Negative nmda-modulating compounds and methods of use thereof

Abstract

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts, isotopic variants, and combinations thereof, and pharmaceutical compositions thereof. Compounds of the present disclosure are contemplated useful for the prevention and treatment of a variety of CNS-related conditions.

Description

NEGATIVE NMDA-MODULATING COMPOUNDS AND METHODS OF USE THEREOF Related Applications

[0001] This application claims the benefit of and priority from U.S. Provisional Application Number 63 / 427,012, filed November 21, 2022, the entire contents of which are incorporated herein by reference. Background

[0002] NMDA receptors are heteromeric complexes comprised of NR1, NR2, and / or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. NMDA receptors are expressed in the peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some circumstances and excitotoxicity in others. These receptors are ligand-gated ion channels that admit Ca2+after binding of the glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function. Negative modulators may be useful as therapeutic agents with potential clinical uses in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (e.g., treatment resistant depression).

[0003] There is a need for new compounds that are negative allosteric modulators of the NMDA receptor for the prevention and treatment of conditions associated with NMDA function. Compounds, compositions, and methods described herein are directed toward this end. Summary

[0004] In one aspect, the disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6alkyl; R19is hydrogen or substituted or unsubstituted C1-6alkyl; R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; provided that R20and R20’are not both hydroxyl; and R22is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted C6-10aryl; provided that when R22is -CH3, R3is not -CH3or hydrogen.

[0005] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA;each of R15and R16is independently hydrogen or C1-6alkyl optionally substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is hydrogen or C1-6alkyl optionally substituted with 1-5 RC; R19is hydrogen or C1-6alkyl optionally substituted with 1-5 RD; R20is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RE; R20’is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RF; provided that R20and R20’are not both hydroxyl; each instance of RA, RB, RC, RD, RE, and RF, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and C1-6alkoxy optionally substituted with 1-5 halo; R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are independently optionally substituted with 1- 5 RGand said C3-6carbocyclyl and C6-10aryl are independently optionally substituted with 1- 5 RH; provided that when R22is -CH3, R3is not -CH3or hydrogen; each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 RG1; each instance of RG1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo; and each instance of RH, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo.

[0006] In some embodiments, the disclosure provides a compound of Formula (I-A) or (I- B):acceptable salt, isotopic variant, or combination thereof.

[0007] In some embodiments, the disclosure provides a compound of Formula (I-A-1) or (I-A-2):acceptable salt, isotopic variant, or combination thereof.

[0008] In some embodiments, the disclosure provides a compound of Formula (I-A-1-i) or (I-A-1-ii):acceptable salt, isotopic variant, or combination thereof.

[0009] In some embodiments, the disclosure provides a compound of Formula (I-A-2-i) or (I-A-2-ii):acceptable salt, isotopic variant, or combination thereof.

[0010] In some embodiments, the disclosure provides a compound of Formula (I-B-1) or (I-B-2):salt, isotopic variant, or combination thereof.

[0011] In some embodiments, the disclosure provides a compound of Formula (I-B-1-i) or (I-B-1-ii):acceptable salt, isotopic variant, or combination thereof.

[0012] In some embodiments, the disclosure provides a compound of Formula (I-B-2-i) or (I-B-2-ii):acceptable salt, isotopic variant, or combination thereof.

[0013] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein (i.e., (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2- ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), (I-B-2-ii)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C2-6alkynyl; R15is hydrogen or substituted or unsubstituted C1-6alkyl and R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is substituted or unsubstituted C1-6alkyl; R20is hydrogen, hydroxyl, or substituted or unsubstituted C1-6alkyl; and R20’is hydrogen or substituted or unsubstituted C1-6alkyl, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0014] In some embodiments, the disclosure provides a compound of any one of the Formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-5 RA; R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RB; R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is C1-6alkyl optionally substituted with 1-5 RC; R20is hydrogen, hydroxyl, or C1-6alkyl optionally substituted with 1-5 RE; andR20’is hydrogen or C1-6alkyl optionally substituted with 1-5 RF.

[0015] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3is substituted or unsubstituted C1-6alkyl; R15is hydrogen or substituted or unsubstituted C1-6alkyl and R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is -CH3; R20is hydrogen; R20’is -CH3; and R22is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C2-6alkynyl.

[0016] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3is C1-6alkyl optionally substituted with 1-5 RA; R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RB; R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is -CH3; R20is hydrogen; R20’is -CH3; and R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-5 RG.

[0017] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3is C1alkyl substituted with 1-3 RA; R15and R16are hydrogen; R18and R19are -CH3; R20is hydrogen; R20’is -CH3; andR22is C1-6alkyl optionally substituted with an unsubstituted C1-6alkoxy. In some embodiments, R22is -CH3or -CH2OCH3.

[0018] In some embodiments, R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R3is hydrogen, C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA. In some embodiments, R3is -H, -CH2F, - CHF2, -CF3, -CH2OCH3, -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C≡C-H, - C≡C-CH3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently optionally substituted with 1-5 RA. In some embodiments, R3is hydrogen. In some embodiments, R3is substituted or unsubstituted C1-6alkyl. In some embodiments, R3is C1-6alkyl optionally substituted with 1-5 RA. In some embodiments, R3is C1-6alkyl substituted with 1-5 RA. In some embodiments, R3is -CH2F, -CHF2, -CF3, -CH2OCH3, or -CH2OH. In some embodiments, R3is -CF3. In some embodiments, R3is unsubstituted C1-6alkyl. In some embodiments, R3is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R3is -CH3or -CH2CH3. In some embodiments, R3is substituted or unsubstituted C2-6alkynyl. In some embodiments, R3is C2-6alkynyl optionally substituted with 1-5 RA. In some embodiments, R3is -C≡C-H or -C≡C-CH3. In some embodiments, R3is substituted or unsubstituted C3-6carbocyclyl. In some embodiments, R3is C3-6carbocyclyl optionally substituted with 1-5 RA. In some embodiments, R3is unsubstituted cyclopropyl. In some embodiments, R3is substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R3is 5-8 membered heteroaryl optionally substituted with 1-5 RA. In some embodiments, R3is unsubstituted pyridyl.

[0019] In some embodiments, R15is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R15is hydrogen or -CH3.

[0020] In some embodiments, R16is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R16is hydrogen or -CH3.

[0021] In some embodiments, R15and R16are hydrogen. In some embodiments, R15is - CH3and R16is hydrogen. In some embodiments, R15is hydrogen and R16is -CH3. In some embodiments, R15and R16are -CH3. In some embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl. In some embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB. In someembodiments, R15and R16, taken together with the carbon atoms to which they are attached, form an unsubstituted cyclopropyl.

[0022] In some embodiments, R18is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R18is hydrogen, -CH3, or -CH2CH3. In some embodiments, R18is -CH3or - CH2CH3.

[0023] In some embodiments, R19is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R19is hydrogen or -CH3. In some embodiments, R19is -CH3. In some embodiments, R19is hydrogen.

[0024] In some embodiments, R18and R19are hydrogen. In some embodiments, R18and R19are -CH3. In some embodiments, R18is -CH3and R19is hydrogen. In some embodiments, R18is -CH2CH3and R19is -CH3.

[0025] In some embodiments, R20is hydrogen, hydroxyl, or unsubstituted C1-6alkyl. In some embodiments, R20is hydrogen, hydroxyl, or -CH3.

[0026] In some embodiments, R20’is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R20’is hydrogen or -CH3.

[0027] In some embodiments, R20and R20’are hydrogen. In some embodiments, R20and R20’are -CH3. In some embodiments, R20is hydrogen and R20’is -CH3. In some embodiments, R20is -CH3and R20’is hydrogen. In some embodiments, R20is hydroxyl and R20’is -CH3.

[0028] In some embodiments, R22is substituted or unsubstituted C1-6alkyl. In some embodiments, R22is C1-6alkyl optionally substituted with 1-5 RG. In some embodiments, R22is substituted C1-6alkyl. In some embodiments, R22is C1-6alkyl substituted with 1-5 RG. In some embodiments, R22is C1-6alkyl substituted with 1-3 RG, wherein each instance of RGis independently selected from the group consisting of: halo, hydroxyl, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl, wherein said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 RG1. In some embodiments, R22is -CH2F, -CHF2, -CF3, -CH2CH2CH(CH3)(CF3), -CH2OH, -CH2OCH3, - CH2OCH2CH2OCH3, -CH2OCH(CH3)2, -CH2OCF3, -CH2OCHF2, -CH3, -CH2CH3, - CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -C(CH3)3, -CH=CH2, - CH2CH=CH2, -CH=CHCH3, -CH=C(CH3)2, -C≡C-H, -C≡C-CH3, -C≡C-CF3,unsubstituted cyclopropyl, unsubstituted cyclobutyl, bicyclo[1.1.1]pentanyl optionally substituted with 1-5 RH, or phenyl optionally substituted with 1-5 RH. In some embodiments, R22is -CH2F, -CHF2, -CF3, or -CH2CH2CH(CH3)(CF3). In some embodiments, R22is -CH2OH, -CH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH(CH3)2, -CH2OCF3, or -CH2OCHF2.

[0029] In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis 5-6 membered heteroaryl optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis a 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis a 5-6 membered nitrogen-containing heteroaryl containing 1-4 nitrogen atoms and optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis a 5-6 membered heteroaryl substituted with 1-3 RG1, wherein each instance of RG1is independently selected from cyano, oxo, and C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with a C3-6carbocyclyl optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis 5-8 membered heterocyclyl optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis a 5-8 membered nitrogen-containing heterocyclyl optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis a 5-8 membered nitrogen-containing heterocyclyl containing 1 nitrogen atom and optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG, wherein RGis an unsubstituted 5-8 membered heterocyclyl.

[0030] In some embodiments, R22is unsubstituted C1-6alkyl. In some embodiments, R22is -CH3, -CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, or - C(CH3)3.

[0031] In some embodiments, R22is substituted or unsubstituted C2-6alkenyl. In some embodiments, R22is C2-6alkenyl optionally substituted with 1-5 RG. In some embodiments, R22is -CH=CH2, -CH2CH=CH2, -CH=CHCH3, or -CH=C(CH3)2.

[0032] In some embodiments, R22is substituted or unsubstituted C2-6alkynyl. In some embodiments, R22is C2-6alkynyl optionally substituted with 1-5 RG. In some embodiments, R22is -C≡C-H, -C≡C-CH3, or -C≡C-CF3.

[0033] In some embodiments, R22is substituted or unsubstituted C3-6carbocyclyl. In some embodiments, R22is C3-6carbocyclyl optionally substituted with 1-5 RH. In some embodiments, R22is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl optionally substituted with 1-3 RH.

[0034] In some embodiments, R22is substituted or unsubstituted C6-10aryl. In some embodiments, R22is C6-10aryl optionally substituted with 1-5 RH. In some embodiments, R22is unsubstituted phenyl. In some embodiments, R22is phenyl substituted with 1-3 RH, wherein each instance of RHis independently selected from the group consisting of: halo, cyano, and C1-6alkyl optionally substituted with 1-5 halo.

[0035] In some embodiments, the compound of Formula (I) is any one compounds 1-118, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one compounds 1-118. In some embodiments, the compound of Formula (I) is any one of compounds 2, 7, 13, 14, 16, 18-21, 27, 29-32, 34-36, 38-40, 53-65, 67, 70, 73, 75, 77-79, 81-84, 86, 88, 90-93, 95, 97-98, 100- 101, 103-106, and 108, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one of compounds 2, 7, 13, 14, 16, 18-21, 27, 29-32, 34-36, 38-40, 53-65, 67, 70, 73, 75, 77-79, 81-84, 86, 88, 90-93, 95, 97-98, 100-101, 103-106, or 108. In some embodiments, the compound is a pharmaceutically acceptable salt of any one of compounds 2, 7, 13, 14, 16, 18-21, 27, 29-32, 34-36, 38-40, 53-65, 67, 70, 73, 75, 77-79, 81-84, 86, 88, 90-93, 95, 97-98, 100-101, 103- 106, or108. In some embodiments, the compound of Formula (I) is any one of compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100-101, or 104-106, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one of compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100-101, or 104-106. In some embodiments, the compound is a pharmaceutically acceptable salt of any one of compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100-101, or 104-106.

[0036] In some embodiments, the compound provided herein is a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii). In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I- B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii). In some embodiments, the compound provided herein is an isotopic variant of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2- i), and (I-B-2-ii). In some embodiments, the compound provided herein is an isotopic variant of a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1- ii), (I-B-2-i), and (I-B-2-ii).

[0037] In some embodiments, one or more hydrogen atoms are replaced by deuterium. In some embodiments, one or more hydrogen atoms are replaced by tritium.

[0038] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I- A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to the disclosure, and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B- 1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of compound of any one of Formulae (I), (I-A), (I-B), (I-A- 1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I- B-2-i), and (I-B-2-ii), and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising an isotopic variant of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I- A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii). In some embodiments, the disclosure provides a pharmaceutical composition comprising an isotopic variant of a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (I- A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1- i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii).

[0039] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I- A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure.

[0040] In one aspect, the disclosure provides a method for effecting negative allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (I), (I-A), (I-B), (I-A- 1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I- B-2-i), and (I-B-2-ii)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure.

[0041] In one aspect, the disclosure provides a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I- B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in treating a CNS-related condition in a subject.

[0042] In one aspect, the disclosure provides a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I- B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in effecting negative allosteric modulation of an NMDA receptor.

[0043] In one aspect, the disclosure provides a use of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I- B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for treating a CNS-related condition in a subject.

[0044] In one aspect, the disclosure provides a use of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I- B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor.

[0045] In some embodiments, the CNS-related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus. In some embodiments, the CNS-related condition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychotic disorder, pain, a seizure disorder, drug induced dyskinesia (e.g., L-DOPA- induced dyskinesia (LID)), stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome (FXS), neuropsychiatric lupus, and tinnitus. Detailed Description

[0046] The present disclosure provides compounds that are NMDA receptor negative allosteric modulators. The compounds of the disclosure are useful as therapeutic agents for treating, for example, CNS-related conditions including, but not limited to an anxiety disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure disorder, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, neuropsychiatric lupus, and tinnitus. General Definitions

[0047] The term “herein” means the entire application.

[0048] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. Generally, nomenclature used in connection with the compounds, compositions, and methods described herein, are those well-known and commonly used in the art.

[0049] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in the Examples), can be combined with one or more other embodiments of the disclosure, unless explicitly disclaimed or improper. Combinations of embodiments are not limited to those specific combinations claimed via the multiple dependent claims. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group.

[0050] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components).

[0051] Throughout the specification, where compositions are described as having, including, or comprising (or variations thereof), specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising (or variations thereof), specific process steps, the processes also may consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order ofsteps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0052] The term “including” as used herein, means “including but not limited to.” “Including” and “including but not limited to” are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components).

[0053] As used herein, “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0054] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0055] The term “or” as used herein should be understood to mean “and / or,” unless the context clearly indicates otherwise.

[0056] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and including the endpoints, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0057] All of the publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forthexplicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Chemical Definitions

[0058] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 102ndEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 8thEdition, John Wiley & Sons, Inc., New Jersey, 2020; Larock, Comprehensive Organic Transformations, 3rdEdition, John Wiley & Sons, Inc., New Jersey, 2018; Kurti and Czako, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier, Inc., 2005; and Carruthers & Coldham, Modern Methods of Organic Synthesis, 4thEdition, Cambridge University Press, Cambridge, 2004.

[0059] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), supercritical fluid chromatograph (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0060] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non–superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- sequencing rules of Cahn, Ingold, and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (–)–isomers respectively). A chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0061] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. As used herein, the term “diastereomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers.

[0062] The term “diastereomerically pure” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of the diastereomer. Methods for determining diastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers,such as high-performance liquid chromatography (HPLC) or supercritical fluid chromatograph (SFC).

[0063] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–position / center / carbon compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R– compound. In certain embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In certain embodiments, the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R– compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0064] Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like.

[0065] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0066] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. It should also be understood that when described herein any of the moieties defined herein may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0067] “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0068] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3– methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 4 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0069] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to a divalent radical of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0070] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more halo, -NO2, -OH, C1-C6alkoxy, C1-C6alkyl (e.g., methyl) groups, including but not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)- , -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), or C1-C6cycloalkyl, and thelike. Alkylene abbreviations include, but are not limited to, -(CH(CH3))–, –(CH(CH2CH3))–, –(CH(CH2CH2CH3))–, –(CH(CH2CH2CH2CH3))–, -(CH2CH(CH2CH2CH2CH3))–, -(CH2CH2CH(CH2CH2CH2CH3))–, –(CH(CH3)CH2)–, -(CH(CH3)CH2CH2)–, -(CH(CH3)CH2CH2CH2)–, –( CH2CH(CH3)CH2)–, -(CH2CH(CH3)CH2CH2)–, and -(CH2CH2CH(CH3)CH2CH2)–.

[0071] “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2–10alkenyl. In certain embodiments, the alkenyl group is substituted C2–10alkenyl.

[0072] “Alkenylene” refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (- CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but arenot limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, - CH(CH3)-CH=CH-,-C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0073] “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2–20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2–10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4 alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2–10alkynyl. In certain embodiments, the alkynyl group is substituted C2–10alkynyl.

[0074] “Alkynylene” refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0075] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur,nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–10alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–7alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1–6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2–6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1–10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1–10alkyl.

[0076] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2– 10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–9alkenyl”). In some embodiments,a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2–6alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2–5alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms (“heteroC2–4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2–3alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2–6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2–10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2–10alkenyl.

[0077] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–10alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–8alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2–6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2–5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms (“heteroC2–4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1heteroatom (“heteroC2–3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2–6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2–10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2–10alkynyl.

[0078] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ^ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). Aryl” also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6–14aryl. In certain embodiments, the aryl group is substituted C6–14aryl.

[0079] In certain embodiments, an aryl group is substituted with one or more of groups selected from halo, C1-C8alkyl, C1-C8haloalkyl, cyano, hydroxy, C1-C8alkoxy, and amino.

[0080] Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1-C8alkyl, C1-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are independently hydrogen, C1-C8alkyl, C1-C4 haloalkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, substituted C6-C10aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl.

[0081] “Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0082] “Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0083] “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).

[0084] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5–14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5–14 membered heteroaryl.

[0085] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.

[0086] Examples of representative heteroaryls include the following:wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, C1-C8alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl.

[0087] “Nitrogen-containing heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ electrons shared in a cyclic array) having ring carbon atoms and containing at least one nitrogen atom. Examples of nitrogen-containing heteroaryl groups included, but are not limited to, pyrrolyl, pyridinyl, pyridinonyl, pyridazinyl, and pyrimidinyl.

[0088] “Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0089] “Carbocyclyl” or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3–10carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3–8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3–6carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3–6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5–10carbocyclyl”). Exemplary C3–6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3–8carbocyclyl groups include, without limitation, the aforementioned C3–6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8),and the like. Exemplary C3–10carbocyclyl groups include, without limitation, the aforementioned C3–8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H–indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group includes either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3–10carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3–10carbocyclyl.

[0090] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3–10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3–8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3–6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5–6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5–10cycloalkyl”). Examples of C5–6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3–6cycloalkyl groups include the aforementioned C5–6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3–8cycloalkyl groups include the aforementioned C3–6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3–10cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3–10cycloalkyl.

[0091] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl.

[0092] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0093] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation,dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0094] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0095] “Acyl” refers to a radical -C(O)R20, where R20is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. “Alkanoyl” is an acyl group wherein R20is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), ––C(O)- C1-C8alkyl, –C(O)-(CH2)t(C6-C10aryl), –C(O)-(CH2)t(5-10 membered heteroaryl), –C(O)- (CH2)t(C3-C10cycloalkyl), and –C(O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R21is C1-C8alkyl, substituted with halo or hydroxy; orC3-C10cycloalkyl, 4-10 membered heterocyclyl,C6-C10aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1- C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0096] “Alkoxy” refers to the group –OR29where R29is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, an alkoxy group has 1 to 6 carbon atoms (“C1–6alkoxy”). In some embodiments, an alkoxy group has 1 to 5 carbon atoms (“C1–5 alkoxy”). In some embodiments, an alkoxy group has 1 to 4 carbon atoms (“C1–4 alkoxy”). In some embodiments, an alkoxy group has 1 to 3 carbon atoms (“C1–3alkoxy”). In some embodiments, an alkoxy group has 1 to 2 carbon atoms (“C1–2alkoxy”). In some embodiments, an alkoxy group has 1 carbon atom (“C1alkoxy”). Examples of C1-6alkoxy groups include methoxy (C1), ethoxy(C2), n-propoxy (C3), isopropoxy (C3), 2-methoxyethoxy (C3), n-butoxy (C4), tert-butoxy (C4), sec-butoxy (C4), n- pentoxy (C5), n-hexoxy (C6), and 1,2-dimethylbutoxy (C6). Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0097] In certain embodiments, R29is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10aryl, aryloxy, carboxyl, cyano, C3-C10cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl–S(O)-, alkyl– S(O)2- and aryl-S(O)2-. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, –O-(CH2)t(C6-C10aryl), –O-(CH2)t(5-10 membered heteroaryl), –O-(CH2)t(C3-C10cycloalkyl), and –O-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1- C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0098] “Amino” refers to the radical -NH2.

[0099] “Substituted amino” refers to an amino group of the formula -N(R38)2wherein R38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or anamino protecting group, wherein at least one of R38is not a hydrogen. In certain embodiments, each R38is independently selected from hydrogen, C1-C8alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C10aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3- C10cycloalkyl; or C1-C8alkyl, substituted with halo or hydroxy; C3-C8alkenyl, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)t(C6-C10aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-C10cycloalkyl), or -(CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

[0100] Exemplary “substituted amino” groups include, but are not limited to, –NR39-C1-C8alkyl, –NR39-(CH2)t(C6-C10aryl), –NR39-(CH2)t(5-10 membered heteroaryl), –NR39- (CH2)t(C3-C10cycloalkyl), and –NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39independently represents H or C1-C8alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4alkyl, halo, unsubstituted C1- C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

[0101] “Carboxy” refers to the radical -C(O)OH.

[0102] “Cyano” refers to the radical -CN.

[0103] “Halo” or ”halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0104] “Hydroxyl” refers to the radical -OH.

[0105] “Nitro” refers to the radical –NO2.

[0106] “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[0107] “Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0108] “Nitrogen-containing heterocyclyl” group means a 5- to 8- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0109] “Thioketo” refers to the group =S.

[0110] “Imino” refers to the group =N-RN, wherein RNis hydrogen, alkyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl, or any combination of selections therefrom.

[0111] “Oxo” refers to the group =O.

[0112] “Thiol” refers to the group -SH.

