3-pyrrolidine-indole derivative compounds useful for the treatment of disorders and methods related thereto

Abstract

The present disclosure relates to 3-pyrrolidine-indole derivative compounds of general Formula (I), compositions including 3- pyrrolidine-indole derivative compounds of general Formula (I), and their use for treating diseases, disorders, or conditions. The diseases, disorders, or conditions include, for example, mental illnesses and neurological disorders.

Description

COMPOUNDS USEFUL FOR THE TREATMENT OF DISORDERS AND METHODS RELATED THERETOCROSS-REFERENCE TO RELATED APPLICATIONS AND CLAIM OF PRIORITY

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 666,429 filed in the U.S. Patent & Trademark Office on July 1, 2024, and U.S. Provisional Application Nos. 63 / 808,963 and 63 / 809,193, both filed in the U.S. Patent & Trademark Office on May 20, 2025, the complete disclosures of which are incorporated herein by reference.FIELD

[0002] The application relates to 3-pyrrolidine indole compounds of general Formula (I), and methods of using such compounds, including methods for the treatment of different diseases, disorders, and conditions, including, for example, mental illnesses and neurological diseases, disorders, and conditions in the fields of psychiatry, neurobiology, and pharmacotherapy, among others.BACKGROUND

[0003] Mental health disorders, or mental illnesses, refer to a wide range of disorders that include, but are not limited to, depressive disorders, anxiety and panic disorders, schizophrenia, eating disorders, substance misuse disorders, post-traumatic stress disorder, attention deficit / hyperactivity disorder, and obsessive-compulsive disorder. Many mental health disorders, as well as neurological disorders, are impacted by alterations, dysfunction, degeneration, and / or damage to the brain.

[0004] There is a need in the art for development of compounds for additional effective treatments for the above and other diseases, disorders, and conditions discussed herein.SUMMARY

[0005] This Summary is provided to introduce a selection of representative concepts in a simplified form, which representative concepts are further described below in the Detailed Description. This Summary is not necessarily intended to identify key features or essential features of the claimed subject matter, nor is it or the objects and benefits described herein intended to be used to limit the scope of the claimed subject matter.

[0006] In some embodiments, the present application includes one or more compounds of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein:X is absent or is selected from O, S, S(O), and S(O)2jR1is selected from halo, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted OC1-C6alkyl, optionally substituted C3- Ciocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C-i- CealkyleneCa-Ciocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted C1-C6alkylene(5- to 10-membered)heteroaryl;R2is selected from H, D, halo, and optionally substituted C1-C6alkyl;R3is selected from H, D, halo, and optionally substituted C1-C6alkyl;R4is selected from H, D, halo, optionally substituted Ci.Cioalkyl, optionally substituted C2- Cealkenyl, optionally substituted C2-Cealkynyl, optionally substituted C1-C6alkyleneOR9, optionally substituted Ci-CealkyleneC(O)R9, optionally substituted Ci-CealkyleneNR10C(O)R9, optionally substituted Ci-CealkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci-C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted C2-CealkenyleneOR9, optionally substituted C2-CealkenyleneC(O)R9, optionally substituted C2-CealkenyleneNR10C(O)R9, optionally substituted C2- CealkenyleneNR10C(O)OR9, optionally substituted C2-CealkenyleneC(O)NR10R11, optionallysubstituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-CealkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-C6alkynyleneNR10R11, optionally substituted Cs-Czcycloalkyl, optionally substituted 3-membered to 10-membered heterocycloalkyl, optionally substituted Ce-Cwaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci CealkyleneCs-Cycycloalkyl, optionally substituted C1- C6alkylene(3- to 10-membered)heterocycloalkyl, optionally substituted Ci-C6alkyleneC6-Cioaryl, and optionally substituted Ci-C6alkylene(5- to 10-membered)heteroaryl;R5is selected from H, D, halo, OH, optionally substituted C1-C6alkyl, and Q-A;R6is selected from H, D, optionally substituted Ci-C3alkyl, optionally substituted C1- C6alkyleneO(Ci-C6alkyl), and optionally substituted Ci-C6alkyleneS(Ci-C6alkyl);R7is selected from H, D, and halo;R8is selected from H, D, and halo;R9is selected from H, D, optionally substituted C1-C6alkyl, optionally substituted Cs-Cycycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, and optionally substituted 5- to 10-membered heteroaryl;R10is selected from H, D, and optionally substituted C1-C6alkyl;R11is selected from H, D, and optionally substituted C1-C6alkyl;Q is absent or is selected from O, S, S(O), and S(O)2;A is selected from H, D, P(O)(OR12)2, CH2P(O)(OR12)2, CH(CH3)P(O)(OR12)2, C(O)Q', CH2(C3- Cycycloalkyl), CH2(C4-Cecycloalkenyl), CH2(3- to 10-membered)heterocycloalkyl, CH2(Ce-Cio)aryl, CH2(5- to 10-membered)heteroaryl, and C^alkyl; each R12is independently selected from H, D, C1-C4 alkyl, and C2-C6 alkenyl;Q’ is selected from:indicates a point of covalent attachment; one or more available hydrogen atoms of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, and Q’ are optionally and independently replaced with one or more respective halogen atoms and / or wherein one or more available atoms of Formula (I) are optionally and independently replaced with one or more respective alternative isotopes, none of R6, R9, R10, R11, and R12consist of only a halogen atom; and the compound of Formula (I) is not selected from the following:provided when R1is phenyl, then R1is substituted with at least one substituent not selected from H, D, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxyl, C1-C6alkyl, and C1-C6alkoxy; and provided when X is absent and R4is H, then R6is neither H nor non-deuterated Ci-Caalkyl; provided when X is absent and R4is halo, then R5is selected from H and D and is not halo;provided when X is absent and R4is selected from H and D but not halo, then R5is selected from halo, OH, optionally substituted C1-C6alkyl, and Q-A; and provided when R4is selected from optionally substituted Ci-Cwalkyl, optionally substituted C2- Cealkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6alkyleneOR9, optionally substituted Ci-C6alkyleneC(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci-C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2- C6alkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2.C6alkynyleneOC(O)NR10R11, optionally substituted C2.C6alkynyleneNR10R11, optionally substituted Cs-Cycycloalkyl, optionally substituted 3-membered to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci-CealkyleneCs-Cycycloalkyl, optionally substituted Ci. C6alkylene(3- to 10-membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-C-ioaryl, and optionally substituted Ci.C6alkylene(5- to 10-membered)heteroaryl, then R5is selected from H, D, and halo.

[0007] In some embodiments, when R1is phenyl, then the phenyl of R1is substituted with at least one substituent selected from OH, SH, and C1-C6alkylthio.

[0008] In some embodiments, provided when X is absent and R4is selected from H and D, then R6is not selected from H, D, C1-C3alkyl, C1-C3deuteroalkyl, C1-C3haloalkyl, and C1- CsdeuterohaloalkyL

[0009] In some embodiments, provided when X is selected from O, S, S(O), and S(O)2, then R4is not halo.

[0010] In some embodiments, the compound is not selected from a deuterated analog of any of the following:(R)-2-ethyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-4-ol;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-5-ol;(R)-5-ethoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2,7-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-isopropyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-ethyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-chloro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-2,5,7-trimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-bromo-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole; and(R)-2,5-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole.

[0011] In some embodiments, the compound is not selected from a deuterated or halogenated analog of any of the following:(R)-2-ethyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-4-ol;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-5-ol;(R)-5-ethoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2,7-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-isopropyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-ethyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-chloro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-2,5,7-trimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-bromo-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole; and(R)-2,5-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole.

[0012] In some embodiments, one or more available hydrogen atoms of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, and Q’ are optionally and independently replaced with one or more respective halogen atoms and / or one or more available atoms of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, and Q’ are optionally and independently replaced with one or more respective alternative isotopes.

[0013] In some embodiments, the present application includes one or more compounds of Formula (I);Formula (I) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein:X is absent or is selected from O, S, S(O), and S(0)2jR1is selected from halo, optionally substituted C1-C6alkyl, optionally substituted C2-Cealkenyl, optionally substituted C2-Cealkynyl, optionally substituted OC1-C6alkyl, optionally substituted C3- Ciocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C1- CealkyleneCs-Ciocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted C1-C6alkylene(5- to 10-membered)heteroaryl;R2is selected from H, D, halo, and optionally substituted CrCealkyl;R3is selected from H, D, halo, and optionally substituted C1-C6alkyl;R4is selected from H, D, halo, optionally substituted Ci-Cioalkyl, optionally substituted C2- Cealkenyl, optionally substituted C2-Cealkynyl, optionally substituted C1-C6alkyleneOR9, optionally substituted Ci C6alkyleneC(O)R9, optionally substituted Ci C6alkyleneNR10C(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci-C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2- C6alkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-C6alkynyleneNR10R11, optionally substituted Cs-Cycycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci-CBalkyleneCs-Cycycloalkyl, optionally substituted Ci-C6alkylene(3- to 10- membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted Ci.C6alkylene(5- to 10-membered)heteroaryl;R5is selected from H, D, halo, OH, optionally substituted C1-C6alkyl, and Q-A;R6is selected from H, D, optionally substituted Ci-Caalkyl, optionally substituted C1- CealkyleneO(Ci-C6alkyl), and optionally substituted Ci-C6alkyleneS(Ci-C6alkyl);R7is selected from H, D, and halo;R8is selected from H, D, and halo;R9is selected from H, D, optionally substituted C1-C6alkyl, optionally substituted Cs-Cycycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, and optionally substituted (5- to 10-membered) heteroaryl;R10is selected from H, D, and optionally substituted C1-C6alkyl;R11is selected from H, D, and optionally substituted C1-C6alkyl;Q is absent or is selected from O, S, S(O), and S(O)2;A is selected from H, D, P(O)(OR12)2, CH2P(O)(OR12)2, CH(CH3)P(O)(OR12)2, C(O)Q', CH2(C3- Cycycloalkyl), CH2(C4-C6cycloalkenyl), CH2(3- to 10-membered)heterocycloalkyl, CH2(C6-Cio)aryl, CH2(5- to 10-membered)heteroaryl, and Ci^alkyl; each R12is independently selected from H, D, C1-C4 alkyl, and C2-Ce alkenyl;Q’ is selected from:indicates a point of covalent attachment; one or more available hydrogen atoms of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, and Q’ are optionally and independently replaced with one or more respective halogen atoms and / or wherein one or more available atoms of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, and Q’ are optionally and independently replaced with one or more respective alternative isotopes, none of R6, R9, R10, R11, and R12consist of only a halogen atom; and the compound of Formula (I) is not selected from the following and stereoisomers thereof:2-ethyl-5-methoxy-3-[[(2R)-1-methyl-2-pyrrolidinyl]methyl]-1 H-indol;2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-4-ol;2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-5-ol; and5-methoxy-2,7-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole. provided when R1is phenyl, then R1is substituted with at least one substituent not selected from H, D, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxyl, C1-C6alkyl, and C1-C6alkoxy; and provided when X is absent and R4is H, then R6is neither H nor non-deuterated C1-C6alkyl; provided when X is absent and R4is halo, then R5is selected from H and D and is not halo; provided when X is absent and R4is selected from H and D but not halo, then R5is selected from halo, OH, optionally substituted C1-C6alkyl, and Q-A; andprovided when R4is selected from optionally substituted Ci-Cwalkyl, optionally substituted C2- Cealkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6alkyleneOR9, optionally substituted Ci-C6alkyleneC(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci-C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2- C6alkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-C6alkynyleneNR10R11, optionally substituted Cs-Czcycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci-CealkyleneCs-Cycycloalkyl, optionally substituted Ci-C6alkylene(3- to 10- membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted Ci.C6alkylene(5- to 10-membered)heteroaryl, then R5is selected from H, D, and halo.

[0014] In a further embodiment, the compounds of the disclosure are used as medicaments. Accordingly, the disclosure also includes a compound of the disclosure for use as a medicament.

[0015] In other embodiments, the compounds of the disclosure as used as ingredients in compositions and pharmaceutical compositions, including medicaments.

[0016] The present disclosure also includes a method of treating a disease, disorder, and / or condition comprising administering a therapeutically effective amount of one or more compounds of the disclosure to a subject in need thereof. In some embodiments, the compounds of the disclosure are used to make medicaments for treatment of disease, disorder, and / or condition. In some embodiments, the present disclosure relates to use of one or more compounds of this disclosure in the making or manufacture of a medicament for treating disease, disorder, and / or condition.

[0017] The present disclosure also includes a method of treating depressive disorder, bipolar disorder, eating disorder, impulse control disorder, personality disorder, substance abusedisorder, behavioral addiction disorder, alcohol use disorder, post-traumatic stress disorder, anxiety disorder, stress disorder, neurodevelopmental disorder, pain disorder, headache disorder, inflammatory disorder, injury-related disorder, neurodegenerative disorder, functional disorder, psychotic disorder, hyperkinetic movement disorder, age-related macular degeneration, atherosclerosis, dissociative disorders, genetic brain disorders, hyperprolactinemia, hypersomnia, obesity, phobias, apathy disorders, and / or burnout. In some embodiments, the compounds of the disclosure are used to make medicaments for treatment of a depressive disorder, bipolar disorder, eating disorder, impulse control disorder, personality disorder, substance abuse disorder, alcohol use disorder, behavioral addiction disorder, post-traumatic stress disorder, anxiety disorder, stress disorder, neurodevelopmental disorder, pain disorder, headache disorder, inflammatory disorder, injury-related disorder, neurodegenerative disorder, functional disorder, psychotic disorder, hyperkinetic movement disorder, age-related macular degeneration, atherosclerosis, dissociative disorders, genetic brain disorders, hyperprolactinemia, hypersomnia, obesity, phobias, apathy disorders, and / or burnout. In some embodiments, the present disclosure relates to use of one or more compounds of this disclosure in the making or manufacture of a medicament for treating depressive disorder, bipolar disorder, eating disorder, impulse control disorder, personality disorder, substance abuse disorder, behavioral addiction disorder, alcohol use disorder, post-traumatic stress disorder, anxiety disorder, stress disorder, neurodevelopmental disorder, pain disorder, headache disorder, inflammatory disorder, injury-related disorder, neurodegenerative disorder, functional disorder, psychotic disorder, hyperkinetic movement disorder, age-related macular degeneration, atherosclerosis, dissociative disorders, genetic brain disorders, hyperprolactinemia, hypersomnia, obesity, phobias, apathy disorders, and / or burnout.

[0018] The disclosure additionally provides a process for the preparation of compounds of the disclosure. The disclosure further provides use of compounds of the disclosure in the making or manufacture of medicines. General and specific processes are discussed in more detail below and set forth in the examples below.

[0019] This disclosure further provides intermediates for the compounds disclosed herein, methods of making the intermediates, and methods for making the compounds from the intermediates.

[0020] Other features of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specificexamples, while indicating embodiments of the disclosure, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.DETAILED DESCRIPTIONI. Definitions

[0021] Unless otherwise indicated, the definitions and embodiments described in this section and other sections are intended to be applicable to all embodiments and aspects of the present disclosure herein described for which they are suitable as would be understood by a person skilled in the art.

[0022] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0023] As used in the present disclosure, the singular forms “a,” “an,” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds. It will be understood by those with skill in the art that if a specific number of an introduced claim element is intended, such intent will be explicitly recited in the claim, and in the absence of such recitation no such limitation is present. For a non-limiting example, as an aid to understanding, the appended claims contain usage of the introductory phrases “at least one” and “one or more” to introduce claim elements. However, the use of such phrases should not be construed to imply that the introduction of a claim element by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim element to embodiments containing only one such element, even when the same claim includes the introductory phrase “one or more” or “at least one” and indefinite articles, such as “a” or “an”; the same holds true for the use in the claims of definite articles.

[0024] The terms “about,” “substantially,” and “approximately,” as used herein, mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0025] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component, as used herein, is not the same component as the other components or first component. A “third” component is not the same component as the other, first and second components and further enumerated or “additional” components are similarly different components. It should be understood, for example, that although a first group and a second group refer to two groups, the first and second groups may be the same species, for example, both C1-C6alkyl, or methyl. “First,” “second,” “third,” etc. in this context is not meant to imply an order or sequence, other than the order in which the terms appear in the claims, unless the claims clearly indicate otherwise.

[0026] The term “administered,” as used herein, means administration of a therapeutically effective amount of one or more compounds or compositions of the disclosure to a cell, tissue, organ, or subject.

[0027] The term “alkenyl,” as used herein, whether it is used alone or as part of another group, means substituted or unsubstituted, straight or branched chain, unsaturated hydrocarbon groups containing at least one double bond. The term C2-Cealkenyl (or C2-ealkenyl) means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. An alkenyl may contain other unsaturated alkyl groups, such as at least one triple bond. Alkenyl groups may be substituted by alkyl or alkynyl groups.

[0028] The term “alkyl,” as used herein, whether it is used alone or as part of another group, means substituted or unsubstituted, straight or branched chain, saturated hydrocarbon groups, unless the context clearly indicates otherwise, e.g., an “unsubstituted alkyl” is not substituted. The term “C1-C6alkyl” (or “Ci-ealkyl”) means an alkyl group having 1 , 2, 3, 4, 5, or 6 carbon atoms and includes, for example, any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and tert-butyl, n- and iso-propyl, ethyl, and methyl. As another example, “Ci-C4alkyl” refers to n-, iso- , sec- and tert-butyl, n- and isopropyl, ethyl, and methyl. Unless otherwise stated, an “alkyl” group includes all isomers. As another example, “Cialkyl” refers to a methyl group; “C2alkyl” refers to an ethyl group; “Caalkyl” refers to a propyl group (e.g., n-propyl or iso-propyl)); “C4alkyl” refers to a butyl group (e.g., n-butyl, sec-butyl, isobutyl, or tert-butyl); “Csalkyl” refers to a pentyl group and any of its isomers; and “Cealkyl” refers to a hexyl group and any of its isomers.

[0029] The term “alkynyl,” as used herein, whether it is used alone or as part of another group, means substituted or unsubstituted, straight or branched chain, unsaturated hydrocarbon groups containing at least one triple bond. The term C2-C6alkynyl (or C2-ealkynyl) means an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Alkynyl groups may be substituted by alkyl or alkenyl groups.

[0030] The term “alternate isotope thereof’ or “alternative isotope thereof,” as used herein, refers to an isotope of an element that is other than the isotope that is most abundant in nature.

[0031] The term “and / or,” as used herein, means that one or more of the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present. The term “and / or” with respect to pharmaceutically acceptable salts and / or solvates thereof means that the compounds of the disclosure exist as individual salts or solvates, as well as a combination of, for example, a salt of a solvate of a compound of the disclosure. As used herein, the term “and / or” means either or both (or any combination or all of the terms or expressions referred to), e.g., “A, B, and / or C” encompasses A alone; B alone; C alone; A and B; A and C; B and C; and A, B, and C.

[0032] The term “any member, combination, or subset thereof,” as used herein, when used to refer to a preceding list of possible members, means that any individual listed member, possible combination of listed members, or subset of listed members may be included. For example, if Z is selected from A, B, C, and D, including any member, combination, or subset thereof, then Z may be A, B, C, and D; A, B, and C; A, B, and D; A, C, and D; B, C, and D; A and B; A and C; A and D; B and C; B and D; C and D; A alone; B alone; C alone; or D alone.

[0033] The term “aryl,” as used herein, whether it is used alone or as part of another group, refers to a substituted or unsubstituted aromatic carbocyclic ring or multi-ring structures (e.g., bicyclic). For example, for an aryl group that contains the prefix Ce-Cw, the corresponding carbocyclic group(s) contains 6, 7, 8, 9, or 10 carbon ring atoms.

[0034] The term “available,” as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

[0035] The term “benzofused,” as used herein, refers to a polycyclic group in which a benzene ring is fused with another ring.

[0036] A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.

[0037] The term “composition(s) of the disclosure” or “composition(s) of the present disclosure” and the like, as used herein, refers to a composition, such a pharmaceutical composition, comprising one or more compounds of the disclosure.

[0038] The term “compound(s) of the disclosure” or “compound(s) of the present disclosure” and the like, as used herein, refers to a compound Formula (I) and includes, in some embodiments, pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

[0039] As used in this disclosure and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open- ended and do not exclude additional, unrecited elements or process steps.

[0040] The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers and / or steps and also exclude the presence of other unstated features, elements, components, groups, integers, and / or steps.

[0041] The term “consisting essentially of,” as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of those features, elements, components, groups, integers, and / or steps.

[0042] All “cyclic” groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups, contain one ring or more than one ring (i.e., are optionally polycyclic), unless otherwise indicated. When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused, or linked by a bond.

[0043] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a substituted or unsubstituted, saturated or unsaturated, non-aromatic, carbocyclic ring or multi-ring structures (e.g., bi-cyclic), unless otherwise specified. The term Ca-Czcycloalkyl (or Cs-ycycloalkyl) means a cycloalkyl group having 3, 4, 5, 6, or 7 ring carbon atoms. A cycloalkyl is optionally fused to another ring, including fused to an aryl ring (e.g., benzofused) or heteroaryl ring.

[0044] The term “deuteroalkenyl,” as used herein, refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective deuterium atoms. Thus, for example, “C2-C6deuteroalkenyl” (or “C2- edeuteroalkenyl”) refers to a two-carbon to six-carbon linear or branched alkenyl group as defined above with one or more deuterium substituents, and optionally one or more non-deuterium substitutes.

[0045] The term “deuteroalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective deuterium atoms. Thus, for example, “Ci-Cedeuteroalkyl” (or “C-i- edeuteroalkyl”) refers to a one-carbon to six-carbon linear or branched alkyl group as defined above with one or more deuterium substituents, and optionally one or more non-deuterium substitutes.

[0046] The term “deuteroalkynyl,” as used herein, refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective deuterium atoms. Thus, for example, “C2-C6deuteroalkynyl” (or “C2- edeuteroalkynyl”) refers to a two-carbon to six-carbon linear or branched alkynyl group as defined above with one or more deuterium substituents, and optionally one or more non-deuterium substitutes.

[0047] The term “deuterohaloalkenyl,” as used herein, refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective deuterium atoms and one or more of the available hydrogen atoms have been independently replaced with one or more respective halogen atoms. Thus, for example, “C2.C6deuterohaloalkenyl” (or “C2-6deuterohaloalkenyl”) refers to a two-carbon to six- carbon linear or branched alkenyl group as defined above with one or more deuterium substituents and one or more halogen substituents, and optionally one or more non-deuterohalo substitutes.

[0048] The term “deuterohaloalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective deuterium atoms and one or more of the available hydrogen atoms have been independently replaced with one or more respective halogen atoms. Thus, for example, “Ci. Csdeuterohaloalkyl” (or “Ci-edeuterohaloalkyl”) refers to a one-carbon to six-carbon linear or branched alkyl group as defined above with one or more deuterium substituents and one or more halogen substituents, and optionally one or more non-deuterohalo substitutes.

[0049] The term “deuterohaloalkynyl,” as used herein, refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective deuterium atoms and one or more of the available hydrogen atoms have been independently replaced with one or more respective halogen atoms. Thus, for example, “C2-Cedeuterohaloalkynyl” (or “C2-6deuterohaloalkynyl”) refers to a two-carbon to six- carbon linear or branched alkynyl group as defined above with one or more deuteriumsubstituents and one or more halogen substituents, and optionally one or more non-deuterohalo substitutes.

[0050] The term “disease, disorder, or condition,” as used herein, refers to a disease, disorder, or condition treated or treatable using one or more compounds of the disclosure herein described.

[0051] The term “effective amount” or “therapeutically effective amount” as used herein means an amount of one or more compounds of the disclosure that is effective, at dosages and for periods of time necessary to achieve the desired result. For example, in the context of treating a disease, disorder, or condition, an effective amount is an amount that, for example, treats, palliates, and / or prevents said disease, disorder, or condition compared to the non-treatment, non-palliation, or non-prevention without administration of the one or more compounds.

[0052] The suffix “ene” at the end of a group (for example “alkylene”) means that the group is bivalent, that is that it is bonded to two variables each on a different end of or location on the group. An alkylene may be substituted or unsubstituted, straight or branched chain. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cn. Cm” and “Co” where n, m, and o are integers. Thus, for example, the term “C1-C6alkylene” (or “C-i- ealkylene”) means an alkylene group having 1 , 2, 3, 4, 5, or 6 carbon atoms and includes, for example, any of the hexylene and pentylene isomers as well as n-, iso-, sec- and tert-butylene, n- and iso-propylene, ethylene, and methylene. Unless otherwise stated, an “alkylene” group includes all isomers. As another example, “Cialkylene” refers to a methylene group; "C2alkylene” refers to an ethylene group; “Csalkylene” refers to a propylene group (e.g., n-propylene or isopropylene)); “C4alkylene” refers to a butylene group (e.g., n-butylene, sec-butylene, isobutylene, or tert-butylene)); “Csalkylene” refers to a pentylene group and any of its isomers; and “Cealkylene” refers to a hexylene group and any of its isomers. As another example, “propylene” includes n- propylene and iso-propylene; “butylene” includes n-butylene, sec-butylene, isobutylene, and tertbutylene)); etc.

[0053] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any implementation described herein as "exemplary” is not necessarily to be construed as preferred or advantageous over other implementations. Reference throughout this specification to “a select embodiment,” “one embodiment,” “an exemplary embodiment,” “exemplary embodiments,” “an embodiment,” or “embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiment(s) is included in at least one embodiment. Thus, appearances of the phrases “in a select embodiment,” “in one embodiment,” “in an exemplary embodiment,” “in exemplary embodiments,” “in someembodiments,” “in an embodiment,” or “in embodiments” in various places throughout this specification are not necessarily referring to the same embodiment(s) or only a single embodiment. The embodiments may be, for example, combined with one another in various combinations and modified to include features of one another.

[0054] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0055] The term “halo” (or “halogen”) whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo, and iodo.

[0056] As used herein, the term “haloalkenyl” refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective halogen atoms. Thus, for example, “C2-C6haloalkenyl” (or “C2-6haloalkenyl”) refers to a two-carbon to six-carbon linear or branched alkenyl group as defined above with one or more halogen substituents, and optionally one or more non-halogen substitutes.

