(hetero)arylalkylamine n-methyl-d-aspartate receptor (NMDAR) antagonists and uses thereof

Abstract

A series of novel (hetero)arylalkylamine and substituted (hetero)arylalkylamine are described which bind to neurologically active receptors, such as N-methyl-D-aspartate receptors (NMDARs) and monoamine transporters (MATs) such as dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs). Such compounds have value in various therapeutic indications including, but not limited to, mood disorders, pain, depression, tinnitus, post-traumatic stress disorder, and the like.

Description

(HETERO)ARYLALKYLAMINE N-METHYL-D-ASPARTATE RECEPTOR (NMD AR) ANTAGONISTS AND USES THEREOFCROSS-REFERENCE(S) TO OTHER APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application 63 / 585,486 filed September 26, 2023, the entirety of which is incorporated by reference herein.BACKGROUND

[0002] N-methyl-D-aspartate receptors (“NMDARs”) are a type of ionotropic glutamate 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 NMDARmustbe open and functional. In order for the channel to open and functional, glutamate and glycine must bind to the NMD AR, and the voltage dependent Mg2+block must be lifted. NMDARs in this state can be called “activated” and cations are able to flow through them.

[0003] Chemicals that inhibit the activity of NMDARs are called antagonists. NMD AR antagonists fall into several categories: competitive antagonists bind to and blockthe orthosteric binding sites of the neurotransmitters glutamate and glycine; noncompetitive antagonists inhibit NMDARs by binding to allosteric sites; uncompetitive antagonists, are a type of noncompetitive antagonist which block the active open channel, these are also called channel blockers. One example of an NMD AR uncompetitive antagonist channel blockers is ketamine, which acts by blocking the ion channel through binding to the PCP-binding site within NMDARs.SUMMARY

[0004] The compounds of the instant disclosure bind to and inhibit neurologically relevant receptors, such as NMDARs, dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs), and may have wide therapeutic activity in psychiatric and neurological indications. NMD AR antagonists have therapeutic potential in various psychiatric and neurological indications including pain indications, depression, bipolar disorder, neurodegenerative diseases, pseudobulbar affect, epilepsies, substance use disorders, obsessive compulsive disorder, etc. Monoamine transporters (MATs) such as those for dopamine, norepinephrine and serotonin (DAT, NET and SERT, respectively) have been targeted in a number of neurological and psychiatric disorders including pain, major depressive disorder, attention deficient disorder, anxiety disorders, narcolepsy, and obsessive compulsivedisorder. Agents targeting one or a combination of NMD AR and monoamine transporters thus have therapeutic potential in a number of important clinical indications. Polypharmacological interventions may have added benefits for both efficacy and tolerability.

[0005] The present disclosure generally relates to (hetero)arylalkylamine and substituted (hetero)arylalkylamine compounds or salts of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) and compositions thereof. The alkylamine and substituted alkylamine compounds or salts of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) disclosed herein may be used to treat physical, psychiatric, or neurological disorder. In some embodiments, a compound or salt of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) is an antagonist of NMD AR. In some embodiments, a compound or salt of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) is an inhibitor of NMD AR. In some embodiments, a compound or salt of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) is inhibitor of a serotonin transporter (SERT). In some embodiments, a compound or salt of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) is an antagonist of a dopamine transporter (DAT).

[0006] The disclosure provides compound and salts thereof for use in treating disease. In certain aspects, the disclosure provides a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (IF) or (Ila), compositions thereof as well as methods of use in the treatment of disease.

[0007] In certain aspects, disclosed herein are compositions and methods of treating a physical, psychiatric, or neurological disease, comprising administering to a subject in need thereof a compound or salt of any one of Formula (I):Formula (I), wherein:Ring A is an aryl or a heterocycle; each RAis halogen, NO2, CN, N(Ra)2, -SRa, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, Ci- C10 haloalkoxy, or two RAtaken together with the atoms to which they are bound form a 3 - to 7-membered carbocycle or a 3 - to 9-membered heterocycle; each of R1and R2is independently H, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C5 carbocycle, C2-C5 heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5- membered carbocycle or a 3 - to 5-membered heterocycle;R3is H, methyl, or ethyl;R4is C3-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C5carbocycle, or C2-C6heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, NRaRb, or Ci-C6alkyl; each RBis independently OH, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, Ci- Cio alkoxy, C3-Cio heteroaryl, (Ci-C3)-aryl, (Ci-C3)-heteroaryl, -SRa, NRaRb; or two RBtaken together with the atom to which they are attached form a 3 - to 6-membered carbocycle or a 4- to 6-membered heterocycle;Y is C(RB)2, NR6, O, S, or Se; each RBis independently H, OH, =0, halogen, Ci-Cio alkyl, C2-Ci0alkenyl, Ci-Cio haloalkyl, C3-Cio heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6-membered heterocycle;R6is a Ci-Cio alkyl, C2-Ci0alkenyl, Ci-Cio haloalkyl, C3-Ci0heteroaryl, (Ci-C3)-aryl, or (Ci- C3)-heteroaryl, wherein each alkyl, alkenyl, haloalkyl, aryl or heteroaryl is optionally substituted with OH, halogen, C1-C5 alkyl, C1-C5 alkoxy, or -SRa; m is an integer from 1 to 5; n is an integer from 0 to 18; and p is an integer from 0 to 7; wherein each Raand Rbis independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6heteroalkyl, C3-Ci0carbocycle, C3-Ci0heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)- heteroaryl; or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, with the proviso that the compound of Formula I is not:

[0008] In certain aspects, disclosed herein are compositions and a method of treating a physical, psychiatric, or neurological disease, comprising administering to a subject in need thereof a compound or salt of any one of Formula (II):Formula (II), whereinRing A is phenyl, furanyl, benzodioxole, or thiophenyl; each RAis independently halogen, C2-Ci0alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl; each of R1and R2is independently H, methyl, or ethyl, wherein R1and R2are not the same; each RBis independently H, OH, =0, halogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C2-Cio heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6-membered heterocycle; each RBis independently H, OH, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-Cio heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6-membered cyclic ketal; n is an integer from 0 to 8; and p is an integer from 0 to 5.

[0009] In certain aspects, disclosed herein are compositions and a method of treating a physical, psychiatric, or neurological disease, comprising administering to a subject in need thereof a compound or salt of any one of Formula (III):Formula (III) wherein each RAis independently halogen, C2-Ci0alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl, C1-C10 haloalkoxy, -SRa, -NRaRb; each of R1and R2is independently H, F, OH, halogen, C1-C10 alkyl, C1-C10 haloalkyl, -SRa, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3- to 5-membered heterocycle;R3is -H or methyl;R4is a C3-C10 alkyl, C3-C10 carbocycle, C2-Ci0heterocycle, or C1-C3 haloalkyl, wherein R4is optionally substituted with a C1-C3 alkyl, each RBis independently OH, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3- C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, -NH2, halogen or C1-C3 alkyl; or two RBtaken together to the carbon to which they are attached form a 5 - or 6-membered carbocycle or a 5 - to 6- membered heterocycle; n is an integer from 0 to 10; and p is an integer from 0 to 5, wherein each Raand Rbis independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ce heteroalkyl, C3-C10 carbocycle, C3-C10 heterocycloalkyl, (Ci-C3)-aryl, or (C1-C3)- heteroaryl; with the proviso that when n is 0, then the compound of Formula III is not:

[0010] In certain aspects, disclosed herein are compositions and a method of treating a physical, psychiatric, or neurological disease, comprising administering to a subject in need thereof a compound or salt of any one of Formula (III):Formula (III) wherein each RAis independently halogen, C2-Ci0alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl, C1-C10 haloalkoxy, -SRa, -NRaRb; each of R1and R2is independently H, F, OH, halogen, C1-C10 alkyl, C1-C10 haloalkyl, -SRa, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle;R3is -H or methyl;R4is a C3-C10 alkyl, C3-C10 carbocycle, C2-Ci0heterocycle, or C1-C3 haloalkyl, wherein R4is optionally substituted with a C1-C3 alkyl, each RBis independently OH, =0, halogen, C1-C10 alkyl, C2-Cio alkenyl, C1-C10 haloalkyl, C3- C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, -NH2, halogen or C1-C3 alkyl; or two RBtaken together to the carbon to which they are attached form a 5 - or 6-membered carbocycle or a 5- to 6- membered heterocycle; n is an integer from 0 to 10; and p is an integer from 0 to 5, wherein each Raand Rbis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-C6heteroalkyl, C3-C10 carbocycle, C3-C10 heterocycloalkyl, (Ci-C3)-aryl, or (C1-C3)- heteroaryl;with the proviso that when n is 0, then the compound of Formula III is not:

[0011] In certain aspects, disclosed herein is a method of treating a physical, psychiatric, or neurological disease, comprising administering to a subject in need thereof a compound or salt of any one of Formula (IV):Formula (IV); wherein:Rxand Rvtogether form a 5- to 9-membered carbocycle or heterocycle, optionally substituted with one or more RB; each of R1and R2is independently H, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C5 carbocycle, C2-C5 heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5- membered carbocycle or a 3 - to 5-membered heterocycle;R4is a C2-Cio alkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0haloalkyl, C2-Ci0alkoxyl, C2-Ci0aminoalkyl, C2-C10 heteroalkyl, C2-C10 cycloalkyl, C2-C10 heterocycloalkyl, (C1-C3 alkylene)aryl, (C1-C3 alkylene)heteroaryl, wherein each R4is independently optionally substituted with one or more R6;Rzis a 5- to 9-membered carbocycle or heterocycle, wherein the 5- to 9-membered carbocycle or heterocycle is optionally substituted with one or more RA; each RBis independently halogen, -CN, OH, -SH, -S(=O)(Ci-C3alkyl), -S(=O)2(Ci-C3 alkyl), - S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCI-C3alkyl)(Ci- C3alkyl), -NH2, -NH(CI-C3alkyl), -N(CI-C3alky 1)2, -C(=O)(Ci-C3alkyl), -C(=O)OH, - C(=O)O(Ci-C3alkyl), -C(=O)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(C C3alkyl)2, Ci-C10alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-Csj-heteroaryl; or two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle, a 3 - to 6-membered heterocycle, or an oxo;each R6is independently halogen, -CN, OH, =0, -SRa, NRaRb, -NRbC(=0)NRaRb, -NRbC(=0)Ra, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(C C3alkyl)2, -S(=O)(=NC C3alkyl)(Ci- C3alkyl), -NH2, -NH(C C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), -C(=O)OH, - C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(C C3alkyl)2, Ci-Cwalkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl; andRaand Rbare each independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-Ce alkylene(heteroaryl).

[0012] 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

[0013] There remains a need for treatment of various physical, psychiatric, or neurological disorders associated with receptor function, such as NMD AR, dopamine transporter (DAT), norepinephrine transporter (NET), or serotonin receptor (SERT). In particular, compounds that selectively bind to NMD AR receptors over other 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.

[0014] The compounds of the present disclosure exhibit varying degrees of selectivity for NMDARs over other CNS targets, such as DAT, NET 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 dextromethorphan (DXM) have various pharmacological limitations and there is thus a need for new NMD AR antagonists with improved clinical profiles.

[0015] Inhibiting NMDARs with uncompetitive antagonists which bind to the PCP site of active NMDARs (i.e., 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 use in suicidality, as well as the clinical use of memantine for Alzheimer’s disease as a neuroprotective agent. Dextromethorphan, an uncompetitive NMD AR antagonist and serotonin reuptake inhibitor, is also used, in combination products to inhibit its metabolism, in pseudobulbar affect and in major depressive disorder. NMD AR antagonism may lead to analgesic actions and can disrupt the processes of hyperalgesia and allodynia in pain disorders, as well as the development of hyperalgesia following treatment with opioid agonists. 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 due to rapid clearance. Ketamine has poor oral bioavailability and a short half-life limiting it's clinical utility for many indications.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 tailored for specific indications.

[0016] 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 theart without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed.

[0017] Disclosed herein are a series of (hetero)arylalkylamine and substituted (hetero)arylalkylamine compounds and compositions for treating a physical, psychiatric, or neurological disorder. The physical, psychiatric, or neurological disorder may comprise pain, mood disorders, obsessive compulsive disorder, tinnitus, post-traumatic stress disorder, psychosis, schizophrenia, depression, post-traumatic stress disorder, agitation, 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, substance use disorders, alcohol use disorders, hallucinations, delusions, insomnia, sleep disorders, epilepsies, bipolar disorder, anorexia, and Parkinson’s disease. In some embodiments, the compounds disclosed herein are N-methyl-D-aspartate receptor (NMD AR) antagonists. In some embodiments, the compounds disclosed herein are monoamine transporter (MAT) antagonists. In some embodiments, the compounds disclosed herein are norepinephrine transporter (NET) antagonists. In some embodiments, the compounds disclosed herein are dopamine transporter (DAT) antagonists. In some embodiments, the compounds disclosed herein are serotonin transporter (SERT) antagonists. In some embodiments, the compounds disclosed herein exhibit antagonism at NMD AR, NET, DAT, SERT, or a combination thereof.Definitions

[0018] 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.

[0019] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0020] 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.6alkyl” refers to substituted or un substituted 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.6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0021] The terms “Cx.Cyalkenyl” and “Cx.Cyalkynyl” 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 un substituted alkenylene chain with fromx to y carbons in the alkenylene chain. For example, -C2-C6 alkenylene- 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 b ond in the alkenylene chain. The term -Cx-Cyalkynylene- refers to a substituted or un substituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, -C2- C6alkynylene- may be selected from ethynylene, 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.

[0022] The term "alkyl" refers to a straight-chain (or “linear”) or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms. In some embodiments, the straight-chain or branched-chain saturated hydrocarbon monoradical has one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l- propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl- 1-propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a Ci-Ce alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a Ci- C4alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more =0, =S, halogen, amino, nitrile, nitro, thiol, thioether, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more =0, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, -NO2, -SMe, NHMe, N(Me)2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0023] The term "alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and H, 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 carb on atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C 1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1.3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C i-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cs-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.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.

[0024] The term "alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and H, 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 (i.e., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-Cs alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (i.e., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.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.

[0025] The term "alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and H, 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 asingle 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 comprisestwo to five carbon atoms (i.e., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C2alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (i.e., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.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.

[0026] The term "alkoxy" refers to a moiety bonded through an oxygen atom of the formula - O-alkyl, where alkyl is an alkyl chain as defined above.

[0027] 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 an exemplary embodiment, 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. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclofl . l . l]pentanyl.

[0028] 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 " (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents such as those substituents described herein.

[0029] 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, bicyclofl .1 , 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.

[0030] 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.

[0031] The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo.

[0032] The term “haloalky 1” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl,1 -chloromethyl-2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein.

[0033] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary 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 some embodiments, anaromatic 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.”

[0034] 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 Huckel 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[b][l,4]dioxepinyl, benzo [b][l,4]oxazinyl, 1,4 -benzodi oxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, 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-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,1 -phenyl- IH-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).

[0035] The term "heterocycloalkyl" refers to a saturated ring with carbon atoms and at least one heteroatom. Exemplary 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 quaternized. 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.

[0036] 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. Exemplary 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 (dihydro triazole), 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.

[0037] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH orNH2of 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, i.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 =0, 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.

[0038] 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)”.

[0039] “Hydrogen” refers to -H.

[0040] “ Oxo” refers to =0.

[0041] “ Amine” refers to -NH2.

[0042] “Hydroxyl” refers to -OH.

[0043] “Carboxyl” refers to -COOH.

[0044] As used herein, the term "administering" means subcutaneous (i.e., "SC," "subQ," or "SQ") administration, oral administration, administration as a suppository, topical contact or administration, intravenous, parenteral, intraperitoneal, intramuscular, intraosseous, intralesional, intrathecal, intracranial, intranasal, epidural, sublingual, buccal, topical, transdermal, intratympanic, intrarectal, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or tran sdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra -arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g. anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). The compound of the disclosure can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered by a transdermal route, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, troche, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, trochs, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present disclosure may additionally include components to provide sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present disclosure can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater S ci. Polym. Ed. 7:623645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).

[0045] By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the disclosure can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of thecompounds individually or in combination (more than one compound) . The compositions of the present disclosure can be delivered by a transdermal route, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0046] 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.

[0047] 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, p-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.COMPOUNDS

[0048] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. The compounds and salts are described in Formulas (I), (la), (lb), (II), (III), and (Illa).

[0049] In some aspects, the present disclosure provides compounds represented by the structure of Formula (I):Formula (I), wherein:Ring A is an aryl or a heterocycle; each RAis halogen, NO2, CN, N(Ra)2, -SRa, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, Ci- C10 haloalkoxy, or two RAtaken together with the atoms to which they are bound form a 3 - to 7-membered carbocycle or a 3 - to 9-membered heterocycle; each of R1and R2is independently H, F, Ci-C6alkyl, Ci-C6alkoxy, C3-C5 carbocycle, C2-C5heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5- membered carbocycle or a 3 - to 5-membered heterocycle;R3is H, methyl, or ethyl;R4is C3-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C5carbocycle, or C2-C6heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, NRaRb, Ci-C6alkyl; each RBis independently =0,0H, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-Cio heteroaryl, Ci-C3alkylene-aryl, Ci-C3alkylene-heteroaryl, -SRa, NRaRb; or two RBtaken together with the atom to which they are attached form a 5 - to 6- membered carbocycle or a 5 - to 6-membered heterocycle;Y is C(R5)2, NR6, O, S, or Se;R6is a C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-Ci0heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, wherein each alkyl, alkenyl, haloalkyl, aryl or heteroaryl is optionally substituted with OH, halogen, C1-C5 alkyl, C1-C5 alkoxy, or -SRa; m is an integer from 1 to 5; n is an integer from 0 to 18; and p is an integer from 0 to 7; wherein each Raand Rbis independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ce heteroalkyl, C3-Cio carbocycle, C3-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci- C3alkylene-heteroaryl; or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, with the proviso that the compound of Formula I is not:

[0050] In some embodiments, R3is H, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C5 carbocycle, or C2-C6heterocycle, wherein R3is optionally substituted with a halogen, OH, =0, NRaRb, Ci-C6alkyl. In some embodiments, R4is C3-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3- C5 carbocycle, or C2-Ce heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, NRaRb, Ci-C6alkyl.

[0051] In some embodiments, the present disclosure provides compounds represented by the structure of Formula (la):or a salt thereof, wherein:Ring A is an aryl; each RAis independently halogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl; each of R1and R2is independently H or C1-C10 alkyl;R3is H or methyl;R4is C3-C5 alkyl, C3-C5 carbocycle, or C2-C5 heterocycle, wherein R4is optionally substituted with a C1-C3 alkyl;Y is C(RB)2, NR6, O, or S; each RBis independently H, OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, Ci-Csalkylene-aryl, or C1-C3 alkylene-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6-membered cyclic ketal or an oxo;R6is C1-C10 alkyl, C2-Ci0alkenyl, C3-C10 heteroaryl, Ci-C3alkylene-aryl, or C1-C3 alkylene- heteroaryl; m is an integer from 1 to 5; n is an integer from 0 to 14; and p is an integer from 0 to 5; or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof , with the proviso that the compound of Formula I is not:

[0052] In certain embodiments, for a compound or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog of Formula (I), Ring A is aryl. In some embodiments, each RAis halogen, NO2, CN, N(R5)2, -SRa, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy. In some embodiments, two RAtaken together with the atoms to which they are bound form a 3- to 7-membered carbocycle or a 3 - to 9-membered heterocycle. In some embodiments, each of R1and R2is independently H, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C5 carbocycle, C2-C5heterocycle, or R1and R2together with the carbon to which they are attached form a 3- to 5-membered carbocycle or a 3 - to 5 -membered heterocycle. In some embodiments, R3is H, methyl, or ethyl. In some embodiments, R4is C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C5 carbocycle, or C2-C6 heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, N(R5)2, CI-C6alkyl. In some embodiments, each RBis independently =O,OH, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-C10 heteroaryl, (Ci-C3)-aryl, (Ci-C3)-heteroaryl, -SRa, NRaRb. In some embodiments, two RBtaken together with the atom to which they are attached form a 5- to 6-membered carbocycle or a 5- to 6-membered heterocycle. In some embodiments, Y is C(R5)2, NR6, O, S, or Se. In some embodiments, each R5is independently H, OH, =0, Ci-C 10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two R5taken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6-membered heterocycle. In some embodiments, R6is a halogen, =0,0H, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, SRa, Ci- C10 alkoxy, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, =0, -NH2, -NRaRb, -SH, =S, -SRa, -SO2Ra, -S03, halogen, Ci-C5alkyl, Ci-C5alkoxy, Ci-C5haloalkyl, -C00H, -C(O)(C C5alkyl), -C(0)NH(C C5 alkyl), or -NH(C(O))(Ci-Cs alkyl). In some embodiments, R6is a C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl,wherein each alkyl, alkenyl, haloalkyl, aryl or heteroaryl is optionally substituted with OH, halogen, C1-C5 alkyl, C1-C5 alkoxy, or -SRa. In some embodiments, m is an integer from 1 to 5. In some embodiments, n is an integer from 0 to 18. In some embodiments, p is an integer from 0 to 7. In some embodiments, each Raand Rbis independently H, halogen, -CN, OH, =0, =S, -SH, -S-(Ci-Cio alkyl), Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, Ci-C6heteroalkyl, C3-C10 carbocycle, C3-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl. In some embodiments, each Raand Rbis independently H, Ci-C6alkyl, Ci- C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6heteroalkyl, C3-C10 carbocycle, C3-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl.

[0053] In certain embodiments, for a compound or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog of Formula (I), Ring A is phenyl. In some embodiments, each RAis halogen, NO2, CN, N(R5)2, -SRa, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy. In some embodiments, each RAis halogen, OH, =0, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, (Ci-C3)-aryl. In some embodiments, two RAtaken together with the atoms to which they are bound form a 3 - to 7-membered carbocycle or a 3- to 9-membered heterocycle. In some embodiments, two RAtaken together form a 5 - or 6-membered cyclic ketal. In some embodiments, each of R1and R2is independently H, F, Ci-C6alkyl, Ci-C6alkoxy, C3- C5 carbocycle, C2-C5 heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle. In some embodiments, R3is H, methyl, or ethyl. In some embodiments, R3is H, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C5 carbocycle, or C2-C6heterocycle, wherein R3is optionally substituted with a halogen, OH, =0, NO2, CN, Ci-Ce alkyl, Ci-Ce haloalkyl, NRaRb, or SRa. In some embodiments, R4is C3-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C5 carbocycle, or C2-C6heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, NRaRb, Ci-C6alkyl. In some embodiments, R4is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C5 carbocycle, or C2-C6heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, N02, CN, Ci- Ce alkyl, Ci-C6haloalkyl, NRaRb, or SRa. In some embodiments, each RBis independently OH, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-C10 heteroaryl, (Ci-C3)-aryl, (Ci-C3)-heteroaryl, -SRa, NRaRb. In some embodiments, two RBtaken together with the atom to which they are attached form a 3 - to 6-membered carbocycle or a 3 - to 6- membered heterocycle. In some embodiments, two RBtaken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6-membered heterocycle. In some embodiments, two RBtaken together with the atom to which they are attached form a 4 - to 6-membered carbocycle or a 4- to 6-membered heterocycle. In some embodiments, Y is C(R5)2,NR6, O, S, or Se. In some embodiments, each R5is independently H, OH, =0, C1-C10 alkyl, C2- C10 alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two R5taken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5- to 6-membered heterocycle. In some embodiments, two R5are taken together with the atom to which they are attached to form a 3 - to 6-membered carbocycle or a 3- to 6-membered heterocycle. In some embodiments, R6is a halogen, =0, OH, C1-C10 alkyl, C2-Ci0alkenyl, Ci- C10 haloalkyl, SRa, SO2Ra, SORaRb, C1-C10 alkoxy, C3-Ci0heteroaryl, (Ci-C3)-aryl, or (Ci-C3)- heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, =0, -NH2, -NRaRb, -SH, =S, -SRa, -SO2Ra, -S03, halogen, Ci-C5alkyl, Ci-C5alkoxy, Ci-C5haloalkyl, -C00H, - C(O)(Ci-C5alkyl), -C(0)NH(C C5alkyl), or -NH(C(0))(CI-C5alkyl). In some embodiments, R6is C1-C10 alkyl, C2-Cio alkenyl, C3-Cio heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkyleneheteroaryl. In some embodiments, m is an integer from 1 to 5. In some embodiments, n is an integer from 0 to 18. In some embodiments, p is an integer from 0 to 7. In some embodiments, each Raand Rbis independently H, halogen, -CN, OH, =0, =S, -SH, -S-(Ci-Ci0alkyl), Ci-C6alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-Cio carbocycle, C3-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl. In some embodiments, each Raand Rbis independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ce heteroalkyl, C3-Cio carbocycle, C3-Cio heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl. In some embodiments, each of R1and R2is independently H, F, Ci-C6alkyl, Ci-C6alkoxy, C3-C5carbocycle, C3-C5heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5- membered heterocycle. In some embodiments, R1and R2are each H or D. In some embodiments, R1and R2are the same. In some embodiments R1and R2are different. In some embodiments, R1is H, and R2is a C1-C10 alkyl. In some embodiments, R1is H, and R2is a Ci- Ce alkyl. In some embodiments, R1is H, and R2is a Ci-C3alkyl. In some embodiments, R1is H, R2is methyl. In some embodiments, R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle. In some embodiments, the R1and R2together with the carbon to which they are attached form a 3 - to 5- membered carbocycle. In some embodiments, R1and R2together with the carbon to which they are attached form a cyclopropyl. In some embodiments, R1and R2together with the carbon to which they are attached form a cyclobutyl. In some embodiments, R1and R2together with the carbon to which they are attached form a cyclopentyl. In some embodiments, R1and R2together with the carbon to which they are attached form a 3 - to 5-membered heterocycle. In some embodiments, R1and R2together with the carbon to which they are attached form a 3 - to 5-membered heterocycle comprising at least one O, S, or N. In some embodiments, R1and R2together with the carbon to which they are attached form a 3 - to 5-membered heterocycle comprising at least one O. In some embodiments, R1and R2together with the carbon to which they are attached form an oxetane, thiooxetane, or an azetidine. In some embodiments, the 3- to 5-membered heterocycle may be further substituted with a Ci-Ce alkyl, OH, =0, halogen, or a combination thereof.

[0054] In some embodiments, each of R1and R2are hydrogen. In some embodiments, R4is C3-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C5carbocycle, or C2-C6heterocycle. In some embodiments, R4is optionally substituted with a halogen, OH, =0, O2, CN, Ci-C6alkyl, Ci-C6haloalkyl, NRaRb, or SRa. In some embodiments, R4is optionally substituted with two or more halogen, OH, =0, NO2, CN, Ci-Ce alkyl, Ci-Ce haloalkyl, NRaRb, or SRa. In some embodiments, R4is a C3-Cs alkyl. In some embodiments, R4is propyl. In some embodiments, R4is butyl. In some embodiments, R4is pentyl.

[0055] In some embodiments, Ring A is a 5- to 6-membered aryl. In some embodiments, Ring A is phenyl.

[0056] In some embodiments, Ring A is a heteroaryl. In some embodiments, the heteroaryl is a bicyclic heteroaryl. In some embodiments, the heteroaryl is pyridine, pyrimidine, triazine, tetrazine, imidazole, furan, thiophene, selenophene, thiazole, pyrrole, oxadiazole, oxazole, thiazole, triazole, pyrazole, isoxazole, isothiazole, pyridone, quinoline, isoquinoline, indole, benzofuran, benzoxazole, benzothiophene, benzimidazole, benzotriazole, benzodioxole, azaindole, azabenzofuran, azabenzothiophene, azabenzimidazole, dihydrobenzofuran, dihydrobenzothiophene, dihydroindole, or benzimidazolone. In some embodiments, Ring A is pyridine. In some embodiments, Ring A is pyrimidine. In some embodiments, Ring A is triazine. In some embodiments, Ring A is tetrazine. In some embodiments, Ring A is imidazole. In some embodiments, Ring A is furan. In some embodiments, Ring A is thiophene. In some embodiments, Ring A is selenophene. In some embodiments, Ring A is thiazole. In some embodiments, Ring A is pyrrole. In some embodiments, Ring A is oxadiazole. In some embodiments, Ring A is oxazole. In some embodiments, Ring A is thiazole. In some embodiments, Ring A is isoxazole. In some embodiments, Ring A is pyridine. In some embodiments, Ring A is quinoline. In some embodiments, Ring A is isoquinoline. In some embodiments, Ring A is isothiazole. In some embodiments, Ring A is indole. In some embodiments, Ring A is benzofuran. In some embodiments, Ring A is benzoxazole. In some embodiments, Ring A is benzothiophene. In some embodiments, Ring A is benzodiazine. In some embodiments, Ring A is benzimidazole. In some embodiments, Ring A is benzotriazole. Insome embodiments, Ring A is benzodioxole. In some embodiments, Ring A is azaindole. In some embodiments, Ring A is azabenzofuran. In some embodiments, Ring A is azabenzothiophene. In some embodiments, Ring A is azabenzimidazole. In some embodiments, Ring A is dihydrobenzo furan. In some embodiments, Ring A is dihydrobenzothiophene. In some embodiments, Ring A is dihydroindole. In some embodiments, Ring A is benzimidazolone. In some embodiments, Ring A is benzodioxole, m is 2, and n is 0. In some embodiments, Ring A is furanyl or thiophenyl. In some embodiments, Ring A is phenyl, n is from 1 to 10.

[0057] In some embodiments, eachRBis independently OH, =0, -NH2, -NHRa, -N(Ra)2, =S, - SH, -SRa, halogen, Ci-Cio alkyl, C2-Ci0alkenyl, Ci-Cio haloalkyl, Ci-Cio alkoxy, C3-C10 heteroaryl, (Ci-C3)-aryl, (Ci-C3)-heteroaryl, -SRa, NRaRb. In some embodiments, two RBtaken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6-membered heterocycle. In some embodiments, two RBtaken together with the atom to which they are attached form a 3- to 6-membered carbocycle or a 3- to 6-membered heterocycle. In some embodiments, each RBis independently OH, =0, -NH2, -NHRa, -N(Ra)2, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, -SRa, NRaRb, or (Ci-C3)-aryl. In some embodiments, two RBtaken together with the atom to which they are attached form a 3 - to 6-membered carbocycle or a 3- to 6-membered heterocycle. In some embodiments, each RBis independently OH, =0, - NH2, -NHRa, -N(Ra)2, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C1-C10 alkoxy, -SRa, NRaRb, or (Ci-C3)-aryl.