[0113] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

[0114] Exemplary carbon atom substituents include, but are not limited to, halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORaa, –ON(Rbb)2, –N(Rbb)2, –N(Rbb)3+X–, –N(ORcc)Rbb, –SH, –SRaa, –SSRcc, –C(=O)Raa, –CO2H, –CHO, –C(ORcc)2, –CO2Raa, –OC(=O)Raa, –OCO2Raa, –C(=O)N(Rbb)2, –OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, –NRbbC(=O)N(Rbb)2, –C(=NRbb)Raa, –C(=NRbb)ORaa, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, –C(=NRbb)N(Rbb)2, –OC(=NRbb)N(Rbb)2, –NRbbC(=NRbb)N(Rbb)2, –C(=O)NRbbSO2Raa, –NRbbSO2Raa, –SO2N(Rbb)2, –SO2Raa, –SO2ORaa, –OSO2Raa, –S(=O)Raa, –OS(=O)Raa, –Si(Raa)3, –OSi(Raa)3–C(=S)N(Rbb)2, –C(=O)SRaa, –C(=S)SRaa, –SC(=S)SRaa, –SC(=O)SRaa, –OC(=O)SRaa, –SC(=O)ORaa, –SC(=O)Raa, –P(=O)2Raa, –OP(=O)2Raa, –P(=O)(Raa)2, –OP(=O)(Raa)2, –OP(=O)(ORcc)2, –P(=O)2N(Rbb)2, –OP(=O)2N(Rbb)2, –P(=O)(NRbb)2, –OP(=O)(NRbb)2, –NRbbP(=O)(ORcc)2, –NRbbP(=O)(NRbb)2, –P(Rcc)2, –P(Rcc)3, –OP(Rcc)2, –OP(Rcc)3, –B(Raa)2, –B(ORcc)2, –BRaa(ORcc), C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Raagroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, –SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, –C(=S)SRcc, –P(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, – P(=O)(NRcc)2, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Rbbgroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;each instance of Rccis, independently, selected from hydrogen, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Rccgroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, –CN, –NO2, –N3, – SO2H, –SO3H, –OH, –ORee, –ON(Rff)2, –N(Rff)2, –N(Rff)3+X–, –N(ORee)Rff, –SH, –SRee, –SSRee, –C(=O)Ree, –CO2H, –CO2Ree, –OC(=O)Ree, –OCO2Ree, –C(=O)N(Rff)2, – OC(=O)N(Rff)2, –NRffC(=O)Ree, –NRffCO2Ree, –NRffC(=O)N(Rff)2, –C(=NRff)ORee, –OC(=NRff)Ree, –OC(=NRff)ORee, –C(=NRff)N(Rff)2, –OC(=NRff)N(Rff)2, –NRffC(=NRff)N(Rff)2,–NRffSO2Ree, –SO2N(Rff)2, –SO2Ree, –SO2ORee, –OSO2Ree, –S(=O)Ree, –Si(Ree)3, –OSi(Ree)3, –C(=S)N(Rff)2, –C(=O)SRee, –C(=S)SRee, –SC(=S)SRee, –P(=O)2Ree, –P(=O)(Ree)2, –OP(=O)(Ree)2, –OP(=O)(ORee)2, C1–6alkyl, C1–6perhaloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, 3–10 membered heterocyclyl, C6–10 aryl, 5–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; each instance of Reeis, independently, selected from C1–6alkyl, C1–6perhaloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, C6–10aryl, 3–10 membered heterocyclyl, and 3–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1–6alkyl, C1–6perhaloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, 3–10 membered heterocyclyl, C6–10 aryl and 5–10 membered heteroaryl, or two Rffgroups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC1–6alkyl, –ON(C1–6alkyl)2, –N(C1–6alkyl)2, –N(C1–6alkyl)3+X–, –NH(C1–6alkyl)2+X–, –NH2(C1–6alkyl)+X–, –NH3+X–, –N(OC1–6alkyl)(C1–6alkyl), –N(OH)(C1–6alkyl), –NH(OH), –SH, –SC1–6alkyl, –SS(C1–6alkyl), –C(=O)(C1–6alkyl), –CO2H, –CO2(C1–6alkyl), –OC(=O)(C1–6alkyl), –OCO2(C1–6alkyl), –C(=O)NH2, –C(=O)N(C1–6alkyl)2, –OC(=O)NH(C1–6alkyl), –NHC(=O)( C1–6alkyl), –N(C1–6alkyl)C(=O)( C1–6alkyl),–NHCO2(C1–6alkyl), –NHC(=O)N(C1–6alkyl)2, –NHC(=O)NH(C1–6alkyl), – NHC(=O)NH2, –C(=NH)O(C1–6alkyl),–OC(=NH)(C1–6alkyl), –OC(=NH)OC1–6alkyl, –C(=NH)N(C1–6alkyl)2, –C(=NH)NH(C1–6alkyl), –C(=NH)NH2, – OC(=NH)N(C1–6alkyl)2, –OC(NH)NH(C1–6alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6alkyl)2, –NHC(=NH)NH2, –NHSO2(C1–6alkyl), –SO2N(C1–6alkyl)2, –SO2NH(C1–6alkyl), –SO2NH2,–SO2C1–6alkyl, –SO2OC1–6alkyl, –OSO2C1–6alkyl, –SOC1–6alkyl, –Si(C1–6alkyl)3, –OSi(C1–6alkyl)3–C(=S)N(C1–6alkyl)2, C(=S)NH(C1–6alkyl), C(=S)NH2, –C(=O)S(C1–6alkyl), –C(=S)SC1–6alkyl, – SC(=S)SC1–6alkyl, –P(=O)2(C1–6alkyl), –P(=O)(C1–6alkyl)2, –OP(=O)(C1–6alkyl)2, – OP(=O)(OC1–6alkyl)2, C1–6alkyl, C1–6perhaloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, C6–10aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X–is a counterion.

[0115] A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HSO4–, SO4-2sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0116] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substitutuents include, but are not limited to, hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, –C(=NRbb)Raa, –C(=NRcc)ORaa, –C(=NRcc)N(Rcc)2, –SO2N(Rcc)2, –SO2Rcc, –SO2ORcc, –SORaa, –C(=S)N(Rcc)2, –C(=O)SRcc, –C(=S)SRcc, –P(=O)2Raa, –P(=O)(Raa)2, –P(=O)2N(Rcc)2, –P(=O)(NRcc)2, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–10carbocyclyl, 3–14 membered heterocyclyl, C6–14aryl, and 5–14 membered heteroaryl, or two Rccgroups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.Other Definitions

[0117] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0118] “Pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non–toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3–(4–hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2–ethane–disulfonic acid, 2– hydroxyethanesulfonic acid, benzenesulfonic acid, 4–chlorobenzenesulfonic acid, 2– naphthalenesulfonic acid, 4–toluenesulfonic acid, camphorsulfonic acid, 4– methylbicyclo[2.2.2]–oct–2–ene–1–carboxylic acid, glucoheptonic acid, 3–phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N– methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter– ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1–79.

[0119] “Pharmaceutically acceptable carrier” refers to compositions, carriers, diluents, and reagents which are pharmaceutically acceptable materials that are capable of administration to or upon a subject. A pharmaceutically acceptable carrier can be involved with carrying ortransporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. The carrier can be in the form of a solid, semi-solid or liquid diluent, cream or a capsule. The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.

[0120] “Isotopic variant” refers to a compound disclosed herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,17O,18O,32P,33P,33S,34S,35S,18F, and37Cl. Compounds disclosed herein which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Certain isotopic variants of the compounds of the present application, for example, those into which radioactive isotopes (e.g.,3H and14C) are incorporated, may be useful in drug and / or substrate distribution assays. Further, substitution with heavier isotopes (e.g.,2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopic variants of compounds and pharmaceutically acceptable salts thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0121] A “subject” to which administration is contemplated includes, but is not limited to, human subject (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0122] Disease, disorder, and condition are used interchangeably herein.

[0123] As used herein, the term “treat,” “treating” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a conditionin manner to improve or stabilize a subject's condition. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation, amelioration, reduction of the severity, or slowing the progression, of one or more symptoms or conditions associated with a condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Exemplary beneficial clinical results are described herein.

[0124] As used herein, and unless otherwise specified, the term “prophylactic,” “prevention” and variations thereof, contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder, or condition.

[0125] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0126] The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” refer to an amount sufficient to treat a disease in a patient, e.g., effecting a beneficial and / or desirable alteration in the health of a patient suffering from a disease, treatment, healing, inhibition or amelioration of a physiological response or condition, delaying or minimizing one or more symptoms associated with the disease, disorder or condition etc. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, the nature and extent of disease, the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation. The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” also refer to the amount required to improve the clinical symptoms of a patient. A therapeutically effective amount of a compound also refersto an amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0127] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0128] As used herein, and unless otherwise specified, “pharmacokinetics” can be defined as the study of bodily absorption, distribution, metabolism, and excretion of drugs. “Pharmacokinetics” can also be defined as the characteristic interactions of a drug and a body in terms of its absorption, distribution, metabolism, and excretion; or a branch of pharmacology concerned with the way drugs are taken into, move around, and are eliminated from, a body.

[0129] “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods. In some embodiments, the administration includes both direct administration, including self- administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and / or who provides a patient with a prescription for a drug is administering the drug to the patient. When a method is part of a therapeutic regimeninvolving more than one agent or treatment modality, the disclosure contemplates that the agents may be administered at the same or differing times and via the same or differing routes of administration. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g. solubility, digestibility, bioavailability, stability and toxicity).

[0130] As generally described herein, the disclosure provides compounds useful for preventing and / or treating a broad range of disorders, including, but not limited to, NMDA– mediated disorders. These compounds are expected to show improved in vivo potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, and / or safety as compared to other compounds. Compounds

[0131] A compound, wherein the compound has the structure of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof (e.g., an isotopic variant of a pharmaceutically acceptable salt), wherein: R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2- 6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6alkyl; R19is hydrogen or substituted or unsubstituted C1-6alkyl;R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; provided that R20and R20’are not both hydroxyl; and R22is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted C6-10aryl; provided that when R22is -CH3, R3is not -CH3or hydrogen.

[0132] In some embodiments, the compound of the disclosure is a compound of Formula (I), wherein: R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA; each of R15and R16is independently hydrogen or C1-6alkyl optionally substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is hydrogen or C1-6alkyl optionally substituted with 1-5 RC; R19is hydrogen or C1-6alkyl optionally substituted with 1-5 RD; R20is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RE; R20’is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RF; provided that R20and R20’are not both hydroxyl; each instance of RA, RB, RC, RD, RE, and RF, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and C1-6alkoxy optionally substituted with 1-5 halo; R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are independently optionally substituted with 1-5 RGand said C3-6carbocyclyl and C6-10aryl are independently optionally substituted with 1-5 RH; provided that when R22is -CH3, R3is not -CH3or hydrogen;each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 RG1; each instance of RG1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo; and each instance of RH, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0133] In some embodiments, the compound of the disclosure is a compound of Formula (I-A) or (I-B):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0134] In some embodiments, the compound of the disclosure is a compound of Formula (I-A-1) or (I-A-2):(I-A-1) (I-A-2), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0135] In some embodiments, the compound of the disclosure is a compound of Formula (I-A-1-i) or (I-A-1-ii):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0136] In some embodiments, the compound of the disclosure is a compound of Formula (I-A-2-i) or (I-A-2-ii): (or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0137] In some embodiments, the compound of the disclosure is a compound of Formula (I-B-1) or (I-B-2):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0138] In some embodiments, the compound of the disclosure is a compound of Formula (I-B-1-i) or (I-B-1-ii):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0139] In some embodiments, the compound of the disclosure is a compound of Formula (I-B-2-i) or (I-B-2-ii):or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0140] In some embodiments, the compound of Formula (I) is a compound wherein:R3is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-5 RA; R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RB; R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is C1-6alkyl optionally substituted with 1-5 RC; R20is hydrogen, hydroxyl, or C1-6alkyl optionally substituted with 1-5 RE; and R20’is hydrogen or C1-6alkyl optionally substituted with 1-5 RF, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0141] In some embodiments, the compound of Formula (I) is a compound wherein: R3is C1-6alkyl optionally substituted with 1-5 RA; R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RB; R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is -CH3; R20is hydrogen; R20’is -CH3; and R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-5 RG, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0142] In some embodiments, the compound of Formula (I) is a compound wherein: R3is C1alkyl substituted with 1-5 RA; R15and R16are hydrogen; R18and R19are -CH3; R20is hydrogen; R20’is -CH3; and R22is C1-6alkyl optionally substituted with an unsubstituted C1-6alkoxy, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0143] In some embodiments, the compound of Formula (I) is a compound wherein: R3is C1 alkyl substituted with 1-5 RA; R15and R16are hydrogen; R18and R19are -CH3;R20is hydrogen; R20’is -CH3; and R22is -CH3or -CH2OCH3, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. Groups R3and RA– as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1-ii), (I-A- 2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii)

[0144] In certain embodiments, R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R3is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C2-6alkynyl.

[0145] In some embodiments, R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA. In some embodiments, R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-3 RA. In some embodiments, R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R3is hydrogen, C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA. In some embodiments, R3is hydrogen, C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-3 RA. In some embodiments, R3is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C2-6alkynyl. In some embodiments, R3is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkenyl are independently optionally substituted with 1-5 RA. In some embodiments, R3is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkenyl are independently substituted with 1-5 RA. In someembodiments, R3is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkenyl are independently optionally substituted with 1-3 RA. In some embodiments, R3is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkenyl are independently substituted with 1-3 RA. In some embodiments, R3is -H, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2OH, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C≡C-H, -C≡C-CH3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently optionally substituted with 1-5 RA. In some embodiments, R3is -H, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2OH, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, -C≡C-H, -C≡C-CH3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently substituted with 1-5 RA. In some embodiments, R3is -H, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2,-C≡C-H, -C≡C-CH3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently optionally substituted with 1-3 RA. In some embodiments, R3is - H, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - C≡C-H, -C≡C-CH3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently substituted with 1-3 RA. In some embodiments, R3is -H, -CH2F, -CHF2, - CF3, -CH2OCH3, -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C≡C-H, -C≡C-CH3, unsubstituted cyclopropyl, or unsubstituted pyridyl.

[0146] In certain embodiments, R3is hydrogen.

[0147] In certain embodiments, R3is substituted or unsubstituted C1-6alkyl. In some embodiments, R3is C1-6alkyl optionally substituted with 1-5 RA. In some embodiments, R3is C1-6alkyl optionally substituted with 1-3 RA. In some embodiments, R3is C1-6alkyl optionally substituted with 1 RA. In some embodiments, R3is C1-3 alkyl optionally substituted with 1-5 RA. In some embodiments, R3is C1-3 alkyl optionally substituted with 1- 3 RA. In some embodiments, R3is methyl optionally substituted with 1-3 RA. In some embodiments, R3is ethyl optionally substituted with 1-5 RA. In some embodiments, R3is n– propyl optionally substituted with 1-5 RA. In some embodiments, R3is isopropyl optionally substituted with 1-5 RA. In some embodiments, R3is C1-6alkyl substituted with 1-5 RA. In some embodiments, R3is C1-6alkyl substituted with 1-3 RA. In some embodiments, R3is C1- 6 alkyl substituted with 1 RA. In some embodiments, R3is C1-3 alkyl substituted with 1-5 RA. In some embodiments, R3is C1-3alkyl substituted with 1-3 RA. In some embodiments, R3is methyl substituted with 1-3 RA. In some embodiments, R3is ethyl substituted with 1-5 RA. In some embodiments, R3is n–propyl substituted with 1-5 RA. In some embodiments, R3is isopropyl substituted with 1-5 RA.

[0148] In certain embodiments, R3is substituted C1-6alkyl. In certain embodiments, R3is C1-6alkyl substituted with 1-5 RA. In certain embodiments, R3is C1-6alkyl substituted with 1-5 RA. In some embodiments, R3is C1-6alkyl substituted with 1-3 RA. In some embodiments, R3is substituted C1-3alkyl. In some embodiments, R3is C1-3alkyl substituted with 1-5 RA. In some embodiments, R3is C1-3 alkyl substituted with 1-3 RA. In some embodiments, R3is C1-3 alkyl substituted with 1 RA. In certain embodiments, R3is methyl substituted with 1-3 RA. In some embodiments, R3is methyl substituted with 1-3 RAand each instance of RAis independently halo, hydroxyl, or unsubstituted C1-6alkoxy. In some embodiments, R3is methyl substituted with 1-3 RAand each instance of RAis independently fluoro, hydroxyl, or -OCH3. In some embodiments, R3is -CH2F, -CHF2, -CF3, -CH2OCH3, or -CH2OH. In some embodiments, R3is methyl substituted with 1-3 RAand RAis fluoro. In some embodiments, R3is -CH2F, -CHF2, or -CF3. In some embodiments, R3is -CH2F. In some embodiments, R3is -CHF2. In some embodiments, R3is -CF3. In some embodiments, R3is methyl substituted with 1-3 RAand RAis hydroxyl. In some embodiments, R3is - CH2OH. In some embodiments, R3is methyl substituted with 1-3 RAand RAis -OCH3. In some embodiments, R3is -CH2OCH3. In some embodiments, R3is ethyl substituted with 1-5 RA. In some embodiments, R3is n–propyl substituted with 1-5 RA. In some embodiments, R3is isopropyl substituted with 1-5 RA.

[0149] In certain embodiments, R3is unsubstituted C1-6alkyl. In some embodiments, R3is unsubstituted C1-3alkyl. In some embodiments, R3is -CH3, -CH2CH3, -CH2CH2CH3, or - CH(CH3)2. In some embodiments, R3is -CH3or -CH2CH3. In some embodiments, R3is - CH3. In some embodiments, R3is -CH2CH3. In some embodiments, R3is -CH2CH2CH3. In some embodiments, R3is -CH(CH3)2.

[0150] In certain embodiments, R3is substituted or unsubstituted C2-6alkynyl. In some embodiments, R3is C2-6alkynyl optionally substituted with 1-5 RA. In some embodiments, R3is C2-6alkynyl optionally substituted with 1-3 RA. In some embodiments, R3is C2-6alkynyl optionally substituted with 1 RA. In some embodiments, R3is unsubstituted C2-6alkynyl. In certain embodiments, R3is substituted or unsubstituted C2-3 alkynyl. In some embodiments, R3is C2-3 alkynyl optionally substituted with 1-5 RA. In some embodiments, R3is C2-6alkynyl substituted with 1-5 RA. In some embodiments, R3is C2-6alkynyl substituted with 1-3 RA. In some embodiments, R3is C2-6alkynyl substituted with 1 RA. In some embodiments, R3is C2-3 alkynyl substituted with 1-5 RA. In some embodiments, R3is unsubstituted C2-3 alkynyl. In some embodiments, R3is -C≡C-H or -C≡C-CH3. In some embodiments, R3is ethynyl optionally substituted with 1 RA. In some embodiments, R3isethynyl substituted with 1 RA. In some embodiments, R3is -C≡C-H. In some embodiments, R3is propynyl optionally substituted with 1-3 RA. In some embodiments, R3is propynyl substituted with 1-3 RA. In some embodiments, R3is -C≡C-CH3.

[0151] In certain embodiments, R3is substituted or unsubstituted C2-6alkenyl. In some embodiments, R3is C2-6alkenyl optionally substituted with 1-5 RA. In some embodiments, R3is C2-6alkenyl optionally substituted with 1-3 RA. In some embodiments, R3is C2-6alkenyl optionally substituted with 1 RA. In some embodiments, R3is substituted C2-6alkenyl. In some embodiments, R3is C2-6alkenyl substituted with 1-5 RA. In some embodiments, R3is C2-6alkenyl substituted with 1-3 RA. In some embodiments, R3is C2-6alkenyl substituted with 1 RA. In some embodiments, R3is unsubstituted C2-6alkenyl. In some embodiments, R3is substituted or unsubstituted C2-4alkenyl. In some embodiments, R3is C2-4 alkenyl optionally substituted with 1-5 RA. In some embodiments, R3is C2-4 alkenyl substituted with 1-5 RA. In some embodiments, R3is unsubstituted C2-4 alkenyl. In certain embodiments, R3is ethenyl optionally substituted with 1-3 RA. In certain embodiments, R3is ethenyl substituted with 1-3 RA. In certain embodiments, R3is unsubstituted ethenyl. In certain embodiments, R3is propenyl optionally substituted with 1-5 RA. In certain embodiments, R3is propenyl substituted with 1-5 RA. In certain embodiments, R3is unsubstituted propenyl. In certain embodiments, R3is butenyl optionally substituted with 1-5 RA. In certain embodiments, R3is butenyl substituted with 1-5 RA. In certain embodiments, R3is unsubstituted butenyl.

[0152] In certain embodiments, R3is substituted or unsubstituted C3-6carbocyclyl. In some embodiments, R3is C3-6carbocyclyl optionally substituted with 1-5 RA. In some embodiments, R3is C3-6carbocyclyl optionally substituted with 1-3 RA. In some embodiments, R3is C3-6carbocyclyl optionally substituted with 1 RA. In some embodiments, R3is unsubstituted C3-6carbocyclyl. In some embodiments, R3is C3-4 carbocyclyl optionally substituted with 1-5 RA. In some embodiments, R3is unsubstituted C3-4 carbocyclyl. In some embodiments, R3is substituted C3-6carbocyclyl. In some embodiments, R3is C3-6carbocyclyl substituted with 1-5 RA. In some embodiments, R3is C3-6carbocyclyl substituted with 1-3 RA. In some embodiments, R3is C3-6carbocyclyl substituted with 1 RA. In some embodiments, R3is C3-4carbocyclyl substituted with 1-5 RA. In certain embodiments, R3is cyclopropyl or cyclobutyl, each of which is independently optionally substituted with 1-5 RA. In certain embodiments, R3is unsubstituted cyclopropyl or unsubstituted cyclobutyl. In certain embodiments, R3is cyclopropyl or cyclobutyl, each of which is independently substituted with 1-5 RA. In certain embodiments, R3is cyclobutyl optionally substituted with1-5 RA. In certain embodiments, R3is cyclobutyl substituted with 1-5 RA.In certain embodiments, R3is unsubstituted cyclobutyl. In certain embodiments, R3is cyclopropyl optionally substituted with 1-5 RA. In certain embodiments, R3is cyclopropyl substituted with 1-5 RA.In certain embodiments, R3is unsubstituted cyclopropyl.

[0153] In certain embodiments, R3is substituted or unsubstituted 5-8 membered heteroaryl. In certain embodiments, R3is 5-8 membered heteroaryl optionally substituted with 1-5 RA. In certain embodiments, R3is 5-8 membered heteroaryl optionally substituted with 1-3 RA. In certain embodiments, R3is 5-8 membered heteroaryl optionally substituted with 1 RA. In some embodiments, R3is substituted 5-8 membered heteroaryl. In certain embodiments, R3is 5-8 membered heteroaryl substituted with 1-5 RA. In certain embodiments, R3is 5-8 membered heteroaryl substituted with 1-3 RA. In certain embodiments, R3is 5-8 membered heteroaryl substituted with 1 RA. In certain embodiments, R3is unsubstituted 5-8 membered heteroaryl. In certain embodiments, R3is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, R3is 5-6 membered heteroaryl optionally substituted with 1-5 RA. In certain embodiments, R3is 5-6 membered heteroaryl substituted with 1-5 RA.In certain embodiments, R3is unsubstituted 5-6 membered heteroaryl. In certain embodiments, R3is 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-5 RA. In certain embodiments, R3is substituted 5-6 membered heteroaryl. In certain embodiments, R3is 5-6 membered heteroaryl substituted with 1-5 RA. In certain embodiments, R3is 5-6 membered nitrogen-containing heteroaryl substituted with 1-5 RA. In certain embodiments, R3is unsubstituted 5-6 membered nitrogen-containing heteroaryl. In certain embodiments, R3is 5-6 membered nitrogen-containing heteroaryl containing 1 nitrogen atom and optionally substituted with 1-5 RA. In certain embodiments, R3is 5-6 membered nitrogen-containing heteroaryl containing 1 nitrogen atom and substituted with 1-5 RA. In certain embodiments, R3is unsubstituted 5-6 membered nitrogen-containing heteroaryl containing 1 nitrogen atom. In some embodiments, R3is pyridyl optionally substituted with 1-5 RA. In some embodiments, R3is pyridyl substituted with 1-5 RA. In some embodiments, R3is unsubstituted pyridyl.