[0057] The term “haloalkyl,” as used herein, refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective halogen atoms. Thus, for example, “C1-C6haloalkyl” (or“Ci-6haloalkyl”) refers to a one- carbon to six-carbon linear or branched alkyl group as defined above with one or more halogen substituents, and optionally one or more non-halogen substitutes.

[0058] As used herein, the term “haloalkynyl” refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with one or more respective halogen atoms. Thus, for example, “C2-C6haloalkynyl” (or “C2-6haloalkynyl”) refers to a two-carbon to six-carbon linear or branched alkynyl group as defined above with one or more halogen substituents, and optionally one or more non-halogen substitutes.

[0059] The term “heteroaryl, ’’ as used herein, whether it is used alone or as part of another group, refers to substituted or unsubstituted aromatic ring or multi-ring structures (e.g., bi-cyclic), in which one or more of the atoms of the aromatic ring are a heteromoiety independently selected from O, S, and N, including oxidized or substituted versions thereof (e.g., S(O) and S(O)2), and the remaining atoms are C, unless otherwise specified. When a heteroaryl group contains the prefix of, for example, C5-C10, this prefix indicates that the corresponding carbocyclic group(s) contains 5, 6, 7, 8, 9, or 10 carbon atoms in the ring, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Heteroaryl groups may also be preceded by, for example, “5- to 10-membered” which refers to the total number of ring atoms (inthis example, 5, 6, 7, 8, 9, or 10 atoms) in the aromatic ring or multi-ring structures, including the heteroatom(s). Heteroaryl groups may be benzofused.

[0060] The term “heterocycloalkyl,” as used herein, whether it is used alone or as part of another group, refers to substituted or unsubstituted, saturated or non -saturated, non-aromatic ring or multi-ring structures (e.g., bi-cyclic), in which one or more of the ring atoms of the non- aromatic ring or multi-ring structure are independently selected from O, S, and N, including oxidized or substituted versions thereof (e.g., S(O) and S(O)2), and the remaining atoms are C, unless otherwise specified. Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds) and / or optionally comprise one or more C=O groups (i.e., one or more carbon atoms in the ring is oxidized to C=O). When a heterocycloalkyl group contains a prefix, such as C3-C10, this prefix indicates that the corresponding carbocyclic group contains 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in the ring, in which one or more, suitably 1 to 5, of the ring atoms are replaced with a heteromoiety independently selected from O, S, and N including oxidized or substituted versions thereof, and the remaining atoms are C. Similarly, heterocycloalkyl groups may also be preceded by a prefix, such as “3- to 10-membered,” which refers to the total number of atoms in the ring(s) (in this example, 3, 4, 5, 6, 7, 8, 9, or 10 atoms). Heterocycloalkyl groups are optionally fused to another ring, including fused to an aryl ring (e.g., benzofused) or heteroaryl ring.

[0061] As used herein, the term “one or more” items includes a single item selected from the list as well as two or more items (e.g., combinations and mixtures) selected from the list.

[0062] The term “one or more available atoms are optionally and independently replaced with one or more respective alternative isotopes thereof,” and the like, as used herein, means that at least one available atom, optionally a plurality, and optionally each and every available atom, is optionally and independently replaced with an isotope of that atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. When a compound comprises an atom that has been replaced with an alternative isotope thereof, the compound comprises that alternative isotope in greater amounts than would otherwise be present in the compound if said replacement had not taken place. In some embodiments, the alternative isotope is deuterium.

[0063] The term “one or more available hydrogen atoms are optionally and independently replaced with one or more respective halogen atoms,” and the like as used herein, means that at least one available hydrogen atom, optionally a plurality, and optionally each and every availablehydrogen atom, is optionally and independently replaced with a halogen atom, and that the replacements are independent of one another.

[0064] The term “one or more available hydrogen atoms are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms,” and the like, as used herein, means that at least one available hydrogen atom, optionally a plurality, and optionally each and every available hydrogen atom, is optionally and independently replaced with a specified halogen atom (e.g., a fluorine atom, a chlorine atom, and / or a bromine atom), and the replacements are independent of one another, e.g., the compound may include only F; only Cl; only Br; both F and Cl; both F and Br; both Cl and Br; or a combination of F, Cl, and Br replacements.

[0065] The term “optionally substituted,” as used herein, means that the subject group is unsubstituted or substituted and the terms “optionally substituted” and “unsubstituted or substituted” are used interchangeably herein. As used herein, when referring to more than one item or “each” item, “optionally substituted” and “unsubstituted or substituted” means that the items are independently unsubstituted or substituted with respect to one another, e.g., for item A and item B, both may be substituted, both may be unsubstituted, or one may be substituted and the other unsubstituted. Additionally, as used herein, the term “optionally substituted” when referring to more than one item means that if more than one of the items is substituted, the substitutions may be independent from one another, e.g., for item A and item B that are both substituted, item A may have a first substitution and item B may have a second substitution that is the same or different from the first substitution of item A.

[0066] “Palliating” a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of a disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0067] The term “pharmaceutically acceptable” means compatible with the treatment of subjects.

[0068] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed or otherwise combined with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0069] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with, the treatment of subjects. An acid additionsalt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0070] The term “prevention” or “prophylaxis,” or synonym thereto, as used herein, refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder, or condition or manifesting a symptom associated with a disease, disorder, or condition.

[0071] The term “prodrug,” as used herein, means a compound, or salt of a compound, that, after administration, is converted into an active drug.

[0072] The term “protecting group” or “PG” and the like, as used herein, refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in "Protective Groups in Organic Chemistry,” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis,” John Wiley & Sons, 3rdEdition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0073] The term “solvate,” as used herein, means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered.

[0074] A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.

[0075] The term “subject,” as used herein, includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus, the methods of the present disclosure are applicable to both human therapy and veterinary applications.

[0076] The term “substituted,” as used herein, means, unless otherwise indicated, that the referenced group is substituted with one or more independently selected substituents. When a group is substituted with more than one substituent selected from a list of substituents, each of the substituents is independently selected from the listed group of substituents unless otherwise indicated.

[0077] The term “suitable,” as used herein, means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio, and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to control the yield of the desired product and it is within their skill to do so.

[0078] The term “therapeutic agent,” as used herein, refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0079] The term “treating” or “treatment,” as used herein, and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay, or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment,” as used herein, also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the disclosure and optionally consist of a single administration, or alternatively comprise a series of administrations.

[0080] The term “treating a disease, disorder, or condition,” as used herein, means that the disease, disorder, or condition to be treated is affected by, modulated by, and / or has some biological basis.II. Compounds

[0081] The present disclosure includes a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein A, Q, Q’, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and X are as defined (and provisos and exclusions provided for) in the Summary above and exemplified below.

[0082] In some embodiments, X is absent. In some embodiments, X is selected from O, S, S(O), and S(O)2, including any member, combination, subset thereof, e.g., O, S, S(O), and S(0)2j O, S, and S(O); O, S, and S(O)2; O, S(O), and S(O)2; S, S(O), and S(O)2; O and S; O and S(O); O and S(O)2; S and S(O); S and S(O)2; S(O) and S(O)2; O alone; S alone; S(O) alone; and S(O)2 alone.

[0083] In some embodiments, R1is halogen (i.e., F, Cl, Br, and / or I, including any member, combination, or subset thereof). In some embodiments, R1is a halogen selected from fluorine, chlorine, and bromine. In some embodiments, R1is a halogen selected from fluorine and bromine. In some embodiments, R1is a halogen selected from fluorine and chlorine. In some embodiments, R1is a halogen selected from chlorine and bromine. In some embodiments, R1is fluorine. In some embodiments, R1is chlorine. In some embodiments, R1is bromine. In some embodiments, R1is iodine. In some embodiments, R1is not halogen.

[0084] In some embodiments, R1is selected from optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted OC1-C6alkyl, optionally substituted Cs-Ciocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C1-C6alkyleneCa-Ciocycloalkyl, optionally substituted C1-C6alkyleneCe-C-ioaryl, andoptionally substituted C C6alkylene(5- to 10-membered)heteroaryl, including any member, combination, or subset thereof.

[0085] In some embodiments, R1is unsubstituted. In some embodiments, R1is substituted. In some embodiments, R1is substituted with a member selected from independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Ci-C4alkyl), CO2H, CO2(Ci- C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), C3-C7cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl), including any member, combination, or subset thereof. In some embodiments, R1is substituted with a member independently selected from halo, Ci.C4alkyl, OCi.C4alkyl, and C(O)Ci.C4alkyl, including any member, combination, or subset thereof.

[0086] In some embodiments, R1includes at least one deuterium atom. In some embodiments, R1includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of R1are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I) and / or one or more available atoms of R1are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R1are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of R1are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R1are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of R1are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R1are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of R1are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R1are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of R1are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R1are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of R1are optionally and independentlyreplaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R1are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of R1are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of R1are replaced with a halogen atom. In some embodiments, none of the available atoms of R1are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of R1are replaced with a halogen atom and none of the available atoms of R1are replaced with an alternative isotope thereof.

[0087] In some embodiments, R1is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6deuteroalkyl, optionally substituted C1-C6haloalkyl, and optionally substituted Ci- Cedeuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R1is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0088] In some embodiments, R1is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2ICH(CD3)2ICH(CHD2)2JCH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3JC(CFH2)3IC(CD3)3IC(CHD2)3IC(CDH2)3JCH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, R1is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2ICH(CF3)2ICD(CD3)2ICF(CF3)2, C(CH3)3, C(CD3)3, and C(CF3)3, including any member, combination, or subset thereof. In some embodiments, R1is selected from CH3, CHF2, CF3ICD3, CH2CH3ICH(CH3)2, CH(CD3)2Iand C(CH3)3, including any member, combination, or subset thereof. In some embodiments, R1is selected from F, CH3, CHD2, CD3, CH2F, CHF2Iand CF3, including any member, combination, or subset thereof. In some embodiments, R1is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0089] In some embodiments, R1is selected from optionally substituted OC1-C6alkyl, optionally substituted OC1-C6deuteroalkyl, optionally substituted OC1-C6haloalkyl, and optionally substituted OC1-C6deuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R1is selected from OCH3, OCH2D, OCHD2, OCD3, OCH2F, OCHF2, OCF3, OCH2CH3, OCD2CD3, OCF2CF3, OCH(CH3)2, OCH(CD3)2, OCH(CF3)2, OCD(CD3)2, OCF(CF3)2, OC(CH3)3, OC(CD3)3, and OCfCFs , including any member, combination, or subset thereof. In some embodiments, R1is selected from OCH3, OCHF2, OCF3, OCD3, OCH2CH3, OCH(CH3)2, OCH(CD3)2, and OC(CH3)3, including any member, combination, or subset thereof. In some embodiments, R1is selected from OCF3 and OCHF2.

[0090] In some embodiments, R1is selected from optionally substituted Cs-Ciocycloalkyl, optionally substituted Cs-Ciodeuterocycloalkyl, optionally substituted Cs-Ciohalocycloalkyl, and optionally substituted Cs-Ciodeuterohalocycloalkyl, including any member, combination, or subset thereof. In some embodiments, R1is selected from branched or unbranched cyclopropyl, branched or unbranched cyclobutyl, branched or unbranched cyclopentyl, and branched or unbranched cyclohexyl, including any member, combination, or subset thereof.

[0091] In some embodiments, R1is selected from optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocyclodeuteroalkyl, optionally substituted 3- to 10-membered heterocyclohaloalkyl, and optionally substituted 3- to 10- membered heterocyclodeuterohaloalkyl, including any member, combination, or subset thereof. In some embodiments, R1is selected from tetrahydrofuryl, pyrrolidinyl, tetrahydrothiophenyl, pyrrolinyl, and piperidinyl, including any member, combination, or subset thereof.

[0092] In some embodiments, R1is selected from optionally substituted 5- to 10-membered heteroaryl, optionally substituted 5- to 10-membered heterocyclodeuteroaryl, optionally substituted 5- to 10-membered heterocyclohaloaryl, and optionally substituted 5- to 10-membered heterocyclodeuterohaloaryl, including any member, combination, or subset thereof. In some embodiments, R1is selected from pyrrolyl, thiazolyl, thiophenyl, and pyridinyl.

[0093] In some embodiments, R2is selected from H, D, halo, and optionally substituted C1- Cealkyl, including any member, combination, or subset thereof. In some embodiments, R2is selected from H, D, and halo, including any member, combination, or subset thereof (e.g., H, D, and halo; H and D; H and halo; D and halo; H alone; D alone; halo alone). In some embodiments, R2is halo. In some embodiments, R2is a halogen selected from fluorine, chlorine, and bromine.In some embodiments, R2is a halogen selected from fluorine and bromine. In some embodiments, R2is a halogen selected from fluorine and chlorine. In some embodiments, R2is a halogen selected from chlorine and bromine. In some embodiments, R2is fluorine. In some embodiments, R2is chlorine. In some embodiments, R2is bromine. In some embodiments, R2is iodine. In some embodiments, R2is H not replaced by a halogen atom or an alternative isotope thereof. In some embodiments, R2is D.

[0094] In some embodiments, R2is unsubstituted C1-C6alkyl. In some embodiments, R2is substituted C1-C6alkyl. In some embodiments, R2is substituted with a member selected from independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Cr C4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), Ca-Cycycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl), including any member, combination, or subset thereof. In some embodiments, R2is substituted with a member independently selected from halo, Ci.C4alkyl, OCiXZ alkyl, and C(O)Ci.C4alkyl, including any member, combination, or subset thereof.

[0095] In some embodiments, R2includes at least one deuterium atom. In some embodiments, R2includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I) and / or one or more available atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective fluorine atoms and / or one or more availableatoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of optionally substituted C1-C6alkyl of R2are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of optionally substituted C1-C6alkyl of R2are replaced with a halogen atom. In some embodiments, none of the available atoms of optionally substituted C1-C6alkyl of R2are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of optionally substituted C1-C6alkyl of R2are replaced with a halogen atom and none of the available atoms of optionally substituted C1-C6alkyl of R2are replaced with an alternative isotope thereof.

[0096] In some embodiments, R2is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6deuteroalkyl, optionally substituted C1-C6haloalkyl, and optionally substituted Ci- Cedeuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R2is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0097] In some embodiments, R2is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3ICH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments,R2is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2ICF3ICH2CH3, CD2CD3ICF2CF3, CH(CH3)2, CH(CD3)2ICH(CF3)2ICD(CD3)2ICF(CF3)2JC(CH3)3IC(CD3)3Iand C(CF3)3Iincluding any member, combination, or subset thereof. In some embodiments, R2is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)3, including any member, combination, or subset thereof. In some embodiments, R2is selected from H, F, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R2is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0098] In some embodiments, R3is selected from H, D, halo, and optionally substituted Ci- Cealkyl, including any member, combination, or subset thereof. In some embodiments, R3is selected from H, D, and halo, including any member, combination, or subset thereof (e.g., H, D, and halo; H and D; H and halo; D and halo; H alone; D alone; halo alone). In some embodiments, R3is halo. In some embodiments, R3is a halogen selected from fluorine, chlorine, and bromine. In some embodiments, R3is a halogen selected from fluorine and bromine. In some embodiments, R3is a halogen selected from fluorine and chlorine. In some embodiments, R3is a halogen selected from chlorine and bromine. In some embodiments, R3is fluorine. In some embodiments, R3is chlorine. In some embodiments, R3is bromine. In some embodiments, R2is iodine. In some embodiments, R3is H not replaced by a halogen atom or an alternative isotope thereof. In some embodiments, R3is D.

[0099] In some embodiments, R3is unsubstituted C1-C6alkyl. In some embodiments, R3is substituted C1-C6alkyl. In some embodiments, R3is substituted with a member selected from independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Cr C4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(C1-C4alkyl), Cs-Czcycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl), including any member, combination, or subset thereof. In some embodiments, R3is substituted with a member independently selected from halo, Ci-C4alkyl, OCi-C4alkyl, and C(O)Ci-C4alkyl, including any member, combination, or subset thereof.

[0100] In some embodiments, R3includes at least one deuterium atom. In some embodiments, R3includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced withone or more respective halogen atoms (i.e., F, Cl, Br, and / or I) and / or one or more available atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of optionally substituted C1-C6alkyl of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of optionally substituted C1-C6alkyl of R3are replaced with a halogen atom. In some embodiments, none of the available atoms of optionally substituted C1-C6alkyl of R3are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of optionally substituted C1-C6alkyl of R3are replaced with a halogen atom and none of the available atoms of optionally substituted C1-C6alkyl of R3are replaced with an alternative isotope thereof.

[0101] In some embodiments, R3is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6deuteroalkyl, optionally substituted C1-C6haloalkyl, and optionally substituted C-i- Cadeuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R3is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0102] In some embodiments, R3is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2ICH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3IC(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, R3is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2, CH(CF3)2, CD(CD3)2ICF(CF3)2, C(CH3)3, C(CD3)3, and C(CF3)3, including any member, combination, or subset thereof. In some embodiments, R3is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)3, including any member, combination, or subset thereof. In some embodiments, R3is selected from H, F, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R3is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0103] In some embodiments, R6is selected from H, D, optionally substituted Ci-C3alkyl, optionally substituted Ci-C6alkyleneO(C1-C6alkyl), and optionally substituted C1-C6alkyleneS(Ci- Cealkyl), including any member, combination, or subset thereof. In some embodiments, R6includes at least one deuterium atom. In some embodiments, R6includes at least one halogen atom.

[0104] In some embodiments, R6is unsubstituted. In some embodiments, R6is substituted. In some embodiments, R6is substituted with a member selected from independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Ci-C4alkyl), CO2H, CO2(Ci- C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), Cs-Czcycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl), including any member, combination, or subset thereof. In some embodiments, R6is substituted with a member independently selected from halo, Ci-C4alkyl, OCi-C4alkyl, and C(O)Ci-C4alkyl, including any member, combination, or subset thereof.

[0105] In some embodiments, R6is selected from H and D, wherein H is not replaced with a halogen atom or an alternative isotope thereof. In some embodiments, R6is H not replaced with a halogen atom or an alternative isotope thereof. In some embodiments, R6is D.

[0106] In some embodiments, R6is selected from optionally substituted C1-C3alkyl, optionally substituted C1-C3deuteroalkyl, optionally substituted C1-C3haloalkyl, and optionally substituted C-i- Cadeuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R6is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0107] In some embodiments, R6is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, and CH(CDH2)2, including any member, combination, or subset thereof. In some embodiments, R6is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2, CH(CF3)2, CD(CD3)2, CF(CF3)2Iincluding any member, combination, or subset thereof. In some embodiments, R6is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)3, including any member, combination, or subset thereof. In some embodiments, R6is CD3. In some embodiments, R6is selected from H, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R6is selected from CH3, CH2F, CHF2ICF3, and CD3, including any member, combination, or subset thereof.

[0108] In some embodiments, R6is selected from optionally substituted C1-C6alkyleneO(Ci- Cealkyl), optionally substituted Ci-C6alkyleneO(Ci-C6deuteroalkyl), optionally substituted C1- C6alkyleneO(C1-C6haloalkyl), optionally substituted Ci-C6alkyleneO(Ci-C6deuterohaloalkyl), optionally substituted Ci-C6deuteroalkyleneO(C1-C6alkyl), optionally substituted C1- C6deuteroalkyleneO(Ci-C6deuteroalkyl), optionally substituted Ci-C6deuteroalkyleneO(Ci- Cehaloalkyl), optionally substituted Ci-C6deuteroalkyleneO(Ci-C6deuterohaloalkyl), optionallysubstituted Ci-C6haloalkyleneO(Ci-C6alkyl), optionally substituted Ci-C6halooalkyleneO(Ci- Cgdeuteroalkyl), optionally substituted Ci-C6haloalkyleneO(Ci-C6haloalkyl), optionally substituted Ci-C6haloalkyleneO(Ci-C6deuterohaloalkyl), optionally substituted Ci- C6deuterohaloalkyleneO(Ci-C6alkyl), optionally substituted Ci-C6deuterohaloalkyleneO(Cr Cedeuteroalkyl), optionally substituted Ci-C6deuterohaloalkyleneO(Ci-C6haloalkyl), and optionally substituted C1-C6deuterohalo alkyleneO(Ci-C6deuterohaloalkyl), including any member, combination, or subset thereof. In some embodiments, R6is CH2CH2OCH3. In some embodiments, R6is selected from CD3 and CH2CH2OCH3.

[0109] In some embodiments, R6is selected from optionally substituted Ci-C6alkyleneS(Ci- Cealkyl), optionally substituted Ci-C6alkyleneS(Ci-C6deuteroalkyl), optionally substituted C1- CoalkyleneSfC1-C6haloalkyl), optionally substituted Ci-C6alkyleneS(Ci-C6deuterohaloalkyl), optionally substituted Ci-C6deuteroalkyleneS(Ci-C6alkyl), optionally substituted C1- C6deuteroalkyleneS(C1-C6deuteroalkyl), optionally substituted Ci-C6deuteroalkyleneS(C-i- Cshaloalkyl), optionally substituted Ci-C6deuteroalkyleneS(Ci-C6deuterohaloalkyl), optionally substituted Ci-C6haloalkyleneS(Ci-C6alkyl), optionally substituted Ci-C6halooalkyleneS(Ci- Csdeuteroalkyl), optionally substituted Ci-C6haloalkyleneS(Ci-C6haloalkyl), optionally substituted Ci-C6haloalkyleneS(Ci-C6deuterohaloalkyl), optionally substituted C1- C6deuterohaloalkyleneS(Ci-C6alkyl), optionally substituted Ci-C6deuterohaloalkyleneS(Ci- Cedeuteroalkyl), optionally substituted Ci-C6deuterohaloalkyleneS(Ci-C6haloalkyl), and optionally substituted C1-C6deuterohalo alkyleneS(Ci-C6deuterohaloalkyl), including any member, combination, or subset thereof.

[0110] In some embodiments, R7is selected from H, D, and halo, including any member, combination, or subset thereof (e.g., H, D, and halo; H and D; H and halo; D and halo; H alone; D alone; halo alone). In some embodiments, R7is halo. In some embodiments, R7is a halogen selected from fluorine, chlorine, and bromine. In some embodiments, R7is a halogen selected from fluorine and bromine. In some embodiments, R7is a halogen selected from fluorine and chlorine. In some embodiments, R7is a halogen selected from chlorine and bromine. In some embodiments, R7is fluorine. In some embodiments, R7is chlorine. In some embodiments, R7is bromine. In some embodiments, R7is iodine. In some embodiments, R7is H not replaced by a halogen atom or an alternative isotope thereof. In some embodiments, R7is D.

[0111] In some embodiments, R8is selected from H, D, and halo, including any member, combination, or subset thereof (e.g., H, D, and halo; H and D; H and halo; D and halo; H alone;D alone; halo alone). In some embodiments, R8is halo. In some embodiments, R8is a halogen selected from fluorine, chlorine, and bromine. In some embodiments, R8is a halogen selected from fluorine and bromine. In some embodiments, R8is a halogen selected from fluorine and chlorine. In some embodiments, R8is a halogen selected from chlorine and bromine. In some embodiments, R8is fluorine. In some embodiments, R8is chlorine. In some embodiments, R8is bromine. In some embodiments, R8is iodine. In some embodiments, R8is H not replaced by a halogen atom or an alternative isotope thereof. In some embodiments, R8is D.

[0112] In some embodiments, R4is selected from H, D, halo (in some embodiments provided X is absent), optionally substituted Ci-Cioalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted Ci-CealkyleneOR9, optionally substituted Ci- C6alkyleneC(O)R9, optionally substituted Ci.C6alkyleneNR10C(O)R9, optionally substituted C-i. C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci.C6alkyleneOC(O)NR10R11, optionally substituted Ci.C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2- C6alkenyleneNR10C(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2.C6alkenyleneNR10R11, optionally substituted C2-C6alkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)OR9, optionally substituted C2- C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-CealkynyleneNR10R11, optionally substituted Ca-Czcycloalkyl, optionally substituted 3-memered to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C1-C6alkyleneCs-Czcycloalkyl, optionally substituted Ci-C6alkylene(3- to 10-membered)heterocycloalkyl, optionally substituted Ci-CealkyleneCe-Cwaryl, and optionally substituted Ci-C6alkylene(5- to 10-membered)heteroaryl, including any member, combination, or subset thereof.

[0113] In some embodiments, R4is selected from H, D, halo (in some embodiments provided X is absent), and optionally substituted Ci-Cwalkyl, including any member, combination, or subset thereof. In some embodiments, R4is selected from H, D, and halo (in some embodiments provided X is absent), including any member, combination, or subset thereof (e.g., H, D, and halo; H and D; H and halo; D and halo; H alone; D alone; halo alone). In some embodiments, R4is halo, in some embodiments provided X is absent. In some embodiments, R4is a halogen selected from fluorine, chlorine, and bromine, in some embodiments provided X is absent. In someembodiments, R4is a halogen selected from fluorine and bromine, in some embodiments provided X is absent. In some embodiments, R4is a halogen selected from fluorine and chlorine, in some embodiments provided X is absent. In some embodiments, R4is a halogen selected from chlorine and bromine, in some embodiments provided X is absent. In some embodiments, R4is fluorine, in some embodiments provided X is absent. In some embodiments, R4is chlorine, in some embodiments provided X is absent. In some embodiments, R4is bromine, in some embodiments provided X is absent. In some embodiments, R4is iodine, in some embodiments provided X is absent. In some embodiments, R4is H not replaced by a halogen atom or an alternative isotope thereof. In some embodiments, R4is D.

[0114] In some embodiments, R4is unsubstituted. In some embodiments, R4is substituted. In some embodiments, R4is substituted with a member selected from independently selected from halo (in some embodiments provided X is absent), Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Ci-C4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(C C4alkyl)(Ci-C4alkyl), Cs-Cycycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl), including any member, combination, or subset thereof. In some embodiments, R4is substituted with a member independently selected from halo, Ci-C4alkyl, OCi-C4alkyl, and C(O)Ci.C4alkyl, including any member, combination, or subset thereof.

[0115] In some embodiments, R4includes at least one deuterium atom. In some embodiments, R4includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of R4are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I) and / or one or more available atoms of R4are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R4are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of R4are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R4are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of R4are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R4are optionally and independently replaced with one or more respective fluorine atoms and / or oneor more available atoms of R4are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R4are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of R4are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R4are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of R4are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R4are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of R4are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of R4are replaced with a halogen atom. In some embodiments, none of the available atoms of R4are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of R4are replaced with a halogen atom and none of the available atoms of R4are replaced with an alternative isotope thereof.