[0058] In some embodiments, for a compound or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog of Formula (I), Y is C(R5)2. In some embodiments, Ring A is an aryl or a heterocycle. In some embodiments, each RAis halogen, NO2, CN, N(R5)2, -SRa, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy. In some embodiments, p is 2 and two RAtaken together with the atoms to which they are bound form a 3- to 7-membered carbocycle or a 3- to 9-membered heterocycle. In some embodiments, each of R1and R2is independently H, Ci-C6alkyl, Ci-C6alkoxy, C3-C5carbocycle, C2-C5heterocycle. In some embodiments, R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle. In some embodiments, R3is H, methyl, or ethyl. In some embodiments, R4is C3-Ce alkyl, C3-Ce alkenyl, C3-C6alkynyl, C3-C5carbocycle, or C2-C6heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, NRaRb, Ci-C6alkyl. In some embodiments, each RBis independently =O,OH, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-Ci0heteroaryl, Ci-C3alkylene-aryl, Ci-C3alkylene-heteroaryl, -SRa, NRaRb. In some embodiments, two RBtaken together with the atom to which they are attached form a 5 - to 6-memberedcarbocycle or a 5- to 6-membered heterocycle. In some embodiments, each R5is independently H, OH, =0, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, Ci-C3alkylene- aryl, Ci-C3alkylene-heteroaryl, or two R5taken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6-membered heterocycle. In some embodiments, both R5are H, such that Y is CH2. In some embodiments, R6is a halogen, =0,0H, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, SRa, C1-C10 alkoxy, C3-Ci0heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl. In some embodiments, each aryl or heteroaryl is optionally substituted with OH, halogen, C1-C5 alkyl, C1-C5 alkoxy, or -SRa. In some embodiments, m is an integer from 1 to 5. In some embodiments, n is an integer from 0 to 18. In some embodiments, p is an integer from 0 to 7. In some embodiments, each Raand Rbis independently H, halogen, -CN, OH, =0, =S, -SH, -S-(Ci-Cio alkyl), Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce hydroxyalkyl, Ci-Ce heteroalkyl, C3-Cio carbocycle, C3-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl. In some embodiments, each Raand Rbis independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ce heteroalkyl, C3-Cio carbocycle, C3-Cio heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl. In some embodiments, when Ring A is phenyl, m is 2, and nsome embodiments, p is at least 1, and RAis halogen or C1-C10 alkyl. In some embodiments, two R5taken together with the carbon to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6-membered heterocycle. In some embodiments, when Ring A is phenyl, and p is from 1 to 5. In some embodiments, each RAis independently halogen, C2-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl. In some embodiments, p is 1 to 3. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments p is at least 2. In some embodiments, p is 2 or 3. In some embodiments, p is 5. In some embodiments, RAis F, Cl, Br, or I. In some embodiments, p is 2 and each of the two RAgroups is the same. In some embodiments, p is 2 and each of the two RAgroups are different. In some embodiments, RBis OH, =0, NRaRb, -SRa, halogen, C1-C10 alkyl, C1-C10 haloalkyl, (Ci-C3)-aryl. In some embodiments, RBis methyl. In some embodiments, two RBtaken together with the atom to which they are attached form a 5 - to 6- membered carbocycle or a 5 - to 6-membered heterocycle. In some embodiments, two RBtaken together with the atom to which they are attached form cyclopropane, cyclobutane, cyclopentane, cyclohexane, phenyl, pyrrole, pyridine, morpholino, or indole. In some embodiments, two RBtaken together with the atom to which they are attached form a 5 - to 6- membered carbocycle or 5- to 6-membered heterocycle, wherein each RBare attached to adjacent atoms. In some embodiments, two RBtaken together with the atom to which they are attached form a 3 - to 6-membered carbocycle or 3- to 6-membered heterocycle, wherein each RBare attached to adjacent atoms.

[0059] In some embodiments, m is 3. In some embodiments, RAis halogen, OH, =0, NO2, CN, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, NRaRb, or SRa. In some embodiments, RAis halogen.

[0060] In some embodiments, Y is NR6, and m is 1 or 2. In some embodiments, RAis F, Cl, Br, I, CH2F, CHF2, CF3, CH2C1, CHC12, CC13, OCH3, OCH2CH3, methyl, or ethyl. In some embodiments, RAis F, Cl, Br, I, CH2F, CHF2, CF3, CHQ2, OCH3, OCH2CH3, methyl, or ethyl. In some embodiments, R6is C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3- C10 heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, halogen, C1-C5 alkoxy, or -SRa. In some embodiments, RBis methyl.

[0061] In some embodiments, a salt or compound of Formula I has the structural Formula (lb):wherein:Ring A is an aryl; each RAis halogen, OH, =0, N02, CN, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, NRaRb, or SRa; each of R1and R2is independently -H or C1-C10 alkyl;R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C5 carbocycle, or C2-C6 heterocycle, wherein R3is optionally substituted with a halogen, OH, =0, N02, CN, Ci-C6alkyl, Ci-C6haloalkyl, NRaRb, or SRa;R4is C3-C5 alkyl, C3-C5 carbocycle, or C2-C5 heterocycle, wherein R4is optionally substituted with a C1-C3 alkyl;Y is C(R5)2, NR6, O, or S; each RBis independently OH, =0, halogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C3- C10 heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; or two RBtaken together with the atom to which they are attached form a 3 - to 6-membered carbocycle or heterocycle;R6is C1-C10 alkyl, C2-C10 alkenyl, C3-C10 heteroaryl, Ci-Csalkylene-aryl, or Ci-Csalkylene- heteroaryl; n is an integer from 0 to 10; and p is an integer from 0 to 5; or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof , with the proviso that the compound of Formula (lb) is not:

[0062] In some embodiments, a compound or a salt thereof of Formula (I) is represented by Formula (II):Formula (II), whereinRing A is phenyl, furanyl, benzodioxole, or thiophenyl; each RAis independently halogen, C2-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl; each of R1and R2is independently H, methyl, or ethyl; each RBis independently OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C2-Ci0heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6-membered carbocycle, a 5- to 6-membered heterocycle, or an oxo; n is an integer from 0 to 10; and p is an integer from 0 to 5.

[0063] In some embodiments, each of R1and R2is independently H, methyl, or ethyl. In some embodiments, R1and R2are both H. In some embodiments, when n is 0, p is 1. In some embodiments, RAis F, Cl, Br, CH2F, CHF2, CF3, CH2C1, CHC12, CC13, OCH3, OCH2CH3, methyl, or ethyl. In some embodiments, p is 2 or 3. In some embodiments, p is 2, and at least of the two RAgroups are halogen. In some embodiments, p is 2, and each of the two RAgroups is the same. In some embodiments, p is 2 and each of the two RAgroups are different. In some embodiments, each RBis independently OH, halogen, C1-C10 alkyl, C2-Cio alkenyl, C1-C10 haloalkyl, C2-Ci0heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl. In some embodiments, two RBtaken together with the carbon to which they are attached form a 5 - to 6-membered cyclic ketal or an oxo. In some embodiments, each R5is independently H, OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-Cio heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two R5taken together with the carbon to which they are attached form a 5 - to 6-membered cyclic ketal or an oxo. In some embodiments, RBis methyl, ethyl, methoxy, ethoxy, CF3, CBr3, CH2F, CHF2, CH2Br, CHBr2, CC13, CH2C1, CHC12, OH, =0, F, Cl, Br, or I. In some embodiments, RBis Ci- C6alkyl, haloalkyl, hydroxy, halogen, or two RBtaken together with the carbon to which they are attached form a 5-membered cyclic ketal or an oxo. In some embodiments, each R5isindependently H, OH, =0, halogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two R5taken together with the carbon to which they are attached form a 5- to 6-membered cyclic ketal. In some embodiments, Ring A is phenyl.

[0064] In some embodiments, a compound or a salt thereof of Formula (I) is represented by Formula (III):Formula (III) whereins each RAis independently halogen, C2-Ci0alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl, C1-C10 haloalkoxy, -SRa, -NRaRb; each of R1and R2is independently H, OH, =0, halogen, C1-C10 alkyl, C1-C10 haloalkyl, -SRa, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle;R3is -H or methyl;R4is a C3-Cio alkyl, C3-Ci0carbocycle, C2-Ci0heterocycle, or Ci-C3haloalkyl, wherein R4is optionally substituted with a Ci-C3alkyl, each RBis independently OH, halogen, C1-C10 alkyl, C2-Cio alkenyl, C1-C10 haloalkyl, C3-Cio heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, -NH2, halogen or Ci-C3alkyl; or two RBtaken together to the carbon to which they are attached form a 5 - or 6-membered carbocycle, a 5- to 6-membered heterocycle, or an oxo; n is an integer from 0 to 10; and p is an integer from 0 to 5, wherein each Raand Rbis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-C6heteroalkyl, C3-Ci0carbocycle, C3-Ci0heterocycloalkyl, Ci-C3alkylene-aryl, or Ci- C3alkylene-heteroaryl; with the proviso that the compound of Formula III is not:

[0065] In certain embodiments, a compound of Formula (III) is represented by Formula (Illa):wherein each RAis independently halogen, C2-Ci0alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl, C1-C10 haloalkoxy; each of R1and R2is independently H, or C1-C10 alkyl, or halogen;R4is a C3-C10 alkyl, C3-C10 carbocycle, C2-Ci0heterocycle, or C1-C3 haloalkyl, wherein R4is optionally substituted with a C1-C3 alkyl, each RBis independently =O,OH, =0, halogen, C1-C10 alkyl, C2-Cio alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together to the carbon to which they are attached form a 5 - or 6-membered cyclic ketal; n is an integer from 0 to 10; and p is an integer from 0 to 5, with the proviso that the compound of Formula (Illa) is not:

[0066] In some embodiments, each of R1and R2is H. In some embodiments, R4is a C2-C5heterocycle. In some embodiments, R4is azetidine, tetrahydrofuran, pyrrolidine, piperidine,oxane, dioxane, morpholine, thiomorpholine, thietane, thiolane, thane, or oxetane. In some embodiments, the C2-C5heterocycle is substituted with a C1-C5 alkyl. In some embodiments, R4is a C3-C5 carbocycle. In some embodiments, R4is cyclopropyl. In some embodiments, the compound of structural Formula (Illa) has the structure:

[0067] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0068] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0069] The compounds disclosed herein, in some embodiments, are usedin different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described inU.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0070] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0071] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0072] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium -containing compounds are known in the art and include, by way of non -limiting example only, the following synthetic methods.

[0073] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development . [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21 ; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. RadioanaL Chem., 1981, 64(1-2), 9-32.

[0074] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium -containing compounds.Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0075] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a saltwith an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0076] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers maybe performed by chromatography or by forming diastereomers and separating 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, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0077] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, 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.

[0078] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0079] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein -de scribed compounds may be a prodrug for another derivative or active compound.

[0080] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas theparent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0081] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak etal., Am. J. Physiol., 269:G210-218 (1995); McLoed etal., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181 -210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above -defined compounds. The compounds may be synthesized using conventional techniques.Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0082] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).THERAPEUTIC APPLICATIONS

[0083] The disclosure provides (hetero)arylalkylamine and substituted (hetero)arylalkylamine compounds and salts thereof of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) for treating a physical, psychiatric, or neurological disorder. In some embodiments, treating the physical, psychiatric, or neurological disorder comprises inhibiting NMD AR by administering a compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), (IVd). In some embodiments, treating the physical, psychiatric, or neurological disorder comprises inhibiting DAT, NET, SERT, or a combination thereof. In some embodiments, treating the physical, psychiatric, or neurological disorder comprises inhibiting DAT by administering a compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc),(IVd). In some embodiments, treating the physical, psychiatric, or neurological disorder comprises inhibiting NET by administering a compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), (IVd). In some embodiments, treating the physical, psychiatric, or neurological disorder comprises inhibiting SERT by administering a compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), (IVd). In some embodiments, inhibiting NMD AR comprises administering a compound or a salt thereof of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), (IVd). In some embodiments, treating the physical, psychiatric, or neurological disorder comprises administering a therapeutically effective amount of the compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), (IVd).

[0084] In some embodiments, treating the physical, psychiatric, or neurological disorder comprises administering a compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), (IVd). In some embodiments, the physical disorder comprises pain, tinnitus, headache, cluster headache, migraine, acute pain, post-operative pain, pain syndromes, neuropathic pain, chronic pain, complex regional pain syndrome, or a combination of two or more thereof. In some embodiments, the psychiatric disorder comprises post-traumatic stress disorder, psychosis, schizophrenia, agitation, obsessive compulsive disorder, anxiety, dementia, substance use disorders, drug addiction, alcoholism, hallucinations, delusions, insomnia, epilepsies, bipolar disorder, anorexia, or a combination of two or more thereof. In some embodiments, the neurological disorder comprises dementia, neurodegenerative disease, pseudobulbar affect, fibromyalgia, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease (HD), or a combination or two or more thereof. In some embodiments, the physical, psychiatric, or neurological disorder comprises pain, depression, tinnitus, post -traumatic stress disorder, psychosis, schizophrenia, agitation, obsessive compulsive disorder, sexual dysfunction, anxiety, dementia, neurodegenerative disease, 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.

[0085] In some aspects, provided herein is a method for treating a physical, psychiatric, or neurological disorders comprising administering a compound of the Formula (IV):Formula (IV); or a salt thereof, wherein:Rxand Rytogether form a 5- to 9-membered heterocycle, wherein the heterocycle is optionally substituted with one or more RB; each of R1and R2is independently H, Ci-C6alkyl, Ci-C6alkoxy, C3-C5 carbocycle, C2-C5heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5- membered carbocycle or a 3 - to 5-membered heterocycle;R4is a C2-Cio alkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0haloalkyl, C2-Ci0alkoxyl, C2-Ci0aminoalkyl, C2-Ci0heteroalkyl, C2-Ci0cycloalkyl, C2-Ci0heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl, wherein each R4is independently optionally substituted with one or more R6;Rzis a 5- to 9-membered carbocycle or heterocycle, wherein the 5- to 9-membered carbocycle or heterocycle is optionally substituted with one or more RA; each RBis independently halogen, CN, OH, SH, S(=O)(Ci-C3alkyl), S(=O)2(Ci-C3alkyl), S(=O)2NH2, S(=O)2NH(CI-C3alkyl), S(=O)2N(CI-C3alkyl)2, S(=O)(=NCrC3alkyl)(Ci-C3alkyl), NH2, NH(CI-C3alkyl), N(C C3alkyl)2, C(=O)(Ci-C3alkyl), C(=O)OH, C(=O)O(CrC3alkyl), C(=O)NH2, C(=O)NH(CI-C3alkyl), C(=O)N(CI-C3alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, Ci- C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci- C3alkylene-heteroaryl; or two RBtogether with the carbon to which they are attached form a 3- to 6-membered carbocycle, a 3 - to 6-membered heterocycle, or an oxo; each R6is independently halogen, -CN, OH, =0, -SRa, NRaRb, -NRbC(=0)NRaRb, - NRbC(=0)Ra, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene)heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCI-C3alkyl)(Ci- C3alkyl), -NH2, -NH(C C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), -C(=0)0H, - C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=0)NH(C C3alkyl), -C(=O)N(C C3alkyl)2, Ci-Cwalkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl; and each Raand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene-cycloalkyl, Ci-C6alkylene- heterocycloalkyl, Ci-C6alkylene-aryl, or Ci-C6alkylene-heteroaryl.

[0086] In certain embodiments, the method comprises administering a compound of Formula (IV) that is represented by Formula (IVa):Formula (IVa) or a salt thereof, wherein:Rzis a 5- to 9-membered carbocycle or heterocycle, wherein the 5- to 9-membered carbocycle or heterocycle is optionally substituted with one or more RA;R4is halogen, C2-C10 alkyl, C2-C10 haloalkyl, C2-C10 hydroxyalkyl, C2-C10 aminoalkyl, C2-C10 heteroalkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0cycloalkyl, C2-Ci0heterocycloalkyl, Ci- C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6; each RBis independently H, halogen, -CN, OH, -SH, -S(=O)(Ci-C3alkyl), -S(=O)2(Ci-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCI-C3alkyl)(Ci- C3alkyl), -NH2, -NH(CI-C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), -C(=O)OH, - C(=O)O(Ci-C3alkyl), -C(=O)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(C C3alkyl)2, Ci-Cwalkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl, or two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle, a 3 - to 6-membered heterocycle, or an oxo; each R6is independently halogen, -CN, OH, =0, -SRa, NRaRb, -NRbC(=0)NRaRb, - NRbC(=0)Ra, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NC C3alkyl)(Ci- C3alkyl), -NH2, -NH(C C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), -C(=0)0H, - C(=O)O(C1-C3alkyl), -C(=0)NH2, -C(=0)NH(CI-C3alkyl), -C(=O)N(CI-C3alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl; and each Raand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, Ci-Cealkylene-cycloalkyl, Ci-Cealkylene- heterocycloalkyl, Ci-C6alkylene-aryl, or Ci-C6alkylene-heteroaryl; and n is an integer from 0 to 10.

[0087] In some embodiments, the compound of Formula (IVa) is substituted with at least one RA.

[0088] In some embodiments, RAis independently C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, Ci- Cio cycloalkyl, C1-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl. In some embodiments, each RBis independently H, halogen, -CN, OH, =0, -SH, -NH2, -NH(CI-C3alkyl), -N(CI-C3alkyl)2, -C(=O)OH, -C(=O)O(C C3alkyl), -C(=O)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(CI-C3alkyl)2, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce hydroxyalkyl, Ci-Ce aminoalkyl, Ci-Ce heteroalkyl, Ci-Ce cycloalkyl, Ci-Ce heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two R5together with the carbon to which they are attached form a 3 - to 6-membered carbocycle or a 3 - to 6-membered heterocycle.

[0089] In some embodiments, eachRBis independently H, halogen, -CN, OH, =0, -SH, -NH2, -NH(CI-C3alkyl), -N(CI-C3alkyl)2, -C(=O)OH, -C(=O)O(Ci-C3alkyl), -C(=O)NH2, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C3-C6cycloalkyl, C3-C6heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtogether with the carbon to which they are attached form a 3 - to 6- membered carbocycle or a 3 - to 6-membered heterocycle. In some embodiments, R4is C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6haloalkyl, C2-C6hydroxyalkyl, C2-C6cycloalkyl, or C2-C6heterocycloalkyl. In some embodiments, each alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, or heterocycloalkyl of R4is optionally substituted with halogen, OH, =0, -SH, =S, -NH2, NRaRb, -COOH, -CO(Ci-C5alkyl), -C(O)NH(CrC5alkyl), Ci-C5alkyl, C C5haloalkyl, or Ci-C5alkoxy.

[0090] In some embodiments, Rzis a 5- to 6-membered aryl or 5- to 6-membered heteroaryl. In some embodiments, Rzis phenyl, furanyl, or thiophenyl. In some embodiments, Rzis phenyl. In some embodiments, Rzis an aryl substituted with at least one R6.

[0091] In certain embodiments, the method comprises administering a compound of Formula (IV) that is represented by Formula (IVb):Formula (IVb) or a salt thereof, wherein:Rxand Rytogether form a 5- to 9-membered heterocycle, wherein the 5- to 9-membered heterocycle is optionally substituted with one or more RB; each of R1and R2is independently H, Ci-C6alkyl, C3-C5carbocycle, C2-C5heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle, wherein R1and R2are not both H;R4is halogen, C2-Ci0alkyl, C2-Ci0haloalkyl, C2-Ci0hydroxyalkyl, C2-Ci0aminoalkyl, C2-Ci0heteroalkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0cycloalkyl, C2-Ci0heterocycloalkyl, Ci- C3alkylene-aryl, Ci-C3alkylene-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6; each RBis independently halogen, -CN, OH, =0, -SH, -S(=O)(Ci-C3alkyl), -S(=O)2(Ci-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCI-C3alkyl)(Ci-C3alkyl), -NH2, -NH(C C3alkyl), -N(C C3alkyl)2, -C(=O)(C C3alkyl), - C(=0)0H, -C(=O)O(C C3alkyl), -C(=0)NH2, -C(=0)NH(C C3alkyl), -C(=0)N(C C3alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, or two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle or a 3 - to 6- membered heterocycle; each R6is independently halogen, CN, OH, =0, SRa, NRaRb, NRbC(=0)NRaRb, NRbC(=0)Ra, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, Ci- C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci- C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), - S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCI-C3alkyl)(Ci- C3alkyl), -NH2, -NH(C C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), -C(=0)0H, - C(=O)O(C1-C3alkyl), -C(=0)NH2, -C(=0)NH(C C3alkyl), -C(=O)N(C C3alkyl)2, Ci-C10alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl; each Raand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl); andp is an integer from 0 to 5.

[0092] In some embodiments, R1and R2are each independently H, methyl, or ethyl. In some embodiments R1and R2are both H. In some embodiments, R1is H, and R2is methyl. In some embodiments, both R1and R2are methyl.

[0093] In some embodiments, Rxand Rytogether form a 6-membered heterocycloalkyl. In some embodiments, Rxand Rytogether form a piperazine. In some embodiments the piperazine is substituted with at least one RB. In some embodiments, RBis a halogen, -CN, OH, =0, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, (Ci-C3)-aryl, or (Ci- C3)-heteroaryl. In some embodiments, two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle or a 3 - to 6-membered heterocycle.

[0094] In some embodiments, R4is C2-C10 alkyl, C2-C10 haloalkyl, C2-C10 hydroxyalkyl, C2- C10 aminoalkyl, C2-Ci0heteroalkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0cycloalkyl, C2-Ci0heterocycloalkyl, (Ci-C3alkylene)aryl, (Ci-C3alkylene)heteroaryl. In some embodiments, R4is propyl, butyl, or pentyl. In some embodiments, R4is propyl. In some embodiments, R4is butyl. In some embodiments, R4is pentyl. In some embodiments, R4is C2-C10 heterocycloalkyl, (Ci-C3alkylene)aryl, (Ci-C3alkylene)heteroaryl. In some embodiments, R4is a C2-Ci0haloalkyl. In some embodiments, R4is a C2 haloalkyl. In some embodiments, R4is a C3haloalkyl. In some embodiments, R4is a C4haloalkyl. In some embodiments, R4is a C5haloalkyl. In some embodiments, R4is CH2CH2F, CH2CHF2, CH2CF3, CH2CH2C1, CH2CHC12, CH2CC13, CH2CH2Br, CH2CHBr2, or CH2CBr3.

[0095] In certain embodiments, the method comprises administering a compound of Formula (IV) that is represented by Formula (IVc):Formula (IVc) or a salt thereof, wherein: each of R1and R2is independently H, Ci-Ce alkyl, C3-Cs carbocycle, C2-C5 heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle, wherein R1and R2are not both H;R4is a C2-C10 alkyl, C2-C10 haloalkyl, C2-C10 hydroxyalkyl, C2-C10 aminoalkyl, C2-C10 heteroalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10 cycloalkyl, C2-C10 heterocycloalkyl, (Ci- C3alkylene)aryl, (Ci-C3alkylene)heteroaryl, -CN, -NO2, OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRaRb, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRaRb, -NRbC(=O)NRaRb, - NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORa, or -C(=O)NRaRb; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6; each RBis independently H, halogen, -CN, -OH, =0, -SH, -SRa, -S(=0)(Ci-C3 alkyl), - S(=O)2(Ci-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(C C3alkyl)2, - S(=O)(=NCI-C3alkyl)(Ci-C3alkyl), -NH2, -NHRa, -NRaRb, -C(=O)(CrC3alkyl), - C(=0)0H, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=0)NHRa, alkyl), -C(=0)NRaRb, Ci-Cwalkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl; each R6is independently halogen, -CN, -OH, =0, -SRa, NRaRb, -NRbC(=0)NRaRb, - NRbC(=0)Ra, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; each RAis independently halogen, -CN, -OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(C C3alkyl)2, -S(=O)(=NC C3alkyl)(Ci- C3alkyl), -NH2, -NH(CI-C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), -C(=O)OH, - C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(C C3alkyl)2, Ci-Cwalkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene- aryl, or Ci-C3alkylene-heteroaryl; each Raand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-Cealkylene-cycloalkyl, Ci-Cealkylene- heterocycloalkyl, Ci-C6alkylene-aryl, or Ci-C6alkylene-heteroaryl; and p is an integer from 0 to 5, and n is an integer from 0 to 10.

[0096] In some embodiments, n is an integer from 1 to 5. In some embodiments, at least one R6is halogen, Ci-Cio alkyl, Ci-Cio haloalkyl, or Ci-Cio alkoxy, OH, ORa, -SRa, -NH2, -NHRa, - NRaRb, CN or NO2.

[0097] In some embodiments, R4is a C3-C5alkyl. In some embodiments, R4is propyl. In some embodiments, R4is butyl. In some embodiments, R4is pentyl. In some embodiments, R4isazetidine, tetrahydrofuran, pyrrolidine, piperidine, oxane, dioxane, morpholine, thiomorpholine, thietane, thiolane, thane, or oxetane.

[0098] In some embodiments, n is 0. In some embodiments, eachR5is independently halogen, -CN, OH, ORa,-SRa, -NH2, -NHRa, -NRaRb, =0, -SH, CN, NO2, -C(=O)(C C3alkyl), - C(=O)OH, -C(=O)O(Ci-C3alkyl), -C(=O)NH2, -C(=O)NH(CI-C3alkyl), -C(=O)N(CI-C3alkyl)2, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl.

[0099] In certain embodiments, the method comprises administering a compound of Formula (IV) that is represented by Formula (IVd):Formula (IVd) or a salt thereof, wherein:R4is a C2-Cio alkyl, C2-Ci0haloalkyl, C2-Ci0hydroxyalkyl, C2-Ci0aminoalkyl, C2-Ci0heteroalkyl, C2-Cio alkenyl, C2-Cio alkynyl, C2-Cio cycloalkyl, C2-Cio heterocycloalkyl, (Ci- C3alkylene)aryl, (Ci-C3alkylene)heteroaryl, -CN, -NO2, OH, -ORa, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRaRb, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRaRb, -NRbC(=O)NRaRb, - NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORa, or -C(=O)NRaRb; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6; each R5is independently halogen, NH2, -NHRa, -NRaRb, -CN, NO2, OH, =0, -SH, -S(=O)(CrC3alkyl), -S(=O)2(Ci-C3alkyl), -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, -S(=O)(-NRa), - NH2, -NHRa, -NRaRb, -N=S(=O) (RaRb), -C(=O)(C C3alkyl), -C(=O)OH, -C(=O)O(C C3alkyl), -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, Ci-Cwalkyl, Ci-Cwalkoxy, Ci-Cwhaloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl; each R6is independently halogen, -CN, OH, =0, NH2, -NHRa, -NRaRb, -NO2, -SRa, NRaRb, - NRbC(=O)NRaRb, -NRbC(=O)Ra, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cw hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, -S(=O)(=NRaRb)(Ci-C3alkyl), NH2, -NHRa, -NRaRb, -C(=O)(Ci-C3alkyl), -C(=O)OH, -C(=O)O(Ci-C3alkyl), -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl;Y is C(RB)2, NRa, O, S, S(=O), S(=O)2, or Se; each Raand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene-cycloalkyl, Ci-C6alkylene- heterocycloalkyl, Ci-C6alkylene-aryl, or Ci-C6alkylene-heteroaryl; and n is an integer from 0 to 10; and p is an integer from 0 to 5.

[0100] In some embodiments, R4is C2-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C2-Ce haloalkyl, C2-C6hydroxyalkyl, C2-C6cycloalkyl, or C2-C6heterocycloalkyl. In some embodiments, each RBis independently halogen, -CN, OH, =0, -SH, -NH2, -NH(CI-C3alkyl), - N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), -C(=O)OH, -C(=O)O(Ci-C3alkyl), -C(=O)NH2, - C(=O)NH(Ci-C3alkyl), -C(=O)N(CI-C3alkyl)2, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl.

[0101] In some embodiments, n is an integer from 1 to 5, and at least one RBis halogen. In some embodiments, each R6is independently H, halogen, -CN, OH, =0, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene- heteroaryl.

[0102] In some embodiments, Y is C(RB)2, NRa, O, S, S=O, S(=O)2, or Se. In some embodiments, Y is substituted with OH, =0, (=O)2, =S, -SH, -COOH, -CO(Ci-Cs alkyl), C1-C5 haloalkyl, Ci-Ce alkyl. In some embodiments, n is 1 or 2. In some embodiments, n is 1 . In some embodiments, n is 2. In some embodiments, Y is C(RB)2. In some embodiments, RBis halogen, hydroxo, methyl, ethyl, propyl, CF3, CHF2, or CH2F. In some embodiments, RBis F, Cl, methyl, or hydroxo.

[0103] In some embodiments, the physical, psychiatric, or neurological 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.

[0104] 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), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may inhibit activity of NMDARs by about 5% to about 90% relative to pre-treatment value or an untreated control. In some embodiments, an inhibitor compound or salt of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd), may inhibit activity of NMDARs by occupying about 5% to about 90% total binding sites relative to pre-treatment value or an untreated control. In some instances, an inhibitor or antagonist compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may inhibit activity of NMDARs by about 5% to about 100% at a physiologically relevant concentration (e.g., (<100,000 nM or < 10,000 nM). In some embodiments, the inhibitor or antagonist compound inhibits NMDARs relative to a physiologically relevant concentration of ketamine, phencyclidine, MK-801, DXM, or other inhibitor of NMDARs. An inhibitor may inhibit activity of NMDARs by at least about 5% relative to pre-treatment value or an untreated control NMDARs, such as without any exogenous antagonist bound. An inhibitor may inhibit activity of NMDARs by at most about 90% at a physiologically relevant concentration relative to pre-treatment value or an untreated control NMDARs. In some embodiments, the inhibitor may inhibit activity of NMDARs by at most 90% at a physiologically relevant concentration relative to pre-treatment value or an untreated control NMDARs, such as without any exogenous antagonist bound. An inhibitor at a physiologically relevant concentration may inhibit activity of NMDARs 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 % , ab out 20 % to ab out 90 %, ab out 30 % to ab out 40 %, ab out 30 % to ab out 50 % , ab out 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 about80% to about 90% relative to pre-treatment capacity or an untreated control NMDARs. An inhibitor may inhibit activity of NMDARs by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to pretreatment capacity or an untreated control NMD AR. In some embodiments, the compound is assessed for interaction with NMDARs using competitive radioligand binding studies with a PCP site inhibitor such as PCP, ketamine, TCP, or MK-801. In some embodiments, the compound binding to an NMD AR competitively displaces the radioligand with a physiologically relevant dissociation constant (Ki) concentration. In some embodiments, the K; is less than about 100,000 nM. In some embodiments, the K;is less than about 10,000 nM. In some embodiments, Ki is less than about 100,000 nM, about 90,000 nM, about 80,000 nM, about 70,000 nM, about 60,000 nM, about 50,000 nM, about 40,000 nM, about 30,000 nM, about 20,000 nM, about 10,000 nM, about 9,000 nM, about 8,000 nM, about 7,000 nM, about 6,000 nM, about 5,000 nM, about 4,000 nM, about 3,000 nM, about 2,000 nM, about 1,000 nM, about 900 nM, about 800 nM, about 700 nM, about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, or about 10 nM. In some embodiments, the Ki is about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about 2,000 nM, about 3,000 nM, about 4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about 20,000 nM, about 30,000 nM, about 40,000 nM, about 50,000 nM, about 60,000 nM, about 70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 1 mM. In some embodiments, the physiologically relevant concentration is about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about 2,000 nM, about 3,000 nM, about 4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about 20,000 nM, about 30,000 nM, about 40,000 nM, about 50,000 nM, about 60,000 nM, about 70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 1 mM of the compound.

[0105] 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), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd), at a physiologically relevant concentration 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), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may inhibit activity of DAT by about 5% to about 100% relative to a physiologically relevant concentration of ketamine, bupropion, citalopram, GBR-12935, methylphenidate or other inhibitor of DAT. An inhibitor may inhibit activity of DAT by at least about 5 % relative to pretreatment value or an untreated control DAT, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of DAT by at most about 90% relative to pre-treatm ent value or an untreated control DAT, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of DAT 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 % , ab out 10 % to ab out 70 %, ab out 10 % to ab out 80 %, ab out 10 % to ab out 90 % , ab out 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 ab out 40 % , ab out 30 % to ab out 50 %, ab out 30 % to ab out 60 %, ab out 30 % to ab out 70 % , ab out 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 DAT. An inhibitor may inhibit activity of DAT by about 5 %, about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to pre-treatment capacity or an untreated control DAT. In some embodiments, the compound is assessed for interaction with DAT using competitive radioligand binding studies with a transporter inhibitor such as cocaine, methylphenidate, bupropion, BGR- 12935 or other DAT inhibitor. In some embodiments, the compound competitively binds to DAT and displaces the radioligand with a physiologically relevant dissociation constant (Ki) concentration. In some embodiments, the Ki is less than about 100,000 nM. In some embodiments, the K;is less than about 10,000 nM. In some embodiments, K; is less than about 100,000 nM, about 90,000 nM, about 80,000 nM, about 70,000 nM, about 60,000 nM, about 50,000 nM, about 40,000 nM, about 30,000 nM, about 20,000 nM, about 10,000 nM, about 9,000 nM, about 8,000 nM, about 7,000 nM, about 6,000 nM, about 5,000 nM, about 4,000 nM, about 3,000 nM, about 2,000 nM, about 1,000 nM, about 900 nM, about 800 nM, about 700 nM,about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, or about 10 nM. In some embodiments, the K; is about 100 nM, about 200 nM, about300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about2,000 nM, about3,000 nM, about4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about 20,000 nM, about 30,000 nM, about 40,000 nM, about 50,000 nM, about 60,000 nM, about 70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 1 mM. In some embodiments, the physiologically relevant concentration is about 100 nM, about200 nM, about300 nM, about 400nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about 2,000 nM, about 3,000 nM, about 4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about 20,000 nM, about 30,000 nM, about 40,000 nM, about 50,000 nM, about 60,000 nM, about 70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about300 pM, about400 pM, about 500 pM, about 600 pM, about700 pM, about 800 pM, about 900 pM, or about 1 mM of the compound.