[0154] In certain embodiments, R3is substituted or unsubstituted C6-10aryl. In some embodiments, R3is C6-10aryl optionally substituted with 1-5 RA. In some embodiments, R3is C6-10aryl optionally substituted with 1-3 RA. In some embodiments, R3is C6-10aryl optionally substituted with 1 RA. In certain embodiments, R3is substituted C6-10aryl. In some embodiments, R3is C6-10aryl substituted with 1-5 RA. In some embodiments, R3is C6-10aryl substituted with 1-3 RA. In some embodiments, R3is C6-10aryl substituted with 1 RA.In certain embodiments, R3is unsubstituted C6-10aryl. In some embodiments, R3is phenyl optionally substituted with 1-5 RA. In some embodiments, R3is phenyl substituted with 1-5 RA. In some embodiments, R3is unsubstituted phenyl. In some embodiments, R3is naphthyl optionally substituted with 1-5 RA. In some embodiments, R3is naphthyl substituted with 1-5 RA. In some embodiments, R3is unsubstituted naphthyl.

[0155] In certain embodiments, each instance of RA, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In certain embodiments, each instance of RA, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of halo, hydroxyl, and unsubstituted C1-6alkoxy. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of fluoro, hydroxyl, and unsubstituted C1-6alkoxy. In some embodiments, each instance of RA, when present, is independently selected from the group consisting of fluoro, hydroxyl, and -OCH3. In some embodiments, each instance of RA, when present, is fluoro. In some embodiments, each instance of RA, when present, is hydroxyl. In some embodiments, each instance of RA, when present, is -OCH3. Groups R15, R16, and RB– as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1-ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B- 2-ii)

[0156] In certain embodiments, R15is hydrogen or substituted or unsubstituted C1-6alkyl. In certain embodiments, R15is hydrogen. In certain embodiments, R15is substituted or unsubstituted C1-6alkyl. In some embodiments, R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RB. In some embodiments, R15is hydrogen or C1-6alkyl optionally substituted with 1-3 RB. In some embodiments, R15is hydrogen or C1-6alkyl optionally substituted with 1 RB. In some embodiments, R15is hydrogen or C1-6alkyl substituted with 1-5 RB. In some embodiments, R15is hydrogen or C1-6alkyl substituted with 1-3 RB. In some embodiments, R15is hydrogen or C1-6alkyl substituted with 1 RB. In certain embodiments, R15is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R15ishydrogen or unsubstituted C1-3alkyl. In some embodiments, R15is hydrogen or -CH3. In some embodiments, R15is hydrogen. In some embodiments, R15is -CH3.

[0157] In certain embodiments, R16is hydrogen or substituted or unsubstituted C1-6alkyl. In certain embodiments, R16is hydrogen. In certain embodiments, R16is substituted or unsubstituted C1-6alkyl. In some embodiments, R16is hydrogen or C1-6alkyl optionally substituted with 1-5 RB. In some embodiments, R16is hydrogen or C1-6alkyl optionally substituted with 1-3 RB. In some embodiments, R16is hydrogen or C1-6alkyl optionally substituted with 1 RB. In some embodiments, R16is hydrogen or C1-6alkyl substituted with 1-5 RB. In some embodiments, R16is hydrogen or C1-6alkyl substituted with 1-3 RB. In some embodiments, R16is hydrogen or C1-6alkyl substituted with 1 RB. In some embodiments, R16is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R16is hydrogen or unsubstituted C1-3 alkyl. In some embodiments, R16is hydrogen or -CH3. In some embodiments, R16is hydrogen.

[0158] In certain embodiments, each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl. In certain embodiments, each of R15and R16is independently hydrogen or C1-6alkyl optionally substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB. In certain embodiments, each of R15and R16is independently hydrogen or C1-6alkyl substituted with 1- 5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl substituted with 1-5 RB. In some embodiments, R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RBand R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB. In some embodiments, R15is hydrogen or C1-6alkyl substituted with 1-5 RBand R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl substituted with 1-5 RB. In certain embodiments, R15and R16are hydrogen. In certain embodiments, R15and R16are substituted or unsubstituted C1-6alkyl. In some embodiments, R15and R16are C1-6alkyl optionally substituted with 1-5 RB. In some embodiments, R15and R16are C1-6alkyl substituted with 1-5 RB. In some embodiments, R15and R16are unsubstituted C1-6alkyl. In some embodiments, R15and R16are unsubstituted C1-3 alkyl. In some embodiments, R15and R16are -CH3. In certain embodiments, R15is substituted or unsubstituted C1-6alkyl and R16is hydrogen. In some embodiments, R15is C1-6alkyl optionally substituted with 1-5 RBand R16is hydrogen. Insome embodiments, R15is C1-6alkyl substituted with 1-5 RBand R16is hydrogen. In some embodiments, R15is unsubstituted C1-6alkyl and R16is hydrogen. In some embodiments, R15is unsubstituted C1-3 alkyl and R16is hydrogen. In some embodiments, R15is -CH3and R16is hydrogen. In certain embodiments, R15is hydrogen and R16is substituted or unsubstituted C1-6alkyl. In some embodiments, R15is hydrogen and R16is C1-6alkyl optionally substituted with 1-5 RB. In some embodiments, R15is hydrogen and R16is C1-6alkyl substituted with 1-5 RB. In some embodiments, R15is hydrogen and R16is unsubstituted C1-6alkyl. In some embodiments, R15is hydrogen and R16is unsubstituted C1-3 alkyl. In some embodiments, R15is hydrogen and R16is -CH3.

[0159] In certain embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl. In certain embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB. In certain embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl substituted with 1-5 RB. In some embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently optionally substituted with 1-5 RB. In some embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently substituted with 1-5 RB. In some embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a cyclopropyl optionally substituted with 1-5 RB. In some embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form a cyclopropyl substituted with 1-5 RB. In some embodiments, R15and R16, taken together with the carbon atoms to which they are attached, form an unsubstituted cyclopropyl.

[0160] In certain embodiments, each instance of RB, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In certain embodiments, each instance of RB, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RB, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RB, when present, is independently selected from the group consisting of halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-5halo. In some embodiments, each instance of RB, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of RB, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. Groups R18, R19, RC, and RD– as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1- ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii)

[0161] In certain embodiments, R18is hydrogen or substituted or unsubstituted C1-6alkyl. In some embodiments, R18is hydrogen or C1-6alkyl optionally substituted with 1-5 RC. In some embodiments, R18is hydrogen or C1-6alkyl substituted with 1-5 RC. In some embodiments, R18is hydrogen or C1-6alkyl optionally substituted with 1-3 RC. In some embodiments, R18is hydrogen or C1-6alkyl substituted with 1-3 RC. In some embodiments, R18is hydrogen or C1-6alkyl optionally substituted with 1 RC. In some embodiments, R18is hydrogen or C1-6alkyl substituted with 1 RC. In some embodiments, R18is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R18is hydrogen or unsubstituted C1-3 alkyl. In some embodiments, R18is hydrogen, -CH3, or -CH2CH3.

[0162] In some embodiments, R18is hydrogen.

[0163] In some embodiments, R18is substituted or unsubstituted C1-6alkyl. In some embodiments, R18is substituted C1-6alkyl. In some embodiments, R18is C1-6alkyl optionally substituted with 1-5 RC. In some embodiments, R18is C1-6alkyl substituted with 1-5 RC. In some embodiments, R18is unsubstituted C1-6alkyl. In some embodiments, R18is unsubstituted C1-3 alkyl. In some embodiments, R18is -CH3or -CH2CH3. In some embodiments, R18is -CH3.

[0164] In certain embodiments, R19is hydrogen or substituted or unsubstituted C1-6alkyl. In some embodiments, R19is hydrogen or C1-6alkyl optionally substituted with 1-5 RD. In some embodiments, R19is hydrogen or C1-6alkyl substituted with 1-5 RD. In some embodiments, R19is hydrogen or C1-6alkyl optionally substituted with 1-3 RD. In some embodiments, R19is hydrogen or C1-6alkyl substituted with 1-3 RD. In some embodiments, R19is hydrogen or C1-6alkyl optionally substituted with 1 RD. In some embodiments, R19is hydrogen or C1-6alkyl substituted with 1 RD. In some embodiments, R19is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R19is hydrogen or unsubstituted C1-3alkyl. In some embodiments, R19is hydrogen or -CH3.

[0165] In certain embodiments, R19is hydrogen.

[0166] In certain embodiments, R19is substituted or unsubstituted C1-6alkyl. In some embodiments, R19is substituted C1-6alkyl. In some embodiments, R19is C1-6alkyl optionally substituted with 1-5 RD. In some embodiments, R19is C1-6alkyl substituted with 1-5 RD. In some embodiments, R19is unsubstituted C1-6alkyl. In some embodiments, R19is unsubstituted C1-3 alkyl. In some embodiments, R19is -CH3.

[0167] In certain embodiments, R18and R19are hydrogen. In some embodiments, R18and R19are substituted or unsubstituted C1-6alkyl. In some embodiments, R18is C1-6alkyl optionally substituted with 1-5 RCand R19is C1-6alkyl optionally substituted with 1-5 RD. In some embodiments, R18is C1-6alkyl substituted with 1-5 RCand R19is C1-6alkyl substituted with 1-5 RD. In some embodiments, R18and R19are unsubstituted C1-6alkyl. In some embodiments, R18and R19are unsubstituted C1-3alkyl. In some embodiments, R18is - CH2CH3and R19is -CH3. In some embodiments, R18and R19are -CH3. In some embodiments, R18is hydrogen and R19is substituted or unsubstituted C1-6alkyl. In some embodiments, R18is hydrogen and R19is C1-6alkyl optionally substituted with 1-5 RD. In some embodiments, R18is hydrogen and R19is C1-6alkyl substituted with 1-5 RD. In some embodiments, R18is hydrogen and R19is unsubstituted C1-6alkyl. In some embodiments, R18is hydrogen and R19is unsubstituted C1-3alkyl. In some embodiments, R18is hydrogen and R19is -CH3. In some embodiments, R18is substituted or unsubstituted C1-6alkyl and R19is hydrogen. In some embodiments, R18is C1-6alkyl optionally substituted with 1-5 RCand R19is hydrogen. In some embodiments, R18is C1-6alkyl substituted with 1-5 RCand R19is hydrogen. In some embodiments, R18is unsubstituted C1-6alkyl and R19is hydrogen. In some embodiments, R18is unsubstituted C1-3 alkyl and R19is hydrogen. In some embodiments, R18is -CH3and R19is hydrogen.

[0168] In certain embodiments, each instance of RC, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In certain embodiments, each instance of RC, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RC, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RC, when present, is independently selected from the group consisting of halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RC, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6alkoxy optionally substituted with 1-5fluoro. In some embodiments, each instance of RC, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3.

[0169] In certain embodiments, each instance of RD, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In certain embodiments, each instance of RD, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RD, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RD, when present, is independently selected from the group consisting of halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RD, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of RD, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. Groups R20, R20’, RE, and RF– as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1- ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii)

[0170] In certain embodiments, R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl. In certain embodiments, R20is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RE. In certain embodiments, R20is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently substituted with 1-5 RE. In certain embodiments, R20is hydrogen, hydroxyl, or C1-6alkyl optionally substituted with 1-5 RE. In certain embodiments, R20is hydrogen, hydroxyl, or C1-6alkyl substituted with 1-5 RE. In certain embodiments, R20is hydrogen, hydroxyl, or C1-6alkyl optionally substituted with 1-3 RE. In certain embodiments, R20is hydrogen, hydroxyl, or C1-6alkyl substituted with 1-3 RE. In certain embodiments, R20is hydrogen, hydroxyl, or unsubstituted C1-6alkyl. In certain embodiments, R20is hydrogen, hydroxyl, or unsubstituted C1-3alkyl. In certain embodiments, R20is hydrogen, hydroxyl, or -CH3.

[0171] In certain embodiments, R20is hydrogen.

[0172] In certain embodiments, R20is hydroxyl.

[0173] In certain embodiments, R20is substituted or unsubstituted C1-6alkyl. In certain embodiments, R20is substituted C1-6alkyl. In some embodiments, R20is C1-6alkyl optionally substituted with 1-5 RF. In some embodiments, R20is C1-6alkyl substituted with 1-5 RF. In some embodiments, R20is unsubstituted C1-6alkyl. In some embodiments, R20is unsubstituted C1-3 alkyl. In some embodiments, R20is -CH3.

[0174] In certain embodiments, R20is substituted or unsubstituted C3-6carbocyclyl. In certain embodiments, R20is substituted C3-6carbocyclyl. In some embodiments, R20is C3-6carbocyclyl optionally substituted with 1-5 RF. In some embodiments, R20is C3-6carbocyclyl substituted with 1-5 RF. In some embodiments, R20is unsubstituted C3-6carbocyclyl. In certain embodiments, R20is unsubstituted C3-4carbocyclyl. In certain embodiments, R20is unsubstituted cyclobutyl. In certain embodiments, R20is unsubstituted cyclopropyl.

[0175] In certain embodiments, R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl. In some embodiments, R20’is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RF. In some embodiments, R20’is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently substituted with 1-5 RF. In some embodiments, R20’is hydrogen or C1-6alkyl optionally substituted with 1-5 RF. In some embodiments, R20’is hydrogen or C1-6alkyl substituted with 1-5 RF. In some embodiments, R20’is hydrogen or C1-6alkyl optionally substituted with 1-3 RF. In some embodiments, R20’is hydrogen or C1-6alkyl o substituted with 1-3 RF. In some embodiments, R20’is hydrogen or unsubstituted C1-6alkyl. In some embodiments, R20’is hydrogen or unsubstituted C1-3 alkyl. In some embodiments, R20’is hydrogen or -CH3.

[0176] In certain embodiments, R20’is hydrogen.

[0177] In certain embodiments, R20’is hydroxyl.

[0178] In certain embodiments, R20’is substituted or unsubstituted C1-6alkyl. In some embodiments, R20’is substituted C1-6alkyl. In some embodiments, R20’is C1-6alkyl optionally substituted with 1-5 RF. In some embodiments, R20’is C1-6alkyl substituted with 1-5 RF. In some embodiments, R20’is unsubstituted C1-6alkyl. In some embodiments, R20’is unsubstituted C1-3alkyl. In some embodiments, R20’is -CH3.

[0179] In certain embodiments, R20’is substituted or unsubstituted C3-6carbocyclyl. In certain embodiments, R20’is substituted C3-6carbocyclyl. In some embodiments, R20’is C3-6carbocyclyl optionally substituted with 1-5 RF. In some embodiments, R20’is C3-6carbocyclyl substituted with 1-5 RF. In some embodiments, R20’is unsubstituted C3-6carbocyclyl. In certain embodiments, R20’is unsubstituted C3-4carbocyclyl. In certain embodiments, R20’is unsubstituted cyclobutyl. In certain embodiments, R20’is unsubstituted cyclopropyl.

[0180] In certain embodiments, R20is hydrogen, hydroxyl, or substituted or unsubstituted C1-6alkyl and R20’is hydrogen or substituted or unsubstituted C1-6alkyl. In some embodiments, R20is hydrogen, hydroxyl, or C1-6alkyl optionally substituted with 1-5 REand R20’is hydrogen or C1-6alkyl optionally substituted with 1-5 RF. In some embodiments, R20is hydrogen, hydroxyl, or C1-6alkyl substituted with 1-5 REand R20’is hydrogen or C1-6alkyl substituted with 1-5 RF. In some embodiments, R20is hydrogen and R20’is substituted C1-6alkyl. In some embodiments, R20is hydrogen and R20’is C1-6alkyl optionally substituted with 1-5 RF. In some embodiments, R20is hydrogen and R20’is C1-6alkyl substituted with 1- 5 RF. In some embodiments, R20is hydrogen and R20’is unsubstituted C1-6alkyl. In some embodiments, R20is hydrogen and R20’is unsubstituted C1-3 alkyl. In some embodiments, R20is hydrogen and R20’is -CH3. In some embodiments, R20is substituted C1-6alkyl and R20’is hydrogen. In some embodiments, R20is C1-6alkyl optionally substituted with 1-5 REand R20’is hydrogen. In some embodiments, R20is C1-6alkyl substituted with 1-5 REand R20’is hydrogen. In some embodiments, R20is unsubstituted C1-6alkyl and R20’is hydrogen. In some embodiments, R20is unsubstituted C1-3 alkyl and R20’is hydrogen. In some embodiments, R20is -CH3and R20’is hydrogen. In some embodiments, R20is hydroxyl and R20’is substituted C1-6alkyl. In some embodiments, R20is hydroxyl and R20’is C1-6alkyl optionally substituted with 1-5 RF. In some embodiments, R20is hydroxyl and R20’is C1-6alkyl substituted with 1-5 RF. In some embodiments, R20is hydroxyl and R20’is unsubstituted C1-6alkyl. In certain embodiments, R20is hydroxyl and R20’is unsubstituted C1-3alkyl. In certain embodiments, R20is hydroxyl and R20’is -CH3. In certain embodiments, R20is C1-6alkyl optionally substituted with 1-5 REand R20’is C1-6alkyl optionally substituted with 1-5 RF. In certain embodiments, R20is C1-6alkyl substituted with 1-5 REand R20’is C1-6alkyl substituted with 1-5 RF. In certain embodiments, R20and R20’are unsubstituted C1-6alkyl. In certain embodiments, R20and R20’are unsubstituted C1-3 alkyl. In certain embodiments, R20and R20’are -CH3. In certain embodiments, R20and R20’are hydrogen.

[0181] In certain embodiments, each instance of RE, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In certain embodiments, each instance of RE, when present, is independently selected from the group consisting ofhalo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RE, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RE, when present, is independently selected from the group consisting of halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RE, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of RE, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3.

[0182] In certain embodiments, each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and substituted or unsubstituted C1-6alkoxy. In certain embodiments, each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RF, when present, is independently selected from the group consisting of halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RF, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of RF, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. Groups R22, RG, RG1, and RH– as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A- 1-ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii)

[0183] In certain embodiments, R22is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted C6-10aryl. In certain embodiments, R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are independently optionally substituted with 1-5 RGand said C3-6carbocyclyl and C6-10aryl are independently optionally substituted with 1-5 RH. In certain embodiments, R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl areindependently substituted with 1-5 RGand said C3-6carbocyclyl and C6-10aryl are independently substituted with 1-5 RH. In certain embodiments, R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are independently optionally substituted with 1-3 RGand said C3-6carbocyclyl and C6-10aryl are independently optionally substituted with 1-3 RH. In certain embodiments, R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are independently substituted with 1-3 RGand said C3-6carbocyclyl and C6-10aryl are independently substituted with 1-3 RH. In certain embodiments, R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl. In some embodiments, R22is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C2-6alkynyl. In some embodiments, R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-5 RG. In some embodiments, R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently substituted with 1-5 RG. In some embodiments, R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-3 RG. In some embodiments, R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently substituted with 1-3 RG. In some embodiments, R22is C1-6 alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1 RG. In some embodiments, R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently substituted with 1 RG. In some embodiments, R22is unsubstituted C1-6alkyl or unsubstituted C2-6alkynyl. In some embodiments, R22is - CH2F, -CHF2, -CF3, -CH2CH2CH(CH3)(CF3), -CH2OH, -CH2OCH3, -CH2OCH2CH2OCH3, - CH2OCH(CH3)2, -CH2OCF3, -CH2OCHF2, -CH3, -CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, - CH2CH(CH3)2, -CH2CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, - CH=C(CH3)2, -C≡C-H, -C≡C-CH3, -C≡C-CF3, unsubstituted cyclopropyl, unsubstituted cyclobutyl, bicyclo[1.1.1]pentanyl optionally substituted with 1-5 RH, or phenyl optionally substituted with 1-5 RH.

[0184] In certain embodiments, R22is substituted or unsubstituted C1-6alkyl. In certain embodiments, R22is C1-6alkyl optionally substituted with 1-5 RG. In certain embodiments, R22is C1-6alkyl optionally substituted with 1-3 RG. In certain embodiments, R22is C1-6alkyl optionally substituted with 1 RG. In some embodiments, R22is methyl optionally substituted with 1-3 RG. In some embodiments, R22is ethyl optionally substituted with 1-5 RG. In some embodiments, R22is n-propyl optionally substituted with 1-5 RG. In some embodiments, R22is isopropyl optionally substituted with 1-5 RG. In some embodiments, R22is n-butyloptionally substituted with 1-5 RG. In some embodiments, R22is isobutyl optionally substituted with 1-5 RG. In some embodiments, R22is sec-butyl optionally substituted with 1- 5 RG. In some embodiments, R22is tert-butyl optionally substituted with 1-5 RG. In some embodiments, R22is n-pentyl optionally substituted with 1-5 RG. In some embodiments, R22is isopentyl optionally substituted with 1-5 RG. In some embodiments, R22is neopentyl optionally substituted with 1-5 RG. In some embodiments, R22is sec-pentyl optionally substituted with 1-5 RG. In some embodiments, R22is tert-pentyl optionally substituted with 1-5 RG.

[0185] In certain embodiments, R22is substituted C1-6alkyl. In certain embodiments, R22is C1-6alkyl substituted with 1-5 RG. In certain embodiments, R22is C1-6alkyl substituted with 1-3 RG. In certain embodiments, R22is unsubstituted C1-6alkyl. In some embodiments, R22is C1-6alkyl substituted with 1-3 RGand each instance of RGis independently selected from the group consisting of: halo, hydroxyl, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl, wherein said C3-6carbocyclyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1-3 RGand each instance of RGis independently selected from the group consisting of: halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with 1-3 RGand RGis halo. In some embodiments, R22is -CH2F, - CHF2, -CF3, or -CH2CH2CH(CH3)(CF3). In some embodiments, R22is C1-6alkyl substituted with 1-3 RGand each instance of RGis independently hydroxyl or C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, R22is methyl substituted with 1-3 RGand each instance of RGis independently selected from the group consisting of: halo, hydroxyl, and C1-6alkoxy optionally substituted with 1-3 fluoro. In some embodiments, R22is methyl substituted with 1-3 RGand RGis halo. In some embodiments, R22is methyl substituted with 1-3 RGand RGis fluoro. In some embodiments, R22is -CH2F, -CHF2, or -CF3. In some embodiments, R22is methyl substituted with 1-3 RGand each instance of RGis independently hydroxyl or C1-6alkoxy optionally substituted with 1-3 fluoro. In some embodiments, R22is - CH2OH, -CH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH(CH3)2, -CH2OCF3, or -CH2OCHF2.