[0116] In some embodiments, R4is selected from optionally substituted Ci-Cioalkyl, optionally substituted Ci-Ciodeuteroalkyl, optionally substituted Ci-Ciohaloalkyl, and optionally substituted Ci-Ciodeuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R4is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0117] In some embodiments, R4is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2ICH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, R4is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2, CH(CF3)2, CD(CD3)2, CF(CF3)2, C(CH3)3IC(CD3)3, and C(CF3)3, including any member, combination, or subset thereof. In some embodiments, R4is selected from CH3,CHF2, CFa, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)s, including any member, combination, or subset thereof. In some embodiments, R4is selected from H, F, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R4is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0118] In some embodiments, provided when X is selected from O, S, S(O), and S(O)2, then R4is not halo.

[0119] In some embodiments, R9is selected from H, D, optionally substituted C-i.Cealkyl, optionally substituted Cs-Czcycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, and optionally substituted 5- to 10-membered heteroaryl, including any member, combination, or subset thereof.

[0120] In some embodiments, R9is selected from H and D.. In some embodiments, R9is H not replaced by a halogen atom or an alternative isotope thereof. In some embodiments, R9is D.

[0121] In some embodiments, R9is unsubstituted. In some embodiments, R9is substituted. In some embodiments, R9is substituted with a member selected from independently selected fromCi-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Ci-C4alkyl), CO2H, CO2(Ci- C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), C3-C7cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl), including any member, combination, or subset thereof. In some embodiments, R9is substituted with a member independently selected from halo, Ci.C4alkyl, OCi.C4alkyl, and C(O)Ci-C4alkyl, including any member, combination, or subset thereof.

[0122] In some embodiments, R9includes at least one deuterium atom. In some embodiments, R9includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of R9are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I) and / or one or more available atoms of R9are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R9are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of R9are optionally and independentlyreplaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R9are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of R9are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R9are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of R9are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R9are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of R9are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R9are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of R9are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R9are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of R9are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of R9are replaced with a halogen atom. In some embodiments, none of the available atoms of R9are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of R9are replaced with a halogen atom and none of the available atoms of R9are replaced with an alternative isotope thereof.

[0123] In some embodiments, R9is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6deuteroalkyl, optionally substituted C1-C6haloalkyl, and optionally substituted Ci- Cedeuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R9is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0124] In some embodiments, R9is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2ICH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3IC(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2,CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3ICH2C(CH3)3, CH2C(CF3)3ICH2C(CD3)3ICH2CH2C(CH3)3, CH2CH2C(CF3)3Iand CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, R9is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2, CH(CF3)2, CD(CD3)2JCF(CF3)2IC(CH3)3, C(CD3)3, and C(CF3)3, including any member, combination, or subset thereof. In some embodiments, R9is selected from CH3, CHF2, CF3ICD3, CH2CH3, CH(CH3)2ICH(CD3)2, and C(CH3)3, including any member, combination, or subset thereof. In some embodiments, R9is selected from H, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R9is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0125] In some embodiments, R10is selected from H, D, and optionally substituted C1-C6alkyl, including any member, combination, or subset thereof. In some embodiments, R10is H not replaced with a halogen or alternative isotope. In some embodiments, R10is D. In some embodiments, R10is selected from optionally substituted C1-C6alkyl, optionally substituted Ci- Cedeuteroalkyl, optionally substituted C1-C6haloalkyl, and optionally substituted Ci- Cgdeuteroheteroalkyl, including any member, combination, or subset thereof.

[0126] In some embodiments, R10includes at least one deuterium atom. In some embodiments, R10includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of Ci-Cealkyl of R10are optionally and independently replaced with one or more respective halogen atoms (i.e. , F, Cl, Br, and / or I) and / or one or more available atoms of C1-C6alkyl of R10are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of C1-C6alkyl of R10are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of R10are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Ci- Cealkyl of R10are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of R10are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of C1-C6alkyl of R10are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of R10are optionally and independently replaced with one or morerespective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Ci Cealkyl of R10are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of R10are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of C1-C6alkyl of R10are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of R10are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of C1-C6alkyl of R10are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of R10are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of Ci- Cealkyl of R10are replaced with a halogen atom. In some embodiments, none of the available atoms of Ci-Cealkyl of R10are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of C1-C6alkyl of R10are replaced with a halogen atom and none of the available atoms of C1-C6alkyl of R10are replaced with an alternative isotope thereof.

[0127] In some embodiments, R10is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6deuteroalkyl, optionally substituted C1-C6haloalkyl, and optionally substituted Ci- Cedeuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R10is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0128] In some embodiments, R10is selected from CH3, CD2H, CDH2, CD3. CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3IC(CDH2)3ICH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, R10is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2, CH(CF3)2, CD(CD3)2, CF(CF3)2, C(CH3)3IC(CD3)3, and C(CF3)3, including any member, combination, or subset thereof. In some embodiments, R10is selected from CH3, CHF2, CF3ICD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)3, including any member,combination, or subset thereof. In some embodiments, R10is selected from H, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R10is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0129] In some embodiments, R11is selected from H, D, and optionally substituted Ci.Cealkyl, including any member, combination, or subset thereof. In some embodiments, R11is H not replaced with a halogen or alternative isotope. In some embodiments, R11is D.

[0130] In some embodiments, R11includes at least one deuterium atom. In some embodiments, R11includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of Ci.Cealkyl of R11are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I) and / or one or more available atoms of Ci.Cealkyl of R11are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Ci.Cealkyl of R11are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of R11are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of C1- Cealkyl of R11are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of R11are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Ci.Cealkyl of R11are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of R11are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Ci.Cealkyl of R11are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of R11are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Ci.Cealkyl of R11are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of R11are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Ci.Cealkyl of R11are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of R11are optionally and independently replaced with one or more respectivealternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of Ci- Cealkyl of R11are replaced with a halogen atom. In some embodiments, none of the available atoms of Ci-Cealkyl of R11are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of C1-C6alkyl of R11are replaced with a halogen atom and none of the available atoms of C1-C6alkyl of R11are replaced with an alternative isotope thereof.

[0131] In some embodiments, R11is selected from optionally substituted C1-C6alkyl, optionally substituted C1-C6deuteroalkyl, optionally substituted C1-C6haloalkyl, and optionally substituted C-i- C6deuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R11is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0132] In some embodiments, R11is selected from CH3, CD2H, CDH2, CD3. CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2, C(CH3)3, C(CF3)3IC(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, R11is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2, CH(CF3)2, CD(CD3)2, CF(CF3)2, C(CH3)3, C(CD3)3, and C(CF3)3, including any member, combination, or subset thereof. In some embodiments, R11is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)3, including any member, combination, or subset thereof. In some embodiments, R11is selected from H, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R11is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0133] In some embodiments, R5is selected from H, D, halo, OH, optionally substituted Ci- Cealkyl, and Q-A, including any member, combination, or subset thereof.

[0134] In some embodiments, R5is selected from H, D, halo, and OH, including any member, combination, or subset thereof (e.g., H, D, halo, and OH; H, D, and halo; H, D, and OH; H, halo,and OH; D, halo, and OH; H and D; H and halo; H and OH; D and halo; D and OH; halo and OH; H alone; D alone; halo alone; OH alone). In some embodiments, R5is halo. In some embodiments, R5is a halogen selected from fluorine, chlorine, and bromine. In some embodiments, R5is a halogen selected from fluorine and bromine. In some embodiments, R5is a halogen selected from fluorine and chlorine. In some embodiments, R5is a halogen selected from chlorine and bromine. In some embodiments, R5is fluorine. In some embodiments, R5is chlorine. In some embodiments, R5is bromine. In some embodiments, R5is iodine. In some embodiments, R5is H not replaced by a halogen atom or an alternative isotope thereof. In some embodiments, R5is D. In some embodiments, R5is selected from OH and OD. In some embodiments, R5is OH. In some embodiments, R5is OD.

[0135] In some embodiments, R5is selected from unsubstituted C1-C6alkyl, unsubstituted C-i- Cedeuteroalkyl, unsubstituted C1-C6haloalkyl, and unsubstituted C1-C6deuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R5is selected from substituted C1-C3alkyl, substituted C1-C3deuteroalkyl, substituted C1-C6haloalkyl, and substituted C1-C6deuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, R5is substituted with a member selected from independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci- C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Ci-C4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), C3-C7cycloalkyl, and a 3- to 6- membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl), including any member, combination, or subset thereof. In some embodiments, R5is substituted with a member independently selected from halo, Ci- C4alkyl, OCi.C4alkyl, and C(O)Ci.C4alkyl, including any member, combination, or subset thereof.

[0136] In some embodiments, R5includes at least one deuterium atom. In some embodiments, R5includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of R5are optionally and independently replaced with one or more respective halogen atoms and / or one or more available atoms of R5are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R5are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of R5are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R5are optionally and independently replaced with one or more respectivefluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of R5are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R5are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of R5are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R5are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of R5are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R5are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of R5are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R5are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of R5are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of R5are replaced with a halogen atom. In some embodiments, none of the available atoms of R5are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of R5are replaced with a halogen atom and none of the available atoms of R5are replaced with an alternative isotope thereof.

[0137] In some embodiments, R5is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0138] In some embodiments, R5is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2ICH(CHD2)2ICH(CDH2)2, C(CH3)3, C(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, R5is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3, CH(CH3)2, CH(CD3)2, CH(CF3)2, CD(CD3)2, CF(CF3)2, C(CH3)3IC(CD3)3, and C(CF3)3, including any member, combination, or subset thereof. In some embodiments, R5is selected from CH3,CHF2, CFa, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)s, including any member, combination, or subset thereof. In some embodiments, R5is selected from H, F, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, R5is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof.

[0139] In some embodiments, R5is Q-A. In some embodiments, Q is selected from O, S, S(O), and S(O)2, including any member, combination, subset thereof, e.g., O, S, S(O), and S(O)2; O, S, and S(O); O, S, and S(O)2; O, S(O), and S(0)2j S, S(O), and S(0)2j O and S; O and S(O); O and S(O)2; S and S(O); S and S(O)2; S(O) and S(O)2; O; S; S(O); and S(O)2.

[0140] In some embodiments, A of R5is selected from H, D, P(O)(OR12)2, CH2P(O)(OR12)2, CH(CH3)P(O)(OR12)2, C(O)Q', CH2(C3-C7cycloalkyl), CH2(C4-C6cycloalkenyl), CH2(3- to 10- membered)heterocycloalkyl, CH2(C6-Cioaryl), CH2(5- to 10-membered)heteroaryl, and C-walkyl. In some embodiments, A is selected from CH2(C3-C7cycloalkyl), CH2(C4-C6cycloalkenyl), CH2(3- to 10-membered)heterocycloalkyl, CH2(C6-Cioaryl), CH2(5- to 10-membered)heteroaryl.

[0141] In some embodiments, A is selected from H and D. In some embodiments, A is nondeuterated H not replaced with an alternative isotope. In some embodiments A is D.

[0142] In some embodiments, A includes at least one deuterium atom. In some embodiments, A includes at least one halogen atom. In some embodiments, A is selected from Ci-C4alkyl, C1- C4deuteroalkyl, Ci-C4haloalkyl, and Ci-C4deuteroheteroalkyl, including any member, combination, or subset thereof. In some embodiments, A is selected from methyl, ethyl, isopropyl, and tert-butyl, including any member, combination, or subset thereof.

[0143] In some embodiments, A is selected from CH3, CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH3, CH2CH2F, CH2CF2H, CH2CF3, CF2CF3, CH2CH2D, CH2CD2H, CH2CD3 CD2CD3, CH2CH2CH3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2ICH(CD3)2ICH(CHD2)2ICH(CDH2)2, C(CH3)3IC(CF3)3, C(CHF2)3, C(CFH2)3, C(CD3)3IC(CHD2)3IC(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CF3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CF3)2, CH(CH3)CH2CH3, CH(CH3)CH2CF3, CH(CH3)CH2CD3, CH2CH(CH3)CH3, CH2CH(CH3)CF3, CH2CH(CH3)CD3, CH2C(CH3)3, CH2C(CF3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CF3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof. In some embodiments, A is selected from CH3, CH2D, CHD2, CD3, CH2F, CHF2, CF3, CH2CH3, CD2CD3, CF2CF3,CH(CH3)2, CH(CD3)2, CH(CF3)2ICD(CD3)2ICF(CF3)2, C(CH3)3IC(CD3)3Iand C(CF3)3Iincluding any member, combination, or subset thereof. In some embodiments, A is selected from CH3, CHF2, CF3ICD3, CH2CH3, CH(CH3)2, CH(CD3)2, and C(CH3)3, including any member, combination, or subset thereof. In some embodiments, A is selected from H, CH3, CHD2, CD3, CH2F, CHF2, and CF3, including any member, combination, or subset thereof. In some embodiments, A is selected from CH3, CH2F, CHF2, CF3, and CD3, including any member, combination, or subset thereof. In some embodiments, A is selected from non-deuterated CH3, CH2F, CHF2Iand CF3. In some embodiments, A is CH3not substituted with a halogen atom or an alternative isotope thereof.

[0144] In some embodiments, A is selected from P(O)(OR12)2, CH2P(O)(OR12)2, and CH(CH3)P(O)(OR12)2, wherein each R12is independently selected from H, D, C1-C4 alkyl, and C2- C3alkenyl.

[0145] In some embodiments, R12includes at least one deuterium atom. In some embodiments, R12includes at least one halogen atom, but R12does not consist of only a halogen atom. In some embodiments, one or more available hydrogen atoms of R12are optionally and independently replaced with one or more respective halogen atoms and / or one or more available atoms of R12are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R12are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of R12are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R12are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of R12are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R12are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of R12are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R12are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of R12are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R12are optionally and independently replaced with one or more respective bromine atoms and / or one ormore available atoms of R12are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of R12are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of R12are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of R12are replaced with a halogen atom. In some embodiments, none of the available atoms of R12are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of R12are replaced with a halogen atom and none of the available atoms of R12are replaced with an alternative isotope thereof.

[0146] In some embodiments, A is C(O)Q', wherein Q' is selected from:

[0147] In some embodiments, Q' includes at least one deuterium atom. In some embodiments, Q' includes at least one halogen atom. In some embodiments, one or more available hydrogen atoms of Q’ are optionally and independently replaced with one or more respective halogen atoms and / or one or more available atoms of R3are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Q' are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of Q' are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Q' are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of Q' are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Q' are optionally and independently replaced with one or more respective fluorine atoms and / or one or more available atoms of Q' are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Q' are optionally and independently replaced with one or more respective chlorine atoms and / or one or more available atoms of Q' are optionally and independently replaced with one or more respectivealternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Q' are optionally and independently replaced with one or more respective bromine atoms and / or one or more available atoms of Q' are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of Q’ are optionally and independently replaced with one or more respective iodine atoms and / or one or more available atoms of Q' are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, none of the available hydrogen atoms of Q' are replaced with a halogen atom. In some embodiments, none of the available atoms of Q' are replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of Q' are replaced with a halogen atom and none of the available atoms of Q' are replaced with an alternative isotope thereof.

[0148] In some embodiments, when R1is phenyl, then R1is substituted with at least one substituent not selected from H, D, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxyl, C-i- Cealkyl, and C-i-Cealkoxy.

[0149] In some embodiments, when X is absent and R4is H, then R6is neither H nor nondeuterated Ci-Caalkyl.

[0150] In some embodiments, when X is absent and R4is halo, then R5is selected from H and D and is not halo.

[0151] In some embodiments, X is absent and R4is selected from H and D but not halo, then R5is selected from halo, OH, optionally substituted C1-C6alkyl, and Q-A.

[0152] In some embodiments, when R4is selected from optionally substituted Ci-Cioalkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted Ci- CsalkyleneOR9, optionally substituted Ci-C6alkyleneC(O)R9, optionally substituted Ci- CealkyleneNR10C(O)R9, optionally substituted Ci.C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci-C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)OR9, optionally substituted C2- C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-CealkenyleneNR10R11, optionally substituted C2-C6alkynyleneOR9, optionally substituted C2-CealkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11,optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2- C6alkynyleneNR10R11, optionally substituted Cs-Czcycloalkyl, optionally substituted (3- to 10- membered)heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10- membered heteroaryl, optionally substituted C1-C6alkyleneCs-Czcycloalkyl, optionally substituted Ci-C6alkylene(3- to 10-membered)heterocycloalkyl, optionally substituted Ci-CgalkyleneCe- Cioaryl, and optionally substituted Ci.C6alkylene(5- to 10-membered)heteroaryl, then R5is selected from H, D, and halo.

[0153] In some embodiments, when R1is phenyl, then the phenyl of R1is substituted with at least one substituent selected from OH, SH, and C1-C6alkylthio.

[0154] In some embodiments, when X is absent and R4is selected from H and D, then R6is not H, D, or C1-C3alkyL

[0155] In some embodiments, the compound is characterized by:X is absent or selected from O, S, S(O), and S(O)2;R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is selected from H, halo provided X is absent, and C1-C3alkyl;R5is selected from H, halo, C1-C6alkyl, and Q-A;R6is selected from C1-C3alkyl and Ci-C6alkyleneO(C1-C6alkyl);R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2iA is C1-4alkyl; andH of each of R2, R3, R7, and R8is not replaced with halogen or a respective isotope.

[0156] In some embodiments, the compound is characterized by:X is absent or is selected from O, S, S(O), and S(0)2jR1is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, C(CH3)3IOCF3, OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine, pyrrole, thiazole, tetrahydrothiophene, thiophene, piperidine, and pyridine;R2is H;R3is H;R4is selected from H, F (provided X is absent), CH3, CHD2CD3, CH2F, CHF2, and CF3;R5is selected from H, F, CF3, and Q-A;R6is selected from CD3and CH2CH2OCH3, or R6is selected from CH3, CD3, and CH2CH2OCH3;R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2;A is selected from H, CH3, CH2F, CHF2, CF3, and CD3; andH of each of R2, R3, R7, and R8is not replaced with halogen or a respective isotope.

[0157] In some embodiments, the compound is characterized by:X is selected from O, S, S(O), and S(O)2;R1is selected from optionally substituted C-i-Cealkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is Ci-C3alkyl;R5is selected from H and halo;R6is Ci-C3alkyl;R7is H;R8is H; andH of each of R2, R3, R7, and R8is not replaced with halogen or a respective isotope.

[0158] In some embodiments, the compound is characterized by:R1is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, C(CH3)3IOCF3, OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine, pyrrole, thiazole, tetrahydrothiophene, thiophene, piperidine, and pyridine;R2is H;R3is H;R4is selected from CH3, CHD2CD3, CH2F, CHF2, and CF3;R5is selected from H and halo;R6is CD3, or R6is selected from CH3and CD3;R7is H;R8is H;H of each of R2, R3, R7, and R8is not replaced with halogen or a respective isotope; and the available hydrogen atoms of R1and R4are not replaced with a halogen atom and the available atoms of R1and R4are not replaced with an alternative isotope.

[0159] In some embodiments, the compound is characterized by:X is absent;R1is selected from optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6- membered heteroaryl;R2is H;R3is H;R4is selected from halo and Ci-C3alkyl;R5is H;R6is Ci-C3alkyl;R7is H;R8is H; andH of each of R2, R3, R5, R7, and R8is not replaced with halogen or a respective isotope.

[0160] In some embodiments, the compound is characterized by:X is absent;R1is selected from CH3, CD3, CH(CH3)2, cyclobutyl, tetrahydrofuran, and pyridine;R2is H;R3is H;R4is selected from F, CHF2, CF3, and CD3, or R4is selected from F, CH3, CHF2, CF3, and CD3;R5is H;R6is CD3, or R6is selected from CH3 and CD3;R7is H;R8is H;H of each of R2, R3, R5, R7, and R8is not replaced with halogen or a respective isotope; and the available hydrogen atoms of R1and R4are not replaced with a halogen atom and wherein the available atoms of R1and R4are not replaced with an alternative isotope.

[0161] In some embodiments, the compound is characterized by:X is absent;R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is H;R5is selected from halo, C1-C6alkyl, and Q-A;R6is selected from C1-C3alkyl and Ci-C6alkyleneO(C1-C6alkyl);R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2iA is C1-4alkyl; andH of each of R2, R3, R4, R7, and R8is not replaced with halogen or a respective isotope.

[0162] In some embodiments, the compound is characterized by:R1is selected from CH3, CHF2, CD3, CH2CH3, CH(CH3)2, C(CH3)3, OCHF2, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, and pyridine;R2is H;R3is H;R4is H;R5is selected from F, CF3, and Q-A;R6is selected from CD3and CH2CH2OCH3, or R6is selected from CH3, CD3, and CH2CH2OCH3;R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2;A is selected from H, CH3, CH2F, CHF2, CF3, and CD3;H of each of R2, R3, R4, R7, and R8is not replaced with halogen or a respective isotope; and the available hydrogen atoms of R1, A, and R6are not replaced with a halogen atom and the available atoms of R1, R2, R3, R4, R5, R6, R7, R8and A, are not replaced with an alternative isotope.

[0163] In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12) are optionally and independently substituted C1-C3alkyl. In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, and A) are optionally and independently substituted Ci-C4alkyl. In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, and A) are optionally and independently substituted Ci-C3alkyl. In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, and A) are optionally and independently substituted Ci-C2alkyl. In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12) are optionally and independently substituted C2-Cealkyl. In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12) are optionally and independently substituted C3-Cealkyl. In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12) are optionally and independently substituted C^CealkyL In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12) are optionally and independently substituted C3-C6alkyl. In some embodiments, the alkyl groups (such as, for example, of R1, R2,R3, R4, R5, R6, R9, R10, R11, R12, and A) are optionally and independently substituted C-ialkyl (that is, methyl). In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, and A) are optionally and independently substituted C2alkyl (that is, ethyl). In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, and A) are optionally and independently substituted Csalkyl (that is, propyl). In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, and A) are optionally and independently substituted C4alkyl (that is, butyl). In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12) are optionally and independently substituted Csalkyl (that is, pentyl). In some embodiments, the alkyl groups (such as, for example, of R1, R2, R3, R4, R5, R6, R9, R10, R11, and R12) are optionally and independently substituted Cealkyl (that is, hexyl). In some embodiments, the alkyl groups are optionally and independently selected from any combination of the above. In some embodiments, the alkyl groups are independently substituted. In some embodiments, the above alkyl groups are independently unsubstituted.

[0164] In some embodiments, the alkyl groups optionally and independently selected from C2- Cehaloalkenyl (e.g., C2-C6fluoroalkenyl), C2-C6deuteroalkenyl, and C2-C6deuterohaloalkenyl (e.g., C2-C6deuterofluoroalkenyl), including any member, combination, or subset thereof. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from F, Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from F, Cl, and Br. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from F, Cl, and I. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from F, Br, and I. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from F and Cl. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from F and Br. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from F and I. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from Cl and Br. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from Cl and I. In some embodiments, the one or more halogen atoms of the alkyl groups are optionally and independently selected from Br and I. In some embodiments,the one or more halogen atoms of the alkyl groups are independently F. In some embodiments, the one or more halogen atoms of the alkyl groups are independently Cl. In some embodiments, the one or more halogen atoms of the alkyl groups are independently Br. In some embodiments, the one or more halogen atoms of the alkyl groups are independently I. In some embodiments, the alkyl groups optionally and independently do not include a halogen atom. In some embodiments, the alkyl groups optionally and independently do not include an alternative isotope. In some embodiments, the alkyl groups optionally and independently include neither a halogen atom nor an alternative isotope.

[0165] In some embodiments, the alkyl groups are optionally and independently selected from CH3, CD2H, CDH2, CD3, CY2H, CYH2ICY3ICH2CH3ICH2CH2Y, CH2CY2H, CH2CY3ICY2CY3, CH2CH2D, CH2CD2H, CH2CD3, CD2CD3, CH2CH2CH3, CH2CH2CHY2, CH2CH2CYH2, CH2CH2CY3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3CH(CH3)2ICH(CY3)2ICH(CHY2)2ICH(CYH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2IC(CH3)3IC(CY3)3IC(CHY2)3IC(CYH2)3, C(CD3)3, C(CHD2)3, C(CDH2)3, CH2CH2CH2CH3, CH2CH2CH2CY3, CH2CH2CH2CD3, CH2CH(CH3)2, CH2CH(CD3)2, CH2CH(CY3)2ICH(CH3)CH2CH3ICH(CH3)CH2CY3, CH(CH3)CH2CD3ICH2CH(CH3)CH3, CH2CH(CH3)CY3, CH2CH(CH3)CD3ICH2C(CH3)3, CH2C(CY3)3, CH2C(CD3)3, CH2CH2C(CH3)3, CH2CH2C(CY3)3, and CH2CH2C(CD3)3, including any member, combination, or subset thereof, wherein each Y is independently a halogen atom. In some embodiments, each Y is optionally and independently selected from F, Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F, Cl, and Br. In some embodiments, each Y is optionally and independently selected from F, Cl, and I. In some embodiments, each Y is optionally and independently selected from F, Br, and I. In some embodiments, each Y is optionally and independently selected from Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F and Cl. In some embodiments, each Y is optionally and independently selected from F and Br. In some embodiments, each Y is optionally and independently selected from F and I. In some embodiments, each Y is optionally and independently selected from Cl and Br. In some embodiments, each Y is optionally and independently selected from Cl and I. In some embodiments, each Y is optionally and independently selected from Br and I. In some embodiments, each Y is F. In some embodiments, each Y is Cl. In some embodiments, each Y is Br. In some embodiments, each Y is I. In some embodiments, the alkyl groups are optionally and independently deuterated and / or fluorinated and selected from CD2H, CDH2, CD3, CF2H, CFH2, CF3, CH2CH2F, CH2CF2H, CH2CF3, CHFCH3, CHFCH2F, CHFCHF2, CHFCF3ICF2CH3ICF2CH2F, CF2CHF2, CF2CF3, CH2CH2D, CH2CD2H,CH2CD3, CHDCHs, CHDCH2D, CHDCHD2, CHDCD3, CD2CH3, CD2CH2D, CD2CHD2, CD2CD3, CH2CH2CHF2, CH2CH2CFH2, CH2CH2CF3, CH2CH2CHD2, CH2CH2CDH2, CH2CH2CD3 CH(CH3)2, CH(CF3)2, CH(CHF2)2, CH(CFH2)2, CH(CD3)2, CH(CHD2)2, CH(CDH2)2IC(CH3)3, C(CF3)3IC(CHF2)3, C(CFH2)3, C(CD3)3, C(CHD2)3, and C(CDH2)3, including any member, combination, or subset thereof.