[0106] In some aspects, the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a serotonin transporter (SERT). An inhibitor compound or salt of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may inhibit activity of SERT by about 5% to about 90% relative to pre-treatment value or an untreated control SERT. In some instances, an inhibitor or antagonist compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may inhibit activity of SERT at a physiologically relevant concentration by about 5% to about 100% relative to a physiologically relevant concentration of ketamine, bupropion, citalopram, fluoxetine, paroxetine, DXM or other inhibitor of SERT. An inhibitor may inhibit activity of SERT by at least about 5% relative to pre-treatment value or an untreated control SERT, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of SERT by at most about 90% relative to pre-treatment value or an untreated control SERT, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of SERT 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 pretreatment capacity or an untreated control SERT. An inhibitor may inhibit activity of SERT 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 SERT. Compounds can also be assessed for interaction with SERT using competitive radioligand binding studies with a transporter inhibitor such as citalopram, escitalopram, fluoxetine, paroxetine or other SERT inhibitor. Compounds binding to SERT competitively displace the radioligand at a concentration (Ki). In some embodiments, the Ki is less than about 100,000 nM. In some embodiments, the Ki is less than about 10,000 nM. In some embodiments, Ki is less than about 100,000 nM, about 90,000 nM, about 80,000 nM, about 70,000 nM, about 60,000 nM, about 50,000 nM, about 40,000 nM, about 30,000 nM, about 20,000 nM, about 10,000 nM, about 9,000 nM, about 8,000 nM, about 7,000 nM, about 6,000 nM, about 5,000 nM, about 4,000 nM, about 3,000 nM, about 2,000 nM, about 1,000 nM, about 900 nM, about 800 nM, about 700 nM, about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, or about 10 nM. In some embodiments, the K; is about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about 2,000 nM, about 3,000 nM, about 4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about 20,000 nM, about 30,000 nM, about 40,000 nM, about 50,000 nM, about 60,000 nM, about 70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 1 mM. In some embodiments, the physiologically relevant concentration is about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about 2,000 nM, about 3,000 nM, about 4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about 20,000 nM, about 30,000 nM, about 40,000nM, about 50,000 nM, about 60,000 nM, about 70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 1 mM of the compound.

[0107] In some aspects, the method of treating a physical, psychiatric, or neurological disorder comprises reducing an activity of a serotonin transporter (NET). An inhibitor compound or salt of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may inhibit activity of NET by about 5% to about 90% relative to pre-treatment value or an untreated control NET. In some instances, an inhibitor or antagonist compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may inhibit activity of NET at a physiologically relevant concentration by about 5% to about 100% relative to a physiologically relevant concentration of atomox etine, reboxetine, viloxazine, nisoxetine, bupropion, methylphenidate, desipramine, nortriptyline, or other inhibitor of NET. An inhibitor may inhibit activity of NET by at least about 5% relative to pre-treatment value or an untreated control NET, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of NET by at most about 90% relative to pre-treatment value or an untreated control NET, such as without any agonist or antagonist bound. An inhibitor may inhibit activity of NET 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%, about30% 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 NET. An inhibitor may inhibit activity of NETby about 5%, about 10%, about20%, about30%, about40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to pre-treatment capacity or an untreated control NET. Compounds can also be assessed for interaction with NET using competitive radioligand binding studies with a transporter inhibitor such as atomoxetine, reboxetine, viloxazine, nisoxetine, bupropion, methylphenidate, desipramine, nortriptyline, or other NETinhibitor. Compounds binding to NET competitively displace the radioligand at a concentration (Ki). In some embodiments, the K; is less than about 100,000 nM. In some embodiments, the K; is less than about 10,000 nM. In some embodiments, K; is less than about 100,000 nM, about 90,000 nM, about 80,000 nM, about 70,000 nM, about 60,000 nM, about 50,000 nM, about 40,000 nM, about 30,000 nM, about 20,000 nM, about 10,000 nM, about 9,000 nM, about 8,000 nM, about 7,000 nM, about6,000nM, about 5,000 nM, about4,000 nM, about3,000 nM, about 2,000 nM, about 1,000 nM, about 900 nM, about 800 nM, about 700 nM, about 600 nM, about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, or about 10 nM. In some embodiments, the K; is about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about 2,000 nM, about 3,000 nM, about 4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about 20,000 nM, about30,000 nM, about 40,000 nM, about 50,000 nM, about 60,000 nM, about70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 1 mM. In some embodiments, the physiologically relevant concentration is about 100 nM, about 200 nM, about 300 nM, about 400 nM, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1,000 nM, about 2,000 nM, about 3,000 nM, about 4,000 nM, about 5,000 nM, about 6,000 nM, about 7,000 nM, about 8,000 nM, about 9,000 nM, about 10,000 nM, about20,000 nM, about 30,000 nM, about 40,000 nM, about 50,000 nM, about 60,000 nM, about 70,000 nM, about 80,000 nM, about 90,000 nM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, or about 1 mM of the compound.

[0108] In some embodiments, the method comprises administering a compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) via an intravenous, a parenteral, an intraperitoneal, an intramuscular, an intraosseous, an intralesional, an intrathecal, an intracranial, an intranasal, an epidural, a sublingual, a buccal, a topical, a transdermal, an intratympanic, or an intrarectal, or a combination of one or more routes of administration. In some embodiments, the compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may be administered intravenously. In some embodiments, the compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may be administered intramuscularly. In some embodiments, the compound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may be administered intranasally. In some embodiments, thecompound of Formula (I), (la), (lb), (II), (III), (Illa), (IV), (IVa), (IVb), (IVc), or (IVd) may be administered subcutaneously.

[0109] In some embodiments, compounds of the disclosure are below in Table 1.TABLE 1EXAMPLES

[0110] Example 1: Synthesis of alkylamine compounds

[0111] Materials and Methods: Pharmacology Reagents

[0112] Reagents used in the pharmacology studies such as HEPES, inorganic salts, and glutamate were obtained from Sigma Aldrich (USA) except for EDTA (Acros,Thermo Scientific, USA), glycine (Fisher Scientific, USA) and those otherwise specified in the individual methods sections.

[0113] Chemicals and Reagents. Reagents for synthesis were purchased from the following commercial suppliers with a minimum purity of 90%: 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), Belle Chemical(Billings, MT). All reagents were used as provided without further purification. Solvents for anhydrous chemistry were dried over 3 A molecular sieves (Alfa Aesar, Ward Hill, MA) under argon atmosphere for typically a minimum 3 days prior to use. The following reagents were used for HPLC buffer preparation: ammonium formate (LiChropur™, >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). Ultra-high purity (UHP) argon for reactions was obtained from AirGas (Radnor, PA).

[0114] Nuclear Magnetic Resonance Spectroscopy. 'H and13C NMR spectra data were recorded on a Bruker Avance III with PA BBO 400S1 BBF-H-D-05 Z plus probe (Bruker Corporation, Billerica, MA, USA). Analytes were prepared at a concentration of ~20 mg / mL in d6-DMSO (Sigma-Aldrich, St. Louis, MO). Chemical shifts are reported in parts per million (ppm) and spectra were standardized to either solvent signals (XH, 5 = 2.50 ppm,13C, 5 = 39.52 ppm) or tetramethylsilane (TMS) (5 = 0.00). CFC13(-100 pL / 500 pL solvent) was used as internal standard for19F NMR (5 = 0.00 ppm).

[0115] 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. 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. 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 either 70% A and 30% B, 50% A and 50% B, or 30% A and 70% B. All samples were injected in duplicate with a wash of the injector (70:30 A:B, 50:50 A:B, or 30:70 A:B) between runs. Chromatograms were analyzed using the Agilent ChemStation Software (Agilent Technologies, Santa Clara, CA, USA).

[0116] Gas chromatography-Mass spectrometry. GC / MS analyses were executed on a Thermo Scientific Trace 1300 Gas Chromatograph coupled to a Thermo Scientific ISQ QD Single Quadrupole Mass Spectrometer. A Thermo Scientific TraceGold TG-5MS GC Column (30 m * 0.25 mm x 0.25 pm) was used for separation. Samples were prepared at a concentration of 0.5-1 mg / mL in ethyl acetate. Ionization was achieved by electron impact (El). The resulting data were analyzed in Thermo Xcalibur TM Software (version 3.1.66.10, Thermo Scientific, Waltham, MA, USA). Transfer line and ion source were set to 210 °C and 200 °C, respectively.The starting temperature of the oven was 100 °C and held for 1 min. Temperature was ramped at a rate of 8 °C / min until reaching 220 °C, at which point it was held for 4 min. The total time of the run was 20 min.

[0117] Atmospheric Solids Analysis Probe Mass Spectroscopy. Low resolution mass spectra were recorded using a Advion Expression8CMS Spectrometer containing a quadrupole mass analyzer. Sample ionization was achieved 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 utilized for measurement: Capillary Temperature = 100 °C, Capillary Voltage = 50 V, Source Gas Temperature = 130 °C, and APCI corona discharge = 5 pA.

[0118] High-Resolution Mass Spectrometry. HRMS data were recorded on a Thermo Orbitrap Exactive Mass Spectrometer with an Orbitrap mass analyzer. The instrument was calibrated directly prior to use via electrospray ionization with Pierce™ LTQ ESI Positive Ion Calibration Solution from ThermoFisher Scientific. Samples were introduced into the instrument and ionized via an Atmospheric Solids Analysis Probe (ASAP). Data were analyzed in the Thermo Xcalibur Qual Browser software and identity was confirmed if error was <5 ppm. Measurement parameters were as follows: Aux gas flow rate-8, Spray Voltage-3.50 kV, Capillary temperature- 275°C, Capillary Voltage-25.00 V, Tube Lens Voltage-65.00 V, Skimmer Voltage-14.00 V, Heater Temperature- 100°C.

[0119] Melting Point. Melting points were obtained using a Digimelt A160 SRS digital melting point apparatus (Stanford Research Systems, Sunnyvale, CA, USA) using a ramp rate of 2 °C / min. The melting point range was defined as the temperature at which the solid to liquid phase change occurred to the temperature at which the solid to liquid phase change was complete.

[0120] Biotage Automated Flash Chromatography . Automated flash chromatography was performed on an Isolera™ One Flash Chromatography System from Biotage (Uppsala, Sweden). Separations were achieved 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 (Sigma-Aldrich, St. Louis, MO). In some instances, triethylamine was used as an additive. SiO2was loaded manually into either Sfar 50 g or Sfar 100 g cartridges and the SiO2was equilibrated with the selected mobile phase prior to loading the sample. Flow rate of the solventwas 100 mL / min and 150 mL / min for 50 g and 100 g cartridge sizes respectively. 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. Chromatogramswere analyzed. Fraction purity was confirmed using aluminum -backed Thin Layer Chromatography (TLC). Fractions deemed to be the desired product and pure were then pooled and the solvent evaporated under vacuum.

[0121] Synthetic Procedures

[0122] General Procedure A: Preparation of l-(l-(3-fluorophenyl)pentan-2-yl)-piperidine (Compound 7). (15.9 mmol) 1.04 g Zn dust, (1.73 mmol) 0.133 mL trifluoroacetic acid and (13.86 mmol) 1.70 mL 3 -fluorobenzyl bromide were added, in that order, to a dry (dried in an oven via hot air) 250 mL round bottom flask containing a teflon coated magnetic stir bar and anhydrous (stored under argon and 3 A molecular sieves) THF (20 mL) with vigorous stirring under argon atmosphere at room temperature (rt). The reaction was slightly exothermic and was stirred for 20 minutes at which point (7.63 mmol) 0.753 mL piperidine and (6.93 mmol) 0.625 mL butyraldehyde were added in quick succession via micropipette. The reaction was then sealed under an argon atmosphere and allowed to stir at rt overnight. The next day formation of the product was confirmed by GC / MS. The reaction was then diluted with EtOAc (50 mL), transferred to a separatory funnel, and the organic phase extracted with IN HC1 (3 x 100 mL). Ammonium hydroxide was added to the pooled aqueous extractions forming a milky white precipitate until the solution was basic (confirmed by the solution reaching a uniform opacity and can be confirmed using pH paper). The basified aqueous layer was then extracted with EtOAc (3 x 100 mL), and the combined organic extractions were washed with distilled water (50 mL), brine (50 mL), dried over anhydrous Na2SO4and the solvent removed under reduced pressure to yield 1.37 g(79.1% crude yield) of yellow oil. The crude freebase was purified by flash column chromatography (SiO2, 80:20 hexanes:EtOAc) to yield 1.30 g (75.1% yield) of isolated l-(l-(3-fluorophenyl)pentan-2-yl)-piperidine freebase as a clear colorless oil.

[0123] HC1 Salt: The freebase was dissolved in 200 proof EtOH (~30 mL) and concentrated HC1 (1.1 molar equiv) was then added while mixing. The solvent was then removed under warm air flow. Additional ethanol was added and the solvent evaporated down several times until the resulting yellow solids were free of excess water andHCl yielding 1 -(l-(3-fluorophenyl)pentan- 2-yl)-piperidine HC1. The resulting salt was crystallized by dissolving in a minimal amount of boiling 40:60 mixture of 200 proof EtOH and acetone and then diluting with ~10 -volumes of Et2O followed by storage in a -20 °C freezer overnight. The resulting crystalline solids were then collected by decanting and washed with 20 mL of Et2O and dried with gentle heating of the beaker. Crystallization was repeated twice more (3X total), then the solids were dried, placed in an oven (~70 °C) for 4 hours (h), followedby drying under vacuum overnight to yield 1 -(l-(3- fluorophenyl)pentan-2-yl)-piperidineHCl as a white crystalline solid (mp: 189.1 -190.2 °C). 'HNMR (400 MHz, DMSO-d6) 6 = 10.62 (bs, 1NH+), 7.36 (q, J= 7.3 Hz, 1H), 7.27 (d, J= 10.1 Hz, 1H), 7.19 (d, .7= 7.6 Hz, 1H), 7.11-7.03 (tm, J= 8.4 Hz, 1H), 3.51-3.35 (m, 4H, overlap with H2O), 3.11-2.92 (m, 2H), 2.82 (dd, J = 12.5, 10.3 Hz, 1H), 2.09-1.89 (m, 2H), 1.89-1.63 (m, 4H), 1.60-1.45 (m, 1H), 1.46-1.35 (m, 1H), 1.16-1.00 (m, 1H), 0.98-0.83 (m, 1H), 0.69 (t, J = 7.2 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 8 = [163.39, 160.97 (d, J= 243 Hz, 1C)], [140.62, 140.55 (d, = 7.0 Hz, 1C)], [130.42, 130.34 (d, J= 8.0 Hz, 1C)], [125.35, 125.32 (d, .7= 3.0 Hz, 1C)], [115.96, 115.75 (d, J= 21.1 Hz, 1C)] [113.63, 113.43 (d, J= 20.1 Hz, 1C)], 65.75 (1C), 49.11 (1C), 48.57 (1C), 35.14 (1C), 30.92 (1C), 22.53 (1C), 21.54 (1C), 19.87 (1C), 13.68 (1C).19F NMR (376.5 MHz, DMSO- d6) 6 = -112.77 (IF). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 98.31%. HRMS: m / z calcd for CI6H24FN+H [M + H]+, 250.1966; found 250.1964, Appm = -0.80.

[0124] l-(l-Phenylpentan-2-yl)piperidine (Compound 31). l-(l-Phenylpentan-2- yl)piperidine was prepared as described for Compound 7 using (159.5 mmol) 10.43 g Zn powder, (17.3 mmol) 1.33 mL trifluoroacetic acid and (138.7 mmol) 16.5 mL benzyl bromide, (76.3 mmol) 7.53 mL piperidine and (69.3 mmol) 6.25 mL butyraldehyde in a 500 mL round bottom flask containing anhydrous (stored under argon and 3 A molecular sieves) THF (100 mL) with vigorous stirring under argon atmosphere at room temperature (rt). Conversion was confirmed by GC / MS. The workup was performed as described as previously described with slight modification; diluted with EtOAc (100 mL), and extracted with 1NHC1 (5 x 100 mL) and EtOAc (5 x 100 mL), to yield crude l-(l-phenylpentan-2-yl)piperidine. The crude freebase was purified by flash chromatography as described to yield 13.26 g of 1 -(l-phenylpentan-2- yl)piperidine as a pale yellow oil. Conversion to the HC1 salt was performed similar to that previously described using 200 proof EtOH and Et2O to yield 13.75 g (74.0% yield) 1 -(1- phenylpentan-2-yl)piperidine HC1 as a chalky white crystalline solid (mp: 165.9-168.4 °C).

[0125] 1H NMR (400 MHz, DMSO-d6) 8 = 10.63 (bs, 1NH+), 7.36-7.29 (m, 4H), 7.46-7.21 (m, 1H), 3.43 (dd, J= 13.2 Hz, 2.7 Hz, 1H), 3.34 (bs, 3H, overlap with H2O), 3.08-2.95 (m, 2H), 2.76 (dd, .7= 13.3 Hz, 10.2 Hz, 1H), 2.08-1.93 (m, 2H), 1.88-1.68 (m, 4H, overlap with 1.71), 1.56-1.45 (m, 1H, overlap with 1.47-1.36), 1.46-1.36 (m, 1H, overlap with 1.56-1.45), 1.11-0.96 (m, 1H), 0.96-0.80 (m, 1H), 0.66 (t, .7= 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 137.57 (1C), 129.16 (2C), 128.51 (2C), 126.7O (1C), 66.12 (1C), 49.07 (1C), 48.63 (1C), 35.45 (1C), 30.92 (1C), 22.57 (1C, overlap with 22.50), 22.50 (1C, overlap with 22.57), 21.56 (1C), 19.94 (1C), 13.69 (1C). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 98.6%. HRMS: m / z calcd for CI6H26N [M + H]+, 232.2060; found 232.2057, Appm = -1.29.

[0126] l-(l-(4-fluorophenyl)pentan-2-yl)-piperidine (Compound 8). l-(l-(4-Fluorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 using (35.10 mmol) 2.29 g Zn Dust, (3.52 mmol) 0.27 mL trifluoroacetic acid, (30.4 mmol) 3.80 mL 4- fluorobenzyl bromide, (15.3 mmol) 1.51 mL piperidine and (13.9 mmol) 1.25 mL butyraldehyde to yield crude 1 -(1 -(4-fluorophenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described except with a mobile phase of 70:30 EtOAc:hexanes to yield1.77 g(5 l% yield) of l-(l-(4-fluorophenyl)pentan-2-yl)-piperidine. The HC1 salt was formed and crystallized as previously described to yield l-(l-(4-fluorophenyl)pentan-2-yl)-piperidine HC1 as a crystalline white solid (mp: 169.5-171.0 °C).

[0127] 'H NMR (400 MHz, DMSO-d6) 8 = 10.57 (bs, 1NH+), 7.43-7.37 (m, 2H), 7.20-7.12 (tm, J = 8.9 Hz, 2H), 3.41 (J = 13.4 Hz, 2.7 Hz, 1H), 3.38-3.31 (m, 3 H, overlap with H2O), 3.08- 2.94 (m, 2H), 2.79 (dd, = 13.5 Hz, 10.1 Hz, 1H), 2.07-1.91 (m, 2H), 1.87-1.65 (m, 4H), 1.56- 1.45 (m, 1H, overlap with 1.45-1.35), 1.45-1.35 (m, 1H, overlap with 1.56-1.45), 1.11-0.97 (m, 1H), 0.97-0.82 (m, 1H), 0.67 (t, = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = [162.26, 159.85 (d, .7=242 Hz, 1C)], [133.72, 133.69 (d, J= 2.9 Hz, 1C)], [131.05, 130.97 (d, .7= 8.0, 2C)], [115.34-115.13 (d, .7 = 21.2 Hz, 2C)], 66.05 (1C), 49.11 (1C), 48.53 (1C), 34.58 (1C),30.77 (1C), 22.53 (1C), 22.50 (1C), 21.55 (1C), 19.96 (1C), 13.68 (1C).19FNMR (376.5 MHz, DMSO-d6) 6 = -115.80 (IF). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 98.9%. HRMS: m / z calcd for CI6H25FN [M + H]+, 250.1966; found 250.1964, Appm = -0.80.

[0128] l-(l-(2-fluorophenyl)pentan-2-yl)-piperidine (Compound 9). l-(l-(2-Fluorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 1.67 mL 2-fluorobenzyl bromide to yield crude 1.15 g of 1 -(l-(2- fluorophenyl)pentan-2-yl)-piperidine. The freebase was not purified further. The HC1 salt was formed and crystallized as previously described to yield 1.20 g (60.6% yield) of 1 -(l-(2- fluorophenyl)pentan-2-yl)-piperidine HC1 as a white crystalline solid (mp: 161.2-163.9 °C).

[0129] iH NMR (400 MHz, DMSO-d6) 6 = 10.57 (bs, 1NH+), 7.50 (td, J= 7.7, 1.6 Hz, 1H), 7.36-7.29 (m, 1H), 7.23-7.16 (m, 2H), 3.42-3.30 (m, 4H, overlap with H2O), 3.11-2.97 (m, 2H), 2.92 (dd, J= 13.0 Hz, 10.3 Hz, 1H), 2.06-1.91 (m, 2H), 1.88-1.65 (m, 4H), 1.57-1.46 (m, 1H, overlap with 1.48-1.37), 1.48-1.37 (m, 1H, overlap with 1.57-1.46), 1.15-0.99 (m, 1H), 0.99- 0.82 (m, 1H), 0.68 (t, .7= 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = [161.72, 159.30 (d, .7=243 Hz, 1C)], [131.75, 131.71 (d, J= 4.0 Hz, 1C)], [129.17, 129.09 (d, J= 8.0 Hz, 1C)], [124.67, 124.64 (d, J= 3.0 Hz, 1C)], [124.12, 123.97 (d, J= 15.21, 1C)], [115.45, 115.23 (d, J = 21.1, 1C)] , 65.00 (1C), 48.99 (1C), 48.79 (1C), 31.16 (1C), 28.43 (1C), 22.51 (2C), 21.53 (1C),19.78 (1C), 13.65 (1C).19F NMR (376.5 MHz, DMSO- d6) 6 = -117.18 (IF). HPLC purity(50:50 Formate bufferACN, 220 nm): 100%. HRMS: m / z calcd for C I6H25FN [M + H]+, 250.1966; found 250.1962, Appm = -1.60.

[0130] l-(l-(3-chlorophenyl)pentan-2-yl)-piperidine (Compound 11). l-(l-(3-Chlorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 1.82 mL 3 -chlorobenzyl bromide to yield crude 1.31 g of l -(l-(3- chlorophenyl)pentan-2-yl)-piperidine freebase as a yellow oil. The freebase was not purified further. The HCl salt was formed and crystallized as described to yield 1.12 g (53.4% yield) of 1 -(1 -(3 -chloroph enyl)pentan-2-yl)-piperidine HC1 as a crystalline white solid (mp: 192.2-198.8 °C).

[0131] iH NMR (400 MHz, DMSO-d6) 8 = 10.26 (bs, 1NH+), 7.49 (t, J= 1 .7 Hz, 1H), 7.39- 7.29 (m, 3H), 3.46-3.35 (m, 4H, overlap with H2O), 3.09-2.95 (m, 2H), 2.81 (dd, J = 13.8 Hz, 10.7 Hz, 1H), 2.01-1.87 (m, 2H), 1.85-1.74 (m, 3H), 1.74-1.66 (d, J= 13.2 Hz, 1H), 1.57-1.46 (m, 1H, overlap with 1.46-1.36), 1.46-1.36 (m, 1H, overlap with 1.57-1.46), 1.12-0.99 (m, 1H), 0.98-0.85 (m, 1H), 0.69 (t, J= 1.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 140.16 (1C), 133.13 (1C), 130.33 (1C), 128.93 (1C), 127.96 (1C), 126.77 (1C), 65.70 (1C), 49.11 (1C), 48.65 (1C), 35.00 (1C), 30.91 (1C), 22.26 (1C), 22.58 (1C), 21.51 (1C), 19.85 (1C), 13.68 (1C).HPLC purity (50:50 Formate bufferACN, 220 nm): 99.3%. HRMS: m / z calcd for Ci6H25QN [M + H]+, 266.1670; found 266.1669, Appm = -0.38.

[0132] l-(l-(4-Chlorophenyl)pentan-2-yl)-piperidine (Compound 12). l-(l-(4-Chlorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 2.85 g 4-chlorobenzyl bromide to yield 0.91 g of crude l -(l-(4- chlorophenyl)pentan-2-yl)-piperidine freebase as a yellow oil. The freebase was not purified by flash column chromatography. The HC1 salt was formed and crystallized as previously described to yield 0.87 g (41.6% yield) of l -(l-(4-chlorophenyl)pentan-2-yl)-piperidine HC1 as a white crystalline solid (mp: 182.3-183.3 °C).

[0133] Tf NMR (400 MHz, DMSO-d6) 8 = 10.48 (bs, 1NH+), 7.39 (s, 4H), 3.44-3.44 (m, 4H, overlap with H2O), 3.08-2.94 (m, 2H), 2.80 (dd, J = 13.5 Hz, 9.8 Hz, 1H), 2.05-1.90 (m, 2H), 1.87-1.63 (m, 4H), 1.57-1.45 (m, 1H, overlap with 1.46-1.35), 1.46-1.35 (m, 1H, overlap with 1.57-1.45), l . l l-0.99 (m, 1H), 0.98-0.85 (1H), 0.68 (t, J = 1.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 136.67 (1C), 131.35 (1C), 131.04 (2C), 128.45 (2C), 65.88 (1C), 49.15 (1C), 48.60 (1C), 34.75 (1C), 30.85 (1C), 22.57 (overlap with 22.53, 1C) 22.53 (overlap with 22.57, 1C), 21.54 (1C), 19.93 (1C), 13.70 (1C). HPLC purity (70:30 Formate bufferACN, 220 nm): 99.1%. HRMS: m / z calcd for CI6H25C1N [M + H]+, 266.1670; found 266.1668, Appm = -0.75.

[0134] 2-(l-Phenylpentan-2-yl)octahydrocyclopenta[c]pyrrole (Compound 13). 2-(l-Phenylpentan-2-yl)octahydrocyclopenta[c]pyrrole was prepared as described for Compound 7 except with (13.9 mmol) 1.65 mL benzyl bromide and (7.63 mmol) 0.91 mL octahydrocyclopenta[c]pyrrole. The reaction was quenched with ammonium hydroxide and extracted with EtOAc (3 x 75 mL) to yield crude 2-(l-phenylpentan-2- yl)octahydrocyclopenta[c]pyrrole. The crude freebase was purified as previously by flash chromatography described to yield 0.42 g (23.6% yield) isolated 2-(l-phenylpentan-2- yl)octahydrocyclopenta[c]pyrrole as a clear, colorless oil. The HC1 salt was formed as previously described, forming a sticky gel which after repeated grinding in 10 mL Et2O, gave 2- (l-phenylpentan-2-yl)octahydrocyclopenta[c]pyrrole HC1 as a white powdery solid and an approximate 80:20 mixture of diastereomers (mp: 140.4-141.4 °C) as determined by 'H NMR NH+shifts. HPLC purity (70:30 Formate buffer: ACN, 220 nm): 98.1%. m / z: calcd for CisH^sN [M + H]+, 258.2216; found 258.2214, Appm = 0.77.

[0135] l-(l-Phenylpentan-2-yl)azepane (Compound 14). l-(l-Phenylpentan-2-yl)azepane was prepared as described for Compound 7 exceptusing (7.63 mmol) 0.86 mL of azepane. The reaction was quenched with ammonium hydroxide and extracted with EtOAc (3 x 75 mL) to yield crude l-(l-phenylpentan-2-yl)azepane. The crude freebase was purified by flash column chromatography as described to yield 0.83 g (48.8% yield) of 1 -(l-phenylpentan-2-yl)azepane as a colorless transparent oil. The HC1 salt was formed and crystallized as previously described to yield l-(l-phenylpentan-2-yl)azepane HC1 as a fine white crystalline powder (mp: 188.8-189.5 °C).

[0136] JH NMR (400 MHz, DMSO-d6) 8 = 10.39 (bs, 1NH+), 7.38-7.34 (dm, J= 8.2 Hz, 2H), 7.34-7.29 (tm, J= 7.5 Hz, 2H), 7.27-7.20 (tm, J = 7.0 Hz, 1H), 3.49-3.42 (m, 1H, overlap with 3.42-3.35), 3.42-3.35 (m, 3H, overlap with 3.49-3.42 and H2O), 3.26-3.13 (m, 2H), 2.80 (dd, J = 12.6, 9.9 Hz, 1H), 2.06-1.94 (m, 2H), 1.88-1.77 (m, 3H), 1.76-1.66 (m, 2H), 1.65-1.50 (m, 3H), 1.08-0.94 (m, 1H), 0.88-0.73 (m, 1H), 0.65 (t, J= 7.2 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 6 = 137.37 (1C), 129.20 (2C), 128.43 (2C), 126.69 (1C), 67.67 (1C), 51.05 (1C), 50.73 (1C), 35.61 (1C), 31.37(1C), 25.56 (overlap with 25.50, 1C), 25.50 (overlap with 25.56, 1C), 24.01 (2C), 20.07 (1C), 13.69 (1C). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 97.2%. HRMS: m / z calcd for CI7H28N [M + H]+, 246.2216; found 246.2214, Appm = -0.81.

[0137] 2-(l-Phenylpentan-2-yl)-2-azabicyclo[2.2.2]octane (Compound 16). 2-(l-Phenylpentan-2-yl)-2-azabicyclo[2.2.2]octane was prepared as described for Compound 7 except with (13.9 mmol) 1.65 mL benzyl bromide and (7.63 mmol) 0.94 mL 2- azabicyclo[2.2.2]octane. The reaction was quenched with ammonium hydroxide and extractedwith EtOAc (3 x 75 mL) to yield crude 2-(l-phenylpentan-2-yl)-2-azabicyclo[2.2.2]octane. The crude freebase was purified by flash chromatography as described except with 100% hexanes gradated to a ratio of 80:20 hexanes:EtOAc over 2 CVs to yield 0.78 g (43.8% yield) of 2-(l- phenylpentan-2-yl)-2-azabicyclo[2.2.2]octane as a clear colorless oil. The HC1 salt was formed and crystallized as previously described to yield 2-(l-phenylpentan-2-yl)-2- azabicyclo[2.2.2]octane HC1 as a fine white crystalline powder and an approximate 70:30 mixture of diastereomers as determined byJH NMR NH+(s) and CH3(t) peaks (mp: 106.9- 108.3 °C). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 99.1%. FIRMS: m / z calcd for CI8H28N [M + H]+, 258.2216; found 258.2214, Appm = -0.77.

[0138] l-(l-(2-Methylphenyl)pentan-2-yl)-piperidine (Compound 17). l-(l-(2-Methylphenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except using (13.9 mmol) 1.86 mL 2 -methylbenzyl bromide to yield crude 1 -(l-(2-methylphenyl)pentan-2- yl)-piperidine. The crude freebase was purified by flash chromatography as described except with a ratio of 70:30 hexanes:EtOAc to yield 1.15 g (66.5% yield) of l-(l-(2- methylphenyl)pentan-2-yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(l-(2-methylphenyl)pentan-2-yl)-piperidine HC1 as a white crystalline solid (mp: 162.6-163.6 °C).