[0186] In certain embodiments, R22is C1-6alkyl substituted with 1 RG. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis substituted or unsubstituted 5- 8 membered heteroaryl. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-8 membered heteroaryl optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-8 membered heteroaryl optionally substitutedwith 1-3 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-8 membered heteroaryl optionally substituted with 1 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-6 membered heteroaryl optionally substituted with 1- 5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-6 membered nitrogen-containing heteroaryl containing 1-4 nitrogen atoms and optionally substituted with 1-5 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis 5-6 membered heteroaryl substituted with 1-3 RG1; and each instance of RG1is independently cyano, oxo or C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis pyrazolyl, tetrazolyl, or pyridinonyl, each of which is independently optionally substituted with 1-3 RG1. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis pyrazolyl, tetrazolyl, or pyridonyl, each of which is independently optionally substituted with 1-3 RG1; and each instance of RG1is independently cyano or C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis pyrazolyl optionally substituted with 1-3 RG1; and each instance of RG1is independently cyano or C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis pyrazolyl substituted with 1-3 RG1; and RG1is cyano. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis pyrazolyl substituted with 1 RG1; and RG1is cyano. In some embodiments, R22is methyl substituted with 1 RG; RGis pyrazolyl substituted with 1 RG1; and RG1is cyano. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis tetrazolyl optionally substituted with 1-3 RG1; and RG1is independently cyano or C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis tetrazolyl optionally substituted with 1-3 RG1; and RG1is C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis tetrazolyl substituted with 1-3 RG1; and RG1is C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis tetrazolyl substituted with 1-3 RG1; and RG1is unsubstituted C1-6alkyl. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis tetrazolyl substituted with 1-3 RG1; and RG1-CH3. In some embodiments, R22is C1-6alkyl substituted with 1 RG; RGis tetrazolyl substituted with 1 RG1; and RG1-CH3. In some embodiments, R22is methyl substituted with 1 RG; RGis tetrazolyl substituted 1 RG1; and RG1-CH3. In some embodiments, R22is C1-6alkyl substituted with 1 RG1and RG1isunsubstituted pyridinonyl. In some embodiments, R22is methyl substituted with 1 RG1and RG1is unsubstituted pyridinonyl.

[0187] In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis substituted or unsubstituted C3-6carbocyclyl. In certain embodiments, R22is C1-6alkyl substituted 1 RGand RGis C3-6carbocyclyl optionally substituted with 1-5 RG1. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis C3-6carbocyclyl optionally substituted with 1-3 RG1. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis C3-6carbocyclyl substituted with 1-3 RG1. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis unsubstituted C3-6carbocyclyl. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis unsubstituted C3-4carbocyclyl. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis unsubstituted cyclopropyl. In certain embodiments, R22is methyl substituted with 1 RGand RGis unsubstituted C3-4 carbocyclyl. In certain embodiments, R22is methyl substituted with 1 RGand RGis unsubstituted cyclopropyl.

[0188] In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis substituted or unsubstituted 5-8 membered heterocyclyl. In some embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-8 membered heterocyclyl optionally substituted with 1-5 RG1. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis 5-8 membered heterocyclyl optionally substituted with 1-3 RG1. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis unsubstituted 5-8 membered heterocyclyl. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis unsubstituted 5-8 membered nitrogen-containing heterocyclyl. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis unsubstituted 5-8 membered nitrogen-containing heterocyclyl containing 1 nitrogen atom. In certain embodiments, R22is C1-6alkyl substituted with 1 RGand RGis unsubstituted pyrrolidinonyl. In certain embodiments, R22is C1-3 alkyl substituted with 1 RGand RGis unsubstituted pyrrolidinonyl. In certain embodiments, R22is methyl substituted with 1 RGand RGis unsubstituted pyrrolidinonyl.

[0189] In certain embodiments, R22is unsubstituted C1-6alkyl. In some embodiments, R22is -CH3, -CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, or - C(CH3)3. In some embodiments, R22is -CH3, -CH2CH3, -CH2CH2CH2CH3, or -CH(CH3)2. In some embodiments, R22is -CH3. In some embodiments, R22is -CH2CH3. In some embodiments, R22is -CH2CH2CH2CH3. In some embodiments, R22is -CH(CH3)2. In some embodiments, R22is -CH2CH(CH3)2. In some embodiments, R22is -CH2CH2CH(CH3)2. In some embodiments, R22is -C(CH3)3.

[0190] In certain embodiments, R22is substituted or unsubstituted C2-6alkenyl. In some embodiments, R22is C2-6alkenyl optionally substituted with 1-5 RG. In some embodiments, R22is C2-6alkenyl optionally substituted with 1-3 RG. In some embodiments, R22is C2-6alkenyl optionally substituted with 1 RG. In some embodiments, R22is C2-4alkenyl optionally substituted with 1-5 RG. In some embodiments, R22is C2-4 alkenyl optionally substituted with 1-3 RG. In certain embodiments, R22is C2-4 alkenyl optionally substituted with 1 RG. In some embodiments, R22is C2-6alkenyl substituted with 1-5 RG. In some embodiments, R22is C2-6alkenyl substituted with 1-3 RG. In some embodiments, R22is C2-6alkenyl substituted with 1 RG. In some embodiments, R22is C2-4 alkenyl substituted with 1-5 RG. In some embodiments, R22is C2-4alkenyl substituted with 1-3 RG. In certain embodiments, R22is C2-4alkenyl substituted with 1 RG. In some embodiments, R22is unsubstituted C2-6alkenyl. In some embodiments, R22is unsubstituted C2-6alkenyl. In some embodiments, R22is unsubstituted C2-4 alkenyl. In some embodiments, R22is -CH=CH2, - CH2CH=CH2, -CH=CHCH3, or -CH=C(CH3)2. In some embodiments, R22is -CH=CH2. In some embodiments, R22is -CH2CH=CH2. In some embodiments, R22is -CH=CHCH3. In some embodiments, R22is -CH=C(CH3)2.

[0191] In certain embodiments, R22is substituted or unsubstituted C2-6alkynyl. In some embodiments, R22is C2-6alkynyl optionally substituted with 1-5 RG. In some embodiments, R22is C2-6alkynyl optionally substituted with 1-3 RG. In some embodiments, R22is C2-6alkynyl optionally substituted with 1 RG. In some embodiments, R22is C2-3alkynyl optionally substituted with 1-5 RG. In some embodiments, R22is C2-3alkynyl optionally substituted with 1-3 RG. In some embodiments, R22is C2-6alkynyl substituted with 1-5 RG. In some embodiments, R22is C2-6alkynyl substituted with 1-3 RG. In some embodiments, R22is C2-6alkynyl substituted with 1 RG. In some embodiments, R22is C2-3alkynyl substituted with 1-5 RG. In some embodiments, R22is C2-3 alkynyl substituted with 1-3 RG. In some embodiments, R22is -C≡C-H, -C≡C-CH3, or -C≡C-CF3. In some embodiments, R22is C2-3alkynyl substituted with 1-3 RG. In some embodiments, R22is C2-3alkynyl substituted with 1-3 RGand RGis halo. In some embodiments, R22is C2-3 alkynyl substituted with 1-3 RGand RGis fluoro. In some embodiments, R22is -C≡C-CF3. In some embodiments, R22is unsubstituted C2-6alkynyl. In some embodiments, R22is unsubstituted C2-3alkynyl. In some embodiments, R22is -C≡C-H or -C≡C-CH3.

[0192] In certain embodiments, R22is substituted or unsubstituted C3-6carbocyclyl. In certain embodiments, R22is C3-6carbocyclyl optionally substituted with 1-5 RH. In some embodiments, R22is C3-6carbocyclyl optionally substituted with 1-3 RH. In someembodiments, R22is C3-6carbocyclyl optionally substituted with 1 RH. In certain embodiments, R22is C3-6carbocyclyl substituted with 1-5 RH. In certain embodiments, R22is a bicyclic C3-6carbocyclyl substituted with 1-5 RH. In some embodiments, R22is a bicyclic C3-6carbocyclyl substituted with 1-3 RH. In some embodiments, R22is a bicyclic C3-6carbocyclyl substituted with 1 RH. In some embodiments, R22is unsubstituted C3-6carbocyclyl. In some embodiments, R22is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentanyl, each of which is independently optionally substituted with 1-5 RH. In some embodiments, R22is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl optionally substituted with 1-3 RH. In some embodiments, R22is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl substituted with 1 RH. In some embodiments, R22is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl substituted with 1 RH, wherein RHis -CH3or -CF3. In some embodiments, R22is unsubstituted cyclopropyl. In some embodiments, R22is unsubstituted cyclobutyl. In some embodiments, R22is bicyclo[1.1.1]pentanyl optionally substituted with 1-3 RH. In some embodiments, R22is bicyclo[1.1.1]pentanyl substituted with 1-3 RH. In some embodiments, R22is bicyclo[1.1.1]pentanyl substituted with 1 RH. In some embodiments, R22is bicyclo[1.1.1]pentanyl substituted with 1 RHand RHis -CH3or -CF3. In some embodiments, R22is bicyclo[1.1.1]pentanyl substituted with 1 RHand RHis -CH3. In some embodiments, R22is bicyclo[1.1.1]pentanyl substituted with 1 RHand RHis -CF3.

[0193] In certain embodiments, R22is substituted or unsubstituted C6-10aryl. In some embodiments, R22is C6-10aryl optionally substituted with 1-5 RH. In some embodiments, R22is C6-10aryl substituted with 1-5 RH. In some embodiments, R22is C6-10aryl optionally substituted with 1-3 RH. In some embodiments, R22is C6-10aryl substituted with 1-3 RH. In some embodiments, R22is phenyl optionally substituted with 1-5 RH. In some embodiments, R22is phenyl substituted with 1-5 RH. In some embodiments, R22is phenyl optionally substituted with 1-3 RH. In some embodiments, R22is phenyl substituted with 1-3 RH. In some embodiments, R22is phenyl optionally substituted with 1-3 RHand each instance of RHis independently selected from the group consisting of: halo, cyano, and C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is phenyl substituted with 1-3 RHand each instance of RHis independently selected from the group consisting of: halo, cyano, and C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, R22is phenyl optionally substituted with 1-3 RHand each instance of RHis independently selected from the group consisting of: halo, cyano, and C1-6alkyl optionally substituted with 1-5 fluoro. In some embodiments, R22is phenyl optionally substituted with 1-3 RHand each instance of RHis independently selected from the group consisting of: fluoro, cyano, and unsubstituted C1-6alkyl. In some embodiments, R22is phenyl optionally substituted with 1-3 RHand each instance of RHis independently selected from the group consisting of: fluoro, cyano, and - CH3. In some embodiments, R22is phenyl optionally substituted with 1-3 RHand RHis fluoro. In some embodiments, R22is phenyl optionally substituted with 1-3 RHand RHis - CH3. In some embodiments, R22is phenyl optionally substituted with 1-3 RHand RHis cyano. In some embodiments, R22is unsubstituted C6-10aryl. In some embodiments, R22is unsubstituted phenyl.

[0194] In certain embodiments, each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, substituted or unsubstituted C1-6alkoxy, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10aryl, substituted or unsubstituted 5-8 membered heteroaryl, and substituted or unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 RG1. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C3-6carbocyclyl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 RG1. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, C1-6alkoxy optionally substituted with 1-5 halo, unsubstituted C3-6carbocyclyl, 5-8 membered heteroaryl optionally substituted with 1-5 RG1, and unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, C1-6alkoxy optionally substituted with 1-3 halo, unsubstituted C3-6carbocyclyl, 5-8 membered heteroaryl optionally substituted with 1-3 RG1, and unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, C1-6alkoxy optionally substituted with 1-3 halo, unsubstituted C3-6carbocyclyl, 5-8 membered heteroaryl optionally substituted with 1 RG1, and unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3,-OCH(CH3)2, -OCHF2, -OCF3, -OCH2CH2OCH3, unsubstituted cyclopropyl, pyrazolyl, tetrazolyl, unsubstituted pyrrolidinonyl, and unsubstituted pyridinonyl, wherein said pyrazolyl and tetrazolyl are substituted with 1 RG1. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of fluoro, hydroxyl, - OCH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CH2OCH3, unsubstituted cyclopropyl, pyrazolyl, tetrazolyl, unsubstituted pyrrolidinonyl, and unsubstituted pyridinonyl, wherein said pyrazolyl and tetrazolyl are substituted with 1 RG1and RG1is cyano or -CH3. In some embodiments, each instance of RG, when present, is independently selected from the group consisting of fluoro, -OCH3, and pyrazolyl substituted with 1 RG1, and RG1is cyano.

[0195] In certain embodiments, each instance of RG1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, substituted or unsubstituted C1-6alkyl, and substituted or unsubstituted C1-6alkoxy. In some embodiments, each instance of RG1, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RG1, when present, is independently selected from the group consisting of halo, cyano, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RG1, when present, is independently selected from the group consisting of cyano and C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, each instance of RG1, when present, is independently selected from the group consisting of cyano and unsubstituted C1-6alkyl. In some embodiments, each instance of RG1, when present, is independently selected from the group consisting of cyano and -CH3. In some embodiments, each instance of RG1, when present, is cyano. In some embodiments, each instance of RG1, when present, is -CH3.

[0196] In certain embodiments, each instance of RH, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of RH, when present, is independently selected from the group consisting of halo, cyano, and C1-6alkyl optionally substituted with 1-5 halo. In some embodiments, each instance of RH, when present, is independently selected from the group consisting of fluoro, cyano, -CH3, and -CF3. In some embodiments, each instance of RH, when present, is independently selected from the group consisting of fluoro, cyano, and -CH3. In some embodiments, each instance of RH, when present, is independently selected from thegroup consisting of -CH3and -CF3. In some embodiments, each instance of RH, when present, is fluoro. In some embodiments, each instance of RH, when present, is cyano. In some embodiments, each instance of RH, when present, is -CH3. In some embodiments, each instance of RH, when present, is -CF3.

[0197] In some embodiments, the compound of Formula (I) is any one of the compounds in Table 1. Table 1and pharmaceutically acceptable salts, isotopic variants, and combinations thereof.

[0198] In some embodiments, the compound of Formula (I) is any one of Compounds 2, 7, 13, 14, 16, 18-21, 27, 29-32, 34-36, 38-40, 53-65, 67, 70, 73, 75, 77-79, 81-84, 86, 88, 90-93, 95, 97-98, 100-101, 103-106, or 108 of Table 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one of Compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100- 101, or 104-106 of Table 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0199] It is to be understood that in any of the preceding embodiments, the compound may be in a non-salt form, or in the form of a pharmaceutically acceptable salt, an isotopic variant, or any chemically permissible combination thereof. For example, in some embodiments, the compound is in a non-salt form. In other embodiments, the compound is in the form of a pharmaceutically acceptable salt. In certain other embodiments, the compound is in the form of an isotopic variant. In certain other embodiments, the compound is in a non-salt form or in the form of an isotopic variant. In some embodiments, the compound is in a non-salt form or in the form of a pharmaceutically acceptable salt. In some embodiments, the compound is in the form of a pharmaceutically acceptable salt and an isotopic variant. Alternative Embodiments

[0200] In some embodiments, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,11C,13C, or14C; oxygen may be, for example18O; nitrogen may be, for example15N, and the like. In other embodiments, a particular isotope (e.g.,2H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0201] In certain embodiments, compounds described herein have one or more hydrogen atoms independently replaced by deuterium or tritium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by deuterium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by tritium. Pharmaceutical Compositions

[0202] In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Formula (I)).

[0203] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

[0204] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier.

[0205] The present disclosure also relates to a compound described herein (e.g., a compound of Formula (I), or pharmaceutical composition thereof) for use as a pharmaceutical or a medicament.

[0206] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0207] The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds provided herein are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0208] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0209] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms (e.g., pills, tablets, capsules) may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0210] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0211] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0212] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0213] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0214] The above-described components for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0215] The compounds of this disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0216] The present disclosure also relates to the pharmaceutically acceptable formulations of a compound described herein (e.g., a compound of Formula (I)). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α–, β– and γ– cyclodextrins consisting of 6, 7 and 8 ^–l ,4–linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β–cyclodextrin, e.g., for example, sulfobutyl ether β–cyclodextrin, also known as Captisol®. See, e.g., U.S.5,376,645. In certain embodiments, the formulation comprises hexapropyl- ^-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl- ^-cyclodextrin (10-50% in water).

[0217] The present disclosure also relates to the pharmaceutically acceptable acid addition salt of a compound described herein (e.g., a compound of Formula (I)). The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0218] For the prevention and / or treatment of long-term conditions the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg.

[0219] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0220] When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0221] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject, the disease or disorder to be treated and the particular mode of administration. As the skilled artisan will appreciate, specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease or disorder, the patient's disposition to the disease or disorder and the judgment of the treating physician. Methods of Treatment and Use

[0222] Compounds of the present disclosure (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to be negative allosteric modulators of NMDA function, and therefore are useful for the treatment and prevention of, e.g., CNS–related conditions in a subject.

[0223] In some embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to penetrate the blood brain barrier (e.g., designed to be transported across the blood brain barrier). In certain embodiments, the compounds of thepresent disclosure, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, may act as negative allosteric modulators (NAM) of NMDA, and inhibit NMDA receptor function.

[0224] In one aspect, the disclosure provides a method for effecting negative allosteric modulation of an NMDA receptor in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0225] In one aspect, the disclosure provides a method for treating a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0226] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0227] In one aspect, the disclosure provides a method for preventing a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0228] In one aspect, the disclosure provides a method for preventing a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein.

[0229] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in effecting negative allosteric modulation of an NMDA receptor in a subject.

[0230] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject.

[0231] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject.

[0232] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject.

[0233] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject.

[0234] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor in a subject.

[0235] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject.

[0236] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a CNS-related condition in a subject.

[0237] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject.

[0238] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing a CNS-related condition in a subject.

[0239] Exemplary CNS conditions related to negative allosteric modulation of NMDA receptors include, but are not limited to, adjustment disorders, stress or stress disorders (including post-traumatic stress disorder (PTSD)), anxiety disorders (including obsessive- compulsive disorder, posttraumatic stress disorder, social phobia, social anxiety disorder, andgeneralized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), psychotic disorders, sleep disorders (including insomnia), substance abuse-related disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), personality disorders (including obsessive-compulsive personality disorder (OCD)), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), addictive disorders, neurodevelopmental disorders (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, and chronic pain; headaches, e.g., migraine headaches), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), vascular diseases (e.g., stroke, ischemia, vascular malformations), traumatic brain injury, movement disorders (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, and tinnitus.

[0240] In certain embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in the treatment or prevention of CNS-related conditions selected from adjustment disorders, anxiety disorders, cognitive disorders, mood disorders, personality disorders, neurodevelopmental disorders, pain, seizures and seizure disorders, stroke, traumatic brain injury, movement disorders, neuropsychiatric lupus, and tinnitus. In some embodiments, the CNS-related condition is a mood disorder selected from depression, post- partum depression, bipolar disorder, dysthymic disorder, and suicidality. In some embodiments, the CNS-related condition is a mood disorder selected from clinical depression, post-partum depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, and suicidal behavior. In some embodiments, the CNS-related condition is selected from a seizure, status epilepticus, Dravet’s disease, or Tuberous Sclerosis Complex. In someembodiments, the CNS-related condition is a seizure selected from a grand-mal seizure, an absence seizure, a myoclonic seizure, a clonic seizure, a tonic seizure, and an atonic seizure. In some embodiments, the CNS-related condition is a movement disorder selected from Parkinson’s disease, Parkinsonism, dystonia, chorea, Huntington’s disease, ataxia, levodopa- induced dyskinesia, tremor, myoclonus and startle, tics and Tourette syndrome, restless leg syndrome, stiff person syndrome, and gait disorders. In some embodiments, the CNS-related condition is a tremor selected from a cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, and rubral tremor. In some embodiments, the CNS-related condition is Huntington’s disease. In some embodiments, the CNS-related condition is Parkinson’s disease. In some embodiments, the CNS is neuropsychiatric lupus.

[0241] In certain embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in the treatment or prevention of a CNS-related condition, wherein the CNS-related condition is selected from the group consisting of: an anxiety disorder, a stress disorder, a cognitive disorder (including Alzheimer’s disease, mild cognitive impairment, and other forms of dementia (e.g., frontotemporal dementia)), a mood disorder (including depression (e.g., postpartum depression)), a personality disorder, an addictive disorder (including drug addiction (e.g., cocaine addiction)), a neurodevelopmental disorder, schizophrenia or other psychotic disorders (including schizoaffective disorder), pain (including acute and chronic pain; neuropathic pain, headaches, e.g., migraine headaches), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), drug induced dyskinesia (e.g., L- DOPA-induced dyskinesia (LID)), stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome (FXS), neuropsychiatric lupus, and tinnitus.

[0242] In certain embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in the treatment or prevention of a CNS-related condition, wherein the CNS-related condition is selected from the group consisting of: a tremor, sleep disorders (e.g., insomnia), mood disorders (e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), eating disorders, stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD)), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), convulsive disorders (e.g., epilepsy (e.g.,status epilepticus (SE)), seizures), neurodegenerative disease and disorders, disorders of memory and / or cognition (e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., anti-social personality disorder, obsessive compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monogenetic causes of autism such as synaptopathies, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain), traumatic brain injury (TBI), vascular diseases (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0243] In some embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in treating Parkinson’s Disease. In some embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful as adjunct treatment to L-DOPA for Parkinson’s Disease. The compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in treating L-DOPA-induced dyskinesia (LID) in a subject suffering from Parkinson’s Disease.

[0244] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present disclosure, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0245] In yet another aspect, the present disclosure provides a combination of a compound of the present disclosure, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration. Movement Disorders

[0246] Also described herein are methods for treating a movement disorder. As used herein, “movement disorders” refers to a variety of diseases and disorders that are associatedwith hyperkinetic movement disorders and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and Parkinsonism (defined particularly by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.

[0247] Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs). Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor.

[0248] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inherited degenerative disorder).

[0249] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and / or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremors occurs irregularly and often can be relieved by complete rest.

[0250] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremorfrequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and / or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset.

[0251] Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occur in patients with essential tremor.

[0252] Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.

[0253] Physiological tremor can occur in normal individuals and have no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.

[0254] Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement. Patient with psychogenic tremor may have a conversion disorder or another psychiatric disease.

[0255] Rubral tremor is characterized by coarse slow tremor which can be present at rest, at posture, and with intention. The tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.

[0256] Parkinson’s disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson’s disease, but is a symptom complex rather than a progressive neurodegenerative disease.

[0257] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.

[0258] Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face.

[0259] Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing.

[0260] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0261] Myoclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.

[0262] Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non- rhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example simple motor tics involve only a few muscles restricted to a specific body part.

[0263] Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.

[0264] Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.

[0265] Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Stiff-legged gait with exaggerated lumbar hyperlordosis typically results. Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.

[0266] Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait. Mood disorders

[0267] Also provided herein are methods for treating a mood disorder, for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressivedisorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior.

[0268] Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.

[0269] Postnatal depression (PND) is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., a refractory depression as described herein).

[0270] In some embodiments, a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression. In an embodiment, a subject experiencing perinatal depression is at increased risk of experiencing PND.

[0271] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.

[0272] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failures to react to pleasurable stimuli, depressed mood more pronounced than that of grief or loss, excessive weight loss, or excessive guilt.

[0273] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.

[0274] Catatonic depression refers to major depression involving disturbances of motor behavior and other symptoms. An individual may become mute and stuporose, and either is immobile or exhibits purposeless or bizarre movements.

[0275] Seasonal affective disorder (SAD) refers to a type of seasonal depression wherein an individual has seasonal patterns of depressive episodes coming on in the fall or winter.

