Negative NMDA modulating compounds and methods of use thereof

Abstract

The compound has the formula (I): TIFF2025538551000193.tif4369 and pharmaceutically acceptable salts, isotopic variants, and combinations thereof, as well as pharmaceutical compositions thereof, are provided according to the present disclosure. The compounds of the present disclosure are believed to be useful for the prevention and treatment of various CNS-related conditions. In one aspect, the present disclosure provides a compound of any one of formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the present disclosure, for use in treating a CNS-related condition in a subject.

Description

[Background technology]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 427,012, filed November 21, 2022, the entire contents of which are incorporated herein by reference.

[0002] NMDA receptors are heterogeneous complexes composed 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 glutamatergic agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some situations and excitotoxicity in others. These receptors transduce Ca after binding of glutamate and glycine. 2+ Glutamate receptors (GTRs) are ligand-gated ion channels that are fundamental to excitatory neurotransmission and normal CNS function. Negative modulators of GTRs may be useful as therapeutic agents with potential clinical applications in the treatment of psychiatric disorders in which glutamate transmission is pathologically increased (e.g., treatment-resistant depression).

[0003] There is a need for novel compounds that are negative allosteric modulators of NMDA receptors for the prevention and treatment of conditions related to NMDA function. The compounds, compositions, and methods described herein are directed to this end. Summary of the Invention

[0004] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R 3 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted 5- to 8-membered heteroaryl; R 15 and R 16 each independently represents hydrogen or a substituted or unsubstituted C 1-6 alkyl, or R 15 and R 16 are substituted or unsubstituted C together with the carbon atoms to which they are attached. 3-6 forming a carbocyclyl, R 18 is hydrogen, or substituted or unsubstituted C 1-6 is alkyl, R 19 is hydrogen, or substituted or unsubstituted C 1-6 is alkyl, R 20 is hydrogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 3-6 is a carbocyclyl, R 20’ is hydrogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 3-6 is a carbocyclyl, However, R 20 and R 20’ are both not hydroxyl, and R 22 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclyl, or substituted or unsubstituted C 6-10 is aryl, However, R 22 is -CH3, R 3 is not -CH3 or hydrogen.

[0005] In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 6-10 aryl or 5- to 8-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 6-10 Aryl and 5- to 8-membered heteroaryl independently have 1 to 5 R A optionally substituted with R 15 and R 16 each independently represents hydrogen or 1 to 5 R B C optionally substituted with 1-6 alkyl, or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 forming a carbocyclyl, R 18 is hydrogen or 1 to 5 R C C optionally substituted with 1-6 is alkyl, R 19 is hydrogen or 1 to 5 R D C optionally substituted with 1-6 is alkyl, R 20 is hydrogen, hydroxyl, C 1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R E optionally substituted with R 20’ is hydrogen, hydroxyl, C1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R F optionally substituted with However, R 20 and R 20’ are both hydroxyl, R A , R B , R C , R D , R E , and R F Each example, when present, is independently selected from halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 C optionally substituted with aryl and 1 to 5 halo 1-6 alkoxy; R 22 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl or C 6-10 aryl, and the aforementioned C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl independently has 1 to 5 R G and optionally substituted with the aforementioned C 3-6 Carbocyclyl and C 6-10 Aryl independently represents 1 to 5 R H optionally substituted with However, R 22 is -CH3, R 3 is not -CH3 or hydrogen, R G Each instance, if present, is independently halo, hydroxyl, cyano, C optionally substituted with 1 to 5 halo. 1-6 Alkoxy, C 3-6 Carbocyclyl, C 6-10 aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl; 3-6 Carbocyclyl, C6-10 Aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl independently represent 1 to 5 R G1 optionally substituted with R G1 Each instance, if present, is independently halo, cyano, oxo, nitro, amino, C optionally substituted with 1 to 5 halo. 1-6 C optionally substituted with alkyl and 1 to 5 halo 1-6 alkoxy; and R H Each instance, if present, is independently halo, cyano, nitro, amino, C optionally substituted with 1 to 5 halo. 1-6 C optionally substituted with alkyl and 1 to 5 halo 1-6 alkoxy is selected from the group consisting of:

[0006] In some embodiments, the present disclosure provides a compound of formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0007] In some embodiments, the present disclosure provides a compound of formula (IA-1) or (IA-2): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0008] In some embodiments, the present disclosure provides a compound of formula (IA-1-i) or (IA-1-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0009] In some embodiments, the present disclosure provides a compound of formula (IA-2-i) or (IA-2-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0010] In some embodiments, the present disclosure provides a compound of formula (IB-1) or (IB-2): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0011] In some embodiments, the present disclosure provides a compound of formula (IB-1-i) or (IB-1-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0012] In some embodiments, the present disclosure provides a compound of formula (IB-2-i) or (IB-2-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0013] In some embodiments, the present disclosure provides a compound of any one of the formulas disclosed herein (i.e., (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), (IB-2-ii)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3 is a substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 2-6 is alkynyl, R 15 is hydrogen, or substituted or unsubstituted C 1-6 alkyl, and R 16 is hydrogen, or R 15 and R 16 are substituted or unsubstituted C together with the carbon atoms to which they are attached. 3-6 forming a carbocyclyl, R 18 is a substituted or unsubstituted C 1-6 is alkyl, R 20 is hydrogen, hydroxyl, or substituted or unsubstituted C 1-6 alkyl, and R 20’ is hydrogen, or substituted or unsubstituted C 1-6 alkyl, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0014] In some embodiments, the present disclosure provides a compound of any one of the formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R 3 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 5 R A optionally substituted with R 15 is hydrogen or 1 to 5 R B C optionally substituted with 1-6 is alkyl, R 16 is hydrogen, or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with3-6 forming a carbocyclyl, R 18 is 1 to 5 R C C optionally substituted with 1-6 is alkyl, R 20 is hydrogen, hydroxyl, or 1 to 5 R E C optionally substituted with 1-6 alkyl, and R 20’ is hydrogen or 1 to 5 R F C optionally substituted with 1-6 It is alkyl.

[0015] In some embodiments, the present disclosure provides a compound of any one of the formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R 3 is a substituted or unsubstituted C 1-6 is alkyl, R 15 is hydrogen, or substituted or unsubstituted C 1-6 alkyl, and R 16 is hydrogen, or R 15 and R 16 are substituted or unsubstituted C together with the carbon atoms to which they are attached. 3-6 forming a carbocyclyl, R 18 is -CH3, R 20 is hydrogen, R 20’ is -CH3, and R 22 is a substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 2-6 It is alkynyl.

[0016] In some embodiments, the present disclosure provides a compound of any one of the formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R 3 is 1 to 5 R A C optionally substituted with 1-6 is alkyl, R 15 is hydrogen or 1 to 5 R B C optionally substituted with 1-6 is alkyl, R 16 is hydrogen, or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 forming a carbocyclyl, R 18 is -CH3, R 20 is hydrogen, R 20’ is -CH3, and R 22 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 5 R G is optionally substituted with

[0017] In some embodiments, the present disclosure provides a compound of any one of the formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R 3 is 1 to 3 R A is a C1 alkyl substituted with R 15 and R 16 is hydrogen, R 18 and R 19 is -CH3, R 20 is hydrogen, R 20’ is -CH3, and R 22 is the unsubstituted C 1-6 C optionally substituted with alkoxy1-6 In some embodiments, R 22 is -CH3 or -CH2OCH3.

[0018] In some embodiments, R 3 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, or 5- to 8-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl and 5- to 8-membered heteroaryl are independently 1 to 5 R A In some embodiments, R 3 is —H, —CH2F, —CHF2, —CF3, —CH2OCH3, —CH2OH, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C≡CH, —C≡C—CH3, cyclopropyl, or pyridyl, and said cyclopropyl and pyridyl are independently selected from 1 to 5 R A In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a substituted or unsubstituted C 1-6 In some embodiments, R 3 is 1 to 5 R A C optionally substituted with 1-6 In some embodiments, R 3 is 1 to 5 R A C replaced by 1-6 In some embodiments, R 3 is —CHF, —CHF, —CF, —CHOCH, or —CHOH. In some embodiments, R 3is -CF3. In some embodiments, R 3 is the unsubstituted C 1-6 In some embodiments, R 3 is —CH, —CHOCH, —CHCHCH, or —CH(CH). In some embodiments, R 3 is -CH3 or -CH2CH3. In some embodiments, R 3 is a substituted or unsubstituted C 2-6 In some embodiments, R is alkynyl. 3 is 1 to 5 R A C optionally substituted with 2-6 In some embodiments, R is alkynyl. 3 is —C≡CH or —C≡C—CH. In some embodiments, R 3 is a substituted or unsubstituted C 3-6 In some embodiments, R 3 is 1 to 5 R A C optionally substituted with 3-6 In some embodiments, R 3 is unsubstituted cyclopropyl. In some embodiments, R 3 is a substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R 3 is 1 to 5 R A In some embodiments, R is a 5-8 membered heteroaryl optionally substituted with 3 is unsubstituted pyridyl.

[0019] In some embodiments, R 15 is hydrogen or unsubstituted C 1-6 In some embodiments, R 15 is hydrogen or -CH3.

[0020] In some embodiments, R 16 is hydrogen or unsubstituted C 1-6 In some embodiments, R 16 is hydrogen or -CH3.

[0021] In some embodiments, R 15 and R 16 is hydrogen. In some embodiments, R 15 is -CH3 and R 16 is hydrogen. In some embodiments, R 15 is hydrogen and R 16 is -CH3. In some embodiments, R 15 and R 16 is -CH3. In some embodiments, R 15 and R 16 are substituted or unsubstituted C together with the carbon atoms to which they are attached. 3-6 In some embodiments, R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 In some embodiments, R 15 and R 16 together with the carbon atom to which they are attached form an unsubstituted cyclopropyl.

[0022] In some embodiments, R 18 is hydrogen or unsubstituted C 1-6 In some embodiments, R 18 is hydrogen, —CH, or —CHCH. In some embodiments, R 18 is -CH3 or -CH2CH3.

[0023] In some embodiments, R 19 is hydrogen or unsubstituted C 1-6 In some embodiments, R 19 is hydrogen or —CH. In some embodiments, R 19 is -CH3. In some embodiments, R 19 is hydrogen.

[0024] In some embodiments, R 18 and R 19is hydrogen. In some embodiments, R 18 and R 19 is -CH3. In some embodiments, R 18 is -CH3 and R 19 is hydrogen. In some embodiments, R 18 is -CH2CH3, and R 19 is -CH3.

[0025] In some embodiments, R 20 is hydrogen, hydroxyl, or unsubstituted C 1-6 In some embodiments, R 20 is hydrogen, hydroxyl, or —CH3.

[0026] In some embodiments, R 20’ is hydrogen or unsubstituted C 1-6 In some embodiments, R 20’ is hydrogen or -CH3.

[0027] In some embodiments, R 20 and R 20’ is hydrogen. In some embodiments, R 20 and R 20’ is -CH3. In some embodiments, R 20 is hydrogen and R 20’ is -CH3. In some embodiments, R 20 is -CH3 and R 20’ is hydrogen. In some embodiments, R 20 is hydroxyl and R 20’ is -CH3.

