dopaminergic signaling; and (c) instructions for treating a condition associated with dysregulated dopaminergicsignaling.

65. The kit of claim 64, wherein the agent is an antiretroviral agent.

66. The kit of claim 65, wherein the antiretroviral agent is a nucleoside / nucleotide reversetranscriptase inhibitor.

67. The kit of claim 66, wherein the nucleoside / nucleotide reverse transcriptase inhibitoris abacavir, emtricitabine, or tenofovir.

68. The kit of any one of claims 64 to 67, wherein the compound and the agent are co-packaged.

69. The kit of any one of claims 64 to 68, wherein the compound and the agent are co-formulated.

70. A compound having a structure represented by a formula selected from:3b3c, wherein n is 0 or 1;. wherein Q is a structure represented by a formula selected from: ;wherein ** denotes a bond connected to ‒(CR4aR4b)n‒; wherein Z is selected from ‒N‒ and ‒CH‒; wherein R10is selected from hydrogen and C1-C4 alkyl;wherein R11is selected from ‒NH2, C1-C4 alkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino; wherein R12is selected from hydrogen and methyl; wherein R1is selected from hydrogen, halogen, ‒CN, C1-C4 alkyl, and C1-C4 haloalkyl; wherein R2is selected from hydrogen, halogen, ‒CN, ‒NH2, C1-C4 alkyl, C1-C4 haloalkyl, ‒CO2H, ‒C(O)NH2, ‒C(O)NH(C1-C4 alkyl), and Cy2; wherein Cy2is selected from a C3-C6 cycloalkyl and a C3-C6 heterocycloalkyl, and is substituted with 0 or 1 C1-C4 alkyl group; wherein each of R3a, R3b, R3c, R3d, and R3eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒CO2(C1-C4 alkyl); wherein R4ais C1-C4 alkyl and wherein R4bis selected from hydrogen and C1-C4 alkyl, or wherein each of R4aand R4btogether comprise an unsubstituted cyclopropyl; and wherein Cy1is selected from a C4-C7 heterocycle and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl, or a pharmaceutically acceptable salt thereof, provided that when n is 0, then each of R1and R2is a non-hydrogen group, provided that when Q is a structure represented by a formula: ,then n is 0, and provided that the compound is not: .

71. The compound of claim 70,w ere n n s .

72. The compound of claim 70, wherein n is 1.

73. The compound of any one of claims 70 to 72, wherein Q is a structure represented bya formula: .

74. The compound of claim 73, wherein Z is ‒N‒.

75. The compound of claim 73, wherein Z is ‒CH‒.

76. The compound of any one of claims 70 to 72, wherein Q is a structure represented bya formula: .

77. The compound of claim 76, wherein R10 is hydrogen.

78. The compound of claim 76, wherein R11 is C1-C4 alkyl and wherein R12 is hydrogen.

79. The compound of any one of claims 70 to 79, wherein R1 is C1-C4 alkyl.

80. The compound of any one of claims 70 to 79, wherein R1 is methyl.

81. The compound of any one of claims 70 to 80, wherein R2 is hydrogen.

82. The compound of any one of claims 70 to 80, wherein R2 is selected from ‒CN, C1-C4 alkyl, and ‒CO2NH2, and Cy2.

83. The compound of any one of claims 70 to 82, wherein each of R3a, R3b, R3c, R3d, andR3eis hydrogen.

84. The compound of any one of claims 70 to 83, wherein R4a is C1-C4 alkyl and R4b ishydrogen.

85. The compound of any one of claims 70 to 83, wherein R4a is methyl and R4b ishydrogen.

86. The compound of any one of claims 70 to 83, wherein each of R4a and R4b togethercomprise an unsubstituted cyclopropyl.

87. The compound of any one of claims 70 to 87, wherein Cy1 is a C4-C7 heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl.

88. The compound of any one of claims 70 to 87, wherein Cy1 is an imidazopyridinesubstituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl.