[0276] Dysthymia refers to a condition related to unipolar depression, where the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e.g., at least 2 years).

[0277] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.

[0278] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features.

[0279] Recurrent Brief Depression (RBD) refers to a condition in which individuals have depressive episodes about once per month, each episode lasting 2 weeks or less and typically less than 2-3 days.

[0280] Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks.

[0281] Bipolar disorder or manic depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder.

[0282] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.

[0283] Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not ease depression symptoms for individuals with treatment-resistant depression. In some cases, individuals with treatment- resistant depression improve symptoms, but come back. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments,including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytic drugs, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0284] Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide. Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again.

[0285] Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of depression, and relief of the same, may be ascertained by a physician or psychologist (e.g., by a mental state examination). Anxiety Disorders

[0286] Provided herein are methods for treating anxiety disorders. Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0287] Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

[0288] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that saidattacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

[0289] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.

[0290] The single largest category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

[0291] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression. Epilepsy

[0292] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.Epileptogenesis

[0293] Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus). Status epilepticus (SE)

[0294] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

[0295] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non- convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non- convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus. Seizure

[0296] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably. During convulsions, the person’s muscles contract and relax repeatedly.

[0297] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.

[0298] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

[0299] There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0300] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time."

[0301] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.

[0302] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

[0303] Tonic seizures are characterized by stiffening of the muscles.

[0304] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

[0305] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non- convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipitallobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, Lennox-Gastaut Syndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy. Examples

[0306] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope.

[0307] The absolute configuration of an asymmetric center can be determined using methods known to one skilled in the art. In some embodiments, the absolute configuration of an asymmetric center in a compound can be elucidated from the X-ray single-crystal structure of the compound. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound obtained from the same or similar synthetic methodologies. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound coupled with a spectroscopic technique, e.g., NMR spectroscopy, e.g., 1H NMR spectroscopy or 19F NMR spectroscopy. Abbreviations

[0308] MeOH: methanol; THF: tetrahydrofuran; Pd / C: palladium on carbon; CDCl3: deuterated chloroform; c-PrMgBr: cyclopropylmagnesium bromide; NH4Cl: ammonium chloride; EtOAc: ethyl acetate; Na2SO4: sodium sulfate; PE: petroleum ether; DMSO: dimethyl sulfoxide; TEA / Et3N: triethylamine; SO3∙pyr: sulfur trioxide-pyridine complex; H2O: water; NaHCO3: sodium bicarbonate; CsF: cesium fluoride; TMSCF3: trifluoromethyltrimethylsilane; TBAF: tetrabutylammonium fluoride; ACN / MeCN: acetonitrile; NH4HCO3: ammonium bicarbonate; TFA: trifluoroacetic acid; EtMgBr: ethylmagnesium bromide; BHT: 2,6-di-t-butyl-4-methylphenoxide; MAD: methylaluminium bis(2,6-di-t-butyl-4-methylphenoxide); DCM: dichloromethane; Et2O: diethyl ether; DMP: Dess-Martin periodinane; Ph3PMeBr / MePPh3Br: bromo(methyl)triphenylphosphorane; t- BuOK: potassium tert-butoxide; Na2S2O3: sodium thiosulfate; O3: ozone; Me2S / DMS: dimethyl sulfide; HBr: hydrobromic acid; TsOH: p-toluenesulfonic acid; Ph3PEtBr / EtPPh3Br:bromo(ethyl)triphenylphosphorane; HCl: hydrochloric acid; NaBH4: sodium borohydride; TBSCl: t-butyldimethylsilyl chloride; 9-BBN: 9-borabicyclo[3.3.1]nonane; NaOH: sodium hydroxide; H2O2: hydrogen peroxide; PCC: pyridinium chlorochromate; EtOH: ethanol; (tBuO)3AlLiH / LiAlH(OtBu)3: lithium tri-(t-butoxy)aluminum hydride; NaH: sodium hydride; MeMgBr: methylmagnesium bromide; i-BuMgBr: isobutylmagnesium bromide; LAH / LiAlH4: lithium aluminum hydride; n-BuMgBr: n-butylmagnesium bromide; i- AmylMgBr: isoamylmagnesium bromide; CBS: Corey-Bakshi-Shibata catalyst; BH3∙SMe2 / BH3∙DMS: borane dimethylsulfide; CaCO3: calcium carbonate; PhI(OAc)2: (diacetoxyiodo)benzene; BnOH: benzyl alcohol; t-BuOH: tertbutanol; DME: dimethyl ether; TosMic: toluenesulfonylmethyl isocyanide; LDA: lithium diisopropyl amide; MeI: methyl iodide; DIBAL-H: diisobutylaluminum hydride; IPA / i-PrOH: isopropanol; PMBCl: p- methoxybenzyl chloride; AlMe3: trimethyl aluminum; DDQ: 2,3-dichloro-5,6- dicyanobenzoquinone; DMF: N,N-dimethylformamide; HMPA: hexamethylphosphoramide; LiHMDS: lithium bis(trimethylsilyl)amide; NaH2PO4: monosodium phosphate; K2CO3: potassium carbonate; NaBH4: sodium borohydride; m-CPBA: meta-chloroperoxybenzoic acid; NaOMe: sodium methoxide; n-PrMgBr: n-propylmagnesium bromide; BzCl: benzoyl chloride; PhMe: toluene; DMAP: 4-dimethylaminopyridine; i-PrMgCl: isopropylmagnesium chloride; t-BuMgCl: tertbutylmagnesium chloride; Cs2CO3: cesium carbonate; DIPEA: N,N- diisopropylethylamine; TMSCF2Br: (bromodifluoromethyl)trimethylsilane; KOAc: potassium acetate; LiOH: lithium hydroxide; n-BuLi: n-butyllithium; TBDPSCl: tert- butylchlorophenylsilane; BnBr: benzylbromide; KHF2: potassium bifluoride; DCE: 1,2- dichloroethane; t-BuLi: tert-butyl lithium; Me3SOI: trimethylsulfonium iodide; CD3OD: deuterated methanol (d4); Na2CO3: sodium carbonate; BH3∙THF: borane tetrahydrofuran complex; Py: pyridine; 2-Me-THF: 2-methyltetrahydrofuran; AgOTf: silver trifluoromethanesulfonate / silver triflate; Selectfluor: chloromethyl-4-fluoro-1,4- diazoniabicyclo[2,.2.2]octane bis(tetrafluoroborate); NFSI: N-fluorobenzenefulonimide; NaOD: deuterated sodium hydroxide; AcOD: deuterated acetic acid; D2O: deuterated water; Ac2O: acetic anhydride; BzOH: benzenol; CeCl3: cerium chloride; DEAD: diethyl azodicarboxylate; PPh3: triphenylphosphine; MeI: methyl iodide; TBSOTf: tert- butyldimethylsilyl trifluoromethansulfonate; NaBT4: [3H] tritium-labeled sodium borohydride; Me: methyl; Et: ethyl; i-Pr: iso-propyl; t-Bu: tertbutyl; Ph: phenyl; Bz: benzoyl; Ts: p-toluenesulfonyl; Bu: butyl; NBS: N-bromosuccinimide.Materials and Methods

[0309] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0310] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 5thEdition, John Wiley & Sons, New Jersey, 2014, and references cited therein.

[0311] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or SFC. The following schemes are presented with details as to the preparation of representative compounds that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of the enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0312] 1H-NMR reported herein (e.g., for the region between δ (ppm) of about 0.5 to about 4 ppm) will be understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integrations) of a compound. Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min.

[0313] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6*50mm, 3.5 μm at 45 C.

[0314] Exemplary general method for SFC: Column: CHIRALPAK® AD CSP (250 mm * 30 mm, 10 μm), Gradient: 45% B, A= NH3H2O, B= MeOH, flow rate: 60 mL / min. For example, AD_3_EtOH_DEA_5_40_25ML would indicate: "Column: Chiralpak AD-3 150×4.6mm I.D., 3um Mobile phase: A: CO2B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL / min Column temp: 35oC.

[0315] Example 1: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-cyclopropyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (1)

[0316] Synthesis of 1.2

[0317] To a solution of 1.1 (100 g, 302 mmol) in MeOH (300 mL) and THF (300 mL) was added Pd / C (10 g, < 1% water). The solution was hydrogenated under 30 psi of hydrogen at 25 °C for 48 h. The mixture was filtered through a pad of Celite. The filter cake was washed with THF (3 x 300 mL) and the filtrate was concentrated under reduced pressure to give 1.2 (98 g).1H NMR (400 MHz, CDCl3) δH3.69-3.60 (m, 1H), 3.41-3.32 (m, 1H), 2.77-2.65 (m,1H), 2.41-1.97 (m, 5H), 1.94-1.76 (m, 3H), 1.67-1.51 (m, 4H), 1.49-1.16 (m, 10H), 1.16-1.08 (m, 2H), 1.07-1.00 (m, 6H), 0.70 (s, 3H).

[0318] Synthesis of 1.3

[0319] A solution of cyclopropylmagnesium bromide (448 mL, 224 mmol, 0.5 M in THF) was reacted with 1.2 (7.5 g, 22.5 mmol) at 65 °C and stirred for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (200 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (50 mL, sat.), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 1.3 (2 g, 24%). 1.3:1H NMR (400 MHz, CDCl3) δH3.70-3.56 (m, 1H), 3.41-3.27 (m, 1H), 2.07-1.71 (m, 6H), 1.67-1.33 (m, 12H), 1.31-1.07 (m, 12H), 0.96 (s, 3H), 0.67 (s, 3H), 0.42-0.31 (m, 4H).

[0320] Synthesis of 1.4

[0321] To a solution of 1.3 (0.55 g, 1.46 mmol) in DMSO (20 mL) was addded TEA (886 mg, 8.76 mmol) and SO3∙pyr (1.39 g, 8.76 mmol) at 25 °C and the resulting mixture was stirred at 30 °C for 16 h. This reaction was combined with another two (2) batches of reaction mixture obtained using similar protocols (1 g of 1.3 starting material), and the mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with NaHCO3(20 mL, sat. aq.), and H2O (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% EtOAc in PE) to give 1.4 (550 mg).1H NMR (400 MHz, CDCl3) δH 9.61-9.53 (m, 1H), 2.37-2.31 (m, 1H), 2.01-1.59 (m, 10H), 1.31-1.24 (m, 14H), 1.23 (s, 4H), 0.97 (s, 3H), 0.70 (s, 3H), 0.40-0.30 (m, 4H).

[0322] Synthesis of 1

[0323] To a solution of 1.4 (700 mg, 1.87 mmol) in anhydrous THF (15 mL) was added CsF (709 mg, 4.67 mmol) at 0 °C. After stirring for 20 min, TMSCF3(663 mg, 4.67 mmol) was added at 0 °C and the mixture was stirred for 1 h. To the mixture was added TBAF∙3H2O (2.36 g, 7.48 mmol) and the mixture was stirred at 50 °C for 1 h. The reaction mixture was poured into ice-water (20 mL) and stirred for 10 min and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel chromatography (PE / EtOAc = 30 / 1 to 5 / 1) to afford 1 (150 mg).

[0324] Compound 1 (150 mg) was further purified by ELSD-HPLC ((column: DuraShell 150*25mm*5um), gradient: 60-90% B (water(10mM NH4HCO3)-MeCN), B= MeCN), flow rate: 25 mL / min) to give 1 (16 mg, 11%).1H NMR (400 MHz, CDCl3) δH 4.10-3.95 (m, 1H), 2.20-2.15 (m, 1H), 2.00-1.75 (m, 5H), 1.75-1.50 (m, 3H), 1.50-1.25 (m, 8H), 1.25-1.00 (m, 12H), 0.96 (s, 3H), 0.83 (s, 1H), 0.67 (s, 3H), 0.45-0.30 (m, 4H).19F NMR (376.5 MHz, CDCl3) δF -72.20. LCMS (Mobile Phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B), using the elution gradient 30%-90% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes at a flow rate of 0.8 mL / min; Column: Xtimate C182.1*30mm,3um; Wavelength: UV 220nm&254nm ; Column temperature: 50 °C; MS ionization: ESI; Detector: PDA&ELSD) MS ionization: ESI for C26H40F3O [M+H-H2O]+calcd.425, found 425, purity 100%.

[0325] Example 2: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (2)

[0326] Synthesis of 2.1

[0327] To a solution of BHT (132 g, 599 mmol) in toluene (1.4 L) under nitrogen at 0 °C was added trimethylaluminum (2 M in toluene, 149 mL, 299 mmol) dropwise and the resulting mixture was stirred at 25 °C for 1 h to generate a solution of MAD. A solution of 1.2 (50 g, 150 mmol) in DCM (500 mL) was added to the MAD solution (0.213 M in toluene) dropwise at -70 °C under N2. After stirring at -70 °C for 1 h, EtMgBr (74.6 mL, 224 mmol, 3M in Et2O) was added dropwise at -70 °C. The resulting solution was stirred at -70°C for 1 h. The reaction mixture was quenched by addition of saturated aqueous citric acid (2 L) at 10 °C and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with saturated aqueous NH4Cl (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified from PE and further purified from MeCN (500 mL) to give 2.1 (32 g, 71%).1H NMR (400 MHz, CDCl3) δH 3.73-3.55 (m, 1H), 3.44-3.30 (m, 1H), 2.1-1.62 (m, 6H), 1.57-1.31 (m, 14H), 1.28-1.04 (m, 11H), 1.03 (d, J = 6.8 Hz, 3H), 0.93 (s, 3H), 0.66 (s, 3H).

[0328] Synthesis of 2.2

[0329] To a solution of 2.1 (8 g, 22 mmol) in DCM (80 mL) at 25 °C was added DMP (18.6 g, 44.0 mmol). After stirring at 25 °C for 30 min, the mixture was quenched with saturated aqueous NaHCO3:Na2S2O3(v:v = 1:1, 80 mL) and the mixture was extracted with DCM (2 x 80 mL). The combined organic layers were washed with saturated aqueous NaHCO3:Na2S2O3(v:v = 1:1, 80 mL) and brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 2.2 (4.3 g, 54.2 %).1H NMR (400 MHz, CDCl3) δH 9.55 (d, J = 3.2 Hz, 1H), 2.42-2.26 (m, 1H), 1.94-1.79 (m, 4H), 1.76-1.48 (m, 8H), 1.47-1.21 (m, 14H), 1.11 (d, J = 6.4 Hz, 3H), 1.09-0.94 (m, 3H), 0.93 (s, 3H), 0.68 (s, 3H).

[0330] Synthesis of 2

[0331] To a solution of 2.2 (5 g, 13.8 mmol) in THF (50 mL) was added CsF (628 mg, 4.14 mmol), and TMSCF3(4.89 g, 34.5 mmol). After stirring at 0 °C under N2for 1 h, TBAF (6.93 g, 22.0 mmol) was added. After stirring at 40 °C for another 2 h, the mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (2 x 50 mL). The layers were separated and the combined organic layer was washed with saturated aqueous NH4Cl (2 x 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~30% EtOAc in PE). The resulting residue was further purified from MeCN (5 mL) to give 2 (172.6 mg, 43.1%).1H NMR (400 MHz, CDCl3) δH4.08-3.99 (m, 1H), 2.21-2.16 (m, 1H), 1.99-1.94 (m, 1H), 1.93-1.63 (m, 5H), 1.63- 1.34 (m, 8H), 1.34-1.18 (m, 7H), 1.18-0.95 (m, 8H), 0.93 (s, 3H), 0.91-0.84 (m, 4H), 0.66(s, 3H). LC-ELSD / MS purity 99%; MS ESI calcd. for C25H40F3O1 [M-H2O+H]+413.3, found 413.3.19F NMR (376.5 MHz, CDCl3) δF-72.207.

[0332] Example 3: Synthesis of (5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-3H- cyclopenta[a]phenanthren-3-one (3)

[0333] Synthesis of 3.1

[0334] To a suspension of Ph3PMeBr (53.5 g, 150 mmol) in anhydrous THF (300 mL) was added t-BuOK (16.8 g, 150 mmol) at 20 °C under N2and the resulting mixture was stirred for 30 min. A solution of 1.2 (20 g, 60.1 mmol) in anhydrous THF (200 mL) was added dropwise. After stirring at 20 °C for 2 h, the mixture was poured into 10% aqueous NH4Cl (600 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 200 mL), and the combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in MeOH (500 mL), and water (500 mL) was added dropwise. A solid appeared which was collected by filtration and dried to give 3.1 (20 g).1H NMR (400 MHz, CDCl3) δH4.60-4.52 (m, 2H), 3.68-3.60 (m, 1H), 3.42-3.30 (m, 1H), 2.51 (t, J = 12Hz, 1H), 2.15-1.73 (m, 7H), 1.65-1.58 (m, 1H), 1.56-1.35 (m, 6H), 1.34-1.15 (m, 6H), 1.14-1.03 (m, 6H), 1.01-0.96 (m, 1H), 0.96 (s, 3H), 0.68 (s, 3H).

[0335] Synthesis of 3.2

[0336] To a solution of 3.1 (20 g, 60.5 mmol) in DCM (600 mL) was added DMP (51.3 g, 121 mmol). After stirring at 20 °C for 30 min, the reaction mixture was quenched by addition of saturated aqueous NaHCO3(600 mL) until the aqueous layer reached a pH of ~9. Saturated aqueous Na2S2O3(600 mL) was added. After stirring at 20 °C for 10 min, the mixture was extracted with DCM (2 x 300 mL) and the combined organic layers were washed with saturated aqueous Na2S2O3(2 x 600 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 3.2 (19 g).1H NMR (400 MHz, CDCl3) δH 9.59-9.55 (m, 1H), 4.62-4.53 (m, 2H), 2.56-2.46 (m, 1H), 2.41-2.29 (m, 1H), 2.18-1.78 (m, 8H), 1.71-1.60 (m, 1H), 1.53-1.37 (m, 5H), 1.36-1.23 (m, 3H), 1.21-1.05 (m, 7H), 1.04-0.95 (m, 1H), 0.94 (s, 3H), 0.71 (s, 3H).

[0337] Synthesis of 3.3

[0338] To a solution of 3.2 (42.3g, 128 mmol) in THF (500 mL) was added TBAF (12.8 ml, 12.8 mmol, 1 M in THF) at 0 °C. After stirring at 0 °C for 10 min, TMSCF3(36.3g, 256 mmol) was added and the mixture was stirred at 25 °C for 1 h. Additional TBAF (40.3g, 128 mmol) was added and the mixture was stirred at 25 °C for 1 h. The mixture was quenched with water (300 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~12% EtOAc in PE) to give 3.3 (26.2g, 51%).1H NMR (400 MHz, CDCl3) δH4.61-4.52 (m, 2H), 4.10-3.99 (m, 1H), 2.50 (t, J = 12Hz, 1H), 2.21-1.58 (m, 9H), 1.56-1.13 (m, 12H), 1.12-0.95 (m, 6H), 0.93 (s, 3H), 0.68 (s, 3H).19F NMR (376.5 MHz, CDCl3) δF -72.191.

[0339] Synthesis of 3.4

[0340] To a solution of 3.3 (5 g, 12.5 mmol) in DCM (50 mL) and MeOH (50 mL) was added NaHCO3(5.25 g, 62.5 mmol). Ozone (1 atm) was passed through the solution at -70 °C. O2was then passed through the solution for 5 min. To the mixture was added Me2S (2.86 g, 46.2 mmol) at -70 °C in portions and the solution was warmed to 20 °C over 1 h and then stirred at 20 °C for 16 h. To the mixture was added 10% aqueous NH4Cl (300 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with 10% aqueous NH4Cl (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated unde reduced pressure. The residue was purified by flash silica gel chromatography (0~5% EtOAc in PE) to give 3.4 (4 g, 80%).1H NMR (400 MHz, CDCl3) δH 4.05 (br s, 1H), 2.78-2.56 (m, 1H), 2.40-2.11 (m, 3H), 2.10-1.75 (m, 7H), 1.72-1.61 (m, 1H), 1.56-1.23 (m, 10H), 1.21-1.06(m, 6H), 1.02 (s, 3H), 0.71 (s, 3H). LC-ELSD / MS purity 100%, MS ESI calcd. for C23H35F3O2[M+H]+401, found 401.

[0341] Synthesis of 3

[0342] To a solution of BHT (1.36 g, 6.19 mmol) in toluene (10 mL) under nitrogen at 0 °C was added AlMe3 (1.54 mL, 3.09 mmol, 2 M in toluene) dropwise and the mixture was stirred at 25 °C for 1 h to generate a solution of MAD. To the MAD solution was added a solution of 3.4 (500 mg, 1.24 mmol) in DCM (10 mL) dropwise at -70 °C. After stirring at - 70 °C for 1 h under N2, MeMgBr (826 µL, 2.48 mmol, 3 M in Et2O) was added dropwise and the resulting solution was stirred for 2 h. The reaction mixture was poured into saturated aqueous citric acid (40 mL) at 10 °C and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc =5 / 1 to 3 / 1) and then further purified from DCM:n-hexane (1:2, 5 mL) at 60 °C for 20 min to give 3 (31.3 mg, 39%).1H NMR (400 MHz, CDCl3) δH4.11-3.96 (m, 1H), 2.16-2.11 (m, 1H), 2.00-1.78 (m, 5H), 1.77-1.68 (m, 1H), 1.66-1.57 (m, 1H), 1.49-1.31 (m, 9H), 1.28-1.20 (m, 7H), 1.14-0.99 (m, 7H), 0.94 (s, 3H), 0.91-0.83 (m, 1H), 0.66 (s, 3H). LC-ELSD / MS purity 100%, MS ESI calcd. for C24H38F3O [M-H2O+H]+399.2, found 399.2.

[0343] Example 4: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-3-ethyl-13-methyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (4)

[0344] Synthesis of 4.2

[0345] To a suspension of 4.1 (100 g, 367 mmol) and Pd / C (10 g, 10% palladium on carbon, 50% water wet) in THF (1000 mL) was added hydrobromic acid (2 mL, 48% in water). The suspension was hydrogenated under 15 psi of hydrogen at 25 °C for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 4.2 (95 g).1H NMR (400MHz, CDCl3) δH2.56 (t, J = 14.4 Hz, 1H), 2.45 (dd, J = 8.4, 19.2 Hz, 1H), 2.33-2.02 (m, 6H), 1.96-1.50 (m, 9H), 1.42-1.14 (m, 6H), 0.89 (s, 3H).

[0346] Synthesis of 4.3

[0347] To a solution of 4.2 (95 g, 346 mmol) in MeOH (1000 mL) was added TsOH (5.95 g, 34.6 mmol) at 20 °C and the resulting mixture was stirred at 60 °C for 3 h. The mixture was quenched with TEA (3.67g) and the mixture was concentrated to a volume of 200 mL. EtOAc (300 mL) and water (300 mL) were added, the layers were separated, and the mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed withwater (2 x 300 mL) and brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4.3 (120 g).