[0028] In some embodiments, R 22 is a substituted or unsubstituted C 1-6 In some embodiments, R 22 is 1 to 5 R G C optionally substituted with 1-6 In some embodiments, R 22 is a substitution C1-6 In some embodiments, R 22 is 1 to 5 R G C replaced by 1-6 In some embodiments, R 22 is 1 to 3 R G C replaced by 1-6 alkyl, and R G Each instance of is independently halo, hydroxyl, C optionally substituted with 1 to 5 halo. 1-6 Alkoxy, C 3-6 carbocyclyl, 5- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl; 3-6 Carbocyclyl, C 6-10 Aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl independently represent 1 to 5 R G1 In some embodiments, R 22 は、-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≡CH、-C≡C-CH3、-C≡C-CF 3、 Unsubstituted cyclopropyl, unsubstituted cyclobutyl, 1 to 5 R H bicyclo[1.1.1]pentanyl optionally substituted with, or 1 to 5 R H In some embodiments, R 22 is —CHF, —CHF, —CF, or —CHCHCH(CH)(CF). In some embodiments, R 22 is —CH2OH, CH2OCH3, —CH2OCH2CH2OCH3, —CH2OCH(CH3)2, —CH2OCF3, or —CH2OCHF2.

[0029] In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1 In some embodiments, R is a 5-6 membered nitrogen-containing heteroaryl optionally substituted with 22 is one R G C replaced by 1-6 alkyl, and R G contains 1 to 4 nitrogen atoms and optionally 1 to 5 R G1 In some embodiments, R is a 5-6 membered nitrogen-containing heteroaryl substituted with 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 and R is a 5- to 6-membered heteroaryl substituted with G1 Each instance of is independently cyano, oxo, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R 22 is 1 to 5 R G1 C optionally substituted with 3-6 Carbocyclyl-substituted C 1-6 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1In some embodiments, R is a 5-8 membered nitrogen-containing heterocyclyl optionally substituted with 22 is one R G C replaced by 1-6 alkyl, and R G contains one nitrogen atom and 1 to 5 R G1 In some embodiments, R is a 5-8 membered nitrogen-containing heterocyclyl optionally substituted with 22 is one R G C replaced by 1-6 alkyl, and R G is an unsubstituted 5-8 membered heterocyclyl.

[0030] In some embodiments, R 22 is the unsubstituted C 1-6 In some embodiments, R 22 is -CH3, -CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2-CH2CH2CH(CH3)2, or -C(CH3)3.

[0031] In some embodiments, R 22 is a substituted or unsubstituted C 2-6 In some embodiments, R is alkenyl. 22 is 1 to 5 R G C optionally substituted with 2-6 In some embodiments, R is alkenyl. 22 is -CH=CH2, -CH2CH=CH2, -CH=CHCH3, or -CH=C(CH3)2.

[0032] In some embodiments, R 22 is a substituted or unsubstituted C 2-6 In some embodiments, R is alkynyl. 22 is 1 to 5 R G C optionally substituted with 2-6 In some embodiments, R is alkynyl. 22 is -C≡CH, -C≡C-CH3, or -C≡C-CF3.

[0033] In some embodiments, R 22 is a substituted or unsubstituted C 3-6 In some embodiments, R 22 is 1 to 5 R H C optionally substituted with 3-6 In some embodiments, R 22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or 1 to 3 R H and bicyclo[1.1.1]pentanyl optionally substituted with

[0034] In some embodiments, R 22 is a substituted or unsubstituted C 6-10 In some embodiments, R 22 is 1 to 5 R H C optionally substituted with 6-10 In some embodiments, R 22 is unsubstituted phenyl. In some embodiments, R 22 is 1 to 3 R H is phenyl substituted with R H Each instance of is independently halo, cyano, and C optionally substituted with 1 to 5 halo. 1-6 alkyl.

[0035] In some embodiments, the compound of Formula (I) is any one of compounds 1-118, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one of 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, or 108. 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 727, 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 Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii). In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of a compound of any one of Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii). In some embodiments, the compounds provided herein are isotopic variants of any one of the compounds of formula (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii). In some embodiments, the compounds provided herein are isotopic variants of a pharmaceutically acceptable salt of any one of the compounds of Formula (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii).

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

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

[0039] In one aspect, the present 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 Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the present disclosure.

[0040] In one aspect, the present disclosure provides a method of 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 Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the present disclosure.

[0041] In one aspect, the present disclosure provides a compound of any one of Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-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 Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in negative allosteric modulation of an NMDA receptor.

[0043] In one aspect, the disclosure provides use of a compound of any one of Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-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 use of a compound of any one of Formulas (I), (IA), (IB), (IA-1), (IA-2), (IA-1-i), (IA-1-ii), (IA-2-i), (IA-2-ii), (IB-1), (IB-2), (IB-1-i), (IB-1-ii), (IB-2-i), and (IB-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 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, seizures or seizure disorders, 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 OF THE INVENTION

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

[0047] General definition The term "herein" means the entire application.

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

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

[0050] It will be understood that throughout this specification the term "comprises" or variations such as "comprises" or "comprises" means 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 this specification, when a composition is described as having, including, or comprising (or variations thereof) specific components, it is contemplated that the composition can also consist essentially of, or consist of, the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process can also consist essentially of, or consist of, the recited processing steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein are operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0052] As used herein, the term "comprises" means "including, but not limited to." "Comprises" 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, the term "about" or "approximately" means within an acceptable error range for a 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] In the context of describing elements (particularly in the context of the claims that follow), the use of the terms "a," "an," and "the" and similar referents should be construed to encompass both the singular and the plural unless otherwise indicated in the specification or clearly contradicted by context.

[0055] The term "or" as used herein should be understood to mean "and / or" unless the context clearly dictates otherwise.

[0056] Recitation of ranges of values ​​herein, unless otherwise indicated herein, is merely intended to serve as a shorthand method of referring individually to each different value falling within the range, including the endpoints, and each different value is incorporated herein as if it were individually referred to herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or 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 illustrate embodiments and does not present a limitation on the scope of the claims unless otherwise expressly stated. No language in the specification should be construed as indicating any non-claimed element as essential.

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

[0058] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the inside cover of the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 102nd edition, and specific functional groups are generally defined as described therein. Further, the 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, 8 th Edition, John Wiley & Sons, Inc., New Jersey, 2020, Larock, Comprehensive Organic Transformations, 3 rd Edition, 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, 4 th Edition, Cambridge University Press, Cambridge, 2004.

[0059] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. 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 chromatography (SFC), and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. 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 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the 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 called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn, Ingold, and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0061] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In certain embodiments, the weights are based on the 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 indicated absolute stereochemistry expressed as a percentage of the total amount of the indicated compound and its diastereomers.

[0062] The term "diastereomerically pure" means that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or more than 99.9% by weight of a 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 diastereomer, such as high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).

[0063] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-position / center / carbon compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipients and about 10% of the enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0064] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3H (T or tritium) and C may be in any isotopic form. 12 C. 13 C, and 14 C may be in any isotopic form, including O 16 O and 18 It may be in any isotopic form, including O.

[0065] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0066] The following terms are intended to have the meanings presented below and are useful in understanding the specification and intended scope of the present disclosure. It is also understood that, as described herein, any moiety defined herein may be substituted with various substituents, and that each definition is intended to include such substituted moieties within its scope, as described below. Unless otherwise specified, the term "substituted" is intended to be defined as described below. It should be further understood that the terms "group" and "radical" can be considered interchangeable when used herein.

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

[0068] "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-20 In some embodiments, an alkyl group refers to a radical of 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has one carbon atom (C alkyl). 1-6 Examples of alkyl 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 with one or more substituents, e.g., 1 to 4 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkyl"). Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0069] As used herein, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl groups, 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 a linear, divalent carbon chain. "Alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0070] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, for example substituted with one or more halo, -NO2, -OH, C1-C6 alkoxy, C1-C6 alkyl (e.g., methyl) groups, include 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)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), or C1-C6 cycloalkyl. 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)-, -(CH2CH(CH3)CH2CH2CH2)-, -(CH2CH(CH3)CH2CH2)-, -(CH2CH(CH3)CH2CH2)-, and -(CH2CH2CH(CH3)CH2CH2)-.

[0071] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 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) ("C 2-20In certain embodiments, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has two carbon atoms (C alkenyl). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl groups include 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 ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0072] "Alkenylene" refers to an alkenyl group in which two hydrogens have been removed to provide a divalent radical, 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=CHCH-, -CH-CH=CH-). Exemplary substituted alkenylene groups, for example, substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH)=CH-, -CH=C(CH)-), substituted propylene (e.g., -C(CH)=CHCH-, -CH=C(CH)CH-, -CH=CHCH(CH)-, -CH=CHC(CH)-, -CH(CH)-CH=CH-, -C(CH)-CH=CH-, -CH-C(CH)=CH-, -CH-CH=C(CH)-).

[0073] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 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) ("C 2-20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms (C alkynyl). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkynyl groups include 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 with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0074] "Alkynylene" refers to a straight-chain alkynyl group in which 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] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2In 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 ("heteroC 2-6 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, a heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is alkyl.

[0076] As used herein, the term "heteroalkenyl" refers to an alkenyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or wherein one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2-10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2-3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-6 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, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0077] As used herein, the term "heteroalkynyl" refers to an alkynyl group, as defined herein, further comprising 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 are inserted between adjacent carbon atoms within the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl"). 2-10In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("heteroC 2-3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-6 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, a heteroalkynyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[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 π electrons shared within the cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms provided within the aromatic ring system ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). "Aryl" also includes ring systems in which the aryl ring, as defined herein, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues 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 ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0079] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0080] Representative examples of substituted aryl include: [ka] In the formula, R 56 and R 57 One of R may be hydrogen; 56 and R 57 At least one of the following is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl, or R 56 and R 57 are joined to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from N, O, or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0081] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or 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 the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared within the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl ring or the heteroaryl ring; in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), and the point of attachment can be on either ring, i.e., the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

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

[0085] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.

[0086] Representative examples of heteroaryls include: [ka] where each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0087] "Nitrogen-containing heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared by the cyclic array) having ring carbon atoms and containing at least one nitrogen atom. Examples of nitrogen-containing heteroaryl groups include, 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" means a ring system of 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 As the carbocyclyl group, the aforementioned C 3-6 Examples of carbocyclyl groups include, but are not limited to, 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. 3-10 As the carbocyclyl group, the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. As the foregoing examples illustrate, in certain embodiments, carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or include fused, bridged, or spiro ring systems, such as bicyclic systems, and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring is fused to one or more aryl or heteroaryl groups, as defined herein, and the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 It is a carbocyclyl.

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

[0091] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups may be either monocyclic (a "monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems (a "bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems, where a heterocyclyl ring, as defined herein, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring, or on the ring system; and where a heterocyclyl ring, as defined herein, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues 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 ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

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

[0093] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6 bicyclic heterocycle) include, but are not limited to, 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 heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0094] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups mentioned above, such as alkyl, e.g., heteroalkyl, having 1 to 5, especially 1 to 3, heteroatoms; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and cycloalkenyl, e.g., cycloheteroalkenyl.

[0095] "Acyl" is the radical -C(O)R 20 refers to R 20 is 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, and R 20 is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21is C1-C8 alkyl substituted with halo or hydroxy, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0096] "Alkoxy" is -OR 29 R refers to the group 29 is 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 is an alkyl group having 1 to 6 carbon atoms ("C 1-6 In some embodiments, the alkoxy group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the alkoxy group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the alkoxy group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the alkoxy group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkoxy group has one carbon atom (C alkoxy). 1-6Examples of alkoxy 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., alkoxy groups having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0097] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 A group having one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and especially 1 substituent, selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 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 -O-(CH2) t (C6-C 10 Aryl)-O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl), and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present can itself be substituted with unsubstituted C-C alkyl, halo, unsubstituted C-C alkoxy, unsubstituted C-C haloalkyl, unsubstituted C-C hydroxyalkyl, or unsubstituted C-C haloalkoxy or hydroxy. Certain exemplary "substituted alkoxy" groups are -OCF, -OCHCF, -OCHPh, -OCH-cyclopropyl, -OCHCHOH, and -OCHCHNMe.