89. The compound of any one of claims 70 to 87, wherein Cy1 is a C2-C10 heteroarylsubstituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and an unsubstituted C3-C6 cycloalkyl.

90. The compound of claim 70, wherein the compound has a structure represented by aformula: , or a pharmaceutically acceptablesalt thereof.

91. The compound of claim 70, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

92. The compound of claim 70, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptable sa ereo .

93. The compound of claim 70, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

94. The compound of claim 70, wherein the compound has a structure represented by aformula: y1,or a pharmaceutically acceptable salt thereof.

95. The compound of claim 70, wherein the compound has a structure represented by aformula: , or a pharmaceutically acceptable sat t ereo .

96. The compound of claim 70, wherein the compound has a structure represented by aformula: R4aR4bR3aR3b3c,or a pharmaceutically acceptable salt thereof.

97. The compound of claim 70, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

98. The compound of claim 70, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptablesa ereo .

99. The compound of claim 70, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

100. The compound of claim 70, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

101. The compound of claim 70, wherein the compound has a structure represented by aformula: , or a pharmaceutically acceptable salt thereof.

102. The compound of claim 70, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

103. The compound of claim 70, wherein the compound has a structure represented by aformula:R4aR4bR3aR3bQ 3c, or a pharmaceutically accepta.

104. The compound of claim 70, wherein the compound has a structure represented by aformula: R4aR4bR3aR3b3c,or a pharmaceutically acceptable salt thereof.

105. The compound of claim 70, wherein the compound has a structure represented by aformula: ,or a pharmaceutically acceptable salt thereof.

106. The compound of claim 70, wherein the compound has a structure represented by aformula:, or a pharmaceutically acceptab.

107. The compound of claim 70, wherein the compound is selected from:, ,,,,,,, , , , or a parmaceutca y acceptabe sat tereo.

108. The compound of claim 70, wherein the compound is selected from:, , , e ,,or a p109. A pharmaceutical composition comprising an effective amount of the compound ofany one of claims 70 to 108 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

110. A method of modifying dopaminergic signaling in a cell, the method comprisingcontacting the cell with an effective amount of the compound of any one of claims 70 to 108 or a pharmaceutically acceptable salt thereof.

111. A method of modifying dopaminergic signaling in a subject in need thereof, themethod comprising administering to the subject an effective amount of the compound of any one of claims 70 to 108 or a pharmaceutically acceptable salt thereof.

112. A method of treating a HAND in a subject in need thereof, the method comprisingadministering to the subject an effective amount of the compound of any one of claims 70 to 108 or a pharmaceutically acceptable salt thereof.

113. A kit comprising the compound of any one of claims 70 to 108 or a pharmaceuticallyacceptable salt thereof, and one or more selected from: (a) an agent associated with the treatment of a HAND;(b) instructions for administering the compound in connection with treating acondition associated with dysregulated dopaminergic signaling; (c) instructions for treating a condition associated with dysregulated dopaminergicsignaling.

114. A compound selected from:O NH F3, ,F , ,, , or a p.

115. A pharmaceutical composition comprising an effective amount of the compound ofclaim 114 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

116. A method of modifying dopaminergic signaling in a cell, the method comprisingcontacting the cell with an effective amount of the compound of claim 114 or a pharmaceutically acceptable salt thereof.

117. A method of modifying dopaminergic signaling in a subject in need thereof, themethod comprising administering to the subject an effective amount of the compound of claim 114 or a pharmaceutically acceptable salt thereof.

118. A method of treating a HAND in a subject in need thereof, the method comprisingadministering to the subject an effective amount of the compound of claim 114 or a pharmaceutically acceptable salt thereof.

119. A kit comprising the compound of claim 114 or a pharmaceutically acceptable saltthereof, and one or more selected from: (a) an agent associated with the treatment of a HAND;(b) instructions for administering the compound in connection with treating acondition associated with dysregulated dopaminergic signaling; and (c) instructions for treating a condition associated with dysregulated dopaminergicsignaling.

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