[0166] In some embodiments, the alkenyl groups (such as, for example, of R1, R4, and R12) are optionally andC3-C6alkenyl. In some embodiments, the alkenyl groups are optionally andC4-Cealkenyl. In some embodiments, the alkenyl groups are optionally andC3-C6alkenyl. In some embodiments, the alkenyl groups are optionally and independently C2-C3alkenyl. In some embodiments, the alkenyl groups are optionally and independently C2-C4alkenyl. In some embodiments, the alkenyl groups are optionally and independently C2-C5alkenyl. In some embodiments, the alkenyl groups are optionally and independently C2alkenyl (i.e., ethenyl). In some embodiments, the alkenyl groups are optionally and independently Csalkenyl (i.e., propenyl). In some embodiments, the alkenyl groups are optionally and independently Cealkenyl (i.e., butenyl). In some embodiments, the alkenyl groups are optionally and independently Csalkenyl (i.e., pentenyl). In some embodiments, the alkenyl groups are optionally and independently Csalkenyl (i.e., hexenyl). In some embodiments, the above alkenyl groups are independently substituted. In some embodiments, the above alkenyl groups are independently unsubstituted.

[0167] In some embodiments, the alkenyl groups optionally and independently selected from C2-C6haloalkenyl (e.g., C2-C6fluoroalkenyl), C2-C6deuteroalkenyl, and C2-C6deuterohaloalkenyl (e.g., C2-C6deuterofluoroalkenyl), including any member, combination, or subset thereof. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from F, Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from F, Cl, and Br. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from F, Cl, and I. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from F, Br, and I. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from F and Cl. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from F and Br. In some embodiments, the one or more halogen atoms ofthe alkenyl groups are optionally and independently selected from F and I. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from Cl and Br. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from Cl and I. In some embodiments, the one or more halogen atoms of the alkenyl groups are optionally and independently selected from Br and I. In some embodiments, the one or more halogen atoms of the alkenyl groups are independently F. In some embodiments, the one or more halogen atoms of the alkenyl groups are independently Cl. In some embodiments, the one or more halogen atoms of the alkenyl groups are independently Br. In some embodiments, the one or more halogen atoms of the alkenyl groups are independently I. In some embodiments, the alkenyl groups optionally and independently do not include a halogen atom. In some embodiments, the alkenyl groups optionally and independently do not include an alternative isotope. In some embodiments, the alkenyl groups optionally and independently include neither a halogen atom nor an alternative isotope.

[0168] In some embodiments, alkenyl groups are optionally and independently selected from CH=CH2, CH2CH=CH2, CY2CH=CH2ICD2CH=CH2ICH=CH2CH3ICH=CH2CY3ICH=CH2CHY2, CH=CH2CH2Y, CH=CH2CD3, CH=CH2CHD2Iand CH=CH2CH2D, including any member, combination, or subset thereof, wherein each Y is independently a halogen atom. In an embodiment, each Y is independently selected from F, Cl, Br, and I. In some embodiments, each Y is independently selected from F, Cl, and Br. In some embodiments, each Y is independently selected from F, Cl, and I. In some embodiments, each Y is independently selected from F, Br, and I. In some embodiments, each Y is independently selected from Cl, Br, and I. In some embodiments, each Y is independently selected from F and Cl. In some embodiments, each Y is independently selected from F and Br. In some embodiments, each Y is independently selected from F and I. In some embodiments, each Y is independently selected from Cl and Br. In some embodiments, each Y is independently selected from Cl and I. In some embodiments, each Y is independently selected from Br and I. In some embodiments, each Y is F. In some embodiments, each Y is Cl. In some embodiments, each Y is Br. In some embodiments, each Y is I.

[0169] In some embodiments, the alkynyl groups such as, for example, of R1and R4) are optionally and independently C3-C6alkynyL In some embodiments, the alkynyl groups are optionally and independently C^CealkynyL In some embodiments, the alkynyl groups are optionally and independently C3-C6alkynyL In some embodiments, the alkynyl groups are optionally and independently C2.C3alkynyl. In some embodiments, the alkynyl groups are optionally and independently C2.C4alkynyl. In some embodiments, the alkynyl groups areoptionally and independently C2-C5alkynyl. In some embodiments, the alkynyl groups are optionally and independently C2alkynyl (i.e., ethynyl). In some embodiments, the alkynyl groups are optionally and independently Csalkynyl (i.e., propynyl). In some embodiments, the alkynyl groups are optionally and independently C4alkynyl (i.e., butynyl). In some embodiments, the alkynyl groups are optionally and independently Csalkynyl (i.e., pentynyl). In some embodiments, the alkynyl groups are optionally and independently Cealkynyl (i.e., hexynyl). In some embodiments, the above alkynyl groups are independently substituted. In some embodiments, the above alkynyl groups are independently unsubstituted.

[0170] In some embodiments, the alkynyl groups optionally and independently selected from C2-C6haloalkynyl (e.g., C2-C6fluoroalkynyl), C2-C6deuteroalkynyl, and C2-C6deuterohaloalkynyl (e.g., C2-C6deuterofluoroalkynyl), including any member, combination, or subset thereof. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from F, Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from F, Cl, and Br. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from F, Cl, and I. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from F, Br, and I. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from F and Cl. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from F and Br. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from F and I. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from Cl and Br. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from Cl and I. In some embodiments, the one or more halogen atoms of the alkynyl groups are optionally and independently selected from Br and I. In some embodiments, the one or more halogen atoms of the alkynyl groups are independently F. In some embodiments, the one or more halogen atoms of the alkynyl groups are independently Cl. In some embodiments, the one or more halogen atoms of the alkynyl groups are independently Br. In some embodiments, the one or more halogen atoms of the alkynyl groups are independently I. In some embodiments, the alkynyl groups optionally and independently do not include a halogen atom. In some embodiments, the alkynyl groups optionally and independently do not include analternative isotope. In some embodiments, the alkynyl groups optionally and independently include neither a halogen atom nor an alternative isotope.

[0171] In some embodiments, C2-Cealkynyl is optionally and independently selected fromCD2CECCD3, CH2CECCY3, CY2CECCY3, CD2CECCY3, CH2C≡CCHD2, CY2C≡CHD2, CD2C≡CHD2, CH2C≡CHY2, CY2C≡CHY2, and CD2C≡CHY2, including any member, combination, or subset thereof, wherein each Y is independently a halogen atom. In an embodiment, each Y is independently selected from F, Cl, Br, and I. In some embodiments, each Y is independently selected from F, Cl, and Br. In some embodiments, each Y is independently selected from F, Cl, and I. In some embodiments, each Y is independently selected from F, Br, and I. In some embodiments, each Y is independently selected from Cl, Br, and I. In some embodiments, each Y is independently selected from F and Cl. In some embodiments, each Y is independently selected from F and Br. In some embodiments, each Y is independently selected from F and I. In some embodiments, each Y is independently selected from Cl and Br. In some embodiments, each Y is independently selected from Cl and I. In some embodiments, each Y is independently selected from Br and I. In some embodiments, each Y is F. In some embodiments, each Y is Cl. In some embodiments, each Y is Br. In some embodiments, each Y is I.

[0172] In some embodiments, the alkylene groups (such as, for example, of R1, R4, and R6) are optionally andC1-C3alkylene. In some embodiments, the alkylene groups are optionally and independently CrC4alkylene. In some embodiments, the alkylene groups are optionally andCrC3alkylene. In some embodiments, the alkylene groups are optionally and independently CrC2alkylene. In some embodiments, the alkylene groups are optionally andC2-Cealkylene. In some embodiments, the alkylene groups are optionally and independently C3-Cealkylene. In some embodiments, the alkylene groups are optionally andC4-Cealkylene. In some embodiments, the alkylene groups are optionally and independently C3-C6alkylene. In some embodiments, the alkylene groups are optionally and independently Cialkylene (i.e., methylene). In some embodiments, the alkylene groups are optionally and independently C2alkylene (i.e., ethylene). In some embodiments, the alkylene groups are optionally and independently C3alkylene (i.e., propylene). In some embodiments, the alkylene groups are optionally and independently C4alkylene (i.e., butylene). In some embodiments, the alkylene groups are optionally and independently Csalkylene (i.e., pentylene). In some embodiments, the alkylene groups are optionally and independentlyCealkylene (i.e., hexylene). In some embodiments, the optionally substituted alkylene is independently selected from any combination of the above.

[0173] In some embodiments, the alkylene groups optionally and independently selected from C2-C6haloalkylene (e.g., C2-C6fluoroalkylene), C2-C6deuteroalkylene, and C2- Cedeuterohaloalkylene (e.g., C2-C6deuterofluoroalkylene), including any member, combination, or subset thereof. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from F, Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from F, Cl, and Br. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from F, Cl, and I. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from F, Br, and I. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from F and Cl. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from F and Br. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from F and I. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from Cl and Br. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from Cl and I. In some embodiments, the one or more halogen atoms of the alkylene groups are optionally and independently selected from Br and I. In some embodiments, the one or more halogen atoms of the alkylene groups are independently F. In some embodiments, the one or more halogen atoms of the alkylene groups are independently Cl. In some embodiments, the one or more halogen atoms of the alkylene groups are independently Br. In some embodiments, the one or more halogen atoms of the alkylene groups are independently I. In some embodiments, the alkylene groups optionally and independently do not include a halogen atom. In some embodiments, the alkylene groups optionally and independently do not include an alternative isotope. In some embodiments, the alkylene groups optionally and independently include neither a halogen atom nor an alternative isotope.

[0174] In some embodiments herein, the alkylene groups are independently selected from - CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)-, -C(CH3)2-, - CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2-, -C(CH3)2CH2CH2-,CH2CH(CH3)CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2C(CH3)2-,CH2CH2CH2CH(CH3)-, -CH(CH3)CH(CH3)CH2-, -CH(CH3)CH2CH(CH3)-, - CH2CH(CH3)CH(CH3), -CH2CH2CH2CH2CH2CH2-, -CH(CH3)CH2CH2CH2CH2-, -C(CH3)2CH2CH2CH2-,CH2CH(CH3)CH2CH2CH2-, -CH2C(CH3)2CH2CH2CH2-, -CH2CH2CH(CH3)CH2CH2-,CH2CH2C(CH3)2CH2CH2-, -CH2CH2CH2CH(CH3)CH2-, -CH2CH2CH2C(CH3)2CH2-,CH2CH2CH2CH2CH(CH3)-, -CH2CH2CH2CH2C(CH3)2-, -CH(CH3)CH(CH3)CH2CH2-,CH(CH3)CH2CH(CH3)CH2-, -CH(CH3)CH2CH2CH(CH3)-, -CH2CH(CH3)CH(CH3)CH2-,CH2CH(CH3)CH2CH(CH3)-, -CH2CH2CH(CH3)CH(CH3)-, -C(CH3)2CH(CH3)CH2-,C(CH3)2CH2CH(CH3)-, -CH2C(CH3)2CH(CH3)-, -CH2CH(CH3)C(CH3)2-, and -C(CH3)2C(CH3)2-, including any member, combination, or subset thereof.

[0175] In some embodiments, available hydrogen(s) on the alkylene groups is / are optionally and independently substituted with one or more deuterium atoms and / or one or more halogen atoms. In some embodiments, the alkylene groups are optionally and independently selected from haloalkylene (e.g., Ci.Cefluoroalkylene), deuteroalkylene (e.g., C1-C3deuteroalkylene), and deuterohaloalkylene (e.g., C1-C3deuterofluoroalkylene), including any member, combination, or subset thereof. In some embodiments, the alkylene groups are independently selected from - CHY-, -CY2-, -CHD-, -CD2-, -CDF-, -CF2CF2-, -CH2CD2-, -CD2CH2-, -CH2CHD-, -CHDCH2-, - CH2CHY-, -CHYCH2-, -CH2CY2-, -CY2CH2-, -CHYCHY-, -CHDCHY-, -CHYCHD-, -CD2CHY-, CHYCD2, -CHDCY2-, -CY2CHD-, -CY2CD2-, -CD2CY2-, -CD2CHD-, -CHDCD2-, -CD2CD2-, - CD2CD2CD2-, -CH2CD2CD2- -CD2CH2CH2-, -CH2CH2CD2-, -CD2CD2CH2-, -CH2CD2CH2-, - CH2CH2CHD-, -CHDCHDCH2-, -CH2CHDCHD-, -CD2CD(CH3)-, -CD2CHDCH2-, -CH2CD(CH3)-, - CH2CHDCH2-, -CD2CH(CH3)-, -CHDCH2CH2-, -CHDCH(CH3)-, etc., including any member, combination, or subset thereof, wherein each Y is independently a halogen atom. In some embodiments, each Y is optionally and independently selected from F, Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F, Cl, and Br. In some embodiments, each Y is optionally and independently selected from F, Cl, and I. In some embodiments, each Y is optionally and independently selected from F, Br, and I. In some embodiments, each Y is optionally and independently selected from Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F and CL In some embodiments, each Y is optionally and independently selected from F and Br. In some embodiments, each Y is optionally and independently selected from F and I. In some embodiments, each Y is optionally and independently selected from Cl and Br. In someembodiments, each Y is optionally and independently selected from Cl and I. In some embodiments, each Y is optionally and independently selected from Br and I. In some embodiments, each Y is F. In some embodiments, each Y is Cl. In some embodiments, each Y is Br. In some embodiments, each Y is I.

[0176] In some embodiments, the alkenylene group (e.g., of R4) is branched. In some embodiments, the alkenylene group is unbranched. In some embodiments, the alkenylene group is substituted. In some embodiments, the alkenylene group is unsubstituted. In some embodiments, the alkenylene has two or more unsaturated double bonds.

[0177] In some embodiments, the alkenylene group is optionally substituted C2-C6alkenylene.In some embodiments, the alkenylene group is optionally substituted C3-C6alkenylene. In some embodiments, the alkenylene group is optionally substituted C4-C6alkenylene. In some embodiments, the alkenylene group is optionally substituted Cs-Csalkenylene. In some embodiments, the alkenylene group is optionally substituted C2-C3alkenylene. In some embodiments, the alkenylene group is optionally substituted C2-C4alkenylene. In some embodiments, the alkenylene group is optionally substituted C2-Csalkenylene. In some embodiments, the alkenylene group is optionally substituted ethenylene. In some embodiments, the alkenylene group is optionally substituted propenylene. In some embodiments, the alkenylene group is optionally substituted butenylene. In some embodiments, the alkenylene group is optionally substituted pentenylene. In some embodiments, the alkenylene group is optionally substituted hexenylene.

[0178] In some embodiments, the alkenylene groups optionally and independently selected from C2-C6haloalkenylene (e.g., C2-C6fluoroalkenylene), C2-C6deuteroalkenylene, and C2- Csdeuterohaloalkenylene (e.g., C2-C6deuterofluoroalkenylene), including any member, combination, or subset thereof. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from F, Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from F, Cl, and Br. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from F, Cl, and I. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from F, Br, and I. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from F and Cl. In some embodiments, the one or more halogen atoms ofthe alkenylene groups are optionally and independently selected from F and Br. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from F and I. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from Cl and Br. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from Cl and I. In some embodiments, the one or more halogen atoms of the alkenylene groups are optionally and independently selected from Br and I. In some embodiments, the one or more halogen atoms of the alkenylene groups are independently F. In some embodiments, the one or more halogen atoms of the alkenylene groups are independently Cl. In some embodiments, the one or more halogen atoms of the alkenylene groups are independently Br. In some embodiments, the one or more halogen atoms of the alkenylene groups are independently I. In some embodiments, the alkenylene groups optionally and independently do not include a halogen atom. In some embodiments, the alkenylene groups optionally and independently do not include an alternative isotope. In some embodiments, the alkenylene groups optionally and independently include neither a halogen atom nor an alternative isotope.

[0179] In some embodiments herein, the alkenylene group is independently selected from - CH=CH-, -CD=CD-, -CY=CY-, -CH=CY-, -CH2CH=CH-, -CH2CD=CD-, -CH2CY=CY-, CH2CD=CY-, CH2CY=CD-, -CY2CH=CH-, -CD2CH=CH-, -CYDCH=CH-, -CYDCY=CY-, - CYDCD=CD-, -C(CH3)=CH-, -C(CD3)=CH-, -C(CH3)=CD-, -C(CY3)=CH-, -C(CH3)=CY-, -CH=CH- (CH2)2-, -CD=CD-(CH2)2-, -CH=CD-(CH2)2-, -CD=CH-(CH2)2-, -CH=CY-(CH2)2-, -CY=CH-(CH2)2-, -CH=CH-CH=CH-, -CD=CD-CH=CH-, -CH=CH-CH(CH3)-, -CD=CD-CH(CH3)-, -CH=CY- CH(CH3)-, -CY=CY-CH(CH3)-, -CH=CD-CHY-CH2-, -CY=CH-CHD-CH2-, -CH=CD-CY2-CH2-, - CD=CY-CH2-CH2-, -CH=CY-CD2-CH2-, -CH=CD-CHY-CY2-, -CY=CH-CHD-CD2-, -CH2=CD- CH=CY-, -CH2=CY-CH=CD-, -CH2=CD-CD=CY-, -CH=CD-CH2=CY-, -CY=CD-CH2=CH-, - CH=CD-CH2=CD-, -CH=CH-(CH2)3-, -CH=CH-CH(CH3)-CH2-, -CH=CH-(CH2)2-CH(CH3)-, - CH=CD-CHY-(CH2)3-, -CY=CH-CHD-(CH2)3-, -CH=CD-CHY-CH(CH3)-CH2-, -CY=CH-CHD- CH(CH3)-CH2-, -CH=CD-CHY-(CH2)2-CH(CH3)-, -CY=CH-CHD-(CH2)2-CH(CH3)-, -CH=CH-CHY- (CH2)3-, -CY=CH-(CH2)3-, -CH=CH-CHY-CH(CH3)-CH2-, -CY=CH-CH(CH3)-CH2-, -CH=CH-CHY- (CH2)2-CH(CH3)-, -CY=CH-(CH2)2-CH(CH3)-, -CH=CD-(CH2)3-, -CD=CH-(CH2)3-, -CH=CD- CH(CH3)-CH2-, -CD=CH-CH(CH3)-CH2-, -CH=CD-(CH2)2-CH(CH3)-, -CD=CH-(CH2)2-CH(CH3)-, - CH=CH-(CH2)4-, -CH=CH-CH(CH3)-(CH2)2-, -CH=CH-(CH2)3-CH(CH3)-, -CH=CH-CH=CH- (CH2)2-, -CH2=CH-CH=CH-(CH2)2-, -CH=CD-CHY-(CH2)4-, -CY=CH-CHD-(CH2)4-, -CH=CD-CHY-CH(CH3)-(CH2)2-, -CY=CH-CHD-CH(CH3)-(CH2)2-, -CH=CD-CHY-(CH2)3-CH(CH3)-, - CY=CH-CHD-(CH2)3-CH(CH3)-, -CH=CD-CH=CH-CHY-(CH2)2-, -CY=CH-CH=CD-CHY-CH2-, - CH=CH-CHY-(CH2)4-, -CY=CH-(CH2)4-, -CH=CH-CHY-CH(CH3)-(CH2)2-, -CY=CH-CH(CH3)- (CH2)2-, -CH=CH-CHY-(CH2)3-CH(CH3)-, -CY=CH-(CH2)3-CH(CH3)-, -CH=CH-CH=CH-CHY- (CH2)-, -CY=CH-CH=CH-CH2-, -CH=CD-(CH2)4-, -CD=CH-(CH2)4-, -CH=CD-CH(CH3)-(CH2)2-, - CD=CH-CH(CH3)-(CH2)2- -CH=CD-(CH2)3-CH(CH3)-, -CD=CH-(CH2)3-CH(CH3)-, -CH=CD- CH=CH-(CH2)2-, -CH=CH-(CH2)S-, -CH=CH-CH=CH-(CH2)3-, -CH=CD-CHY-(CH2)5-, -CY=CH- CHD-(CH2)5- -CH=CD-CH=CH-CHY-(CH2)3-, -CY=CH-CH=CD-CHY-(CH2)2-, -CH=CH-CHY- (CH2)5-, -CY=CH-(CH2)5-, -CH=CH-CH=CH-CHY-(CH2)2-, -CY=CH-CH=CH-CH2-CHY-, - CH=CD-(CH2)5-, -CD=CH-(CH2)S-, -CH=CD-CH=CH-(CH2)3-, -CD=CH-CH=CH-(CH2)2-, - CH=CH-(CH2)6-, -CH=CH-CH=CH-(CH2)4-, -CH=CD-CHY-(CH2)5-, -CY=CH-CHD-(CH2)5-, - CH=CD-CH=CH-CHY-(CH2)3-, -CY=CH-CH=CD-CHY-(CH2)3-, -CH=CH-CHY-(CH2)5-, -CY=CH- (CH2)6-, -CH=CH-CH=CH-CHY-(CH2)3-, -CY=CH-CH=CH-(CH2)3-CHY-, -CH=CD-(CH2)6-, - CD=CH-(CH2)6-, -CH=CD-CH=CH-(CH2)4-, -CD=CH-CH=CH-(CH2)4-, -CH=CD-CHY-(CH2)5-, - CH=CD-(CH2)6-, -CH=CH-CHY-(CH2)5-, -CH=CH-(CH2)6-, -CH=CD-CH=CH-(CH2)4-, -CH=CH- CH=CH-(CH2)4-, -CH=CD-CHY-(CH2)6-, -CH=CD-(CH2)7-, -CH=CH-CHY-(CH2)6-, -CH=CH- (CH2)7-, -CH=CD-CH=CH-(CH2)5-, -CH=CH-CH=CH-(CH2)5-, -CH=CD-CH=CH-CH=CH-(CH2)3-, -CH=CD-CHY-(CH2)7- -CH=CD-(CH2)8-, -CH=CH-CHY-(CH2)7-, -CH=CH-(CH2)8-, -CH=CD- CH=CH-(CH2)8-, -CH=CH-CH=CH-(CH2)6-, -CH=CD-CH=CH-CH=CH-(CH2)6-, -CH=CH-CH=CH- CH=CH-(CH2)4-, -CH=CD-CHY-(CH2)8-, -CH=CD-(CH2)9-, -CH=CH-CHY-(CH2)8-, -CH=CH- (CH2)9-, -CH=CD-CH=CH-(CH2)7-, -CH=CH-CH=CH-(CH2)7-, -CH=CD-CH=CH-CH=CH-(CH2)5-, -CH=CH-CH=CH-CH=CH-(CH2)5-, -CH=CD-CHY-(CH2)9-, -CH=CD-(CH2)10-, -CH=CH-CHY- (CH2)9-, -CH=CH-(CH2)10-, -CH=CD-CH=CH-(CH2)B-, -CH=CH-CH=CH-(CH2)8-, -CH=CD- CH=CH-CH=CH-(CH2)6-, -CH=CH-CH=CH-CH=CH-(CH2)6-, -CH=CD-CHY-(CH2)10-, -CH=CD- (CH2)11-, -CH=CH-CHY-(CH2)10-, -CH=CH-(CH2)11-, -CH=CD-CH=CH-(CH2)9-, -CH=CH-CH=CH- (CH2)9-, -CH=CD-CH=CH-CH=CH-(CH2)7-, -CH=CH-CH=CH-CH=CH-(CH2)7-, -CH=CD-CHY- (CH2)11-, -CH=CD-(CH2)12-, -CH=CH-CHY-(CH2)11-, -CH=CH-(CH2)12-, -CH=CD-CH=CH-(CH2)1O- , -CH=CH-CH=CH-(CH2)10- -CH=CD-CH=CH-CH=CH-(CH2)8-, -CH=CH-CH=CH-CH=CH- (CH2)B-, -CH=CD-CHY-(CH2)12-, -CH=CD-(CH2)13-, -CH=CH-CHY-(CH2)12-, -CH=CH-(CH2)13-, - CH=CD-CH=CH-(CH2)11-, -CH=CH-CH=CH-(CH2)11-, -CH=CD-CH=CH-CH=CH-(CH2)9-, - CH=CH-CH=CH-CH=CH-(CH2)9-, -CH=CD-CHY-(CH2)13-, -CH=CD-(CH2)14-, -CH=CH-CHY- (CH2)13-, -CH=CH-(CH2)14-, -CH=CD-CH=CH-(CH2)12-, -CH=CH-CH=CH-(CH2)12-, -CH=CD- CH=CH-CH=CH-(CH2)10-, -CH=CH-CH=CH-CH=CH-(CH2)10-, -CH=CD-CHY-(CH2)14-, -CH=CD- (CH2)15-, -CH=CH-CHY-(CH2)14-, -CH=CH-(CH2)15-, -CH=CD-CH=CH-(CH2)13-, -CH=CH-CH=CH-(CH2)i3- -CH=CD-CH=CH-CH=CH-(CH2)II-, -CH=CH-CH=CH-CH=CH-(CH2)11-, - CH=CD-CHY-(CH2)15- -CH=CD-(CH2)16-, -CH=CH-CHY-(CH2)15-, -CH=CH-(CH2)16-, -CH=CD- CH=CH-(CH2)14- -CH=CH-CH=CH-(CH2)14-, -CH=CD-CH=CH-CH=CH-(CH2)12-, -CH=CH- CH=CH-CH=CH-(CH2)12-, -CH=CD-CHY-(CH2)16-, -CH=CD-(CH2)17-, -CH=CH-CHY-(CH2)16-, - CH=CH-(CH2)17-, -CH=CD-CH=CH-(CH2)15-, -CH=CH-CH=CH-(CH2)15-, -CH=CD-CH=CH- CH=CH-(CH2)13-, -CH=CH-CH=CH-CH=CH-(CH2)13-, -CH=CD-CHY-(CH2)17-, -CH=CD-(CH2)18-, -CH=CH-CHY-(CH2)17-, -CH=CH-(CH2)18-, -CH=CD-CH=CH-(CH2)16-, -CH=CH-CH=CH-(CH2)16-, -CH=CD-CH=CH-CH=CH-(CH2)14-, and -CH=CH-CH=CH-CH=CH-(CH2)i4-, including any member, combination, or subset thereof, wherein each Y is independently a halogen atom. In some embodiments, each Y is optionally and independently selected from F, Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F, Cl, and Br. In some embodiments, each Y is optionally and independently selected from F, Cl, and I. In some embodiments, each Y is optionally and independently selected from F, Br, and I. In some embodiments, each Y is optionally and independently selected from Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F and Cl. In some embodiments, each Y is optionally and independently selected from F and Br. In some embodiments, each Y is optionally and independently selected from F and I. In some embodiments, each Y is optionally and independently selected from Cl and Br. In some embodiments, each Y is optionally and independently selected from Cl and I. In some embodiments, each Y is optionally and independently selected from Br and I. In some embodiments, each Y is F. In some embodiments, each Y is Cl. In some embodiments, each Y is Br. In some embodiments, each Y is I.