[0098] "Amino" refers to the radical -NH2.

[0099] "Substituted amino" refers to a group of the formula -N(R 38 )2, and R 38 is 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 an amino protecting group; R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6-C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3-C 10 cycloalkyl), or -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted with 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 R 38 The groups are linked to form an alkylene group.

[0100] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 cycloalkyl), and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent H or C1-C8 alkyl, and any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkyl or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups as defined below. Substituted amino includes both mono- and di-substituted amino groups.

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

[0102] "Cyano" refers to the radical -CN.

[0103] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, a halo group is either fluorine or chlorine.

[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.

[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] A "nitrogen-containing heterocyclyl" group refers to a 5- to 8-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but not limited to, 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-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0109] "Thioketo" refers to the group ═S.

[0110] "Imino" is R N is hydrogen, alkyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl, or any combination selected therefrom; N Refers to...

[0111] "Oxo" refers to the group =O.

[0112] "Thiol" refers to the group --SH.

[0113] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups 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," means that at least one hydrogen (e.g., a carbon or nitrogen atom) present on the group is replaced with a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, 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 substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein, that result 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 substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0114] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSRcc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2Raa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or substituted with a group, Or two geminal hydrogens on a carbon atom can be =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc is substituted with a group R aa Each example of C 1-10 Alkyl, C 1-10Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R aa Each example is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bbThe groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd is substituted with a group, R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NRff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2,-NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2,-OP(=O)(OR ee ) 2、 C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents combine to form =O or =S; R ee Each instance of 1-6 Alkyl, C 1-6 Perhaloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg is substituted with a group, R ff Each instance of is independently hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff The groups may be joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may independently contain 0, 1, 2, 3, 4, or 5 R gg substituted with a group, and R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S, where X - is the counterion.

[0115] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electron neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2 Examples of such ions include sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonic acid-5-sulfonate ion, and ethane-1-sulfonic acid-2-sulfonate ion), and carboxylate ions (e.g., acetate ion, ethanoate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, and glycolate ion).

[0116] Nitrogen atoms can be substituted or unsubstituted where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined above. Other definitions

[0117] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government, or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0118] "Pharmaceutically acceptable salts" refers to salts of the compounds disclosed herein that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with 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-hydroxybenzoic acid)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-methylbis(2-methyl- ... (2) acid addition salts formed with organic acids such as chloro[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylbutyric acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (3) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts further include, by way of example only, salts of non-toxic organic or inorganic acids such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and, if the compound contains a basic functional group, hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion 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 that are pharmaceutically acceptable materials that can be administered to or by a subject. A pharmaceutically acceptable carrier may be involved in carrying or transporting the subject agent from one organ or part of the body to another. The carrier may be in the form of a solid, semi-solid, or liquid diluent, cream, or capsule. The active ingredient may be mixed with an excipient that is pharmaceutically acceptable, compatible with the active ingredient, and in an amount suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, and 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) in which one or more atoms are 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 may be incorporated into compounds of the present application include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 18 F, and 37 Compounds disclosed herein that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopic variants of the compounds of the present application, such as radioactive isotopes (e.g., 3 H and 14Isotopic variants incorporating heavier isotopes (e.g., 2 H) can confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopic variants of the compounds disclosed herein and pharmaceutically acceptable salts thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and / or Examples, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0121] "Subjects" to which administration is contemplated include, but are not limited to, human subjects (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, 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 terms "treat," "treating," or "treatment" include reversing, alleviating, or halting symptoms, clinical signs, and underlying pathology in a manner that improves or stabilizes the subject's condition. As used herein and as known 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, improvement, lessening of severity, or delay in progression of one or more symptoms or conditions associated with a condition, whether detectable or undetectable, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation of the condition, and remission (partial or complete). "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment. Exemplary beneficial clinical results are described herein.

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

[0125] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present disclosure can vary depending on factors such as the desired biological end point, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health and condition of the subject.The effective amount encompasses both 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, for example, to effect a beneficial and / or desirable change in the health of a patient suffering from the disease, to treat, cure, inhibit, or ameliorate a physiological response or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. The full therapeutic effect does not necessarily occur by administration of a single dose, but 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 required for a subject will depend, for example, on the subject's size, health, and age, the nature and extent of the disease, the therapeutic agent or combination of therapeutic agents selected for administration, and the mode of administration. One of ordinary skill in the art 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 refers to the amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness 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 an amount sufficient to prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, that 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 effectiveness of another prophylactic agent.

[0128] As used herein, and unless otherwise specified, "pharmacokinetics" may be defined as the study of the absorption, distribution, metabolism, and excretion of a drug in the body. "Pharmacokinetics" may also be defined as the characteristic interactions of a drug with the body in terms of its absorption, distribution, metabolism, and excretion, or the branch of pharmacology that pertains to the way drugs are taken up, moved into, and eliminated from the body.

[0129] "Administering" or "administration of" a substance, compound, or agent to a subject can be performed using one of a variety of methods known to those of skill in the art. For example, a compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through the skin tract). A compound or agent can also be suitably introduced by rechargeable or biodegradable polymeric or other devices, e.g., patches and pumps, or formulations that provide extended, delayed, or controlled release of the compound or agent. Administration can be performed, for example, once, multiple times, and / or over one or more extended periods of time. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a patient is administered a drug by a physician who instructs the patient to self-administer the drug or have the drug administered by another person and / or provides the patient with a prescription for the drug. If the method is part of a treatment regimen involving more than one agent or treatment modality, the present disclosure contemplates that the agents may be administered at the same or different times and via the same or different routes of administration. The appropriate method of administering a substance, compound, or agent to a subject will also depend, for example, on the subject's age, whether the subject is active or inactive at the time of administration, whether the subject is cognitively impaired at the time of administration, the degree of impairment, and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability, and toxicity) of the compound or agent.

[0130] As generally described herein, the present disclosure provides compounds useful for the prevention and / or treatment of a wide range of disorders, including, but not limited to, NMDA-mediated disorders. These compounds are expected to exhibit improved in vivo efficacy, pharmacokinetic (PK) properties, oral bioavailability, formulation, stability, and / or safety compared to other compounds. compound

[0131] A compound having the structure of formula (I): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof (e.g., an isotopic variant of a pharmaceutically acceptable salt), wherein: R 3 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted 5- to 8-membered heteroaryl; R 15 and R 16 each independently represents hydrogen or a substituted or unsubstituted C 1-6 alkyl, or R 15 and R 16 are substituted or unsubstituted C together with the carbon atoms to which they are attached. 3-6 forming a carbocyclyl, R 18 is hydrogen, or substituted or unsubstituted C 1-6 is alkyl, R 19 is hydrogen, or substituted or unsubstituted C 1-6 is alkyl, R 20 is hydrogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 3-6 is a carbocyclyl, R 20’ is hydrogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 3-6 is a carbocyclyl, However, R 20 and R 20’ are both not hydroxyl, and R 22 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclyl, or substituted or unsubstituted C 6-10 is aryl, However, R 22 is -CH3, R 3 is not —CH 3 or hydrogen, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0132] In some embodiments, the compound of the present disclosure is a compound of formula (I), wherein: R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 6-10 aryl or 5- to 8-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 6-10 Aryl and 5- to 8-membered heteroaryl independently have 1 to 5 R A optionally substituted with R 15 and R 16 each independently represents hydrogen or 1 to 5 R B C optionally substituted with 1-6 alkyl, or R 15 and R16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 forming a carbocyclyl, R 18 is hydrogen or 1 to 5 R C C optionally substituted with 1-6 is alkyl, R 19 is hydrogen or 1 to 5 R D C optionally substituted with 1-6 is alkyl, R 20 is hydrogen, hydroxyl, C 1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R E optionally substituted with R 20’ is hydrogen, hydroxyl, C 1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R F optionally substituted with However, R 20 and R 20’ are both hydroxyl, R A , R B , R C , R D , R E , and R F Each example, when present, is independently selected from halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 C optionally substituted with aryl and 1 to 5 halo 1-6 alkoxy; R 22 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl or C6-10 aryl, and the aforementioned C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl independently has 1 to 5 R G and optionally substituted with the aforementioned C 3-6 Carbocyclyl and C 6-10 Aryl independently represents 1 to 5 R H optionally substituted with However, R 22 is -CH3, R 3 is not -CH3 or hydrogen, R G Each instance, if present, is independently halo, hydroxyl, cyano, C optionally substituted with 1 to 5 halo. 1-6 Alkoxy, C 3-6 Carbocyclyl, C 6-10 aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl; 3-6 Carbocyclyl, C 6-10 Aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl independently represent 1 to 5 R G1 optionally substituted with R G1 Each instance, if present, is independently halo, cyano, oxo, nitro, amino, C optionally substituted with 1 to 5 halo. 1-6 C optionally substituted with alkyl and 1 to 5 halo 1-6 alkoxy; and R H Each instance, if present, is independently halo, cyano, nitro, amino, C optionally substituted with 1 to 5 halo. 1-6 C optionally substituted with alkyl and 1 to 5 halo 1-6 A compound of formula (I) selected from the group consisting of alkoxy, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0133] In some embodiments, the compounds of the present disclosure are compounds of formula (IA) or (IB): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0134] In some embodiments, the compounds of the present disclosure are compounds of formula (IA-1) or (IA-2): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0135] In some embodiments, the compounds of the present disclosure are compounds of formula (IA-1-i) or (IA-1-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0136] In some embodiments, the compounds of the present disclosure are compounds of formula (IA-2-i) or (IA-2-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0137] In some embodiments, the compounds of the present disclosure are compounds of formula (IB-1) or (IB-2): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0138] In some embodiments, the compounds of the present disclosure are compounds of formula (IB-1-i) or (IB-1-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0139] In some embodiments, the compounds of the present disclosure are compounds of formula (IB-2-i) or (IB-2-ii): [ka] or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0140] In some embodiments, the compound of formula (I) is a compound, wherein: R 3 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 5 R A optionally substituted with R 15 is hydrogen or 1 to 5 R B C optionally substituted with 1-6 is alkyl, R 16 is hydrogen, or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 forming a carbocyclyl, R 18 is 1 to 5 R C C optionally substituted with 1-6 is alkyl, R 20 is hydrogen, hydroxyl, or 1 to 5 R E C optionally substituted with 1-6 alkyl, and R 20’ is hydrogen or 1 to 5 R F C optionally substituted with 1-6 a compound which is alkyl, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0141] In some embodiments, the compound of formula (I) is a compound, wherein: R 3 is 1 to 5 R A C optionally substituted with 1-6 is alkyl, R 15 is hydrogen or 1 to 5 R B C optionally substituted with 1-6 is alkyl, R 16 is hydrogen, or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 forming a carbocyclyl, R 18 is -CH3, R 20 is hydrogen, R 20’ is -CH3, and R 22 is C 1-6 Alkyl or C 2-6 alkynyl, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 5 R G a compound optionally substituted with or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0142] In some embodiments, the compound of formula (I) is a compound, wherein: R 3 is 1 to 5 R A is a C1 alkyl substituted with R 15 and R 16 is hydrogen, R 18 and R 19 is -CH3, R20 is hydrogen, R 20’ is -CH3, and R 22 is the unsubstituted C 1-6 C optionally substituted with alkoxy 1-6 a compound which is alkyl, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0143] In some embodiments, the compound of formula (I) is a compound, wherein: R 3 is 1 to 5 R A is a C1 alkyl substituted with R 15 and R 16 is hydrogen, R 18 and R 19 is -CH3, R 20 is hydrogen, R 20’ is -CH3, and R 22 is -CH3 or -CH2OCH3, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. R 3 and R A Groups—these relate to formulae (I), (IA), (IA-1), (IA-1-i), (IA-1-ii), (IA-2), (IA-2-i), (IA-2-ii), (IB), (IB-1), (IB-1-1), (IB-1-ii), (IB-2), (IB-2-i), and (IB-2-ii)

[0144] In certain embodiments, R 3 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R 3 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R 3 is a substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 2-6 It is alkynyl.

