N-methyl-d-aspartate receptor (NMDAR) antagonists and uses thereof

Abstract

A series of novel substituted (hetero)arylmethanamines is described which bind to the N-methyl-D-aspartate receptor. Such compounds have value in various therapeutic indications including, but not limited to, pain, depression, tinnitus, post-traumatic stress disorder, etc.

Description

N-METHYL-D-ASPARTATE RECEPTOR (NMD AR) ANTAGONISTSAND USES THEREOFCROSS REFERENCE TO OTHER APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application no. 63 / 407,052, filed September 15, 2022, the entirety of which is incorporated by reference herein.INCORPORATION BY REFERENCE

[0002] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BACKGROUND

[0003] The N-methyl-D-aspartate receptor (“NMD AR”) is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal cord. For electrical signals to pass, the NMD AR must be open. In order for the channel to open, glutamate and glycine must bind to the NMD AR and the voltage dependent Mg2+block must be lifted. NMDARs in this state are called “activated.”

[0004] Chemicals that inhibit activation of the NMD AR are called antagonists. NMD AR antagonists fall into several categories: Competitive antagonists bind to and block the binding site of the neurotransmitter glutamate; glycine antagonists, which bind to and block the glycine site; noncompetitive antagonists inhibit NMDARs by binding to allosteric sites; and uncompetitive antagonists, which block the active channel. One example of NMD AR uncompetitive antagonists are compounds called channel blockers, like ketamine, that act by blocking the ion channel through binding to a site within NMDARs. These compounds show use dependent inhibition as they bind to “activated” NMDARs.SUMMARY

[0005] There remains a need for treatment of various physical, psychiatric, or neurological disorders associated with ionotropic receptor function, such as NMD AR, dopamine transporter (DAT), or serotonin receptor (SERT). In particular, compounds that selectively bind to NMD AR receptors over other ionotropic receptors may be valuable for the treatment of the various disorders, such as pain, depression, tinnitus, post-traumatic stress disorder, psychosis,schizophrenia, agitation, obsessive compulsive disorder, sexual dysfunction, anxiety, dementias, neurodegenerative diseases, pseudobulbar affect, headache, cluster headache, migraine, acute pain, post-operative pain, pain syndromes, neuropathic pain, chronic pain, complex regional pain syndrome, fibromyalgia, substance use disorders, drug addiction, alcoholism, hallucinations, delusions, insomnia, epilepsies, bipolar disorder, anorexia, or Parkinson’s disease.

[0006] The compounds of the present disclosure exhibit varying degrees of selectivity for NMDARs over other CNS targets, such as DAT or SERT. NMD AR dysfunction has been implicated in various somatic and central nervous system diseases and disorders. Selectivity for NMDARs can reduce undesired off-target interactions which can improve drug efficacy and tolerability for certain therapeutic indications. However, in some instances, such as certain therapeutic indications including certain types of chronic and neuropathic pain, and mood disorders, polypharmacology for NMD AR and monoamine transporters including DAT, SERT and NET may enhance the efficacy and tolerability of NMD AR antagonists. While effective, existing NMD AR antagonists like ketamine, memantine and DXM have various pharmacological limitations there is thus a need for new NMD AR antagonists with improved clinical profiles.

[0007] Inhibiting NMDARs with uncompetitive antagonists which bind to the PCP site of active NMDARs (use-dependent channel blockers) is believed to underlie the therapeutic activity of ketamine as a general anesthetic and for its use in treatment resistant depression and memantine for Alzheimer’s disease as a neuroprotective agent. Dextromethorphan, an uncompetitive NMD AR antagonist, is also used, in combination products to inhibit its metabolism, in pseudobulbar affect and in depression. NMD AR antagonism may lead to analgesic actions and can disrupt the processes of hyperalgesia and allodynia in pain disorders. However, these existing NMD AR antagonists have limitations related to their pharmacokinetic and pharmacodynamic properties. For example, DXM has potent off-target effects at SERT, which may contribute to its side effects, and has to be administered in combination with other compounds to inhibit its metabolism. Ketamine has poor oral bioavailability and a short half-life. Additionally, there are ambiguities as to the extent of dissociative effects as well as bladder issues that ketamine has been associated with. Thus, there remains a need for novel NMD AR antagonists with improved clinical profiles.

[0008] The present disclosure generally relates to substituted methanamine compounds, conjugates, or salts of Formula (I), (II), (III), (IV), (V), or (VI) and pharmaceutical compositions thereof. In certain aspects, the disclosure provides a compound represented by Formula (I):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R6;R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl;with the proviso that the compound of Formula I is not

[0009] In certain aspects, the disclosure provides a compound represented by Formula (II):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl;

[0010] In certain aspects, the disclosure provides a compound represented by Formula (III):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected fromhydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl, provided that the compound of Formula (III) is not

[0011] In certain aspects, the disclosure provides a compound represented by Formula (IV):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

[0012] In certain aspects, the disclosure provides a compound represented by Formula (V):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

[0013] In certain aspects, the disclosure provides a compound represented by Formula (VI):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

[0014] In certain aspects, the disclosure provides a pharmaceutical composition comprising a compound or salt of any one of Formulas (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable excipient.

[0015] Furthermore, the present disclosure generally relates to methods for treating a physical, psychiatric, or neurological disorder comprising inhibiting an ionotropic receptor by contacting the ionotropic receptor with a compound represented by the structure of Formula (I), (II), (III), (IV), (V), or (VI) and pharmaceutical compositions thereof.

[0016] In another aspect, the present disclosure provides a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a compound represented by the structure of Formula (I):R® ,R4N RliR3R(I), or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R6;R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-s alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl; provided that the compound of Formula (I) is not

[0017] In some aspects, provided herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (II):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl; provided that the compound of Formula (II) is not

[0018] In another aspect, provided herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (III):(ill); or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

[0019] In another aspect, provided herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (IV):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH,=0, =S, =NH, -SH, -N02, -NH2, -0-C1-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -N02, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

[0020] In another aspect, provided herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (V):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-s alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH,=0, =S, =NH, -SH, -N02, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -N02, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

[0021] In another aspect, provided herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (VI):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -N02, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

[0022] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.DETAILED DESCRIPTION

[0023] While various embodiments of the disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed.

[0024] Disclosed herein are a series of substituted methanamine compounds and pharmaceutical compositions for treating a physical, psychiatric, or neurological disorder. Examples of a physical, psychiatric, or neurological disorder include, but are not limited to, pain, depression, tinnitus, post-traumatic stress disorder, etc. In some embodiments, the compounds disclosed herein are V-m ethyl -D-aspartate receptor (NMD AR) antagonists. Further disclosed herein are methods for treating a physical, psychiatric, or neurological disorder comprising inhibiting an ionotropic receptor by contacting the ionotropic receptor with a compound disclosed herein and pharmaceutical compositions thereof.COMPOUNDS

[0025] The following is a discussion of compounds and salts thereof that may be used in the methods of this disclosure. In certain embodiments, the compounds and salts are described in Formulas (I), (II), (III), (IV), (V), or (VI).

[0026] In one aspect, disclosed herein is a compound represented by Formula (I):R5-N-R4R1iR3R(i); or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R6;R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-s alkyl; with the proviso that the compound of Formula (I) is not

[0027] In some aspects, disclosed herein is a compound of Formula (I):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R6;R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from: Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; and C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen; Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, and C3-5 cycloalkyl, wherein Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -N02, -NH2, -O-Ci-6alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; and C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -N02, -NH2, -O-Ci-6alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6 alkyl), and Ci-8 alkyl; orR4and R5are combined with the nitrogen to which it is attached to form a 6-membered heterocycle; with the proviso that the compound of Formula I is not

[0028] In some embodiments, for the compound or salt of Formula I, R1is selected from phenyl and 5- to 10-membered heteroaryl; wherein the phenyl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R6;R2is selected from hydrogen, Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-5 carbocycle, each of which is optionally substituted with one or more R7;R3is C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one or more R8;R4and R5are each independently selected from: hydrogen, CMO alkyl, and C3-5 cycloalkyl, wherein the CMO alkyl is optionally substituted with C3-5 cycloalkyl; or R4and R5are combined with the nitrogen to which it is attached to form a 6-membered heterocycle;R6is C O alkyl, wherein the CMO alkyl is optionally substituted with halogen;R7is C3-5 cycloalkyl; andR8is CMO alkyl.

[0029] In some embodiments, R1is selected from phenyl, imidazolyl, thiophenyl, and selenophenyl; wherein the phenyl, imidazolyl, thiophenyl, and selenophenyl are each optionally substituted with one or more R6. In some embodiments, R2is selected from hydrogen, methyl, ethyl, propyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, and cyclopentyl, each of which is optionally substituted with one or more R7. In some embodiments, R3is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R4and R5are each independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, iso-butyl, tert-butyl, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, cyclopropyl, cyclobutyl, or cyclopentyl; or R4and R5are combined with the nitrogen to which it is attached to form piperidinyl. In some embodiments, R6is methyl or CF3. In some embodiments, R7is cyclopropyl or cyclobutyl.In some embodiments, R1is selected from phenyl and selenophenyl; wherein the phenyl and selenophenyl are each optionally substituted with one or more R6. In some embodiments, R2is selected from hydrogen, methyl, butyl, ethenyl, propenyl, butenyl, ethynyl, cyclopropyl, and cyclobutyl, each of which is optionally substituted with one or more R7. In some embodiments, R3is cyclopentyl. In some embodiments, R4and R5are each independently selected from: hydrogen, methyl, ethyl, isopropyl, sec-butyl, methyl-cyclopropyl, cyclobutyl; or R4and R5are combined with the nitrogen to which it is attached to form piperidinyl. In some embodiments, R6is CF3. In some embodiments, R7is cyclopropyl or cyclobutyl. In some embodiments,

[0030] In some embodiments, R1is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R6.

[0031] In some embodiments, R1is phenyl, optionally substituted with one or more R6.

[0032] In some embodiments, R1is a cycloalkyl. In some embodiments, R1is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R6.

[0033] In some embodiments, R1is a cycloalkenyl. In some embodiments, R1is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R6. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0034] In some embodiments, R1is a 6-membered heteroaryl. In some embodiments, R1is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0035] In some embodiments, R1is a 5-membered heteroaryl. In some embodiments, R1is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0036] In some embodiments, R1is a 6-membered heterocycloalkenyl. In some embodiments, R1is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0037] In some embodiments, R1is a 5-membered heterocycloalkenyl. In some embodiments, R1is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0038] In some embodiments, R1is a 6-membered heterocycloalkyl. In some embodiments, R1is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0039] In some embodiments, R1is a 5-membered heterocycloalkyl. In some embodiments, R1is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0040] In some embodiments, R1is a 4-membered heterocycloalkyl. In some embodiments, R1is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0041] In some embodiments, R1is a 6-6 fused ring system. In some embodiments, R1is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R6.

[0042] In some embodiments, R1is a 5-6 fused ring system. In some embodiments, R1is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R6.

[0043] In some embodiments, R1is a 5-5 fused ring system. In some embodiments, R1is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole,imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R6.

[0044] In some embodiments, R1is a bridged ring system. In some embodiments, R1is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R6. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0045] In some embodiments, R2is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0046] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0047] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0048] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0049] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0050] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7.

[0051] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0052] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine,dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0053] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0054] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0055] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0056] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0057] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0058] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine,oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0059] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0060] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0061] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0062] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0063] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0064] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0065] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0066] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which isoptionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0067] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0068] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0069] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0070] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0071] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0072] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which isoptionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0073] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0074] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0075] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0076] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0077] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0078] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0079] In some embodiments, the compound has the structure:or a pharmaceutically acceptable salt of the compound.

[0080] In another aspect, disclosed herein is a compound represented by Formula (II):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-8 alkyl; with the proviso that the compound of Formula I is not

[0081] In some embodiments, R2is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0082] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0083] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0084] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0085] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0086] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0087] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0088] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0089] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. Insome embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0090] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0091] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0092] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0093] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0094] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0095] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0096] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0097] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0098] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0099] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0100] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0101] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0102] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0103] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0104] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0105] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0106] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0107] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0108] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0109] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0110] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene,benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0111] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0112] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0113] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0114] In some embodiments, each of R4or R5may independently be a 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be a 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0115] In some embodiments, compound of Formula (II) is selected from:

[0116] In another aspect, disclosed herein is a compound represented by Formula (III):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituentsindependently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-s alkyl.

[0117] In some embodiments, R2is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0118] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0119] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0120] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0121] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0122] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).

[0123] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).

[0124] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (III).

[0125] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline,triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (III).

[0126] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).

[0127] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).

[0128] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).

[0129] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0130] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0131] In some embodiments, R2is a 5-5 fused ring system selected. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2- c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2- d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4- c]thiophene, any of which is optionally substituted with one or more R7.

[0132] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0133] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0134] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0135] In some embodiments, the compound of Formula (III) is selected from:

[0136] In some embodiments, the compound of Formula (III) is selected from:

[0137] In another aspect, disclosed herein is a compound represented by Formula (IV):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-8 alkyl.

[0138] In some embodiments, R2is hydrogen, Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0139] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0140] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0141] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0142] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0143] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).

[0144] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).

[0145] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (IV).

[0146] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (IV).

[0147] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).

[0148] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).

[0149] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).

[0150] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0151] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0152] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole,imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0153] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0154] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0155] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0156] In some embodiments, the compound of Formula (IV) is selected from:

[0157] In another aspect, disclosed herein is a compound represented by Formula (V):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-8 alkyl.

[0158] In some embodiments, R2is hydrogen, Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0159] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0160] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0161] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0162] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0163] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0164] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0165] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0166] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0167] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substitutedwith one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0168] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0169] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0170] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0171] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5- c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0172] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0173] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, bicyclofl.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0174] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0175] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0176] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0177] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0178] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0179] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0180] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0181] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which isoptionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0182] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0183] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0184] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0185] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0186] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0187] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4-b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5- c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0188] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0189] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0190] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0191] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0192] In some embodiments, compound of Formula (V) is selected from:

[0193] In another aspect, disclosed herein is a compound represented by Formula (VI):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R3is selected from:Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-s alkyl.