[0180] In some embodiments, the alkynylene group (of R4) is branched. In some embodiments, the alkynylene group is unbranched. In some embodiments, the alkynylene group is substituted. In some embodiments, the alkynylene group is unsubstituted. In some embodiments, the alkynylene has two or more unsaturated triple bonds.

[0181] In some embodiments, the alkynylene group is optionally substituted C2-Cealkynylene.In some embodiments, the alkynylene group is optionally substituted C3-C6alkynylene. In some embodiments, the alkynylene group is optionally substituted C4-Cealkynylene. In some embodiments, the alkynylene group is optionally substituted C3-C6alkynylene. In some embodiments, the alkynylene group is optionally substituted C2-C3alkynylene. In some embodiments, the alkynylene group is optionally substituted C2-C4alkynylene. In some embodiments, the alkynylene group is optionally substituted C2-Csalkenylene. In someembodiments, the alkynylene group is optionally substituted ethynylene. In some embodiments, the alkynylene group is optionally substituted propynylene. In some embodiments, the alkynylene group is optionally substituted butynylene. In some embodiments, the alkynylene group is optionally substituted pentynylene. In some embodiments, the alkynylene group is optionally substituted hexynylene.

[0182] In some embodiments, the alkenylyne groups optionally and independently selected from C2-C6haloalkenylene (e.g., C2-C6fluoroalkenylene), C2-C6deuteroalkenylene, and C2- Cedeuterohaloalkenylene (e.g., C2-C6deuterofluoroalkenylene), including any member, combination, or subset thereof. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from F, Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from F, Cl, and Br. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from F, Cl, and I. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from F, Br, and I. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from Cl, Br, and I. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from F and Cl. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from F and Br. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from F and I. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from Cl and Br. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from Cl and I. In some embodiments, the one or more halogen atoms of the alkynylene groups are optionally and independently selected from Br and I. In some embodiments, the one or more halogen atoms of the alkynylene groups are independently F. In some embodiments, the one or more halogen atoms of the alkynylene groups are independently Cl. In some embodiments, the one or more halogen atoms of the alkynylene groups are independently Br. In some embodiments, the one or more halogen atoms of the alkynylene groups are independently L in some embodiments, the alkynylene groups optionally and independently do not include a halogen atom. In some embodiments, the alkynylene groups optionally and independently do not include an alternative isotope. In some embodiments, the alkynylene groups optionally and independently include neither a halogen atom nor an alternative isotope.

[0183] In some embodiments herein, the C2-C2oalkynylene is independently selected from - C≡C-, -C≡C-CH2-, -C≡C-CHD-, -C≡C-CHY-, -C≡C-CD2-, -C≡C-CDY-, -C≡C-(CH2)2-, -C≡C-C≡C-, -C≡C-CH2-CHD- -C≡C-CH2-CHY-, -C≡C-CH2-CD2-, -C≡C-CH2-CDY-, -C≡C-CHD-CH2-, -C≡C- (CHD)2-, -C≡C-CHD-CHY-, -C≡C-CHD-CD2-, -C≡C-CHD-CDY-, -C≡C-CHY-CH2-, -C≡C-CHY- CHD-, -C≡C-(CHY)2-, -C≡C-CHY-CD2-, -C≡C-CHY-CDY-, -C≡C-CD2-CH2-, -C≡C-CD2-CHD-, - C≡C-CD2-CHY-, -C≡C-(CD2)2-, -C≡C-CD2-CDY-, -C≡C-CDY-CH2-, -C≡C-CDY-CHD-, -C≡C-CDY- CHY-, -C≡C-CDY-CD2-, -C≡C-(CDY)2-, -C≡C-(CY2)2-, -C≡C-CH(CH3)-, -C≡C-CH(CH2D)-, -C≡C- CH(CH2Y)-, -C≡C-CD(CH3)-, -C≡C-CD(CH2D)-, -C≡C-CD(CH2Y)-, -C≡C-(CH2)3-, -C≡C-(CHD)3-, -C≡C-(CHY)3-, -C≡C-(CD2)3- -C≡C-(CDY)3-, -C≡C-(CY2)3-, -C≡C-(CYD)3-, -C≡C-C≡C-CH2-, - C≡C-C≡C-CHD-, -C≡C-C≡C-CHY-, -C≡C-C≡C-CD2-, -C≡C-C≡C-CDY-, -C≡C-CH(CH3)-CH2-, - C≡C-CH(CH2D)-CH2-, -C≡C-CH(CH2Y)-CH2-, -C≡C-CD(CH3)-CH2-, -C≡C-CD(CH2D)-CH2-, - C≡C-CD(CH2Y)-CH2-, -C≡C-C≡C-CH(CH3)-, -C≡C-C≡C-CH(CH2D)-, -C≡C-C≡C-CH(CH2Y)-, - C≡C-(CH2)4-, -C≡C-(CHD)4-, -C≡C-(CHY)4-, -C≡C-(CD2)4-, -C≡C-(CDY)4-, -C≡C-(CY2)4-, -C≡C- (CYD)4-, -C≡C-C≡C-(CH2)2-, -C≡C-C≡C-(CHD)2-, -C≡C-C≡C-(CHY)2-, -C≡C-C≡C-(CD2)2-, -C≡C- C≡C-(CDY)2-, -C≡C-CH(CH3)-(CH2)2-, -C≡C-CH(CH2D)-(CH2)2-, -C≡C-CH(CH2Y)-(CH2)2-, -C≡C- CD(CH3)-(CH2)2-, -C≡C-CD(CH2D)-(CH2)2-, -C≡C-CD(CH2Y)-(CH2)2-, -C≡C-C≡C-CH(CH3)-, - C≡C-C≡C-CH(CH2D)-, -C≡C-C≡C-CH(CH2Y)-, -C≡C-(CH2)5-, -C≡C-(CH2)6-, -C≡C-(CH2)7-, -C≡C- (CH2)8-, -C≡C-(CH2)9-, -C≡C-(CH2)10-, -C≡C-(CH2)11-, -C≡C-(CH2)12-, -C≡C-(CH2)13-, -C≡C- (CH2)14-, -C≡C-(CH2)15-, -C≡C-(CH2)16-, -C≡C-(CH2)17-, -C≡C-(CH2)18-, -C≡C-(CHD)5-, -C≡C- (CHD)6-, -C≡C-(CHD)7- -C≡C-(CHD)8-, -C≡C-(CHD)9-, -C≡C-(CHD)10-, -C≡C-(CHD)11-, -C≡C- (CHD)12-, -C≡C-(CHD)13-, -C≡C-(CHD)14-, -C≡C-(CHD)15-, -C≡C-(CHD)16-, -C≡C-(CHD)17-, -C≡C- (CHD)18-, -C≡C-(CHY59-, -C≡C-(CHY)6-, -C≡C-(CHY)7-, -C≡C-(CHY)8-, -C≡C-(CHY)9-, -C≡C- (CHY)10-, -C≡C-(CHY)11-, -C≡C-(CHY)12-, -C≡C-(CHY)13-, -C≡C-(CHY)14-, -C≡C-(CHY)15-, -C≡C- (CHY)16-, -C≡C-(CHY)17-, -C≡C-(CHY)18-, -C≡C-(CD2)5-, -C≡C-(CD2)6-, -C≡C-(CD2)7-, -C≡C- (CD2)8-, -C≡C-(CD2)9-, -C≡C-(CD2)10-, -C≡C-(CD2)11-, -C≡C-(CD2)12-, -C≡C-(CD2)13-, -C≡C- (CD2)14-, -C≡C-(CD2)15-, -C≡C-(CD2)16-, -C≡C-(CD2)17-, -C≡C-(CD2)18-, -C≡C-(CDY)5-, -C≡C- (CDY)6-, -C≡C-(CDY)7- -C≡C-(CDY)8-, -C≡C-(CDY)9-, -C≡C-(CDY)10-, -C≡C-(CDY)11-, -C≡C- (CDY)12-, -C≡C-(CDY)13-, -C≡C-(CDY)14-, -C≡C-(CDY)15-, -C≡C-(CDY)16-, -C≡C-(CDY)17-, -C≡C- (CDY)18-, -C≡C-(CY2)5-, -C≡C-(CY2)6-, -C≡C-(CY2)7-, -C≡C-(CY2)8-, -C≡C-(CY2)9-, -C≡C-(CY2)10-, -C≡C-(CY2)11-, -C≡C-(CY2)12-, -C≡C-(CY2)13-, -C≡C-(CY2)14-, -C≡C-(CY2)15-, -C≡C-(CY2)ie-, -C≡C- (CY2)17-, -C≡C-(CY2)18-, -C≡C-C≡C-(CH2)3-, -C≡C-C≡C-(CH2)4-, -C≡C-C≡C-(CH2)5-, -C≡C-C≡C- (CH2)6-, -C≡C-C≡C-(CH2)7- -C≡C-C≡C-(CH2)8-, -C≡C-C≡C-(CH2)9-, -C≡C-C≡C-(CH2)10-, -C≡C- C≡C-(CH2)11-, -C≡C-C≡C-(CH2)12-, -C≡C-C≡C-(CH2)13-, -C≡C-C≡C-(CH2)14-, -C≡C-C≡C-(CH2)15-, -C≡C-C≡C-(CH2)18-, -C≡C-C≡C-(CHD)3-, -C≡C-C≡C-(CHD)4-, -C≡C-C≡C-(CHD)5-, -C≡C-C≡C-(CHD)6-, -C≡C-C≡C-(CHD)7-, -C≡C-C≡C-(CHD)8-, -C≡C-C≡C-(CHD)9-, -C≡C-C≡C-(CHD)10-, - C≡C-C≡C-(CHD)11-, -C≡C-C≡C-(CHD)12-, -C≡C-C≡C-(CHD)13-, -C≡C-C≡C-(CHD)14-, -C≡C-C≡C- (CHD)15-, -C≡C-C≡C-(CHD)16-, -C≡C-C≡C-(CHY)3-, -C≡C-C≡C-(CHY)4-, -C≡C-C≡C-(CHY)5-, - C≡C-C≡C-(CHY)9-, -C≡C-C≡C-(CHY)7-, -C≡C-C≡C-(CHY)8-, -C≡C-C≡C-(CHY)9-, -C≡C-C≡C- (CHY)10-, -C≡C-C≡C-(CHY)ii-, -C≡C-C≡C-(CHY)12-, -C≡C-C≡C-(CHY)13-, -C≡C-C≡C-(CHY)14-, - C≡C-C≡C-(CHY)15-, -C≡C-C≡C-(CHY)16-, -C≡C-C≡C-(CD2)3-, -C≡C-C≡C-(CD2)4-, -C≡C-C≡C- (CD2)5-, -C≡C-C≡C-(CD2)6-, -C≡C-C≡C-(CD2)7-, -C≡C-C≡C-(CD2)8-, -C≡C-C≡C-(CD2)9-, -C≡C- C≡C-(CD2)10-, -C≡C-C≡C-(CD2)11-, -C≡C-C≡C-(CD2)12-, -C≡C-C≡C-(CD2)13-, -C≡C-C≡C-(CD2)14-, -C=C-C=C-(CD2)15-, -C=C-C=C-(CD2)16-, -C≡C-C≡C-(CDY)3-, -C≡C-C≡C-(CDY)4-, -C=C-C=C- (CDY)5-, -C≡C-C≡C-(CDY)6-, -C≡C-C≡C-(CDY)7-, -C≡C-C≡C-(CDY)8-, -C≡C-C≡C-(CDY)9-, - C≡C-C≡C-(CDY)10-, -C≡C-C≡C-(CDY)ii-, -C≡C-C≡C-(CDY)12-, -C≡C-C≡C-(CDY)13-, -C≡C-C≡C- (CDY)14-, -C≡C-C≡C-(CDY)15- -C≡C-C≡C-(CDY)16-, -C≡C-CH(CH3)-(CH2)3-, -C≡C-CH(CH3)- (CH2)4-, -C≡C-CH(CH3)-(CH2)5-, -C≡C-CH(CH3)-(CH2)6-, -C≡C-CH(CH3)-(CH2)7-, -C≡C-CH(CH3)- (CH2)8-, -C≡C-CH(CH3)-(CH2)9-, -C≡C-CH(CH3)-(CH2)10-, -C≡C-CH(CH3)-(CH2)11-, -C≡C- CH(CH3)-(CH2)12-, -C≡C-CH(CH3)-(CH2)13-, -C≡C-CH(CH3)-(CH2)14-, -C≡C-CH(CH3)-(CH2)15-, - C≡C-CH(CH3)-(CH2)16-, -C≡C-CH(CH2D)-(CH2)3-, -C≡C-CH(CH2D)-(CH2)4-, -C≡C-CH(CH2D)- (CH2)5-, -C≡C-CH(CH2D)-(CH2)6-, -C≡C-CH(CH2D)-(CH2)7-, -C≡C-CH(CH2D)-(CH2)8-, -C≡C- CH(CH2D)-(CH2)9-, -C≡C-CH(CH2D)-(CH2)10-, -C≡C-CH(CH2D)-(CH2)11-, -C≡C-CH(CH2D)- (CH2)12-, -C≡C-CH(CH2D)-(CH2)13-, -C≡C-CH(CH2D)-(CH2)14-, -C≡C-CH(CH2D)-(CH2)15-, -C≡C- CH(CH2D)-(CH2)16-, -C≡C-CH(CH2Y)-(CH2)3-, -C≡C-CH(CH2Y)-(CH2)4-, -C≡C-CH(CH2Y)-(CH2)5- , -C≡C-CH(CH2Y)-(CH2)6-, -C≡C-CH(CH2Y)-(CH2)7-, -C≡C-CH(CH2Y)-(CH2)8-, -C≡C-CH(CH2Y)- (CH2)9-, -C≡C-CH(CH2Y)-(CH2)10-, -C≡C-CH(CH2Y)-(CH2)11-, -C≡C-CH(CH2Y)-(CH2)12-, -C≡C- CH(CH2Y)-(CH2)13-, -C≡C-CH(CH2Y)-(CH2)14-, -C≡C-CH(CH2Y)-(CH2)15-, -C≡C-CH(CH2Y)- (CH2)16-, -C≡C-CD(CH3)-(CH2)3-, -C≡C-CD(CH3)-(CH2)4-, -C≡C-CD(CH3)-(CH2)5-, -C≡C- CD(CH3)-(CH2)6-, -C≡C-CD(CH3)-(CH2)7-, -C≡C-CD(CH3)-(CH2)8-, -C≡C-CD(CH3)-(CH2)9-, -C≡C- CD(CH3)-(CH2)10-, -C≡C-CD(CH3)-(CH2)11-, -C≡C-CD(CH3)-(CH2)12-, -C≡C-CD(CH3)-(CH2)13-, - C≡C-CD(CH3)-(CH2)14-, -C≡C-CD(CH3)-(CH2)15-, and -C≡C-CD(CH3)-(CH2)16-, including any member, combination, or subset thereof, wherein each Y is independently a halogen atom. In some embodiments, each Y is optionally and independently selected from F, Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F, Cl, and Br. In some embodiments, each Y is optionally and independently selected from F, Cl, and I. In some embodiments, each Y is optionally and independently selected from F, Br, and I. In some embodiments, each Y is optionally and independently selected from Cl, Br, and I. In some embodiments, each Y is optionally and independently selected from F and Cl. In someembodiments, each Y is optionally and independently selected from F and Br. In some embodiments, each Y is optionally and independently selected from F and I. In some embodiments, each Y is optionally and independently selected from Cl and Br. In some embodiments, each Y is optionally and independently selected from Cl and I. In some embodiments, each Y is optionally and independently selected from Br and I. In some embodiments, each Y is F. In some embodiments, each Y is Cl. In some embodiments, each Y is Br. In some embodiments, each Y is I.

[0184] In some embodiments, cycloalkyl group (such as, for example, of R1, R4, R9, and A) is optionally and independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, including any member, combination, or subset thereof, wherein one or more available hydrogen atoms are optionally replaced with one or more respective halogen atoms, and / or one or more available atoms are optionally replaced with one or more respective alternate isotopes thereof. In some embodiments, the cycloalkyl is unsubstituted, and in some embodiments the cycloalkyl is substituted.

[0185] In some embodiments, one or more available hydrogen atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I), and / or one or more available atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I). In some embodiments, one or more available atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective fluorine atoms, and / or one or more available atoms of the cycloalkyl groups areoptionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective chlorine atoms, and / or one or more available atoms of the cycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof.

[0186] In some embodiments, none of the available hydrogen atoms of the cycloalkyl are independently replaced with a halogen atom. In some embodiments, none of the available atoms of the cycloalkyl are independently replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of the cycloalkyl are independently replaced with a halogen atom, and none of the available atoms of the cycloalkyl are independently replaced with an alternative isotope thereof.

[0187] In some embodiments, one or more available hydrogen atoms of the heterocycloalkyl groups (e.g., of R1, R4, R9, and A) are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I), and / or one or more available atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I). In some embodiments, one or more available atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective fluorine atoms, and / or one or more available atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heterocycloalkyl groups are optionally and independentlyreplaced with one or more respective chlorine atoms, and / or one or more available atoms of the heterocycloalkyl groups are optionally and independently replaced with one or more respective alternative isotopes thereof.

[0188] In some embodiments, none of the available hydrogen atoms of the heterocycloalkyl are independently replaced with a halogen atom. In some embodiments, none of the available atoms of the heterocycloalkyl are independently replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of the heterocycloalkyl are independently replaced with a halogen atom, and none of the available atoms of the heterocycloalkyl are independently replaced with an alternative isotope thereof.

[0189] In some embodiments, the heterocycloalkyl groups are optionally and independently selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, 1 ,3-dioxolanyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2H-1A3-thiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxothiolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, imidazolinyl, dioxolanyl, dithiolanyl, triazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, dihydropyranyl, isothiazolidinyl, morpholinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl dioxide, dioxanyl, thiazolinyl, thianyl, thianyl oxide, thianyl dioxide, dithianyl, azepanyl, pyrazolidinyl, oxepanyl, thiepanyl, diazepanyl, and 2,5-pyrrolidinedionyl (e.g., succinimidyl), including any member, combination, or subset thereof, each of which is optionally substituted as indicated in Formula (I) and the accompanying descriptions herein. In some embodiments, the heterocycloalkyl is optionally and independently fused to a benzene ring, i.e. , benzofused. In some embodiments, the heterocycloalkyl is optionally and independently substituted. In some embodiments, the heterocycloalkyl is optionally and independently unsubstituted.

[0190] In some embodiments, one or more available hydrogen atoms of the heteroaryl groups (e.g., of R1, R4, R9, and A) are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I), and / or one or more available atoms of the heteroaryl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heteroaryl groups are optionally and independently replaced with one or more respective halogen atoms (i.e., F, Cl, Br, and / or I). In some embodiments, one or more available atoms of the heteroaryl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heteroaryl groups areoptionally and independently replaced with one or more respective fluorine atoms, one or more respective chlorine atoms, and / or one or more respective bromine atoms, and / or one or more available atoms of the heteroaryl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heteroaryl groups are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective chlorine atoms, and / or one or more available atoms of the heteroaryl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heteroaryl groups are optionally and independently replaced with one or more respective fluorine atoms, and / or one or more available atoms of the heteroaryl groups are optionally and independently replaced with one or more respective alternative isotopes thereof. In some embodiments, one or more available hydrogen atoms of the heteroaryl groups are optionally and independently replaced with one or more respective chlorine atoms, and / or one or more available atoms of the heteroaryl groups are optionally and independently replaced with one or more respective alternative isotopes thereof.

[0191] In some embodiments, none of the available hydrogen atoms of the heteroaryl are independently replaced with a halogen atom. In some embodiments, none of the available atoms of the heteroaryl are independently replaced with an alternative isotope thereof. In some embodiments, none of the available hydrogen atoms of the heteroaryl are independently replaced with a halogen atom, and none of the available atoms of the heteroaryl are independently replaced with an alternative isotope thereof.

[0192] In some embodiments, the 5- to 10-membered heteroaryl is optionally and independently selected from azepinyl, benzofuranyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolyl, thienofuranyl, triazolyl, and thienyl (e.g., thiophenyl), each of which is optionally and independently substituted as indicated in Formula (I) and the accompanying descriptions herein. One or more available hydrogen atoms of the 5- to 10-membered heteroaryl are optionally and independently replaced with one or more respective halogen atoms and / or one or more available atoms of the 5- to 10-membered heteroaryl are optionally and independently replaced with one or more respective alternative isotopes thereof, e.g., deuterium. In some embodiments, the 5- to 10-membered heteroaryl is optionally and independently fused to a benzene ring, i.e.,benzofused. In some embodiments, the 5- to 10-membered heteroaryl is optionally and independently substituted. In some embodiments the 5- to 10-membered heteroaryl is optionally and independently unsubstituted.

[0193] In some embodiments, the compound of Formula (I) is selected from the following Table1 :

[0194] Table 1or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0195] In some embodiments, the compound of Formula (I) is selected from the following Table 1A:

[0196] Table 1Aor a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0197] In some embodiments, the compound of Formula (I) is selected from the following Table 2:

[0198] Table 2or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0199] In some embodiments, the compound of Formula (I) is selected from the following Table3:

[0200] Table 3or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0201] IUPAC names were generated with CHEMDRAW Professional 22.2.0 64-bit and 23.1.7 64-bit.

[0202] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et aL, Camille G. (eds.) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al., Journal of Pharmaceutical Sciences 197766(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food and Drug Administration, Washington, D.C. on their website).

[0203] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group.Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di-, and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid, and other sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts also include acetates, ascorbates, besylates, gentisates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates ("mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates), and the like. In some embodiments, the mono- or di-acid salts are formed and such salts exist in either a hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non -pharmaceutically acceptable salts, such as, but not limited to, oxalates may be used, for example in the isolation of compounds of the disclosure for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0204] A base addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate saltmay be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts, such as sodium, lithium, and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (for example, organic amines), such as dicyclohexylamine, butyl amine, choline, and salts with amino acids, such as arginine, lysine, and the like. Basic nitrogen containing groups may be quartemized with agents, such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands, such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0205] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the disclosure and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the disclosure. In addition, when a compound of the disclosure contains both a basic moiety, such as, but not limited to, an aliphatic primary, secondary, tertiary, or cyclic amine, an aromatic or heteroaryl amine, pyridine, or imidazole and an acidic moiety, such as, but not limited to, tetrazole or carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the terms “salt(s),” as used herein. It is understood that certain compounds of the disclosure may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the disclosure.

[0206] Solvates of compounds of the disclosure include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0207] Prodrugs of the compounds of the present disclosure include, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. Some common esterswhich in some embodiments described herein may be utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0208] It is understood and appreciated that in some embodiments, compounds of the present disclosure may have at least one chiral center and therefore can exist as enantiomers and / or diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present disclosure having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure, or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present disclosure.

[0209] In some embodiments, the compounds of the present disclosure can also include tautomeric forms. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present disclosure.

[0210] The compounds of the present disclosure may further exist in varying amorphous and polymorphic forms and it is contemplated that any amorphous forms, polymorphs, or mixtures thereof, which form are included within the scope of the present disclosure.

[0211] In the compounds of general Formula (I) and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is meant to include all suitable isotopic variations of the compounds of the disclosure and pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. For example, different isotopic forms of hydrogen (H) include protium (1 H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature.

[0212] The compounds of the present disclosure may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the disclosure are included within the scope of thepresent disclosure. Therefore, the compounds of the disclosure also include those in which one or more radioactive atoms are incorporated within their structure.III. Compositions

[0213] The compounds of the present disclosure are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present disclosure also includes a composition comprising one or more compounds of the disclosure and a carrier. The compounds of the disclosure are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present disclosure further includes a pharmaceutical composition comprising one or more compounds of the disclosure and a pharmaceutically acceptable carrier. In embodiments of the disclosure the pharmaceutical compositions are used in the treatment of any of the diseases, disorders, or conditions described herein.

[0214] In embodiments, compounds and / or compositions of the disclosure are administered to a subject in one or more of a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound and / or composition of the disclosure is administered by oral, inhalation, parenteral, buccal, sublingual, insufflation, epidurally, nasal, rectal, vaginal, patch, pump, minipump, topical, or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0215] Parenteral administration includes systemic delivery routes other than the gastrointestinal (Gl) tract and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal, and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0216] In some embodiments, a compound and / or composition of the disclosure is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard- or soft-shell gelatin capsules, or it is compressed into tablets, or it isincorporated directly with the food of the diet. In some embodiments, the compound and / or composition is incorporated with excipient(s) and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, suspensions, and the like. In the case of tablets, carriers that are used include lactose, com starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); wetting agents (e.g., sodium lauryl sulphate); and / or solvents (e.g., medium chain triglycerides, ethanol, or water). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets, or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™, designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed -release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed -release compositions are formulated, for example, as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. For oral administration in a capsule form, useful carriers, solvents, or diluents include lactose, medium chain triglycerides, ethanol, and dried corn starch.

[0217] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups, or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the disclosure is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparationsfor oral administration are prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., medium chain triglycerides, almond oil, oily esters, or ethyl alcohol); and / or preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0218] It is also possible to freeze-dry the compounds of the disclosure and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0219] In some embodiments, a compound and / or composition of the disclosure is administered parenterally. For example, solutions of a compound of the disclosure are prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds and / or compositions of the disclosure are usually prepared and the pH's of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments, or droppable liquids are delivered, for example, by ocular delivery systems known to the art, such as applicators or eye droppers. In some embodiments, such compositions include mucomimetics, such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol, preservatives, such as sorbic acid, EDTA, or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0220] In some embodiments, a compound and / or composition of the disclosure is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles and contain formulating agents, such as suspending, stabilizing, and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringabilityexists. Alternatively, the compounds and / or compositions of the disclosure are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen -free water, before use.