[0145] In some embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, or 5- to 8-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 6-10 Aryl and 5- to 8-membered heteroaryl independently have 1 to 5 R A In some embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, or 5- to 8-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, C 6-10 Aryl and 5- to 8-membered heteroaryl independently have 1 to 3 R A In some embodiments, R 3 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, or substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, or 5- to 8-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl and 5- to 8-membered heteroaryl are independently 1 to 5 R A In some embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 carbocyclyl, or 5- to 8-membered heteroaryl, 1-6 Alkyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl and 5- to 8-membered heteroaryl are independently 1 to 3 R A In some embodiments, R 3 is a substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 2-6 In some embodiments, R is alkynyl. 3 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkenyl independently has 1 to 5 R A In some embodiments, R 3 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkenyl independently has 1 to 5 R A In some embodiments, R 3 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6Alkenyl independently has 1 to 3 R A In some embodiments, R 3 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkenyl independently has 1 to 3 R A In some embodiments, R 3 is —H, —CH2F, —CHF2, —CF3, —CH2OCH3, —CH2OH, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C≡CH, —C≡C—CH3, cyclopropyl, or pyridyl, and said cyclopropyl and pyridyl are independently selected from 1 to 5 R A In some embodiments, R 3 is —H, —CH2F, —CHF2, —CF3, —CH2OCH3, —CH2OH, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C≡CH, —C≡C—CH3, cyclopropyl, or pyridyl, and said cyclopropyl and pyridyl are independently selected from 1 to 5 R A In some embodiments, R 3 is —H, —CH2F, —CHF2, —CF3, —CH2OCH3, —CH2OH, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C≡CH, —C≡C—CH3, cyclopropyl, or pyridyl, and said cyclopropyl and pyridyl are independently selected from 1 to 3 R A In some embodiments, R 3 is —H, —CH2F, —CHF2, —CF3, —CH2OCH3, —CH2OH, —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —C≡CH, —C≡C—CH3, cyclopropyl, or pyridyl, and said cyclopropyl and pyridyl are independently selected from 1 to 3 R A In some embodiments, R 3is -H, -CH2F, -CHF2, -CF3, -CH2OCH3, -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C≡CH, -C≡C-CH3, unsubstituted cyclopropyl, or unsubstituted pyridyl.

[0146] In certain embodiments, R 3 is hydrogen.

[0147] In certain embodiments, R 3 is a substituted or unsubstituted C 1-6 In some embodiments, R 3 is 1 to 5 R A C optionally substituted with 1-6 In some embodiments, R 3 is 1 to 3 R A C optionally substituted with 1-6 In some embodiments, R 3 is one R A C optionally substituted with 1-6 In some embodiments, R 3 is 1 to 5 R A C optionally substituted with 1-3 In some embodiments, R 3 is 1 to 3 R A C optionally substituted with 1-3 In some embodiments, R 3 is 1 to 3 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A C replaced by 1-6In some embodiments, R 3 is 1 to 3 R A C replaced by 1-6 In some embodiments, R 3 is one R A C replaced by 1-6 In some embodiments, R 3 is 1 to 5 R A C replaced by 1-3 In some embodiments, R 3 is 1 to 3 R A C replaced by 1-3 In some embodiments, R 3 is 1 to 3 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A isopropyl substituted with

[0148] In certain embodiments, R 3 is a substitution C 1-6 In certain embodiments, R 3 is 1 to 5 R A C replaced by 1-6 In certain embodiments, R 3 is 1 to 5 R A C replaced by 1-6 In some embodiments, R 3 is 1 to 3 R A C replaced by 1-6 In some embodiments, R 3 is a substitution C 1-3 In some embodiments, R 3 is 1 to 5 R A C replaced by 1-3In some embodiments, R 3 is 1 to 3 R A C replaced by 1-3 In some embodiments, R 3 is one R A C replaced by 1-3 In certain embodiments, R 3 is 1 to 3 R A In some embodiments, R 3 is 1 to 3 R A is methyl substituted with R A Each instance of is independently halo, hydroxyl, or unsubstituted C 1-6 In some embodiments, R 3 is 1 to 3 R A is methyl substituted with R A Each instance of is independently fluoro, hydroxyl, or —OCH. In some embodiments, R 3 is —CHF, —CHF, —CF, —CHOCH, or —CHOH. In some embodiments, R 3 is 1 to 3 R A is methyl substituted with R A is fluoro. In some embodiments, R 3 is —CHF, —CHF, or —CF. In some embodiments, R 3 is -CHF. In some embodiments, R 3 is -CHF. In some embodiments, R 3 is -CF3. In some embodiments, R 3 is 1 to 3 R A is methyl substituted with R A is hydroxyl. In some embodiments, R 3 is —CHOH. In some embodiments, R 3 is 1 to 3 R A is methyl substituted with R A is —OCH. In some embodiments, R 3is —CH2OCH3. In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A isopropyl substituted with

[0149] In certain embodiments, R 3 is the unsubstituted C 1-6 In some embodiments, R 3 is the unsubstituted C 1-3 In some embodiments, R 3 is —CH, —CHOCH, —CHCHCH, or —CH(CH). In some embodiments, R 3 is -CH3 or -CH2CH3. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CH2CH3. In some embodiments, R 3 is -CH2CH2CH3. In some embodiments, R 3 is -CH(CH3)2.

[0150] In certain embodiments, R 3 is a substituted or unsubstituted C 2-6 In some embodiments, R is alkynyl. 3 is 1 to 5 R A C optionally substituted with 2-6 In some embodiments, R is alkynyl. 3 is 1 to 3 R A C optionally substituted with 2-6 In some embodiments, R is alkynyl. 3 is one R A C optionally substituted with 2-6 In some embodiments, R is alkynyl. 3 is the unsubstituted C 2-6In certain embodiments, R 3 is a substituted or unsubstituted C 2-3 In some embodiments, R is alkynyl. 3 is 1 to 5 R A C optionally substituted with 2-3 In some embodiments, R is alkynyl. 3 is 1 to 5 R A C replaced by 2-6 In some embodiments, R is alkynyl. 3 is 1 to 3 R A C replaced by 2-6 In some embodiments, R is alkynyl. 3 is one R A C replaced by 2-6 In some embodiments, R is alkynyl. 3 is 1 to 5 R A C replaced by 2-3 In some embodiments, R is alkynyl. 3 is the unsubstituted C 2-3 In some embodiments, R is alkynyl. 3 is —C≡CH or —C≡C—CH. In some embodiments, R 3 is one R A In some embodiments, R 3 is one R A In some embodiments, R is ethynyl substituted with 3 is -C≡CH. In some embodiments, R 3 is 1 to 3 R A In some embodiments, R 3 is 1 to 3 R A In some embodiments, R 3 is -C≡C-CH3.

[0151] In certain embodiments, R 3 is a substituted or unsubstituted C 2-6 In some embodiments, R is alkenyl. 3is 1 to 5 R A C optionally substituted with 2-6 In some embodiments, R is alkenyl. 3 is 1 to 3 R A C optionally substituted with 2-6 In some embodiments, R is alkenyl. 3 is one R A C optionally substituted with 2-6 In some embodiments, R is alkenyl. 3 is a substitution C 2-6 In some embodiments, R is alkenyl. 3 is 1 to 5 R A C replaced by 2-6 In some embodiments, R is alkenyl. 3 is 1 to 3 R A C replaced by 2-6 In some embodiments, R is alkenyl. 3 is one R A C replaced by 2-6 In some embodiments, R is alkenyl. 3 is the unsubstituted C 2-6 In some embodiments, R is alkenyl. 3 is a substituted or unsubstituted C 2-4 In some embodiments, R is alkenyl. 3 is 1 to 5 R A C optionally substituted with 2-4 In some embodiments, R is alkenyl. 3 is 1 to 5 R A C replaced by 2-4 In some embodiments, R is alkenyl. 3 is the unsubstituted C 2-4 In certain embodiments, R 3 is 1 to 3 R A In certain embodiments, R 3 is 1 to 3 R A In certain embodiments, R is ethenyl substituted with 3 is unsubstituted ethenyl. In certain embodiments, R 3 is 1 to 5 RA In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is unsubstituted propenyl. In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is unsubstituted butenyl.

[0152] In certain embodiments, R 3 is a substituted or unsubstituted C 3-6 In some embodiments, R 3 is 1 to 5 R A C optionally substituted with 3-6 In some embodiments, R 3 is 1 to 3 R A C optionally substituted with 3-6 In some embodiments, R 3 is one R A C optionally substituted with 3-6 In some embodiments, R 3 is the unsubstituted C 3-6 In some embodiments, R 3 is 1 to 5 R A C optionally substituted with 3-4 In some embodiments, R 3 is the unsubstituted C 3-4 In some embodiments, R 3 is a substitution C 3-6 In some embodiments, R 3 is 1 to 5 R A C replaced by 3-6 In some embodiments, R 3 is 1 to 3 R AC replaced by 3-6 In some embodiments, R 3 is one R A C replaced by 3-6 In some embodiments, R 3 is 1 to 5 R A C replaced by 3-4 In certain embodiments, R 3 is cyclopropyl or cyclobutyl, each of which independently represents 1 to 5 R A In certain embodiments, R 3 is unsubstituted cyclopropyl or unsubstituted cyclobutyl. In certain embodiments, R 3 is cyclopropyl or cyclobutyl, each of which independently represents 1 to 5 R A In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is unsubstituted cyclobutyl. In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is unsubstituted cyclopropyl.

[0153] In certain embodiments, R 3 is a substituted or unsubstituted 5-8 membered heteroaryl. In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is 1 to 3 R A In certain embodiments, R 3 is one RA In some embodiments, R is a 5-8 membered heteroaryl optionally substituted with 3 is a substituted 5-8 membered heteroaryl. In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is 1 to 3 R A In certain embodiments, R 3 is one R A In certain embodiments, R 3 is unsubstituted 5-8 membered heteroaryl. In certain embodiments, R 3 is a substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is unsubstituted 5-6 membered heteroaryl. In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is a substituted 5-6 membered heteroaryl. In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R 3 is 1 to 5 R A In certain embodiments, R is a 5-6 membered nitrogen-containing heteroaryl substituted with 3 is an unsubstituted 5-6 membered nitrogen-containing heteroaryl. In certain embodiments, R 3 contains one nitrogen atom and optionally 1 to 5 R A In certain embodiments, R is a 5-6 membered nitrogen-containing heteroaryl substituted with 3 contains one nitrogen atom and 1 to 5 R AIn certain embodiments, R is a 5-6 membered nitrogen-containing heteroaryl substituted with 3 is an unsubstituted 5-6 membered nitrogen-containing heteroaryl containing one nitrogen atom. In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is unsubstituted pyridyl.