[0194] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0195] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0196] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0197] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0198] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, andcyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0199] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).

[0200] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).

[0201] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (VI).

[0202] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (VI).

[0203] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).

[0204] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In someembodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).

[0205] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).

[0206] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0207] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0208] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0209] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane,any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0210] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0211] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0212] In some embodiments, compound of Formula (VI) is selected from:

[0213] In some embodiments, a compound of Formula (I), (II), (III), (IV), (V), or (VI) is selected from Table 1 or Table la.TABLE 1. Compounds.TABLE la. Compounds.

[0214] Methods of administration of a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) as discussed herein may be used for the treatment of a physical, psychiatric, or neurological disorder. In some embodiments, the compounds disclosed herein are n-methyl-d-aspartate receptor (NMD AR) antagonists. In some embodiments, the compounds disclosed herein are ionotropic receptor inhibitors.Pharmaceutical Formulations

[0215] The compositions and methods described herein may be considered useful as pharmaceutical compositions for administration to a subject in need thereof. Pharmaceutical compositions may comprise at least a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and / or thickening agents.

[0216] Pharmaceutical compositions comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation may be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate may be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions may also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.

[0217] Methods for formulation of a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may include formulating any of the compounds, salts or conjugates with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granulesand capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. Alternatively, the compounds, salts or conjugates may be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0218] Pharmaceutical compositions comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may comprise at least one active ingredient (e.g., a compound, salt or conjugate and other agents). The active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.

[0219] The compositions and formulations may be sterilized. Sterilization may be accomplished by filtration through sterile filtration, heat, light, radiation, chemicals or other forms.

[0220] The compositions described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The compositions described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0221] The compositions comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be formulated for administration as an injection. Non-limiting examples of formulations for injection may include a sterile suspension, solution or emulsion in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity or tonicity of the solution or suspension. The solution or suspension may also contain suitable stabilizers. Injections may be formulated for bolus injection or continuous infusion. Alternatively, the compositions may be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0222] For parenteral administration, a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles may be inherently non-toxic, and non-therapeutic. Vehicles may be water, saline, Ringer’s solution, dextrose solution, organic solvents (e.g., ethanol, DMF, DMSO), human serum albumin, and combinations thereof. Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used. Liposomes may be used as carriers. The vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0223] In one embodiment the disclosure relates to methods and compositions of Formula (I), (II), (III), (IV), (V), or (VI) formulated for formulated into a pharmaceutical composition suitable for injection into the body including intramuscular, subcutaneous, intravenous, intratympanic, intraocular, epidural injection. In one aspect, formulations suitable for injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, complexing agents (e.g., cyclodextrins) or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, cremophor and the like), vegetable oils and organic esters, such as ethyl oleate. In some aspects of the disclosure, formulations suitable for subcutaneous injection contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0224] For intravenous injections, compounds described herein are formulated in aqueous solutions, in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0225] Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In one aspect, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0226] In certain aspects of the disclosure, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain aspects of the disclosure, compositions provided herein can also include an mucoadhesive polymer, selectedfrom among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0227] In one embodiment the disclosure relates to methods and compositions of Formula (I), (II), (III), (IV), (V), or (VI) formulated for oral delivery to a subject in need. In one embodiment a composition is formulated so as to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the mouth or esophagus. In another embodiment the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the stomach and / or intestines.

[0228] In one embodiment compositions of Formula (I), (II), (III), (IV), (V), or (VI) are provided in modified release dosage forms. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multi-particulate devices, and combinations thereof. The compositions may also comprise non-release controlling excipients.

[0229] In another embodiment compositions of Formula (I), (II), (III), (IV), (V), or (VI) are provided in enteric coated dosage forms. These enteric coated dosage forms can also comprise non-release controlling excipients. In one embodiment the compositions are in the form of enteric-coated granules, as controlled-release capsules for oral administration. The compositions can further comprise cellulose, cyclodextrins, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate. In another embodiment the compositions are in the form of enteric-coated pellets, as controlled-release capsules for oral administration. The compositions can further comprise cyclodextrins, glycerol monostearate 40- 50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.

[0230] In another embodiment the compositions of Formula (I), (II), (III), (IV), (V), or (VI) are enteric-coated controlled-release tablets for oral administration. The compositions can further comprise carnauba wax, crospovidone, cyclodextrins, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow ferric oxide.

[0231] Sustained-release preparations comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may also be prepared. Examples of sustained-release preparations may include semipermeable matrices of solid hydrophobic polymers that may contain the compound, salt or conjugate, and these matrices may be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices may include polyesters, hydrogels (e.g., poly(2-hydroxy ethyl -methacrylate), or poly(vinyl alcohol)), polylactides, copolymers ofL-glutamic acid and y ethyl -L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO™ (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3 -hydroxybutyric acid.

[0232] Pharmaceutical formulations comprising a compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and / or a stabilizer. This formulation may be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers may be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and / or non-ionic surfactants or polyethylene glycol.

[0233] In another embodiment the compositions of Formula (I), (II), (III), (IV), (V), or (VI) can further comprise calcium stearate, crospovidone, cyclodextrins, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0234] In another embodiment compositions of Formula (I), (II), (III), (IV), (V), or (VI) are provided in effervescent dosage forms. These effervescent dosage forms can also comprise nonrelease controlling excipients.

[0235] In another embodiment compositions of Formula (I), (II), (III), (IV), (V), or (VI) can be provided in a dosage form that has at least one component that can facilitate the immediate release of an active agent, and at least one component that can facilitate the controlled release of an active agent. In a further embodiment the dosage form can be capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours. The compositions can comprise one or more release controlling and non-release controlling excipients, such as those excipients suitable for a disruptable semi- permeable membrane and as swellable substances.

[0236] In another embodiment compositions Formula (I), (II), (III), (IV), (V), or (VI) are provided in a dosage form for oral administration to a subject, which comprise one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layercomprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.

[0237] In some embodiments, the compositions of Formula (I), (II), (III), (IV), (V), or (VI) provided herein can be in unit-dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human or non-human animal subjects and packaged individually. Each unit-dose can contain a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container, which can be administered in segregated unit-dosage form. Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment the multiple dosage forms comprise different pharmaceutically active agents.

[0238] In some embodiments, the compositions of Formula (I), (II), (III), (IV), (V), or (VI) may also be formulated as a modified release dosage form, including immediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, extended, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to known methods and techniques (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126, which are herein incorporated by reference in their entirety).Therapeutic Applications

[0239] The disclosure provides methanamines and substituted methanamine compounds and salts thereof of Formula (I), (II), (III), (IV), (V), or (VI) for treating physical, psychiatric, or neurological disorders. In some embodiments, treating physical, psychiatric, or neurological disorders comprises inhibiting an ionotropic receptor. In some embodiments, the ionotropic receptor comprises NMD AR or DAT. In some embodiments, treating physical, psychiatric, or neurological disorders comprises inhibiting NMD AR. In some embodiments, treating physical, psychiatric, or neurological disorders comprises inhibiting DAT. In some embodiments, inhibiting an ionotropic receptor comprises administering a compound or a salt thereof of Formula (I), (II), (III), (IV), (V), or (VI). In some embodiments, the physical, psychiatric, orneurological disorder comprises pain, depression, tinnitus, post-traumatic stress disorder, psychosis, schizophrenia, agitation, obsessive compulsive disorder, sexual dysfunction, anxiety, dementias, neurodegenerative diseases, pseudobulbar affect, headache, cluster headache, migraine, acute pain, post-operative pain, pain syndromes, neuropathic pain, chronic pain, complex regional pain syndrome, fibromyalgia, substance use disorders, drug addiction, alcoholism, hallucinations, delusions, insomnia, epilepsies, bipolar disorder, anorexia, or Parkinson’s disease.

[0240] In some aspects, provided herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an ionotropic receptor by contacting the ionotropic receptor with a compound represented by the structure of Formula (I):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R6;R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH,=0, =S, =NH, -SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl; provided that the compound of Formula (I) is not

[0241] In some embodiments, R1is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R6.

[0242] In some embodiments, R1is phenyl, optionally substituted with one or more R6.

[0243] In some embodiments, R1is a cycloalkyl. In some embodiments, R1is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R6.

[0244] In some embodiments, R1is a cycloalkenyl. In some embodiments, R1is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R6. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0245] In some embodiments, R1is a 6-membered heteroaryl. In some embodiments, R1is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0246] In some embodiments, R1is a 5-membered heteroaryl. In some embodiments, R1is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0247] In some embodiments, R1is a 6-membered heterocycloalkenyl. In some embodiments, R1is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine,dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0248] In some embodiments, R1is a 5-membered heterocycloalkenyl. In some embodiments, R1is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0249] In some embodiments, R1is a 6-membered heterocycloalkyl. In some embodiments, R1is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0250] In some embodiments, R1is a 5-membered heterocycloalkyl. In some embodiments, R1is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0251] In some embodiments, R1is a 4-membered heterocycloalkyl. In some embodiments, R1is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R6. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0252] In some embodiments, R1is a 6-6 fused ring system. In some embodiments, R1is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R6.

[0253] In some embodiments, R1is a 5-6 fused ring system. In some embodiments, R1is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine,pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R6.

[0254] In some embodiments, R1is a 5-5 fused ring system. In some embodiments, R1is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R6.

[0255] In some embodiments, R1is a bridged ring system. In some embodiments, R1is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R6. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0256] In some embodiments, R2is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0257] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0258] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0259] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0260] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0261] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7.

[0262] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0263] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0264] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0265] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0266] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0267] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which isoptionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0268] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0269] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0270] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0271] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0272] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0273] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0274] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0275] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0276] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0277] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0278] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (I).

[0279] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0280] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (I).

[0281] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0282] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0283] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (I).

[0284] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0285] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0286] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole,imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0287] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0288] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0289] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0290] In some embodiments, the compound of Formula (I) is selected from:

[0291] In another aspect, disclosed herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (II):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-s alkyl; provided that the compound of Formula II is not

[0292] In some embodiments, R2is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0293] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0294] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0295] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0296] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0297] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0298] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0299] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine,dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0300] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0301] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0302] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0303] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0304] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0305] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine,oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0306] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b ] thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0307] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0308] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0309] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0310] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0311] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0312] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0313] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which isoptionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0314] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (II).

[0315] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0316] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (II).

[0317] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0318] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0319] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which isoptionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (II).

[0320] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0321] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0322] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0323] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0324] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0325] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0326] In some embodiments, compound of Formula (II) is selected from:

[0327] In another aspect, disclosed herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (III):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R4, R5, R6, R7, and R8are each independently selected from:hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-s alkyl.

[0328] In some embodiments, R2is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0329] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0330] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0331] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0332] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0333] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).

[0334] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (III).

[0335] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine,dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (III).

[0336] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (III).

[0337] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).

[0338] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).

[0339] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (III).

[0340] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0341] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine,pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0342] In some embodiments, R2is a 5-5 fused ring system selected. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2,l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2- c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2- d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4- c]thiophene, any of which is optionally substituted with one or more R7.

[0343] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0344] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0345] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0346] In some embodiments, the compound of Formula (III) is selected from:

[0347] In another aspect, disclosed herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (IV):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-8 alkyl.

[0348] In some embodiments, R2is hydrogen, Ci-8 alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0349] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0350] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0351] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0352] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, andcyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0353] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).

[0354] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (IV).

[0355] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (IV).

[0356] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (IV).

[0357] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).

[0358] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In someembodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).

[0359] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (IV).

[0360] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0361] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0362] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0363] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane,any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0364] In some embodiments, each of R4or R5may independently be hydrogen, Ci-io alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0365] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0366] In some embodiments, the compound of Formula (IV) is selected from:

[0367] In another aspect, disclosed herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by Formula (V):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-s alkyl.

[0368] In some embodiments, R2is hydrogen, Ci-s alkyl, C2-8 alkenyl, or C2-8 alkynyl, each of which is optionally substituted with one or more R7.

[0369] In some embodiments, R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

[0370] In some embodiments, R2is phenyl, optionally substituted with one or more R7.

[0371] In some embodiments, R2is a cycloalkyl. In some embodiments, R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

[0372] In some embodiments, R2is a cycloalkenyl. In some embodiments, R2is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R7. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0373] In some embodiments, R2is a 6-membered heteroaryl. In some embodiments, R2is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0374] In some embodiments, R2is a 5-membered heteroaryl. In some embodiments, R2is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0375] In some embodiments, R2is a 6-membered heterocycloalkenyl. In some embodiments, R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0376] In some embodiments, R2is a 5-membered heterocycloalkenyl. In some embodiments, R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0377] In some embodiments, R2is a 6-membered heterocycloalkyl. In some embodiments, R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0378] In some embodiments, R2is a 5-membered heterocycloalkyl. In some embodiments, R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0379] In some embodiments, R2is a 4-membered heterocycloalkyl. In some embodiments, R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0380] In some embodiments, R2is a 6-6 fused ring system. In some embodiments, R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

[0381] In some embodiments, R2is a 5-6 fused ring system. In some embodiments, R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5- c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

[0382] In some embodiments, R2is a 5-5 fused ring system. In some embodiments, R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

[0383] In some embodiments, R2is a bridged ring system. In some embodiments, R2is a bridged ring system selected from norbornane, bicyclofl.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0384] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0385] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0386] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0387] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0388] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0389] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0390] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (V).

[0391] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0392] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (V).

[0393] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substitutedwith one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0394] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0395] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (V).

[0396] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0397] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5- c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0398] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0399] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0400] In some embodiments, each of R4or R5may independently be hydrogen, CMO alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0401] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, and 1,4-piperazine, 1,4-oxazepane, 1,4-diazepane.

[0402] In some embodiments, compound of Formula (V) is selected from:

[0403] In another aspect, disclosed herein is a method for treating a physical, psychiatric, or neurological disorder comprising inhibiting an inotropic receptor by contacting the receptor with a pharmaceutical composition comprising a compound represented by the structure of Formula (VI):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R3is selected from:Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, - NO2, -NH2, -O-Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), and Ci-s alkyl.

[0404] In some embodiments, R3is hydrogen, Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more R8.