[0221] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels, and powders. For intranasal administration or administration by inhalation, the compounds of the disclosure are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas, such as compressed air, or an organic propellant, such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound and / or composition of the disclosure and a suitable powder base, such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0222] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound of the disclosure is formulated with a carrier, such as sugar, acacia, tragacanth, or gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

[0223] Suppository forms of the compounds and / or compositions of the disclosure are useful for vaginal, urethral, and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil(also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0224] In some embodiments a compound of the disclosure is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the disclosure is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

[0225] A compound of the disclosure including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the disclosure (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt%, or about 0.10 wt% to about 70 wt%, of the active ingredient and from about 1 wt% to about 99.95 wt%, or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.

[0226] In some embodiments, the compounds of the disclosure including pharmaceutically acceptable salts, solvates, and / or prodrugs thereof are used are administered in a composition comprising an additional therapeutic agent. Therefore, the present disclosure also includes a pharmaceutical composition comprising one or more compounds of the disclosure, or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent useful for treatment of a disease, disorder, or condition, for example those listed in the Methods and Uses section below.

[0227] In the above, the term “a compound" also includes embodiments wherein one or more compounds are referenced.IV. Methods and Uses of the Disclosure

[0228] Compounds and / or compositions disclosed herein may be administered alone or in combination with other compounds and / or compositions to treat a wide range of disorders, diseases, and conditions that include, but are not limited to, depressive disorder, bipolar disorder, eating disorder, impulse control disorder, personality disorder, substance abuse disorder, behavioral addiction disorder, alcohol use disorder, post-traumatic stress disorder, anxiety disorder, stress disorder, neurodevelopmental disorder, pain disorder, headache disorder, inflammatory disorder, injury-related disorder, neurodegenerative disorder, functional disorder, psychotic disorder, hyperkinetic movement disorder, age-related macular degeneration, atherosclerosis, dissociative disorders, genetic brain disorders, hyperprolactinemia, hypersomnia, obesity, phobias, apathy disorders, burnout, and a combination thereof.

[0229] The compounds and / or compositions of the present disclosure are useful as medicaments. Accordingly, the disclosure also includes a compound and / or composition of the disclosure for use as, among other things, a medicament.

[0230] The present disclosure also includes a method of treating a disease, disorder, or condition by administering a therapeutically effective amount of one or more compounds and / or compositions of the disclosure to a subject in need thereof. The present disclosure also includes use of one or more compounds and / or compositions of the disclosure to manufacture a medicine or medicament that in a therapeutically effect amount treats a disease, disorder, or condition.

[0231] The present disclosure also includes use of one or more compounds and / or compositions of the disclosure for treatment of a disease, disorder, or condition as well as use of one or more compounds and / or compositions of the disclosure for the preparation and manufacture of a medicine or medicament for treatment of a disease, disorder, or condition.

[0232] In some embodiments, the compounds and / or compositions of the disclosure are useful for preventing, treating, and / or reducing the severity of a disease, disorder, and / or condition in a subject. Accordingly, the present disclosure also includes a method of preventing, treating, and / or reducing the severity of a disease, disorder, and / or condition comprising administering a therapeutically effective amount of one or more compounds and / or compositions of the disclosure to a subject in need thereof. The present disclosure also includes use of one or more compounds and / or compositions of the disclosure for treatment a disease, disorder, and / or condition, as well as use of one or more compounds and / or compositions of the disclosure for the preparation of amedicament for preventing, treating, and / or reducing the severity of a disease, disorder, and / or condition in a subject.

[0233] Some embodiments disclosed herein are directed to a method of treating a depressive disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the depressive disorder is selected from major depressive disorder (MDD), MDD with suicidal ideation, persistent depressive disorder, dysthymia, dysthymic disorder, seasonal affective disorder, pre-menstrual dysphoric disorder, antenatal depression, postpartum depression, postnatal depression, treatment-resistant depression, depression related to a medical condition, depression in bipolar disorder, depression related to substance use, depression related to medicine use, psychotic depression, and a combination thereof.

[0234] Some embodiments disclosed herein are directed to a method of treating a bipolar disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the bipolar disorder is selected from Bipolar I disorder, Bipolar II disorder, cyclothymia, cyclothymic disorder, bi-polar related to a medicinal condition, and a combination thereof.

[0235] Some embodiments disclosed herein are directed to a method of treating an eating disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the eating disorder is selected from anorexia nervosa, bulimia nervosa, avoidant restrictive food intake disorder, other specified feeding and eating disorder, pica, rumination disorder, avoidant / restrictive food intake disorder, and a combination thereof.

[0236] Some embodiments disclosed herein are directed to a method of treating an impulsecontrol disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the impulse-control disorder is selected from binge-eating disorder, obsessive compulsive disorder, and a combination thereof.

[0237] Some embodiments disclosed herein are directed to a method of treating a personality disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the personality disorder is selected from avoidant personality disorder, dependent personalitydisorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder, paranoid personality disorder, and a combination thereof.

[0238] Some embodiments disclosed herein are directed to a method of treating a substance use / abuse and / or behavioral addiction disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the substance abuse and / or behavioral addiction disorder is selected from alcohol use disorder, stimulant use disorder, cannabis use disorder, opioid use disorder, tobacco use disorder, nicotine use disorder, inhalant use disorder, sedative -hypnotic use disorder, anxiolytic use disorder, gambling disorder, gaming disorder, compulsive sexual behavior disorder, and a combination thereof.

[0239] Some embodiments disclosed herein are directed to a method of treating an anxiety and / or stress disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the anxiety disorder and / or the stress disorder is selected from acute stress disorder, adjustment disorder in chronic illness, body dysmorphic disorder, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, prolonged grief disorder, social anxiety disorder, agoraphobia, separation anxiety disorder, specific phobias, anxiety due to a medical condition, anxiety in advanced stage illness, selective mutism, and a combination thereof.

[0240] Some embodiments disclosed herein are directed to a method of treating a neurodevelopmental disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the neurodevelopmental disorder is selected from attention deficit hyperactivity disorder and subtypes, autism spectrum disorder, behavioral symptoms of Fragile X syndrome, and a combination thereof.

[0241] Some embodiments disclosed herein are directed to a method of treating a pain disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the pain disorder is selected from fibromyalgia, neuropathic pain, phantom limb pain, chronic pain, and a combination thereof.

[0242] Some embodiments disclosed herein are directed to a method of treating a headache disorder comprising administering a therapeutically effective amount of one or more compoundsand / or compositions disclosed herein to a subject in need thereof. In some embodiments, the headache disorder is selected from cluster headaches, short-lasting unilateral neuralgiform headaches, tension-type headaches, chronic daily headache syndrome, migraine headaches, and a combination thereof.

[0243] Some embodiments disclosed herein are directed to a method of treating an inflammatory disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the inflammatory disorder is selected from inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, system lupus erythematosus, systemic sclerosis, vasculitis, and a combination thereof.

[0244] Some embodiments disclosed herein are directed to a method of treating an injury- related disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the injury-related disorder is selected from cognitive and / or behavioral symptoms of TBI, functional recovery in stroke, and a combination thereof.

[0245] Some embodiments disclosed herein are directed to a method of treating a neurodegenerative disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the neurodegenerative disorder is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), behavioral symptoms in ALS, frontotemporal dementia, Parkinson’s disease, vascular dementia, Huntington’s disease, and a combination thereof.

[0246] Some embodiments disclosed herein are directed to a method of treating a functional disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the functional disorder is selected from chronic fatigue syndrome, functional neurological disorder, irritable bowel syndrome, long COVID, post-treatment Lyme, and a combination thereof.

[0247] Some embodiments disclosed herein are directed to a method of treating a psychotic disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the psychotic disorder is selected from schizophrenia, delusional disorder, schizoaffective disorder, and a combination thereof.

[0248] Some embodiments disclosed herein are directed to a method of treating a hyperkinetic disorder comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof. In some embodiments, the hyperkinetic movement disorder is selected from chorea, akathisia, asterixis, dystonia, tremor, myoclonus, tics, stereotypies, movement disorders caused by neurodegenerative disease, metabolic derangements, vascular and autoimmune disease, infections, medications, recreational drugs, and / or pregnancy, and a combination thereof.

[0249] The present disclosure also includes a method of treating age-related macular degeneration, atherosclerosis, dissociative disorders, genetic brain disorders, hyperprolactinemia, hypersomnia, obesity, phobias, apathy disorders, and / or burnout, comprising administering a therapeutically effective amount of one or more compounds and / or compositions disclosed herein to a subject in need thereof.

[0250] In some embodiments, the subject is a non-human mammal. In other embodiments, the subject is human. Accordingly, the compounds, compositions, methods, and uses of the present disclosure are directed to human and non-human diseases, disorders, and conditions.

[0251] In some embodiments, the “subject in need thereof’ is a subject having the disease, disorder, or condition to be treated.

[0252] The present disclosure also includes a method of treating a disease, disorder, or condition comprising administering a therapeutically effective amount of one or more compounds and / or compositions of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition to a subject in need thereof. The present disclosure also includes use of one or more compounds and / or compositions of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition for treatment of a disease, disorder, or condition, as well as use of one or more compounds and / or compositions of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition for the preparation of a medicament for treatment of a disease, disorder, or condition. The disclosure further includes one or more compounds and / or compositions of the disclosure in combination with another known agent useful for treatment of a disease, disorder, or condition for use in treating a disease, disorder, or condition.

[0253] In some embodiments, the one or more compounds and / or compositions of the disclosure are administered in combination with one or more additional treatments for a disease, disorder, or condition.

[0254] In some embodiments, the one or more compounds and / or compositions of the disclosure are administered in combination with one or more additional medicaments for the treatment of the disease, disorder, or condition.

[0255] In some embodiments, effective amounts vary according to factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease, or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.

[0256] In some embodiments, the compounds and / or compositions of the disclosure are administered one, two, three, or four times a year. In some embodiments, the compounds and / or compositions of the disclosure are administered at least once a week. However, in another embodiment, the compounds and / or compositions are administered to the subject from about one time per one week, two weeks, three weeks, or one month. In another embodiment, the compounds and / or compositions are administered about one time per week to about once daily. In another embodiment, the compounds and / or compositions are administered 1, 2, 3, 4, 5, or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or the activity of the compounds of the disclosure and / or a combination thereof. It will also be appreciated that the effective dosage of the compound and / or compositions used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds and / or compositions are administered to the subject in an amount and for duration sufficient to treat the subject.

[0257] In some embodiments, the compounds and / or compositions of the disclosure are administered at doses that may occur once, twice, three, or four times a year. However, in some embodiments, the compounds and / or compositions and / or compositions are administered to thesubject once daily, once every two days, once every 3 days, once a week, once every two weeks, once a month, once every two months, or once every three months at doses.

[0258] A compound and / or composition of the disclosure is either used alone or in combination with other known agent(s) useful for treating diseases, disorders, or conditions. When used in combination with other known agents useful in treating diseases, disorders, or conditions, it is an embodiment that a compound and / or composition of the disclosure is administered contemporaneously with those agents. As used herein, “contemporaneous administration” of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. The design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present disclosure that a combination of agents is administered to a subject in a noncontemporaneous fashion. In some embodiments, a compound and / or composition of the present disclosure is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising one or more compounds of the disclosure, an additional therapeutic agent and / or a pharmaceutically acceptable carrier.

[0259] The dosage of a compound and / or composition of the disclosure varies depending on many factors, such as the pharmacodynamic properties of the compound, the mode of administration, the age, health, and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment, and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In some embodiments, one or more compounds and / or compositions of the disclosure are administered initially in a suitable dosage that is adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of the one or more compounds of the disclosure from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of one or more compounds of the disclosure will range between about 10 pg per day to about 1000 mg per day for an adult, suitably about 10 pg per day to about 500 mg per day, moresuitably about 10 pg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 pg / kg to about 10 mg / kg, about 0.1 pg / kg to about 10 mg / kg, about 0.01 pg / kg to about 1 mg / kg, or about 0.1 pg / kg to about 1 mg / kg. For administration in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the disclosure, compositions are formulated for oral administration and the one or more compounds are suitably in the form of tablets containing 0.1 , 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of active ingredient (one or more compounds of the disclosure) per tablet. In some embodiments of the disclosure the one or more compounds of the disclosure are administered in a single daily, weekly, or monthly dose or the total daily dose is divided into two, three, or four daily doses.

[0260] To be clear, in the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced. Likewise, the term “compounds of the disclosure” also includes embodiments wherein only one compound is referenced.V. Preparation of Compounds

[0261] Compounds of the present disclosure can be synthesized by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of the disclosure is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present disclosure are available from commercial chemical sources or may be extracted from cells, plants, animals, or fungi. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. In the Schemes below showing some embodiments of methods of preparation of compounds of the disclosure, all variables are as defined in Formula (I), unless otherwise stated.

[0262] In some embodiments of the application, the compounds of the application are generally prepared according to the process illustrated in Schemes l-XI.

[0263] In some embodiments, the compounds of Formula (I) are prepared as shown in SchemeScheme I

[0264] Therefore, ortho-iodoanilin compounds of Formula (A) are coupled with suitable unsaturated precursors such as disubstituted alkyne compound of Formula (B) in the presence of a catalyst, such as a Pd catalyst, to provide a compound of Formula (I) through known methods, for example, using the Pd catalysis procedure found in Chem. Eur. J. 2019, 25, 897 - 903.

[0265] In some embodiments, the compounds of Formula (I) are synthesized according to Scheme II.Scheme II

[0266] Therefore, a substituted indole compound of Formula (C) is coupled with a suitable pyrrolidine carboxylic acid compound of Formula (E) in the present of suitable coupling reagents such as oxalyl chloride to provide compounds of Formula (D). The compounds of Formula (D) are reduced with suitable reducing agents such as Al-based reducing agents to provide the compounds of general Formula (I).

[0267] In some embodiments, the compounds of Formula (I) are synthesized according to Scheme IIIScheme III

[0268] In some embodiments, as shown in Scheme III, the compounds of Formula (I) are prepared using known methods, for example using the synthetic procedures found in Gerasimov et al., J. Med. Chem. 1999, 42, 4257-4263 and / or Macor et al., J. Med. Chem. 1992, 35, 4503- 4505. Therefore, a substituted indole compound of Formula (C) is brominated with a suitable brominated reagent such as N-bromosuccinimide (NBS) to provide brominated indole compounds of Formula (F). The compounds of Formula (F) are coupled with a suitable pyrrolidine carboxylic acid compound of Formula (E) in the present of suitable coupling reagents such as oxalyl chloride to provide compounds of Formula (D). The compounds of Formula (D) are reduced with suitable reducing agents such as Al-based reducing agents to provide the compounds of general Formula (I)-

[0269] In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme IV.Scheme IV

[0270] Therefore, in some embodiments, as shown in Scheme IV, compounds of Formula (C) wherein X is S are synthesized by coupling the indole of compound (G) wherein Hal is halide, such as I or Br with a thiol compound of Formula R4SH under suitable coupling conditions such as in the presence of a suitable catalyst such as a palladium catalyst (e.g., bis(dibenzylideneacetone)palladium(0) (Pd(dba)2)), ligand (e.g., 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthen (Xantphos)), and base such as ethyldiisopropylamine in a suitable inert solvent such as dioxane.

[0271] In some embodiments, compounds of Formula (C) wherein X is S are synthesized using methods known in the art as shown in Scheme IV, for example, the methods described in Shmatova, O. I., Eur. J. Org. Chem. 2015, 6479-6488.

[0272] In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme V.Scheme V

[0273] Therefore, in some embodiments, as shown in Scheme V, compounds of Formula (C) wherein X is S are synthesized by the desulfenylation of a compound of Formula (H) wherein Y is a suitable alkyl or aryl group in the presence of trifluoroacetic acid and a thiol as trapping agent, such as methyl thiosalicylate.

[0274] In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme V using methods known in the art, for example, the methods described in Hamel, P„ J. Org. Chem. 1994, 59, 6372-6377.

[0275] In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme VI.Scheme VI

[0276] Therefore, in some embodiments, as shown in Scheme VI, compounds of Formula (C) wherein X is S are synthesized using the Fischer indole synthesis method. For example, in some embodiments, hydrazine compounds of compound J are reacted with pyruvic acid under suitable conditions such as in the presence of zinc chloride and phosphorus pentachloride to provide the compounds of Formula (C).

[0277] In some embodiments, compounds of Formula (C) wherein X is S are prepared as shown in Scheme VI using methods known in the art, for example, the methods described in Bratulescu, G., Letters 49 (2008) 984-986.

[0278] In some embodiments, compounds of Formula (I) wherein X is S(O) (compounds of Formula 1(b)) and X is SO2 (compounds of Formula 1(c)) are prepared from compounds of Formula (I) wherein X is S (compounds of Formula 1(a)) according to Scheme VII.Scheme VII

[0279] In some embodiments, as shown in Scheme VII, compounds of Formula (I) wherein X is S (compounds of Formula 1(a)) are oxidized to compounds of Formula (I) wherein X is S(O) compounds of Formula 1(b)) under suitable oxidizing conditions such about one equivalent of meta-chloroperoxybenzoic acid (m-CPBA). Compounds of Formula (I) wherein X is S(O) (compounds of Formula 1(b)) are then oxidized under suitable oxidizing conditions such as meta- chloroperoxybenzoic acid (m-CPBA) to compounds of Formula (I) wherein X is SO2 (compounds of Formula 1(c)).

[0280] In some embodiments, compounds of Formula (I) wherein X is S(O) (compounds of Formula 1(b)) and X is SO2 (compounds of Formula 1(c)) are prepared from compounds of Formula (I) wherein X is S (compounds of Formula 1(a)) as shown in Scheme VII using methods known in the art, for example, the methods described in United States patent application 2004 / 0043965.

[0281] In some embodiments, compounds of Formula (C) wherein X is S and R4is CD3 (compounds of Formula C’) are prepared as shown in Scheme VIII.Scheme VIII

[0282] Therefore, in some embodiments, as shown in Scheme VII, compounds of Formula (C) wherein X is S and R4is CD3 (compounds of Formula (C’)) are synthesized by coupling the indole of compound (G) wherein Hal is I (compound of Formula G’) in the presence of a suitable catalyst such as a nickel based catalyst (e.g., nickel acetate) with a suitable electrophilic SCD3 reagent such as S-(methyl-D3) 4-methylbenzenesulfonothioatethe presence of a suitable reductant such as zinc powder and a base such as 2 ,2-bipyridyl to provide compounds of Formula (C) wherein X is S and R4is CD3 (compounds of Formula O’).

[0283] In some embodiments, compounds of Formula (C) wherein X is S and R6is CD3 (compounds of Formula O’) as shown ins Scheme VII are synthesized using methods known in the art, for example, the methods described in Zhang, Y., Org. Lett. 2022, 24, 6794-6799.

[0284] Compounds of Formula (I), wherein one or more of R1-R5are deuterium are available, for example, using a hydrogen-deuterium exchange reaction on a suitable starting substrate, wherein this exchange reaction is catalyzed by Pd / C in D2O as described in Esaki, H. et al., Tetrahedron, 2006, 62:10954-10961, and modifications thereof known to a person skilled in the art.

[0285] Especially for embodiments in which X is absent or oxygen, as well as for other embodiments of X, compounds of Formula (I) wherein X-R4is OCD3 are available, for example, using methods as described in Xu, Y-Z and Chen, C. J. Label Compd. Radiopharm. (2006) 49:897-902, and modifications thereof and modifications thereof known to a person skilled in the art.

[0286] In some embodiments in which X is absent, the compounds of Formula (I) are prepared as shown in Scheme IX. Therefore, ortho-iodoanilin compounds of Formula (A) are coupled with suitable unsaturated precursors such as disubstituted alkyne compound of Formula (B) in the presence of a catalyst, such as a Pd catalyst, to provide a compound of Formula (I) through known methods, for example, using the Pd catalysis procedure found in Chem. Eur. J. 2019, 25, 897 - 903.Scheme IX

[0287] In some embodiments, the compounds of Formula (I) in which X is absent are synthesized according to Scheme X. Therefore, a substituted indole compound of Formula (C) is coupled with a suitable pyrrolidine carboxylic acid compound of Formula (E) in the present of suitable coupling reagents such as oxalyl chloride to provide compounds of Formula (D). The compounds of Formula (D) are reduced with suitable reducing agents such as Al-based reducing agents to provide the compounds of general Formula (I).Scheme X

[0288] In some embodiments, as shown in Scheme XI, the compounds of Formula (I) in which X is absent are prepared using known methods, for example using the synthetic procedures found in Gerasimov et al., J. Med. Chem. 1999, 42, 4257-4263 and / or Macor et al. J. Med. Chem. 1992, 35, 4503-4505. Therefore, a substituted indole compound of Formula (C) is brominated with a suitable brominated reagent such as N-bromosuccinimide (NBS) to provide brominated indole compounds of Formula (F). The compounds of Formula (F) are coupled with a suitable pyrrolidine carboxylic acid compound of Formula (E) in the present of suitable coupling reagents such as oxalyl chloride to provide compounds of Formula (D). The compounds of Formula (D) are reducedwith suitable reducing agents such as Al-based reducing agents to provide the compounds of general Formula (I).Formula (I)Scheme XIA. Synthesis of Exemplary Compounds of the Disclosure

[0289] Example 1 : (R)-5-methoxy-2-methyl-3-((1 -methylpyrrolidin-2-yl)methyl)-1 H-indole (1-17)

[0290] Synthesis of (R)-2-(2-(5-methoxy-2-methyl-1 H-indole-3-carbonyl)pyrrolidin-1-yl)-1- phenyl-2l2-ethan-1-one (2): A solution of (2-oxo-2-phenyl-1 l2-ethyl)-D-proline (1.0 g, 4.01 mmol) in dry THF (20 mL) was treated with thionyl chloride (0.58 mL, 8.02 mmol) at 0 °C. The reaction was brought to room temperature, then refluxed for 2 h. The reaction was brought to room temperature, solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0291] A solution of 5-methoxy-2-methyl-1 H-indole (0.64 g, 4.01 mmol) in dry CH2CI2 (20 mL) at 5-10 °C was treated with above crude acid chloride in dry CH2CI2 (10 mL) and ethyl magnesium bromide (2.67 mL, 8.02 mmol, 3 M in diethyl ether) simultaneously over a period of 5 min. and stirred at same temperature for additional 15 min. The reaction was quenched with sat. NH4CI solution (10 mL) followed by water (50 mL) and product was extracted into CH2CI2 (2 x 50 mL). The CH2CI2 layer was washed with sat. NaHCOs solution (50 mL), brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude was purified by flash column chromatography (CH2CI2 to EtOAc: Hexanes, 2:3) on silica gel to obtain the title compound (1 .31 g, 83.4%) as a yellow foam.1H NMR (DMSO-cfe): 5 11.85 (s, 1H), 7.49 (s, 1H), 7.40-7.28 (m, 3H), 7.17-7.10 (m, 3H), 6.79 (d, 1H, J = 3.0 Hz), 5.20-4.89 (m, 3H), 3.79 (s, 3H), 3.78-3.42 (m, 2H), 2.68, 2.62 (2s, 3H), 2.46-2.40 (m, 2H), 1.99-1.84 (m, 2H); ESI-MS (m / z, %): 415 (M+Na, 100), 393 (MH+).

[0292] Synthesis of (R)-5-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole (I- 17): A suspension of (R)-2-(2-(5-methoxy-2-methyl-1 H-indole-3-carbonyl)pyrrolidin-1-yl)-1- phenyl-2l2-ethan-1-one (1.3 g, 3.31 mmol) in dry THF (25 mL) was treated with lithium aluminum hydride (0.62 g, 16.56 mmol) at 0 °C. The reaction was brought to room temperature, then refluxed for an additional 18 h. The reaction was cooled to 0 °C and quenched with the sequential addition of water (0.62 mL), 4 N NaOH solution (0.62 mL) and water (0.62 mL). The reaction was brought to room temperature and stirred for additional 30 min. The reaction was filtered through a pad of Na2SO4 and washed with THF (2 x 25 mL). The combined THF layer was evaporated and the crude was purified by column chromatography (2 M NH3 in MeOH: CH2CI2, 5:95) on silica gel to obtain the title compound (0.66 g, 77.6%) as a pale yellow solid.1H NMR (DMSO-cfe): 6 10.50 (s,1 H), 7.10 (d, 1 H, J = 6.0 Hz), 6.86 (s, 1 H), 6.62 (d, 1 H, J = 6.0 Hz), 3.74 (s, 3H), 2.97-2.89 (m, 2H), 2.45-2.27 (m, 8H), 2.10-2.05 (m, 1 H), 1.61-1.43 (m, 4H); ESI-MS (m / z, %): 259 (MH+, 100); HPLC purity: 99.3%.

[0293] Example 2: (R)-5-fluoro-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole (1-18)

[0294] Synthesis of (R)-2-(2-(5-fluoro-2-methyl-1 H-indole-3-carbonyl)pyrrolidin-1 -yl)-1 -phenyl- 2l2-ethan-1-one (5): A solution of (2-oxo-2-phenyl-1 l2-ethyl)-D-proline (1.0 g, 4.01 mmol) in dry THF (20 mL) was treated with thionyl chloride (0.58 mL, 8.02 mmol) at 0 °C. The reaction was brought to room temperature, then refluxed for 2 h. The reaction was brought to room temperature, the solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0295] A solution of 5-fluoro-2-methyl-1 H-indole (0.6 g, 4.01 mmol) in dry CH2CI2 (20 mL) at 5- 10 °C was treated with above crude acid chloride in dry CH2CI2 (10 mL) and ethyl magnesium bromide (2.67 mL, 8.02 mmol, 3 M in diethyl ether) simultaneously over a period of 5 min. and stirred at same temperature for additional 15 min. The reaction was quenched with sat. NH4CI solution (10 mL) followed by water (50 mL) and product was extracted into CH2CI2 (2 x 50 mL). The CH2CI2 layer was washed with sat. NaHCOa solution (50 mL), brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude was purified by flash column chromatography (CH2CI2 to EtOAc: Hexanes, 2:3) on silica gel to obtain the title compound (1.1 g, 72.4%) as a light brown foam.1H NMR (DMSO-d6): 5 12.09, 12.08 (2s, 1 H), 7.72 (d, 1 H, J = 9.0 Hz), 7.42-7.32 (m, 3H), 7.16-6.95 (m, 4H), 5.19-4.89 (m, 3H), 3.60-3.42 (m, 2H), 2.70, 2.65 2s, 3H), 2.50-2.40 (m, 2H), 1.91-1.85 (m, 2H); ESI-MS (m / z, %): 403 (M+Na), 381 (MH+).