[0348] Synthesis of 4.4

[0349] To a solution of bromo(ethyl)triphenylphosphorane (416 g, 1121 mmol) in THF (1000 mL) was added t-BuOK (125 g, 1121 mmol) at 20 °C. The mixture was warmed to 40 °C and stirred for 30 min under N2. A solution of 4.3 (120 g, 374 mmol) in THF (500 mL) was added, and the internal temperature of the resulting mixture was kept below 40 °C while stirring for 17 h. The mixture was quenched with a solution of NH4Cl (60 g, 10% aq.) and the organic phase was separated and concentrated under reduced pressure to give 4.4, which was then dissolved in MeOH (3000 mL). After stirring at 20 °C for 30 min, the mixture was treated with water (3000 mL) and stirred at 20 °C for 1 h and let stand for 17 h. The residue was collected and re-dissolved in DCM (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4.4 (110 g), which was purified by silica gel chromatography (0~0.5% EtOAc in PE) to give 4.4 (48.5 g, 44.4%).1H NMR (CDCl3400MHz) δH 5.18-5.03 (m, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.44- 2.11 (m, 3H), 1.95-1.59 (m, 11H), 1.55-1.34 (m, 5H), 1.29-1.02 (m, 7H), 0.87 (s, 3H).

[0350] Synthesis of 4.5

[0351] To a solution of 4.4 (47.5 g, 142 mmol) in THF (200 mL) was added aq. HCl (213 mL, 1 M) at 20 °C and the resulting mixture was stirred for 1 h. The mixture was combined with another batch of a reaction mixture obtained using similar conditions (1 g of 4.4 starting material). EtOAc (200 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with water (2 x 300 mL), saturated aqueous NaHCO3(200 mL), and brine (2 x 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4.5 (39.2 g).1H NMR (CDCl3400MHz) δH 5.21-5.02 (m, 1H), 2.69-2.53 (m, 1H), 2.46-1.99 (m, 8H), 1.82- 1.47 (m, 11H), 1.41-1.05 (m, 6H), 0.91 (s, 3H).

[0352] Synthesis of 4.6

[0353] To a solution of 4.5 (40 g, 139 mmol) in MeOH (400 mL) was added NaBH4 (9.45 g, 278 mmol) in portions and the resulting mixture was stirred at 10 °C for 40 min. The mixture was treated with water (500 mL) and DCM (2 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 4.6 (39 g).

[0354] Synthesis of 4.7

[0355] To a solution of 4.6 (39 g, 135 mmol) in DCM (400 mL) was added imidazole (18.3 g, 270 mmol) and TBSCl (30.3 g, 202 mmol) at 10 °C and the resulting mixture was stirred for 12 h. The mixture was treated with water (500 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 100 / 1) to afford 4.7 (45 g, 83%).

[0356] Synthesis of 4.8

[0357] To a solution of 4.7 (45 g, 111 mmol) in THF (400 mL) was added 9-BBN dimer (31.1 g, 127.65 mmol) and the resulting mixture was stirred at 50 °C for 2 h. After cooling to 0 °C, a solution of NaOH (222 mL, 1.11 mol, 5 M in H2O) was added slowly. After the addition, H2O2(125 g, 1.11 mol, 30%) was added slowly and the internal temperature of the reaction mixture was maintained below 15 °C during the course of the addition. The resulting solution was stirred at 10 °C for 2 h. The mixture was treated with water (500 mL), filtered, and the filtrate was extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with saturated aqueous Na2S2O3(2 x 500 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 4.8 (65 g).

[0358] Synthesis of 4.9

[0359] To a solution of 4.8 (65 g, 154 mmol) and silica gel (50 g) in DCM (600 mL) was added PCC (49.4 g, 230 mmol) at 10 °C and the resulting mixture was stirred for 2 h. The mixture was filtered and the filtered cake was washed with DCM (2 x 200 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 50 / 1) to afford 4.9 (25 g, 38%).

[0360] Synthesis of 4.10

[0361] Compound 4.9 (25 g, 59.7 mmol) was dissolved in TBAF (238 mL, 238 mmol, 1 M in THF) at 10 °C and the resulting mixture was stirred at 45 °C for 12 h. The mixture was treated with water (1000 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (2 x 300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to afford 4.10 (13 g, 52%).1H NMR (400 MHz, CDCl3) δH3.65-3.62 (m, 1H), 2.53 (t, J = 8Hz, 1H), 2.18-2.10 (m, 4H), 2.15-2.05 (m, 1H), 2.04-1.96 (m, 1H), 1.80-1.71 (m, 2H), 1.70-1.58 (m, 5H), 1.56-1.46 (m, 5H), 1.45-1.35 (m, 1H), 1.34-1.16 (m, 5H), 1.14-0.96 (m, 3H), 0.60 (s, 3H).

[0362] Synthesis of 4.11

[0363] To a solution of 4.10 (3.5 g, 11.4 mmol) in DCM (50 mL) was added PCC (4.9 g, 22.8 mmol) at 25 °C and the resulting mixture was stirred for 2 h. The solution was filtered, and the filter cake was washed with DCM (2 x 50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (PE / EtOAc = 6 / 1) to afford 4.11 (2.8 g, 77%).1H NMR (400 MHz, CDCl3) δH 2.65-2.50 (m, 2H), 2.25-2.01 (m, 9H), 1.80-1.55 (m, 7H), 1.54-1.44 (m, 3H), 1.43-1.20 (m, 6H), 0.65 (s, 3H).

[0364] Synthesis of 4.12

[0365] To a solution of BHT (72.7 g, 329 mmol) in toluene (200 mL) under N2 at 0 °C was added trimethylaluminum (82.0 mL, 2 M in toluene, 164 mmol) dropwise and the resulting mixture was stirred at 25 °C for 1 h to generate a solution of MAD. To the MAD (78.8 g in toluene, 165 mmol) solution was added a solution of 4.11 (10 g, 33.0 mmol) in DCM (200 mL) dropwise at -70 °C and the resulting solution was stirred at -70 °C for 1 h under N2. EtMgBr (33 mL, 3M in ethyl ether, 99 mmol) was added dropwise at -70 °C and the mixture was stirred for 2 h. The reaction mixture was poured into citric acid (500 mL, sat. aq.) at 10 °C and extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (5~10% EtOAc in PE) to give 4.12 (9.0 g). 4.12 (9.0 g, 27.0 mmol) was further purified by flash silica gel chromatography (10~30% EtOAc in PE) to afford 4.12 (5.54 g, 61.7%).1H NMR (400 MHz, CDCl3) δH2.57-2.51 (m, 1H), 2.25-2.09 (m, 4H), 2.06-1.97 (m, 1H), 1.85-1.55 (m, 10H), 1.52-0.99 (m, 14H), 0.90-0.86 (t, J = 7.4 Hz, 3H), 0.68-0.57 (m, 3H).

[0366] Synthesis of 4.13

[0367] To a solution of MePPh3Br (17.6 g, 49.5 mmol) in THF (30 mL) was added t-BuOK (5.55 g, 49.5 mmol) at 25 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.4.12 (5.5 g, 16.5 mmol) in THF (20 mL) was added in portions to keep the internal temperature of the mixture below 50 °C during the course of the addition. After stirring at 50 °C for 2 h, the reaction mixture was poured into water (300 mL) at 25 °C and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with water (300 mL) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~10% EtOAc in PE) to give 4.13 (6.0 g, 60%).1H NMR(400 MHz, CDCl3) δH 4.84 (s, 1H), 4.70 (s, 1H), 2.07- 2.00 (m, 1H), 1.86-1.79 (m, 2H), 1.77-1.73 (m, 5H), 1.71-1.64 (m, 3H), 1.64-1.56 (m, 4H),1.48-1.42 (m, 3H), 1.37-1.31 (m, 3H), 1.27-1.24 (m, 2H), 1.20-1.14 (m, 2H), 1.10-0.97 (m, 3H), 0.91-0.84 (m, 5H), 0.57 (s, 3H).

[0368] Synthesis of 4.14

[0369] To a solution of 14.13 (6.0 g, 18.1 mmol) in THF (100 mL) was added 9-BBN dimer (8.76 g, 36.2 mmol) and the resulting mixture was stirred at 50 °C under N2 for 2 h. The mixture was cooled to 0 °C and EtOH (10.3 mL, 181 mmol) and NaOH (54.2 mL, 5 M, 271 mmol) were added. H2O2(27.1 mL, 10 M, 271 mmol) was added dropwise at 15 °C. After stirring at 50 °C for 2 h, the mixture was cooled, poured into saturated aqueous Na2S2O3(500 mL), stirred for 30 min, then extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 4.14 (3.0 g). 4.14 (50 mg, 0.1434 mmol) was purified from MeCN (5 mL) at 25 °C to give 4.14 (29.9 mg, 59.9%).1H NMR (400 MHz, CDCl3) δH 3.71-3.58 (m, 1H), 3.37-3.34 (m, 1H), 1.96 (td, J = 3.2, 12.4 Hz, 1H), 1.84-1.71 (m, 4H), 1.61-1.57 (m, 6H), 1.50-1.43 (m, 2H), 1.40-1.24 (m, 8H), 1.23-1.15 (m, 3H), 1.11- 0.98 (m, 8H), 0.88 (t, J = 7.4 Hz, 3H), 0.68 (s, 3H). LC-ELSD / MS: purity>99%, MS ESI calcd. for C23H39O [M-H2O+H]+331.3, found 331.3.

[0370] Synthesis of 4.15

[0371] To a solution of 4.14 (1.0 g, 2.86 mmol) in DCM (10 mL) was added DMP (2.42 g, 5.72 mmol) dropwise and the resulting mixture was stirred at 15 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO3(30 mL) and saturated aqueous Na2SO4(30 mL), then extracted with DCM (3 x 15 mL). The combined organic layers were washed with saturated aqueous Na2S2O3(2 x 10 mL) and brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified from PE (20 mL) at 15 °C to give 4.15 (1.1 g, 87%).1H NMR (400 MHz, CDCl3) δH9.56-9.55 (d, J = 3.2 Hz, 1H), 2.36-2.33 (m, 1H), 1.94-1.78 (m, 5H), 1.76-1.72 (m, 2H), 1.70-1.55 (m, 8H), 1.45-1.30 (m, 8H), 1.12-1.10 (d, J = 5.2 Hz, 6H), 0.92-0.84 (m, 4H), 0.73-0.69 (m, 3H).

[0372] Synthesis of 4

[0373] To a solution of 4.15 (1.0 g, 2.88 mmol) in THF (10 mL) was added CsF (874 mg, 5.76 mmol) at 10 °C under N2. TMSCF3(1.22 g, 8.63 mmol) was added dropwise at 10 °C and the mixture was stirred for 1 h. TBAF (2.25 g, 8.63 mmol) was added dropwise at 10 °C and stirred for 2 h. The mixture was poured into water (10 mL), stirred for 20 min, and then extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 4 (130 mg, 10.9%).1H NMR (400 MHz, CDCl3) δH4.08-3.97 (m, 1H), 2.14-2.12 (d, J = 6.4 Hz, 1H), 1.96-1.95(m, 1H), 1.92-1.68 (m, 5H), 1.67-1.57 (m, 4H), 1.54 (s, 3H), 1.49-1.42 (m, 3H), 1.34-1.20 (m, 7H), 1.15-0.98 (m, 8H), 0.88-0.86 (t, J = 7.8 Hz, 3H), 0.67 (s, 3H).19F NMR (376.5 MHz, CDCl3) δF -72.207. LC-ELSD / MS: purity>99%, MS ESI calcd. for C24H37F3O [M- H2O+H]+399.2, found 399.2.

[0374] Example 5: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (5)

[0375] To a suspension of 3.4 (300 mg, 0.7490 mmol) in anhydrous THF (10 mL) under N2 was slowly added (tBuO)3AlLiH (378 mg, 1.49 mmol) at 0 °C and the resulting mixture was stirred under N2for 2 h. The mixture was poured into 10% aqueous NH4Cl (20 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) twice to afford 5 (11.8 mg, 11.8 %).1H NMR (400 MHz, CDCl3) δH 4.08-3.98 (m, 1H), 3.70-3.55 (m, 1H), 2.12 (d, J = 6.0 Hz, 1H), 2.02-1.94 (m, 1H), 1.94-1.57 (m, 7H), 1.52-1.21 (m, 13H), 1.18-1.04 (m, 6H), 1.03-0.94 (m, 1H), 0.92 (s, 3H), 0.67 (s, 3H). LC- ELSD / MS purity 99%, MS ESI calcd. For C23H38F3O2[M-H2O+H]+385, found 385.

[0376] Example 6: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-(methoxymethyl)- 10,13-dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (6)

[0377] Synthesis of 6.1

[0378] To a solution of Me3SI (607 mg, 2.98 mmol) in THF (10 mL) and DMSO (5 mL) was added NaH (119 mg, 60%, 2.98 mmol) at 0 °C in portions under N2, followed by addition of a solution of 3.4 (1 g, 2.49 mmol) in DMSO (5 mL). The reaction mixture was poured into ice-water (w / w = 1 / 1, 500 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 6.1 (1 g, 97.0 %).1H NMR (400 MHz, CDCl3) δH4.09-3.97 (m, 1H), 2.62 (s, 1H), 2.58 (s, 1H), 2.42-2.31 (m, 1H), 2.03-1.49 (m, 14H), 1.32 (s, 7H), 1.10 (br d, J = 1.8 Hz, 6H), 0.99 (d, J = 8.0 Hz, 3H), 0.68 (d, J = 2.5 Hz, 3H).19F NMR (376.5 MHz, CDCl3) δF -72.175.

[0379] Synthesis of 6

[0380] To a mixture of sodium methoxide (777 mg, 14.4 mmol) in MeOH (20 mL) was slowly added 6.1 (1 g, 2.41 mmol) and the resulting mixture was stirred at 75 °C for 36 h. The reaction mixture was poured into ice-water (w / w = 1 / 1, 30 mL) and stirred for 20 min. The mixture was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 4 / 1). The resulting residue was further purified from DCM:n-hexane (2:1, 4 ml) at 60 °C for 20 min to give 6 (39.5 mg, 39.5%).1H NMR (400 MHz, CDCl3) δH 4.09-3.97 (m, 1H), 3.45-3.30 (m, 5H), 2.56 (s, 1H), 2.23-2.15 (m, 1H), 2.01-1.76 (m, 5H), 1.71 (td, J = 3.2, 14.4 Hz, 1H), 1.63 (dd, J= 4.8, 8.4 Hz, 1H), 1.55-1.19 (m, 13H), 1.18-1.04 (m, 6H), 1.02-0.95 (m, 1H), 0.93 (s, 3H), 0.66 (s, 3H). LC-ELSD / MS purity 100%, MS ESI calcd. for C24H36F3O [M-CH3OH- H2O+H]+397.3, found 397.3.

[0381] Example 7: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0382] A solution of MeMgBr (2.2 mL, 6.63 mmol, 3 M in Et2O) in THF (2 mL) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into saturated aqueous NH4Cl (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 7 (50 mg).1H NMR (400 MHz, CDCl3) δH 4.00-3.80 (m, 1H), 2.00-1.70 (m, 6H), 1.69-1.25 (m, 12H), 1.24-1.01 (m, 11H), 1.00-0.78 (m, 11H), 0.66 (s, 3H). LC-ELSD / MS purity >99%, MS ESI calcd. for C25H41[M-2H2O+H] 341, found 341.

[0383] Example 8: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)-3- hydroxypentan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0384] A solution of EtMgBr (2.2 mL, 6.63 mmol, 3 M in Et2O) in THF (2 mL) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into saturated aqueous NH4Cl (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 8 (57.5 mg, 5.79 %).1H NMR (400 MHz, CDCl3) δH3.68- 3.48 (m, 1H), 2.00-1.80 (m, 3H), 1.77-1.50 (m, 5H), 1.49-1.33 (m, 9H), 1.32-1.02 (m, 10H), 1.01-0.85 (m, 6H), 0.84-0.73 (m, 9H), 0.66 (s, 3H). LC-ELSD / MS purity >99%, MS ESI calcd. for C26H43[M-2H2O+H]+355.4, found 355.4.

[0385] Example 9: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)-3- hydroxy-5-methylhexan-2-yl)-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (9)

[0386] A solution of i-BuMgBr (3.31 mL, 2.0 M in THF, 6.63 mmol) in THF (2 mL) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into saturated aqueous NH4Cl (10 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 9 (60 mg, 6.5%).1H NMR (400 MHz, CDCl3) δH3.85-3.65 (m, 1H), 2.05-1.85 (m, 2H), 1.77-1.50 (m, 5H), 1.49-1.28 (m, 13H), 1.27-1.18 (m, 12H), 1.17-1.01 (m, 13H), 0.74-0.60 (m, 4H). LC-ELSD / MS purity >99%, MS ESI calcd. for C28H47 [M-2H2O+H]+383, found 383.

[0387] Example 10: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1R,2S)-1- cyclopropyl-1-hydroxypropan-2-yl)-3-ethyl-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (10)

[0388] Synthesis of 10.1

[0389] A solution of cyclopropylmagnesium bromide (22.0 mL, 11 mmol, 0.5 M in THF) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 0.5 h. The mixture was poured into saturated aqueous NH4Cl (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~35% EtOAc in PE) to give 10.1 (500 mg, 56.2%).1H NMR (400 MHz, CDCl3) δH2.83-2.70 (m, 1H), 2.02-1.78 (m, 4H), 1.69-1.52 (m, 4H), 1.50-1.33 (m, 9H), 1.30- 1.15 (m, 7H), 1.14-1.00 (m, 8H), 0.87 (s, 3H), 0.86-0.73(m, 3H), 0.66 (s, 3H), 0.63-0.55 (m, 2H), 0.45-0.14 (m, 1H), 0.13-0.06 (m, 1H).

[0390] Synthesis of 10.2

[0391] To a solution of 10.1 (400 mg, 0.993 mmol) in DCM (5 mL) was added DMP (839 mg, 1.98 mmol) and the resulting mixture was stirred at 25 °C for 30 min. The mixture was quenched with saturated aqueous NaHCO3:Na2S2O3(v:v = 1:1, 12 mL) and the mixture was extracted with DCM (2 x 12 mL). The combined organic layers were washed with saturated aqueous NaHCO3:Na2S2O3(v:v = 1:1, 12 mL) and brine (12 mL), dried over anhydrousNa2SO4, filtered, and concentrated to give 10.2 (450 mg).1H NMR (400 MHz, CDCl3) δH2.64-2.53 (m, 1H), 2.00-1.77 (m, 5H), 1.74-1.52 (m, 7H), 1.48-1.24 (m, 10H), 1.17 (d, J = 6.8 Hz, 3H), 1.15-0.94 (m, 7H), 0.93 (s, 3H), 0.89-0.81 (m, 5H), 0.68 (s, 3H).

[0392] Synthesis of 10

[0393] To a solution of 10.2 (450 mg, 1.12 mmol) in THF (5 mL) was added LiAlH4 (127 mg, 3.36 mmol) at 0 °C under N2 and the resulting mixture was stirred for 30 min. The mixture was poured into water (8 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3 x 8 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 10 (40 mg).10 (40 mg, 0.099 mmol) was dried in an oven at 80 °C to afford 10 (38.2 mg, 95.7 %).1H NMR (400 MHz, CDCl3) δH3.00-2.95 (m, 1H), 2.02-1.86 (m, 1H), 1.85-1.76 (m, 2H), 1.75-1.65 (m, 3H), 1.64-1.52 (m, 2H), 1.50-1.33 (m, 9H), 1.30-1.15 (m, 6H), 1.14-1.00 (m, 7H), 0.87-73(m, 8H), 0.66 (s, 3H), 0.63-0.55 (m, 1H), 0.53-0.46 (m, 1H), 0.45-0.14 (m, 1H), 0.13-0.06 (m, 1H). LC-ELSD / MS purity >99%, MS ESI calcd. for C27H43 [M-2H2O+H]+367, found 367.

[0394] Example 11: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)- 3-hydroxyheptan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3- ol (11)

[0395] A solution of 2.2 (1 g, 2.77 mmol) in THF (10 mL) was reacted with a solution of n- BuMgBr (6.47 mL, 16.2 mmol, 2.5 M in hexanes) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into H2O (30 mL) and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE), further purified by flash silica gel chromatography (0~20% EtOAc in PE), and dried in an oven at 80 °C to give 11 (93.6 mg, 93.6%).1H NMR (400 MHz, CDCl3) δH3.70-3.57 (m, 1H), 2.15-1.76 (m, 4H), 1.75-1.50 (m, 5H), 1.49-1.28(m, 10H), 1.27-1.18 (m, 9H), 1.17-1.05 (m, 5H), 1.04-0.95 (m, 5H), 0.94-0.75 (m, 8H), 0.66 (s, 3H). LC-ELSD / MS purity >99%, MS ESI calcd. for C28H47 [M-2H2O+H] 383, found 383.

[0396] Example 12: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)- 3-hydroxy-6-methylheptan-2-yl)-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (12)

[0397] A solution of 2.2 (1 g, 2.77 mmol) in THF (10 mL) was reacted with isoamylmagnesium bromide (4.15 mL, 8.30 mmol, 2 M in Et2O) at 0 °C under N2and the resulting mixture was stirred for 30 min. The mixture was poured into water (10 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3 x 10 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 12 (12.2 mg, 1.02 %).1H NMR (400 MHz, CDCl3) δH3.70-3.57 (m, 1H), 2.20-1.76 (m, 4H), 1.75- 1.50 (m, 9H), 1.49-1.28 (m, 9H), 1.27-1.03 (m, 10H), 1.02-0.95 (m, 7H), 0.94-0.78 (m, 9H), 0.66 (s, 3H). LC-ELSD / MS purity >99%, MS ESI calcd. for C29H49 [M-2H2O+H]+397, found 397.

[0398] Example 13: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (13)

[0399] To a solution of 3.4 (400 mg, 0.9986 mmol) in THF (10 mL) was added CsF (302 mg, 1.99 mmol) at 10 °C under N2, followed by addition of TMSCF3(425 mg, 2.99 mmol)dropwise at 10 °C. After stirring at 10 °C for 1 h, TBAF (781 mg, 2.99 mmol, 1 M in THF) was added dropwise at 20 °C. After stirring at 20 °C for 2 h, the mixture was poured into water (10 mL) and stirred for 20 min. The mixture was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 13 (120 mg), which was purified by HPLC (column: C18 (250mm*50mm, 5um), gradient: 65-95% B (B=water (0.05%HCl)-MeCN), flow rate: 30mL / min) to give 13 (19 mg, 15.9%).1H NMR (400 MHz, CDCl3) δH4.15-3.93 (m, 1H), 2.22-2.12 (m, 1H), 2.04-1.63 (m, 7H), 1.55-1.19 (m, 15H), 1.17-1.04 (m, 6H), 0.96 (s, 3H), 0.68 (s, 3H).19F NMR (376.5 MHz, CDCl3) δF -72.208, -78.789.

[0400] Example 14: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-13-ethyl-3,10- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (14)

[0401] Synthesis of 14.2

[0402] To a solution of compound 14.1 (5.0 g, 15.9 mmol) in 3-picoline (50 mL) was added 5% Pd / C (0.5 g). The flask was evacuated and flushed with hydrogen and the reaction was stirred at 30 °C for 15 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in PE) to give 14.2 (3.2 g, 64 %).1H NMR: (400 MHz, CDCl3) δH2.69 (t, J = 13.6 Hz, 1H), 2.55 (t, J = 8.8 Hz, 1H), 2.34 (dt, J1=13.6, J2= 4.8 Hz, 1H), 2.25-2.00 (m, 8H), 1.95-1.80 (m, 2H), 1.75-1.63 (m, 2H), 1.58-1.63 (m, 7H), 1.28-1.08 (m, 4H), 1.02 (s, 3H), 0.63 (s, 3H).