[0405] In some embodiments, R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

[0406] In some embodiments, R3is phenyl, optionally substituted with one or more R8.

[0407] In some embodiments, R3is a cycloalkyl. In some embodiments, R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

[0408] In some embodiments, R3is a cycloalkenyl. In some embodiments, R3is a cycloalkenyl selected from cyclooctene, cycloheptene, cyclohexene, cyclopentene, cyclobutene, and cyclopropane, any of which is optionally substituted with one or more R8. In some embodiments, the cycloalkenyl can have 1, 2, 3, 4, or more degrees of unsaturation.

[0409] In some embodiments, R3is a 6-membered heteroaryl. In some embodiments, R3is a 6- membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).

[0410] In some embodiments, R3is a 5-membered heteroaryl. In some embodiments, R3is a 5- membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionallysubstituted with one or more R8. In some embodiments, the heteroatom of the heteroaryl is not bound to the methylene carbon of Formula (VI).

[0411] In some embodiments, R3is a 6-membered heterocycloalkenyl. In some embodiments, R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (VI).

[0412] In some embodiments, R3is a 5-membered heterocycloalkenyl. In some embodiments, R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkenyl is not bound to the methylene carbon of Formula (VI).

[0413] In some embodiments, R3is a 6-membered heterocycloalkyl. In some embodiments, R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).

[0414] In some embodiments, R3is a 5-membered heterocycloalkyl. In some embodiments, R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).

[0415] In some embodiments, R3is a 4-membered heterocycloalkyl. In some embodiments, R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8. In some embodiments, the heteroatom of the heterocycloalkyl is not bound to the methylene carbon of Formula (VI).

[0416] In some embodiments, R3is a 6-6 fused ring system. In some embodiments, R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

[0417] In some embodiments, R3is a 5-6 fused ring system. In some embodiments, R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

[0418] In some embodiments, R3is a 5-5 fused ring system. In some embodiments, R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l- b ] thi azole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2- b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

[0419] In some embodiments, R3is a bridged ring system. In some embodiments, R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8. In some embodiments, the bridged ring system can have 1, 2, 3, 4, or more degrees of unsaturation.

[0420] In some embodiments, each of R4or R5may independently be hydrogen, CMO alkyl, C2- 10 alkenyl, or C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -NO2, -NH2, -O- Ci-6 alkyl, -S-Ci-6 alkyl, -N(CI-6 alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl.

[0421] In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle. In some embodiments, each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

[0422] In some embodiments, compound of Formula (VI) is selected from:

[0423] In some embodiments, provided herein is a m ethod of treating a physical, psychiatric, or neurological disorder comprises administering a composition comprising a compound of Table 1. In some embodiments, provided herein is a m ethod of treating a physical, psychiatric, or neurological disorder comprises administering a composition comprising a compound of Table la.

[0424] In some aspects, the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a N-methyl-D-aspartate receptor (NMD AR). An inhibitor compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of NMD AR by about 5% to about 90% relative to pre-treatment value or an untreated control NMD AR. In some instances, an inhibitor or antagonist compound of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of NMD AR by about 5% to about 90% relative to ketamine, phencyclidine (PCP), or other inhibitor of NMD AR. An inhibitor may inhibit activity of NMD AR by at least about 5% relative to pre-treatment value or an untreated control NMD AR, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of NMD AR by at most about 90% relative to pre-treatment value or an untreated control NMD AR, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of NMD AR by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90% relative to pre-treatment capacity or an untreated control NMD AR. An inhibitor may inhibit activity of NMD AR by about 5%, about10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to pre-treatment capacity or an untreated control NMD AR.

[0425] In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI) show PCP site NMD AR binding affinities (e.g., measured as a dissociation constant Kd or Ki) in the range of 0.1-100,000. In some instances, the inhibitors may fully inhibit NMDARs. In some embodiments, the inhibitors may inhibit 100% activity of NMDARs. In some embodiments, the compound may inhibit activity NMD AR such as by competitively binding to NMD AR, such as displacing MK-801 or TCP. In some embodiments, the compounds of Formula (I), (II), (III), (IV), (V), or (VI) may displace a ligand bound to NMD AR. In some embodiments, the compound binds to the PCP site within the NMD AR, thus acting as a channel blocker. The binding activity of the compound may be determined by a radioligand binding assay. In some embodiments, the binding activity of the compound may be determined by a competitive radioligand binding assay. In some instances, the measured activity of the compound may be determined by a competitive radioligand binding assay relative to3H-MK-801 or3H-TCP. In some embodiments, the compound binds to NMD AR with a binding affinity (e.g., Ki). In some embodiments, the compound binds with a Ki less than 100 pM. In some embodiments, the compound binds with a Ki of about 0.1 nM to about 1 x 106nM, about 0.2 nM to about 9* 105nM, about 0.3 nM to about 8* 105nM, about 0.4 nM to about 7* 105nM, about 0.5 nM to about 6* 105nM, about 0.6 nM to about 5* 105nM, about 0.7 nM to about 4* 105nM, about 0.8 nM to about 3 * 105nM, about 0.9 nM to about 2* 105nM, about 1 nM to about 1 * 105nM, about 5 nM to about 5* 104nM, about 10 nM to about 1 * 103nM, about 50 nM to about 5* 103nM, about 100 nM to about 2* 103nM, or about 500 nM to about 1 * 103nM. In some embodiments, the compound may bind to NMDARs with a Ki of about 5 * 104nM, about 2 * 104nM, about 1 * 104nM, 5 * 103nM, about 2* 103nM, about 1 * 103nM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, or about 10 nM.

[0426] In some aspects, the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a dopamine transporter (DAT). An inhibitor compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of DAT by about 5% to about 100% relative to pre-treatment value or an untreated control DAT. In some instances, an inhibitor or antagonist compound of Formula (I), (II), (III), (IV), (V), or (Vl)may inhibit activity of DAT by about 5% to about 90% relative to desipramine, GBR 12935, cocaine, methylphenidate, bupropion 12935 or other inhibitor of DAT. An inhibitor may inhibit activity of DAT by at least about 5% relative to pre-treatment value or an untreated control DAT. An inhibitor may inhibit activity of DAT by at most about 90% relative to pre-treatment value or an untreated controlI l lDAT. An inhibitor may inhibit activity of DAT at a physiologically relevant concentration by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 10% to about 100%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 50% to about 100%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 60% to about 100%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90% relative to pre-treatment capacity or an untreated control DAT. In some embodiments, an inhibitor may inhibit DAT activity at physiologically relevant concentrations by about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 60% to about 90%, about 70% to about 90%, or about 50% to about 100%. An inhibitor may inhibit activity of DAT by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to pre-treatment capacity or an untreated control DAT. A physiologically relevant inhibitor of DAT may have a potency estimate, such as a receptor binding affinity (e.g., I<d or Ki) of about 0.1 to about 100,000 nM. The binding affinity of the compounds disclosed herein may be determined by a radioligand binding assay. Alternatively, potency to inhibit substrate uptake at DAT (IC50) can be measured from a transporter functional assay. In some embodiments, the binding affinity of the compounds disclosed herein may be determined by a competitive radioligand binding assay or a functional assay of DAT transport.

[0427] In some aspects, the method of treating a physical, psychiatric, or neurological disorder comprises binding to and reducing an activity of an ionotropic receptor, such as NMD AR, or a transporter such as DAT, or SERT. An inhibitor of Formula (I), (II), (III), (IV), (V), or (VI) may show selectivity forNMDARs relative to SERT and / or DAT by about 1-fold, 2-fold, 3-fold, 5- fold, 10-fold, about 20-fold, about 30-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 500-fold, about 1,000-fold, about 2,000-fold, about 3,000-fold, 5,000-fold or about 10,000-fold. In some embodiments, the inhibitor reduces activity of the ionotropic receptor with selectivity for NMD AR relative to SERT and / or DAT by about 10-fold to about 1,000-fold,by about 20-fold to about 500-fold, by about 30-fold to about 300-fold, by about 50-fold to about 200-fold, by about 10-fold to about 500-fold, by about 20-fold to about 1,000-fold, by about 30- fold to about 2,000-fold, by about 50-fold to about 5,000-fold, by about 1,000-fold to about 5,000-fold, by about 1-fold to about 10-fold, by about 2-fold to about 20-fold, by about 3-fold to about 30-fold, or by about 5-fold to about 50-fold. The binding affinity of the compounds disclosed herein may be determined by a radioligand binding assay. In some embodiments, the binding affinity of the compounds disclosed herein may be determined by a competitive radioligand binding assays. In some instances, selectivity can be determined using functional assays of channel or transporter activity. In some instances, selectivity can be determined using a combination of radioligand binding and functional assays. In some instances, the inhibitor of Formula (I), (II), (III), (IV), (V), or (VI) selectively inhibits NMDARs with selectivity over other targets, such as the monoamine transporters DAT or SERT. In some instances, the inhibitor of Formula (I), (II), (III), (IV), (V), or (VI) shows polypharmacology for NMD AR and one or more additional receptors or transporters such as the monoamine transporters DAT, NET and SERT.

[0428] In some aspects, the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a serotonin receptor (SERT). An inhibitor compound or salt of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of SERT by about 5% to about 100% relative to pre-treatment value or an untreated control SERT. In some instances, an inhibitor or antagonist compound of Formula (I), (II), (III), (IV), (V), or (VI) may inhibit activity of SERT at a physiologically relevant concentration by about 5% to about 90% relative to untreated control. An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by at least about 5% relative to pre-treatment value or an untreated control SERT, such as without any inhibitor bound. An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by up to 100% relative to pre-treatment value or an untreated control SERT, such as without any inhibitor bound. An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90% relative to pre-treatment capacity or an untreated control SERT. An inhibitor may inhibit activity of SERT at a physiologically relevant concentration by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% relative to pre-treatment capacity or an untreated control. A physiologically relevant inhibitor of SERT may have a potency estimate, such as a receptor binding affinity (e.g., I<d or Ki) of about 0.1 to about 100,000 nM. The binding activity of the compounds disclosed herein may be determined by a radioligand binding assay. In some embodiments, the binding activity of the compounds disclosed herein may be determined by a competitive radioligand binding assay.

[0429] In some embodiments, the method of treating a physical, psychiatric, or neurological disorder comprises selectively binding to an NMD AR as compared to another ionotropic receptor. In some embodiments the other ionotropic receptor comprises SERT or DAT. In some embodiments, at a given physiologically relevant concentration, the compound selectively binds to NMD AR by about 10% to about 100%, by about 20% to about 100%, by about 30% to about 100%, by about 40% to about 100%, by about 50% to about 100%, by about 60% to about 100%, by about 70% to about 100%, by about 80% to about 100%, by about 90% to about 100%, by about 10% to about 90%, by about 20% to about 90%, by about 30% to about 90%, by about 40% to about 90%, by about 50% to about 90%, by about 60% to about 90%, by about 70% to about 90%, by about 80% to about 90%, by about 20% to about 80%, by about 30% to about 80%, by about 40% to about 80%, by about 50% to about 80%, by about 60% to about 80%, by about 70% to about 80%, by about 80% to about 80%, by about 20% to about 70%, by about 30% to about 70%, by about 40% to about 70%, by about 50% to about 70%, by about 60% to about 70%, by about 70% to about 70%, or by about 80% to about 70% as compared to binding of the compound to another ionotropic receptor. In some embodiments, binding of the compound to NMD AR may be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% greater than binding of the compound to another ionotropic receptor.

[0430] In some aspects, the method of the method of treating a physical, psychiatric, or neurological disorder comprises binding an compound of Formula (I), (II), (III), (IV), (V), or (VI) to NMDARs with a Ki of about 0.1 nM to about 100,000 nM. In some embodiments, the inhibitor may bind to NMDARs with a Ki of about 0.1 nM to about 1 * 106nM, about 0.2 nM toabout 9* 105nM, about 0.3 nM to about 8* 105nM, about 0.4 nM to about 7* 105nM, about 0.5 nM to about 6* 105nM, about 0.6 nM to about 5* 105nM, about 0.7 nM to about 4* 105nM, about 0.8 nM to about 3 * 105nM, about 0.9 nM to about 2* 105nM, about 1 nM to about 1 * 105nM, about 5 nM to about 5* 104nM, about 10 nM to about 1 * 103nM, about 50 nM to about 5* 103nM, about 100 nM to about 2* 103nM, or about 500 nM to about 1 * 103nM. In some embodiments, the compound may bind to NMDARs with a Ki of about 5* 104nM, about 2* 104nM, about 1 x 104nM, 5* 103nM, about 2* 103nM, about 1 x 103nM, about 500 nM, about 200 nM, about 100 nM, about 50 nM, about 20 nM, or about 10 nM. The binding affinity of the compounds disclosed herein may be determined by a radioligand binding assay. In some embodiments, the binding affinity of the compounds disclosed herein may be determined by a competitive radioligand binding assay.Definitions

[0431] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0432] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0433] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “Ci-ealkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term -Cx.yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example -Ci-ealkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0434] The terms “Cx.yalkenyl” and “Cx.yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term -Cx.yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, -C2-ealkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term -Cx.yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, -C2-ealkynylene- may be selected fromethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0435] "Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkylene comprises one to five carbon atoms (z.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (z.e., Ci- C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (z.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (z.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (z.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (z.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (z.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (z.e., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0436] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons, respectively. In other embodiments, an alkenylene comprises two to five carbon atoms (z.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (z.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (z.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (z.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (z.e., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (z.e., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0437] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkynylene comprises two to five carbon atoms (z.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (z.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (z.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (z.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (z.e., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (z.e., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0438] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle further includes spiro bicylic rings such as spiropentane. A bicyclic carbocycle includes any combination of ring sizes such as 3-3 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. In some embodiments, carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, norbornyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclofl. l.l]pentanyl.

[0439] The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) 7t-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar" (suchas in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents such as those substituents described herein.

[0440] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbomyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclo[l. l.l]pentanyl, and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals that are optionally substituted by one or more substituents such as those substituents described herein.

[0441] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise stated specifically in the specification, the term "cycloalkenyl" is meant to include cycloalkenyl radicals that are optionally substituted by one or more substituents such as those substituents described herein.