[0154] In certain embodiments, R 3 is a substituted or unsubstituted C 6-10 In some embodiments, R 3 is 1 to 5 R A C optionally substituted with 6-10 In some embodiments, R 3 is 1 to 3 R A C optionally substituted with 6-10 In some embodiments, R 3 is one R A C optionally substituted with 6-10 In certain embodiments, R 3 is a substitution C 6-10 In some embodiments, R 3 is 1 to 5 R A C replaced by 6-10 In some embodiments, R 3 is 1 to 3 R A C replaced by 6-10 In some embodiments, R 3 is one R A C replaced by 6-10 In certain embodiments, R 3 is the unsubstituted C 6-10 In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 RA In some embodiments, R 3 is unsubstituted phenyl. In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is 1 to 5 R A In some embodiments, R 3 is unsubstituted naphthyl.

[0155] In certain embodiments, R A Examples of each, when present, are halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 Aryl, and substituted or unsubstituted C 1-6 In certain embodiments, R A Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C 1-6 In some embodiments, R A Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R A Each example, when present, includes halo, hydroxyl, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R A Each example, when present, is halo, hydroxyl, and unsubstituted C 1-6 In some embodiments, R A Each example, when present, is fluoro, hydroxyl, and unsubstituted C 1-6 In some embodiments, R A Each instance of, when present, is independently selected from the group consisting of fluoro, hydroxyl, and —OCH. In some embodiments, RA Each instance of R, when present, is fluoro. A Each instance of R, when present, is hydroxyl. In some embodiments, R A Each instance, when present, is -OCH3. R 15 , R 16 , and R B Groups - which are related to formula (I), (IA), (IA-1), (IA-1-i), (IA-1-ii), (IA-2), (IA-2-i), (IA-2-ii), (IB), (IB-1), (IB-1-1), (IB-1-ii), (IB-2), (IB-2-i), and (IB-2-ii)

[0156] In certain embodiments, R 15 is hydrogen or substituted or unsubstituted C 1-6 In certain embodiments, R 15 is hydrogen. In certain embodiments, R 15 is a substituted or unsubstituted C 1-6 In some embodiments, R 15 is hydrogen or 1 to 5 R B C optionally substituted with 1-6 In some embodiments, R 15 is hydrogen or 1 to 3 R B C optionally substituted with 1-6 In some embodiments, R 15 is hydrogen or one R B C optionally substituted with 1-6 In some embodiments, R 15 is hydrogen or 1 to 5 R B C replaced by 1-6 In some embodiments, R 15 is hydrogen or 1 to 3 R B C replaced by 1-6 In some embodiments, R 15 is hydrogen or one R B C replaced by 1-6In certain embodiments, R 15 is hydrogen or unsubstituted C 1-6 In some embodiments, R 15 is hydrogen or unsubstituted C 1-3 In some embodiments, R 15 is hydrogen or —CH. In some embodiments, R 15 is hydrogen. In some embodiments, R 15 is -CH3.

[0157] In certain embodiments, R 16 is hydrogen or substituted or unsubstituted C 1-6 In certain embodiments, R 16 is hydrogen. In certain embodiments, R 16 is a substituted or unsubstituted C 1-6 In some embodiments, R 16 is hydrogen or 1 to 5 R B C optionally substituted with 1-6 In some embodiments, R 16 is hydrogen or 1 to 3 R B C optionally substituted with 1-6 In some embodiments, R 16 is hydrogen or one R B C optionally substituted with 1-6 In some embodiments, R 16 is hydrogen or 1 to 5 R B C replaced by 1-6 In some embodiments, R 16 is hydrogen or 1 to 3 R B C replaced by 1-6 In some embodiments, R 16 is hydrogen or one R B C replaced by 1-6 In some embodiments, R 16 is hydrogen or unsubstituted C 1-6 In some embodiments, R 16 is hydrogen or unsubstituted C1-3 In some embodiments, R 16 is hydrogen or —CH. In some embodiments, R 16 is hydrogen.

[0158] In certain embodiments, R 15 and R 16 each independently represents hydrogen or a substituted or unsubstituted C 1-6 alkyl or R 15 and R 16 are substituted or unsubstituted C together with the carbon atoms to which they are attached. 3-6 In certain embodiments, R 15 and R 16 each independently represents hydrogen or 1 to 5 R B C optionally substituted with 1-6 alkyl or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 In certain embodiments, R 15 and R 16 each independently represents hydrogen or 1 to 5 R B C replaced by 1-6 alkyl or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C replaced by 3-6 In some embodiments, R 15 is hydrogen or 1 to 5 R B C optionally substituted with 1-6 alkyl, and R 16 is hydrogen or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 In some embodiments, R 15 is hydrogen or 1 to 5 R BC replaced by 1-6 alkyl, and R 16 is hydrogen or R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C replaced by 3-6 In certain embodiments, R 15 and R 16 is hydrogen. In certain embodiments, R 15 and R 16 is a substituted or unsubstituted C 1-6 In some embodiments, R 15 and R 16 is 1 to 5 R B C optionally substituted with 1-6 In some embodiments, R 15 and R 16 is 1 to 5 R B C replaced by 1-6 In some embodiments, R 15 and R 16 is the unsubstituted C 1-6 In some embodiments, R 15 and R 16 is the unsubstituted C 1-3 In some embodiments, R 15 and R 16 is -CH3. In certain embodiments, R 15 is a substituted or unsubstituted C 1-6 alkyl, and R 16 is hydrogen. In some embodiments, R 15 is 1 to 5 R B C optionally substituted with 1-6 alkyl, and R 16 is hydrogen. In some embodiments, R 15 is 1 to 5 R B C replaced by 1-6 alkyl, and R 16 is hydrogen. In some embodiments, R 15 is the unsubstituted C 1-6 alkyl, and R 16is hydrogen. In some embodiments, R 15 is the unsubstituted C 1-3 alkyl, and R 16 is hydrogen. In some embodiments, R 15 is -CH3 and R 16 is hydrogen. In certain embodiments, R 15 is hydrogen and R 16 is a substituted or unsubstituted C 1-6 In some embodiments, R 15 is hydrogen and R 16 is 1 to 5 R B C optionally substituted with 1-6 In some embodiments, R 15 is hydrogen and R 16 is 1 to 5 R B C replaced by 1-6 In some embodiments, R 15 is hydrogen and R 16 is the unsubstituted C 1-6 In some embodiments, R 15 is hydrogen and R 16 is the unsubstituted C 1-3 In some embodiments, R 15 is hydrogen and R 16 is -CH3.

[0159] In certain embodiments, R 15 and R 16 are substituted or unsubstituted C together with the carbon atoms to which they are attached. 3-6 In certain embodiments, R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C optionally substituted with 3-6 In certain embodiments, R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B C replaced by 3-6 In some embodiments, R15 and R 16 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which independently contains 1 to 5 R B In some embodiments, R 15 and R 16 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which independently contains 1 to 5 R B In some embodiments, R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B In some embodiments, R 15 and R 16 are made up of 1 to 5 R atoms, along with the carbon atoms to which they are attached. B In some embodiments, R 15 and R 16 together with the carbon atom to which they are attached form an unsubstituted cyclopropyl.

[0160] In certain embodiments, R B Examples of each, when present, are halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 Aryl, and substituted or unsubstituted C 1-6 In certain embodiments, R B Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C 1-6 In some embodiments, R B Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R BEach example, when present, includes halo, hydroxyl, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R B Each example, when present, includes fluoro, hydroxyl, and C optionally substituted with 1 to 5 fluoro. 1-6 In some embodiments, R B Each instance, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. R 18 , R 19 , R C , and R D Groups—these relate to formulae (I), (IA), (IA-1), (IA-1-i), (IA-1-ii), (IA-2), (IA-2-i), (IA-2-ii), (IB), (IB-1), (IB-1-1), (IB-1-ii), (IB-2), (IB-2-i), and (IB-2-ii)

[0161] In certain embodiments, R 18 is hydrogen or substituted or unsubstituted C 1-6 In some embodiments, R 18 is hydrogen or 1 to 5 R C C optionally substituted with 1-6 In some embodiments, R 18 is hydrogen or 1 to 5 R C C replaced by 1-6 In some embodiments, R 18 is hydrogen or 1 to 3 R C C optionally substituted with 1-6 In some embodiments, R 18 is hydrogen or 1 to 3 R C C replaced by 1-6 In some embodiments, R 18 is hydrogen or one R C C optionally substituted with 1-6In some embodiments, R 18 is hydrogen or one R C C replaced by 1-6 In some embodiments, R 18 is hydrogen or unsubstituted C 1-6 In some embodiments, R 18 is hydrogen or unsubstituted C 1-3 In some embodiments, R 18 is hydrogen, -CH3, or -CH2CH3.

[0162] In some embodiments, R 18 is hydrogen.

[0163] In some embodiments, R 18 is a substituted or unsubstituted C 1-6 In some embodiments, R 18 is a substitution C 1-6 In some embodiments, R 18 is 1 to 5 R C C optionally substituted with 1-6 In some embodiments, R 18 is 1 to 5 R C C replaced by 1-6 In some embodiments, R 18 is the unsubstituted C 1-6 In some embodiments, R 18 is the unsubstituted C 1-3 In some embodiments, R 18 is -CH3 or -CH2CH3. In some embodiments, R 18 is -CH3.

[0164] In certain embodiments, R 19 is hydrogen or substituted or unsubstituted C 1-6 In some embodiments, R 19 is hydrogen or 1 to 5 R D C optionally substituted with 1-6In some embodiments, R 19 is hydrogen or 1 to 5 R D C replaced by 1-6 In some embodiments, R 19 is hydrogen or 1 to 3 R D C optionally substituted with 1-6 In some embodiments, R 19 is hydrogen or 1 to 3 R D C replaced by 1-6 In some embodiments, R 19 is hydrogen or one R D C optionally substituted with 1-6 In some embodiments, R 19 is hydrogen or one R D C replaced by 1-6 In some embodiments, R 19 is hydrogen or unsubstituted C 1-6 In some embodiments, R 19 is hydrogen or unsubstituted C 1-3 In some embodiments, R 19 is hydrogen or -CH3.

[0165] In certain embodiments, R 19 is hydrogen.

[0166] In certain embodiments, R 19 is a substituted or unsubstituted C 1-6 In some embodiments, R 19 is a substitution C 1-6 In some embodiments, R 19 is 1 to 5 R D C optionally substituted with 1-6 In some embodiments, R 19 is 1 to 5 R D C replaced by 1-6 In some embodiments, R 19 is the unsubstituted C 1-6 In some embodiments, R19 is the unsubstituted C 1-3 In some embodiments, R 19 is -CH3.

[0167] In certain embodiments, R 18 and R 19 is hydrogen. In some embodiments, R 18 and R 19 is a substituted or unsubstituted C 1-6 In some embodiments, R 18 is 1 to 5 R C C optionally substituted with 1-6 alkyl, and R 19 is 1 to 5 R D C optionally substituted with 1-6 In some embodiments, R 18 is 1 to 5 R C C replaced by 1-6 alkyl, and R 19 is 1 to 5 R D C replaced by 1-6 In some embodiments, R 18 and R 19 is the unsubstituted C 1-6 In some embodiments, R 18 and R 19 is the unsubstituted C 1-3 In some embodiments, R 18 is -CH2CH3, and R 19 is -CH3. In some embodiments, R 18 and R 19 is -CH3. In some embodiments, R 18 is hydrogen and R 19 is a substituted or unsubstituted C 1-6 In some embodiments, R 18 is hydrogen and R 19 is 1 to 5 R D C optionally substituted with 1-6 In some embodiments, R 18 is hydrogen and R 19is 1 to 5 R D C replaced by 1-6 In some embodiments, R 18 is hydrogen and R 19 is the unsubstituted C 1-6 In some embodiments, R 18 is hydrogen and R 19 is the unsubstituted C 1-3 In some embodiments, R 18 is hydrogen and R 19 is -CH3. In some embodiments, R 18 is a substituted or unsubstituted C 1-6 alkyl, and R 19 is hydrogen. In some embodiments, R 18 is 1 to 5 R C C optionally substituted with 1-6 alkyl, and R 19 is hydrogen. In some embodiments, R 18 is 1 to 5 R C C replaced by 1-6 alkyl, and R 19 is hydrogen. In some embodiments, R 18 is the unsubstituted C 1-6 alkyl, and R 19 is hydrogen. In some embodiments, R 18 is the unsubstituted C 1-3 alkyl, and R 19 is hydrogen. In some embodiments, R 18 is -CH3 and R 19 is hydrogen.