[0403] Synthesis of 14.3

[0404] To a solution of 14.2 (2 g, 6.31 mmol) in THF (20 mL) was added LiAlH(OtBu)3(1.76, 6.94 mmol) at -40 °C under N2 and stirred for 1 h. The mixture was poured into water (200 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 300 mL), and the combined organic layers were washed with saturated aqueous citric acid (300 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE) to give 14.3 (2.3 g).1H NMR (400 MHz, CDCl3) δH3.71-3.55 (m, 1H), 2.14-2.11 (m, 1H), 2.07-1.99 (m, 1H), 1.90-1.74 (m, 4H), 1.72-1.58 (m, 1H), 1.49-1.39 (m, 2H), 1.30-1.21 (m, 13H), 1.04-0.99 (m, 5H), 0.92 (s, 1H), 0.63 (d, J = 2.4 Hz, 2H), 0.61-0.58 (m, 3H).

[0405] Synthesis of 14.4

[0406] To a solution of 14.3 (5.2 g, 16.3 mmol) in DCM (20 mL) was added TBSCl (3.67 g, 24.4 mmol) and imidazole (2.21 mg, 32.6 mmol) at 20 °C under N2 and the resulting mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with H2O (20 mL) and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 14.4 (7.0 g, 99%).1H NMR (400 MHz, CDCl3) δH3.64-3.56 (m, 1H), 2.52 (br t, J = 8.8 Hz, 1H), 2.15 (br d, J = 11.2 Hz, 1H), 2.11 (s, 3H), 2.03-1.95 (m, 1H), 1.87-1.73 (m, 3H), 1.69-1.63 (m, 2H), 1.49-1.34 (m, 9H), 1.27-1.13 (m, 6H), 0.90-0.89 (m, 12H), 0.58 (s, 3H), 0.06 (s, 6H).

[0407] Synthesis of 14.5

[0408] To a solution of (R)-CBS (892 mg, 3.22 mmol) in toluene (50 mL) was added a solution of BH3∙SMe2(3.22 mL, 32.2 mmol) and the resulting mixture was stirred at 0°C for 30 min under N2. To the mixture was added a solution of 14.4 (7 g, 16.1 mmol) in toluene (50 mL) dropwise at 0 °C and the mixture was stirred for 1 h. The mixture was quenched with the dropwise addition of MeOH (20 mL) and concentrated. The product was purified by silica gel chromatography (2~7% EtOAc in PE) to give 14.5 (4.02 g, 57.5%).1H NMR (400 MHz, CDCl3) δH 3.69 (qd, J = 6.0, 12.8 Hz, 1H), 3.62-3.50 (m, 1H), 1.95-1.70 (m, 5H), 1.68-1.29 (m, 12H), 1.23-1.06 (m, 10H), 0.92-0.86 (m, 12H), 0.63 (s, 3H), 0.09-0.01 (m, 6H).

[0409] Synthesis of 14.6

[0410] To a solution of 14.5 (2 g, 4.60 mmol) in cyclohexane (200 mL) was added CaCO3(1.37 g, 13.7 mmol), PhI(OAc)2(4.41 g, 13.7 mmol), and I2 (1.37 g, 9.20 mmol) at 25 °C under N2. The mixture was heated to reflux (80 °C) by irradiating with an infrared lamp (250 W) for 30 min. The mixture was quenched with saturated aqueous Na2S2O3(200 mL), and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 14.6 (3 g).

[0411] Synthesis of 14.7

[0412] To a solution of MePh3PBr (6.53 g, 18.3 mmol) in THF (30 mL) was added t-BuOK (2.05 g, 18.3 mmol) at 25 °C. The temperature was increased to 50 °C and the mixture wasstirred for 1 h. A solution of 14.6 (3.0 g, 6.11 mmol) in THF (10 mL) was added to the reaction mixture at 50 °C and stirred for 16 h. The mixture was poured into saturated aqueous NH4Cl (100 mL) and the aqueous layer extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was combined with another batch of a reaction mixture obtained using similar conditions (3 g of 14.6 starting material). The residue was purified by silica gel chromatography (0~25% EtOAc in PE) to give 14.7 (6 g).1H NMR (400 MHz, CDCl3) δH5.79-5.72 (dd, J = 11.2, 17.7 Hz, 1H), 5.30-5.27 (dd, J = 1.4, 11.3 Hz, 1H), 5.16-5.11 (dd, J = 1.6, 18.0 Hz, 1H), 3.91-3.77 (m, 1H), 3.64-3.49 (m, 1H), 2.36-2.32 (td, J = 3.2, 13.1 Hz, 1H), 1.88-1.66 (m, 7H), 1.57 (s, 3H), 1.49-1.26 (m, 10H), 1.12 -1.10 (d, J = 6.4 Hz, 5H), 0.97-0.86 (m, 10H), 0.81 (s, 3H), 0.05 (s, 6H).

[0413] Synthesis of 14.8

[0414] To a solution of 14.7 (3.5 g, 7.83 mmol) in THF (50 mL) was added Pd / C (500 mg, 10% palladium on carbon, 50% water wet) and the solution was hydrogenated under 15 psi of hydrogen at 20 °C for 16 h. The mixture was filtered through a pad of Celite, and the filter cake was washed with THF (3 x 50 mL). The filtrate was concentrated under reduced pressure to give 14.8 (3.5 g).1H NMR (400 MHz, CDCl3) δH3.82 (s, 1H), 3.63-3.52 (m, 1H), 2.11 (d, J = 12.4 Hz, 1H), 1.91-1.72 (m, 7H), 1.62-1.53 (m, 5H), 1.48-1.31 (m, 8H), 1.28-1.21 (m, 6H), 1.14-1.07 (m, 2H), 0.89 (s, 12H), 0.86-0.81 (m, 3H), 0.06 (s, 6H).

[0415] Synthesis of 14.9

[0416] To a solution of 14.8 (300 mg, 0.672 mmol) in THF (10 mL) was added TBAF∙3H2O (634 mg, 2.01 mmol) in one portion at 20 °C and the resulting mixture was stirred for 17 h. The mixture was poured into water (50 mL) and DCM (100 mL), and the layers were separated. The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified from methanol (100 mL) at 20 °C to give 14.9 (190 mg, 85%).

[0417] Synthesis of 14.10

[0418] To a solution of 14.9 (3.5 g, 10.4 mmol) in DCM (50 mL) was added DMP (13.2 g, 31.2 mmol) and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO3(100 mL) and saturated aqueous Na2S2O3(100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with saturated aqueous Na2S2O3(2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 14.10, which was purified by flash silica gel chromatography (0~30% EtOAc in PE) to give 14.10 (1.9 g, 55.3%).1H NMR(400 MHz, CDCl3) δH2.75-2.63 (m, 1H), 2.48 (t, J = 8.8 Hz, 1H), 2.40-2.23 (m, 3H), 2.21 (s, 4H), 2.09-2.00 (m, 2H), 1.93-1.80 (m, 2H), 1.70-1.47 (m, 7H), 1.43-1.20 (m, 8H), 1.01 (s, 3H), 0.65 (t, J = 7.2 Hz, 3H).

[0419] Synthesis of 14.11

[0420] To a MAD (6.53 g, 13.6 mmol) solution was added a solution of 14.10 (1.8 g, 5.44 mmol) in DCM (20 mL) dropwise slowly at -70 °C under N2. After stirring at -70 °C for 1 h under N2, MeMgBr (3.6 mL, 10.8 mmol) was added dropwise slowly. After stirring for 2 h, the reaction mixture was poured slowly into saturated aqueous citric acid (100 mL) at 10 °C and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~30% EtOAc in PE) to give 14.11 (1.1 g, 58.5%).1H NMR (400 MHz, CDCl3) δH2.45 (t, J = 8.8 Hz, 1H), 2.35-2.25 (m, 1H), 2.24-2.16 (m, 4H), 2.03-1.79 (m, 2H), 1.74 (td, J = 3.2, 14.4 Hz, 1H), 1.66-1.59 (m, 3H), 1.56-1.35 (m, 8H), 1.32-1.21 (m, 9H), 1.10-1.00 (m, 3H), 0.93 (s, 3H), 0.62 (t, J = 7.5 Hz, 3H). LC-ELSD / MS purity > 99%, MS ESI calcd. for C23H37O [M-H2O+H]+329.3, found 329.3.

[0421] Synthesis of 14.12

[0422] To a solution of MePh3PBr (1.53 g, 4.31 mmol) in THF (10 mL) was added t-BuOK (482 mg, 4.31 mmol) at 25 °C. The temperature was increased to 50 °C and the mixture was stirred for 1 h. A solution of 14.11 (0.5 g, 1.44 mmol) in THF (10 mL) was added to the reaction mixture at 50 °C and the mixture was stirred for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was combined with another batch of a reaction mixture obtained using similar conditions (1.53 g of 14.11 starting material). The residue was purified by flash silica gel chromatography (10~20% EtOAc in PE) to give 14.12 (890 mg).1H NMR (400 MHz, CDCl3) δH4.80 (s, 1H), 4.77 (s, 1H), 2.22 (dd, J = 3.2, 9.2 Hz, 1H), 2.01-1.92 (m, 2H), 1.90-1.86 (m, 1H), 1.81 (s, 3H), 1.74 (td, J = 3.6, 14.2 Hz, 1H), 1.67- 1.60 (m, 2H), 1.56 (s, 3H), 1.43 (s, 3H), 1.38-1.35 (m, 1H), 1.26 (s, 4H), 1.23-1.12 (m, 5H), 1.06-0.99 (m, 3H), 0.93 (s, 3H), 0.90-0.82 (m, 3H), 0.74 (t, J = 7.2 Hz, 3H). LC-ELSD / MS purity >99%, MS ESI calcd. for C24H39[M-H2O+H]+327.3 found 327.3.

[0423] Synthesis of 14.13

[0424] To a solution of 14.12 (0.85 g, 2.46 mmol) in THF (20 mL) was added 9-BBN dimer (1.19 g, 4.92 mmol) in portions slowly under N2. The reaction mixture was stirred at 50°C under N2for 2 h. After cooling to 0 °C, the reaction mixture was quenched with EtOH (1.41 mL, 24.6 mmol) and NaOH (7.38 mL, 36.9 mmol, 5 M in H2O) dropwise slowly under N2, followed by addition of H2O2(3.69 mL, 36.9 mmol, 10 M in H2O) dropwise slowly under N2at 15 °C. The mixture was stirred at 50 °C for 2 h, cooled, and poured into saturated aqueous Na2S2O3(100 mL) slowly and stirred for 30 min. The aqueous phase was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 14.13 (690 mg, 77.4%).1H NMR (400 MHz, CDCl3) δH 3.68-3.60 (m, 1H), 3.42-3.31 (m, 1H), 2.25 (br d, J = 12.5 Hz, 1H), 2.01-1.62 (m, 6H), 1.56-1.48 (m, 3H), 1.45-1.34 (m, 7H), 1.33-1.14 (m, 9H), 1.10 (br d, J = 6.5 Hz, 8H), 0.96-0.87 (m, 6H). LC-ELSD / MS purity>99%, MS ESI calcd. for C24H41O [M-H2O+H]+345.3, found 345.3.

[0425] Synthesis of 14.14

[0426] To a solution of 14.13 (580 mg, 1.59 mmol) in DCM (5 mL) was added DMP (1.34 g, 3.18 mmol) and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO3(100 mL) and saturated aqueous Na2S2O3(100 mL). The aqueous layer was extracted with DCM (2 x 100 mL) and the combined organic layers were washed with saturated aqueous Na2S2O3(2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 14.14, which was purified from PE (50 mL) at 25 °C to give 14.14 (650 mg).1H NMR (400 MHz, CDCl3) δH9.47 (d, J = 4.0 Hz, 1H), 2.42 (ddd, J = 4.0, 6.6, 10.4 Hz, 1H), 2.22 (dd, J = 3.2, 9.2 Hz, 1H), 2.03-1.68 (m, 6H), 1.63-1.53 (m, 5H), 1.43-1.40 (m, 3H), 1.26 (s, 5H), 1.20- 1.15 (m, 4H), 1.07 (dd, J = 3.6, 14.8 Hz, 7H), 0.95-0.86 (m, 7H).

[0427] Synthesis of 14

[0428] To a solution of 14.14 (650 mg, 1.80 mmol) in THF (10 mL) was added CsF (546 mg, 3.60 mmol) at 10 °C under N2. TMSCF3(767 mg, 5.40 mmol) was added dropwise at 10 °C and the mixture was stirred for 1 h. TBAF (1.41 g, 8.63 mmol, 1 M in THF) was added dropwise at 20 °C and the mixture was stirred at 10 °C for 2 h. The mixture was poured into water (10 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 20 mL), and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 14 (105 mg, 13.5%).1H NMR (400 MHz, CDCl3) δH4.13-4.05 (m, 1H), 2.28-2.19 (m, 2H), 2.06-1.69 (m, 5H), 1.58 (s, 7H), 1.46-1.34 (m, 9H), 1.25 (s, 4H), 1.17-1.02 (m, 9H), 0.92-0.82 (m, 4H).19F NMR (376.5 MHz, CDCl3) δF -72.256. LC-ELSD / MS purity >99%, MS ESI calcd. for C25H40F3O [M- H2O+H]+413.3, found 413.3.

[0429] Example 15: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-(hydroxymethyl)- 10,13-dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (15)

[0430] Synthesis of 15.1

[0431] Sodium metal (441 mg, 19.2 mmol) was slowly added to anhydrous BnOH (5 ml) in portions and the resulting mixture was stirred at 80 °C for 4 h. A solution of 6.1 (400 mg, 0.9648 mmol) was added in portions and the mixture was stirred at 80 °C under N2 for 16 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. BnOH was removed by reduced pressure distillation. The residue was purified by silica gel chromatography (PE / EtOAc = 50 / 1 to 5 / 1). The resulting residue was further purified by SFC (column: C18 (250mm*50mm, 5um), gradient: 65-95% B (B=water (0.05%HCl)-ACN), flow rate: 30mL / min) to give 15.1 (40 mg, 15.0%).1H NMR (400 MHz, CDCl3) δH 7.43-7.28 (m, 5H), 4.56 (s, 2H), 4.12-3.96 (m, 1H), 3.56-3.39 (m, 2H), 2.63 (s, 1H), 2.10-1.98 (m, 1H), 2.01-1.76 (m, 5H), 1.70-1.59 (m, 3H), 1.53-1.19 (m, 12H), 1.15-1.03 (m, 6H), 0.94-0.85 (m, 4H), 0.66 (s, 3H).

[0432] Synthesis of 15

[0433] To a solution of 15.1 (20 mg, 0.07652 mmol) in MeOH (3 mL) was added Pd / C (dry, 10%, 20 mg) under N2. The suspension was degassed under vacuum and purged with H2three times. After stirring at 25 °C under H2(15 psi) for 24 h, the reaction mixture wasfiltered through a pad of Celite, washed with EtOAc (3 x 10 mL) and the filtrate concentrated. The residue was purified by silica gel chromatography (10~20% EtOAc in PE) to afford 15 (29 mg, 87.6%).1H NMR (400 MHz, CDCl3) δH 4.12-3.94 (m, 1H), 3.66-3.56 (m, 2H), 2.23-2.19 (m, 1H), 1.98-1.68 (m, 8H), 1.52-1.33 (m, 9H), 1.28-0.89 (m, 15H), 0.67 (s, 3H).LC-ELSD / MS purity 99%, MS ESI calcd. for C24H35F3O [M+H-2H2O]+ 397.3, found 397.3.19F NMR (376.5 MHz, CDCl3) δF -72.207.

[0434] Example 16: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-isopropyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (16)

[0435] Synthesis of 16.1

[0436] A solution of isopropenylmagnesium bromide (90.0 mL, 45.0 mmol, 0.5 M in THF) was reacted with 1.2 (5 g, 15.0 mmol) at 0 °C under N2 and the resulting solution was stirred at 50 °C for 2 h. The mixture was slowly poured into ice-water (20 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, andconcentrated to give 16.1a (1.2 g, 21.3%) and 16.1 (800 mg, 14.2%).1H NMR (400 MHz, CDCl3) δH 5.01 (d, J = 4.8 Hz, 2H), 3.64 (d, J = 10.4 Hz, 1H), 3.36 (br s, 1H), 2.05-1.93 (m, 2H), 1.92-1.73 (m, 6H), 1.71-1.58 (m, 3H), 1.55-1.49 (m, 2H), 1.48-1.12 (m, 13H), 1.10-0.97 (m, 6H), 0.95-0.86 (m, 3H), 0.71-0.62 (m, 3H).

[0437] Synthesis of 16.2

[0438] To a solution of 16.1 (800 mg, 0.7474 mmol) in THF (5 mL) was added 10% Pd / C (0.8 g, dry). The suspension was degassed under vacuum and purged with H2three times. After stirring under H2(15 psi) at 15 °C for 16 h, the reaction mixture was filtered through a pad of Celite and washed with MeOH (3 x 20 mL). The filtrate was concentrated to give 16.2 (650 mg).1H NMR (400 MHz, CDCl3) δH3.64 (dd, J = 3.2, 10.4 Hz, 1H), 3.35 (dd, J = 7.2, 10.6 Hz, 1H), 2.11-1.93 (m, 2H), 1.88-1.74 (m, 3H), 1.71-1.63 (m, 2H), 1.56 (s, 6H), 1.50- 1.32 (m, 7H), 1.29-1.13 (m, 7H), 1.09-1.01 (m, 6H), 0.93 (s, 2H), 0.88 (d, J = 6.8 Hz, 4H), 0.66 (s, 3H).

[0439] Synthesis of 16.3

[0440] To a suspension of 16.2 (450 mg, 0.398 mmol) in anhydrous DCM (5 mL) was added DMP (337 mg, 0.7964 mmol) at 20 °C under N2 and the resulting mixture was stirred for 30 min. The mixture was poured into a mixture of10% aqueous NaHCO3(20 mL) and saturated aqueous Na2S2O3(20 mL), stirred for 10 min, and extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), filtered, and concentrated to give 16.3 (300 mg). The residue was purified by silica gel chromatography (PE / EtOAc =2 / 1 to 1 / 2) to give 16.3 (300 mg, 67.1 %).1H NMR (400 MHz, CDCl3) δH9.56 (d, J = 3.6 Hz, 1H), 2.35 (tdd, J = 3.6, 6.8, 10.2 Hz, 1H), 1.96-1.74 (m, 5H), 1.71-1.61 (m, 3H), 1.51-1.33 (m, 10H), 1.26 (t, J = 7.2 Hz, 5H), 1.11 (d, J = 6.8 Hz, 6H), 0.94 (s, 3H), 0.88 (d, J = 6.8 Hz, 5H), 0.69 (s, 3H).

[0441] Synthesis of 16

[0442] To a solution of 16.3 (300 mg, 0.8008 mmol) in THF (10 mL) was added CsF (60.8 mg, 0.40 mmol) at 0 °C, and then TMSCF3(227 mg, 1.60 mmol) was added slowly. After stirring at 25 °C for 1 h, TBAF (1.26 g, 4.00 mmol, 1 M in THF) was added, and the mixture was stirred for 1 h. The mixture was quenched with 10% aqueous NH4Cl (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with 10% aqueous NH4Cl (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (15~20% EtOAc in PE) to give 16 (50 mg, 14.0%). 16 (40 mg, 0.045 mmol) was further purified from DCM:n-hexane (1:2, 5 mL) at 60 °C for 20 min to give 16 (17.8 mg, 89.4%).1H NMR (400 MHz, CDCl3) δH4.14-3.96 (m, 1H), 2.16 (d, J = 6.0 Hz, 1H), 2.10-1.95 (m, 2H), 1.94-1.72 (m, 4H), 1.71-1.59 (m, 3H), 1.53-1.28 (m, 9H), 1.26-0.98 (m, 11H), 0.93 (s, 3H), 0.88 (d, J = 6.8 Hz, 6H), 0.67 (s, 3H). LC-ELSD / MS purity 100%, MS ESI calcd. for C26H44F3O2[M-H2O+H]+427, found 427.

[0443] Example 17: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17S)-3,10,13-trimethyl-17- ((S)-4,4,4-trifluoro-3-hydroxy-2-methylbutan-2-yl)hexadecahydro-1H-

[0444] Synthesis of 17.2

[0445] To a solution of 17.1 (100 g, 315 mmol) in DCM (1 L) was added imidazole (32.1 g, 472 mmol) and TBSCl (52.2 g, 346 mmol) and the resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (2 x 1000 mL) and the DCM layer was separated. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give 17.2 (150 g, 95%).1H NMR (400 MHz, CDCl3) δH 5.37-5.25 (m, 1H), 3.57-3.41 (m, 1H), 2.53 (t, J = 8.8 Hz, 1H), 2.32-2.15 (m, 3H), 2.12 (s, 3H), 2.07-1.96 (m, 2H), 1.82 (td, J = 3.6, 13.2 Hz, 1H), 1.73-1.59 (m, 4H), 1.50-1.42 (m, 3H), 1.29-1.04 (m, 3H), 1.00 (s, 3H), 0.91-0.91 (m, 3H), 0.90-0.86 (m, 9H), 0.63 (s, 3H), 0.06 (s, 6H).

[0446] Synthesis of 17.3

[0447] To a mixture of t-BuOH (300 mL) and t-BuOK (38.9 g, 347 mmol) underN2was added 17.2 (30 g, 69.6 mmol) in DME (150 mL) and the mixture was stirred for 30 min. TosMic (27.0 g, 139 mmol) in DME (150 mL) was added and the mixture was stirred at 25 °C for 16 h. Water (100 mL) was added, the resulting mixture was stirred, and then extracted with EtOAc (2 x 1 L). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified from MeCN (500 mL) at 25 °C to give 17.3 (123 g, 56%).1H NMR (400 MHz, CDCl3) δH5.38-5.23 (m, 1H), 3.55-3.40 (m, 1H), 2.70-2.60 (m, 1H), 2.45-2.14 (m, 3H), 2.10-1.77 (m, 3H), 1.76-1.40 (m, 9H), 1.37-1.27 (m, 3H), 1.26-1.03 (m, 4H), 1.02-0.99 (m, 3H), 0.98-0.92 (m, 1H), 0.89 (s, 9H), 0.77-0.71 (m, 3H), 0.06 (s, 6H).

[0448] Synthesis of 17.4

[0449] A solution of 17.3 (20 g, 45.2 mmol) in THF (200 mL) was added to LDA (113 mL, 2 M, 226 mmol) and the resulting mixture was stirred at -70 °C under N2 for 1 h. Methyl iodide (32.0 g, 226 mmol) was added and the reaction mixture was stirred for 16 h. The mixture was warmed to 25 °C, quenched with ammonium chloride (200 mL, sat. aq.), and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 17.4 (21 g).1H NMR (400 MHz, CDCl3) δH5.31 (br d, J = 5.2 Hz, 1H), 3.54-3.41 (m, 1H), 2.65-2.37 (m, 1H), 2.31-2.13 (m, 2H), 2.08-1.88 (m, 3H), 1.83-1.64 (m, 5H), 1.59-1.49 (m, 5H), 1.44 (s, 3H), 1.34 (s, 2H), 1.31-1.16 (m, 3H), 1.06-0.98 (m, 5H), 0.95 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H).