[0442] The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0443] The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein.

[0444] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. In some embodiments, heteroatoms include N, O, Si, P, B, S, and Se atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In someembodiments, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. A bicyclic heterocycle further includes spiro bicylic rings such as 2-oxa-6-azaspiro[3.3]heptane. The term “heterocycle” is meant to encompass “heteroaryl,” “heterocycloalkyl,” and “heterocycloalkenyl.”

[0445] The term "heteroaryl" refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, sulfur and selenium. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) 7t-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1.6-naphthyri dinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- UT-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, selenophenyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl).

[0446] The term "heterocycloalkyl" refers to a saturated ring with carbon atoms and at least one heteroatom. In some embodiments, heteroatoms include N, O, Si, P, B, S, and Se atoms. Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents such as those substituents described herein.

[0447] The term "heterocycloalkenyl" refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. In some embodiments, heteroatoms include N, O, Si, P, B, S, and Se atoms. Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms. The heterocycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine,tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine. Unless otherwise stated specifically in the specification, the term "heterocycloalkenyl" is meant to include heterocycloalkenyl radicals that are optionally substituted by one or more substituents such as those substituents described herein.

[0448] The term “alkoxy” or “alkoxyl” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0449] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes 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, z.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. 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, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. In some embodiments, substitution may cause a compound to have a formal charge.

[0450] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, - Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), - Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, - Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, - Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0451] Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “=O” and “(O)”. Double bonds to nitrogen atoms are represented as both “=NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “=S” and “(S)”.

[0452] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.Further Forms of Compounds

[0453] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0454] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0455] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, cyclodextrins; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) preservatives, (22) antioxidants, and (23) osmolality modifying substances, and (24) other non-toxic compatible substances employed in pharmaceutical formulations.

[0456] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, ion exchange resins, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0457] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0458] The methods and formulations described herein include the use of A-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure disclosed herein, as well as active metabolites of these compounds having the same type of activity.

[0459] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds disclosed herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0460] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0461] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36C1,123I,124I,125I,1311,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0462] In some embodiments, the compounds disclosed herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. Insome embodiments, the compound disclosed herein exists in the R configuration. In some embodiments, the compound disclosed herein exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0463] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds disclosed herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0464] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0465] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N- alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.EXAMPLES

[0466] Chemicals and Reagents - All reagents for used for synthesis were > 90% in purity and purchased from the following commercial suppliers: Sigma-Aldrich (St. Louis, MO), Fisher Scientific (Waltham, MA), IPlusChem (San Diego, CA), Oakwood Chemical (Estill, SC), AK Scientific (Union City, CA), Combi-Blocks (San Diego, CA), Enamine (Kyiv, Ukraine), Accela (San Diego, CA), Pharmco (Brookfield, CT), and Alfa Aesar (Ward Hill, MA). All reagents were used without further purification. Dry solvents were dried over 3 A molecular sieves (Alfa Aesar, Ward Hill, MA) under argon atmosphere for at a minimum of 3 days prior to use. The following reagents were used for HPLC: ammonium formate (LiChropurTM, > 99.0%, Sigma- Aldrich, St. Louis, MO), formic acid (> 98%, Sigma-Aldrich, St. Louis, MO), water (HPLC grade, Sigma- Aldrich, St. Louis, MO), acetonitrile (HPLC grade, Sigma-Aldrich, St. Louis, MO).

[0467] Nuclear Magnetic Resonance Spectroscopy - 'H and13C NMR spectra data were obtained using a Bruker Avance III with PA BBO 400S1 BBF-H-D-05 Z plus probe (Bruker Corporation, Billerica, MA, USA). Samples were prepared at a concentration of ~20 mg / mL in DMSO-de (Sigma-Aldrich, St. Louis, MO) or CDCE (Sigma-Aldrich, St. Louis, MO). 'H spectrawere collected at 400 MHz,13C (APT or CPD experiments) at 100.6 MHz, and19F (decoupled) at 376.5 MHz. Chemical shifts (5) are reported in parts per million (ppm) and spectra were standardized to either residual solvent signals (d6-DMSOXH: 2.5 ppm,13C: 39.52 ppm, CDCL: 'H 7.26 ppm,13C: 77.2 ppm) or tetramethylsilane (TMS).19F reference CFCh was set to 0.00 ppm.

[0468] pH Measurements - pH readings were obtained using an Orion 3 star (Thermo Scientific, USA) pH meter coupled with either a Thermo pH electrode (9142BN) or an Orion 8103BNUWP Ross Ultra Semi-micro pH probe (Thermo Scientific, USA) containing 3M KC1 ROSS Orion filling solution (Thermos Scientific, USA).

[0469] High Performance Liquid Chromatography - HPLC spectra were obtained on an Agilent 1260 Infinity system that includes a 1260 quaternary pump VL, a 1260 ALS autosampler, a 1260 Thermostatted Column Compartment, and a 1200 DAD Multiple Wavelength Detector (Agilent Technologies, Santa Clara, CA, USA). The detection wavelength was set at 220 nm for purity. Separation for compounds was achieved using a Zorbax Eclipse Plus-C18 analytical column (5 pm, 4.6 x 150 mm) from Agilent (Agilent Technologies, Santa Clara, CA, USA). Mobile phase A consisted of 10 mM aqueous ammonium formate buffer titrated to pH 4.5 (with 10 mM formic acid) and mobile phase B consisted of acetonitrile. Compounds were prepared as 2 mg / mL solutions in 70:30 A:B or 50:50 A:B. The injection volume of samples was 10 pL, flow rate was 1.0 mL / min, and the column temperature was set at 25 °C. Run time was 10 minutes with a mobile phase ratio (isocratic) of 70% A and 30% B or 50% A and 50% B. All samples were run in duplicate with a wash of the injector (70:30 A:B or 50:50 A:B) between runs. Chromatograms were analyzed using the Agilent ChemStation Software (Agilent Technologies, Santa Clara, CA, USA).

[0470] Atmospheric Solids Analysis Probe Mass Spectroscopy - Low resolution mass spectra were obtained using a Advion Expression5CMS Spectrometer equipped with a quadrupole mass analyzer. Samples were ionized via Atmospheric Solids Analysis (ASAP) source using an Atmospheric Pressure Chemical Ionization (APCI) attachment. Data was processed and analyzed in Advion Data Express software. The following parameters were used for measurement: Capillary Temperature = 100 °C, Capillary Voltage = 50 V, Source Gas Temperature = 130 °C, and APCI corona discharge = 5 pA.

[0471] Biotage Automated Flash Chromatography - Automated flash chromatography was performed using Isolera™ One Flash Chromatography Systems from Biotage (Uppsala, Sweden). Separations were performed using SiO2 (Sigma-Aldrich, St. Louis, MO) as a stationary phase and the following organic solvents as mobile phases: hexanes (Sigma-Aldrich, St. Louis,MO) and ethyl acetate (EtOAc) (Sigma-Aldrich, St. Louis, MO). In some cases, triethylamine was used as an additive. SiO2 was manually loaded into either SNAP KP Sil 50 g or SNAP KP Sil 100 g cartridges and equilibrated with the selected mobile phase prior to loading the sample. Flow rate of solvent was 100 mL / min. UV absorbance was monitored (254 and 280 nm) and the absorbance threshold for fraction collection was set to either 10 or 40 mAu. Fractions (14 mL) were collected in a 16 x 100 mm rack. Chromatograms were analyzed in the internal Spektra software (Biotage, Uppsala, Sweden).

[0472] Example 1: Synthesis of Compounds

[0473] Synthesis of 7V-(cyclopropyl(phenyl)methylene)-2-methylpropane-2-sulfinamide(la)To a heated dried 3-neck round-bottom flask containing a Teflon coated magnetic stir bar was added racemic tert-butyl sulfmamide (5.04 g, 41.5 mmol) and dry (3 A molecular sieves) toluene (50 mL) under argon atmosphere. To the solution was added in a continuous portion Ti(OEt)4 (5.8 mL, 6.31 g, 27.7 mmol) via syringe and the round-bottom was fitted with a reflux condenser. The solution was heated with a heating mantle to maintain a temperature between 80- 90°C and then cyclopropyl phenyl ketone (1.9 mL, 2.01 g, 13.7 mmol) in dry (3 molecular sieves) toluene (10 mL) was added dropwise over ~1 hour (h) via an addition funnel. The reaction was allowed to stir between 80-90°C for 1 h and then cooled to room temperature (rt) overnight. The reaction was quenched by the addition of a saturated NaHCOs solution (~20 mL), diluted with EtOAc (-100 mL), and the resulting thick white suspension filtered through a pad of celite. The filter cake was washed with EtOAc (3 x 75 mL) and the combined filtrate and washes was transferred to a separatory funnel. The organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to a crude yellow oil. The product was purified via flash chromatography (SiO2, 8:2 hexanes:EtOAc to 6:4 hexanes:EtOAc) to afford la (2.52 g, 73.9%) as a viscous, yellow oil.Synthesis of 7V-(cyclopentyl(phenyl)methylene)-2-methylpropane-2-sulfinamide (1c)

[0474] To a heated dried 3-neck round-bottom flask containing a Teflon coated magnetic stir bar was added racemic tert-butyl sulfmamide (15.0 g, 124 mmol) and dry (3 A molecular sieves) toluene (150 mL) under argon atmosphere. To the solution was added Ti(OEt)4(24 mL, 26.1 g,114 mmol) via syringe in a single portion and the round-bottom was fitted with a reflux condenser. The solution was heated with a heating mantle to maintain a temperature between 80- 90°C and then cyclopentyl phenyl ketone (9.8 mL, 10.2 g, 58.2 mmol) was added over 5 min via syringe. The reaction was allowed to stir between 80-90°C for 4 h and then cooled to rt overnight. The reaction was quenched with brine (~20 mL), diluted with EtOAc (-100 mL), and the resulting thick white suspension filtered through a pad of celite. The filter cake was washed with EtOAc (3 x 50 mL) and the combined washes and filtrate were transferred to a separatory funnel. The organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to a crude yellow oil. The product was purified via flash chromatography (SiO2, 8:2 hexanes:EtOAc to 7:3 hexanes:EtOAc) to afford 1c (9.0 g, 55%) as a viscous, yellow oil.Synthesis of 7V-(cyclohexyl(phenyl)methylene)-2-methylpropane-2-sulfinamide (Id)

[0475] To a heated dried 3 -neck round-bottom flask containing a Teflon coated magnetic stir bar was added racemic Zc / V-butyl sulfinamide (3.90 g, 32.1 mmol) and dry (3 A molecular sieves) toluene (30 mL) under argon atmosphere. To the solution was added Ti(OEt)4 (4.5 mL, 4.89 g, 21.4 mmol) in a single portion via syringe and the round-bottom was fitted with a reflux condenser. The solution was heated with a heating mantle to maintain a temperature between 80- 90°C and then cyclohexyl phenyl ketone (2.02 g, 10.7 mmol) in dry (3 A molecular sieves) toluene (20 mL) was added over 30 minutes (min) via an addition funnel. The reaction was allowed to stir between 80-90°C for 2.5 h, cooled to rt, and quenched with brine (-20 mL). The mixture was diluted with EtOAc (-100 mL) and the resulting thick white suspension filtered through a pad of celite. The filter cake was washed with EtOAc (3 x 50 mL) and the combined washes and filtrate were transferred to a separatory funnel. The organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to a crude yellow oil. The product was purified via flash chromatography (SiO2, 8:2 hexanes :EtO Ac) to afford Id (2.51 g, 81%) as a viscous, yellow oil that solidified upon storage in a -20°C freezer.

[0476] 1-cyclopropyl-l-phenylethan-l-amine (Compound 2). To a heated dried roundbottom flask containing a Teflon coated magnetic stir bar was added a solution of la (1.0 g, 4.01 mmol) in dry (3 A molecular sieves) THF (15 mL) under argon atmosphere. The solution was cooled to 0°C and a solution of methylmagnesium bromide (1.4 M in THF Toluene, 8.6 mL, 12.0 mmol) was added dropwise over 15 min. The reaction was allowed to warm to rt, stirred for -5 h, and carefully quenched with 3M HC1 (15 mL). The biphasic mixture was stirred vigorously for 1 h at rt and then diluted with diH2O (deionized water, 15mL) and EtOAc (-100 mL). The mixture was extracted and the organic layer was extracted further with IM HC1 (3 x 100 mL). Thecombined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 75 mL). The pooled organic extractions were washed with diEEO (20 mL) and brine (20 mL), dried over anhydrous ISfeSCU, and concentrated under vacuum to afford a colorless transparent oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (20 mL) and titrating with concentrated HC1 until pH < 2 as determined using a pH meter. The mixture was concentrated under a warm stream of air with repeat evaporation of EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solids were washed with Et2O (3 x -5 mL) and dried to afford 1 -cyclopropyl- 1-phenylethan-l -amine (2) hydrochloride (200 mg, 30.9% yield) as a white powder. The solid was crystalized 3X by dissolving in a minimum volume of EtOH and layering with Et2O and storing at 0°C to give a white crystalline solid.1H NMR HC1 salt (400 MHz, DMSO-d6) 5 ppm = 8.78 (s, NH3+), 7.59 (dm, J= 7.9 Hz, 2H), 7.41 (tm, J= 7.5 Hz, 2H), 7.34 (tm, J= 7.2 Hz, 1H), 1.46 (s, 3H), 1.36 (tt, J= 8.4, 5.5 Hz, 1H), 0.59 - 0.37 (m, 4H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 141.43 (1 C), 128.32 (2 C), 127.79 (1 C), 125.68 (2 C), 58.56 (1 C), 22.27 (1 C), 20.26 (1 C), 2.06 (1 C), 1.52 (1 C). Melting point (mp): 195.9- 197.8°C. HPLC Purity (70:30 Formate buffer: ACN, 220 nm): 96.6%. ASAP MS: 146.1 (30%, [M+2]-NH3), 145.1 (100%, [M+1]-NH3). HRMS: m / z calcd for C11H15N+H [M + H]+, 162.1277; found 162.1279, Appm = 1.23; m / z calcd for C11H13 [M - NH3]+, 145.1012; found 145.1013, Appm = 0.69.