[0139] XH NMR (400 MHz, DMSO-d6) 8 = 10.63 (bs, 1NH+), 7.33-7.22 (m, 1H), 7.21-7.08 (m, 3H), 3.47-3.34 (m, 3H, overlap with H2O), 3.33-3.23 (m, 1H, overlap with H2O), 3.13-2.97 (m, 2H), 2.88-2.77 (tm, J= 12.2 Hz, 1H), 2.34 (d, J= 2.1 Hz, 3H), 2.14-1.93 (m, 2H), 1.89-1.66 (m, 4H), 1.58-1.34 (m, 2H), 1.07-0.92 (m, 1H), 0.81-0.67 (m, 1H), 0.62 (td, J= 7.0, 1.5 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 136.27 (1C), 135.15 (1C), 130.32 (1C), 130.08 (1C), 126.83 (1C), 125.86 (1C), 64.59 (1C), 48.98 (1C), 48.44 (1C), 32.81 (1C), 30.81 (1C), 22.41 (2C), 21.57 (1 C), 20.01 (1 C), 19.32 (1 C), 13.62 (1 C). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 98.7% HRMS: m / z calcd for CI7H28N [M + H]+, 246.2216; found 246.2215, Appm = - 0.41.

[0140] l-(l-(4-Methylphenyl)pentan-2-yl)-piperidine (Compound 18). l-(l-(4-Methylphenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 2.57 g 4 -methylbenzyl bromide to yield crude 1 -(l-(4-methylphenyl)pentan-2-yl)- piperidine. The crude freebase was purified by flash chromatography as described except with a ratio of 90:10 hexanes:EtOAc to yield 0.94 g(55.0% yield) of 1 -(l-(4-methylphenyl)pentan-2- yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield l-(l-(4-methylphenyl)pentan-2-yl)-piperidineHCl as a crystalline white solid (mp: 187.2-188.3 °C).

[0141] JH NMR (400 MHz, DMSO-d6) 6 = 10.55 (bs, 1NH+), 7.22 (d, J= 7.7 Hz, 2H), 7.12 (d, J= 7.7 Hz, 2H), 3.40-3.26 (m, 4H, overlap with H2O), 3.08-2.92 (m, 2H), 2.72 (dd, J = 13.4, 10.0 Hz, 1H), 2.27 (s, 3H), 2.09-1.93 (m, 2H), 1.87-1.62 (m, 4H), 1.56-1.45 (m, 1H, overlap with 1.45-1.33), 1.45-1.33 (m, 1H, overlap with 1.56-1.45), 1.14-0.99 (m, 1H), 0.99-0.85 (m, 1H), 0.67 (t, J= 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 5 = 135.65 (1C), 134.38 (1C), 129.07 (2C), 129.00 (2C), 66.19 (1C), 49.03 (1C), 48.70 (1C), 34.99 (1C), 30.93 (1C), 22.51 (2C), 21.56 (1C), 20.62 (1C), 19.93 (1C), 13.72 (1C). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 99.4% HRMS: m / z calcd for CI7H28N [M + H]+, 246.2216; found 246.2215, Appm = - 0.41.

[0142] l-(l-(3-Iodophenyl)pentan-2-yl)-piperidine (Compound 19). l-(l-(3-Iodophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (6.38 mmol) 0.42 g Zn dust, 0.69 mmol (0.05 mL) trifluoroacetic acid, (5.55 mmol) 1.65 g 3 - iodobenzyl bromide, 5.05 mmol (0.301 mL) piperidine, and 2.78 mmol (0.25 mL) butyraldehyde to yield crude l-(l-(3-iodophenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described to yield 0.51 g (51.5% yield) of 1 -(l-(3-iodophenyl)pentan- 2-yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 0.47 g of l-(l-(3-iodophenyl)pentan-2-yl)-piperidine HC1 as a white crystalline solid (mp: 193.2-193.9 °C).

[0143] Tf NMR (400 MHz, DMSO-d6) 6 = 10.48 (bs, 1NH+), 7.79 (t, J= 1.6 Hz, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 3.45-3.31 (m, 4H, overlap with H2O), 3.08-2.98 (m, 2H), 2.76 (dd, J = 13.2, 10.4 Hz, 1H), 2.05-1.90 (m, 2H), 1.87-1.64 (m, 4H), 1.57-1.45 (m, 1H, overlap with 1.45-1.35), 1.46-1.35 (m, 1H, overlap with 1.57-1.45), 1.13-0.98 (m, 1H), 0.98-0.83 (m, 1H), 0.68 (t, J = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 8 = 140.26 (1C), 137.56 (1C), 135.45 (1C), 130.56 (1C), 128.66 (1C), 94.98 (1C), 65.65 (1C), 49.10 (1C), 48.48 (1C), 34.83 (1C), 30.78 (1C), 22.53 (1C), 22.48 (1C), 21.51 (1C), 19.86 (1C), 13.65 (1C). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 99.7%. HRMS: m / z calcd for CI6H25IN [M + H]+, 358.1026; found 358.1024, Appm = -0.56.

[0144] l-(l-(2-Chlorophenyl)pentan-2-yl)-piperidine (Compound 20). l-(l-(2-Chlorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 1.80 mL 2 -chlorobenzyl bromide to yield crude l-(l-(2-chlorophenyl)pentan-2-yl)- piperidine. The crude freebase was purified by flash chromatography as described to yield 1.29 g (70.1%) of l-(l-(2-chlorophenyl)pentan-2-yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(l-(2-chlorophenyl)pentan-2-yl)- piperidine HC1 as a white crystalline solid (mp: 169.2-172.8 °C).

[0145] JH NMR (400 MHz, DMSO-d6) 6 = 10.63 (bs, 1NH+), 7.55 (dd, J = 1.2, 2.0 Hz, 1H), 7.46 (dd, J=7.3, 2.0 Hz, 1H), 7.36-7.28 (m, 2H), 3.46 (dd, = 13.0, 3.1 Hz, 1H), 3.42-3.35 (m, 3 H), 3.17-3.06 (m, 2H, overlap with 3.02), 3.02 (dd, J = 13.0, 10.6 Hz, 1H, overlap with 3.17- 3.06), 2.10-1.92 (m, 2H), 1.91-1.82 (m, 1H, overlap with 1.82-1.65) 1.82-1.65 (m, 3H, overlap with 1.91-1.82), 1.60-1.50 (m, 1H), 1.50-1.37 (m, 1H), 1.10-0.96 (m, 1H), 0.85-0.71 (m, 1H), 0.65 (t, J = 1.2 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 134.62 (1C), 133.21 (1C), 132.01 (1C), 129.49 (1C), 128.95 (1C), 127.46 (1C), 64.49 (1C), 49.31 (1C), 48.45 (1C), 32.50 (1C), 31.17 (1C), 22.50 (2C), 21.53 (1C), 19.94 (1C), 13.64 (1C). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 98.9%. HRMS: m / z calcd for CI6H25C1N [M + H]+, 266.1670; found 266.1670, Appm = 0.00.

[0146] 3-Methoxy-l-(l-phenylpentan-2-yl)piperidine (Compound 21). 3 -Methoxy -1-(1- phenylpentan-2-yl)piperidine was prepared as described for Compound 7 except with (7.63 mmol) 0.94 mL 3 -methoxypiperidine to yield crude 1.54 g crude 3 -methoxy- l-(l-phenylpentan- 2-yl)piperidine freebase as a yellow oil. The freebase was not purified further. The HC1 salt was formed and crystallized as previously described to yield 1.33 g (64.4% yield) of 3 -methoxy-1- (l-phenylpentan-2-yl)piperidineHCl as a white crystalline solid and an approximately a 65:35 mixture of diastereomers as determined by 'H NMR NH peaks (mp: 151.3-153.9 °C). HPLC purity (50:50 Formate buffer: ACN, 220 nm): 97.9%. HRMS: m / z calcd for CrzH^NO [M + H]+, 263.2199; found 263.2195, Appm = -1.52 ppm.

[0147] 3-Fluoro-l-(l-phenylpentan-2-yl)piperidine (Compound 22). 3-Fluoro-l-(l- phenylpentan-2-yl)piperidine was prepared as described for Compound 7 except with (10.1 mmol) 0.67 gZn dust, (8.81 mmol) 0.84 mL trifluoroacetic acid, (0.81 mmol) 1.05 mL benzyl bromide, (4.85 mmol) 0.50 g 3 -fluoropiperidine, and (4.41 mmol) 0.40 mL butyraldehyde to yield crude 3-fluoro-l-(l-phenylpentan-2-yl)piperidine. The crude freebase was purified by flash chromatography as described to yield 0.60 g(34.7% yield) of 3 -fluoro- 1-(1 -phenylpentan- 2-yl)piperidine pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 3-fluoro-l-(l-phenylpentan-2-yl)piperidine HC1 as a white crystalline solid and an approximate 80:20 mixture of diastereomers as determined by1H NMR NH+shifts (mp: 173.6-175.2 °C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 99.1%. HRMS: m / z calcd for CI6H25FN [M + H]+, 251.1999; found 251.1995, Appm = -1.59 ppm.

[0148] l-(l-(3-Bromophenyl)pentan-2-yl)-piperidine (Compound 23). l-(l-(3-Bromophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 3.47 g 3 -bromobenzyl bromide to yield crude l-(l-(3-bromophenyl)pentan-2-yl)- piperidine freebase as a yellow oil. The crude freebase was purified by flash chromatography asdescribed but with a mobile phase of 70:30 hexanes:EtOAc to yield 1.13 g (52.8% yield) of 1 - (l-(3-bromophenyl)pentan-2-yl)-piperidine. The HC1 salt was formed and crystallized as previously described to yield l-(l-(3-bromophenyl)pentan-2-yl)-piperidine HC1 as a white crystalline solid (mp: 172.7-173.5 °C).

[0149] JH NMR (400 MHz, DMSO-d6) 8 = 10.62 (bs, 1NH+), 7.63 (t, J= 1.7 Hz, 1H), 7.45 (d, 7.9 Hz, 1H), 7.37 (d, J = 7.' 7 Hz, 1H), 7.28 (t, J= 7.8 Hz, 1H), 3.49-3.33 (m, 4H, overlap with H2O), 3.08-2.94 (m, 2H), 2.80 (dd, J = 13.0, 10.1 Hz, 1H), 2.07-1.92 (m, 2H), 1.88-1.63 (m, 4H), 1.56-1.45 (m, 1H, overlap with 1.47-1.35), 1.47-1.35 (m, 1H, overlap with 1.56-1.45), 1.12-0.99 (m, 1H), 0.98-0.83 (m, 1H), 0.68 (t, J = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 6 = 140.49 (1C), 131.77 (1C), 130.57 (1C), 129.61 (1C), 129.32 (1C), 121.75 (1C), 65.67 (1C), 49.15 (1C), 48.44 (1C), 35.00 (1C), 30.80 (1C), 22.53 (1C, overlap with 22.48), 22.48 (1C, overlap with 22.53), 21.54 (1C), 19.89 (1C), 13.67 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 100%. HRMS: m / z calcd for Ci6H2579BrN [M + H]+, 310.1165; found 310.1165, Appm = 0.00, m / z calcd Ci6H2481BrN+H [M + H]+ 312.1144, found 312.1142.

[0150] 8-(l-Phenylpentan-2-yl)-l,4-dioxa-8-azaspiro[4.5]decane (Compound 24). 8-(l-Phenylpentan-2-yl)-l,4-dioxa-8-azaspiro[4.5]decane was prepared as described for Compound 7 except with (31.9 mmol) 2.09 g Zn dust, (3.50 mmol) 0.27 mL TFA, (27.7 mmol) 3.32 mL benzyl bromide, (15.3 mmol) 1.56mL l,4-Dioxa-8-azaspiro[4.5]decane, and (13.9 mmol) 1.25 mL butyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with EtOAc (3x 75 mL) to yield crude 8-(l-phenylpentan-2-yl)-l,4-dioxa-8-azaspiro[4.5]decane freebase as a clear, colorless oil. The crude freebase was purified by flash chromatography as described but with a mobile phase of 90:10 hexanes:EtOAc increased to 70:30 hexanes:EtOAc over 3 CVs to yield 3.28 g (81.8% yield) of 8-(l-phenylpentan-2-yl)-l,4-dioxa-8- azaspiro[4.5]decane. The HC1 salt was formed and crystallized from 1.0 g of the freebase as previously described to yield 8-(l-phenylpentan-2-yl)-l,4-dioxa-8-azaspiro[4.5]decane HCl as a white crystalline solid. -2.4% (HPLC) of 1 -(l-phenylpentan-2-yl)piperidin-4-one was detected in the salt presumably formed during the formation of the HC1 salt and was unable to be separated by the crystallization method used (mp: 75.5-79.2 °C).

[0151] JH NMR (400 MHz, DMSO-d6) 5 = 11.02 (bs, 1NH+), 7.37-7.30 (m, 4H), 7.28-7.22 (m, 1H), 3.93 (s, 4H), 3.56-3.43 (m, 3H, overlap with 3.40), 3.40 (dd, J = 13.2, 3.2 Hz, 1H, overlap with 3.56-3.43 and H2O), 3.17-3.00 (m, 2H), 2.81 (dd, J= 13.5, 10.0 Hz, 1H), 2.38-2.25 (m, 2H), 1.91-1.79 (m, 2H, overlap with 1.79-1.70), 1.79-1.70 (m, 1H, overlap with 1.79-1.79), 1.61-1.48 (m, 1H), 1.15-1.01 (m, 1H), 1.01-0.87 (m, 1H), 0.68 (t, J= 7.3, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 137.35 (1C), 129.14 (2C), 128.52 (2C), 126.74 (1C), 104.06 (1C), 65.42(1 C), 64.18 (1C), 63.97 (1C), 47.07 (1C), 46.93 (1C), 35.24 (1C), 31.51 (2C), 31.02 (1 C), 19.65 (1C), 13.67 (1C). HPLC purity (50:50 Formate buffer: can, 220 nm): 97.6%. HRMS: m / z calcd for CI8H28NO2[M + H]+, 290.2115; found 290.2114, Appm = -0.34.

[0152] l-(l-Phenylpentan-2-yl)piperidin-4-one (Compound 25). (3.46 mmol) 1g of 8-(l- Phenylpentan-2-yl)-l,4-dioxa-8-azaspiro[4.5]decane (Compound 24) was added to a dry (dried in an oven via hotair) 250 mL round bottom flask containing (224.9 mmol) 75 mL 3NHC1 at rt. The reaction was stirred overnight and was confirmed complete by TLC. The reaction was diluted with 75 mL DI H2O, moved to a separatory funnel, and extracted with EtOAc (3 x 75 mL). An acid / base workup was performed on the collected organic layers as described for Compound 7 and the solvent was removed under reduced pressure to yield 0.77 g (90.8% yield) l-(l-phenylpentan-2-yl)piperidin-4-one as a clear, colorless oil. The HC1 salt was formed as previously described to yield a sticky gel. The gel was washed with 30 mL Et2O and dried with heat to yield 700 mg l-(l-phenylpentan-2-yl)piperi din -4-one HC1 as a fluffy white powder (mp: 182.8-185.0 °C).

[0153] 'H NMR (400 MHz, DMSO-d6) 5 = 11.70 (bs, 1NH+), 7.39-7.30 (m, 4H), 7.28-7.21 (tm, J= 6.9 Hz, 1H), 3.72-3.52 (m, 5H), 3.45 (dd, J= 13.7, 2.6 Hz, 1H), 3.24-3.08 (m, 2H), 2.82 (dd, J= 14.0, 10.5 Hz, 1H), 2.46 (d, J = 16.5 Hz, 2H, overlap with DMSO-d6), 1.91-1.78 (m, 1H), 1.62-1.47 (m, 1H), 1.19-1.03 (m, 1H), 1.03-0.88 (m, 1H), 0.67 (t, J= 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 5 = 202.85 (1C), 137.18 (1C), 129.17 (2C), 128.54 (2C), 126.77 (1C), 65.69 (1C), 46.62 (1C, overlap with 46.52), 46.52 (1C, overlap with 46.62), 37.39 (1C, overlap with 37.33), 37.33 (1C, overlap with 37.39), 35.27 (1C), 30.94 (1C), 19.68 (1C), 13.65 (1C). ASAP MS: m / z: found for CI6H23NO; 246.2 [M + H]+(100), 247.2 [M + 2]+(20).

[0154] l-(l-Phenylpentan-2-yl)piperidin-3-ol (Compound 26). l-(l-Phenylpentan-2- yl)piperidin-3-ol was prepared as described for Compound 7 with (27.7 mmol) 3.32 mL benzyl bromide, (31.9 mmol) 2.09 g Zn dust, (3.50 mmol) 0.27 mL trifluoroacetic acid, (15.3 mmol) 1.55 g 3-hydroxypiperidine, and (13.9 mmol) 1.25 mL butyraldehyde to yield crude 1 -(1- phenylpentan-2-yl)piperidin-3-ol. The crude freebase was purified by flash chromatography as described but with a mobile phase of 100% EtOH to yield 1.31g (38.2% yield) isolated 1 -(1- phenylpentan-2-yl)piperidin-3-ol as a yellow oil. The HC1 salt was formed as previously described to yield l-(l-phenylpentan-2-yl)piperidin-3-ol HC1 as a crystalline white solid and an approximate 60:40 mixtureof diastereomers as determinedby 'H NMR NH shifts, (mp: 166.2- 167.8 °C).

[0155] HPLC purity (70:30 Formate buffer:ACN, 220 nm): 100%. HRMS: m / z: calcd for CI6H25NO [M + H]+, 248.2009; found 248.2008, Appm = -0.40 ppm.

[0156] l-(l-(2-Bromophenyl)pentan-2-yl)-piperidine (Compound 27). l-(l-(2-Bromophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 1.70 g2-bromobenzyl bromide to yield crude l-(l-(2-bromophenyl)pentan-2-yl)- piperidine. The crude freebase was purified by flash chromatography as described but gradated to a 70:30 ratio of hexanes :EtO Ac to yield 1.54 g (78.0% yield) of 1 -(l-(2-bromophenyl)pentan- 2-yl)-piperidine. The HC1 salt was formed and crystallized as previously described to yield 1 - (l-(2-bromophenyl)pentan-2-yl)-piperidine HC1 as a crystalline white solid (mp: 213.9-215.0 °C).

[0157] JH NMR (400 MHz, DMSO-d6) 8 = 10.58 (bs, 1NH+), 7.63 (dd, J = 8.0, 1.1 Hz, 1H), 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.38 (td, J = 7.5 Hz, 1.1 Hz, 1H), 7.23 (td, J = 7.7 Hz, 1.6 Hz, 1H), 4.46-3.36 (m, 4H), 3.19-3.09 (m, 1H, overlap with 3.10-2.99), 3.10-2.99 (m, 2H, overlap with 3.19-3.09), 2.10-1.92 (m, 2H), 1.91-1.67 (m, 4H), 1.64-1.51 (m, 1H), 1.51-1.37 (m, 1H), 1.10-0.96(m, 1H), 0.83-0.69 (m, 1H), 0.65 (t, J= 7.1 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 6 = 136.23 (1C), 132.82 (1C), 132.08 (1C), 129.19 (1C), 128.01 (1C), 124.06 (1C), 64.55 (1C), 49.49 (1C), 48.35 (1C), 34.79 (1C), 31.18 (1C), 22.52 (2C), 21.51 (1C), 19.97 (1C), 13.62 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 100%. HRMS: m / z calcd for Ci6H2579BrN [M + H]+, 310.1165; found 310.1166, Appm = -0.32, m / z calcd for Ci6H2581BrN [M + H]+312.1144, found 312.1143.

[0158] (3S)-3-Methyl-l-(l-phenylpentan-2-yl)piperidine (Compound 28). (3 S)-3 -Methyl- 1- (l-phenylpentan-2-yl)piperidine was prepared as described for Compound 7 except with (7.63 mmol) 0.95 mL (S)-(+)-3 -methylpiperidine to yield crude (3S)-3-methyl-l-(l-phenylpentan-2- yl)piperidine. The crude freebase was purified by flash chromatography as described to yield 0.55 g (32.4% yield) of (3 S)-3 -methyl- l-(l-phenylpentan-2-yl)piperidine as a yellow oil. The HC1 salt was formed and crystallized as previously described to yield (3S)-3-methyl-l-(l- phenylpentan-2-yl)piperidine HC1 as a crystalline white solid (mp: 210.3-211.7 °C).

[0159] JH NMR (400 MHz, DMSO-d6) 6 = 10.60 (bs, 1NH+), 7.37-7.30 (m, 4H), 7.28-7.22 (m, 1H), 3.44 (dd, = 12.8, 2.6 Hz, 1H), 3.40-3.35 (m, 2H, overlap with H2O), 3.27 (d, J= 12.0 Hz, 1H), 3.01-2.89 (m, 1H), 2.79 (dd, J= 13.6, 10.5 Hz, 1H), 2.67 (q, J= 11.5 Hz, 1H), 2.25- 2.10 (m, 1H), 2.10-1.95 (m, 1H), 1.89-1.68 (m, 3H), 1.58-1.46 (m, 1H), 1.21-1.07 (m, 1H, overlap with 1.07-0.96), 1.07-0.96 (m, 1H, overlap with 1.21-1.06), 0.94-0.78 (m, 1H, overlap with 0.89), 0.89 (d, J= 6.7 Hz, 3H), 0.65 (t, = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 5 = 137.49 (1C), 129.17 (2C), 128.49 (2C), 126.70 (1C), 66.16 (1C), 53.83 (1C), 48.58 (1C), 35.59 (1C), 30.88 (lC), 30.16 (1C), 28.52 (1C), 22.24 (1C), 2O.O5 (1C), 18.66 (1C), 13.68 (1C).HPLC purity (50:50 Formate buffer: ACN, 220 nm): 99.4%. ASAP MS: m / z: found for C17H27N; 246.2 [M + H]+ (100), 247.2 [M + 2]+ (20).

[0160] l-(l-(3-Methoxyphenyl)pentan-2-yl)-piperidine (Compound 29). 3 -Methoxybenzyl bromide was synthesized by dissolving (108.57 mmol) 13.48 mL 3 -methoxybenzyl alcohol in 50 mL anhydrous (stored under argon and 3 A molecular sieves) CH2Q2 (DCM) in a dry (dried in an oven via hot air) 250 mL round bottom flask. The temperature was reduced to 0 °C and (108.57 mmol) 10.31 mLPBr3was added dropwise. The reaction was allowed to stir for 2 hours and was confirmed to be complete by TLC. The reaction was slowly quenched with 30 mL of ice cold brine and the DCM was floated with EtOAc (50 mL). The reaction was transferred to a separatory funnel and the aqueous layer was separated and extracted with EtOAc (3x 75 mL). The combined organic extractions were washed with DI water (50 mL), and brine (50 mL), dried with anhydrous NaSO4 and the solvent removed under reduced pressure to yield 19.50 g (89.3%) 3 -methoxybenzyl bromide as a viscous golden oil, which was used in the next step without further purification.

[0161] l-(l-(3-Methoxyphenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 1.94 mL of freshly prepared 3 -methoxybenzyl bromide to yield crude l-(l-(3-methoxyphenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described to yield 1.48 g (81.8% yield) isolated crude 1 -(l-(3- methoxyphenyl)pentan-2-yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(l-(3-methoxyphenyl)pentan-2-yl)-piperidineHCl as a white crystalline solid (mp: 171.9-173.3 °C).

[0162] JH NMR (400 MHz, DMSO-d6) 8 = 10.45 (bs, 1NH+), 7.23 (t, J= 7.8 Hz, 1H), 6.95 (t, J= 1.8 Hz, 1H), 6.90 (d, J= 7.5 Hz, 1H), 6.81 (dd, J= 8.3, 2.2 Hz, 1H), 3.74 (s, 3H), 3.42-3.35 (m, 4H, overlap with H2O), 3.08-2.93 (m, 2H), 2.74 (dd, J = 13.5, 11.0 Hz, 1H), 2.06-1.91 (m, 2H), 1.87-1.63 (m, 4H), 1.57-1.48 (m, 1H, overlap with 1.48-1.35), 1.48-1.35 (m, 1H, overlap with 1.57-1.48), 1.15-1.01 (m, 1H), 1.00-0.87 (m, 1H), 0.69 (t, = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 159.37 (1C), 139.07 (lC), 129.52 (1C), 121.35 (1C), 114.84 (1C), 112.09 (1C), 65.95 (1C), 55.03 (1C), 49.02 (1C), 48.75 (1C), 35.39 (1C), 31.03 (1C), 22.55 (overlap with 22.52, 1C), 22.52 (overlap with 22.55, 1C), 21.57 (1C), 19.88 (1C), 13.73 (1C). HPLC purity (50:50 Formate buffercan, 220 nm): 99.7%. HRMS: m / z calcd for C17H28NO [M + H]+, 262.2165; found 262.2165, Appm = 0.00.

[0163] l-(l-(Thiophen-2-yl)pentan-2-yl)-piperidine (Compound 30). 2-Thiophenemethyl bromide was synthesized by dissolving (57.9 mmol) 5.49 mL 2 -thiophenemethanol in 30 mL anhydrous (stored under argon and 3 A molecular sieves) Et2O in a dry (dried in an oven via hotair) 250 mL round bottom flask. The temperature was reduced to 0 °C and (57.9 mmol) 5.58 mL PBr3was added dropwise. The reaction was allowed to stir for 2 hours and was confirmed to be complete by TLC. The reaction was quenched dropwise at 0 °C with 40 mL of ice cold brine. The reaction was then transferred to a separatory funnel and the aqueous layer was separated and extracted with Et2O (3 x 75 mL). The combined organic extractions were washed with DI water (50 mL), and brine (50 mL) and dried with anhydrous NaSO4. The solvent was removed under reduced pressure until about20 mL of solvent remained to stabilize the volatile and unstable 2- thiophenemethyl bromide which was used without further purification.

[0164] l-(l-(Thiophen-2-yl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (55.5 mmol) 9.82 g, (assuming quantitative yield), of freshly prepared 2- thiophenylmethyl bromide, (63.8 mmol) 4.17 g Zn dust, (6.93 mmol) 0.53 mL trifluoroacetic acid, (30.5 mmol) 3.51 mL piperidine, and (27.7 mmol) 2.50 mL butyraldehyde to yield crude l-(l-(thiophen-2-yl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described but with a mobile phase of 70:30 hexanes:EtOAc. The lower Rffractions were combined and the resulting product was then further purified in a mobile phase of 95 :5 hexanes:EtOAc to yield 1.92 g (29.2% yield) of 1 -(l-(thiophen-2-yl)pentan-2-yl)- piperidine. The HC1 salt was formed and crystallized as previously described to yield 1 -(1- (thiophen-2-yl)pentan-2-yl)-piperidine HC1 as a pale yellow fine crystalline powder (mp: 153.9- 155.0 °C).

[0165] AT NMR (400 MHz, DMSO-d6) 6 = 10.55 (bs, 1NH+), 7.41 (dd, J= 5.1, 1.0 Hz, 1H), 7.05 (d, .7= 3.2 Hz, 1H), 6.99 (dd, J = 5.2, 3.4 Hz, 1H), 3.55 (dd, J = 14.6, 3.9 Hz, 1H), 3.35- 3.27 (m, 3H, overlap with H2O), 3. 15 (dd, J = 15.0, 9.6 Hz, 1H), 3.07-2.94 (m, 2H), 2.04-1.90 (m, 2H), 1.90-1.79 (m, 1H, overlap with 1.79-1.63), 1.79-1.63 (m, 3H, overlap with 1.90-1.79), 1.61-1.50 (m, 1H), 1.48-1.34 (m, 1H), 1.25-1.11 (m, 1H, overlap with 1.12-0.98), 1.12-0.98 (m, 1H, overlap with 1.25-1.11), 0.76 (t, J= 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 139.30 (1C), 127.24 (1C), 126.66 (1C), 125.12 (1C), 66.16 (1C), 49.27 (1C), 48.75 (1C), 30.84 (1C), 29.53 (1C), 22.54 (overlap with 22.50, 1C), 22.50 (overlap with 22.54, 1C), 21.50 (1C), 19.88 (1C), 13.76 (IC).HPLC purity (70:30 Formate buffer:ACN, 220 nm): 100% HRMS: m / z calcd for C14H24NS [M + H]+, 238.1624; found 238.1621, Appm = -1.26.

[0166] l-(2-Phenylhexan-3-yl)piperidine (Compound 32). l-(2-Phenylhexan-3-yl)piperidine was prepared as described for Compound 7 except with (47.8 mmol) 3.13 g Zn dust, (5.20 mmol) 0.40 mL trifluoroacetic acid, (41.6 mmol) 5.68 mL 2-(l-bromoethyl)benzene, (22.9 mmol) 2.63 mL piperidine, and (20.8 mmol) 1.875 mL butyraldehyde to yield crude 1 -(2- phenylhexan-3-yl)piperidine. The crude freebase was purified by flash chromatography asdescribed but gradiated from mobile phase of90: 10 hexanes:EtOAc to a mobile phase of 50:50 hexanes:EtOAc over2 CVs to yield 1.94 g (25.2% yield) of l-(2-phenylhexan-3-yl)piperidine freebase as a yellow oil. The HC1 salt was formed and crystallized as previously described to yield l-(2-phenylhexan-3-yl)piperidine HC1 as a white crystalline solid in an approximate 3 :1 ratio of diastereomers as determinedby 'H NMR NH shifts (mp: 173.3-174.5 °C). HRMS: m / z: calcd for CI7H28N [M + H]+, 246.2216; found 246.2206 , Appm = -4.06.

[0167] l-(l-(2-Methoxyphenyl)pentan-2-yl)-piperidine (Compound 33). 2-Meth oxybenzyl bromide was synthesized by dissolving (108.6 mmol) 14.14 mL 2-methoxybenzyl alcohol in 50 mL anhydrous (stored under argon and 3 A molecular sieves) DCM in a dry (dried in an oven via hot air) 250 mL round bottom flask. The temperature was reduced to 0 °C and (108.6 mmol) 10.31 mL PBr3was added dropwise. The reaction was allowed to stir for 2 hours and was confirmed to be complete by TLC. The reaction was slowly quenched with 30 mL of ice cold brine and the DCM was floated with EtOAc (50 mL). The reaction was transferred to a separatory funnel and the aqueous layer was separated and extracted with EtOAc (3 x 75 mL). The combined organic extractions were washed with distilled water (50 mL), and brine (50 mL), dried with anhydrous NaSO4 and the solvent removed under reduced pressure to yield 20.4 g (93.4% yield) 2-methoxybenzyl bromide as a thick pale yellow paste and was used without further purification.

[0168] l-(l-(2-Methoxyphenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.90 mmol) 2.79 g of previously prepared 3 -methoxybenzyl bromide to yield crude l-(l-(2-methoxyphenyl)pentan-2-yl)-piperidine freebase as a yellow oil. The crude freebase was purified by flash chromatography as described except with a mobile phase of 100% EtOAc gradated to a ratio of 80:20 EtOAc :EtOH to yield 1.26 g (69.6% yield) 1 - (1 -(2-methoxyphenyl)pentan-2-yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 1.43 g of 1 -(l-(2-methoxyphenyl)pentan-2-yl)- piperidine HC1 as a white crystalline solid (mp: 187.8-189.1 °C).

[0169] iff NMR (400 MHz, DMSO-d6) 8 = 10.36 (bs, 1NH+), 7.28 (dd, J= 7.5, 1.5 Hz, 1H, overlap with 7.32-7.22), 7.32-7.22 (tm, J= 7.7 Hz, 1H, overlap with 7.28), 6.99 (dd, J= 8.2, 0.6 Hz, 1H), 6.90 (td, J= 7.4, 0.9 Hz, 1H), 3.81 (s, 3H), 3.41-3.36 (m, 1H, overlap with H2O), 3.32- 3.26 (m, 2H, overlap with H2O and 3.23), 3.23 (dd, J = 13.2, 3.6 Hz, 1H, overlap with 3.32- 3.26), 3.13-2.95 (m, 2H), 2.79 (dd, 13.6, 9.9 Hz, 1H), 2.08-1.89 (m, 2H, overlap with 1.78), 1.88-1.66(m, 4H), 1.58-1.47 (m, 1H, overlap with 1.48-1.35), 1.48-1.35 (m, 1H, overlap with 1.58-1.47), 1.17-1.03 (m, 1H), 0.99-0.85 (m, 1H), 0.67 (t, J = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 157.12 (1C), 13O.86 (1C), 128.44 (1C), 124.92 (1C), 120.47 (1C), 110.90(1 C), 64.69 (1C), 55.36 (1C), 49.85 (1C), 47.95 (1C), 31.67 (1C), 29.71 (1C), 22.52 (1C), 22.48 (1C), 21.57 (1C), 19.81 (1C), 13.62 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 100%. HRMS: m / z calcd for CI7H28NO [M + H]+, 262.2165; found 262.2159 , Appm = -2.29.