[0168] In certain embodiments, R C Examples of each, when present, are halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 Aryl, and substituted or unsubstituted C 1-6 In certain embodiments, R C Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C 1-6In some embodiments, R C Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R C Each example, when present, includes halo, hydroxyl, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R C Each example, when present, includes fluoro, hydroxyl, and C optionally substituted with 1 to 5 fluoro. 1-6 In some embodiments, R C Each instance, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3.

[0169] In certain embodiments, R D Examples of each, when present, are halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 Aryl, and substituted or unsubstituted C 1-6 In certain embodiments, R D Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C 1-6 In some embodiments, R D Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R D Each example, when present, includes halo, hydroxyl, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R D Each example, when present, includes fluoro, hydroxyl, and C optionally substituted with 1 to 5 fluoro.1-6 In some embodiments, R D Each instance, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. R 20 , R 20’ , R E , and R F Groups - which are related to formula (I), (IA), (IA-1), (IA-1-i), (IA-1-ii), (IA-2), (IA-2-i), (IA-2-ii), (IB), (IB-1), (IB-1-1), (IB-1-ii), (IB-2), (IB-2-i), and (IB-2-ii)

[0170] In certain embodiments, R 20 is hydrogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 3-6 In certain embodiments, R 20 is hydrogen, hydroxyl, C 1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R E In certain embodiments, R 20 is hydrogen, hydroxyl, C 1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R E In certain embodiments, R 20 is hydrogen, hydroxyl, or 1 to 5 R E C optionally substituted with 1-6 In certain embodiments, R 20 is hydrogen, hydroxyl, or 1 to 5 R E C replaced by 1-6 In certain embodiments, R 20is hydrogen, hydroxyl, or 1 to 3 R E C optionally substituted with 1-6 In certain embodiments, R 20 is hydrogen, hydroxyl, or 1 to 3 R E C replaced by 1-6 In certain embodiments, R 20 is hydrogen, hydroxyl, or unsubstituted C 1-6 In certain embodiments, R 20 is hydrogen, hydroxyl, or unsubstituted C 1-3 In certain embodiments, R 20 is hydrogen, hydroxyl, or —CH3.

[0171] In certain embodiments, R 20 is hydrogen.

[0172] In certain embodiments, R 20 is a hydroxyl.

[0173] In certain embodiments, R 20 is a substituted or unsubstituted C 1-6 In certain embodiments, R 20 is a substitution C 1-6 In some embodiments, R 20 is 1 to 5 R F C optionally substituted with 1-6 In some embodiments, R 20 is 1 to 5 R F C replaced by 1-6 In some embodiments, R 20 is the unsubstituted C 1-6 In some embodiments, R 20 is the unsubstituted C 1-3 In some embodiments, R 20 is -CH3.

[0174] In certain embodiments, R 20 is a substituted or unsubstituted C 3-6In certain embodiments, R 20 is a substitution C 3-6 In some embodiments, R 20 is 1 to 5 R F C optionally substituted with 3-6 In some embodiments, R 20 is 1 to 5 R F C replaced by 3-6 In some embodiments, R 20 is the unsubstituted C 3-6 In certain embodiments, R 20 is the unsubstituted C 3-4 In certain embodiments, R 20 is unsubstituted cyclobutyl. In certain embodiments, R 20 is unsubstituted cyclopropyl.

[0175] In certain embodiments, R 20’ is hydrogen, hydroxyl, substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 3-6 In some embodiments, R 20’ is hydrogen, hydroxyl, C 1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R F In some embodiments, R 20’ is hydrogen, hydroxyl, C 1-6 Alkyl or C 3-6 carbocyclyl, and the aforementioned C 1-6 Alkyl and C 3-6 Carbocyclyl independently has 1 to 5 R F In some embodiments, R 20’ is hydrogen or 1 to 5 R F C optionally substituted with 1-6 In some embodiments, R 20’ is hydrogen or 1 to 5 RF C replaced by 1-6 In some embodiments, R 20’ is hydrogen or 1 to 3 R F C optionally substituted with 1-6 In some embodiments, R 20’ is hydrogen or 1 to 3 R F C replaced by 1-6 In some embodiments, R 20’ is hydrogen or unsubstituted C 1-6 In some embodiments, R 20’ is hydrogen or unsubstituted C 1-3 In some embodiments, R 20’ is hydrogen or -CH3.

[0176] In certain embodiments, R 20’ is hydrogen.

[0177] In certain embodiments, R 20’ is a hydroxyl.

[0178] In certain embodiments, R 20’ is a substituted or unsubstituted C 1-6 In some embodiments, R 20’ is a substitution C 1-6 In some embodiments, R 20’ is 1 to 5 R F C optionally substituted with 1-6 In some embodiments, R 20’ is 1 to 5 R F C replaced by 1-6 In some embodiments, R 20’ is the unsubstituted C 1-6 In some embodiments, R 20’ is the unsubstituted C 1-3 In some embodiments, R 20’ is -CH3.

[0179] In certain embodiments, R20’ is a substituted or unsubstituted C 3-6 In certain embodiments, R 20’ is a substitution C 3-6 In some embodiments, R 20’ is 1 to 5 R F C optionally substituted with 3-6 In some embodiments, R 20’ is 1 to 5 R F C replaced by 3-6 In some embodiments, R 20’ is the unsubstituted C 3-6 In certain embodiments, R 20’ is the unsubstituted C 3-4 In certain embodiments, R 20’ is unsubstituted cyclobutyl. In certain embodiments, R 20’ is unsubstituted cyclopropyl.

[0180] In certain embodiments, R 20 is hydrogen, hydroxyl, or substituted or unsubstituted C 1-6 alkyl, and R 20’ is hydrogen or substituted or unsubstituted C 1-6 In some embodiments, R 20 is hydrogen, hydroxyl, or 1 to 5 R E C optionally substituted with 1-6 alkyl, and R 20’ is hydrogen or 1 to 5 R F C optionally substituted with 1-6 In some embodiments, R 20 is hydrogen, hydroxyl, or 1 to 5 R E C replaced by 1-6 alkyl, and R 20’ is hydrogen or 1 to 5 R F C replaced by 1-6 In some embodiments, R 20 is hydrogen and R 20’ is a substitution C 1-6In some embodiments, R 20 is hydrogen and R 20’ is 1 to 5 R F C optionally substituted with 1-6 In some embodiments, R 20 is hydrogen and R 20’ is 1 to 5 R F C replaced by 1-6 In some embodiments, R 20 is hydrogen and R 20’ is the unsubstituted C 1-6 In some embodiments, R 20 is hydrogen and R 20’ is the unsubstituted C 1-3 In some embodiments, R 20 is hydrogen and R 20’ is -CH3. In some embodiments, R 20 is a substitution C 1-6 alkyl, and R 20’ is hydrogen. In some embodiments, R 20 is 1 to 5 R E C optionally substituted with 1-6 alkyl, and R 20’ is hydrogen. In some embodiments, R 20 is 1 to 5 R E C replaced by 1-6 alkyl, and R 20’ is hydrogen. In some embodiments, R 20 is the unsubstituted C 1-6 alkyl, and R 20’ is hydrogen. In some embodiments, R 20 is the unsubstituted C 1-3 alkyl, and R 20’ is hydrogen. In some embodiments, R 20 is -CH3 and R 20’ is hydrogen. In some embodiments, R 20 is hydroxyl and R 20’ is a substitution C 1-6 In some embodiments, R 20is hydroxyl and R 20’ is 1 to 5 R F C optionally substituted with 1-6 In some embodiments, R 20 is hydroxyl and R 20’ is 1 to 5 R F C replaced by 1-6 In some embodiments, R 20 is hydroxyl and R 20’ is the unsubstituted C 1-6 In certain embodiments, R 20 is hydroxyl and R 20’ is the unsubstituted C 1-3 In certain embodiments, R 20 is hydroxyl and R 20’ is —CH3. In certain embodiments, R 20 is 1 to 5 R E C optionally substituted with 1-6 alkyl, and R 20’ is 1 to 5 R F C optionally substituted with 1-6 In certain embodiments, R 20 is 1 to 5 R E C replaced by 1-6 alkyl, and R 20’ is 1 to 5 R F C replaced by 1-6 In certain embodiments, R 20 and R 20’ is the unsubstituted C 1-6 In certain embodiments, R 20 and R 20’ is the unsubstituted C 1-3 In certain embodiments, R 20 and R 20’ is -CH3. In certain embodiments, R 20 and R 20’ is hydrogen.

[0181] In certain embodiments, R EExamples of each, when present, are halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 Aryl, and substituted or unsubstituted C 1-6 In certain embodiments, R E Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C 1-6 In some embodiments, R E Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R E Each example, when present, includes halo, hydroxyl, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R E Each example, when present, includes fluoro, hydroxyl, and C optionally substituted with 1 to 5 fluoro. 1-6 In some embodiments, R E Each instance, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3.

[0182] In certain embodiments, R F Examples of each, when present, are halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C 6-10 Aryl, and substituted or unsubstituted C 1-6 In certain embodiments, R F Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C 1-6 In some embodiments, R F Each example, when present, includes halo, hydroxyl, cyano, nitro, amino, and C optionally substituted with 1 to 5 halo. 1-6In some embodiments, R F Each example, when present, includes halo, hydroxyl, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R F Each example, when present, includes fluoro, hydroxyl, and C optionally substituted with 1 to 5 fluoro. 1-6 In some embodiments, R F Each instance, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH3, and -OCF3. R 22 , R G , R G1 , and R H Groups—these relate to formulae (I), (IA), (IA-1), (IA-1-i), (IA-1-ii), (IA-2), (IA-2-i), (IA-2-ii), (IB), (IB-1), (IB-1-1), (IB-1-ii), (IB-2), (IB-2-i), and (IB-2-ii).