[0477] 1-cyclopentyl-l-phenylethan-l-amine (Compound 3). To a heated, dried roundbottom flask containing a Teflon coated stir bar was added a solution of 1c (3.0 g, 10.8 mmol) in dry (3 A molecular sieves) THF (50 mL). The solution was cooled to 0°C and a solution of methylmagnesium bromide (1.4 M in THF Toluene, 23 mL, 33.2 mmol) was added via syringe over 1 min. The reaction was allowed to warm naturally to rt overnight and then quenched with 3M HC1 (50 mL). The biphasic mixture was stirred vigorously for 2 h at rt and then diluted with diH2O (50 mL) and EtOAc (-150 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diftO (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum to afford a light yellow oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (40 mL) and adding concentrated HC1 (485 pL). The mixture was concentrated under a warm stream of air with EtOH additions (3 x -5 mL) to remove excess HC1. The resulting solid was washed with Et2O (3 x -10 mL) and dried to afford 1 -cyclopentyl- 1-phenylethan-l -amine (3) hydrochloride (1.10 g, 67.9% yield) as a light yellow powdery solid. The solid was crystalized 3X by dissolving in a minimum volume of EtOH and layering with Et2O to give a white crystalline solid. 'H NMRHC1 salt (400 MHz, DMSO-d6) 5 ppm = 8.69 (s, NH3+), 7.54 (dm, J= 8.1 Hz, 2H), 7.42 (tm, J= 7.3 Hz, 2H), 7.34 (tm, J= 7.2 Hz, 1H), 2.47-2.35 (m, 1H), 1.62 (s, 3H, overlap with 1.60-1.53), 1.60-1.53 (m, 1H, overlap with 1.62), 1.52-1.30 (m, 6H), 1.27-1.13 (m, 1H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 141.54 (1 C), 128.26 (2 C), 127.58 (1 C), 125.69 (2 C), 60.41 (1 C), 49.28 (1 C), 26.91 (1 C), 26.80 (1 C), 24.84 (1 C), 24.65 (1 C), 21.28 (1 C). mp: 245.3- 245.7°C. HPLC Purity (70:30 Formate buffer:ACN, 220 nm): 97.7%. ASAP MS: 191.4 (5%, [M+2]), 190.0 (10%, [M+l]), 174.2 (15%, [M+2]-NH3) 173.2 (100%, [M+1]-NH3). HRMS: m / z calcd for Ci3Hi9N+H [M + H]+, 190.1590; found 190.1590, Appm = 0.00; m / z calcd for Ci3Hn [M - NH3]+, 173.1325; found 173.1326, Appm = 0.58.

[0478] 1-cyclopentyl-l-phenylpropan-l-amine (Compound 4). To a heated, dried roundbottom flask containing a Teflon coated magnetic stir bar was added a solution of 1c (720 mg, 2.59 mmol) in dry (3 molecular sieves) THF (15 mL) under argon atmosphere. The solution was cooled to 0°C using an ice water bath and a solution of ethylmagnesium bromide (3 M in diethyl ether, 2.5 mL, 7.5 mmol) was added via syringe over 1 min. The reaction was allowed to warm naturally to rt overnight and then quenched with 3M HC1 (15 mL). The biphasic mixture was stirred vigorously for 1.5 h at rt and then diluted with deionized water (diftO) (15 mL) and EtOAc (-100 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous extractions were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diH2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford a colorless transparent oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (20 mL) and adding concentrated HC1 (189 pL). The mixture was concentrated under a warm stream of air with evaporation of additional EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solids were washed with Et2O (2 x -10 mL) and dried to afford 1- cyclopentyl-l-phenylpropan-1 -amine (4) hydrochloride (430 mg, 69.2% yield) as a white solid. The solid was crystalized 3X by dissolving in a minimum volume of EtOH and layering with Et2O then storing at 0°C to give a white crystalline solid.1H NMR HC1 salt (400 MHz, DMSO- d6) 5 ppm = 8.59 (s, NH3+), 7.47-7.36 (m, 4H), 7.31 (tm, J= 6.9 Hz, 1H), 2.45-2.30 (m, 1H), 2.19 (sextet, 1H), 2.00 (sextet, 1H), 1.61-1.50 (m, 1H), 1.50-1.28 (m, 7H), 0.74 (t, J= 7.3 Hz, 3H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 139.11 (1 C), 128.26 (2 0), 127.32 (1 C), 126.13 (2 C), 64.34 (1 C), 49.24 (1 C), 28.20 (1 C), 26.55 (1 C), 26.29 (1 C), 24.71 (1 C), 24.48 (1 C), 7.80 (1 C). mp: > 260°C. HPLC Purity (70:30 Formate buffer:ACN, 220 nm): 99.3%. ASAP MS: 205.4 (10%, [M+2]), 204.3 (50%, [M+l]), 188.2 (20%, [M+2]-NH3) 187.2 (100%,[M+1]-NH3). HRMS: m / z calcd for C14H21N+H [M + H]+, 204.1747; found 204.1747, Appm = 0.00; m / z calcd for C13H17 [M - NH3]+, 187.1481; found 187.1483, Appm = 1.07.

[0479] Cyclopentyl(cyclopropyl)(phenyl)methanamine (Compound 5). To a heated, dried round-bottom flask containing a Teflon coated stir bar was added crushed Mg turnings (260 mg, 10.7 mmol), dry (3A molecular sieves) THF (15 mL), and a catalytic amount of iodine crystals under argon atmosphere. Bromocyclopropane (800 pL, 1.21 g, 10.0 mmol) was added via syringe and the mixture was gently heated until initiation. The resulting dark solution then returned to rt and stirred for 1 hr. The reaction was cooled to 0°C and a solution of 1c (1.0 g, 3.60 mmol) in dry (3 A molecular sieves) THF (5 mL) was added via syringe over 5 min. The mixture was allowed to warm to rt overnight and then carefully quenched with 3M HC1 (30 mL). The biphasic mixture was vigorously stirred for 3 h at rt and then diluted with diH2O (60 mL) and EtOAc (-100 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (2 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diH2O (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under vacuum to afford a colorless transparent oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (30 mL) and titrating with concentrated HC1 until pH < 2 as determined by pH probe. The mixture was concentrated under a warm stream of air with evaporations of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solid was washed with Et2O (3 x -10 mL) and dried to afford cyclopentyl(cyclopropyl)(phenyl)methanamine (Compound 5) hydrochloride (600 mg, 66.0% yield) as a white powder. The solid was crystalized 3X by dissolving in a minimum volume of EtOH and layering with Et2O followed by storing at 0°C. 'H NMR HC1 salt (400 MHz, DMSO-de) 5 ppm = 8.39 (s, NH3+), 7.65 (dm, J= 8.1 Hz, 2H), 7.39 (tm, J= 7.7 Hz, 2H), 7.31 (tm, J= 7.3 Hz, 1H), 2.72-2.58 (m, 1H), 1.61-1.37 (m, 9H), 0.78-0.68 (m, 1H), 0.58 (tt, J = 8.8, 5.6 Hz, 1H), 0.48 (tt, J= 9.1, 5.3 Hz, 1H), 0.43-0.33 (m, 1H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 140.29 (1 C), 128.02 (2 C), 127.52 (1 C), 126.45 (2 C), 62.91 (1 C), 48.67 (1 C), 26.97 (1 C), 26.63 (1 C), 24.79 (1 C), 24.77 (1 C), 16.91 (1 C), 2.43 (1 C), 0.27 (1 C). mp: > 260°C. HPLC Purity (70:30 Formate buffer:ACN, 220 nm): 100%. ASAP MS: 217.2 (5%, [M+2]), 216.3 (30%, [M+l]), 200.2 (20%, [M+2]-NH3) 199.2 (100%, [M+1]-NH3). HRMS: m / z calcd for C15H21N+H [M + H]+, 216.1747; found 216.1748, Appm = 0.46; m / z calcd for C15H19 [M - NH3]+, 199.1481; found 199.1483, Appm = 1.00.

[0480] l-cyclopentyl-l-phenylbut-3-en-l-amine (Compound 6). To a heated, dried roundbottom flask containing a Teflon coated stir bar was added a solution of 1c (1.0 g, 3.60 mmol) in dry (3 A molecular sieves) THF (20 mL) under argon atmosphere. The solution was cooled to0°C and a solution of allylmagnesium chloride (2.0 M in THF:toluene, 5.4 mL, 10.8 mmol) was added dropwise via addition funnel over 20 min. The reaction was allowed to warm to rt over 3 h and then quenched with 3M HC1 (20 mL). The biphasic mixture was stirred vigorously for 2 h at rt and then diluted with diLLO (20 mL) and EtOAc (-100 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 75 mL). The organic layer was washed with diELO (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford a colorless transparent oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (20 mL) and adding concentrated HC1 (259 pL). The mixture was concentrated under a warm stream of air with evaporations of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solid was washed with Et2O (3 x -10 mL) and dried to afford 1 -cyclopentyl- l-phenylbut-3-en-l -amine (Compound 6) hydrochloride (510 mg, 56.0% yield) as a white powdery solid. The solid was crystalized 3 times by dissolving in a minimum volume of EtOH and layering with Et2O followed by storing at 0°C. 'H NMR HC1 salt (400 MHz, DMSO-d6) 5 ppm = 8.63 (s, NH3+), 7.47 (dm, J= 8.2 Hz, 2H), 7.40 (tm, J= 7.5 Hz, 2H), 7.31 (tm, J= 7.2 Hz, 1H), 5.66-5.51 (m, 1H), 5.22 (dd, J= 17.1, 1.3 Hz, 1H), 5.07 (dd, J= 10.4, 1.8 Hz, 1H), 3.01 (dd, J= 15.0, 7.0 Hz, 1H), 2.75 (dd, J= 15.0, 7.0 Hz, 1H), 2.46-2.32 (m, 1H), 1.64-1.52 (m, 1H), 1.52-1.28 (m, 7H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 138.92 (1 C), 131.69 (1 C), 128.17 (2 C), 127.46 (1 C), 126.31 (2 C), 120.32 (1 C), 63.48 (1 C), 48.90 (1 C), 39.86 (1 C, overlap with DMSO-d6), 26.54 (1 C), 26.30 (1 C), 24.65 (1 C), 24.46 (1 C). mp: > 260°C. HPLC Purity (70:30 Formate buffer:ACN, 220 nm): 100%. ASAP MS: 217.4 (5%, [M+2]), 216.3 (40%, [M+l]), 200.2 (20%, [M+2]-NH3), 199.2 (90%, [M+1]-NH3). HRMS: m / z calcd for C15H21N+H [M + H]+, 216.1747; found 216.1748, Appm = 0.46; m / z calcd for C15H19 [M - NH3]+, 199.1481; found 199.1482, Appm = 0.50.

[0481] Cyclobutyl(cyclopentyl)(phenyl)methanamine (Compound 7). To a heated, dried pear-shaped flask containing a Teflon coated stir bar was added crushed Mg turnings (460 mg, 18.9 mmol), dry (3A molecular sieves) THF (10 mL), and a catalytic amount of iodine crystals under argon atmosphere. Bromocyclobutane (1.5 mL, 2.15 g, 15.9 mmol) was added via syringe in one portion and the mixture immediately became warm. The mixture was cooled briefly (-2 min) on an ice bath and then allowed to return to rt for 4 h. In a separate round-bottom flask, a solution of 1c (1.52 g, 5.47 mmol) in dry (3 A molecular sieves) THF (20 mL) was stirred at 0°C and the flask was fitted with an addition funnel. The freshly prepared Grignard reagent was transferred to the addition funnel via syringe and added dropwise over 10 min. The reaction was allowed to naturally warm to rt overnight and then carefully quenched with 3M HC1 (30 mL).The biphasic mixture was vigorously stirred for 3 h at rt and immediately basified with KOH solution (pH > 12). The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with diH2O (20 mL) and brine (20 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated under vacuum to afford a colorless transparent oil. The crude product was purified by flash chromatography with a stepwise gradient (SiO2, 9: 1 hexanes:EtOAc to 8:2 hexanes:EtOAc to 7:3 hexanes :EtO Ac) to afford cyclobutyl(cyclopentyl)(phenyl)methanamine (7) (300 mg, 24%) as a colorless transparent oil. The purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding concentrated HC1 (119 pL). The mixture was concentrated under a warm stream of air with evaporation of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solids were washed with Et2O (3 x -5 mL) and dried to afford a white powdery solid. The salt was crystallized by dissolving in a minimum volume of absolute EtOH and layering with Et2O followed by storing at 0°C to give a white crystalline powder.1H NMR HC1 salt (400 MHz, DMSO-d6) 5 ppm = 8.49 (s, NH3+), 7.50 (dm, J= 8.2 Hz, 2H), 7.39 (tm, J= 7.6 Hz, 2H), 7.30 (tm, J= 7.2 Hz, 1H), 3.25-3.09 (m, 1H), 2.47-2.32 (m, 1H), 2.18 (pentet, 1H), 1.98-1.81 (m, 2H), 1.78-1.59 (m, 2H), 1.59-1.30 (m, 8H), 1.29-1.09 (m, 1H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 138.17 (1 C), 128.12 (2 C), 127.35 (1 C), 126.25 (2 C), 65.03 (1 C), 46.95 (1 C), 41.73 (1 C), 26.85 (1 C), 26.13 (1 C), 24.79 (1 C), 24.10 (1 C), 23.60 (1 C), 23.13 (1 C), 16.57 (1 C). mp: > 260°C. HPLC Purity: (70:30 Formate buffer:ACN, 200 nm): 100%. ASAP MS: 231.4 (10%, [M+2]), 230.3 (60%, [M+l]), 214.2 (20%, [M+2]-NH3) 213.3 (100%, [M+1]-NH3). HRMS: m / z calcd for CI6H23N+H [M + H]+, 230.1903; found 230.1904, Appm = 0.43; m / z calcd for CI6H2I [M - NH3]+, 213.1638; found 213.1639, Appm = 0.47. l-cyclopentyl-l-phenylpent-4-en-l-amine (Compound 8). To a heated, dried pear-shaped flask containing a Teflon coated stir bar was added crushed Mg turnings (310 mg, 12.8 mmol), dry (3 A molecular sieves) THF (10 mL), and a catalytic amount of iodine crystals under argon atmosphere. Bromomethylcyclopropane (1.0 mL, 1.39 g, 10.3 mmol) was added via syringe in one portion and stirred vigorously. As the reaction became warm, it was cooled on a cool water bath and then allowed to stir for 2 h. In a separate round-bottom flask, a solution of 1c (1.0 g, 3.60 mmol) in dry (3 molecular sieves) THF (10 mL) was stirred at 0°C. The freshly prepared Grignard reagent was added to the imine solution via syringe over 10 min and stirred for 1 h at 0°C. The reaction was then allowed to warm to rt for 2 h and carefully quenched with 3M HC1 (30 mL). The biphasic mixture was vigorously stirred for 2 h at rt and then diluted with diH2O (30 mL) and EtOAc (-100 mL). The aqueous phase was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified withNH4OH and extracted with EtOAc (3 x 75 mL). The organic layer was washed with diH2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford a yellow oil. The crude product was purified by flash chromatography (SiO2, 8:2 hexanes :EtO Ac) to afford 1 -cyclopentyl- l-phenylpent-4-en-l -amine (8) (320 mg, 38.8%) as a colorless transparent oil. The purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (128 pL). The mixture was concentrated under a warm stream of air with evaporation of repeat EtOH additions (3 x ~5 mL) to remove excess HC1 and water. The resulting solids were washed with hexanes (3 x ~10 mL) and dried to afford a white powdery solid. 'H NMR HC1 salt (DMSO-de, 400 MHz) 5 ppm = 8.67 (s, NH3+), 7.45 (dm, J= 7.9 Hz, 2H overlap with 7.41), 7.41 (tm, J= 7.5 Hz, 2H, overlap with 7.45), 7.32 (tm, J= 7.0 Hz, 1H), 5.85-5.68 (m, 1H), 4.90 (d, J= 18.9 Hz, 1H), 4.94 (d, J= 11.3 Hz, 1H), 2.47-2.33 (m, 1H), 2.29-2.16 (m, 1H), 2.12-1.97 (m, 2H), 1.76- 1.63 (m, 1H), 1.63-1.52 (m, 1H), 1.52-1.28 (m, 7H). °C NMR HC1 salt (DMSO-d6, 100.6 MHz) 5 ppm = 139.22 (1 C), 137.55 (1 C), 128.34 (2 C), 127.42 (1 C), 125.90 (2 C), 115.11 (1 C), 63.73 (1 C), 49.40 (1 C), 34.65 (1 C), 27.22 (1 C), 26.51 (1 C), 26.25 (1 C), 24.72 (1 C), 24.48 (1 C). mp: >260 °C. HPLC Purity: (50:50 Formate buffer: ACN, 220 nm): 99.1%. ASAP MS: 231.6 (10%, [M+l]), 230.2 (40%, [M+2]), 214.3 (20%, [M+2]-NH3], 213.2 (100%, [M+1]-NH3], HRMS: m / z calcd for CI6H23N+H [M + H]+, 230.1904; found 230.1903, Appm = -0.43; m / z calcd for C16H21 [M - NH3]+, 213.1638; found 213.1639, Appm = 0.46.