[0170] l-(l-(4-Methoxyphenyl)pentan-2-yl)-piperidine (Compound 34). 4-Meth oxybenzyl bromide was synthesized by dissolving (108.6 mmol) 13.48 mL 4-methoxybenzyl alcohol in 50 mL anhydrous (stored under argon and 3 A molecular sieves) DCMin a dry (dried in an oven via hot air) 250 mL round bottom flask. The temperature was reduced to 0 °C and (108.6 mmol) 10.31 mL PBr3was added dropwise. The reaction was allowed to stir for 2 hours and was confirmed to be complete by TLC. The reaction was slowly quenched with 30 mL of ice cold brine and the DCM was floated with EtOAc (50 mL). The reaction was transferred to a separatory funnel and the aqueous layer was separated and extracted with EtOAc (3 x 75 mL). The combined organic extractions were washed with DI water (50 mL), and brine (50 mL), dried with anhydrous NaSO4and the solvent removed under reduced pressure to yield 18.40 g (84.25%) 4-methoxybenzyl bromide as a thick yellow oil and was used without further purification.

[0171] l-(l-(4-Methoxyphenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 2.00 mL of previously prepared 4-methoxybenzyl bromide to yield crude l-(l-(4-methoxyphenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described except with a mobile phase of 50:50 hexanes:EtOAc to yield 1.19 g (71.3% yield) of 1 -(1 -(4-methoxyphenyl)pentan-2-yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield l-(l-(4-methoxyphenyl)pentan-2-yl)-piperidine HC1 as a white crystalline solid (mp: 172.9- 174.1 °C).

[0172] JH NMR (400 MHz, DMSO-d6) 8 = 10.53 (bs, 1NH+), 7.25 (dm, J= 8.6 Hz, 2H), 6.88 (dm, J = 8.6 Hz, 2H), 3.73 (s, 3H), 3.38-3.25 (m, 4H, overlap with H2O), 3.07-2.93 (m, 2H), 2.71 (dd, J= 13.2, 9.9 Hz, 1H), 2.08-1.92 (m, 2H), 1.87-1.64 (m, 4H), 1.55-1.46 (m, 1H), 1.46- 1.35 (m, 1H), 1.14-1.00 (m, 1H), 1.00-0.86 (m, 1H), 0.68 (t, J= 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 157.98 (1C), 130.14 (2C), 129.18 (1C), 113.88 (2C), 66.26 (1C), 54.98 (1C), 49.04 (1C), 48.63 (1C), 34.51 (1C), 30.84 (1C), 22.52 (overlap with 22.49, 1C), 22.49 (overlap with 22.52, 1C), 21.56 (1C), 19.96 (1C), 13.73 (1C). HPLC purity (50:50 Formate bufferACN, 220 nm): 98.9%. HRMS: m / z calcd for CI7H28NO [M + H]+, 262.2159; found 262.2165, Appm = -2.29.

[0173] l-(l-(2,3-Dichlorophenyl)pentan-2-yl)-piperidine (Compound 35). l-(l-(2,3-Dichlorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with(13.9 mmol) 3.33 g 2,3 -dichlorobenzyl bromide to yield crude l-(l-(2,3-dichlorophenyl)pentan- 2-yl)-piperidine. The crude freebase was purified by flash chromatography as described but gradiated from a mobile phase of 60:40 hexanes:EtOAc to 80:20 EtOAc:EtOH over 3 CVs to yield 1.54 g (74.0% yield) of 1 -(l-(2,3-dichlorophenyl)pentan-2-yl)-piperidine as a clear, colorless oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(1- (2,3-dichlorophenyl)pentan-2-yl)-piperidine HC1 as a white crystalline solid (mp: 180.8-181.2 °C).

[0174] iff NMR (400 MHz, DMSO-d6) 5 10.50 (bs, 1NH+), 7.60-7.53 (ddd, J = 10.8, 8.0, 1.4 Hz, 2H), 7.36 (t, .7= 7.8 Hz, 1H), 3.52 (dd, J = 13.3, 3.0 Hz, 1H), 3.46-3.38 (m, 3H, overlap with H2O), 3.17-3.01 (m, 3H), 2.08-1.91 (m, 2H), 1.90-1.65 (m, 4H), 1.61-1.50 (m, 1H), 1.50- 1.37 (m, 1H), 1.13-0.98 (m, 1H), 0.85-0.71 (m, 1H), 0.66 (t, .7= 7.2 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 8 = 137.37 (1C), 132.03 (lC), 131.34 (1C), 13O.64 (1C), 129.48 (1C), 128.29 (1C), 64.20 (1C), 49.28 (1C), 48.63 (1C), 33.49 (1C), 31.09 (1C), 22.54 (2C), 21.50 (1C), 19.95 (1C), 13.62 (1C). HPLC purity (50:50 Formate buffer: ACN, 220 nm): 100%. HRMS: m / z calcd for Ci6H24N35Cl2[M + H]+, 300.1280; found 300.1276, Appm = -1.33.

[0175] l-(l-(2,3-Difluorophenyl)pentan-2-yl)-piperidine (Compound 36). l-(l-(2,3-Difluorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 1.76 mL 2,3 -difluorobenzyl bromide to yield 1.46 g of crude l -(l-(2,3- difluorophenyl)pentan-2-yl)-piperidine freebase as a pale yellow oil and used without further purification. The HCl salt was formed and crystallized as previously described to yield 1.57 g (74.5% yield) of l-(l-(2,3-difluorophenyl)pentan-2-yl)-piperidine HC1 as a chalky white solid (mp: 181.0-182.3 °C).

[0176] JH NMR (400 MHz, DMSO-d6) 6 = 10.61 (bs, 1NH+), 7.39-7.30 (m, 2H), 7.24-7.17 (m, 1H), 3.47-3.37 (m, 4H, overlap with H2O), 3.11 -2.95 (m, 3H), 2.07-1.92 (m, 2H), 1.91 -1.64 (m, 4H), 1.57-1.46 (m, 1H, overlap with 1.48-1.36), 1.48-1.36 (m, 1H, overlap with 1.57-1.46), 1.18-1.02 (m, 1H), 1.01-0.85 (m, 1H), 0.70 (t, J = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 5 = [151.00, 150.87, 148.56, 148.44 (dd, J= 245, 13.0 Hz, 1C)], [149.56, 149.44, 147.13, 147.00 (dd, .7=245, 13.0Hz, 1C)], 126.91 (1C), [126.83, 126.80, 126.77 (apparent t, J = 3.0 Hz, 1C)], [125.00, 124.96, 124.93, 124.89 (dd, .7= 7.3, 4.5 Hz, 1C)], [116.23, 116.07 (d, J= 17.0 Hz, 1C)], 64.78 (1C), 48.96 (1C), 48.89 (1C), 31.09 (1C), 28.30 (1C), 22.51 (2C), 21.51 (1C), 19.75 (1C), 13.65 (1C).19F NMR (376.5 MHz, DMSO- d6) 6 = -138.44 (d, .7 = 21.7 Hz, IF), 142.73 (d, .7=21.7 Hz, IF). HPLC purity (50:50 Formate buffer: ACN, 220 nm): 99.1%. HRMS: m / z calcd for CI6H24NF2[M + H]+, 268.1871; found 268.1866, Appm = -1.86.

[0177] l-(l-(3,4-Dichlorophenyl)pentan-2-yl)-piperidine (Compound 37). l-(l-(3,4-Dichlorophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (48.8 mmol) 6.88 mL 3, 4 -dichlorobenzyl bromide, (56.1 mmol) 3.70 g Zn dust, (6.10 mmol) 0.47 mL, (26.8 mmol) 3.08 mL piperidine, and (24.4 mmol) 2.20 mL butyraldehyde to yield crude l-(l-(3,4-dichlorophenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described to yield 1.17 g (16.1% yield) of l -(l-(3,4- dichlorophenyl)pentan-2-yl)-piperidine as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield l -(l-(3,4-dichlorophenyl)pentan-2-yl)-piperidine HC1 as a white sparkling crystalline solid (mp: 195.8-197.2 °C).

[0178] Tf NMR (400 MHz, DMSO-d6) 6 = 10.57 (bs, 1NH+), 7.72 (d, J= 1.9 Hz, 1H), 7.60 (d, J= 8.3 Hz, 1H), 7.38 (dd, J = 8.3, 2.0 Hz, 1H), 3.47-3.39 (m, 2H), 3.35 (d, J = 10.5 Hz, 2H), 3.09-2.93 (m, 2H), 2.83 (dd, = 13.2 Hz, 10.5 Hz, 1H), 2.06-1.90 (m, 2H), 1.87-1.64 (m, 4H), 1.58-1.48 (m, 1H, overlap with 1.49-1.36), 1.49-1.36 (m, 1H, overlap with 1.58-1.48), 1.13-1.01 (m, 1H), 1.01-0.85 (m, 1H), 0.70 (t, J = 1.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 8 = 139.01 (1C), 131.08 (1C), 131.02 (1C), 130.55 (1C), 129.63 (1C), 129.31 (1C), 65.48 (1C), 49.17 (1C), 48.45 (1C), 34.46 (1C), 30.80 (1C), 22.54 (1C, overlap with 22.48), 22.48 (1C, overlap with 22.54), 21.52 (1C), 19.88 (1C), 13.69 (1C). HPLC purity (50:50 Formate buffercan, 220 nm): 99.8%. HRMS: m / z calcd for Ci6H24N35C12 [M + H]+, 300.1280; found 300.1277, Appm = -1.00.

[0179] l-(l-(2-Fluoro-3-chloro-phenyl)pentan-2-yl)-piperidine (Compound 38). l-(l-(2- Fluoro-3-chloro-phenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 3.10 mL 2 -fluoro-3 -chlorobenzyl bromide to yield crude l -(l-(2- fluoro-3-chloro-phenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described except with a mobile phase of 60:40 hexanes:EtOAc to yield 1.27 g (63.5% yield) of l-(l-(2-fluoro-3-chloro-phenyl)pentan-2-yl)-piperidine freebase as a clear, colorless oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(1 -(2- fluoro-3-chloro-phenyl)pentan-2-yl)-piperidine HC1 as an off-white crystalline solid (mp: 153.9-154.5 °C).

[0001] JH NMR (400 MHz, DMSO-d6) 6 = 10.48 (bs, 1NH+), 7.54-7.47 (m, 2H), 7.22 (td, J = 7.9, 0.7 Hz, 1H), 3.46-3.37 (m, 4H, overlap with H2O), 3.12-2.99 (m, 2H, overlap with 2.97), 2.97 (dd, J= 13.1, 10.1 Hz, 1H), 2.05-1.90 (m, 2H), 1.89-1.74(m, 3H), 1.74-1.65 (dm, J = 12.8 Hz, 1H), 1.57-1.48 (m, 1H, overlap with 1.48-1.36), 1.48-1.36 (m, 1H, overlap with 1.57-1.48), 1.17-1.02 (m, 1H), 0.99-0.84 (m, 1H), 0.70 (t, J = 1.3 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 6 = [156.94 154.49 (d, J= 246 Hz, 1C)], [130.61, 130.57 (d, J = 3.1 Hz, 1C)], 129.46 (1C),[126.35, 126.20 (d, J= 14.7 Hz, 1C)], 125.54, 125.50 (d, = 4.5 Hz, 1C), 119.87, 119.69 (d, J = 18.0 Hz, 1C)], 64.71 (1C), 48.94 (2C), 31.10 (1C), 28.72 (1C), 22.54 (2C), 21.51 (1C), 19.76 (1 C), 13.66 (1C).19F NMR (376.5 MHz, DMSO- d6) 8 = -119.37 (IF). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 99.1%. HRMS: m / z calcd for CI6H2335C1FN+H [M + H]+, 284.1576; found 284.1572, Appm = -1.41, m / z calcd for CI6H2437C1FN [M + H]+268.1546, found 268.1541.

[0180] l-(l-Cyclobutyl-2-phenylethyl)piperidine (Compound 39). l-(l-Cyclobutyl-2- phenylethyl)piperidine was prepared as described for Compound 7 except with (13.70 mmol) 0.90 g Zn dust, (1.49 mmol) 0.11 mL trifluoroacetic acid, (11.90 mmol) 1.42 mL benzyl bromide, (6.54 mmol) 0.75 mL piperidine and (5.94 mmol) 0.53 mL cyclobutane carboxaldehyde to yield l-(l-cyclobutyl-2-phenylethyl)piperidine. The crude freebase was purified by flash chromatography as described to yield 0.94 g (63.2% yield) of 1 -(1-cyclobutyl- 2-phenylethyl)piperidine freebase as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(l-cyclobutyl-2-phenylethyl)piperidine HC1 as a fluffy whitepeach crystalline needles (mp: 206.5-207.6 °C).

[0181] JH NMR (400 MHz, DMSO-d6) 6 = 10.46 (bs, 1NH+), 7.42-7.38 (dm, J = 7.7 Hz, 2H), 7.33-7.28 (tm, J = 7.2 Hz, 2H), 7.24-7.19 (tm, J= 7.2 Hz, 1H), 3.61-3.53 (m, 1H), 3.42 (dd, J = 14.2, 2.9 Hz, 1H), 3.35 (d, J= 12.1 Hz, 1H), 3.29 (d, J= 11.9 Hz, 1H), 3.00-2.87 (m, 2H), 2.86- 2.74 (m, 2H), 2.08-1.97 (m, 2H, overlap with 1.99-1.88), 1.99-1.88 (m, 2H, overlap with 2.08- 1.97), 1.78-1.69 (m, 3H), 1.69-1.59 (m, 2H), 1.57-1.47 (m, 1H), 1.47-1.34 (m, 2H).13C NMR (100.6 MHz, DMSO-d6) 6 = 138.20 (1C), 129.12 (2C), 128.26 (2C), 126.46 (1C), 69.86 (1C), 50.92 (1C), 48.41 (1C), 35.61 (1C), 34.34 (1C), 28.12 (1C), 26.81 (1C), 22.70 (1C), 22.41 (1C), 21.56 (1C), 18.60 (1C). HPLC purity (50:50 Formate bufferACN, 220 nm): 100%. HRMS: m / z calcd for CI7H26N [M + H]+, 244.2060; found 244.2057, Appm = -1.23.

[0182] l-(l,3-Benzodioxol-5-yl)pentan-2-yl)-piperidine (Compound 40). 5-(bromomethyl)- 1,3 -benzodioxole was synthesized by dissolving (46.5 mmol) 7.08 g piperonyl alcohol in 50 mL anhydrous (stored under argon and 3 A molecular sieves) DCM in a dry (dried in an oven via hot air) 250 mL round bottom flask. The temperature was reduced to 0 °C and (46.5 mmol) 4.42 mL PBr3was added dropwise. The reaction was allowed to stir for 2 hours and was confirmed to be complete by TLC. The reaction was slowly quenched with 30 mL of ice cold brine and the DCM was floated with EtOAc (50 mL). The reaction was transferred to a separatory funnel and the aqueous layer was separated and extracted with EtOAc (3x 75 mL). The combined organic extractions were washed with distilled water (50 mL), and brine (50 mL), dried with anhydrousNaSC and the solvent removed under reduced pressure to yield 8.75 g (87.5%) 5- (bromomethyl)-l,3-benzodioxole as a golden oil and was used without further purification.

[0183] l-(l,3-Benzodioxol-5-yl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (40.7 mmol) 8.75 g of freshly prepared 5-(bromomethyl)-l,3- benzodioxole, (46.8 mmol) 3.06 g Zn dust, (5.10 mmol) 0.39 mL trifluoroacetic acid, (22.4 mmol) 2.58 mL piperidine and (20.3 mmol) 1.83 mL butyraldehyde to yield crude 1 -(1,3- benzodioxol-5-yl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described but gradated to a mobile phase of 50:50 hexanes:EtOAc to yield 2.11 g (37.7% yield) of l-(l,3-benzodioxol-5-yl)pentan-2-yl)-piperidine as a yellow oil. The HC1 salt was formed and crystallized as previously described to yield l-(l,3-benzodioxol-5- yl)pentan-2-yl)-piperidine HC1 as a sparkling white crystalline solid (mp: 178.1 -179.2 °C).

[0184] JH NMR (400 MHz, DMSO-d6) 8 = 10.40 (bs, 1NH+), 6.98 (d, J= 1.4 Hz, 1H), 6.85 (d, J= 7.9 Hz, 1H), 6.78 (dd, J= 7.9, 1.5 Hz, 1H), 5.99 (s, 2H), 3.37-3.27 (m, 4H, overlap with H2O), 3.07-2.93 (m, 2H), 2.70 (dd, J = 14.0, 10.7 Hz, 1H), 2.05-1.89 (m, 2H), 1.85-1.64 (m, 4H), 1.57-1.46 (m, 1H, overlap with 1.47-1.34), 1.47-1.34 (m, 1H, overlap with 1.57-1.46), 1.17-1.03 (m, 1H), 1.03-0.90 (m, 1H), 0.71 (t, = 7.15 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 6 = 147.34 (1C), 145.90 (1C), 131.11 (1C), 127.17 (1C), 109.34 (1C), 109.19 (1C), 100.85 (1C), 66.12 (1C), 49.02 (1C), 48.64 (1C), 35.09 (1C), 30.89 (1C), 22.54 (1C, overlap with 22.51), 22.51 (1C, overlap with 22.54), 21.54 (1C), 19.94 (1C), 13.75 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 96.3%. ASAP MS: m / z found for C I7H28N [M + H]+ 276.1 (100), [M + 2]+ 277.2 (20).

[0185] l-(l-(3-Trifluoromethylphenyl)pentan-2-yl)-piperidine (Compound 41). l-(l-(3- Trifluoromethylphenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 2.11 mL 3 -trifluoromethylbenzyl bromide to yield crude l -(l-(3- trifluoromethylphenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described to yield 0.65 g (31.4% yield) of l-l-(l-(3- trifluoromethylphenyl)pentan-2-yl)-piperidineas a clear, colorless oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(l-(3-trifluoromethylphenyl)pentan-2-yl)- piperidine HC1 as a white crystalline solid (mp: 173.9-175.0 °C).

[0186] JH NMR (400 MHz, DMSO-d6) 8 = 10.63 (bs, 1NH+), 7.78 (s, 1H), 7.69 (apparent d, J = 7.6 Hz, 1H), 7.61 (apparent d, . / = 7.6 Hz, 1H) 7.56 (apparentt, J= 7.5 Hz, 1H), 3.54 (dd, J = 13.5, 2.5 Hz, 1H), 3.49-3.40 (m, 1H, overlap with 3.41 -3.33), 3.41-3.33 (m, 2H, overlap with 3.49-3.40), 3.10-2.97 (m, 2H, overlap with 2.94), 2.94 (dd, J = 13.4, 10.5 Hz, 1H, overlap with 3.10-2.97), 2.07-1.92 (m, 2H), 1.88-1.81 (m, 3H, overlap with 1.74-1.65), 1.74-1.65 (dm, J =13.2 Hz, 1H, overlap with 1.88-1.81), 1.58-1.47 (m, 1H, overlap with 1.49-1.36), 1.49-1.36 (m,IH, overlap with 1.58-1.47), 1.11-0.94 (m, 1H), 0.91-0.77 (m, 1H), 0.65 (t, J = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 139.11 (1C), 133.44 (1C), 129.50 (1C), [129.70, 129.28, 129.07, 128.76 (q, J= 31.4 Hz, 1C)], [125.78, 125.74, 125.70, 125.66 (q, J= 4.0 Hz, 1C)], [128.24, 125.53, 122.83, 120.12 (q, J= 272 Hz, 1C)], [123.52, 123.48, 123.44, 123.40 (q, J = 4.0 Hz, 1C)], 65.56 (1C), 49.17 (1C), 48.42 (1C), 35.07 (1C), 30.70 (1C), 22.54 (1C), 22.48 (1C), 21.54 (1C), 19.89 (1C), 13.55 (1C).19F NMR (376.5 MHz, DMSO- d6) 6 = -60.57 (3F). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 99.3%. HRMS: m / z calcd for C17H25F3N [M + H]+, 300.1934; found 300.1928, Appm = -2.00.

[0187] l-(l-(2-Trifluoromethylphenyl)pentan-2-yl)-piperidine (Compound 42). l-(l-(2- Trifluoromethylphenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 exceptwith (31.9 mmol) 2.09gZn dust, (3.48 mmol) 0.27 mL trifluoroacetic acid, (27.8 mmol) 4.23 mL 2-trifluoromethylbenzyl bromide, (15.3 mmol) 1.76 mL piperidine, and (13.9 mmol) 1.25 mL butyraldehyde to yield crude 1 -(l-(2-trifluoromethylphenyl)pentan-2-yl)-piperidine. The crude freebase was purified by flash chromatography as described to yield 1.05 g (25.2% yield) of l-l-(l-(2-trifluoromethylphenyl)pentan-2-yl)-piperidine as a yellow oil. The HC1 salt was formed and crystallized as previously described to yield l -(l-(2- trifluoromethylphenyl)pentan-2-yl)-piperidineHCl as a white crystalline solid (mp: 166.8-167.6 °C).

[0188] Tf NMR (400 MHz, DMSO-d6) 6 = 10.73 (bs, 1NH+), 7.75 (dd, J= 14.5, 7.8 Hz, 2H), 7.67 (t, J= 7.5 Hz, 1H), 7.48 (t, J= 7.6 Hz, 1H), 3.62 (dd, J= 14.0 Hz, 2.5 Hz, 1H), 3.55-3.47 (m, 1H), 3.40 (d, J= 11.6 Hz, 2H), 3.15-3.02 (m, 2H, overlap with 2.98), 2.98 (dd, J = 13.9,I I .5 Hz, 1H, overlap with 3.15-3.02), 2.11-1.95 (m, 2H), 1.95-1.85 (m, 1H), 1.79 (d, J = 13.8 Hz, 2H), 1.75-1.66 (dm, = 13.0 Hz, 1H), 1.56-1.49 (m, 1H, overlap with 1.49-1.37), 1.49-1.37 (m, 1H, overlap with 1.56-1.49), 1.00-0.83 (m, 1H), 0.71-0.60 (m, 4H).13C NMR (100.6 MHz, DMSO-d6) 6 = [135.56, 135.55 (1C)], 132.59 (1C), 131.88 (1C), 127.51 (1C), [127.70, 127.41, 127.12, 126.83 (q, J = 29.1 Hz, 1C)], [126.24, 126.18, 126.12, 126.07 (q, J= 6.0 Hz, 1C)], [128.50, 125.77, 123.05, 120.33 (q, = 273 Hz, 1C)], 65.38 (1C), 48.82 (1C), 48.74 (1C), 31.60 (1C), 31.16 (1C), 22.54 (1C), 22.50 (1C), 21.48 (1C), 19.79 (1C), 13.53 (1C).19F NMR (376.5 MHz, DMSO- d6) 6 = -57.19 (3 F). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 97.1 %. HRMS: m / z calcd for CI7H25F3N [M + H]+, 300.1934; found 300.1928, Appm = -2.00.

[0189] l-(l-Phenylhexan-2-yl)piperidine (Compound 43). l-(l-Phenylhexan-2-yl)piperidine was prepared as described for Compound 7 except with (53.4 mmol) 3.49 g Zn dust, (5.81 mmol) 0.45 mL trifluoroacetic acid, (46.4 mmol) 5.55 mL benzyl bromide, (25.5 mmol) 2.94mL piperidine, and (24.2 mmol) 2.47 mL valeraldehyde. The reaction was quenched with ammonium hydroxide and extracted with EtO Ac (3 x 75 mL) to yield crude l -(l-phenylhexan- 2-yl)piperidine. The crude freebase was purified by flash chromatography as described but with a mobile phase of 90:10 hexanes:EtOAc to yield 1.08 g (18.8% yield) of isolated 1 -(1- phenylhexan-2-yl)piperidine as a yellow oil. The HC1 salt was formed and crystallized as previously described to yield l -(l-phenylhexan-2-yl)piperidine HC1 as a white crystalline solid (mp: 164.6-165.3 °C).

[0190] 'H NMR (400 MHz, DMSO-d6) 8 = 10.38 (bs, 1NH+), 7.37-7.30 (m, 4H), 7.28-7.22 (m, 1H), 3.44-3.33 (m, 4H, overlap with H2O), 3.08-2.95 (m, 2H), 2.78 (dd, J = 13.0, 9.8 Hz, 1H), 2.05-1.89 (m, 2H), 1.88-1.64 (m, 4H), 1.60-1.49 (m, 1H, overlap with 1 .49-1.35), 1.49-1.35 (m, 1H, overlap with 1.60-1.49), 1.13-0.98 (m, 3H), 0.91 -0.77 (m, 1H), 0.68 (t, J= 7.2 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 137.49 (1C), 129.16 (2C), 128.48 (2C), 126.69 (1C), 66.32 (1C), 48.99 (1C), 48.80 (1C), 35.35 (1C), 28.58 (1C), 28.49 (1C), 22.57 (1C, overlap with 22.54), 22.54 (1C, overlap with 22.57), 21.83 (1C), 21.53 (1C), 13.47 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 98.4%. HRMS: m / z calcd for Ci7H28N [M + H]+, 246.2216 ; found 246.2210, Appm = -2.43.

[0191] l-(3-Methyl-l-phenylpentan-2-yl)piperidine (Compound 44). 1 -(3 -Methyl- 1- phenylpentan-2-yl)piperidine was prepared as described for Compound 7 except with (26.7 mmol) 1.75 gZn dust, (2.90 mmol) 0.32 mL trifluoroacetic acid, (23.2 mmol) 2.77 mL benzyl bromide, (12.8 mmol) 1.47 mL piperidine, and (11.6 mmol) 1.24 mL 2 -methylbutyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with EtO Ac (3 x 75 mL) to yield crude l-(3-methyl-l-phenylpentan-2-yl)piperidine. The crude freebase was purified by flash chromatography as described but with a mobile phase of 100% hexanes, gradated to 90:10 hexanes:EtOAc over 3 CVs to yield 2.18 g (76.8% yield) of l -(3-methyl-l-phenylpentan-2- yl)piperidine as a clear, colorless oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(3 -methyl- l-phenylpentan-2-yl)piperidine HC1 as a white crystalline solid as an approximate 60:40 ratio of diastereomers as determined by 'H NMR NH shifts (mp: 169.2-170.6 °C).

[0192] HPLC purity (50:50 Formate buffer:ACN, 220 nm): 98.6%. MS ASAP m / z: calcd for CI7H28N [M + H]+, 246.2216; found 246.2211, Appm = -2.03.

[0193] l-(2-Methyl-l-phenylbutan-2-yl)piperidine (Compound 58). 1 -(2 -Methyl- 1- phenylbutan-2-yl)piperidine was prepared as described for Compound 7 except the entire reaction was maintained at 40 °C and was performed with (63.8 mmol) 4.17 g Zn dust, (6.93 mmol) 0.50 mL trifluoroacetic acid, (55.5 mmol) 6.64 mL benzyl bromide, (30.5 mmol) 3.51mL piperidine, and (27.7 mmol) 2.48 mL 2-butanone. The reaction was quenched with ammonium hydroxide and extracted with EtOAc ( 3x 75 mL) to yield crude 1 -(2-methyl-l- phenylbutan-2-yl)piperidine. The crude freebase was purified by flash chromatography as described but with a mobile phase of 90:10 hexanes:EtOAc to yield 0.66 g (10.3% yield) of 1 - (2-methyl-l-phenylbutan-2-yl)piperidine as a sweet smelling clear, colorless oil. The HC1 salt was formed and crystallized as previously described to yield l -(2-methyl-l-phenylbutan-2- yl)piperidine HC1 as a white crystalline solid (mp: 201.8-202.5 °C).

[0194] JH NMR (400 MHz, DMSO-d6) 6 = 9.64 (bs, 1NH+), 7.36-7.25 (m, 5H), 3.52 (t, J = 12.4 Hz, 2H), 3.11 (s, 2H), 3.06-2.93 (m, 2H), 2.21-2.04 (m, 2H), 1.79 (d, J = 14.7 Hz, 2H, overlap with 1.76-1.67), 1.76-1.67 (m, 2H), 1.60-1.50 (m, 1H, overlap with 1.50-1.37), 1.50- 1.37 (m, 1H, overlap with 1.60-1.50), 1.20 (s, 3H), 0.87 (t, J= 7.4 Hz).13C NMR (100.6 MHz, DMSO-d6) 6 = 135.80 (1C), 130.75 (2C), 128.21 (2C), 126.93 (1C), 68.54 (1C), 47.32 (1C), 47.26 (1C), 38.85 (1C), 27.16 (1C), 22.78 (1C), 22.72 (1C), 21.70 (1C), 19.13 (1C), 8.30 (1C). HPLC purity (50:50 Formate buffer: ACN, 220 nm): 100.0%. HRMS: m / z calcd for CieH26N [M + H]+, 232.2060; found 232.2055, Appm = -2.15.

[0195] l-(l-(3-Chlorophenyl)hexan-2-yl)azepane (Compound 45). l-(l-(3-Chlorophenyl)hexan-2-yl)azepane was prepared as described for Compound 7 except with (10.5 mmol) 0.69 gZn dust, (1.14 mmol) 0.08 mL trifluoroacetic acid, (9.14 mmol) 1.20 mL 3 - chlorobenzyl bromide, (5.03 mmol) 0.57 mL azepane, and (4.57 mmol) 0.41 mL butyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with EtOAc (3 x 75 mL) to yield crude l-(l-(3-chlorophenyl)hexan-2-yl)azepane freebase. The crude freebase was purified by flash column chromatography as described but gradated from a mobile phase of 100% hexanes to 90:10 hexanes:EtOAc to yield 0.98 g (76.5% yield) of 1 -(l-(3-chlorophenyl)hexan-2- yl)azepane freebase as a clear, colorless oil. The HC1 salt was formed and crystallized as previously described to yield l -(l-(3-chlorophenyl)hexan-2-yl)azepane HC1 as fine, white, crystalline needles (mp: 210.9-212.1 °C).

[0196] JH NMR (400 MHz, DMSO-d6) 6 = 10.50 (bs, 1NH+), 7.52 (s, 1H), 7.38-7.29 (m, 3H), 3.53-3.42 (m, 2H, overlap with 3.42-3.34), 3.42-3.34 (m, 2H, overlap with 3.53-3.42 and H2O), 3.26-3.15 (m, 2H), 2.85 (dd, J= 13.0, 10.2Hz, 1H), 2.10-1.94 (m, 2H), 1.88-1.77 (m, 3H), 1.76- 1.66 (m, 2H), 1.65-1.50 (m, 3H), 1.09-0.95 (m, 1H), 0.89-0.75 (m, 1H), 0.67 (t, J= 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 = 140.10 (1C), 133.07 (1C), 130.26 (1C), 129.01 (1C), 128.03 (1C), 126.73 (1C), 67.29 (1C), 51.25 (1C), 50.52 (1C), 35.25 (1C), 31.22 (1C), 25.59 (1C), 25.49 (1C), 24.02 (1C, overlap with 23.97), 23.97 (1C, overlap with 25.49), 20.09 (1C),13.70 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 97.8%. HRMS: m / z calcd for CI7H2735C1N [M + H]+, 280.1827; found 280.1822, Appm = -1.78.