[0183] In certain embodiments, R 22 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclyl, or substituted or unsubstituted C 6-10 In certain embodiments, R 22 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, or C 6-10 aryl, and the aforementioned C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl independently has 1 to 5 R G and optionally substituted with the aforementioned C 3-6 Carbocyclyl and C6-10 Aryl independently represents 1 to 5 R H In certain embodiments, R 22 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, or C 6-10 aryl, and the aforementioned C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl independently has 1 to 5 R G is replaced by the aforementioned C 3-6 Carbocyclyl and C 6-10 Aryl independently represents 1 to 5 R H In certain embodiments, R 22 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, or C 6-10 aryl, and the aforementioned C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl independently has 1 to 3 R G and optionally substituted with the aforementioned C 3-6 Carbocyclyl and C 6-10 Aryl independently contains 1 to 3 R H In certain embodiments, R 22 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, or C 6-10 aryl, and the aforementioned C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl independently has 1 to 3 R G is replaced by the aforementioned C 3-6 Carbocyclyl and C 6-10 Aryl independently contains 1 to 3 R H In certain embodiments, R 22 is C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclyl, or C 6-10 In some embodiments, R 22 is a substituted or unsubstituted C 1-6 Alkyl, or substituted or unsubstituted C 2-6 In some embodiments, R is alkynyl. 22 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 5 R G In some embodiments, R 22 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 5 R G In some embodiments, R 22 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 3 R G In some embodiments, R 22 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has 1 to 3 R G In some embodiments, R 22 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6 Alkyl and C 2-6 Alkynyl independently has one R G In some embodiments, R 22 is C 1-6 Alkyl or C 2-6 Alkynyl, as defined above, 1-6Alkyl and C 2-6 Alkynyl independently has one R G In some embodiments, R 22 is the unsubstituted C 1-6 Alkyl or unsubstituted C 2-6 In some embodiments, R is alkynyl. 22 -CH2F, -CHF2, -CF3, -CH2CH2CH(CH3)(CF3), -CH2OH, -CH2OCH3, -CH2OCH2CH2OCH3, -CH2OCH(CH3)2, -CH2OCF3, -CH2OCHF2, -CH3, -CH2CH3, -CH2 CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CH=C(CH3)2, -C≡CH, -C≡C-CH3, -C≡C-CF 3、 Unsubstituted cyclopropyl, unsubstituted cyclobutyl, 1 to 5 R H bicyclo[1.1.1]pentanyl optionally substituted with, or 1 to 5 R H is phenyl optionally substituted with

[0184] In certain embodiments, R 22 is a substituted or unsubstituted C 1-6 In certain embodiments, R 22 is 1 to 5 R G C optionally substituted with 1-6 In certain embodiments, R 22 is 1 to 3 R G C optionally substituted with 1-6 In certain embodiments, R 22 is one R G C optionally substituted with 1-6 In some embodiments, R 22 is 1 to 3 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 RG In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G In some embodiments, R 22 is 1 to 5 R G is tert-pentyl optionally substituted with

[0185] In certain embodiments, R 22 is a substitution C 1-6 In certain embodiments, R 22 is 1 to 5 R G C replaced by 1-6 In certain embodiments, R 22 is 1 to 3 R G C replaced by 1-6 In certain embodiments, R 22 is the unsubstituted C 1-6 In some embodiments, R22 is 1 to 3 R G C replaced by 1-6 alkyl, and R G Each instance of is independently halo, hydroxyl, C optionally substituted with 1 to 5 halo. 1-6 Alkoxy, C 3-6 carbocyclyl, 5- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl; 3-6 Carbocyclyl, 5- to 8-membered heterocyclyl, and 5- to 8-membered heteroaryl each independently represent 1 to 5 R G1 In some embodiments, R 22 is 1 to 3 R G C replaced by 1-6 alkyl, and R G Each instance of is independently halo, hydroxyl, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R is selected from the group consisting of alkoxy. 22 is 1 to 3 R G C replaced by 1-6 alkyl, and R G is halo. In some embodiments, R 22 is —CHF, —CHF, —CF, or —CHCHCH(CH)(CF). In some embodiments, R 22 is 1 to 3 R G C replaced by 1-6 alkyl, and R G Each instance of is independently hydroxyl, or C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R 22 is 1 to 3 R G is methyl substituted with R G Each instance of is independently C optionally substituted with halo, hydroxyl, and 1 to 3 fluoro. 1-6 In some embodiments, R is selected from the group consisting of alkoxy. 22 is 1 to 3 R G is methyl substituted with R G is halo. In some embodiments, R 22is 1 to 3 R G is methyl substituted with R G is fluoro. In some embodiments, R 22 is —CHF, —CHF, or —CF. In some embodiments, R 22 is 1 to 3 R G is methyl substituted with R G Each instance of is independently C optionally substituted with hydroxyl or 1 to 3 fluoro. 1-6 In some embodiments, R 22 is —CH2OH, —CH2OCH3, —CH2OCH2CH2OCH3, —CH2OCH(CH3)2, —CH2OCF3, or —CH2OCHF2.

[0186] In certain embodiments, R 22 is one R G C replaced by 1-6 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is a substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1 In some embodiments, R is a 5-8 membered heteroaryl optionally substituted with 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 In some embodiments, R is a 5-8 membered heteroaryl optionally substituted with 22 is one R G C replaced by 1-6 alkyl, and R G is one R G1 In some embodiments, R is a 5-8 membered heteroaryl optionally substituted with 22 is one R GC replaced by 1-6 alkyl, and R G is 1 to 5 R G1 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1 In some embodiments, R is a 5-6 membered nitrogen-containing heteroaryl optionally substituted with 22 is one R G C replaced by 1-6 alkyl, and R G contains 1 to 4 nitrogen atoms and 1 to 5 R G1 In some embodiments, R is a 5-6 membered nitrogen-containing heteroaryl optionally substituted with 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 and R is a 5- to 6-membered heteroaryl substituted with G1 Each instance of is independently a C optionally substituted with cyano, oxo, or 1 to 5 halo. 1-6 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is pyrazolyl, tetrazolyl, or pyridinonyl, each of which independently represents 1 to 3 R G1 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is pyrazolyl, tetrazolyl, or pyridonyl, each of which independently represents 1 to 3 R G1 optionally substituted with R G1 Each instance of is independently cyano or C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R 22 is one R G C replaced by1-6 alkyl, and R G is 1 to 3 R G1 pyrazolyl optionally substituted with R G1 Each instance of is independently cyano or C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 and R is a pyrazolyl substituted with G1 is cyano. In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is one R G1 and R is a pyrazolyl substituted with G1 is cyano. In some embodiments, R 22 is one R G is methyl substituted with R G is one R G1 and R is a pyrazolyl substituted with G1 is cyano. In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 tetrazolyl optionally substituted with R G1 are independently cyano or C optionally substituted with 1 to 5 halo 1-6 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 tetrazolyl optionally substituted with R G1 is C optionally substituted with 1 to 5 halo 1-6 In some embodiments, R 22 is one R G C replaced by 1-6alkyl, and R G is 1 to 3 R G1 tetrazolyl substituted with R G1 is C optionally substituted with 1 to 5 halo 1-6 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 tetrazolyl substituted with R G1 is the unsubstituted C 1-6 In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 tetrazolyl substituted with R G1 is -CH3. In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is one R G1 tetrazolyl substituted with R G1 is -CH3. In some embodiments, R 22 is one R G is methyl substituted with R G is one R G1 tetrazolyl substituted with R G1 is -CH3. In some embodiments, R 22 is one R G1 C replaced by 1-6 alkyl, and R G1 is unsubstituted pyridinonyl. In some embodiments, R 22 is one R G1 is methyl substituted with R G1 is unsubstituted pyridinonyl.

[0187] In certain embodiments, R 22 is one R G C replaced by 1-6alkyl, and R G is a substituted or unsubstituted C 3-6 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1 C optionally substituted with 3-6 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 C optionally substituted with 3-6 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 C replaced by 3-6 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is the unsubstituted C 3-6 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is the unsubstituted C 3-4 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is unsubstituted cyclopropyl. In certain embodiments, R 22 is one R G is methyl substituted with R G is the unsubstituted C 3-4 In certain embodiments, R 22 is one R G is methyl substituted with R G is unsubstituted cyclopropyl.

[0188] In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is a substituted or unsubstituted 5-8 membered heterocyclyl. In some embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 5 R G1 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is 1 to 3 R G1 In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is unsubstituted 5-8 membered heterocyclyl. In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is an unsubstituted 5-8 membered nitrogen-containing heterocyclyl. In certain embodiments, R 22 is one R G C replaced by 1-6 alkyl, and R G is an unsubstituted 5-8 membered nitrogen-containing heterocyclyl containing one nitrogen atom. 22 is one R G C replaced by 1-6 alkyl, and R G is unsubstituted pyrrolidinonyl. In certain embodiments, R 22 is one R G C replaced by 1-3 alkyl, and R G is unsubstituted pyrrolidinonyl. In certain embodiments, R 22 is one R G is methyl substituted with RG is unsubstituted pyrrolidinonyl.

[0189] In certain embodiments, R 22 is the unsubstituted C 1-6 In some embodiments, R 22 is -CH3, -CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R 22 is -CH3, -CH2CH3, -CH2CH2CH2CH3, or -CH(CH3)2. In some embodiments, R 22 is -CH3. In some embodiments, R 22 is -CH2CH3. In some embodiments, R 22 is -CH2CH2CH2CH3. In some embodiments, R 22 is —CH(CH). In some embodiments, R 22 is —CHCH(CH)2. In some embodiments, R 22 is -CH2CH2CH(CH3)2. In some embodiments, R 22 is -C(CH3)3.

[0190] In certain embodiments, R 22 is a substituted or unsubstituted C 2-6 In some embodiments, R is alkenyl. 22 is 1 to 5 R G C optionally substituted with 2-6 In some embodiments, R is alkenyl. 22 is 1 to 3 R G C optionally substituted with 2-6 In some embodiments, R is alkenyl. 22 is one R G C optionally substituted with 2-6 In some embodiments, R is alkenyl. 22 is 1 to 5 R G C optionally substituted with 2-4In some embodiments, R is alkenyl. 22 is 1 to 3 R G C optionally substituted with 2-4 In certain embodiments, R 22 is one R G C optionally substituted with 2-4 In some embodiments, R 22 is 1 to 5 R G C replaced by 2-6 In some embodiments, R is alkenyl. 22 is 1 to 3 R G C replaced by 2-6 In some embodiments, R is alkenyl. 22 is one R G C replaced by 2-6 In some embodiments, R is alkenyl. 22 is 1 to 5 R G C replaced by 2-4 In some embodiments, R is alkenyl. 22 is 1 to 3 R G C replaced by 2-4 In certain embodiments, R 22 is one R G C replaced by 2-4 In some embodiments, R is alkenyl. 22 is the unsubstituted C 2-6 In some embodiments, R is alkenyl. 22 is the unsubstituted C 2-6 In some embodiments, R is alkenyl. 22 is the unsubstituted C 2-4 In some embodiments, R is alkenyl. 22 is -CH=CH, -CHCH=CH, -CH=CHCH, or -CH=C(CH). In some embodiments, R 22 is -CH=CH2. In some embodiments, R 22 is -CHCH=CH. In some embodiments, R 22 is -CH=CHCH3. In some embodiments, R 22is -CH=C(CH3)2.

[0191] In certain embodiments, R 22 is a substituted or unsubstituted C 2-6 In some embodiments, R is alkynyl. 22 is 1 to 5 R G C optionally substituted with 2-6 In some embodiments, R is alkynyl. 22 is 1 to 3 R G C optionally substituted with 2-6 In some embodiments, R is alkynyl. 22 is one R G C optionally substituted with 2-6 In some embodiments, R is alkynyl. 22 is 1 to 5 R G C optionally substituted with 2-3 In some embodiments, R is alkynyl. 22 is 1 to 3 R G C optionally substituted with 2-3 In some embodiments, R is alkynyl. 22 is 1 to 5 R G C replaced by 2-6 In some embodiments, R is alkynyl. 22 is 1 to 3 R G C replaced by 2-6 In some embodiments, R is alkynyl. 22 is one R G C replaced by 2-6 In some embodiments, R is alkynyl. 22 is 1 to 5 R G C replaced by 2-3 In some embodiments, R is alkynyl. 22 is 1 to 3 R G C replaced by 2-3 In some embodiments, R is alkynyl. 22 is —C≡CH, —C≡C—CH3, or —C≡C—CF3. In some embodiments, R 22 is 1 to 3 R G C replaced by2-3 In some embodiments, R is alkynyl. 22 is 1 to 3 R G C replaced by 2-3 alkynyl, and R G is halo. In some embodiments, R 22 is 1 to 3 R G C replaced by 2-3 alkynyl, and R G is fluoro. In some embodiments, R 22 is —C≡C—CF. In some embodiments, R 22 is the unsubstituted C 2-6 In some embodiments, R is alkynyl. 22 is the unsubstituted C 2-3 In some embodiments, R is alkynyl. 22 is -C≡CH or -C≡C-CH3.