[0482] 2-cyclobutyl-l-cyclopentyl-l-phenylethan-l-amine (Compound 9). To a heated, dried pear-shaped flask containing a Teflon coated stir bar was added crushed Mg turnings (310 mg, 12.8 mmol), dry (3 A molecular sieves) THF (10 mL), and a catalytic amount of iodine crystals under argon atmosphere. Bromomethylcyclobutane (1.2 mL, 1.59 g, 10.7 mmol) was added via syringe in one portion and stirred vigorously. As the reaction became warm, it was cooled on a cool water bath and then allowed to stir for 2 h. In a separate round-bottom flask, a solution of 1c (1.0 g, 3.60 mmol) in dry (3 molecular sieves) THF (10 mL) was stirred at 0°C. The freshly prepared Grignard reagent was added to the imine solution via syringe over ~ 1 min at 0°C and allowed to naturally return to rt overnight. The reaction was then carefully quenched with 3M HC1 (30 mL) and the biphasic mixture was vigorously stirred for 3 h at rt. The mixture was diluted with diH?O (30 mL) and EtOAc and then extracted. The organic layer was extracted further with IM HC1 (3 x 100 mL) and the combined aqueous layers were basified with NH4OH. The aqueous layer was extracted with EtOAc (3 x 75 mL), washed with diH2O (20 mL) and brine (20 mL), and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum to afford a yellow oil. The crude product was purified by flash chromatography (SiO2, 9: 1hexanes :EtO Ac to 7:3 hexanes :EtO Ac) to afford 2-cy cl obutyl-1 -cyclopentyl- 1-phenylethan-l - amine (9) (200 mg, 22.8%) as a colorless transparent oil. The purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (75 pL). The mixture was concentrated under a warm stream of air with evaporation of repeat EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solid was washed with hexanes (3 x -10 mL) and dried to afford a shiny white solid. 'H NMR HC1 salt (DMSO-d6, 400 MHz) 5 ppm = 8.49 (s, NH3+), 7.47 (dm, J= 8.0 Hz, 2H), 7.37 (tm, J= 7.6 Hz, 2H), 7.29 (tm, J= 7.2 Hz, 1H), 2.48-2.41 (m, 1H, overlap with DMSO- d6), 2.34-2.21 (m, 1H, overlap with 2.20), 2.20 (dd, J= 14.0, 7.3 Hz, 1H, overlap with 2.34-2.21), 2.06 (dd, J= 14.4, 5.4 Hz, 1H), 1.94-1.79 (m, 1H), 1.67-1.51 (m, 4H), 1.51-1.23 (m, 9H).13C NMR HC1 salt (DMSO-d6, 100.6 MHz) 5 ppm = 139.55 (1 C), 127.97 (2 C), 127.25 (1 C), 126.07 (2 C), 63.97 (1 C), 48.20 (1 C), 43.59 (1 C), 30.65 (1 C), 29.31 (1 C), 29.07 (1 C), 26.52 (1 C), 26.16 (1 C), 24.86 (1 C), 24.52 (1 C), 18.53 (1 C). mp: > 260 °C. HPLC Purity: (50:50 Formate buffer:ACN, 220 nm): 100%. ASAP MS: 245.2 (5%, [M+2]), 244.2 (20%, [M+l]), 228.0 (10%, [M+2]-NH3), 227.2 (50%, [M+1]-NH3). HRMS: m / z calcd for C17H25N+H [M + H]+, 244.2060; found 244.2059, Appm = -0.41; m / z calcd for CI6H23[M - NH3]+, 227.1794; found 227.1794, Appm = 0.00.

[0483] l-cyclopentyl-l-phenylprop-2-en-l-amine (Compound 10). To a heated, dried roundbottom flask containing a Teflon coated stir bar was added a solution of 1c (1.01 g, 3.64 mmol) in dry (3 molecular sieves) THF (30 mL) under argon atmosphere. The solution was cooled to 0°C and a solution of vinylmagnesium bromide (1.0 M in THF, 11 mL, 11 mmol) was added dropwise via syringe over 5 min. The reaction was allowed to warm to rt overnight and then quenched with 3M HC1 (30 mL). The biphasic mixture was stirred vigorously for 3 h at rt and then diluted with diH2O (30 mL) and EtOAc (-100 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diH2O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford a yellow transparent oil. The crude product was purified by flash chromatography with a stepwise gradient (SiO2, 8:2 hexanes:EtOAc to 7:3 hexanes:EtOAc) to afford l-cyclopentyl-l-phenylprop-2-en-l-amine (10) (200 mg, 27.3%) as a colorless transparent oil. The purified freebase was converted to the hydrochloride salt by dissolving in absolute EtOH (15 mL) and adding a slight excess of concentrated HC1 (91 pL). The mixture was concentrated under a warm stream of air with evaporation of repeat EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solid was washed with hexanes (3 x -10 mL) and dried toafford a white powdery solid. 'H NMR HC1 salt (400 MHz, DMSO-de) 8 ppm = 8.88 (s, NH3+), 7.58 (dm, J= 7.7 Hz, 2H), 7.45-7.37 (m, 2H), 7.37-7.30 (m, 1H), 6.36-6.23 (m, 1H), 5.52 (dm, J = 12.0 Hz, 1H), 5.46 (d, J= 17.7 Hz, 1H), 2.85-2.71 (m, 1H), 1.69-1.57 (m, 1H), 1.57-1.20 (m, 7H). °C NMR HC1 salt (100.6 MHZ, DMSO-d6) 6 ppm = 140.25 (1 C), 135.85 (1 C), 128.37 (2 C), 128.00 (1 C), 126.66 (2 C), 117.39 (1 C), 64.30 (1 C), 47.12 (1 C), 27.25 (1 C), 27.04 (1 C), 25.40 (1 C), 25.18 (1 C). mp: > 260°C. HPLC Purity: (70:30 Formate buffer:ACN, 200 nm): 100%. ASAP MS: 203.3 (5%, [M+2]), 202.3 (25%, [M+l]), 186.3 (20%, [M+2]-NH3), 185.3 (100%, [M+1]-NH3). HRMS: m / z calcd for C14H19N+H [M + H]+, 202.1590; found 202.1591, Appm = 0.49; m / z calcd for C14H17N [M - NH3]+, 185.1325; found 185.1326, Appm = 0.54.

[0484] 1-cyclohexyl-l-phenylethan-l-amine (Compound 11). To a heated, dried roundbottom flask containing a Teflon coated stir bar was added a solution of Id (2.0 g, 6.89 mmol) in dry (3 A molecular sieves) THF (50 mL). The solution was cooled to 0°C and a solution of methylmagnesium bromide (1.4 M in THF Toluene, 14 mL, 19.6 mmol) was added via syringe over 1 min. The reaction was allowed to warm naturally to rt overnight and then quenched with 3M HC1 (30 mL). The biphasic mixture was stirred vigorously for 1 h at rt and then diluted with diH2O (40 mL) and EtOAc (-100 mL). The aqueous layer was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diH3O (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford a colorless transparent oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (40 mL) and adding concentrated HC1 (575 pL). The mixture was concentrated under a warm stream of air with EtOH additions (3 x -5 mL) to remove excess HC1. The resulting solid was washed with Et2O (3 x -10 mL) and dried to afford 1 -cyclohexyl- 1-phenylethan-l -amine (11) (870 mg, 52.6% yield) as a white powdery solid. The solid was crystalized 3X by dissolving in a minimum volume of EtOH and layering with Et2O to give a white crystalline solid. 'H NMR HC1 salt (400 MHz, DMSO-d6) 6 ppm = 8.66 (s, NH3+), 7.54-7.48 (dm, J= 8.1 Hz, 2H), 7.44- 7.38 (tm, J= 7.4 Hz, 2H), 7.37-7.31 (tm, = 7.3 Hz, 1H), 1.89-1.76 (m, 2H), 1.76-1.67 (dm, J = 12.5 Hz, 1H), 1.65-1.51 (m, 2H, overlap with 1.58), 1.58 (s, 3H, overlap with 1.65-1.51), 1.32- 1.23 (dm, J= 12.3 Hz, 1H), 1.22-1.07 (m, 1H), 1.07-0.88 (m, 3H), 0.88-0.74 (m, 1H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 141.41 (1 C), 128.27 (2 C), 127.63 (1 C), 125.88 (2 C), 61.34 (1 C), 46.73 (1 C), 26.75 (1 C), 26.68 (1 C), 25.75 (2 C), 25.57 (1 C), 20.15 (1 C). mp: 246.8-249.4°C. HPLC Purity (70:30 Formate buffer:ACN, 220 nm): 97.4%. ASAP MS: 205.3 (10%, [M+2]), 204.3 (60%, [M+l]), 188.2 (15%, [M+2]-NH3), 187.2 (100%, [M+1]-NH3).HRMS: m / z calcd for C14H21N+H [M + H]+, 204.1747; found 204.1748, Appm = 0.49; m / z calcd for C14H19 [M - NH3]+, 187.1481; found 187.1482, Appm = 0.53.

[0485] Cyclopentyl(3-methoxyphenyl)methanone. To a heated, dried 3-neck round-bottom flask containing a Teflon coated stir bar was added Mg° turnings (10.9 g, 448 mmol) and dry (3A molecular sieves) THF (200 mL) at rt under argon atmosphere. Cyclopentyl bromide (16.1 mL, 22.4 g, 150 mmol) was added in one portion and vigorously stirred at rt until signs of reaction initiation (grey slurry and heat). The mixture was cooled on a water bath until it returned to rt and then stirred at rt for an additional 1.5 h. The mixture was then cooled to 0°C and fitted with an addition funnel. A solution of 3 -methoxybenzonitrile (9.2 mL, 10.0 g, 75.1 mmol) in dry (3 A molecular sieves) THF (50 mL) was then added dropwise over 30 min at 0°C and the mixture was allowed to warm to rt overnight. The reaction was slowly poured into a 5% H2SO4 solution (300 mL) with vigorous stirring in a 1 L Erlenmeyer flask at rt and allowed to stir at rt for 30 min. The mixture was extracted with EtOAc (3 x 100 mL) and the combined organics were washed with KOH solution (~1M, 100 mL), diftO (100 mL), and brine (100 mL). The organics were dried over anhydrous Na2SO4 and concentrated under vacuum to a crude dark amber oil. The product was purified via flash chromatography (SiO2, 100% hexanes to 9: 1 hexanes:EtOAc) to afford cyclopentyl(3-methoxyphenyl)methanone (4.80 g, 31.3%) as a yellow oil.