[0296] Synthesis of (R)-5-fluoro-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole (1-18): A suspension of (R)-2-(2-(5-fluoro-2-methyl-1 H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2l2- ethan-1-one (1.05 g, 2.76 mmol) in dry THF (20 mL) was treated with lithium aluminum hydride (13.8 mL, 13.80 mmol, 1 M solution in THF) at 0 °C. The reaction was brought to room temperature, then refluxed for additional 18 h. The reaction was cooled to 0 °C and quenched with the sequential addition of water (0.52 mL), 4 N NaOH solution (0.52 mL) and water (0.52mL). The reaction was brought to room temperature and stirred for additional 30 min. The reaction was filtered through a pad of Na2SO4 and washed with THF (2 x 25 mL). The combined THF layer was evaporated and the crude was purified by column chromatography (2 M NH3 in MeOH: CH2CI2, 5:95) on silica gel to obtain the title compound (0.57 g, 83.8%) as a beige solid.1H NMR (DMSO-cfe): 6 10.79 (s, 1 H), 7.09 (d, 1 H, J = 9.0 Hz), 6.81 (d, 1 H, J = 3.0 Hz), 6.78 (t, 1 H, J = 3.0, 6,.O Hz), 2.99-2.89 (m, 2H), 2.46-2.07 (m, 9H), 1.61-1.41 (m, 4H); ESI-MS (m / z, %): 247 (MH+, 100); HPLC purity: 98.4%.

[0297] Example 3: (R)-4-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole (II- 94)8 II-94

[0298] Synthesis of (R)-2-(2-(4-methoxy-2-methyl-1 H-indole-3-carbonyl)pyrrolidin-1-yl)-1- phenyl-2l2-ethan-1-one (8): A solution of (2-oxo-2-phenyl-1 l2-ethyl)-D-proline (0.5 g, 2.00 mmol) in dry THF (10 mL) was treated with thionyl chloride (0.29 mL, 4.01 mmol) at 0 °C. The reaction was brought to room temperature, then refluxed for 2 h. The reaction was brought to room temperature, the solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0299] A solution of 4-methoxy-2-methyl-1 H-indole (0.32 g, 2.00 mmol) in dry CH2CI2 (10 mL) at 5-10 °C was treated with above crude acid chloride in dry CH2CI2 (5 mL) and ethyl magnesium bromide (1.33 mL, 4.01 mmol, 3 M in diethyl ether) simultaneously over a period of 5 min. and stirred at same temperature for additional 15 min. The reaction was quenched with sat. NH4CI solution (10 mL) followed by water (50 mL) and product was extracted into CH2CI2 (2 x 50 mL). The CH2CI2 layer was washed with sat. NaHCOs solution (50 mL), brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude was purified by flash column chromatography (CH2CI2 to EtOAc: Hexanes, 2:3) on silica gel to obtain the title compound (0.65 g, 83.3%) as a yellow foam.1H NMR (DMSO-cfe): 5 11.83 (s, 1H), 7.40-7.35 (m, 2H), 7.20-7.00 (m, 5H), 6.67 (t, 1 H, J = 6.0 Hz), 5.66, 5.55 (2d, 1 H, 6.0 Hz), 5.08, 4.99 (2s, 2H), 3.89, 3.82 (2s, 3H), 3.77-3.39 (m, 2H), 2.48, 2.41 (2s, 3H), 2.18-2.00 (m, 2H), 1.80-1.74 (m, 2H); ESI-MS (m / z, %): 415 (M+Na), 393 (MH+).

[0300] Synthesis of (R)-4-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole (II- 94): A suspension of (R)-2-(2-(4-methoxy-2-methyl-1 H-indole-3-carbonyl)pyrrolidin-1-yl)-1- phenyl-2l2-ethan-1-one (0.6 g, 1 .53 mmol) in dry THF (20 mL) was treated with lithium aluminum hydride (7.6 mL, 7.64 mmol, 1 M solution in THF) at 0 °C. The reaction was brought to room temperature, then refluxed for additional 18 h. The reaction was cooled to 0 °C and quenched with the sequential addition of water (0.29 mL), 4 N NaOH solution (0.29 mL) and water (0.29 mL). The reaction was brought to room temperature and stirred for additional 30 min. The reaction was filtered through a pad of Na2SO4 and washed with THF (2 x 25 mL). The combined THF layer was evaporated and the crude was purified by column chromatography (2 M NH3 in MeOH: CH2CI2, 5:95) on silica gel to obtain the title compound (0.27 g, 69.2%) as a beige solid.1H NMR (DMSO-cfe): 6 10.62 (s, 1 H), 6.88-6.81 (m, 2H), 6.39 (d, 1 H, J = 6.0 Hz), 3.80 (s, 3H), 3.15 (d, 1 H J = 9.0 Hz), 3.00-2.96 (m, 1H), 2.43-2.27 (m, 8H), 2.10-2.06 (m, 1 H), 1.64-1.50 (m, 4H); ESI-MS (m / z, %): 259 (MH+, 100); HPLC purity: 97.3%. A person skilled in the art would appreciate that further manipulation of the substituent groups using known chemistry can be performed on the intermediates and final compounds in the Schemes above to provide alternative compounds of the disclosure.

[0301] Salts of compounds of the disclosure may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.

[0302] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water, and the like. When water is the solvent, the molecule is referred to as a "hydrate." The formation of solvates of the compounds of the disclosure will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0303] Isotopically-enriched compounds of the disclosure and pharmaceutically acceptable salts, solvates, and / or prodrug thereof, can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using suitable isotopically-enriched reagents and / or intermediates.

[0304] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis,” T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations,” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry,” March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis,” Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0305] It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examplesof transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations,” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry," March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis," Smith, McGraw Hill, (1994).

[0306] Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation, and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0307] The products of processes disclosed in the disclosure may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography, or other suitable method.

[0308] Prodrugs of the compounds of the present disclosure may be, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g., an acid chloride in pyridine).

[0309] One skilled in the art will recognize that where a reaction step of the present disclosure is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.B. Biological Testing

[0310] Compounds of the invention are tested in binding assays and in functional assays of the human 5-hydroxytryptamine receptor subfamilies.

[0311] Human 5-Hydroxytryptamine Receptor 1 A (5-HTIA) CAMP assay

[0312] Compounds of the invention are tested for potency (EC50) and efficacy (Max response) against the human 5-HTIA receptor in a cAMP assay using stably transfected CHO-K1 cells. The results are expressed as a percent efficacy relative to the maximum response of the control ligand (serotonin).

[0313] Human 5-Hydroxytryptamine Receptor 1A (5-HTIA) Functional FLIPR assay

[0314] Compounds of the invention are tested to assess the potential excitatory effects of compounds targeting on 5-HTIA under agonist mode, using FLIPR functional assay.

[0315] The results are expressed in EC50 (nM) concentrations. This assay confirms compounds of the disclosure are effective agonists of the target human 5-HTIA receptors.

[0316] Human 5-Hydroxytryptamine Receptor 1A (5-HTIA) Radioligand binding assay.

[0317] Compounds of the invention are tested to evaluate the binding properties in radioligand binding assay on human 5-HTIA receptor.

[0318] Human 5-Hydroxytryptamine Receptor 2A (5-HT2A) 0-arrestins Assay

[0319] Compounds of the invention are tested for potency (EC50) and efficacy (Max response) against the human 5-HT2A receptor in stably transfected U2OS cells in a GPCR cell based 0- arrestins reporter assay. The results are expressed as a percent efficacy relative to the maximum response of the control ligand (serotonin).

[0320] Human 5-Hydroxytryptamine Receptor 2A (5-HT2A) Functional FLIPR Assay

[0321] Compounds of the invention are tested to assess the potential excitatory effects of compounds targeting human 5-HT2A under agonist mode, using FLIPR functional assay.

[0322] The results are expressed in EC50 (nM) concentrations This assay confirms compounds of the disclosure are effective agonists of the target human 5-HT2A receptors.

[0323] Human 5-Hydroxytryptamine Receptor 2A (5-HT2A) Radioligand binding assay

[0324] Compounds of the invention are tested in the human 5-HT2A, by radioligand binding assay, to evaluate the binding properties of compounds targeting on 5-HT2A. Ketanserin, known 5-HT2A antagonist, is used as reference compound. The results are expressed in % inhibition IC50.

[0325] Human 5-Hydroxytryptamine Receptor 2B (5-HT2B) FLIPR assay

[0326] Compounds of the invention are tested for potency (EC50) and efficacy (Max response) against the human 5-HT2B receptor in stably transfected HEK293 cells, in a calcium mobilizationbased assay.

[0327] The results are expressed as a percent efficacy relative to the maximum response of the control ligand (serotonin).

[0328] Human 5-Hydroxytryptamine Receptor 2B (5-HT2B) Positive Allosteric Modulator (PAM) Assay

[0329] Compounds of the invention are tested for potency (EC50) and efficacy (Max response) against the human 5-HT2B receptor in stably transfected HEK293 cells, in a GPCR cell-based assay. The results are expressed as a percent efficacy relative to the maximum response of the control ligand (serotonin).

[0330] Human 5-Hydroxytryptamine Receptors 2B (5-HT2B) Radioligand binding assay

[0331] Compounds of the invention are tested in the 5-HT2B, by radioligand binding assay. Yohimbine, known 5-HT2B antagonist, are used as a reference compound. The results are expressed as % inhibition IC50.

[0332] Human 5-Hydroxytryptamine Receptors 2C (5-HT2c) FLIPR assay

[0333] Compounds of the invention are tested for potency potency (EC50) and efficacy (Max response) against the human 5-HT2C receptor in stably transfected U2OS cells, in a calcium mobilization-based assay.

[0334] The results are expressed as a percent efficacy relative to the maximum response of the control ligand (serotonin).

[0335] Exemplary Embodiments

[0336] E1 : A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof,wherein:X is absent or is selected from O, S, S(O), and S(O)2jR1is selected from halo, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted OC1-C6alkyl, optionally substituted C3- Ciocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C-i- CealkyleneCa-Ciocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted C1-C6alkylene(5- to 10-membered)heteroaryl;R2is selected from H, D, halo, and optionally substituted C1-C6alkyl;R3is selected from H, D, halo, and optionally substituted C1-C6alkyl;R4is selected from H, D, halo, optionally substituted Ci-Cioalkyl, optionally substituted C2- Cealkenyl, optionally substituted 02-Cealkynyl, optionally substituted C1-C6alkyleneOR9, optionally substituted Ci.C6alkyleneC(O)R9, optionally substituted Ci.C6alkyleneNR10C(O)R9, optionally substituted Ci.C6alkyleneNR10C(O)OR9, optionally substituted Ci.C6alkyleneC(O)NR10R11, optionally substituted Ci.C6alkyleneOC(O)NR10R11, optionally substituted Ci.C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2- C6alkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-C6alkynyleneNR10R11, optionally substituted Cs-Czcycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci-CealkyleneCs-Czcycloalkyl, optionally substituted C1-C6alkylene(3- to 10- membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted Ci.Cealkylene(5- to 10-membered)heteroaryl;R5is selected from H, D, halo, OH, optionally substituted C1-C6alkyl, and Q-A;R6is selected from H, D, optionally substituted Ci-Caalkyl, optionally substituted C1- C6alkyleneO(C1-C6alkyl), and optionally substituted Ci-C6alkyleneS(C1-C6alkyl);R7is selected from H, D, and halo;R8is selected from H, D, and halo;R9is selected from H, D, optionally substituted C1-C6alkyl, optionally substituted Cs-Czcycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-C-ioaryl, and optionally substituted 5- to 10-membered heteroaryl;R10is selected from H, D, and optionally substituted C1-C6alkyl;R11is selected from H, D, and optionally substituted C1-C6alkyl;Q is absent or is selected from O, S, S(O), and S(O)2;A is selected from H, D, P(O)(OR12)2, CH2P(O)(OR12)2, CH(CH3)P(O)(OR12)2, C(O)Q', CH2(C3- Cycycloalkyl), CH2(C4-C6cycloalkenyl), CH2(3- to 10-membered)heterocycloalkyl, CH2(C6-Cio)aryl, CH2(5- to 10-membered)heteroaryl, and C^alkyl; each R12is independently selected from H, D, C1-C4 alkyl, and C2-Ce alkenyl;Q’ is selected from:indicates a point of covalent attachment; one or more available hydrogen atoms of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, and Q’ are optionally and independently replaced with one or more respective halogen atoms and / or wherein one or more available atoms of Formula (I) are optionally and independently replaced with one or more respective alternative isotopes, none of R6, R9, R10, R11, and R12consist of only a halogen atom; and the compound of Formula (I) is not selected from the following:(R)-2-ethyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 / 7-indol-4-ol;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-5-ol;(R)-5-ethoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2,7-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-isopropyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-ethyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-chloro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-2,5,7-trimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-bromo-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole; and(R)-2,5-dimethyl-3-(pyrrolidin-2-ylmethyl)-lH-indole, provided when R1is phenyl, then R1is substituted with at least one substituent not selected from H, D, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxyl, C1-C6alkyl, and C1-C6alkoxy; and provided when X is absent and R4is H, then R6is neither H nor non-deuterated Ci-Caalkyl; provided when X is absent and R4is halo, then R5is selected from H and D and is not halo; provided when X is absent and R4is selected from H and D but not halo, then R5is selected from halo, OH, optionally substituted C1-C6alkyl, and Q-A; and provided when R4is selected from optionally substituted Ci.Cwalkyl, optionally substituted C2- Cealkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6alkyleneOR9, optionally substituted Ci-C6alkyleneC(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)R9, optionally substituted Ci.CealkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci-C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted C2-CealkenyleneOR9, optionally substituted C2-CealkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2- CealkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- CealkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-C6alkynyleneNR10R11, optionally substituted Ca-Czcycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl,optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci CealkyleneCs-Cycycloalkyl, optionally substituted C1-C6alkylene(3- to 10- membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted Ci-C6alkylene(5- to 10-membered)heteroaryl, then R5is selected from H, D, and halo.

[0337] E2: The compound of E1 , wherein one or more available hydrogen atoms are optionally and independently replaced with one or more respective bromine atoms, one or more respective chlorine atoms, one or more respective fluorine atoms, and / or one or more respective deuterium atoms.

[0338] E3: The compound of E1 , wherein one or more available hydrogen atoms are optionally and independently replaced with one or more respective chlorine atoms, one or more respective fluorine atoms, and / or one or more respective deuterium atoms.

[0339] E4: The compound of E1 , wherein one or more available hydrogen atoms are optionally and independently replaced with one or more respective chlorine atoms and / or one or more respective deuterium atoms.

[0340] E5: The compound of E1 , wherein one or more available hydrogen atoms are optionally and independently replaced with one or more respective fluorine atoms and / or one or more respective deuterium atoms.

[0341] E6: The compound of E1 , wherein the compound is non-deuterated.

[0342] E7: The compound of E1 or E6, wherein none of R2, R3, R4, R5, R7, and R8optionally and independently consist of a halo atom, and wherein none of the available hydrogen atoms of R1, R2, R3, R4, R5, R7, R8, R9, R12, A, and Q’ are replaced with one or more respective halogen atoms.

[0343] E8: The compound of any one of E1 to E7, provided when R1is phenyl, then the phenyl is substituted with at least one substituent selected from OH, SH, and C1-C6alkylthio.

[0344] E9: The compound of any one of E1 to E8, provided when X is absent and R4is selected from H and D, then R6is not selected from H, D, C1-C3alkyl, Ci-Cadeuteroalkyl, C1-C3haloalkyl, and C1-C3deuterohaloalkyl.

[0345] E10: The compound of any one of E1 to E9, wherein the compound is not a deuterated analog of a member selected from the following:(R)-2-ethyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1H-indol-4-ol;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-5-ol;(R)-5-ethoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2,7-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-isopropyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-ethyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-chloro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-2,5,7-trimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-bromo-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole; and(R)-2,5-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole.

[0346] E11: The compound of any one of E1 to E10, wherein the compound is not a halogenated analog of a member selected from the following:(R)-2-ethyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 / 7-indol-4-ol;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-5-ol;(R)-5-ethoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2,7-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-isopropyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-ethyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-chloro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-2,5,7-trimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-bromo-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-(pyrrolid in-2-ylmethyl)-1 H-indole; and(R)-2,5-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole.

[0347] E12: The compound of any one of E1 to E11 , wherein X is O.

[0348] E13: The compound of any one of E1 to E11 , wherein X is S.

[0349] E14: The compound of any one of E1 to E11 , wherein X is S(O).

[0350] E15: The compound of any one of E1 to E11 , wherein X is S(O)2.

[0351] E16: The compound of any one of E1 to E11 , provided when X is selected from O, S, S(O), and S(O)2, then R4is not halo.

[0352] E17: The compound of any one of E1 to E16, wherein R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-Cecycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6- membered heteroaryl.

[0353] E18: The compound of any one of E1 to E16, wherein R1is selected from substituted C1-C6alkyl, substituted OC1-C6alkyl, substituted C3-Cecycloalkyl, substituted 5- to 6-membered heterocycloalkyl, and substituted 5- to 6-membered heteroaryl.

[0354] E19: The compound of E18, wherein R1is substituted with at least one substituent independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Ci- C4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), Ca-Czcycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl).

[0355] E20: The compound of any one of E1 to E16, wherein R1is selected from unsubstituted C1-C6alkyl, unsubstituted OC1-C6alkyl, unsubstituted C3-Cecycloalkyl, unsubstituted 5- to 6- membered heterocycloalkyl, and unsubstituted 5- to 6-membered heteroaryl.

[0356] E21 : The compound of any one of E1 to E20, wherein R1is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, tetrahydrofuryl, pyridinyl, pyrrolidinyl, pyrrolyl, tetrahydrothio phenyl, thiazolyl, thiophenyl, and piperidinyl.

[0357] E22: The compound of any one of E1 to E20, wherein R1is selected from CH3, CHF2, CF31CD3ICH2CH3ICH(CH3)2ICH(CD3)2IC(CH3)3, OCF3IOCHF2, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine, pyrrole, thiazole, tetrahydrothiophene, thiophene, piperidine, and pyridine.

[0358] E23: The compound of any one of E1 to E22, wherein R2is H not replaced with a halogen atom or a respective alternative isotope thereof.

[0359] E24: The compound of any one of E1 to E6 and E8 to E22, wherein R2is D.

[0360] E25: The compound of any one of E1 to E24, wherein R3is H not replaced with a halogen atom or a respective alternative isotope thereof.

[0361] E26: The compound of any one of E1 to E6 and E8 to E24, wherein R3is D.

[0362] E27: The compound of any one of E1 to E26, wherein:R4is selected from optionally substituted Cs-Cycycloalkyl, optionally substituted 3- to 10- membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10- membered heteroaryl, optionally substituted C1-C6alkyleneCs-Cycycloalkyl, optionally substituted Ci.C6alkylene(3-to 10-membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-C-ioaryl, and optionally substituted Ci.C6alkylene(5- to 10-membered)heteroaryl;R4is optionally substituted with one to four substituents independently selected from halo, Ci- Cealkyl, OR13, and C(O)R13;R5is selected from H, D, and halo; andR13is selected from H, D, halo, and optionally substituted Ci.Cealkyl.

[0363] E28: The compound of any one of E1 to E11 and E17 to E26, wherein X is absent, R4is halo, and R5is H.

[0364] E29: The compound of any one of E1 to E26, wherein X is selected from O, S, S(O), and S(O)2, wherein R4is methyl, and wherein R5is selected from hydrogen and halo.

[0365] E30: The compound of any one of E1 to E11 and E17 to E26, wherein X is absent, R4is methyl, and R5is H.

[0366] E31: The compound of E30, wherein R4is selected from CH3, CH2F, CHF2, CF3, and CD3.

[0367] E32: The compound of any one of E1 to E26, wherein R4is selected from H, F, CH3, CHD2, CD3, CH2F, CHF2, and CF3.

[0368] E33: The compound of E32, wherein X is absent R4is H.

[0369] E34: The compound of any one of E1 to E11 and E17 to E26, wherein X is absent, R4is H, and R5is halo.

[0370] E35: The compound of any one of E1 to E11 and E17 to E26, wherein X is absent, R4is H, and R5is OH.

[0371] E36: The compound of any one of E1 to E11 and E17 to E26, wherein X is absent, R4is H, and R5is unsubstituted C1-C6alkyl.

[0372] E37: The compound of any one of E1 to E11 and E17 to E26, wherein X is absent, R4is H, and R5is substituted C1-C6alkyl.

[0373] E38: The compound of any one of E1 to E26, wherein R4is selected from optionally substituted Ci-C6alkyleneOR9, Ci-C6alkyleneC(O)R9, optionally substituted Ci- C6alkyleneNR10C(O)R9, optionally substituted Ci.C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci.C6alkyleneOC(O)NR10R11, optionally substituted Ci.C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2.C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)OR9, optionally substituted C2- C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C2-C6alkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, and optionally substituted C2- C6alkynyleneNR10R11.

[0374] E39: The compound of E38, wherein R9is selected from optionally substituted C3- Cycycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce- Cioaryl, and optionally substituted 5- to 10-membered heteroaryl.

[0375] E40: The compound of E39, wherein R9is substituted with one to four substituents independently selected from halo, Ci-C4alkyl, OCi-C4alkyl, and C(O)Ci-C4alkyl.

[0376] E41: The compound of E38, wherein R9is selected from H and D.

[0377] E42: The compound of E38, wherein R9is selected from unsubstituted Ci-Cealkyl, unsubstituted Ce-Czcycloalkyl, unsubstituted 3- to 10-membered heterocycloalkyl, unsubstituted Ce-Cioaryl, and unsubstituted 5- to 10-membered heteroaryl.

[0378] E43: The compound of E38, wherein R9is selected from substituted Ci-Cealkyl, substituted Cs-Cycycloalkyl, substituted 3- to 10-membered heterocycloalkyl, substituted C^ Cioaryl, and substituted 5- to 10-membered heteroaryl.

[0379] E44: The compound of E43, wherein R9is substituted with at least one substituent independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(CrC4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), Cs-Cycycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl).

[0380] E45: The compound of any one of E36 to E44, wherein R10is selected from D and H not replaced with a halogen atom or an alternative substitute thereof.

[0381] E46: The compound of any one of E36 to E44, wherein R10is C1-C6alkyl.

[0382] E47: The compound of any one of E36 to E46, wherein R11is selected from D and H not replaced with a halogen atom or an alternative substitute thereof.

[0383] E48: The compound of any one of E36 to E46, wherein R11is C1-C6alkyl.

[0384] E49: The compound of any one of E1 to E48, wherein R5is selected from D and H not replaced with a halogen atom or an alternative substitute thereof.

[0385] E50: The compound of any one of E1 to E48, wherein R5is halo.

[0386] E51: The compound of any one of E1 to E48, wherein R5is selected from halo and H, and wherein H of R5is not replaced with a halogen atom or an alternative isotope thereof.

[0387] E52: The compound of any one of E1 to E48, wherein R5is OH.

[0388] E53: The compound of any one of E1 to E48, wherein R5is unsubstituted C1-C6alkyl.

[0389] E54: The compound of any one of E1 to E48, wherein R5is substituted C1-C6alkyl.

[0390] E55: The compound of E54, wherein R5is substituted with at least one substituent independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(0)2(Cr C4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), Cs-Czcycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl).

[0391] E56: The compound of any one of E1 to E48, wherein R5is Q-A.

[0392] E57: The compound of E56, wherein Q is O.

[0393] E58: The compound of E56, wherein Q is S.

[0394] E59: The compound of E56, wherein Q is S(O).

[0395] E60: The compound of E56, wherein Q is S(O)2.

[0396] E61: The compound of any one of E56 to E60, wherein A is selected from D and H not replaced with a halogen atom or an alternative substitute thereof.

[0397] E62: The compound of any one of E56 to E60, wherein A is selected from, P(O)(OR12)2, CH2P(O)(OR12)2, and CH(CH3)P(O)(OR12)2.

[0398] E63: The compound of E62, wherein each R12is independently selected from H, D, Ci- 04 alkyl, and C2-C6 alkenyl.

[0399] E64: The compound of any one of E56 to E60, wherein A is C(O)Q', wherein Q' is selected from:

[0400] E65: The compound of any one of E56 to E60, wherein A is selected from CH2(C3- Czcycloalkyl), CH2(C4-C6cycloalkenyl), CH2(3- to 10-membered)heterocycloalkyl, CH2(Ce- Cio)aryl, and CH2(5- to 10-membered)heteroaryl.

[0401] E66: The compound of any one of E56 to E60, wherein A is C1-4alkyl.

[0402] E67: The compound of E66, wherein A is methyl not substituted with a halogen atom or an alternative isotope thereof.

[0403] E68: The compound of E66, wherein A is selected from CH3 not substituted with a halogen atom or an alternative isotope thereof, CH2F, CHF2, and CF3.

[0404] E69: The compound of any one of E1 to E68, wherein R6is selected from CH3, CH2D, CHD2, and CD3.

[0405] E70: The compound of E69, wherein R6is selected from CH3 and CD3.

[0406] E71: The compound of any one of E1 to E68, wherein R6is CH2CH2OCH3.

[0407] E72: The compound of any one of E1 to E68, wherein R6is selected from unsubstituted C1-C3alkyl, unsubstituted C1-C3alkyleneOfC1-C6alkyl), and unsubstituted Ci-C3alkyleneS(Ci- Csalkyl).

[0408] E73: The compound of any one of E1 to E68, wherein R6is selected from substituted C1-C3alkyl, substituted Ci-C3alkyleneO(Ci-C6alkyl), and substituted Ci-C6alkyleneS(Ci-C3alkyl).