[0197] l-(3-Ethyl-l-phenylpentan-2-yl)piperidine (Compound 46). l-(3-Ethyl-l- phenylpentan-2-yl)piperidine was prepared as described for Compound 7 except with (11.4 mmol) 0.75 g Zn dust, (1.25 mmol) 0.90 mL trifluoracetic acid, (9.98 mmol) 1.19 mL benzyl bromide, (6.37 mmol) 0.63 mL piperidine, and (4.99 mmol) 0.61 mL 2 -ethylbutyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with EtOAc (3 x 75 mL) to yield crude l-(3-ethyl-l-phenylpentan-2-yl)piperidine freebase. The crude freebase was purified by flash chromatography as described but with a mobile phase of 50:50 hexanes :EtO Ac to yield 0.69 g(53.5% yield) of l-(3-ethyl-l-phenylpentan-2-yl)piperidine freebase as a yellow oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(3 -ethyl-1 - phenylpentan-2-yl)piperidine HC1 as a white crystalline solid (mp: 185.8-186.6 °C).

[0198] JH NMR (400 MHz, DMSO-d6) 8 10.42 (bs, 1NH+), 7.38-7.30 (m, 4H), 7.26-7.20 (m, 1H), 3.59-3.52 (m, 1H), 3.42 (dd, J= 14.5, 3.9 Hz, 2H), 3.32-3.27 (m, 1H, overlap with H2O), 3.13-2.99 (m, 2H), 2.93-2.80 (m, 1H), 2.13-1.90 (m, 2H), 1.84-1.63 (m, 5H), 1.47-1.35 (m, 1H, overlap with 1.37-1.27), 1.37-1.27 (m, 1H, overlap with 1.47-1.35), 1.25-1.11 (m, 1H), 0.90 (t, J = 7.3 Hz, 3H), 0.78 (t, J= 7.1 Hz, 3H), 0.74-0.62 (m, 1H).13C NMR (100.6 MHz, DMSO-d6) 6 138.39 (1C), 128.80 (2C), 128.51 (2C), 126.56 (1C), 68.06 (1C), 51.03 (1C), 49.20 (1C), 40.35 (1C), 31.73 (1C), 23.89 (1C), 22.64 (1C), 22.55 (1C), 22.40 (1C), 21.33 (1C), 12.06 (1C), 11.89 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 98.0%. HRMS: m / z calcd for CI8H30N [M + H]+, 260.2373; found 260.2368, Appm = -1.92.

[0199] l-(4,4-Dimethyl-l-phenylpentan-2-yl)piperidine (Compound 47). l-(4,4-Dimethyl- l-phenylpentan-2-yl)piperidine was prepared as described for Compound 7 with (22.9 mmol) 1.50 gZn dust, (2.50 mmol) 0.18 mL trifluoroacetic acid, (19.9 mmol) 2.39 mL benzyl bromide, (10.9 mmol) 1.27 mL piperidine, and (9.98 mmol) 1.25 mL 3,3 -dimethylbutyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with EtOAc (3 x 75 mL) to yield crude l-(4,4-dimethyl-l-phenylpentan-2-yl)piperidine. The crude freebase was purified by flash chromatography as described but with a solvent system of 70:30 hexanes:EtOAc to yield 1.25 g (48.3% yield) of l-(4,4-dimethyl-l-phenylpentan-2-yl)piperidine as a sweet smelling transparent, colorless oil. The HC1 salt was formed and crystallized as previously described to yield l-(4,4-dimethyl-l-phenylpentan-2-yl)piperidine HC1 as a fluffy white crystalline solid (mp: 222.5-223.3 °C).

[0200] Tf NMR (400 MHz, DMSO-d6) 6 10.24 (bs, 1NH+), 7.41-7.37 (dm, J= 8.2 Hz, 2H), 7.36-7.30 (tm, = 7.4 Hz, 2H), 7.26-7.21 (tm, J= 7.3 Hz, 1H), 3.50-3.41 (m, 2H), 3.33-3.26 (d,J= 13.1 Hz, 2H, overlap with H20), 3.10-2.98 (m, 1H), 2.92-2.80 (m, 2H), 2.11 -1.85 (m, 3H), 1.80-1.63 (m, 3H), 1.50-1.42 (m, 1H, overlap with 1.43 -1.33), 1.43-1.33 (m, 1H, overlap with 1.50-142), 0.67 (s, 9H).13C NMR (100.6 MHz, DMSO-d6) 6 137.15 (1C), 129.51 (2C), 128.48 (2C), 126.84 (1C), 63.57 (1C), 49.70 (1C), 48.10 (1C), 41.59 (1C), 38.13 (1C), 30.00 (1C), 29.37 (3C), 22.56 (1C), 22.47 (1C), 21.37 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 97.8%. HRMS: m / z calcd for CI8H30N [M + H]+, 260.2373; found 260.2368, Appm = - 1.92.

[0201] l-(l-(Furan-2-yl)pentan-2-yl)piperidine Compound 48). 2-(bromomethyl)furan was synthesized by dissolving (62.1 mmol) 5.40 mL furfural in 30 mL anhydrous (stored under argon and 3 A molecular sieves) Et2O in a dry (dried in an oven via hot air) 250 mL dry round bottom flask. The temperature of the reaction solution was reduced to ~0 °C using an ice-water bath and (62.1 mmol) 5.90 mL PBr3was added dropwise, turning the reaction opaque black. The reaction was allowed to stir for 2 hours and was confirmed to be complete by TLC. The reaction was quenched dropwise at 0 °C with 40 mL of ice cold brine. The reaction was then transferred to a separatory funnel and the aqueous layer was separated and extracted with Et2O (3x 75 mL). The combined organic extractions were washed with DI water (50 mL), and brine (50 mL) and dried with anhydrous NaSO4to yield 2-(bromomethyl)furan. The opaque black solution of 2- (bromomethyl)furan in Et2O was immediately added to the next reaction, as removing solvent risked losing the highly volatile and chemically unstable 2-(bromomethyl)furan.

[0202] l-(l-(Furan-2-yl)pentan-2-yl)piperidine was prepared as described for Compound 7 except the reaction was performed in a dry (dried in an oven via hot air) 500 mL three-neck round bottom flask with a reflux condenser and an addition funnel, and with (62.1 mmol) 10.00 g, assuming 100% yield, of freshly prepared 2-(Bromomethyl)furan solution in Et2O, (71.4 mmol) 4.67 g Zn dust, (7.76 mmol) 0.56 mL trifluoroacetic acid, (34.2 mmol) 3.93 mL piperidine, and (31.1 mmol) 2.78 mL butyraldehyde to yield crude 1 -(l-(furan-2-yl)pentan-2- yl)piperidine. The crude freebase was purified by flash chromatography as described but gradated from a mobile phase of 70:30 hexanes:EtOAc to 60:40 EtOAc:MeOH over 8 CVs to yield 1.86 g (27.1% yield) of l -(l-(furan-2-yl)pentan-2-yl)piperidine as a brown oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(l-(thiophen-2-yl)pentan-2- yl)-piperidine HC1 as a chalky brown powder (mp: 157.9-158.8 °C).

[0203] JH NMR (400 MHz, DMSO-d6) 6 = 10.65 (bs, 1NH+), 7.59 (dd, J= 1.9, 0.6 Hz, 1H), 6.40 (dd, .7 = 3.3, 1.9 Hz, 1H), 6.31 (d, J = 3.3 Hz, 1H), 3.42-3.35 (m, 2H, overlap with H2O), 3.34-3.23 (m, 2H, overlap with H2O), 3.04-2.88 (m, 3H), 2.05-1.91 (m, 2H, overlap with 1.91 - 1.82), 1.91-1.82 (m, 1H, overlap with 2.05-1.91), 1.80-1.64 (m, 3H), 1.58-1.47 (m, 1H), 1.45-1.32 (m, 1H), 1.21-0.99 (m, 2H), 0.78 (t, J= 7.30, 3H).13C NMR (100.6 MHz, DMSO-d6) 6 150.71 (1C), 142.15 (1C), 11O.78 (1C), 1O7.8O (1C), 63.70 (1C), 48.90 (1C), 48.79 (1C), 30.96 (1C), 27.54 (1C), 22.45 (1C, overlap with 22.42), 22.42 (1C, overlap with 22.45), 21.49 (1C), 19.26 (1C), 13.69 (1C). HPLC purity (50:50 Formate buffer: ACN, 220 nm): 98.6%. HRMS: m / z calcd for C14H24NO [M + H]+, 222.1852; found 222.1852, Appm = 0.00.

[0204] l-(l-(3-Ethyloxetan-3-yl)-2-phenylethyl)piperidine (Compound 59). l-(l-(3-Ethyloxetan-3-yl)-2-phenylethyl)piperidine was prepared as described for Compound 7 except with, (10.1 mmol) 0.66 gZn dust, (1.10 mmol) 0.08 mL trifluoroacetic acid, (8.76 mmol) 1.05 mL benzyl bromide, (4.82 mmol) 0.56 mL piperidine, and (4.38 mmol) 0.50 g 3 -ethyloxetane-3- carbaldehyde. The reaction was worked up as previously described to yield crude 1 -(l-(3- ethyloxetan-3-yl)-2-phenylethyl)piperidine. The crude freebase was purified as previously described but with a solvent system of90:10 hexanes:EtOAc to yield 0.52 g(48.6% yield) of 1 - (l-(3-ethyloxetan-3-yl)-2-phenylethyl)piperidineas a pale yellow oil. The HC1 salt was formed as previously described to yield l-(l-(3-ethyloxetan-3-yl)-2-phenylethyl)piperidine HC1 as a fluffy white crystalline solid.

[0205] 1H NMR (400 MHz, DMSO-d6) 8 10.47 (bs, 1NH+), 7.40-7.33 (m, 4H), 7.30-7.23 (m, 1H), 4.80 (d, = 6.50 Hz, 1H), 4.43 (d, = 6.47 Hz, 1H), 4.24 (dd, J= 6.70 Hz, 6.21 Hz), 4.16 (d, J= 6.63 Hz), 4.09 (d, J = 6.56 Hz), 3.41-3.31 (m, 2H, overlap with H2O), 3.01-2.74 (m, 3H), 2.70 (dd, = 8.54 Hz, 4.67 Hz, 1H), 2.12-1.87 (m, 2H, overlap with 1.87-1.74), 1.87-1.74 (m, 2H, overlap with 2.12-1.87, 1.74-1.55), 1.55 (m, 3H, overlap with 1.87-1.74), 1.33-1.18 (m, 4H).13C NMR (100.6 MHz, DMSO-d6) 5 138.82 (1C), 129.38 (1C), 128.94 (1C), 127.32 (1C), 77.32 (1C), 76.16 (1C), 72.44 (1C), 53.04 (1C), 51.98 (1C), 45.54 (1C), 32.70 (1C), 23.10 (1C), 22.98 (1C), 22.54 (1C), 21.83 (1C), 8.50 (1C). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 91.6%. ASAP MS: m / z: found for CI8H28NO; 274.2 [M + H]+ (100), 275.2 [M + 2]+ (20).

[0206] l-(l-(4-Iodophenyl)pentan-2-yl)-piperidine (Compound 49). l-(l-(4-Iodophenyl)pentan-2-yl)-piperidine was prepared as described for Compound 7 except with (13.9 mmol) 4.13 g 4-iodobenzyl bromide to yield crude 1 -(l-(4-iodophenyl)pentan-2-yl)- piperidine freebase. The crude freebase was purified by flash chromatography as described but with a solvent system of 70:30 hexanes:EtOAc gradated to 50:50 hexanes:EtOAc over 2 CVs to yield 0.90 g (36.3% yield) of 1 -(l-(4-iodophenyl)pentan-2-yl)-piperidine freebase as a pale yellow oil. The HC1 salt was formed and crystallized as previously described to yield 1 -(l-(4- iodophenyl)pentan-2-yl)-piperidine HC1 as a shimmering fibrous white crystalline solid (mp: 191.6-192.7 °C).

[0207] JH NMR (400 MHz, DMSO-d6) 6 = 10.56 (bs, 1NH+), 7.70-7.65 (dm, J = 8.2 Hz, 2H), 7.21-7.16 (dm, 7= 8.2 Hz, 2H), 3.41-3.34 (m, 4H, overlap with H2O), 3.08-2.93 (m, 2H), 2.76 (dd, J= 13.2, 10.1 Hz, 1H), 2.07-1.91 (m, 2H), 1.86-1.63 (m, 4H), 1.57-1.45 (m, 1H, overlap with 1.46-1.35), 1.46-1.35 (m, 1H, overlap with 1.57-1.45), 1.12-0.99 (m, 1H, overlap with 0.99-0.86), 0.99-0.86 (m, 1H, overlap with 1.12-0.99), 0.69 (t, 7 = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 5 = 137.46 (1C), 137.21 (2C), 131.55 (2C), 92.55 (1C), 65.80 (1C), 49.13 (1C), 48.57 (1C), 34.92 (1C), 30.86 (1C), 22.53 (1C, overlap with 22.50), 22.50 (1C, overlap with 22.53), 21.53 (1C), 19.90 (1C), 13.71 (1C). HPLC purity (50:50 Formate buffer: ACN, 220 nm): 98.9%. HRMS: m / z calcd for CI6H25IN [M + H]+, 358.1026; found 358.1017, Appm = - 2.51.

[0208] 4-(l-(3-fluorophenyl)pentan-2-yl)thiomorpholine (Compound 50). Compound 50 was prepared as described for Compound 7 except with (13.90 mmol) 1.70 mL 3 -fluorobenzyl bromide and (7.63 mmol) 0.77 mL thiomorpholine to yield crude freebase as a yellow oil. The freebase was purified as previously described to yield 0.95 g (51.4% yield) 4-(l-(3- fluorophenyl)pentan-2-yl)thiomorpholine. The HC1 salt was formed as previously described except using MeOH to yield 4-(l-(3-fluorophenyl)pentan-2-yl)thiomorpholine HC1 as a rusty red solid (mp: 153.0-153.6 °C).

[0209] JH NMR (400 MHz, DMSO-d6) 6 11.29 (s, 1NH+), 7.37 (q, J = 7.4 Hz, 1H), 7.28 (d, J = 10.1 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.08 (t, 7= 7.5 Hz, 1H), 3.72 (d, J = 10.2 Hz, 2H), 3.60-3.42 (m, 4H, overlap with H2O), 3.24 (p, 7= 11.5 Hz, 2H), 2.90-2.81 (m, 1H, overlap with 2.78), 2.81-2.71 (m, 2H, overlap with 2.86), 1.95-1.83 (m, 1H), 1.61-1.47 (m, 1H), 1.15-1.00 (m, 1H), 1.00-0.84 (m, 1H), 0.69 (t, J = 1A Hz, CH3).13C NMR (100.6 MHz, DMSO-d6) 6 162.17 (d, J = 243.5 Hz, 1C), 140.35 (d, J= 7.60 Hz, 1C), 130.39 (d, J= 8.34 Hz, 1C), 125.37 (d, J = 2.25 Hz, 1C), 115.91 (d, 7=21.73 Hz, 1C), 113.59 (d, 7=20.78 Hz, 1C), 66.90 (1C), 50.55 (d, 7 = 11.41 Hz, 1C), 34.81 (1C), 31.03 (1C), 23.97 (d, 7= 6.06 Hz, 1C), 19.85 (1C), 13.63 (1C).19F NMR (376.5 MHz, DMSO- d6) 6 = -113.25 (IF). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 96.9%. MS ASAP: m / z calcd for CI5H22FNS [M+H+], m / z: 268.4 (100%, M+l), 269.4 (50%, M+2), 270.4 (20%, M+3).

[0210] l-(4,4,4-trifluoro-l-phenylbutan-2-yl)piperidine (Compound 64). Compound 64 was prepared as described for Compound 7 except with (17.90 mmol) 2.14 mL benzyl bromide, (20.50 mmol) 1.34 g Zn dust, (2.23 mmol) 0.65 mL trifluoracetic acid, (9.82 mmol) 0.97 mL piperidine, and (8.93 mmol) 1 g 3,3,3 -trifluoropropanal. The reaction was quenched with ammonium hydroxide and extracted with EtOAc (3x 75 mL) to yield the crude freebase. 50 mL of a 50:50 mixture of hexanes and EtOAc were added to the product, forming a waxy yellowprecipitate. This precipitate was triturated with 3x50 mL 50:50 mixture hexanes and EtOAc and the solvent washes were collected. The presence of the product in the solvent was confirmed by ASAP MS. The solvent was stripped to give the crude freebase as a yellow oil and the product was purified as previously described but with 100%hexanes, to yield 0.36g (16.4% yield) of 1- (4,4,4-trifluoro-l-phenylbutan-2-yl)piperidine. The HC1 salt was formed as previously described, except with MeOH to yield l-(4,4,4-trifluoro-l-phenylbutan-2-yl)piperidine HC1 as a fluffy white crystalline solid (mp: 234.0-235.2 °C).

[0211] Tf NMR (400 MHz, DMSO-d6) 6 11.27 (s, 1NH+), 7.39 (ad, J= 7.1 Hz, 2H), 7.33 (at, J= 7.5 Hz 2H), 7.29-7.21 (m, 1H), 3.72-3.62 (m, 1H), 3.58 (dd, J= 6.34 Hz, 2.43 Hz, 1H), 3.49- 3.34 (m, 2H, overlap with H2O), 3.31 (dd, J= 11.9, 3.3 Hz, 1H), 3.20-3.09 (m, 1H), 3.09-2.97 (m, 1H), 2.92 (dd, J = 13.2 Hz, 10.1 Hz, 1H), 2.75-2.57 (m, 1H), 2.04 (qt, J = 13.1, 3.7, 1H),1.96 (qt, J= 13.1, 3.9 Hz 2H), 1.80 (d, J= 14.0 Hz, 2H), 1.71 (d, = 12.7 Hz, 1H), 1.44 (qt, J = 13.2, 3.9 Hz, 1H).13C NMR (100.6 MHz, DMSO-d6) 135.82 (1C), 125.68 (q, 1CF3), 129.41 (2C), 128.47 (2C), 126.98 (1C), 60.59 (q, = 2.1 Hz, 1C), 49.92 (1C), 47.28 (1C), 36.19 (1C), 31.90 (q, .7 = 29.04 Hz, 1C), 22.50 (d, J = 2.00 Hz, 1C), 21.18 (1C). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 96.6%. MS ASAP: calc for CI5H2OF3N, m / z: 272.4 (100%, M+l), 273.4 (80%, M+2).

[0212] 4-(l-(m-tolyl)pentan-2-yl)thiomorpholine (Compound 72). Compound 72 was prepared as described for Compound 7 except with (27.74 mmol) 3.74 mL 3 -methylbenzyl bromide, (31.90) mmol 2.09 gZn dust, (3.47) mmol 0.26 mL trifluoroacetic acid, (15.25 mmol) 1.54 mL thiomorpholine, and (13.87 mmol) 1.25 mL butyraldehyde to yield the crude freebase. The freebase was purified as previously described but with a ratio of 90:10 hexanes:EtOAc to yield 0.68 g(18.5% yield) of 4-(l-(m-tolyl)pentan-2-yl)thiomorpholine as a yellow oil. The HC1 salt was formed as previously described to yield 4-(l-(m-tolyl)pentan-2-yl)thiomorpholine HC1 as a off-white crystalline solid (mp: 183.4-184.2 °C).

[0213] Tf NMR (400 MHz, DMSO-d6) 6 = 11.15 (s, 1NH+), 7.21 (t, J = 7.5 Hz, 1H), 7.17 (s, 1H), 7.13 (d, .7 = 7.6 Hz, 1H), 7.06 (d, .7 = 7.5 Hz, 1H), 3.71 (t, = 9.42 Hz, 2H), 3.57-3.38 (m, 4H, overlap with H2O), 3.31-3.14 (m, 2H), 2.83-2.70 (m, 3H), 2.29 (s, aromatic CH3), 1.92-1.80 (m, 1H), 1.59-1.46 (m, 1H), 1.15-1.00 (m, 1H), 0.99-0.83 (m, 1H), 0.68 (t, .7=7.3 Hz, CH3).13C NMR (100.6 MHz, DMSO-d6) 6 = 137.60 (1C), 137.15 (1C), 129.71 (1C), 128.38 (1C), 127.37 (1C), 126.23 (1C), 67.28 (1C), 50.74 (1C), 50.40 (1C), 34.99 (1C), 31.08 (1C), 24.01 (1C),23.96 (1C), 2O.96(1C), 19.88 (1C), 13.65 (1C). HPLC purity (70:30 Formate buff er:ACN, 220 nm): 98.7%. MS ASAP, calcd for CI6H25NS m / z: 264.4 (100%, M+l), 265.4 (50%, M+2), 266.4 (20%, M+3).

[0214] l-(l-(3-fluorophenyl)-3-methylbutan-2-yl)piperidine (Compound 69). Compound69 was prepared as described for Compound 7 except with (27.74 mmol) 3.40 mL 3- fluorobenzyl bromide, (31.90) mmol 2.09 gZn dust, (3.48) mmol 0.26 mL trifluoroacetic acid, (15.25 mmol) 1.51 mL piperidine, and (13.87 mmol) 1.27 mL isobutyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with (3x 75 mL) EtOAc. The pooled organic layers were then extracted with (3x 100 mL) IN HC1. The pooled aqueous layers were basified with ammonium hydroxide and extracted with (3x 75 mL) EtOAc to yield the crude freebase. The freebase was purified by flash column chromatography as described but with a ratio of 90:10 hexanes:EtOAc to yield 1.72 g (49.7% yield) of l-(l-(3-fluorophenyl)-3- methylbutan-2-yl)piperidine as a pale yellow oil. The HC1 salt was formed as described to yield 1-(1 -(3 -fluorop henyl)-3-methy lb utan-2-yl)piperidineHCl as an off-white crystalline solid (mp: 170.4-171.1 °C).

[0215] JH NMR (400 MHz, DMSO-d6) 8 = 10.93 (bs, 1NH+), 7.38 (td, J = 8.0, 6.3 Hz, 1H), 7.27 (dt, J = 10.5, 2.1 Hz, 1H), 7.22 (d, J = 1.1 Hz, 1H), 7.07 (td, J = 8.6, 2.6 Hz, 1H), 3.59-3.51 (m, 1H), 3.42-3.30 (m, 2H, overlap with H2O), 3.09-2.89 (m, 3 H), 2.38 (septd, J = 6.9, 2.2 Hz, 1H), 2.08-1.88 (m, 2H), 1.80-1.63 (m, 3H), 1.38 (qt, J = 12.9, 3.6 Hz, 1H), 1.03 (d, J= 6.8 Hz, 3H), 0.77 (d, 7.1 Hz, 3H).13CNMR (100.6 MHz, DMSO-d6) 6 = 162.23 (d, J = 242.4 Hz, 1C), 141.65 (d, = 7.4 Hz, 1C), 130.43 (d, = 8.2 Hz, 1C), 125.00 (d, J = 2.5 Hz, 1C), 115.53 (d, .7= 21.2 Hz, 1C), 113.37 (d, J= 21.1 Hz, 1C), 70.31 (1C), 50.42 (1C), 49.71 (1C), 30.72 (1C), 26.92 (1C), 22.40 (d, J= 15.64 Hz, 1C), 21.76 (1C), 21.41 (1C), 17.44 (1C). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 97.3%. MS ASAP, calcd for CI6H24FN m / z: 250.4 (100%, M+l), 251.4 (70%, M+2).

[0216] l-(3-methyl-l-(o-tolyl)butan-2-yl)piperidine (Compound 67). Compound 67 was prepared as described for Compound 7 except with (27.74 mmol) 3.71 mL 2 -methylbenzyl bromide, (31.90) mmol 2.09 gZn dust, (3.48) mmol 0.26 mL trifluoroacetic acid, (15.25 mmol)1.51 mL piperidine, and (13.87 mmol) 1.27 mL isobutyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with (3x 75 mL) EtOAc. The pooled organic layers were then extracted with (3x 100 mL) IN HC1. The pooled aqueous layers were basified with ammonium hydroxide and extracted with (3x 75 mL) EtOAc to yield the crude freebase. The freebase was purified as previously described to yield 2.22 g (65.1% yield) of pure l-(3-methyl- l-(o-tolyl)butan-2-yl)piperidine as a pale yellow oil. The HC1 salt was formed as previously described to yield 1 -(3 -methyl- l-(o-tolyl)butan-2-yl)piperidine HC1 as a crystalline white solid (mp: 184.4-185.5 °C).

[0217] JH NMR (400 MHz, DMSO-d6) 5 = 10.31 (bs, 1NH+), 7.38-7.31 (m, 1H), 7.20-7.11 (m, 3H), 3.64-3.57 (m, 1H), 3.43 (d, J= 12.0 Hz, 1H), 3.34-3.23 (m, 2H, overlap with H2O), 3.04- 2.88 (m, 3H), 2.38 (ddd, .7 = 7.2, 1.9 Hz, 3H overlap with 2.35), 2.35 (s, 1CH3, overlap with 2.38), 2.07-1.93 (m, 2H), 1.79-1.71 (m, 1H), 1.71-1.61 (m, 2H), 1.36 (qt, J= 12.5, 4.1 Hz, 1H), 1.04 (d, J= 6.82 Hz, 1CH3), 0.84 (d, J= 7.02 Hz, 1CH3).13C NMR (100.6 MHz, DMSO-d6) 5 = 136.47 (1C), 135.88 (1C) 130.58 (1C), 128.92 (1C), 126.54 (1C), 125.93 (1C), 69.18 (1CH), 50.94 (1CH2), 49.93 (1CH2), 28.23 (1CH2), 27.02 (1CH), 22.37 (1CH2), 22.14 (1CH2), 21.43 (1CH2), 20.96 (1CH3), 19.63 (1CH3), 17.14 (1CH3) HPLC purity (70:30 Formate buffer: ACN, 220 nm): 99.0% MS ASAP, calcd for CI7H27N m / z: 246.4 (100%, M+l).

[0218] 4-(l-(2-bromophenyl)pentan-2-yl)thiomorpholine (Compound 71). Compound 70 was prepared as described for Compound 7 except with (13.90 mmol) 3.47 g 2-bromobenzyl bromide and (7.63 mmol) 0.77 mL thiomorpholine to yield the crude freebase. The freebase was purified as previously described to yield 0.45 g (19.7% yield) 4-(l-(2-bromophenyl)pentan-2- yl)thiomorpholine freebase as a pale yellow oil. The HC1 salt was formed as previously described to yield 4-(l-(2-bromophenyl)pentan-2-yl)thiomorpholineHCl as a chalky white solid (mp: 226.3-227.5 °C).

[0219] JH NMR (400 MHz, DMSO-d6) 5 (100.6 MHz, DMSO-d6) 5 = 11.34 (s, 1H), 7.63 (dd, J = 8.1 Hz, 0.9 Hz, 1H), 7.56 (dd, .7 = 7.7 Hz, 1.1 Hz, 1H), 7.38 (td, J= 7.6 Hz, 1.3 Hz, 1H), 7.22 (td, .7= 7.8 Hz, 1.4 Hz, 1H), 3.74 (d, J= 11.8 Hz, 2H), 3.62-.3.47 (m, 3H), 3.40-3.23 (m, 2H), 3.06 (td, J= 11.8, 2.4 Hz, 1H), 2.84-2.74 (m, 2H), 1.99-1.87 (m, 1H), 1.66-1.54 (m, 1H), 1.12- 0.95 (m, 1H), 0.82-0.68 (m, 1H, overlap with 0.66), 0.66 (t, J = 7.2 Hz).13C NMR (100.6 MHz, DMSO-d6) 5 = 136.07 (1C), 132.82 (1C), 132.10 (1C), 129.23 (1C), 128.02 (1C), 124.05 (1C), 65.86 (1C), 51.39 (1C), 49.81 (1C), 34.54 (1C), 31.24 (1C), 24.01 (1C), 23.96 (1C), 20.02 (1C), 13.60 (1C). HPLC purity (70:30 Formate buffer: ACN, 220 nm): 98.9%. MS ASAP: calcd for Ci5H22BrNS m / z: 328.4 (90%), 329.5 (20%, M+l), 330.4 (100%, M+2), 331.4 (20%, M+3).

[0220] l-(l-(2-bromophenyl)-3-methylbutan-2-yl)piperidine (Compound 74). Compound 74 was prepared as described for Compound 7 except with (13.90 mmol) 3.47 g 2- bromobenzyl-bromide and (6.93 mmol) 0.63 mL isobutyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with (3x 75 mL) EtOAc. The pooled organic layers were then extracted with (3x 100 mL) 1NHC1. The pooled aqueous layers were made basic with ammonium hydroxide and extracted with (3x 75 mL) EtOAc to yield the crude freebase as an amber oil. The freebase was purified by column chromatography as described to yield 0.50 g (23.3% yield) of pure l-(l-(3-fhrorophenyl)-3-methylbutan-2-yl)piperidine as a pale yellow oil.The HC1 salt was formed as described to yield 1 -(l-(2-bromophenyl)-3-methylbutan-2- yl)piperidine HC1 as an off-white crystalline solid (mp: 245.0-245.6 °C).

[0221] Tf NMR (400 MHz, DMSO-d6) 6 = 10.12 (s, 1NH+), 7.64 (dd, J= 8.0 Hz, 1.3 Hz 1H), 7.60 (dd, = 7.8, 1.7 Hz, 1H) 7.40 (td, J = 7.5 Hz, 1.3 Hz, 1H), 7.22 (td, J= 7.7 Hz, 1.7 Hz), 3.72-3.64 (m, 1 CH), 3.47-3.31 (m, 3H, overlap with H2O), 3.18 (dd,J= 15.4, 7.8 Hz, 1H), 3.08- 2.95 (m, 2H), 2.43 (sepd, = 6.8, 2.3 Hz, 1CH), 2.06-1.88 (m, 2H), 1.81-1.62 (m, 3H), 1.37 (qt, J= 13.0, 3.6 Hz, 1H), 1.06 (d, J= 6.8 Hz, 1CH3), 0.82 (d, J= 7.0 Hz, 1CH3).13C NMR (100.6 MHz, DMSO-d6) 5 = 137.25 (1C), 133.09 (1C), 131.28 (1C), 128.92 (1C), 127.98 (1C), 123.76 (1C), 69.55 (1CH), 50.62 (1CH2), 50.49 (1CH2), 30.83 (1CH2), 27.42 (1CH), 22.53 (1CH2), 22.37 (1CH2), 21.36 (1CH2), 21.11 (1CH3), 17.36 (1CH3). HPLC purity (70:30 Formate bufferACN, 220nm): 98.0% MS ASAP: calcd for Ci6H24BrN m / z: 310.4 (100%), 311.5 (20%, M+l), 312.5 (75%, M+2), 313.4 (20%, M+3).

[0222] l-(l-(2-bromo-5-chlorophenyl)pentan-2-yl)piperidine (Compound 60). Compound 59 was prepared as described for Compound 7 except with (13.90 mmol) 3.94 g l-bromo-2- (bromomethyl)-4-chlorobenzene to yield crude freebase. The freebase was purified by flash column chromatography as described but with a ratio of 90:10 hexanes:EtOAc to yield 0.78 g (32.6% yield) of pure l-(l-(2-bromo-5-chlorophenyl)pentan-2-yl)piperidine as a transparent colorless oil. The HC1 salt was formed as previously described to yield 1 -(l-(2-bromo-5- chlorophenyl)pentan-2-yl)piperidine HC1 as a white crystalline solid (mp: 191.4-192.4 °C).