[0486] V-(cyclopentyl(3-methoxyphenyl)methylene)-2-methylpropane-2-sulfinamide. To a heated, dried 3-neck round-bottom flask containing a Teflon coated stir bar was added racemic Zc / V-butyl sulfinamide (7.1 g, 58.5 mmol) and dry (3 A molecular sieves) toluene (100 mL) under argon atmosphere. To the solution was added Ti(OEt)4 (8.2 mL, 8.92 g, 39.1 mmol) via syringe and the round-bottom was fitted with a reflux condenser. The solution was heated with a heating mantle to maintain a temperature between 80-90°C and then a solution of cyclopentyl(3-methoxyphenyl)methanone (4.01 g, 19.6 mmol) in dry (3 molecular sieves) toluene (15 mL) was added over 45 min via syringe. The reaction was allowed to stir between 80-90°C for 2.5 h and then cooled to rt overnight. The reaction was quenched with 1 : 1 sat’d NaHCCh brine (~20 mL), diluted with EtOAc (-150 mL), and the resulting suspension filtered through a pad of celite. The filter cake was washed with EtOAc (2 x 100 mL) and the filtrate was transferred to a separatory funnel. The organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to a crude orange oil. The product was purified via flash chromatography (SiO2, 9:1 hexanes:EtOAc to 2: 1 hexanes:EtOAc) to afford / V-(cyclopentyl(3- methoxyphenyl)methylene)-2-methylpropane-2-sulfinamide (3.20 g, 53.3%) as a viscous, yellow oil.

[0487] Cyclopentyl(3-methoxyphenyl)methanamine (Compound 12). To a heated, dried round-bottom flask containing a Teflon coated magnetic stir bar was added A-(cyclopentyl(3- methoxyphenyl)methylene)-2-methylpropane-2-sulfinamide (1.50 g, 4.88 mmol) and absolute EtOH (25 mL) under argon atmosphere. The solution was cooled to 0°C on an ice water bath and NaBEL (550 mg, 14.5 mmol) was added in one portion. The reaction was allowed to warm naturally to rt overnight and then quenched with KOH solution (-1 M, 200 mL). The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with diH2O (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to afford a yellow transparent oil. The intermediate was dissolved in THF (30 mL) and 3M HC1 (30 mL) was added. The biphasic mixture was allowed to stir at rt for 4 h and then diluted with diftO (30 mL) and EtOAc (100 mL). The mixture was extracted and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diftO (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to afford a yellow cloudy oil. The oil was directly converted to the HC1 salt by dissolving in EtOH (40 mL) and adding a slight excess of concentrated HC1 (308 pL). The mixture was concentrated under a warm stream of air with evaporations of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting solid was washed with Et2O (3 x -20 mL) and dried to afford cy cl opentyl(3-methoxyphenyl)m ethanamine (12) hydrochloride (730 mg, 61.8% yield) as a white fluffy solid. The solid was crystalized 3X by dissolving in a minimum volume of EtOH and layering with Et2O followed by storing at 0°C to give a white fluffy solid. 'H NMR HC1 salt (400 MHz, DMSO-de) 8 ppm = 8.65 (s, NHL), 7.30 (t, J= 7.9 Hz, 1H), 7.22-7.17 (m, 1H), 7.09 (d, J= 7.6 Hz, 1H), 6.91 (dd, J= 8.3, 2.2 Hz, 1H), 3.99-3.88 (1H), 3.76 (s, 3H), 2.43-2.28 (m, 1H), 1.95-1.84 (m, 1H), 1.70-1.57 (m, 1H), 1.57-1.33(m, 4H), 1.27-1.15 (m, 1H), 1.13-0.99 (m, 1H). °C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 159.36 (1 C), 140.01 (1 C), 129.60 (1 C), 119.78 (1 C), 113.70 (1 C), 113.24 (1 C), 59.08 (1 C), 55.22 (1 C), 44.46 (1 C), 29.84 (1 C), 29.46 (1 C), 24.79 (1 C), 24.29 (1 C). mp: >260°C. HPLC Purity: (70:30 Formate buffer:ACN, 200 nm): 100%. ASAP MS: 207.3 (10%, [M+2]), 206.3 (35%, [M+l]), 190.3 (15%, [M+2]-NH3), 189.2 (100%, [M+1]-NH3). HRMS: m / z calcd for CI3HI9NO+H [M + H]+, 206.1539; found 206.1541, Appm = 0.97; CI3HI7O+H [M + H]+, 189.1274; found 189.1275, Appm = 0.53.

[0488] l-cyclopentyl-l-(3-methoxyphenyl)ethan-l-amine (Compound 13). To a heated, dried round-bottom flask containing a Teflon coated magnetic stir bar was added a solution of N- (cyclopentyl(3-methoxyphenyl)methylene)-2-methylpropane-2-sulfmamide (1.50 g, 4.88 mmol) in dry (3 A molecular sieves) THF (25 mL) under argon atmosphere. The solution was cooled to 0°C and a solution of methylmagnesium bromide (1.4 M in THF Toluene, 10 mL, 14 mmol) was added via syringe over 5 min. The reaction was allowed to warm to rt overnight and then carefully quenched with 3M HC1 (30 mL). The biphasic mixture was stirred vigorously for 5 h at rt and then diluted with diftO (30 mL) and EtOAc (-100 mL). The aqueous phase was collected and the organic layer was extracted further with IM HC1 (3 x 100 mL). The combined aqueous layers were basified with NH4OH and extracted with EtOAc (3 x 100 mL). The organic layer was washed with diH3O (20 mL) and brine (20 mL), dried over anhydrous Na7SO4, and concentrated under vacuum to afford an amber transparent oil. The product was purified via flash chromatography (SiO2, 4:1 hexanes :EtO Ac to 1 : 1 hexanes:EtOAc) to afford 1 -cyclopentyl- 1 -(3- methoxyphenyl)ethan-l -amine (13) (470 mg, 43.9%) as a cloudy, colorless oil. The purified free base was converted to the hydrochloride salt by dissolving in absolute EtOH (20 mL) and adding a slight excess of concentrated HC1 (196 pL). The mixture was concentrated under a warm stream of air with evaporation of repeated EtOH additions (3 x -5 mL) to remove excess HC1 and water. The resulting salt was a gummy yellow solid that was vigorously scratched in the presence of hexanes. The salt was cooled to -20°C and scratched with a metal spatula periodically over 3 days to afford a light yellow powdery solid.1H NMR HC1 salt (400 MHz, DMSO-d6) 5 ppm = 8.67 (s, NH3+), 7.32 (t, J= 8.0 Hz, 1H), 7.18-7.14 (m, 1H), 7.07 (dm, J= 7.7 Hz, 1H), 6.90 (dd, J= 8.2, 2.1 Hz, 1H), 3.78 (s, 3H), 2.46-2.34 (m, 1H), 1.62-1.53 (m, 1H, overlap with 1.60), 1.60 (s, 3H, overlap with 1.62-1.53), 1.53-1.30 (m, 6H), 1.30-1.15 (m, 1H).13C NMR HC1 salt (100.6 MHz, DMSO-d6) 5 ppm = 159.20 (1 C), 143.23 (1 C), 129.34 (1 C), 117.87 (1 C), 112.76 (1 C), 112.06 (1 C), 60.42 (1 C), 55.30 (1 C), 49.20 (1 C), 26.91 (1 C), 26.80 (1 C), 24.87 (1 C), 24.68 (1 C), 21.26 (1 C). mp: 112.4-115.8°C. HPLC Purity: (70:30Formate buffer: ACN, 200 nm): 100%. ASAP MS: 221.3 (10%, [M+2]), 220.3 (50%, [M+l]), 204.3 (20%, [M+2]-NH3), 203.3 (100%, [M+1]-NH3).

[0489] 1-cyclopentyl-l-phenylbutan-l-ol. To a heated, dried round-bottom flask containing a Teflon coated magnetic stir bar was added a solution of cyclopentyl phenyl ketone (965 pL, 1.0 g, 5.73 mmol) in dry (3A molecular sieves) THF (15 mL) under argon atmosphere. The solution was cooled to 0°C and a solution of n-propylmagnesium bromide (2.0 M in diethyl ether, 8.6 mL, 17.2 mmol) was added via syringe over 10 min. The reaction was allowed to warm naturally to rt overnight and then slowly quenched with saturated NH4CI (15 mL) at 0°C. The mixture was then diluted with diftO (~50 ...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A composition comprising a compound of Formula (I):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R6;R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl;with the proviso that the compound of Formula I is notA pharmaceutical composition comprising a compound of Formula (I):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R6;R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from: Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; and C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8;R4, R5, R6, R7, and R8are each independently selected from: hydrogen; Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, and C3-5 cycloalkyl, wherein Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl are optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -N02, -NH2, -O-Ci-6alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6 alkyl), Ci-6 alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; and C3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, -SH, -N02, -NH2, -O-Ci-6alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6 alkyl), and Ci-8 alkyl; orR4and R5are combined with the nitrogen to which it is attached to form a 6-membered heterocycle;3. The compound of claim 2, or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is selected from phenyl and 5- to 10-membered heteroaryl; wherein the phenyl and 5- to 10-membered heteroaryl are each optionally substituted with one or more R6;R2is selected from hydrogen, Ci-s alkyl, C2-8 alkenyl, C2-8 alkynyl, and C3-5 carbocycle, each of which is optionally substituted with one or more R7;R3is C3-6 carbocycle, wherein the C3-6 carbocycle is optionally substituted with one or more R8;R4and R5are each independently selected from: hydrogen, CMO alkyl, and C3-5 cycloalkyl, wherein the CMO alkyl is optionally substituted with C3-5 cycloalkyl; or R4and R5are combined with the nitrogen to which it is attached to form a 6-membered heterocycle;R6is C O alkyl, wherein the CMO alkyl is optionally substituted with halogen;R7is C3-5 cycloalkyl; andR8is CMO alkyl.

4. The compound of claim 3, or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is selected from phenyl, imidazolyl, thiophenyl, selenophenyl, and benzothiophenyl; wherein the phenyl, imidazolyl, thiophenyl, selenophenyl, and benzothiophenyl are each optionally substituted with one or more R6;R2is selected from hydrogen, methyl, ethyl, propyl, butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, cyclopropyl, cyclobutyl, and cyclopentyl, each of which is optionally substituted with one or more R7;R3is cyclobutyl, cyclopentyl, or cyclohexyl;R4and R5are each independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, methyl-cyclopropyl, methyl-cyclobutyl,methyl-cyclopentyl, cyclopropyl, cyclobutyl, or cyclopentyl; or R4and R5are combined with the nitrogen to which it is attached to form piperidinyl;R6is methyl or CF3; andR7is cyclopropyl or cyclobutyl.

5. The compound of claim 4, or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R1is selected from phenyl and selenophenyl; wherein the phenyl and selenophenyl are each optionally substituted with one or more R6;R2is selected from hydrogen, methyl, butyl, ethenyl, propenyl, butenyl, ethynyl, cyclopropyl, and cyclobutyl, each of which is optionally substituted with one or more R7;R3is cyclopentyl;R4and R5are each independently selected from: hydrogen, methyl, ethyl, isopropyl, sec-butyl, methyl-cyclopropyl, cyclobutyl; or R4and R5are combined with the nitrogen to which it is attached to form piperidinyl;R6is CF3; andR7is cyclopropyl or cyclobutyl.

6. The composition of claim 1, wherein R1is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R6.

7. The composition of claim 1 or 2, wherein R1is phenyl, optionally substituted with one or more R6.

8. The composition of claim 1 or 2, wherein R1is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R6.

9. The composition of claim 1 or 2, wherein R1is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R6.

10. The composition of claim 1 or 2, wherein R1is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R6.

11. The composition of claim 1 or 2, wherein R1is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran,dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R6.

12. The composition of claim 1 or 2, wherein R1is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R6.

13. The composition of claim 1 or 2, wherein R1is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R6.

14. The composition of claim 1 or 2, wherein R1is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R6.

15. The composition of claim 1 or 2, wherein R1is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R6.

16. The composition of claim 1, wherein R1is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R6.

17. The composition of claim 1, wherein R1is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotriazole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]-pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5- b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5- b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4-b]pyridine, isooxazolo[3,4- c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R6.

18. The composition of claim 1, wherein R1is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5, l-b]thiazole, imidazo[5, l-b]thiazole, imidazo[2, l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2-c][l,2,4]triazole, imidazo[2,l-b]thiadiazole,imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3- b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R6.

19. The composition of claim 1, wherein R1is a bridged ring system selected from norbomane, norbornene, bicyclofl.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R6.

20. The composition of any of claims 1 to 19, wherein R3is C3-7 carbocycle or 3- to 7- membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

21. The composition of any of claims 1 to 20, wherein R3is phenyl, optionally substituted with one or more R8.

22. The composition of any of claims 1 to 20, wherein R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

23. The composition of any of claims 1 to 20, wherein R3is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8.

24. The composition of any of claims 1 to 20, wherein R3is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8.

25. The composition of any of claims 1 to 20, wherein R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8.

26. The composition of any of claims 1 to 20, wherein R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8.

27. The composition of any of claims 1 to 20, wherein R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8.

28. The composition of any of claims 1 to 20, wherein R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8.

29. The composition of any of claims 1 to 20, wherein R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8.

30. The composition of any of claims 1 to 19, wherein R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

31. The composition of any of claims 1 to 19, wherein R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

32. The composition of any of claims 1 to 19, wherein R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2,l- b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2-c][l,2,4]triazole, imidazo[2,l- b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

33. The composition of any of claims 1 to 19, wherein R3is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane,bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8.

34. The composition of any of claims 1 to 33, wherein R2is C3-7 carbocycle or 3- to 7- membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

35. The composition of any of claims 1 to 34, wherein R2is phenyl, optionally substituted with one or more R7.

36. The composition of any of claims 1 to 34, wherein R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

37. The composition of any of claims 1 to 34, wherein R2is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7.

38. The composition of any of claims 1 to 34, wherein R2is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7.

39. The composition of any of claims 1 to 34, wherein R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7.

40. The composition of claims 1 to 34, wherein R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7.

41. The composition of any of claims 1 to 34, wherein R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7.

42. The composition of any of claims 1 to 34, wherein R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7.

43. The composition of any of claims 1 to 34, wherein R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7.

44. The composition of any of claims 1 to 33, wherein R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

45. The composition of any of claims 1 to 33, wherein R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

46. The composition of any of claims 1 to 33, wherein R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2,l- b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2-c][l,2,4]triazole, imidazo[2,l- b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

47. The composition of any of claims 1 to 33, wherein R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7.

48. The composition of claims 1 to 47, wherein each of R4or R5is independently hydrogen or selected from azacyclopropane, azetidine, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, 1,4-diazepane, tropane, azanorb ornane, and 2-azaadamantane.