[0450] Synthesis of 17.5

[0451] To a solution of 17.4 (1 g, 2.19 mmol) in DCM (40 mL) was added DIBAL-H (1 M in toluene, 10.9 mL, 10.9 mmol) slowly at -70 °C and the resulting mixture was stirred for 30 min. The mixture was warmed to 25 °C and stirred for 1.5 h. The mixture was carefully poured into HCl (50 mL, 3 M in water) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous NaHCO3(2 x 100 mL), brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~15% EtOAc in PE) to give 17.5 (170 mg, 23%).1H NMR (400 MHz, CDCl3) δH 9.64 (s, 1H), 5.39-5.28 (m, 1H), 3.54-3.48 (m, 1H), 2.35-2.16 (m, 2H), 2.02-1.80 (m, 4H), 1.78-1.62 (m, 4H), 1.53-1.34 (m, 6H), 1.21-1.14 (m, 1H), 1.10 (d, J = 6.8 Hz, 7H), 1.08-1.00 (m, 2H), 0.99 (s, 3H), 0.96-0.87 (m, 1H), 0.70 (s, 3H).

[0452] Synthesis of 17.6

[0453] To a solution of 17.5 (170 mg, 0.493 mmol) in THF (10 mL) was added CsF (74.9 mg, 0.493 mmol) and TMSCF3(210 mg, 1.48 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 3 h. TBAF (4.93 mL, 1 M in THF) was added and the mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~20% of EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD(250mm*30mm,10um); Condition: 0.1%NH3H2O IPA; Gradient: from 30% to 30% of B; Flow rate: 65 mL / min; Injections: 60) to give 17.6 (28.6 mg, 29%).17.6:1H NMR (400 MHz, CDCl3) δH5.37-5.32 (m, 1H), 4.09-3.92 (m, 1H), 3.55-3.49 (m, 1H), 2.36-2.16 (m, 2H), 2.11 (d, J = 6.4 Hz, 1H), 2.03-1.91 (m, 2H), 1.89-1.76 (m, 3H), 1.71- 1.61 (m, 3H), 1.53-1.35 (m, 7H), 1.14-1.04 (m, J = 1.8 Hz, 5H), 1.03-0.98 (m, 6H), 0.97-0.88 (m, 2H), 0.80 (s, 3H).19F NMR (376.5 MHz, CDCl3) δF-70.174. LC-ELSD / MS purity 99%, MS ESI calcd. for C24H36F3O [M+H-H2O]+397.3, found 397.3.

[0454] Synthesis of 17.7

[0455] To a solution of 17.6 (60 g, 144 mmol) in DCM (600 mL) was added TBSCl (32.5 g, 216 mmol) and imidazole (19.6 g, 288 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The reaction was quenched with water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 17.7 (80 g).1H NMR (400MHz, CDCl3) δH5.38-5.25 (m, 1H), 3.55-3.41 (m, 1H), 2.34-1.93 (m, 5H), 1.81-1.58 (m, 6H), 1.30-1.21 (m, 1H), 1.17-1.07 (m, 4H), 1.03-0.97 (m, 5H), 0.96-0.87 (m, 15H), 0.86-0.76 (m, 4H), 0.09 (s, 3H), 0.05 (s, 6H).19F NMR (376.5 MHz, CDCl3) δF-69.943, -70.137.

[0456] Synthesis of 17.8

[0457] To a solution of 17.7 (80 g, 151 mmol) in THF (1 L) was added NaH (12.0 g, 302 mmol, 60%) and the resulting mixture was stirred at 25 °C for 30 min. PMBCl (30.5 g, 196 mmol) was added under N2 and the mixture was stirred at 70 °C for 16 h. The mixture was slowly poured into 10% aqueous NH4Cl (600 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 17.8 (100 g).

[0458] Synthesis of 17.9

[0459] To a solution of 17.8 (100 g) in THF (800 mL) was added TBAF (308 mL, 1 M in THF) at 25 °C and the resulting mixture was stirred at 60 °C for 16 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL), washed with water (2 x 800 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by flash silica gel chromatography (20%~25% EtOAc in PE) to give 17.9 (59 g, 72%).1H NMR (400MHz, CDCl3): δH 7.32-7.28 (m, 2H), 6.92-6.88 (m, 2H), 5.38-5.30 (m, 1H), 4.88-4.72 (m, 1H), 4.62 (s, 2H), 4.53-4.40 (m, 1H), 3.81 (s, 3H), 3.53-3.44 (m, 1H), 2.33-2.18 (m, 2H), 2.01-1.92 (m, 1H), 1.88-1.80 (m, 2H), 1.70-1.61 (m, 2H), 1.59-1.39 (m, 10H), 1.15-0.98 (m, 10H), 0.97-0.86 (m, 2H), 0.85-0.75 (m, 3H).19F NMR (376.5 MHz, CDCl3) δF -66.801, -67.307.

[0460] Synthesis of 17.10

[0461] To a mixture of 17.9 (5 g, 9.35 mmol) in toluene (50 mL) and cyclohexanone (5 mL) was added aluminum isopropoxide (2.08 g, 10.2 mmol) at 25 °C under N2 and the resulting mixture was stirred at 100 °C for 16 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (5~10% of EtOAc in PE) to give 17.10 (3.5 g, 70%).1H NMR (400 MHz, CDCl3) δH 7.28 (br d, J = 1.9 Hz, 2H), 6.88 (br d, J = 8.6 Hz, 2H), 5.73 (br s, 1H), 4.85-4.75 (m, 1H), 4.45 (dd, J = 2.4, 10.9 Hz, 1H), 3.86-3.83 (m, 1H), 3.80 (d, J = 3.6 Hz, 3H), 2.45- 2.26 (m, 4H), 1.95-1.88 (m, 3H), 1.79-1.67 (m, 6H), 1.51-1.36 (m, 5H), 1.20-1.15 (m, 5H), 1.08-1.00 (m, 5H), 0.86-0.77 (m, 4H).

[0462] Synthesis of 17.11

[0463] To a solution of 17.10 (3.5 g, 6.57 mmol) in THF (50 mL) was added Pd / C (2 g, wet, 10%) at 25 °C. The mixture was degassed under vacuum and purged with H2several times. After stirring under H2(15 psi) at 25 °C for 16 h, the reaction mixture was filtered through a Celite pad to remove Pd / C and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5%~12% EtOAc in PE) to afford 17.11 (1.2 g, 34.1%).1H NMR (400 MHz, CDCl3) δH 7.31-7.27 (m, 2H), 6.89 (dd, J = 2.4, 8.7 Hz, 2H), 4.89-4.74 (m, 1H), 4.46 (d, J = 10.8 Hz, 1H), 3.80 (d, J=3.0 Hz, 3H), 3.78 (s, 1H), 2.10-1.94 (m, 4H), 1.43 (s, 4H), 1.26 (br s, 5H), 1.21 (d, J = 6.0 Hz, 2H), 1.14 (br s, 4H), 1.07-1.00 (m, 6H), 0.88-0.84 (m, 7H), 0.79 (d, J = 18.8 Hz, 3H).

[0464] Synthesis of 17.12

[0465] To a solution of BHT (1.5 g, 6.80 mmol) in toluene (5 mL) was added AlMe3 (2 M in toluene, 1.70 mL, 3.40 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 1 h. To the MAD solution was added 17.11 (500 mg, 0.935 mmol) in toluene (5 mL). After stirring at -70 °C for 1 h, MeMgBr (0.933 mL, 3M in ethyl ether) was added dropwise at -70 °C and the mixture was stirred for 3 h. The reaction was quenched with citric acid (30 mL, sat. aq.) at -70 °C and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~15% of EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD-H(250mm*30mm,5um); Condition: 0.1%NH3H2O EtOH; Gradient: from 15% to 15% of B; Flow rate: 60 mL / min; Injections: 12) to give 17.12 (185 mg, 43%).1H NMR (400 MHz, CDCl3) δH 7.29 (s, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.79 (d, J = 10.4 Hz, 1H), 4.47 (d, J = 10.4 Hz, 1H), 3.81 (s, 3H),3.53 (q, J = 7.6 Hz, 1H), 2.01-1.67 (m, 6H), 1.60 (br d, J = 7.8 Hz, 5H), 1.45-1.35 (m, 7H), 1.24 (s, 4H), 1.19 (br d, J = 7.2 Hz, 3H), 1.10 (s, 3H), 1.04 (s, 5H), 0.93 (s, 3H), 0.77 (s, 3H).

[0466] Synthesis of 17

[0467] To a solution of 17.12 (185 mg, 0.336 mmol) in DCM (5 mL) was added water (0.5 mL) and DDQ (152 mg, mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with NaHCO3(20 mL, sat. aq.) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (15~20% of EtOAc in PE) to give 17 (56.1 mg, 39%).1H NMR (400 MHz, CDCl3) δH4.06 -3.90 (m, 1H), 2.12 (d, J=6.3 Hz, 1H), 1.99-1.58 (m, 8H), 1.55-1.34 (m, 9H), 1.30-1.25 (m, 6H), 1.15-0.98 (m, 10H), 0.94 (s, 3H), 0.76 (s, 3H). LC-ELSD / MS purity 99%, MS ESI calcd. for C25H40N3O [M+H-H2O]+413.3 found 413.3.19F NMR (376.5 MHz, CDCl3) δF -70.182.

[0468] Example 18: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17S)-3-ethyl-10,13- dimethyl-17-((S)-4,4,4-trifluoro-3-hydroxy-2-methylbutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (18)

[0469] Synthesis of 18.1

[0470] To a solution of BHT (1.5 g, 6.80 mmol) in toluene (5 mL) was added AlMe3(2 M in toluene, 1.70 mL, 3.40 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 1h. To the MAD solution was added 17.11 (700 mg, 1.30 mmol) in toluene (10 mL) and the mixture was stirred at -70 °C for 1 h. EtMgBr (1.29 mL, 3M in ethyl ether) was added dropwise at -70 °C and the mixture was stirred at -70 °C for 3 h. The reaction was quenched with citric acid (30 mL, sat. aq.) at -70 °C and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~15% EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD-H(250mm*30mm,5um); Condition: 0.1%NH3H2O EtOH; 20% of B; Flow rate: 60mL / min; Injections: 240) to give 18.1 (241 mg, 44%).18.1 (241 mg, 0.427 mmol) was further purified by SFC (DAICEL CHIRALPAK AD-H (250mm*30mm, 5um); Condition: 0.1%NH3H2O EtOH; 20% of B; Flow rate: 50 mL / min; Injections: 120) to give 18.1 (120 mg, 50%). 18.1: LC-ELSD / MS purity 99%, MS ESI calcd. for C34H51F3O3Na [M+Na]+587.4 found 587.4.

[0471] Synthesis of 18

[0472] To a solution of 18.1 (120 mg, 0.212 mmol) in DCM (5 mL) was added water (0.5 mL) and DDQ (96.4 mg, 0.425 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with NaHCO3(20 mL, sat. aq.) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (15~20% EtOAc in PE) to give 18 (80 mg), which was further purified from MeCN (2 mL) at 25 °C to give 18 (33.9 mg, 36%).1H NMR (400 MHz, CDCl3) δH 4.02-3.94 (m, 1H), 2.09 (d, J = 6.4 Hz, 1H), 1.97-1.77 (m, 4H), 1.72-1.57 (m, 5H), 1.53-1.33 (m, 9H), 1.32-1.18 (m, 4H), 1.17-1.11 (m, 1H), 1.10-1.07 (m, 4H), 1.06-1.02 (m, 1H), 1.00 (s, 3H), 0.99-0.94 (m, 1H), 0.92 (s, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.76 (s, 3H).19F NMR (376.5 MHz, CDCl3) δF -70.174. LC-ELSD / MS purity 99%, MS ESI calcd. for C26H42F3O [M+H-H2O]+427.3, found 427.3.

[0473] Example 19: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethynyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (19)

[0474] Synthesis of 19.1

[0475] To a solution of 3.3 (10 g, 28.1 mmol) in THF:DMF (112 mL, 3:1) was added NaH (2.98 g, 75 mmol，60% in mineral oil) at 25 °C under N2 and the resulting mixture was stirred for 10 min. PMBCl (5.85 g, 37.5 mmol) was added and the mixture was stirred at 68 °C for 30 min. The mixture was poured into 10% aqueous NH4Cl (120 mL) and stirred for 10 min and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 19.1 (12 g).1H NMR (400 MHz, CDCl3) δH 7.29 (br d, J = 2.4 Hz, 2H), 6.91-6.89 (m, 2H), 4.67-4.62 (m, 1H), 4.56 (br d, J = 6.4 Hz, 2H), 4.46 (s, 1H), 3.81 (s, 3H), 3.72-3.67 (m, 1H), 2.49 (br t, J=13.2 Hz, 1H), 2.07-1.94 (m, 3H), 1.89-1.78 (m, 4H), 1.45-1.37 (m, 5H), 1.26-1.19 (m, 5H), 1.10-1.04 (m, 6H), 0.92 (s, 3H), 0.89-0.82 (m, 3H), 0.60 (s, 3H).

[0476] Synthesis of 19.2

[0477] To a solution of 19.1 (10 g, 19.2 mmol) in DCM (200 mL) and MeOH (110 mL) was added NaHCO3(8.05 g, 95.9 mmol). Ozone (1 atm) was passed through the mixture at -70 °C for 30 min. O2was then passed through the solution for 5 min. Me2S (3.56 g, 57.5 mmol) was slowly added in portions to the mixture at -70 °C, the solution was allowed to warm to 20 °C over 1 h and then was stirred for 16 h. The reaction mixture was quenched with 10% aqueous NH4Cl (300 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with 10% aqueous NH4Cl (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~10% EtOAc in PE) to give 19.2 (3.94 g, 39.4%).1H NMR (400 MHz, CDCl3) δH 7.27 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 3.81 (s, 3H), 3.76-3.63 (m, 1H), 2.74-2.57 (m, 1H), 2.40-2.25 (m, 1H), 2.20-2.10 (m, 1H), 2.08-1.95 (m, 3H), 1.89-1.70 (m, 4H), 1.54-1.19 (m, 10H), 1.18-1.03 (m, 7H), 1.01 (s, 3H), 0.63 (s, 3H).

[0478] Synthesis of 19.3

[0479] A solution of ethynylmagnesium bromide (5.76 mL, 22.5 mmol, 1 M) in THF (20 mL) was reacted with a solution of 19.2 (1 g, 1.92 mmol) in THF (20 mL) at 50 °C under N2. After stirring for 16 h, the mixture was slowly poured into 10% aqueous NH4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH4Cl (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 19.3 (1.3 g), which was purified by SFC ( (Column:DAICEL CHIRALCEL OD(250mm*50mm,10um); Condition:0.1%NH3H2O ETOH); Begin B: 55; End B: 55) to give the 19.3 (500 mg, 73.9%).1H NMR (400MHz, CDCl3) δH7.30-7.26 (m, 2H), 6.92-6.85 (m, 2H), 4.69-4.49 (m, 2H), 3.81 (s, 3H), 3.74-3.65 (m, 1H), 2.47 (s, 1H), 2.11-1.89 (m, 3H), 1.85-1.62 (m, 6H), 1.40-1.33 (m, 4H), 1.31-1.22 (m, 4H), 1.09-0.99 (m, 7H), 0.99-0.92 (m, 4H), 0.91-0.81 (m, 3H), 0.59 (s, 3H).19F NMR (376.5MHz, CDCl3) δ -69.48.

[0480] Synthesis of 19

[0481] To solution of 19.3 (500 mg, 0.914 mmol) in DCM (12 mL) was added DDQ (413 mg, 1.81 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The reaction mixt...

Claims

CLAIMS What is Claimed is:

1. A compound, wherein the compound has the structure of Formula (I):or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2- 6 alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, substituted or unsubstituted C6-10aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15and R16is independently hydrogen or substituted or unsubstituted C1-6alkyl; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is hydrogen or substituted or unsubstituted C1-6alkyl; R19is hydrogen or substituted or unsubstituted C1-6alkyl; R20is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; R20’is hydrogen, hydroxyl, substituted or unsubstituted C1-6alkyl, or substituted or unsubstituted C3-6carbocyclyl; provided that R20and R20’are not both hydroxyl; and R22is substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkenyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted C6-10aryl; provided that when R22is -CH3, R3is not -CH3or hydrogen.

2. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to claim 1, wherein:R3is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, C6-10aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA; each of R15and R16is independently hydrogen or C1-6alkyl optionally substituted with 1-5 RB; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is hydrogen or C1-6alkyl optionally substituted with 1-5 RC; R19is hydrogen or C1-6alkyl optionally substituted with 1-5 RD; R20is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RE; R20’is hydrogen, hydroxyl, C1-6alkyl, or C3-6carbocyclyl, wherein said C1-6alkyl and C3-6carbocyclyl are independently optionally substituted with 1-5 RF; provided that R20and R20’are not both hydroxyl; each instance of RA, RB, RC, RD, RE, and RF, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10aryl, and C1-6alkoxy optionally substituted with 1-5 halo; R22is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or C6-10aryl, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are independently optionally substituted with 1-5 RGand said C3-6carbocyclyl and C6-10aryl are independently optionally substituted with 1-5 RH; provided that when R22is -CH3, R3is not -CH3or hydrogen; each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6alkoxy optionally substituted with 1-5 halo, C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C3-6carbocyclyl, C6-10aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 RG1; each instance of RG1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo; and each instance of RH, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6alkyl optionally substituted with 1-5 halo, and C1-6alkoxy optionally substituted with 1-5 halo.

3. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 1 or 2, wherein the compound of Formula (I) is a compound of Formula (I-A) or (I-B):

4. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 3, wherein the compound of Formula (I-A) is a compound of Formula (I-A-1) or (I-A-2):(I-A-1) (I-A-2).

5. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 4, wherein the compound of Formula (I-A-1) is a compound of Formula (I-A-1-i) or (I-A-1-ii):(I-A-1-i) (I-A-1-ii).

6. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 4, wherein the compound of Formula (I-A-2) is a compound of Formula (I-A-2-i) or (I-A-2-ii): (7. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 3, wherein the compound of Formula (I-B) is a compound of Formula (I-B-1) or (I-B-2):

8. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 7, wherein the compound of Formula (I-B-1) is a compound of Formula (I-B-1-i) or (I-B-1-ii):

9. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 7, wherein the compound of Formula (I-B-2) is a compound of Formula (I-B-2-i) or (I-B-2-ii):

10. The compound according to claim 1 or 3, wherein: R3is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C2-6alkynyl; R15is hydrogen or substituted or unsubstituted C1-6alkyl and R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is substituted or unsubstituted C1-6alkyl; R20is hydrogen, hydroxyl, or substituted or unsubstituted C1-6alkyl; and R20’is hydrogen or substituted or unsubstituted C1-6alkyl.

11. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-3, wherein: R3is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-5 RA;R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RB; R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is C1-6alkyl optionally substituted with 1-5 RC; R20is hydrogen, hydroxyl, or C1-6alkyl optionally substituted with 1-5 RE; and R20’is hydrogen or C1-6alkyl optionally substituted with 1-5 RF.

12. The compound according to any one of claims 1, 3 and 10, wherein: R3is substituted or unsubstituted C1-6alkyl; R15is hydrogen or substituted or unsubstituted C1-6alkyl and R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl; R18is -CH3; R20is hydrogen; R20’is -CH3; and R22is substituted or unsubstituted C1-6alkyl or substituted or unsubstituted C2- 6 alkynyl.

13. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-3 and 10-11, wherein: R3is C1-6alkyl optionally substituted with 1-5 RA; R15is hydrogen or C1-6alkyl optionally substituted with 1-5 RB; R16is hydrogen; or R15and R16, taken together with the carbon atoms to which they are attached, form a C3-6carbocyclyl optionally substituted with 1-5 RB; R18is -CH3; R20is hydrogen; R20’is -CH3; and R22is C1-6alkyl or C2-6alkynyl, wherein said C1-6alkyl and C2-6alkynyl are independently optionally substituted with 1-5 RG.

14. The compound according to any one of claims 1 and 3-9, wherein R3is hydrogen, substituted or unsubstituted C1-6alkyl, substituted or unsubstituted C2-6alkynyl, substituted or unsubstituted C3-6carbocyclyl, or substituted or unsubstituted 5-8 membered heteroaryl.

15. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-9, wherein R3is hydrogen, C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, or 5-8 membered heteroaryl, wherein said C1-6alkyl, C2-6alkynyl, C3-6carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA.

16. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-15, wherein R15is hydrogen or unsubstituted C1-6alkyl.

17. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-16, wherein R16is hydrogen or unsubstituted C1-6alkyl.

18. The compound according to any one of claims 1-15, wherein R15and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6carbocyclyl.

19. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-3 and 10-18, wherein R18is hydrogen or unsubstituted C1-6alkyl.

20. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-2 and 10-19, wherein R19is hydrogen or unsubstituted C1-6alkyl.

21. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-20, wherein R20is hydrogen, hydroxyl, or unsubstituted C1-6alkyl.

22. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-20, wherein R20’is hydrogen or unsubstituted C1-6alkyl.

23. The compound according to any one of claims 1-22, wherein R22is substituted or unsubstituted C1-6alkyl.

24. The compound according to any one of claims 1-11 and 14-22, wherein R22is substituted or unsubstituted C2-6alkenyl.

25. The compound according to any one of claims 1-22, wherein R22is substituted or unsubstituted C2-6alkynyl.

26. The compound according to any one of claims 1-11 and 14-22, wherein R22is substituted or unsubstituted C3-6carbocyclyl.

27. The compound according to any one of claims 1-11 and 14-22, wherein R22is substituted or unsubstituted C6-10aryl.

28. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-3, 11-15, 16-17, and 19-23, wherein: R3is C1 alkyl substituted with 1-3 RA; R15and R16are hydrogen; R18and R19are -CH3; R20is hydrogen; R20’is -CH3; and R22is C1-6alkyl optionally substituted with an unsubstituted C1-6alkoxy.

29. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 28, wherein R22is -CH3or -CH2OCH3.

30. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of any one compounds 1-118, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

31. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-30, and a pharmaceutically acceptable carrier.

32. A method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-30, or a pharmaceutical composition according to claim 31.

33. The method according to claim 32, wherein the CNS-related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus.

34. The method according to claim 32, wherein the CNS-related condition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychiatric disorder, pain, a seizure disorder, drug-induced dyskinesia, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome, neuropsychiatric lupus, and tinnitus.

35. A method for effecting negative allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-30, or a pharmaceutical composition according to claim 31.

36. A compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-30, or a pharmaceutical composition according to claim 31, for use in treating a CNS-related condition in a subject.

37. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to claim 36, wherein the CNS- related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus.

38. The compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition for use according to claim 36, wherein the CNS-relatedcondition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychiatric disorder, pain, a seizure disorder, drug-induced dyskinesia, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome, neuropsychiatric lupus, and tinnitus.

39. A compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-30, or a pharmaceutical composition according to claim 31, for use in effecting negative allosteric modulation of an NMDA receptor.

40. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-30, or a pharmaceutical composition according to claim 31, in the manufacture of a medicament for treating a CNS-related condition in a subject.

41. The use according to claim 40, wherein the CNS-related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus.

42. The use according to claim 40, wherein the CNS-related condition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychiatric disorder, pain, a seizure disorder, drug-induced dyskinesia, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome, neuropsychiatric lupus, and tinnitus.

43. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of claims 1-30, or a pharmaceutical composition according to claim 31, in the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor.

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