[0223] JH NMR (400 MHz, DMSO-d6) 5 = 10.64 (bs, 1NH+), 7.73 (d, = 2.6 Hz, 1H), 7.66 (d, J= 8.6 Hz, 1H), 7.31 (dd, J= 8.6 Hz, 2.6 Hz, 1H), 3.51-3.34 (m, 4H, overlap with H2O), 3.16- 3.00 (m, 3H), 2.09-1.92 (m, 2H), 1.92-1.83 (m, 1H, overlap with 1.84-1.67), 1.85-1.74 (m, 2H, overlap with 1.92-1.83), 1.74-1.69 (m, 1H), 1.64-1.52 (m, 1H), 1.44 (qt, J = 13.1, 3.5 Hz, 1H), 1.11-0.97 (m, 1H), 0.85-0.71 (m, 1H), 0.68 (t, J= 7.03 Hz, 1CH3).13C NMR (100.6 MHz, DMSO-d6) 5 = 138.69 (1C), 134.31 (1C), 132.64 (1C), 131.47 (1C), 128.99 (1C), 122.46, 64.36 (1CH), 49.15 (1CH2), 48.57 (1CH2), 34.66 (1CH2), 31.00 (1CH2), 22.53 (1CH2), 22.50 (1CH2), 21.5O (1CH2), 19.96 (1CH2), 13.64 (1CH3). HPLC purity (70:30 Formate bufferACN, 220 nm): 98.4% MS ASAP: calcd for Ci6H23BrClN m / z: 344.4 (90%), 345.5 (20%, M+l), 346.4 (95%, M+2), 347.5 (25%, M+3), 348.5% (35%, M+4).

[0224] l-(l-(2-bromophenyl)pentan-2-yl)azepane (Compound 70). Compound 70 was prepared as described for Compound 7 except with (13.90 mmol) 3.47 g 2-bromobenzyl bromide, (7.63 mmol) 0.86 mL azepane. The reaction was quenched with ammonium hydroxide and extracted with (3x 75 mL) EtOAc to yield the crude freebase. The freebase was purified by flash column chromatography as described but with 100% hexanes gradated to a ratio of 95:5hexanes:EtOAc over 6 CVs to yield 1 .61 g (71.6% yield) of pure 1 -(1 -(2-bromophenyl)pentan- 2-yl)azepane as a transparent colorless oil. The HCl salt was formed as previously described to yield l-(l-(2-bromophenyl)pentan-2-yl)azepane HC1 as a white crystalline powder (mp: 177.7-178.5 °C).

[0225] JH NMR (400 MHz, DMSO-d6) 5 = 10.58 (s, 1NH+), 7.61 (dd, = 8.0 Hz, 1.3 Hz, 1H), 7.59 (dd, J= 7.7, 1.7 Hz, 1H) 7.38 (td, J= 7.5 Hz, 1.3 Hz, 1H), 7.23 (td, J= 7.7 Hz, 1.7 Hz, 1H), 3.52-3.35 (m, 4H, overlap with H2O), 3.33-3.20 (m, 2H, overlap with H2O), 3.05 (dd, J = 13.9, 11.6 Hz), 2.10-1.96 (m, 2H), 1.93-1.79 (m, 3H), 1.78-1.66 (m, 2H, overlap with 1.67- 1.54), 1.67-1.54 (m, 3H, overlap with 1 .78-1 .66), 1.06-0.92 (m, 1H), 0.67-0.65 (m, 1H, overlap with 0.64), 0.64 (t, J= 3.5 Hz, 1CH3, overlap with 0.67-0.65).13C NMR (100.6 MHz, DMSO-d6) 5 = 136.13 (1C), 132.77 (1C), 132.19 (1C), 129.20 (1C), 127.98 (1C), 124.11 (1C), 66.00 (1CH), 51.68 (1CH2), 50.21 (1CH2), 34.88 (1CH2), 31.64 (1CH2), 25.65 (1CH2), 25.44 (1CH2), 23.99 (1CH2), 23.93 (1CH2), 20.19 (1CH2), 13.65 (1CH3). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 99.1%MS ASAP: calcd for Ci7H26BrN m / z: 324.5 (100%), 325.5 (20%, M+l), 326.5 (90%, M+2), 327.5 (25%, M+3)

[0226] 4-(l-(2-iodophenyl)pentan-2-yl)piperidine (Compound 62). Compound 62 was prepared as described for Compound 7 except with (27.74 mmol) 8.24 g 2-iodobenzyl bromide, (31.90) mmol 2.09 gZn dust, (3.48) mmol 0.26 mL trifluoroacetic acid, (15.25 mmol) 1 .54 mL piperidine, and (13.87 mmol) 1.25 mL butyraldehyde to yield the crude freebase. The freebase was purified as previously described to yield 1 .47 g (29.6% yield) of 4-(l-(2-iodophenyl)pentan- 2-yl)piperidine as a colorless transparent oil. The HC1 salt was formed as previously described to yield 4-(l-(2-iodophenyl)pentan-2-yl)piperidine HC1 as a chalky white solid, (mp: 249.3-250.1 °C).

[0227] Tf NMR (400 MHz, DMSO-d6) 6 = 10.51 (s, 1NH+), 7.87 (dd, J= 7.9 Hz, 1.3 Hz, 1H), 7.50 (dd, 7 = 7.7 Hz, 1.7 Hz, 1H), 7.39 (td, J= 7.5 Hz, 1.3 Hz, 1H), 7.03 (td, 7= 7.6 Hz, 1.7 Hz), 3.48-3.36 (m, 4H, overlap with H2O), 3.21-3.05 (m, 2H, overlap with 3.02), 3.02 (dd, J = 11.6,6.5 Hz Hz, overlap with 3.21 -3.05), 2.09-1.90 (m, 2H), 1.90-1.75 (m, 3H), 1.76-1.67 (m, 1H), 1.66-1.54 (m, 1H), 1.44 (qt, J= 13.0, 3.8 Hz, 1H), 1.11-0.94 (m, 1H), 0.78-0.68 (m, 1H, overlap with 0.65), 0.65 (t, J = 6.6 Hz, 1CH3, overlap with 0.78-0.68).13C NMR (100.6 MHz, DMSO-d6) 5 = 139.48 (1C), 131.17 (1C), 129.12 (1C), 128.60 (1C), 101.36 (1C), 64.86 (1CH), 49.63 (1CH2), 48.34 (1CH2), 38.93 (1CH2), 31.17 (1CH2), 22.57 (1CH2), 22.55 (1CH2), 21.49 (1CH2), 20.02 (1CH2), 13.65 (1CH3). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 99.1% MS ASAP: calcd for CI6H24IN m / z: 358.5 (100%, M+l), 359.7 (20%, M+2).

[0228] l-(l-(2-bromophenyl)hexan-2-yl)piperidine (Compound 66). Compound 66 was prepared as described for Compound 7 except with (45.00 mmol) 11.25 g 2 -bromobenzyl bromide, (51.70) mmol 3.38 gZn dust, (5.62) mmol 0.43 mL trifluoroacetic acid, (22.50 mmol) 2.44 mL piperidine, and (22.50 mmol) 2.39 mL valeraldehyde. The reaction was quenched with ammonium hydroxide and extracted with (3x 75 mL) EtOAc to yield the crude freebase. The freebase was purified as previously described but with a ratio of 90: 10 hexanes:EtOAc to yield 1.07 g (14.7% yield) of pure l -(l-(2-bromophenyl)hexan-2-yl)piperidine as a pale yellow oil. The HC1 salt was formed as previously described to yield l -(l-(2-bromophenyl)hexan-2- yl)piperidine HC1 as a fine white crystalline solid (mp: 141.3 -141.7 °C).

[0229] 'HNMR (400 MHz, DMSO-d6) 5 10.62 (s, 1NH+), 7.63 (dd, J= 8.0, 1.3 Hz, 1H), 7.55 (dd, J = 7.6, 1.7 Hz, 1H), 7.38 (td, J = 7.5 Hz, 1.3 Hz, 1H), 7.23 (td, J= 7.8 Hz, 1.7 Hz, 1H), 3.49-3.35 (m, 4H), 3.19-3.08 (m, 1H, overlap with 3.04), 3.04 (dd, J= 10.7, 6.7 Hz, 2H), 2.10- 1.93 (m, 2H, overlap with 1.93-1.67), 1.93-1.67 (m, 4H, overlap with 2.10-1.93), 1.66-1.54 (m, 1H), 1.44 (qt, J= 13.2, 3.9 Hz, 1H), 1.12-0.96 (m, 3H), 0.74-0.60 (m, 1H, overlap with 0.66), 0.66 (t, J= 6.87 Hz, 1CH3).13C NMR (100.6 MHz, DMSO-d6) 5 = 136.24 (1C), 132.79 (1C), 132.11 (1C), 129.15 (1C), 127.98 (1C), 124.08 (lC), 64.78 (1CH), 49.50 (1CH2), 48.31 (1CH2), 34.74 (1CH2), 28.77 (1CH2), 28.70 (1CH2), 22.50 (1CH2), 21.80 (1CH2), 21.51 (1CH2), 13.44 (1CH3). HPLC purity (70:30 Formate buffer:ACN, 220 nm): 99.3%. MS ASAP, MW: calcd for Ci7H26BrN m / z: 324.5 (100%), 325.5 (20%, M+l), 326.5 (90%, M+2), 327.6 (25%, M+3).

[0230] l-(l-(2,3,6-trifluorophenyl)pentan-2-yl)piperidine (Compound 74). Compound 74 was prepared as described for Compound 7 except with (20.80 mmol) 2.72 mL 2,3,6- triflouorobenzyl bromide, (23.92) mmol 1.56 g Zn dust, (2.60) mmol 0.20 mL trifluoroacetic acid, (11.44 mmol) 1.13 mL piperidine, and (10.40 mmol) 0.93 mL butyraldehyde. The reaction was quenched with ammonium hydroxide and extracted with (3x 75 mL) EtOAc. The pooled organic layers were then extracted with (3x 100 mL) IN HC1. The pooled aqueous layers were basified with ammonium hydroxide and extracted with (3x 75 mL) EtOAc to yield the crude freebase. The freebase was purified as previously described but in 100% hexanes, gradated to a ratio of 70:30 hexanes:EtOAC over 8 CVs to yield 1.42 g (47.8% yield) of pure 1 -(1 -(2,3,6- trifluorophenyl)pentan-2-yl)piperidine as a slightly yellow-tinted transparent oil. The HC1 salt was formed as previously described to yield 1 -(l-(2,3,6-trifluorophenyl)pentan-2-yl)piperidine HC1 as a fluffy white crystalline solid (mp: 179.6-180.1 °C).

[0231] Tf NMR (400 MHz, DMSO-d6) 6 10.69 (s, 1 NH+), 7.49 (qd, = 9.5, 5.1 Hz, 1H), 7.20 (tdd, J= 9.3, 3.9 Hz, 1H), 3.47-3.36 (m, 3H, overlap with H2O), 3.34-3.26 (m, 1H, overlap with H2O), 3. 15-2.97 (m, 3H), 2.09-1.94 (m, 2H, overlap with 1.94-1.84), 1.94-1.84 (m, 1H, overlapwith 2.09-1.94), 1.83-1.67 (m, 3H), 1.57-1.46 (m, 1H, overlap with 1.47-1.36), 1.47-1.36 (m, 1H, overlap with 1.57-1.46), 1.25-1.10 (m, 1H), 1.01 -0.91 (m, 1H), 0.73 (t, 7= 7.3 Hz, CH3).13C NMR (100.6 MHz, DMSO-d6) 5 = 156.27 (ddd, 7= 242.6, 6.2, 2.2 Hz, 1C), 148.32 (ddd, J = 247.1, 14.5, 9.0 Hz, 1C), 146.47 (ddd, J= 243.0, 11.0, 3.3 Hz, 1C), 116.66 (dd, J = 19.3, 10.2 Hz, 1C), 114.85 (dd, 7= 22.0, 16.1 Hz, 1C), 111.58 (ddd, 7 = 25.0, 6.9, 3.9 Hz, 1C), 63.75 (1CH), 49.34 (1CH2), 48.55 (1 CH2), 31.40 (1CH2), 22.68 (1 CH2), 22.41 (1CH2), 22.36 (1CH2), 21.47 (1CH2), 19.7O (1CH2), 13.63 (1CH3).19F NMR (376.5 MHz, DMSO- d6) 5 = -118.34 (d, J = 16.0 Hz, IF), -137.10 (d, J= 21 .8 Hz, IF), -142.36 (dd, J = 15.2, 11.4 Hz, IF). MS ASAP: CI6H22F3N m / z: 286.5 (100%, M+l), 287.5 (20%, M+2).

[0232] \. \-diethyl-l -phenylpentan-2-amine (Compound 1). A,A-diethyl-l-phenylpentan-2- amine was prepared as described for Compound 7 except with (16.8 mmol) 1.09 g Zn dust, (1.72 mmol) 0.132 mL trifluoroacetic acid and (16.8 mmol), 1.70 mL benzyl bromide, (7.63 mmol) 0.790 mL diethylamine, and (6.93 mmol) 0.625 mL butyraldehyde to yield 1.17 g of a clear, colorless oil. The freebase was directly dissolved in acetone (~40 mL) and concentrated HC1 (0.488 mL, 1. 1 equiv) was then added while mixing. The solvent was then removed under warm air flow. Additional acetone was added and evaporated several times until the resulting white solids were free of excess water and HC1. The resulting salt was washed Et2O (3 x 10 mL) and crystallized by dissolving in a minimal volume of hot acetone and diluting with ~10- volumes of Et2O. The solution was stored at -20°C resulting in white, crystalline solids. The solvent was decanted and the solids were washed with Et2O (3 x 10 mL). The solids were dried with gentle heating, placed in an oven (70 °C) for 4 h, and further dried in a vacuum oven overnight to yield 890 mg of A,A-diethyl-l-phenylpentan-2-amine HC1 (49.0% yield) as a white crystalline solid.

[0233] Tf NMR (400 MHz, DMSO-d6) 8 10.41 + 10.30 (2 x bs, 1NH+), 7.37-7.30 (m, 4H), 7.29-7.21 (m, 1H), 3.49-3.40 (m, 1H), 3.40-3.31 (m, 1H, overlap with H2O), 3.25-3.08 (m, 4H), 2.82 (dd, 7= 13.3, 9.9 Hz, 1H), 1.84-1.69 (m, 1H), 1.62-1.46 (m, 1H), 1.33 (q, 7 = 7.5 Hz, 6H), 1.19-1.00 (m, 1H), 0.99-0.82 (m, 1H), 0.68 (t, 7 = 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO- d6) 8 137.37 (1C), 129.16 (2C), 128.55 (2C), 126.76 (1C), 62.16 (1C), 45.06 (1C), 44.90 (1C), 34.98 (1C), 30.97 (1C), 19.73 (1C), 13.66 (1C), 10.15 (1C), 10.06 (1C). HPLC purity (50:50 Formate buffer:ACN, 220 nm): 100%. HRMS: m / z calcd for CI6H26N [M + H]+, 220.2060; found 220.2058, Appm = -0.90.

[0234] 4-(l-Phenylpentan-2-yl)thiomorpholine (Compound 2). 4-(l-Phenylpentan-2- yl)thiomorpholine was prepared as described for Compound 1 except with (7.62 mmol) 0.767 mL thiomorpholine. The acid / base extraction was performed with 5% acetic acid rather than INHC1. The freebase was used as is and converted to the HC1 salt as previously described and crystallized twice from acetone:Et2O to yield 770 mg (39.0% yield) of 4-(l-phenylpentan-2- yl)thiomorpholine HC1 as a light brown crystalline solid, (mp: 143.8-144.7 °C).

[0235] !H NMR (400 MHz, DMSO-d6) 5 = 11.27 (bs, 1NH+), 7.38-7.29 (m, 4H), 7.27-7.20 (tm, J= 1A Hz, 1H), 3.71 (dd, J = 12.2, 2.2 Hz, 2H), 3.52 (ddd, J = 15.0, 12.2, 2.1 Hz, 2H overlap with 3.49-3.40), 3.49-3.40 (tm, J= 12.6 Hz, 2H, overlap with 3.52), 3.31 -3.15 (m, 2H), 2.86-2.68 (m, 3H), 1.94-1.80 (m, 1H), 1.60-1.46 (m, 1H), 1.12-0.97 (1H), 0.97-0.80 (m, 1H), 0.66 7.3 Hz, 3H).13C NMR (100.6 MHz, DMSO-d6) 8 = 137.28 (1C), 129.18 (2C),128.50 (2C), 126.73 (1C), 67.30 (1C), 50.68 (1C), 50.46 (1C), 35.11 (1C), 31.01 (1C), 23.99 (1C), 23.94 (1C), 19.90 (1C), 13.63 (1C). HPLC purity (50:50 Formate buff er:ACN, 220 nm): 97.8%. HRMS: m / z: calcd for CI5H24NS [M + H]+, 250.1624; found 250.1624, Appm = 0.00.

[0236] 3,5-Dimethyl-l-(l-phenylpentan-2-yl)piperidine (Compound 3). 3, 5 -Dimethyl- 1-(1- phenylpentan-2-yl)piperidine was prepared as described for Compound 1 except with (7.60 mmol) 1.01 mL 3, 5 -dimethylpiperidine (mixture of cis and trans isomers). The freebase was directly converted to the HC1 salt previously described and crystallized 3X from acetone :Et2O to yield 1.01 g(51.7% yield) of 3,5-dimethyl-l-(l-phenylpentan-2-yl)piperidine HC1 as a fluffy, white crystalline solid and as an approximate 65:35 mixture of diastereomers as determined by HPLC.

[0237] HPLC purity (50:50 Formate buffer:ACN, 220 nm): 97% (64.3% and 32.7%). HRMS: m / z: calcd for CI8H30N [M + H]+, 260.2373; found 260.2371, Appm = -0.76.

[0238] (2S)-2-Methyl-l-(l-phenylpentan-2-yl)piperidine (Compound 55). (2S)-2-Methyl-l- (l-phenylpentan-2-yl)piperidine was prepared as described for Compound 7 except with (18.5 mmol) 2.20 mL benzyl bromide, (21.4 mmol) 1.4 g Zn dust, (2.28 mmol) 0.175 mL trifluoroacetic acid, (10.1 mmol) 1.0 g S-2 -methylpiperidine, and (9.17 mmol) 0.826 mL butyraldehyde. The freebase was purified via flash chromatography (hexanes :EtO Ac 90:10 to 80:20) and concentrated to afford (2S)-2-methyl-l-(l-phenylpentan-2-yl)piperidine0.45 g (20% yield) as a clear, colorless oil. The freebase was converted to the HC1 salt as previously described except with EtOH (30 mL) and crystallized 3X from EtOH:Et2O to yield (2S)-2- methyl-l-(l-phenylpentan-2-yl)piperidine HC1 as a shiny white crystalline solid, (mp: 221.1 - 221.4 °C).

[0239] HPLC purity (50:50 Formate buffer:ACN, 220 nm): 100%. ASAP MS: m / z: found for CI7H28N; 246.2 [M + H]+ (100), 247.2 [M + 2]+ (20).

[0240] l-Methyl-4-(l-phenylpentan-2-yl)piperazine (Compound 56). 4-Methyl-l-(l- phenylpentan-2-yl)piperidine was prepared as described for Compound 1 except with (7.61mmol) 0.902 mL 4-methylpiperidine. The freebase was directly converted to the HC1 salt previously described and crystallized 3X from acetone:Et2O to yield 1.01 g (51.7% yield) of 4- methyl-l-(l-phenylpentan-2-yl)piperidine HC1 as a fluffy, white solid . (mp: 195.5-196.1 °C).

[0241] iff NMR (400 MHz, DMSO-d6) 5 = 10.52 (m, 1NH+), 7.37-7.28 (m, 4H), 7.27-7.20 (m, 1H), 3.46-3.33 (m, 4H, overlap with H2O), 3.12-2.97 (m, 2H), 2.76 (dd, J= 13.0, 9.9 Hz, 1H), 1.88-1.59 (m, 6H), 1.58-1.44 (m, 1H), 1.11 -0.96 (m, 1H), 0.95-0.82 (m, 1H, overlap with 0.91), 0.91 (d, J= 5.2 Hz, 3H, overlap with 0.95-0.82), 0.667.3 Hz, 3H).13C NMR (100.6MHz, DMSO-d6) 6 137.51 (1C), 129.12 (2C), 128.48 (2C), 126.67 (1C), 65.86 (1C), 48.68 (1C), 48.33 (1C), 35.46 (1C), 30.97 (1C), 3O.62 (1C), 30.60 (1C), 28.27 (1C), 21 .08 (1C), 19.90 (1C), 13.62 (1C). HPLC purity (50:50 Formate buffer: ACN, 220 nm): 100%. HRMS: m / z: calcd for CI7H28N [M + H]+, 246.2216 ; found 246.2217, Appm = 0.40.

[0242] Example 2: NMDA Receptor Competitive Radioligand Binding Studies

[0243] Thawed (stored in a -80 °C freezer prior to use) Sprague-Dawley rat forebrains from 7- 8 week old rats (BioChemed, USA) were homogenized using a mechanical homogenizer (Janke- Kunkel Ultra-Turrax T25) in a 10 mM HEPES and 1 mM EDTA buffer (pH 7.4). For each forebrain, lO mL of buffer was used for all steps involving suspension of the brain homogenate tissue. The resulting brain homogenate was centrifuged (15 minutes at 20,000 RPM and 4 °C). The supernatant was carefully removed and the pellet resuspended in fresh 10 mM HEPES and 1 mM EDTA (pH 7.4) buffer. An effort was made to ensure the tissue was kept cold during this process. The washing step was repeated a total of 5 times. Following the 5thcentrifugation, the 10 mM HEPES and 1 mM EDTA (pH 7.4) buffer was replaced with a buffer containing 10 mM HEPES (pH 7.4). The resulting suspended homogenate was then incubated in a water bath at 37 °C while in the dark (covered with aluminium foil). Centrifugation as described above was then repeated three additional times using the 10 mM HEPES (pH 7.4) buffer. Upon the final resuspension in the HEPES buffer, the resulting homogenate was aliquoted (1 mL aliquots) into plastic microcentrifuge tubes and stored at -80 °C until use (aliquots were discarded after one month). The protein concentration of the homogenate was calculated using the Bradford method via Coomassie protein assay reagent (Sigma, USA) with Bovine Serum albumin (Sigma, USA) as the protein standard.

[0244] On the day of the assay, 10 mM HEPES Buffer (pH 7.4) was prepared. Additionally, a 1 OX stock solution of HEPES buffer (pH 7.4) containing 1 mM glutamate and 0.1 mM glycine was prepared. 10-fold dilutions of test compound, and (+)-MK-801 were prepared as seven concentrations per compound from the range 10-3- 10-11M in HEPES buffer (pH 7.4). At this time, 100 pL of the 1 mM glutamate and 0.1 mM glycine 10X stock solution was added to everywell of a 96 deep-well plate (Nunc polypropylene 2 mL deep-well, Thermo Scientific, USA). Next, 50 pL of 20 nM (+)-[3H]-MK-801 (Perkin Elmer, USA) was added. Each concentration (in 100 pL) of test compound, or 100 pL control stock solutions were then added to their respective wells, dose response curves were obtained in duplicate. (+)-MK-801 (30 pM) was used for non-specific binding and HEPES buffer with a compound was used for total binding At this time, rat forebrain homogenate was thawed and diluted to a concentration of 133 pg / mL in HEPES buffer. 750 pL of this solution (to give a final protein concentration of 100 pg / mL) was added to each well, bringing the total volume of each well up to 1 mL, addition of the protein marked the initiation of the binding assay. Final conditions for each well were as follows: 1 nM (+)-[3H]-MK-801, 100 pM Glutamate, 10 pM glycine, 100 pg of rat forebrain homogenate and test compound (or controls). Plates were then covered with aluminum foil, and placed on a mechanical shaker (250 RPM) and incubated for 2 h at ambient temperature (~25 °C). Next, the protein homogenate with bound radioligand was collected by vacuum filtration using a Unifilter- 96 Cell Harvester (Perkin Elmer, USA) onto presoaked UniFilter-96 GF / C P Microplates (Perkin Elmer). Filters were washed with room temperature 10 mM HEPES buffer (pH 7.4) (3 x 1 mL). Filter plates were then allowed to dry overnight in a fume hood. The next day, the bound tritium was measured using liquid scintillation counting by adding 30 pL MicroScint-0 (Perkin Elmer, USA) to each well. Counts were obtained using a MicroBeta2 Plate Reader scintillation counter (Perkin Elmer, USA) with 6-PMT detectors at 55% efficiency. IC50value estimates were determined in GraphPad Prism 9.3.1 using non-linear regression (single site fit) with logconcentration plotted against percent specific binding. K; values were calculated from the IC50using the equation of Cheng and Prusoff. The Ka value used for MK-801 (1.67 nM), was determined via independent homologous binding experiments. Experiments were always performed in duplicate. (+)-MK-801 was run on each plate as a plate control. N = 1 -4 biological replicates were performed per test compound. Test compounds were prepared as fresh stock for each experiment and generally weighed not less than 3 mg (for mass accuracy). The analytical balance was calibrated before weighing and accuracy confirmed using a 5 mg reference weight (Troemner, PA). Compounds were initially screened at 10 pM and those showing >50% inhibition were evaluated with the full concentration range. Results are presented in Table 2. The inhibition efficacy (expressed in percent (%)) of NMD AR antagonists of the present disclosure relative to MK-801 are presented in Table 3.

[0245] Example 3: Human Serotonin Reuptake Transporter (SERT) Radio-Ligand Binding Studies

[0246] Valiscreen Serotonin Transporter (SERT) (Human) Cell Line (Perkin Elmer, USA) grown in DMEM / F12 media with 10% FBS (Gibco, USA), 0.1 mg / ml Geneticin (Gibco, USA), 1% Glutamax (Gibco, USA), and 1% Penicillin-Streptomycin (Gibco, USA) were used to prepare SERT membrane fractions. Briefly, cells were grown in 150 mm dishes (CellTreat, Massachusetts, USA) and harvested between 70-90% confluency at passages 5-20, to maintain SERT expression. Cells were detached using a buffer containing 1 mM HEPES and 2 mM EDTA (pH 7.4). After detachment, the cells were homogenized using a handheld homogenizer, and the lysate was centrifuged (30 minutes at 30,000 x G, 4°C). The resulting pellet was resuspended in a storage buffer containing 20 mM HEPES, 10 mM MgCG , 0. 1 mM EDTA, 10% Sucrose, pH 7.4, aliquoted and stored in a -80 °C freezer until needed. Protein concentration was determined via the Bradford method using Coomassie protein assay reagent (Sigma, USA) with Bovine Serum albumin (Sigma, USA) as standard.

[0247] Buffer containing 10 mM HEPES, 120 mM NaCl, and 5 mM KC1 (pH 7.4) was prepared. 10-fold serial dilutions of 1 OX stock solutions of test compounds were prepared in this buffer using concentrations from the range of 10-11M to 10'3M, seven concentrations were prepared for each compound being tested in the concentration response experiments. 100 pL of each concentration of test compound was also added to the plate (in duplicate). 30 pM (final concentration) of citalopram is used for non-specific binding and buffer used for total binding A 10X stock solution of 10 nM [3H]-citalopram (Perkin Elmer, USA) (diluted in the above described buffer) was also prepared in the described buffer and 50 pL of this solution added to each well on the plate. To initiate the assay, 750 pL of 5.88 pg / mL SERT membrane prep protein diluted in the above de scribed buffer was added to every well to initiate the experiment brining the final volume to 1 mL. Final conditions for each well are as follows: 0.5 nM [3H]- citalopram and 5 pg / mL of SERT membrane prep protein, non-specific controls contain 30 pM citalopram, total binding controls contain 100 pL buffer in place of test compound and 10 mM HEPES, 120 mM NaCl, and 5 mM KCl (pH 7.4). Each plate contains a full citalopram (MedChem Express, NJ, USA) dose response as a plate control. Compounds are initially screened at 10,000 nM and those showing >50% inhibition of radioligand binding underwent a concentration response experiment. The plates were protected from light with aluminum foil and incubated at ambient temperature (~25 °C) on a mechanical shaker (250 RPM) for 2 hours. After two hours, SERT protein was captured via vacuum filtration using a Unifilter-96 Cell Harvester (Perkin Elmer, USA) over presoaked UniFilter-96 GF / C P Microplates (Perkin Elmer, USA) and filters were washed with room temperature 10 mM HEPES, 120 mM NaCl, and 5 mM KCl buffer (pH 7.4) (3 x 1 mL). The filter plates are then processed further to measure boundradioactivity and ICso / K; calculated as described for NMD AR binding studies previously, dried overnight in a fume hood. Each plate contained a full dose response for citalopram (MedChem Express, NJ, USA) as a plate control. Experiments were performed in duplicate. N = 1 -3 biological replicates per compound. Results are presented in Table 2.

[0248] Example 4: Human Dopamine Reuptake Transporter (DAT) Inhibition Functional Studies

[0249] CHO cells stably expressing human Dopamine Transporter Protein (Valiscreen® Perkin Elmer RBHDATM-K) were cultured in 150 mm Tissue Culture dishes (Cell Treat 229651) at 37 °C and 5% CO2. Ham’s F-12 NutrientMix (Gibco, USA) was supplemented with 10% dialyzed FBS (Gibco, USA), 100 pg / ml Geneticin (Gibco, USA), and 100 units / ml Penicillin and Streptomycin (Gibco, USA) as the culture media. Cells were maintained on a consistent splitting and assay schedule and utilized until passage 30 (no change in control experiments were observed up to this point).

[0250] Cells were detached from their growth dishes using Trypsin-EDTA (0.25%) (Gibco, USA) at 70-80% confluency. The cells were counted and diluted in culture media to a density of 300,000 cells / mL. 200 pl of this mixture was added to each well of a clear bottom, black -walled 96 well plate (Coming 3603, USA). Plates were incubated in the laminar flow hood for one hour prior to being placed in the cell culture incubator in order to encourage even cell distribution across the entire well surface.

[0251] The next day, Krebs-Ringer HEPES (KRH) Buffer pH 7.4 was prepared (10 mM HEPES, 130 mM NaCl, 1.3 mM KCl, 2.2 mM CaCl2, 1.2 mM MgS04, 1.2 mM KH2PO4) and titrated with 6NNaOH. This buffer was stored in a 4°C refrigerator for up to 4 days (after which it was discarded). Additionally, a solution containing KRH buffer and 330 pM Trypan Blue (Sigma T6146-25 G), a solution of 20 mM APP+ (MedChem Express, NJ, USA) dissolved in DMSO, were both prepared. The 20 mM DMSO stock of APP+ was diluted to a working concentration of 40 pM in KRH buffer. DMSO solutions of 40 mM GBR-12935 dihydrochloride (MedChem Express, NJ, USA) and 40 mMtest compounds were also prepared. DMSO solutions of test compounds were then diluted to a range of 400 pM-40 pM in KRH Buffer with 1% additional DMSO added to provide consistent DMSO concentration in all samples. Compounds were initially screened at 10,000 nM. Those showing >50% inhibition of specific fluorescence uptake underwent a full concentration response experiment. Seven total concentrations were used to generate concentration response curves for each compound. The final DMSO concentration in each well was 0.3%. A 400 pM solution of GBR-12935 served as a non-specific fluorescence control to represent the amount of fluorescence present whensubstrate uptake via DAT is maximally inhibited. KRH buffer with DMSO “vehicle control” served as the total fluorescence control to represent the maximum amount of substrate uptake without DAT transporter inhibition.

[0252] At the time of assay, cell media was carefully removed from the wells via pipette aspiration. 100 pL of KRH buffer was then added to all wells. Both controls, non-specific and total fluorescence stock solutions were then added to the plate (50 pL of either 400 pM GBR- 12935 orKRHDMSO buffer respectively). Additionally, GBR-12935 andtest compounds were added to the plate (50 pL for each sample). Concentration responses were run in triplicate for each compound. Next, 50 pL APP+ (final concentration of 10 pM) was added to each well initiating the experiment. Cells were placed in the cell culture incubator for one hour, at which point 20 pL of 330 pM Trypan Blue was added to each well to quench extracellular fluorescence. The cells were then placed in the microplate reader (BioTek Synergy Neo 2), using Gen5 Ver 3.11 software. The reader was preheated to 37 °C and following a brief orbital shake, intracellular fluorescence was measured using a fluorescence intensity reading.Intracellular APP+ was excited at 430 nm and emission read at 510 nm via a bottom read using the extended gain settings and high lamp energy setting. Data was then analyzed in GraphPad Prism 9.3.1 using non-linear regression with log-concentration plotted against percent specific fluorescence. IC50 value estimates were determined from the resulting concentration response curves. Experiments were repeated for a total of N = 1 -3 biological replicates per compound. Results are presented in Table 2.TABLE 2. NMD AR competitive radioligand binding studies in rat forebrain, human SERT competitive radioligand binding studies and human DAT, NET and SERT transporter uptake inhibition assays.TABLE 3. NMD AR competitive radioligand binding using [3H]-MK-801 displacement from rat forebrain. % inhibition of [3H]-MK-801 with 10 pMof compound. Biological replicates, N=l -2.