49. The composition of claim 1, wherein the compound has the structure:or a pharmaceutically acceptable salt of the compound.

50. A method for treating a physical, psychiatric, or neurological disorder comprising administering to a subject in need thereof the pharmaceutical composition of any one of claims 1 to 49.

51. A composition comprising a compound of Formula (II):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7; R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl;with the proviso that the compound of Formula II is not52. The composition of claim 51, wherein R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

53. The composition of claim 51 or 52, wherein R3is phenyl, optionally substituted with one or more R8.

54. The composition of claim 51 or 52, wherein R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

55. The composition of claim 51 or 52, wherein R3is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8.

56. The composition of claim 51 or 52, wherein R3is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8.

57. The composition of claim 51 or 52, wherein R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8.

58. The composition of claim 51 or 52, wherein R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8.

59. The composition of claim 51 or 52, wherein R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8.

60. The composition of claim 51 or 52, wherein R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8.

61. The composition of claim 51 or 52, wherein R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8.

62. The composition of claim 51, wherein R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

63. The composition of claim 51, wherein R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotriazole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]-pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5- b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5- b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4-b]pyridine, isooxazolo[3,4- c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

64. The composition of claim 51, wherein R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5, l-b]thiazole, imidazo[5, l-b]thiazole, imidazo[2, l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2-c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3- b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

65. The composition of claim 51, wherein R3is a bridged ring system selected from norbomane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8.

66. The composition of any of claims 51 to 65, wherein R2is C3-7 carbocycle or 3- to 7- membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

67. The composition of any of claims 51 to 66, wherein R2is phenyl, optionally substituted with one or more R7.

68. The composition of any of claims 51 to 66, wherein R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

69. The composition of any of claims 51 to 66, wherein R2is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7.

70. The composition of any of claims 51 to 66, wherein R2is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7.

71. The composition of any of claims 51 to 66, wherein R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7.

72. The composition of any of claims 51 to 66, wherein R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7.

73. The composition of any of claims 51 to 66, wherein R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7.

74. The composition of any of claims 51 to 66, wherein R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7.

75. The composition of any of claims 51 to 66, wherein R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7.

76. The composition of any of claims 51 to 65, wherein R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

77. The composition of any of claims 51 to 65, wherein R2is a 5-6 fused ring system selected from benzimidazole, indole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotriazole, and purine, any of which is optionally substituted with one or more R7.

78. The composition of any of claims 51 to 65, wherein R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2, 1 - b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

79. The composition of any of claims 51 to 65, wherein R2is a bridged ring system selected from norbornane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7.

80. The composition of claims 51 to 79, wherein each of R4or R5is independently selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

81. The composition of claim 47, wherein the compound of Formula (II) is selected from:

82. A method for treating a physical, psychiatric, or neurological disorder comprising administering to a subject in need thereof the pharmaceutical composition of any one of claims 51 to 81.

83. A composition comprising a compound of Formula (III):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

84. The composition of claim 83, wherein R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

85. The composition of claim 83 or 84, wherein R2is phenyl, optionally substituted with one or more R7.

86. The composition of claim 83 or 84, wherein R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

87. The composition of claim 83 or 84, wherein R2is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7.

88. The composition of claim 83 or 84, wherein R2is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7.

89. The composition of claim 83 or 84, wherein R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7.

90. The composition of claim 83 or 84, wherein R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7.

91. The composition of claim 83 or 84, wherein R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7.

92. The composition of claim 83 or 84, wherein R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7.

93. The composition of claim 83 or 84, wherein R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7.

94. The composition of claim 83, wherein R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

95. The composition of claim 83, wherein R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotriazole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]-pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5- b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5- b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4-b]pyridine, isooxazolo[3,4- c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

96. The composition of claim 79, wherein R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5, l-b]thiazole, imidazo[5, l-b]thiazole, imidazo[2, l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2-c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3- b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

97. The composition of claim 83, wherein R2is a bridged ring system selected from norbomane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7.

98. The composition of claims 83 to 97, wherein each of R4or R5is independently hydrogen or a 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4- oxazepane, and 1,4-diazepane.

99. The composition of claim 83, wherein the compound of Formula (III) is selected from:

100. A method for treating a physical, psychiatric, or neurological disorder comprising administering to a subject in need thereof the pharmaceutical composition of any one of claims 83 to 99.

101. A composition comprising a compound of Formula (IV):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

102. The composition of claim 101, wherein R2is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

103. The composition of claim 101 or 102, wherein R2is phenyl, optionally substituted with one or more R7.

104. The composition of claim 101 or 102, wherein R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

105. The composition of claim 101 or 102, wherein R2is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7.

106. The composition of claim 101 or 102, wherein R2is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7.

107. The composition of claim 101 or 102, wherein R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7.

108. The composition of claim lOlor 102, wherein R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7.

109. The composition of claim 101 or 102, wherein R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7.

110. The composition of claim 101 or 102, wherein R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7.

111. The composition of claim 101 or 102, wherein R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7.

112. The composition of claim 101 , wherein R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

113. The composition of claim 101 , wherein R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotriazole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]-pyridine, pyrazolo[3,4-b]pyridine,pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5- b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5- b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4-b]pyridine, isooxazolo[3,4- c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

114. The composition of claim 101 , wherein R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5, l-b]thiazole, imidazo[5, l-b]thiazole, imidazo[2, l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2-c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3- b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

115. The composition of claim 101 , wherein R2is a bridged ring system selected from norbomane, norbornene, bicyclofl.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R7.

116. The composition of claims 101 to 115, wherein each of R4or R5may independently be 3- to 10-membered heterocycle selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4- diazepane.

117. The composition of claim 101 , wherein the compound of Formula (IV) is selected118. A method for treating a physical, psychiatric, or neurological disorder comprising administering to a subject in need thereof the pharmaceutical composition of any one of claims 101 to 117.

119. A pharmaceutical composition comprising a compound of Formula (V):or an enantiomer, a mixture of enantiomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:R2is selected from hydrogen; halogen;Ci-8 alkyl, C2-8 alkenyl, and C2-8 alkynyl, each of which is optionally substituted with one or more R7; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R7;R3is selected from:Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more R8; andC3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R8; R4, R5, R6, R7, and R8are each independently selected from: hydrogen;Ci-io alkyl, C2-10 alkenyl, and C2-10 alkynyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -NO2, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), Ci-6alkyl, Ci-6 cycloalkyl, and Ci-6 cycloalkenyl; andC3-10 carbocycle or 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or moresubstituents independently selected from hydrogen, halogen, -CN, -OH, =0, =S, =NH, - SH, -N02, -NH2, -O-CI-6 alkyl, -S-Ci-6alkyl, -N(CI-6alkyl)2, -NH(CI-6alkyl), and Ci-8alkyl.

120. The composition of claim 119, wherein R3is C3-7 carbocycle or 3- to 7-membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R8.

121. The composition of claim 119 or 120, wherein R3is phenyl, optionally substituted with one or more R8.

122. The composition of claim 119 or 120, wherein R3is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R8.

123. The composition of claim 119 or 120, wherein R3is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R8.

124. The composition of claim 119 or 120, wherein R3is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R8.

125. The composition of claim 119 or 120, wherein R3is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R8.

126. The composition of claim 119 or 120, wherein R3is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R8.

127. The composition of claim 119 or 120, wherein R3is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R8.

128. The composition of claim 119 or 120, wherein R3is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R8.

129. The composition of claim 119 or 120 wherein R3is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R8.

130. The composition of claim 119, wherein R3is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R8.

131. The composition of claim 119, wherein R3is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotriazole, benzothiazole, benzisothi azole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]-pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5- b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5- b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4-b]pyridine, isooxazolo[3,4- c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4-b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R8.

132. The composition of claim 119, wherein R3is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5, l-b]thiazole, imidazo[5, l-b]thiazole, imidazo[2, l-b]thiazole, thiazolo[3,2-b][l,2,4]triazole, thiazolo[3,2-c][l,2,4]triazole, imidazo[2,l-b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3- b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R8.

133. The composition of claim 119, wherein R3is a bridged ring system selected from norbomane, norbornene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l. l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, housane, any of which is optionally substituted with one or more R8.

134. The composition of any of claims 119 to 133, wherein R2is C3-7 carbocycle or 3- to 7- membered heterocycle; wherein the C3-7 carbocycle and 3- to 7-membered heterocycle are each optionally substituted with one or more R7.

135. The composition of any of claims 119 to 134, wherein R2is phenyl, optionally substituted with one or more R7.

136. The composition of any of claims 119 to 134, wherein R2is a cycloalkyl selected from cyclooctane, cycloheptane, cyclohexane, cyclopentane, cyclobutane, and cyclopropane, any of which is optionally substituted with one or more R7.

137. The composition of any of claims 119 to 134, wherein R2is a 6-membered heteroaryl selected from pyridine, pyrazine, and pyrimidine, any of which is optionally substituted with one or more R7.

138. The composition of any of claims 119 to 134, wherein R2is a 5-membered heteroaryl selected from thiophene, furan, pyrrole, pyrazole, selenophene, imidazole, thiazole, isothiazole, oxatriazole, oxadiazole, oxazole, and thiadiazole, any of which is optionally substituted with one or more R7.

139. The composition of any of claims 119 to 134, wherein R2is a 6-membered heterocycloalkenyl selected from dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxine, dihydrodioxine, oxazine, dihydrooxazine, thiazine, and dihydrothiazine, any of which is optionally substituted with one or more R7.

140. The composition of any of claims 119 to 134, wherein R2is a 5-membered heterocycloalkenyl selected from pyrroline, pyrazoline, imidazoline, triazoline, dihydrofuran, dihydrothiophene, oxazoline, isooxazoline, thiazoline, isothiazoline, oxadiazoline, and thiadiazoline, any of which is optionally substituted with one or more R7.

141. The composition of any of claims 119 to 134, wherein R2is a 6-membered heterocycloalkyl selected from piperidine, piperazine, tetrahydrothiopyran, tetrahydropyran, dioxane, morpholine, and thiomorpholine, any of which is optionally substituted with one or more R7.

142. The composition of any of claims 119 to 134, wherein R2is a 5-membered heterocycloalkyl selected from tetrahydrofuran, pyrrolidone, and tetrahydrothiophene, any of which is optionally substituted with one or more R7.

143. The composition of any of claims 119 to 134, wherein R2is a 4-membered heterocycloalkyl selected from azetidine, oxetane, and thietane, any of which is optionally substituted with one or more R7.

144. The composition of any of claims 119 to 133, wherein R2is a 6-6 fused ring system selected from naphthalene, quinoline, isoquinoline, pteridine, benzopyran, dihydroquinoline, dihydroisoquinoline, dihydronapthalene, and tetrahydronapthalene, any of which is optionally substituted with one or more R7.

145. The composition of any of claims 119 to 133, wherein R2is a 5-6 fused ring system selected from benzimidazole, indole, azaindole, indazole, benzothiophene, benzofuran, benzoselenophene, benzimidazole, benzotri azole, benzothiazole, benzisothiazole, benzoxadiazole, benzoxazole, and benzothiadi azole, imidazo[4,5-b]-pyridine, imidazo[4,5-c]- pyridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[4,3-b]pyridine, pyrazolo[4,3-b]pyridine, oxazolo[4,5-b]pyridine, oxazolo[4,5-c]pyridine, oxazolo[5,4-b]pyridine, oxazolo[5,4-c]pyridine, thiazolo[4,5-b]pyridine, thiazolo[4,5-c]pyridine, thiazolo[5,4-b]pyridine, thiazolo[5,4-c]pyridine , isooxazolo[4,5-b]pyridine, isooxazolo[4,5-c]pyridine, isooxazolo[3,4- b]pyridine, isooxazolo[3,4-c]pyridine, isooxazolo[4,3-b]pyridine, isooxazolo[4,3-c]pyridine, isooxazolo[5,4-b]pyridine, isooxazolo[5,4-c]pyridine, isothiazolo[4,5-b]pyridine, isothiazolo[4,5-c]pyridine, isothiazolo[5,4-b]pyridine, isothiazolo[5,4-c]pyridine, isothiazolo[3,4- b]pyridine, isothiazolo[3,4-c]pyridine, isothiazolo[4,3-b]pyridine, isothiazolo[4,3-c]pyridine and purine, any of which is optionally substituted with one or more R7.

146. The composition of any of claims 119 to 133, wherein R2is a 5-5 fused ring system selected from pyrrolo[2,l-b]thiazole, pyrazolo[5,l-b]thiazole, imidazo[5,l-b]thiazole, imidazo[2, 1 -b]thi azole, thiazolo[3 ,2-b] [ 1 ,2,4]triazole, thiazolo[3 ,2-c] [ 1 ,2,4]triazole, imidazo[2, 1 - b]thiadiazole, imidazo[l,2-d][l,2,4]thiadiazole, thiazolo[3,2-d]tetrazole, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, thieno[3,4-b]thiophene, thieno[3,4-c]thiophene, any of which is optionally substituted with one or more R7.

147. The composition of any of claims 119 to 133, wherein R2is a bridged ring system selected from norbomane, norbomene, bicyclo[1.1.0]butane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[l.l.l]pentane, bicyclo[2.2.1]hexane, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane, adamantane, cubane, and housane, any of which is optionally substituted with one or more R7.

148. The composition of claims 119 to 147, wherein each of R4or R5is independently selected from azacyclopropane, pyrrolidine, piperidine, azepane, azocane, azonane, morpholine, thiomorpholine, 1,4-piperazine, 1,4-oxazepane, and 1,4-diazepane.

149. The composition of claim 119, wherein the compound of Formula (V) is selected from:

150. A method for treating a physical, psychiatric, or neurological disorder comprising administering to a subject in need thereof the pharmaceutical composition of any one of claims 119 to 149.

151. A compound selected from Table la.

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