[0409] E74: The compound of E73, wherein R6is substituted with at least one substituent independently selected from halo, Ci-C4alkyl, O(Ci-C4alkyl), Ci-C4haloalkyl, O(Ci-C4haloalkyl), CN, OH, NH2, NH(Ci-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), S(Ci-C4alkyl), S(O)Ci-C4alkyl, S(O)2(Ci- C4alkyl), CO2H, CO2(Ci-C4alkyl), C(O)NH2, C(O)NH(Ci-C4alkyl), C(O)N(Ci-C4alkyl)(Ci-C4alkyl), Cs-Cycycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 3 ring heteromoieties independently selected from O, S, S(O), S(O)2, N, NH, and N(Ci-C4alkyl).

[0410] E75: The compound of any one of E1 to E68, wherein R6is selected from CH3, CD3, and CH2CH2OCH3.

[0411] E76: The compound of any one of E1 to E75, wherein R7and R8are each H, and wherein H of each of R7and R8is not replaced with a halogen atom or an alternative isotope thereof.

[0412] E77: The compound of any one of E1 to E5 and E7 to E75, wherein R7and R8are each D.

[0413] E78: The compound of any one of E1 to E16 and E23 to E77, wherein R1is a halogen selected from F, Cl, Br, and I; preferably F, Cl, and Br; more preferably F and Cl; even more preferably F.

[0414] E79: The compound of E1 , wherein:X is absent or selected from O, S, S(O), and S(O)2;R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is selected from H, halo, and Ci-C3alkyl;R5is selected from H, halo, C1-C6alkyl, and Q-A;R6is selected from Ci-C3alkyl and Ci-C6alkyleneO(C1-C6alkyl);R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2jA is C1-4alkyl; andH of each of R2, R3, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

[0415] E80: The compound of E1 , wherein:X is absent or is selected from O, S, S(O), and S(O)2;R1is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, C(CH3)3, OCF3, OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine, pyrrole, thiazole, tetrahydrothiophene, thiophene, piperidine, and pyridine;R2is H;R3is H;R4is selected from H, F, CH3, CHD2CD3, CH2F, CHF2, and CF3;R5is selected from H, F, CF3, and Q-A;R6is selected from CH3, CD3, and CH2CH2OCH3;R7is H;R8is H,Q is selected from O, S, S(O), and S(O)2iA is selected from H, CH3, CH2F, CHF2, CF3, and CD3; andH of each of R2, R3, R7, and R8is not replaced with a halogen atom or an alternative isotope.

[0416] E81 : The compound of E1 , wherein:X is selected from O, S, S(O), and S(O)2iR1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is C1-C3alkyl;R5is selected from H and halo;R6is Ci-C3alkyl;R7is H;R8is H; andH of each of R2, R3, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

[0417] E82: The compound of E81 , wherein:R1is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, C(CH3)3, OCF3, OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine, pyrrole, thiazole, tetrahydrothiophene, thiophene, piperidine, and pyridine;R4is selected from CH3, CHD2CD3, CH2F, CHF2, and CF3;R8is selected from CH3and CD3; and the available hydrogen atoms of R1and R4are not replaced with a halogen atom and wherein the available atoms of R1and R4are not replaced with an alternative isotope thereof.

[0418] E83: The compound of E1 , wherein:X is absent;R1is selected from optionally substituted C1-C6alkyl, optionally substituted C3-Cecycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6- membered heteroaryl;R2is H;R3is H;R4is selected from halo and Ci-C3alkyl;R5is H;R6is C1-C3alkyl;R7is H;R8is H; andH of each of R2, R3, R5, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

[0419] E84: The compound of E83, wherein:R1is selected from CH3, CD3, CH(CH3)2, cyclobutyl, tetrahydrofuran, and pyridine;R4is selected from F, CHF2, CF3, and CD3;R6is selected from CH3 and CD3; and the available hydrogen atoms of R1and R4are not replaced with a halogen atom and wherein the available atoms of R1and R4are not replaced with an alternative isotope thereof.

[0420] E85: The compound of E1 , wherein:X is absent;R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is H;R5is selected from halo, C1-C6alkyl, and Q-A;R6is selected from C1-C3alkyl and C1-C6alkyleneO(C1-C6alkyl);R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2iA is C1-4alkyl; andH of each of R2, R3, R4, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

[0421] E86: The compound of E85, wherein:R1is selected from CH3, CHF2, CD3, CH2CH3, CH(CH3)2, CfCHs , OCHF2, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, and pyridine;R5is selected from F, CF3, and Q-A;A is selected from H, CH3, CH2F, CHF2, CF3, and CD3;R6is selected from CH3, CD3, and CH2CH2OCH3; and the available hydrogen atoms of R1, A, and R6are not replaced with a halogen atom and the available atoms of R1, R5, A, and R6are not replaced with an alternative isotope thereof .

[0422] E87: The compound of E1 , wherein the compound is selected from the following:(R)-5-methoxy-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;5-methoxy-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;5-methoxy-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;(R)-2-(difluoromethyl)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(trifluoromethyl)-1 H-indole;(R)-5-(difluoromethyl)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-(difluoromethoxy)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-5-methoxy-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-2-ethyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-((1-nnethylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;5-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;5-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;(R)-2-(difluoromethyl)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(trifluoromethyl)-1 H-indole;(R)-5-(difluoromethyl)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-(difluoromethoxy)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-5-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1 -methylpyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole; and(R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0423] E88: The compound of E1 , wherein the compound is selected from (R)-2-methyl-3-((1 - (methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indol-4-ol and (R)-2-methyl-3-((1-methylpyrrolidin-2- yl)methyl)-1 H-indol-4-ol, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0424] E89: The compound of E1 , wherein the compound is selected from the following:(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-methyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-4-((difluoromethyl)thio)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-((fluoromethyl)thio)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-(methyl-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-4-fluoro-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclopropyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclopropyl-4-((difluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-4-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclobutyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclobutyl-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-4-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-4-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;4-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H- indole;4-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H- indole;(R)-4-methoxy-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylth io )-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylth io )-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylth io )-2-(trifluoromethoxy)-1 H-indole;(R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(trifluoromethoxy)-1 H-indole;(R)-2-(difluoromethoxy)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(difluoromethyl)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(tert-butyl)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclohexyl-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-methoxy-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(trifluoromethyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(trifluoromethoxy)-1 H-indole;(R)-4-(difluoromethoxy)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-ethyl-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-methoxy-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-2-methyl-1 H-indole;(R)-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-2-methyl-4-(methylthio)-1 H-indole;(R)-4-fluoro-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-2-methyl-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-methyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-4-((difluoromethyl)thio)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-((fluoromethyl)thio)-2-methyl-3-((1 -methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-(methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclopropyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclopropyl-4-((difluoromethyl)thio)-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-((fluoromethyl)thio)-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-4-((fluoromethyl)thio)-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclobutyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclobutyl-4-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;4-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;4-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1 -methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(trifluoromethoxy)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(trifluoromethoxy)-1 H-indole;(R)-2-(difluoromethoxy)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(difluoromethyl)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(tert-butyl)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclohexyl-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(trifluoromethyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(trifluoromethoxy)-1 H-indole;(R)-4-(difluoromethoxy)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole; and(R)-2-ethyl-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

[0425] E90: The compound of E1 , wherein the compound is selected from the following:(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-methyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;2-(methyl-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;(R)-5-fluoro-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-cyclopropyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-cyclopropyl-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclopropyl-5-((difluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-5-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-((difluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole ;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;2-cyclobutyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;(R)-2-cyclobutyl-5-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-fluoro-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-isopropyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-((fluoromethyl)thio)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(propan-2-yl-1, 1 ,1 , 3, 3, 3-d6)-1 H-indole;(R)-2-isopropyl-5-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-5-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;5-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H- indole;5-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H- indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-5-((trifluoromethyl)thio)- 1 H-indole;5-fluoro-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;5-fluoro-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-5-((trifluoromethyl)thio)- 1 H-indole;3-(((R)-1 -(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylth io )-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-5-(trifluoromethyl)-1 H- indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-5-(trifluoromethyl)-1 H- indole;(R)-3-((1-(methy...

Claims

WHAT IS CLAIMED IS:1 . A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, wherein:X is absent or is selected from O, S, S(O), and S(O)2;R1is selected from halo, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted OC1-C6alkyl, optionally substituted C3- Ciocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C-i- CealkyleneCa-Ciocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted Ci-C6alkylene(5- to 10-membered)heteroaryl;R2is selected from H, D, halo, and optionally substituted C1-C6alkyl;R3is selected from H, D, halo, and optionally substituted C1-C6alkyl;R4is selected from H, D, halo, optionally substituted Ci-Cioalkyl, optionally substituted C2- Coalkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6alkyleneOR9, optionally substituted Ci-C6alkyleneC(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci.C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted C2-C6alkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-C6alkynyleneNR10R11, optionally substituted C3.C7cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci-CealkyleneCs-Cycycloalkyl, optionally substituted Ci-C6alkylene(3- to 10- membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted Ci-C6alkylene(5- to 10-membered)heteroaryl;R5is selected from H, D, halo, OH, optionally substituted C1-C6alkyl, and Q-A;R6is selected from H, D, optionally substituted Ci-C3alkyl, optionally substituted C-i- C6alkyleneO(Ci-C6alkyl), and optionally substituted Ci-C6alkyleneS(Ci-C6alkyl);R7is selected from H, D, and halo;R8is selected from H, D, and halo;R9is selected from H, D, optionally substituted C1-C6alkyl, optionally substituted C3.C7cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, and optionally substituted (5- to 10-membered) heteroaryl;R10is selected from H, D, and optionally substituted C1-C6alkyl;R11is selected from H, D, and optionally substituted C1-C6alkyl;Q is absent or is selected from O, S, S(O), and S(O)2;A is selected from H, D, P(O)(OR12)2, CH2P(O)(OR12)2, CH(CH3)P(O)(OR12)2, C(O)Q', CH2(C3- Cycycloalkyl), CH2(C4-C6cycloalkenyl), CH2(3- to 10-membered)heterocycloalkyl, CH2(Ce-Cio)aryl, CH2(5- to 10-membered)heteroaryl, and Ci^alkyl; each R12is independently selected from H, D, C1-C4 alkyl, and C2-C6 alkenyl;Q’ is selected from:indicates a point of covalent attachment; one or more available hydrogen atoms of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, and Q’ are optionally and independently replaced with one or more respective halogen atoms and / or wherein one or more available atoms of Formula (I) are optionally and independently replaced with one or more respective alternative isotopes, none of R6, R9, R10, R11, and R12consist of only a halogen atom; and the compound of Formula (I) is not selected from the following:(R)-2-ethyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1W-indol-4-ol;(R)-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indol-5-ol;(R)-5-ethoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-methoxy-2,7-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-isopropyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-ethyl-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-chloro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-2,5,7-trimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-bromo-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole; and(R)-2,5-dimethyl-3-(pyrrolidin-2-ylmethyl)-1 H-indole, provided when R1is phenyl, then R1is substituted with at least one substituent not selected from H, D, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxyl, C1-C6alkyl, and C Cealkoxy; and provided when X is absent and R4is H, then R6is neither H nor non-deuterated Ci-Caalkyl; provided when X is absent and R4is halo, then R5is selected from H and D and is not halo; provided when X is absent and R4is selected from H and D but not halo, then R5is selected from halo, OH, optionally substituted C1-C3alkyl, and Q-A; and provided when R4is selected from optionally substituted Ci-Cioalkyl, optionally substituted C2- Cealkenyl, optionally substituted C2-C6alkynyl, optionally substituted C1-C6alkyleneOR9, optionallysubstituted Ci.C6alkyleneC(O)R9, optionally substituted Ci.C6alkyleneNR10C(O)R9, optionally substituted Ci-C6alkyleneNR10C(O)OR9, optionally substituted Ci-C6alkyleneC(O)NR10R11, optionally substituted Ci-C6alkyleneOC(O)NR10R11, optionally substituted Ci-C6alkyleneNR10R11, optionally substituted Cz-CsalkenyleneOR9, optionally substituted C2-C6alkenyleneC(O)R9, optionally substituted C2-C6alkenyleneNR10C(O)R9, optionally substituted C2- C6alkenyleneNR10C(O)OR9, optionally substituted C2-C6alkenyleneC(O)NR10R11, optionally substituted C2-C6alkenyleneOC(O)NR10R11, optionally substituted C2-C6alkenyleneNR10R11, optionally substituted C^CealkynyleneOR9, optionally substituted C2-C6alkynyleneC(O)R9, optionally substituted C2-C6alkynyleneNR10C(O)R9, optionally substituted C2- C6alkynyleneNR10C(O)OR9, optionally substituted C2-C6alkynyleneC(O)NR10R11, optionally substituted C2-C6alkynyleneOC(O)NR10R11, optionally substituted C2-C6alkynyleneNR10R11, optionally substituted Cs-Czcycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted Ce-Cioaryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ci-CealkyleneCs-Cycycloalkyl, optionally substituted Ci-C6alkylene(3- to 10- membered)heterocycloalkyl, optionally substituted C1-C6alkyleneCe-Cioaryl, and optionally substituted Ci.C6alkylene(5- to 10-membered)heteroaryl, then R5is selected from H, D, and halo.

2. The compound of claim 1 , provided when R1is phenyl, then the phenyl of R1is substituted with at least one substituent selected from OH, SH, and C1-C6alkylthio.

3. The compound of claim 1 or claim 2, provided when X is absent and R4is selected from H and D, then R6is not selected from H, D, C1-C3alkyl, Ci-Cadeuteroalkyl, C1-C3haloalkyl, and C1- Csdeuterohaloalkyl.

4. The compound of any one of claims 1 to 3, wherein X is O.

5. The compound of any one of claims 1 to 3, wherein X is S.

6. The compound of any one of claims 1 to 3, wherein X is S(O).

7. The compound of any one of claims 1 to 3, wherein X is S(O)2.

8. The compound of any one of claims 1 to 3, provided when X is selected from O, S, S(O), and S(O)2, then R4is not halo.

9. The compound of any one of claims 1 to 8, wherein R5is Q-A.

10. The compound of claim 9, wherein Q is O.

11. The compound of claim 9, wherein Q is S.

12. The compound of claim 9, wherein Q is S(O).

13. The compound of claim 9, wherein Q is S(O)2.

14. The compound of claim 1, wherein:X is absent or selected from O, S, S(O), and S(O)2;R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is selected from H, halo, and C1-C3alkyl;R5is selected from H, halo, C1-C6alkyl, and Q-A;R6is selected from C1-C3alkyl and Ci-C6alkyleneO(C1-C6alkyl);R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2;A is C1-4alkyl; andH of each of R2, R3, R7, and R8is not replaced with halogen or a respective isotope.

15. The compound of claim 1 , wherein:X is absent or is selected from O, S, S(O), and S(O)2;R1is selected from CH3, CHF2, CF3, CD3ICH2CH3, CH(CH3)2ICH(CD3)2IC(CH3)3IOCF3>OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine, pyrrole, thiazole, tetrahydrothiophene, thiophene, piperidine, and pyridine;R2is H;R3is H;R4is selected from H, F, CH3, CHD2, CD3, CH2F, CHF2, and CF3;R5is selected from H, F, CF3, and Q-A;R6is selected from CH3, CD3, and CH2CH2OCH3;R7is H;R8is H,Q is selected from O, S, S(O), and S(O)2;A is selected from H, CH3, CH2F, CHF2, CF3, and CD3; andH of each of R2, R3, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

16. The compound of claim 1 , wherein:X is selected from O, S, S(O), and S(O)2;R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is C1-C3alkyl;R5is selected from H and halo;R6is Ci-C3alkyl;R7is H;R8is H; andH of each of R2, R3, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

17. The compound of claim 16, wherein:R1is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH(CH3)2, CH(CD3)2, C(CH3)3, OCF3, OCHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine, pyrrole, thiazole, tetrahydrothiophene, thiophene, piperidine, and pyridine;R4is selected from CH3, CHD2CD3, CH2F, CHF2, and CF3;R6is selected from CH3and CD3; and wherein the available hydrogen atoms of R1and R4are not replaced with a halogen atom and wherein the available atoms of R1and R4are not replaced with an alternative isotope thereof.

18. The compound of claim 1 , wherein:X is absent;R1is selected from optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6- membered heteroaryl;R2is H;R3is H;R4is selected from halo and Ci-C3alkyl;R5is H;R6is Ci-C3alkyl;R7is H;R8is H; andH of each of R2, R3, R5, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

19. The compound of claim 18, wherein:R1is selected from CH3, CD3, CH(CH3)2, cyclobutyl, tetrahydrofuran, and pyridine;R4is selected from F, CH3, CHF2, CF3, and CD3;R6is selected from CH3 and CD3; and wherein the available hydrogen atoms of R1and R4are not replaced with a halogen atom and wherein the available atoms of R1and R4are not replaced with an alternative isotope thereof.

20. The compound of claim 1 , wherein:X is absent;R1is selected from optionally substituted C1-C6alkyl, optionally substituted OC1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 6-membered heterocycloalkyl, and optionally substituted 5- to 6-membered heteroaryl;R2is H;R3is H;R4is H;R5is selected from halo, C1-C6alkyl, and Q-A;R6is selected from C1-C3alkyl and C1-C6alkyleneOfC1-C6alkyl);R7is H;R8is H;Q is selected from O, S, S(O), and S(O)2iA is C1-4alkyl; andH of each of R2, R3, R4, R7, and R8is not replaced with a halogen atom or an alternative isotope thereof.

21. The compound of claim 20, wherein:R1is selected from CH3, CHF2, CD3, CH2CH3, CH(CH3)2, C(CH3)s, OCHF2, OCF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran, and pyridine;R5is selected from F, CF3, and Q-A;A is selected from H, CH3, CH2F, CHF2, CF3, and CD3;R6is selected from CH3, CD3, and CH2CH2OCH3; and the available hydrogen atoms of R1, A, and R6are not replaced with a halogen atom and the available atoms of R1, R5, A, and R6are not replaced with an alternative isotope thereof.

22. The compound of claim 1 , wherein the compound is selected from the following:(R)-5-methoxy-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;5-methoxy-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;5-methoxy-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;(R)-2-(difluoromethyl)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(trifluoromethyl)-1 H-indole;((R)-5-(difluoromethyl)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-(difluoromethoxy)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-5-methoxy-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-5-methoxy-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-2-ethyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-fluoro-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;5-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;5-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;(R)-2-(difluoromethyl)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(trifluoromethyl)-1 H-indole;(R)-5-(difluoromethyl)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-(difluoromethoxy)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-5-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1 -methylpyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole; and(R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

23. The compound of claim 1 , wherein the compound is selected from (R)-2-methyl-3-((1 - (methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indol-4-ol and (R)-2-methyl-3-((1-methylpyrrolidin-2- yl)methyl)-1 H-indol-4-ol, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

24. The compound of claim 1 , wherein the compound is selected from the following:(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-methyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-methyl-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-4-((difluoromethyl)thio)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-((fluoromethyl)thio)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-(methyl-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-4-fluoro-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-fluora-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclopropyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclopropyl-4-((difluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-4-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclobutyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclobutyl-4-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-4-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-4-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;4-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H- indole;4-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H- indole;(R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(methylthio)-2-(trifluoromethoxy)-1 H-indole;(R)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(trifluoromethoxy)-1 H-indole;(R)-2-(difluoromethoxy)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(difluoromethyl)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(tert-butyl)-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclohexyl-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-methoxy-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(trifluoromethyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-4-(trifluoromethoxy)-1 H-indole;(R)-4-(difluoromethoxy)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-ethyl-4-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-methoxy-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-2-methyl-1 H-indole;(R)-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-2-methyl-4-(methylthio)-1 H-indole;(R)-4-fluoro-3-((1-(2-methoxyethyl)pyrrolidin-2-yl)methyl)-2-methyl-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-methyl-3-(((R)-1 -methylpyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-4-((difluoromethyl)thio)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-((fluoromethyl)thio)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-(methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclopropyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclopropyl-4-((difluoromethyl)thio)-3-((1 -methylpyrrolid in-2 -yl)methyl)-1 H-indole;(R)-2-cyclopropyl-4-((fluoromethyl)thio)-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-4-((fluoromethyl)thio)-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-1 H-indole;2-cyclobutyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfinyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylsulfonyl)-1 H-indole;(R)-2-cyclobutyl-4-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-4-methoxy-3-((1 -methylpyrrolid in-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;4-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;4-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-4-(methylthio)-2-(trifluoromethoxy)-1 H-indole;(R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(trifluoromethoxy)-1 H-indole;(R)-2-(difluoromethoxy)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(difluoromethyl)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(tert-butyl)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclohexyl-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-methoxy-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-4-fluoro-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(trifluoromethyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-4-(trifluoromethoxy)-1 H-indole;(R)-4-(difluoromethoxy)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole; and(R)-2-ethyl-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

25. The compound claim 1 , wherein the compound is selected from the following:(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-methyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-methyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-(methyl-d3)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;2-(methyl-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;(R)-5-fluoro-2-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-cyclopropyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclopropyl-5-((difluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-5-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-((fluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-((difluoromethyl)thio)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole ;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;2-cyclobutyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;(R)-2-cyclobutyl-5-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-fluoro-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-isopropyl-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-((fluoromethyl)thio)-2-isopropyl-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(propan-2-yl-1, 1 ,1 , 3, 3, 3-d6)-1 H-indole;(R)-2-isopropyl-5-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopentyl-5-(methoxy-d3)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;5-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H- indole;5-(methoxy-d3)-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H- indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylthio)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-5-((trifluoromethyl)thio)- 1 H-indole;5-fluoro-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;5-fluoro-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-5-((trifluoromethyl)thio)- 1 H-indole;3-(((R)-1 -(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylth io )-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-5-(trifluoromethyl)-1 H- indole;3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-5-(trifluoromethyl)-1 H- indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-5-(trifluoromethyl)-1 H-indole(R)-5-(methyl-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylth io )-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((methyl-d3)thio)-2-(pyridin-2-yl)-1 H-indole;(R)-5-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-5-(methoxy-d3)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-5-((methyl-d3)thio)-2-(pyridin-3-yl)-1 H-indole;(R)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylth io )-2-(pyridin-3-yl)-1 H-indole;(R)-5-fluoro-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-5-fluoro-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1 -(methyl-d3)pyrrolidin-2-yl)methyl)-5-(methylth io )-2-(pyridin-4-yl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(trifluoromethoxy)-1 H-indole;(R)-2-(difluoromethoxy)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(trifluoromethyl)-1 H-indole;(R)-2-(difluoromethyl)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-(tert-butyl)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclohexyl-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-1 H-indole;5-methoxy-3-(((R)-1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(pyrrolidin-2-yl)-1 H-indole;(R)-4-(5-methoxy-3-((1-(methyl-d3)pyrralidin-2-yl)methyl)-1 H-indol-2-yl)thiazole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(3H-pyrrol-5-yl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrrolidin-2-yl)methyl)-2-(thiophen-3-yl)-1 H-indole;5-methoxy-3-(((R)-1 -(methyl-d3)pyrrolidin-2-yl)methyl)-2-(tetrahyd rath iophen-3-yl)-1 H-indole;5-methoxy-3-(((R)-1-(methyl-d3)pyrralidin-2-yl)methyl)-2-(piperidin-2-yl)-1 H-indole;(R)-5-methoxy-3-((1-(methyl-d3)pyrralidin-2-yl)methyl)-2-(piperidin-4-yl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-methyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-cyclopropyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-cyclopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclopropyl-5-((difluoromethyl)thio)-3-((1 -methylpyrrolid in-2 -yl)methyl)-1 H-indole;(R)-2-cyclopropyl-5-((fluoromethyl)thio)-3-((1 -methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-((fluoromethyl)thio)-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-5-((difluoromethyl)thio)-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;2-cyclobutyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-cyclobutyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;(R)-2-cyclobutyl-5-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-fluoro-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-1 H-indole;2-isopropyl-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfinyl)-1 H-indole;(R)-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylsulfonyl)-1 H-indole;(R)-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-5-((difluoromethyl)thio)-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-((fluoromethyl)thio)-2-isopropyl-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;3-(((R)-1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-5-((trifluoromethyl)thio)-1 H- indole;5-fluoro-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-1 H-indole;5-fluoro-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-5-((trifluoromethyl)thio)-1 H- indole;3-(((R)-1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-2-((S)-tetrahydrofuran-3-yl)-1 H-indole;3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((S)-tetrahydrofuran-3-yl)-5-(trifluoromethyl)-1 H-indole;3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-((R)-tetrahydrofuran-3-yl)-5-(trifluoromethyl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-5-(trifluoromethyl)-1 H-indole;(R)-5-methyl-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-2-(pyridin-2-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-2-yl)-5-((trifluoromethyl)thio)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-2-(pyridin-3-yl)-1 H-indole;(R)-5-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-3-yl)-1 H-indole;(R)-5-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(pyridin-4-yl)-1 H-indole;(R)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(methylthio)-2-(pyridin-4-yl)-1 H-indole;(R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(trifluoromethoxy)-1 H-indole;(R)-2-(difluoromethoxy)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(trifluoromethyl)-1 H-indole;(R)-2-(tert-butyl)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;(R)-2-cyclohexyl-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole;5-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-(pyrrolidin-2-yl)-1 H-indole;(R)-4-(5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indol-2-yl)thiazole;(R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(3H-pyrrol-5-yl)-1 H-indole;(R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(thiophen-3-yl)-1 H-indole;5-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)-2-(tetrahydrothiophen-3-yl)-1 H-indole;5-methoxy-3-(((R)-1 -methylpyrrolidin-2-yl)methyl)-2-(piperidin-2-yl)-1 H-indole; and (R)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-2-(piperidin-4-yl)-1 H-indole, or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof.

26. A composition comprising one or more compounds of any one of claims 1 to 25 and a carrier.

27. A method of treating depressive disorder, bipolar disorder, eating disorder, impulse control disorder, personality disorder, substance abuse disorder, behavioral addiction disorder, alcoholuse disorder, post-traumatic stress disorder, anxiety disorder, stress disorder, neurodevelopmental disorder, pain disorder, headache disorder, inflammatory disorder, injury- related disorder, neurodegenerative disorder, functional disorder, psychotic disorder, hyperkinetic movement disorder, age-related macular degeneration, atherosclerosis, dissociative disorders, genetic brain disorders, hyperprolactinemia, hypersomnia, obesity, phobias, apathy disorders, and / or burnout comprising administering a therapeutically effective amount of one or more compounds ofany one of claims 1 to 25 or the composition of claim 26 to a subject in need thereof.

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