[0253] While embodiments of the present 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. Itis notintended that the disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions,configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the disclosure shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.-I l l-

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound represented by Formula (I):or a salt thereof, wherein:Ring A is an aryl or a heterocycle; each RAis halogen, NO2, CN, N(Ra)2, -SRa, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, or two RAtaken together with the atoms to which they are bound form a 3 - to 7-membered carbocycle or a 3 - to 9-membered heterocycle; each of R1and R2is independently H, Ci-C6alkyl, Ci-C6alkoxy, C3-C5carbocycle, C2-C5heterocycle, or R1and R2together with the carbon to which they are attached form a 3- to 5-membered carbocycle or a 3- to 5 -membered heterocycle;R3is H, methyl, or ethyl;R4is C3-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C5carbocycle, or C2-C6heterocycle, wherein R4is optionally substituted with a halogen, OH, =0, NRaRb, or Ci-C6alkyl; each RBis independently OH, halogen, Ci-Cio alkyl, C2-Ci0alkenyl, Ci-Cio haloalkyl, Ci-Cio alkoxy, C3-Ci0heteroaryl, Ci-C3alkylene-aryl, Ci-C3alkylene- heteroaryl, -SRa, NRaRb; or two RBtaken together with the atom to which they are attached form a 3 - to 6-membered carbocycle, a 4- to 6-membered heterocycle, or an oxo;Y is C(RB)2, NR6, O, S, or Se;R6is a Ci-Cio alkyl, C2-Ci0alkenyl, Ci-Cio haloalkyl, C3-Ci0heteroaryl, (Ci-C3)- aryl, or (Ci-C3)-heteroaryl, wherein each alkyl, alkenyl, haloalkyl, aryl or heteroaryl is optionally substituted with OH, halogen, Ci-C5alkyl, Ci-C5alkoxy, or -SRa; m is an integer from 1 to 5; n is an integer from 0 to 14; and p is an integer from 0 to 7;wherein each Raand Rbis independently H, Ci-Ce alkylCi-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci-C6heteroalkyl, C3-C10 carbocycle, C3-C10 heterocycloalkyl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl; or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, with the proviso that the compound of Formula I is not:

2. The compound of claim 1, wherein R1and R2are each H.

3. The compound of claims 1 to 2, wherein R4is a C3-C5 alkyl.

4. The compound of claim 3, wherein R4is propyl.

5. The compound of any one of the preceding claims, wherein m is 2.

6. The compound of any one of the preceding claims, wherein Ring A is 5- to 6-membered aryl.

7. The compound of claim 6, wherein Ring A is phenyl.

8. The compound of any one of claims 1 to 5, wherein Ring A is a heteroaryl.

9. The compound of claim 8, wherein the heteroaryl is a bicyclic heteroaryl.

10. The compound of claim 8, wherein the heteroaryl is pyridine, pyrimidine, imidazole, furan, thiophene, thiazole, pyrrole, oxazole, thiazole, triazole, pyrazole, isoxazole, isothiazole, indole, benzofuran, benzothiophene, benzimidazole, benzodioxole, azaindole, azabenzofuran, azabenzothiophene, azabenzimidazole, dihydrobenzofuran, dihydrobenzothiophene, dihydroindole, or benzimidazolone.

11. The compound of claim 10, wherein Ring A is pyridine.

12. The compound of claim 10, wherein Ring A is pyrimidine.

13. The compound of claim 10, wherein Ring A is triazine.

14. The compound of claim 10, wherein Ring A is tetrazine.

15. The compound of claim 10, wherein Ring A is imidazole.

16. The compound of claim 10, wherein Ring A is furan.

17. The compound of claim 10, wherein Ring A is thiophene.

18. The compound of claim 10, wherein Ring A is selenophene.

19. The compound of claim 10, wherein Ring A is thiazole.

20. The compound of claim 10, wherein Ring A is pyrrole.

21. The compound of claim 10, wherein Ring A is oxadiazole.

22. The compound of claim 10, wherein Ring A is oxazole.

23. The compound of claim 10, wherein Ring A is thiazole.

24. The compound of claim 10, wherein Ring A is isoxazole.

25. The compound of claim 10, wherein Ring A is isothiazole.

26. The compound of claim 10, wherein Ring A is pyridone.

27. The compound of claim 10, wherein Ring A is quinoline.

28. The compound of claim 10, wherein Ring A is isoquinoline.

29. The compound of claim 10, wherein Ring A is indole.

30. The compound of claim 10, wherein Ring A is benzofuran.

31. The compound of claim 10, wherein Ring A is benzoxazole.

32. The compound of claim 10, wherein Ring A is benzothiophene.

33. The compound of claim 10, wherein Ring A is benzodiazine.

34. The compound of claim 10, wherein Ring A is benzimidazole.

35. The compound of claim 10, wherein Ring A is benzotriazole.

36. The compound of claim 10, wherein Ring A is benzodioxole.

37. The compound of claim 10, wherein Ring A is azaindole.

38. The compound of claim 10, wherein Ring A is azabenzofuran.

39. The compound of claim 10, wherein Ring A is azabenzothiophene.

40. The compound of claim 10, wherein Ring A is azabenzimidazole.

41. The compound of claim 10, wherein Ring A is dihydrobenzofuran.

42. The compound of claim 10, wherein Ring A is dihydrobenzothiophene.

43. The compound of claim 10, wherein Ring A is dihydroindole.

44. The compound of claim 10, wherein Ring A is benzimidazolone.

45. The compound of claim 8, wherein Ring A is benzodioxole, m is 2, and n is 0.

46. The compound of any one of claims 1 to 8, wherein Ring A is furanyl or thiophenyl.

47. The compound of any one of claims 1 to 7, wherein when Ring A is phenyl, n is from 1 to 10.

48. The compound of any one of claims 1 to 47, wherein RBis OH, =0, halogen, Ci-Cio alkyl, Ci-Cio haloalkyl, Ci-Cio alkoxy, -SRa, NRaRb, or (Ci-C3)-aryl.

49. The compound of any one claims 1 to 48, wherein Y is S.

50. The compound of claim 49, wherein p is at least 1, and RAis halogen or Ci-Cio alkyl.

51. The compound of any one of claims 1 to 48, wherein Y is C(RB)2.

52. The compound of claim 51, wherein two RBtaken together with the carbon to which they are attached form a 5- to 6-membered carbocycle or a 5 - to 6-membered heterocycle.

53. The compound of claim 1 to 7, wherein when Ring A is phenyl, and p is from 1 to 5.

54. The compound of claim 53, wherein each RAis independently halogen, C2-Ci0alkyl, Ci- Cio alkoxy, or Ci-Cio haloalkyl.

55. The compound of claim 53 or 54, wherein p is 1 to 3.

56. The compound of any one of claims 53 to 55, wherein RAis halogen.

57. The compound of any one of claims 53 to 56, wherein p is 2 and each of the two RAgroups is the same.

58. The compound of any one of claims 53 to 57, wherein p is 2 and each of the two RAgroups are different.

59. The compound of any one of claims 49 to 58, wherein RBis OH, =0, NRaRb, -SRa, halogen, Ci-Cio alkyl, Ci-Cio haloalkyl, or Ci-C3alkylene-aryl.

60. The compound of any one of claims 49 to 58, wherein two RBtaken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5 - to 6- membered heterocycle.

61. The compound of any one of claims 1 to 60, wherein m is 3.

62. The compound of claim 61, wherein RAis halogen, C1-C10 alkyl, C1-C10 alkoxy, or Ci- C10 haloalkyl.

63. The compound of any one of claims 61 to 62, wherein RAis F, Cl, Br, or I.

64. The compound of any one of claims 1 to 50 and 53 to 60, wherein Y is NR6, m is 1 or 2.

65. The compound of claim 64, wherein R6is C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C1-C10 alkoxy, C3-C 10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, halogen, C1-C5 alkoxy, or -SRa.

66. The compound of claim any one of claims 1 to 65, wherein RBis methyl.

67. The compound of claim 1, wherein the compound has the structural Formula (la):Formula (la), or a salt thereof, wherein:Ring A is an aryl; each RAis independently halogen, C1-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl; each of R1and R2is independently H or C1-C10 alkyl;R3is -H or methyl;R4is C3-C5 alkyl, C3-C5 carbocycle, or C2-C5heterocycle, wherein R4is optionally substituted with a C1-C3 alkyl;Y is C(RB)2, NR6, O, or S; each RBis independently H, OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-C 10 heteroaryl, Ci-C3alkylene-aryl, or C1-C3 alkylene-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6- membered cyclic ketal or an oxo;R6is C1-C10 alkyl, C2-Ci0alkenyl, C3-C10 heteroaryl, Ci-C3alkylene-aryl, or C1-C3 alkylene-heteroaryl; m is an integer from 1 to 5; n is an integer from 0 to 14; andp is an integer from 0 to 5; or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, with the proviso that the compound of Formula I is not:

68. The compound of claim 1, wherein the compound has the structural Formula (lb):or a salt thereof, wherein:Ring A is an aryl; each RAis halogen, Ci-Cio alkyl, Ci-Cio alkoxy, or Ci-Cio haloalkyl; each of R1and R2is independently H or Ci-Cio alkyl;R3is H or methyl;R4is C3-C5 alkyl, C3-C5 carbocycle, or C2-C5 heterocycle, wherein R4is optionally substituted with a C1-C3 alkyl; each RBis independently OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl; or two RBtaken together with the atom to which they are attached form a 3 - to 6-membered carbocycle, 3- to 6-membered heterocycle, or an oxo; n is an integer from 0 to 10; and p is an integer from 0 to 5; or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, with the proviso that the compound of Formula I is not:

69. The compound of claim 67, wherein the compound represented by Formula (II):Formula (II), or a salt thereof, wherein:Ring A is phenyl, furanyl, benzodioxole, naphthyl, or thiophenyl; each RAis independently halogen, C2-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl; each of R1and R2is independently H, methyl, or ethyl, wherein R1and R2are not the same; each RBis independently OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C2-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6-membered carbocycle or a 5- to 6-membered heterocycle; each RBis independently H, OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-C 10 heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6- membered cyclic ketal or an oxo; n is an integer from 0 to 8; and p is an integer from 0 to 5.

70. The compound of claim 69, wherein when n is 0, p is 1.

71. The compound of claim 69 or 70, wherein RAis halogen, methoxy, or CF3.

72. The compound of claim 69, wherein p is 2 or 3.

73. The compound of claim 72, wherein p is 2 and at least of the two RAgroups are halogen.

74. The compound of claim 72 or 73, wherein p is 2 and each of the two RAgroups is the same.

75. The compound of claim 72 or 73, wherein p is 2 and each of the two RAgroups are different.

76. The compound of any one of claims 69 to 75, wherein each RBis independently =O,OH, =0, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C2-Ci0heteroaryl, (C1-C3)- aryl, or (Ci-C3)-heteroaryl, or taken together with the atom to which they are attached form a 5- to 6-membered cyclic ketal.

77. The compound of any one of claims 69 to 75, wherein each RBis independently H, =O,OH, =0, halogen, Ci-Cio alkyl, C2-Ci0alkenyl, Ci-Cio haloalkyl, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5 - to 6-membered cyclic ketal.

78. The compound of any one of claims 69 to 76, wherein RBis methyl, ethyl, methoxy, ethoxy, CF3, CBr3, CH2F, CHF2, CH2Br, CHBr2, CC13, CH2C1, CHC12, OH, F, Cl, Br, or I.

79. The compound of any one of claims 69 to 76, wherein RBis Ci-C6alkyl, haloalkyl, OH, F, or two RBtaken together with the atom to which they are attached form a 5 -membered cyclic ketal or an oxo.

80. The compound of any one of claims 69to 76, eachRBis independently H, =0, OH, =0, halogen, C1-C10 alkyl, C2-Cio alkenyl, C1-C10 haloalkyl, C3-Cio heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together with the atom to which they are attached form a 5- to 6-membered cyclic ketal.81 . The compound of any one of claims 69 to 80, wherein Ring A is phenyl.

82. The compound of claim 69, wherein the compound has the structure:

83. A compound represented by Formula (III):or a salt thereof, wherein: each RAis independently halogen, C2-C10 alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl, C1-C10 haloalkoxy, -SRa, -NRaRb; each of R1and R2is independently H, OH, =0, halogen, C1-C10 alkyl, C1-C10 haloalkyl, -SRa, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3 - to 5-membered heterocycle;R3is -H or methyl;R4is a C3-C10 alkyl, C3-C10 carbocycle, C2-Ci0heterocycle, or C1-C3 haloalkyl, wherein R4is optionally substituted with a C1-C3 alkyl, each RBis independently OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, wherein each aryl or heteroaryl is optionally substituted with OH, -NH2, halogen or C1-C3 alkyl; or two RBtaken together to the carbon to which they are attached form a 5 - or 6-membered carbocycle, a 5- to 6- membered heterocycle, or an oxo; n is an integer from 0 to 10; and p is an integer from 0 to 5, wherein each Raand Rbis independently H, Ci-Ce alkylCi-Ce haloalkyl, Ci-Ce hydroxy alkyl, Ci-C6heteroalkyl, C3-C10 carbocycle, C3-C10 heterocycloalkyl, (Ci-C3)-aryl, or (C1-C3)- heteroaryl; with the proviso that the compound of Formula (III) is not:

84. A compound represented by Formula (Illa):or a salt thereof, wherein: each RAis independently halogen, C2-Ci0alkyl, C1-C10 alkoxy, or C1-C10 haloalkyl, C1-C10 haloalkoxy; each of R1and R2is independently H, or C1-C10 alkyl, or halogen;R4is a C3-C10 alkyl, C3-C10 carbocycle, C2-Ci0heterocycle, or C1-C3 haloalkyl, wherein R4is optionally substituted with a C1-C3 alkyl, each RBis independently OH, halogen, C1-C10 alkyl, C2-Ci0alkenyl, C1-C10 haloalkyl, C3-C10 heteroaryl, (Ci-C3)-aryl, or (Ci-C3)-heteroaryl, or two RBtaken together to the carbon to which they are attached form a 5- or 6-membered cyclic ketal or an oxo; n is an integer from 0 to 10; and p is an integer from 0 to 5, with the proviso that the compound of Formula Illa is not:

85. The compound of claim 83 or 84, wherein each of R1and R2is H.

86. The compound of any one of claims 83 to 85, wherein R4is a C2-C5 heterocycle.

87. The compound of any one of claims 83 to 86, wherein R4is azetidine, tetrahydrofuran, pyrrolidine, piperidine, oxane, dioxane, morpholine, thiomorpholine, thietane, thiolane, thane, or oxetane.

88. The compound of any one of claims 83 to 87, wherein the C2-C5 heterocycle is substituted with a C1-C5 alkyl.

89. The compound of claims 83 or 84, wherein R4is a C3-C5 carbocycle.

90. The compound of claim 89, wherein R4is cyclopropyl.

91. The compound of claim 89, wherein the compound has the structure:

92. A method for treating a physical, psychiatric, or neurological disorder comprising administering a compound of the Formula:Formula (IV); or a salt thereof, wherein:Rxand Rytogether form a 5 - to 9-membered heterocycle, wherein the heterocycle is optionally substituted with one or more RB; each of R1and R2is independently H, Ci-C6alkyl, Ci-C6alkoxy, C3-C5 carbocycle, C2-C5heterocycle, orR1and R2together with the carbon to which they are attached form a 3- to 5-membered carbocycle or a 3 - to 5-membered heterocycle;R4is a C2-Cio alkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0haloalkyl, C2-Ci0alkoxyl, C2- 0 aminoalkyl, C2-C10 heteroalkyl, C2-C10 cycloalkyl, C2-C10 heterocycloalkyl, Ci- Csalkylene-aryl, or Ci-Csalkylene-heteroaryl, wherein each R4is independently optionally substituted with one or more R6;Rzis a 5- to 9-membered carbocycle or heterocycle, wherein the 5- to 9-membered carbocycle or heterocycle is optionally substituted with one or more RA; each RBis independently halogen, CN, OH, SH, S(=O)(Ci-C3alkyl), S(=O)2(Ci-C3alkyl), S(=O)2NH2, S(=O)2NH(CI-C3alkyl), S(=O)2N(CI-C3alkyl)2, S(=O)(=NC C3alkyl)(Ci- C3alkyl), NH2, NH(CI-C3alkyl), N(CI-C3alkyl)2, C(=O)(Ci-C3alkyl), C(=O)OH, C(=O)O(Ci-C3alkyl), C(=O)NH2, C(=O)NH(CI-C3alkyl), C(=O)N(CrC3alkyl)2, CCio alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, Ci- Cio aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci- C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; or two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle, a 3 - to 6-membered heterocycle, or an oxo; each R6is independently halogen, -CN, OH, =0, -SRa, NRaRb, -NRbC(=0)NRaRb, - NRbC(=0)Ra, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene)heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCI-C3alkyl)(Ci-C3alkyl), -NH2, -NH(CI-C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), - C(=0)0H, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(CrC3alkyl)2, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; andRaand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- Ce aminoalkyl, Ci-Ce heteroalkyl, C2-Ce alkenyl, C2-Ce alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene-cycloalkyl, Ci-C6alkylene- heterocycloalkyl, Ci-C6alkylene-aryl, or Ci-C6alkylene-heteroaryl.

93. The method of claim 92, wherein the compound has a structure of Formula IVa:Formula (IVa) or a salt thereof, wherein:Rzis a 5- to 9-membered carbocycle or heterocycle, wherein the 5- to 9-membered carbocycle or heterocycle is optionally substituted with one or more RA;R4is halogen, C2-Ci0alkyl, C2-Ci0haloalkyl, C2-Ci0hydroxyalkyl, C2-Ci0aminoalkyl, C2- Cio heteroalkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0cycloalkyl, C2-Ci0heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6;each RBis independently H, halogen, -CN, OH, -SH, -S(=O)(Ci-C3 alkyl), -S(=O)2(Ci-C3 alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCrC3alkyl)(Ci-C3alkyl), -NH2, -NH(C C3alkyl), -N(CrC3alkyl)2, -C(=O)(CrC3alkyl), - C(=O)OH, -C(=O)O(Ci-C3alkyl), -C(=O)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(CrC3alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, or two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle, a 3 - to 6-membered heterocycle, or an oxo; each R6is independently halogen, -CN, OH, =0, -SRa, NRaRb, -NRbC(=0)NRaRb, - NRbC(=0)Ra, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCI-C3alkyl)(Ci-C3alkyl), -NH2, -NH(CI-C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), - C(=O)OH, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(CrC3alkyl)2, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; andRaand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- Ce aminoalkyl, Ci-Ce heteroalkyl, C2-Ce alkenyl, C2-Ce alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene-cycloalkyl, Ci-C6alkylene- heterocycloalkyl, Ci-C6alkylene-aryl, or Ci-C6alkylene-heteroaryl; and n is an integer from 0 to 10.

94. The method of any one of claims 92 or 93, wherein each RAis independently Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci- C3alkylene-aryl, or Ci-C3alkylene-heteroaryl.

95. The method of any one of claims 92 to 94, wherein eachRBis independently H, halogen, CN, OH, SH, NH2, NH(CI-C3alkyl), N(C C3alkyl)2, C(=O)OH, C(=O)O(C C3alkyl), C(=0)NH2, C(=O)NH(CI-C3alkyl), C(=O)N(C C3alkyl)2, CrC6alkyl, C C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-C6heteroalkyl, Ci-C6cycloalkyl, Ci-C6heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, or two RBtogether with the carbon to which they are attached form a 3- to 6-membered carbocycle, a 3- to 6-membered heterocycle, or an oxo.

96. The method of any one of claims 92 to 94, wherein eachRBis independently H, halogen, -CN, OH, =0, -SH, -NH2, -NH(CI-C3alkyl), -N(C C3alkyl)2, -C(=O)OH, -C(=O)O(CrC3alkyl), -C(=0)NH2, CI-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, C3-C6cycloalkyl, C3- C6heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, or two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle, a 3 - to 6-membered heterocycle, or an oxo.

97. The method of any one of claims 92 to 96, wherein R4is C2-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C2-C6haloalkyl, C2-C6hydroxyalkyl, C2-C6cycloalkyl, or C2-C6heterocycloalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6.

98. The method of any one of claims 92 to 96, wherein Rzis a heteroaryl.

99. The method of claim 98, wherein the heteroaryl is pyridine, pyrimidine, imidazole, furan, thiophene, thiazole, pyrrole, oxazole, thiazole, triazole, pyrazole, isoxazole, isothiazole, indole, benzofuran, benzothiophene, benzimidazole, benzodioxole, azaindole, azabenzofuran, azabenzothiophene, azabenzimidazole, dihydrobenzofuran, dihydrobenzothiophene, dihydroindole, or benzimidazolone.

100. The method of any one of claims 92 to 97, wherein Rzis phenyl, furanyl, or thiophenyl.

101. The method of any one of claims 92 to 97, wherein Rzis aryl substituted with at least one R6.

102. The method of any one of claims 92 to 101, wherein the compound of Formula (IVa) is substituted with at least one RA.

103. The method of claim 92, wherein the compound has a structure of Formula (IVb):Formula (IVb) or a salt thereof, wherein:Rxand Ry together form a 5- to 9-membered heterocycle, wherein the 5- to 9-membered heterocycle is optionally substituted with one or more RB;each of R1and R2is independently H, Ci-Ce alkyl, C3-C5 carbocycle, C2-C5 heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3- to 5-membered heterocycle, wherein R1and R2are not both H;R4is halogen, C2-Ci0alkyl, C2-Ci0haloalkyl, C2-Ci0hydroxyalkyl, C2-Ci0aminoalkyl, C2- C10 heteroalkyl, C2-Cio alkenyl, C2-Cio alkynyl, C2-Cio cycloalkyl, C2-Cio heterocycloalkyl, Ci-C3alkylene-aryl, Ci-C3alkylene-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6; each RBis independently halogen, -CN, OH, =0, -SH, -S(=O)(Ci-C3alkyl), -S(=O)2(Ci-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCrC3alkyl)(Ci-C3alkyl), -NH2, -NH(CI-C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), - C(=0)0H, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=0)NH(CI-C3alkyl), -C(=0)N(CI-C3alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl, or two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle or a 3 - to 6-membered heterocycle; each R6is independently halogen, CN, OH, =0, SRa, NRaRb, NRbC(=0)NRaRb, NRbC(=0)Ra, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCrC3alkyl)(Ci-C3alkyl), -NH2, -NH(C C3alkyl), -N(CrC3alkyl)2, -C(=O)(CrC3alkyl), - C(=0)0H, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=0)NH(CI-C3alkyl), -C(=O)N(CI-C3alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl;Raand Rbare each independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci- C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene(cycloalkyl), Ci-C6alkylene(heterocycloalkyl), Ci-C6alkylene(aryl), or Ci-C6alkylene(heteroaryl); and p is an integer from 0 to 5.

104. The method of claim 103, wherein Rxand Rytogether form a 6-membered heterocycloalkyl, substituted with at least one RB.

105. The method of claim 104, wherein RBis a halogen, CN, OH, =0, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci- C3alkylene-aryl, or Ci-C3alkylene-heteroaryl.

106. The method of claim 104, wherein two RBtogether with the carbon to which they are attached form a 3 - to 6-membered carbocycle or a 3 - to 6-membered heterocycle.

107. The method of claim 92, wherein the compound has the structure of Formula (IVc):Formula (IVc) or a salt thereof, wherein: each of R1and R2is independently H, Ci-C6alkyl, C3-C5 carbocycle, C2-C5heterocycle, or R1and R2together with the carbon to which they are attached form a 3 - to 5-membered carbocycle or a 3- to 5-membered heterocycle, wherein R1and R2are not both H;R4is a C2-Cio alkyl, C2-Ci0haloalkyl, C2-Ci0hydroxyalkyl, C2-Ci0aminoalkyl, C2-Ci0heteroalkyl, C2-Cio alkenyl, C2-Cio alkynyl, C2-Cio cycloalkyl, C2-Cio heterocycloalkyl, (C1-C3 alkylene)aryl, (C1-C3 alkylene)heteroaryl, -CN, -NO2, OH, -ORa, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRaRb, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRaRb, -NRbC(=O)NRaRb, - NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORa, or -C(=O)NRaRb; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6; each RBis independently H, halogen, -CN, -OH, =0, -SH, -SRa, -S(=O)(Ci-C3alkyl), - S(=O)2(Ci-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, - S(=O)(=NCI-C3alkyl)(Ci-C3alkyl), -NH2, -NHRa, -NRaRb, -C(=O)(C C3alkyl), - C(=0)0H, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=0)NHRa, alkyl), -C(=0)NRaRb, CrC10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, Ci- C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci- C3alkylene-aryl, or Ci-C3alkylene-heteroaryl;each R6is independently halogen, -CN, -OH, =0, -SRa, NRaRb, -NRbC(=0)NRaRb, -NRbC(=O)Ra, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl; each RAis independently halogen, -CN, -OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NH(CI-C3alkyl), -S(=O)2N(CI-C3alkyl)2, -S(=O)(=NCrC3alkyl)(Ci-C3alkyl), -NH2, -NH(C C3alkyl), -N(CI-C3alkyl)2, -C(=O)(Ci-C3alkyl), - C(=O)OH, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=O)NH(C C3alkyl), -C(=O)N(CrC3alkyl)2, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl;Raand Rbare each independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, Ci- C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene-cycloalkyl, Ci-C6alkylene- heterocycloalkyl, Ci-Ce alkylene-aryl, or Ci-Cealkylene-heteroaryl; and p is an integer from 0 to 5, and n is an integer from 0 to 10.

108. The method of claim 107, wherein n is an integer from 1 to 5.

109. The method of any one of claims 107 or 108, wherein at least one R6is halogen,Ci-Cio alkyl, Ci-Cwhaloalkyl, ORa, SRa, NRaRb, CN or NO2.

110. The method of claim 107, wherein n is 0.

111. The method of claim 110, wherein each RBis independently halogen, -CN, OH,ORa,-SRa, -NH2, -NHRa, -NRaRb, =0, -SH, CN, NO2, -C(=O)(CrC3alkyl), -C(=O)OH, - C(=O)O(C1-C3alkyl), -C(=O)NH2, -C(=O)NH(CrC3alkyl), -C(=O)N(C C3alkyl)2, CrCio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci- Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci- C3alkylene-aryl, or Ci-C3alkylene-heteroaryl.

112. The method of any one of claims 92 to 111, wherein R4is a C3-C3alkyl.

113. The method of claim 112, wherein R4is propyl.

114. The method of claim 112, wherein R4is butyl.

115. The method of claim 112, wherein R4is pentyl.

116. The method of any one of claims 92 to 111, wherein R4is azetidine, tetrahydrofuran, pyrrolidine, piperidine, oxane, dioxane, morpholine, thiomorpholine, thietane, thiolane, thane, or oxetane.-B l117. The method of or claim 116, wherein R4is azetidine, tetrahydrofuran, oxane, dioxane, morpholine, thiomorpholine, thietane, thiolane, thane, or oxetane.

118. The method of claim 92, wherein the compound has the structure:or a pharmaceutically acceptable salt of the compound.

119. The method of claim 92, wherein the compound is represented by Formula (IVd):Formula (IVd) or a salt thereof, wherein:R4is a C2-Cio alkyl, C2-Ci0haloalkyl, C2-Ci0hydroxyalkyl, C2-Ci0aminoalkyl, C2-Ci0heteroalkyl, C2-Ci0alkenyl, C2-Ci0alkynyl, C2-Ci0cycloalkyl, C2-Ci0heterocycloalkyl,Ci-C3alkylene-aryl, Ci-C3alkylene-heteroaryl, -CN, -NO2, OH, -ORa, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRaRb, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRaRb, -NRbC(=O)NRaRb, - NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORa, or -C(=O)NRaRb; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6; each RBis independently halogen, NH2, -NHRa, -NRaRb, -CN, NO2, OH, =0, -SH, - S(=O)(Ci-C3alkyl), -S(=O)2(Ci-C3alkyl), -S(=O)2NH2, -S(=0)2NHRa, -S(=0)2NRaRb, - S(=O)(-NRa), -NH2, -NHRa, -NRaRb, -N=S(=O) (RaRb), -C(=O)(C C3alkyl), - C(=0)0H, -C(=O)O(Ci-C3alkyl), -C(=0)NH2, -C(=0)NHRa, -C(=0)NRaRb, Ci-Cwalkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci- C3alkylene-aryl, or (Ci-C3)-heteroaryl; each R6is independently halogen, -CN, OH, =0, NH2, -NHRa, -NRaRb, -N02, -SRa, NRaRb, - NRbC(=0)NRaRb, -NRbC(=0)Ra, Ci-C10alkyl, Ci-C10alkoxy, Ci-C10haloalkyl, Ci-C10haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or (Ci-C3)-heteroaryl; each RAis independently halogen, -CN, OH, -SRa, -S(=O)(Ci-C3alkyl), -S(=O)2(C1-C3alkyl), -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, -S(=O)(=NRaRb)(Ci-C3alkyl), NH2, -NHRa, -NRaRb, -C(=O)(Ci-C3alkyl), -C(=O)OH, -C(=O)O(C C3alkyl), -C(=0)NH2, - C(=0)NHRa, -C(=0)NRaRb, Ci-C10alkyl, Ci-C10alkoxy, Ci-C10haloalkyl, Ci-C10haloalkoxy, C1-C10 hydroxyalkyl, C1-C10 aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci-C3alkylene-aryl, or Ci-C3alkylene-heteroaryl;Y is C(RB)2, NRa, O, S, S(=0), S(=0)2, or Se;Raand Rbare each independently H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- Ce aminoalkyl, Ci-Ce heteroalkyl, C2-Ce alkenyl, C2-Ce alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C6alkylene-cycloalkyl, Ci-C6alkylene- heterocycloalkyl, Ci-C6alkylene-aryl, or Ci-C6alkylene-heteroaryl; and n is an integer from 0 to 10; and p is an integer from 0 to 5.

120. The method of claim 119, wherein R4is C2-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6haloalkyl, C2-C6hydroxyalkyl, C2-C6cycloalkyl, or C2-C6heterocycloalkyl.

121. The method of claim 119 or 120, wherein eachRBis independently halogen, CN, OH, =0, SH, NH2, NH(CI-C3alkyl), N(C C3alkyl)2, C(=O)(Ci-C3alkyl), C(=O)OH, -C(=O)O(C1-C3alkyl), C(=O)NH2, C(=O)NH(CI-C3alkyl), C(=O)N(CI-C3alkyl)2, Ci- Cio alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 hydroxyalkyl, Ci- Cio aminoalkyl, C1-C10 heteroalkyl, C1-C10 cycloalkyl, C1-C10 heterocycloalkyl, Ci- C3alkylene-aryl, or (Ci-C3)-heteroaryl.

122. The method of any one of claims 119 to 121, wherein n is an integer from 1 to 5, and at least one RBis halogen.

123. The method of any one of claims 119 to 122, wherein each R6is independently halogen, -CN, OH, =0, Ci-Cio alkyl, Ci-Cio alkoxy, Ci-Cio haloalkyl, Ci-Cio haloalkoxy, Ci-Cio hydroxyalkyl, Ci-Cio aminoalkyl, Ci-Cio heteroalkyl, Ci-Cio cycloalkyl, Ci-Cio heterocycloalkyl, Ci-C3alkylene-aryl, or (Ci-C3)-heteroaryl.

124. The method of any one of claims 92 to 123, wherein the physical, psychiatric, or neurological disorder comprisespain, 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.

125. A compound having a structure:or a salt of the compound.

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