[0192] In certain embodiments, R 22 is a substituted or unsubstituted C 3-6 In certain embodiments, R 22 is 1 to 5 R H C optionally substituted with 3-6 In some embodiments, R 22 is 1 to 3 R H C optionally substituted with 3-6 In some embodiments, R 22 is one R H C optionally substituted with 3-6 In certain embodiments, R 22 is 1 to 5 R H C replaced by 3-6 In certain embodiments, R 22 is 1 to 5 R H Bicyclic C substituted with 3-6 In some embodiments, R 22 is 1 to 3 R H Bicyclic C substituted with 3-6 In some embodiments, R22 is one R H Bicyclic C substituted with 3-6 In some embodiments, R 22 is the unsubstituted C 3-6 In some embodiments, R 22 is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentanyl, each of which independently represents 1 to 5 R H In some embodiments, R 22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or 1 to 3 R H In some embodiments, R is bicyclo[1.1.1]pentanyl optionally substituted with 22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or one R H In some embodiments, R is bicyclo[1.1.1]pentanyl substituted with 22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or one R H bicyclo[1.1.1]pentanyl substituted with R H is —CH or —CF. In some embodiments, R 22 is unsubstituted cyclopropyl. In some embodiments, R 22 is unsubstituted cyclobutyl. In some embodiments, R 22 is 1 to 3 R H In some embodiments, R is bicyclo[1.1.1]pentanyl optionally substituted with 22 is 1 to 3 R H In some embodiments, R is bicyclo[1.1.1]pentanyl substituted with 22 is one R H In some embodiments, R is bicyclo[1.1.1]pentanyl substituted with 22 is one R H bicyclo[1.1.1]pentanyl substituted with R H is —CH or —CF. In some embodiments, R 22 is one R Hbicyclo[1.1.1]pentanyl substituted with R H is -CH3. In some embodiments, R 22 is one R H bicyclo[1.1.1]pentanyl substituted with R H is -CF3.

[0193] In certain embodiments, R 22 is a substituted or unsubstituted C 6-10 In some embodiments, R 22 is 1 to 5 R H C optionally substituted with 6-10 In some embodiments, R 22 is 1 to 5 R H C replaced by 6-10 In some embodiments, R 22 is 1 to 3 R H C optionally substituted with 6-10 In some embodiments, R 22 is 1 to 3 R H C replaced by 6-10 In some embodiments, R 22 is 1 to 5 R H In some embodiments, R 22 is 1 to 5 R H In some embodiments, R 22 is 1 to 3 R H In some embodiments, R 22 is 1 to 3 R H In some embodiments, R 22 is 1 to 3 R H phenyl optionally substituted with R H Each instance of is independently halo, cyano, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R 22 is 1 to 3 R H is phenyl substituted with RH Each instance of is independently halo, cyano, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R 22 is 1 to 3 R H phenyl optionally substituted with R H Each instance of is independently C optionally substituted with halo, cyano, and 1 to 5 fluoro. 1-6 In some embodiments, R 22 is 1 to 3 R H phenyl optionally substituted with R H Each instance of is independently fluoro, cyano, and unsubstituted C 1-6 In some embodiments, R 22 is 1 to 3 R H phenyl optionally substituted with R H Each instance of is independently selected from the group consisting of fluoro, cyano, and —CH. In some embodiments, R 22 is 1 to 3 R H phenyl optionally substituted with R H is fluoro. In some embodiments, R 22 is 1 to 3 R H phenyl optionally substituted with R H is -CH3. In some embodiments, R 22 is 1 to 3 R H phenyl optionally substituted with R H is cyano. In some embodiments, R 22 is the unsubstituted C 6-10 In some embodiments, R 22 is unsubstituted phenyl.

[0194] In certain embodiments, R G Each example, when present, is selected from halo, hydroxyl, cyano, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 6-10In some embodiments, R is independently selected from the group consisting of aryl, substituted or unsubstituted 5-8 membered heteroaryl, and substituted or unsubstituted 5-8 membered heterocyclyl. G Each instance, if present, is independently halo, hydroxyl, cyano, C optionally substituted with 1 to 5 halo. 1-6 Alkoxy, C 3-6 Carbocyclyl, C 6-10 aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl; 3-6 Carbocyclyl, C 6-10 Aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl independently represent 1 to 5 R G1 In some embodiments, R G Each instance, if present, is independently halo, hydroxyl, C optionally substituted with 1 to 5 halo. 1-6 Alkoxy, C 3-6 carbocyclyl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl; 3-6 Carbocyclyl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl independently have 1 to 5 R G1 In some embodiments, R G Each instance, if present, is independently halo, hydroxyl, C optionally substituted with 1 to 5 halo. 1-6 Alkoxy, unsubstituted C 3-6 Carbocyclyl, 1 to 5 R G1 In some embodiments, R is selected from the group consisting of 5-8 membered heteroaryl optionally substituted with R, and unsubstituted 5-8 membered heterocyclyl. G Each instance, if present, is independently halo, hydroxyl, C optionally substituted with 1 to 3 halo. 1-6 Alkoxy, unsubstituted C 3-6 Carbocyclyl, 1 to 3 R G1 In some embodiments, R is selected from the group consisting of 5-8 membered heteroaryl optionally substituted with R, and unsubstituted 5-8 membered heterocyclyl. GEach instance, if present, is independently halo, hydroxyl, C optionally substituted with 1 to 3 halo. 1-6 Alkoxy, unsubstituted C 3-6 Carbocyclyl, one R G1 In some embodiments, R is selected from the group consisting of 5-8 membered heteroaryl optionally substituted with R, and unsubstituted 5-8 membered heterocyclyl. G Each instance, when present, is independently selected from fluoro, hydroxyl, —OCH, —OCH(CH), —OCHF, —OCF, —OCHCHOCH, unsubstituted cyclopropyl, pyrazolyl, tetrazolyl, unsubstituted pyrrolidinonyl, and unsubstituted pyridinonyl, wherein the foregoing pyrazolyl and tetrazolyl are independently selected from one R G1 In some embodiments, R G Each instance, when present, is independently selected from fluoro, hydroxyl, —OCH, —OCH(CH), —OCHF, —OCF, —OCHCHOCH, unsubstituted cyclopropyl, pyrazolyl, tetrazolyl, unsubstituted pyrrolidinonyl, and unsubstituted pyridinonyl, wherein the foregoing pyrazolyl and tetrazolyl are independently selected from one R G1 is replaced by R G1 is cyano or —CH. In some embodiments, R G Each example, when present, is fluoro, -OCH, and one R G1 R is independently selected from the group consisting of: G1 is cyano.

[0195] In certain embodiments, R G1 Each example, when present, is selected from halo, cyano, oxo, nitro, amino, substituted or unsubstituted C 1-6 Alkyl, and substituted or unsubstituted C 1-6 In some embodiments, R G1 Each example, when present, is halo, cyano, nitro, amino, C optionally substituted with 1 to 5 halo. 1-6 C optionally substituted with alkyl and 1 to 5 halo 1-6In some embodiments, R G1 Each example, when present, is halo, cyano, C optionally substituted with 1 to 5 halo. 1-6 C optionally substituted with alkyl and 1 to 5 halo 1-6 In some embodiments, R G1 Each example, when present, is C optionally substituted with cyano and 1 to 5 halo. 1-6 In some embodiments, R G1 Each example, when present, is cyano and unsubstituted C 1-6 In some embodiments, R G1 Each instance of, when present, is independently selected from the group consisting of cyano and —CH. In some embodiments, R G1 Each instance of R, when present, is cyano. In some embodiments, R G1 Each instance, if present, is -CH3.

[0196] In certain embodiments, R H Each example, when present, is halo, cyano, nitro, amino, C optionally substituted with 1 to 5 halo. 1-6 C optionally substituted with alkyl and 1 to 5 halo 1-6 In some embodiments, R H Each instance, when present, includes halo, cyano, and C optionally substituted with 1 to 5 halo. 1-6 In some embodiments, R H Each instance of, when present, is independently selected from the group consisting of fluoro, cyano, —CH, and —CF. In some embodiments, R H Each instance of, when present, is independently selected from the group consisting of fluoro, cyano, and —CH. In some embodiments, R H Each instance of, when present, is independently selected from the group consisting of -CH3 and -CF3. In some embodiments, R HEach instance of R, when present, is fluoro. H Each instance of R, when present, is cyano. In some embodiments, R H Each instance of, when present, is -CH3. In some embodiments, R H Each instance, when present, is -CF3.

[0197] In some embodiments, the compound of Formula (I) is any one of the compounds in Table 1: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] and 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 in 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 in Table 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

[0199] It should 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, isotopic variant, or any chemically acceptable 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 an isotopic variant. In some embodiments, the compound is in a non-salt form or a pharmaceutically acceptable salt form. In some embodiments, the compound is in the form of a pharmaceutically acceptable salt and an isotopic variant.

[0200] Alternative Embodiments In some embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium), and carbon can be, for example, 11 C. 13 C, or 14 C, and oxygen may be, for example, 18 O, and the nitrogen may be, for example,15 In other embodiments, a specific isotope (e.g., 2 H, 13 C. 14 C. 18 O, or 15 N) 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 least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site on the compound.

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

[0202] Pharmaceutical Compositions 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, which can be prepared in a manner well known in the pharmaceutical arts and can contain at least one active compound.

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

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

[0206] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being 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 ointments, lotions, or patches, all for transdermal administration.

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

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

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

[0211] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient in an amount generally 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 an ointment, the active ingredient is typically combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream having, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance dermal penetration of the active ingredient or the stability of 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 of orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, as well as processing techniques and equivalents, are described 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-mentioned components of the orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described 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 the present 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 pharmaceutically acceptable formulations of the compounds described herein (e.g., compounds 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, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, and optionally contain one or more substituents on the attached sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0217] The present disclosure also relates to pharmaceutically acceptable acid addition salts of the compounds described herein (e.g., compounds of Formula (I)). Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, paratoluenesulfonate, and the like.

[0218] For the prevention and / or treatment of long-term conditions, treatment regimens typically span several months or years, and oral administration is preferred for patient convenience and tolerability. A typical oral administration regimen involves oral administration 1 to 5 times daily, particularly 2 to 4 times daily, and typically 3 times daily. Using these administration patterns, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

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

[0220] When used to prevent the onset of a CNS disorder, the compounds provided herein are typically administered at the dosage levels described above to subjects at risk of developing the condition under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0221] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending on the subject, the disease or disorder being treated, and the particular mode of administration. As one skilled in the art would understand, the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease or disorder, predisposition of the patient to the disease or disorder, and the judgment of the treating physician. Methods of Treatment and Use

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

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

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

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

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

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

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

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

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

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

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

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

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

[0235] In one aspect, the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition 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 present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition for the manufacture of a medicament for treating a CNS-related condition in a subject.

[0237] In one aspect, the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition 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 present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition for the manufacture of a medicament for preventing a CNS-related condition in a subject.

[0239] Examples of CNS conditions associated with negative allosteric modulation of NMDA receptors include adjustment disorders, stress or stress disorders (including post-traumatic stress disorder (PTSD)), anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, social anxiety disorder, and generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia), and attention disorders such as attention deficit hyperactivity disorder (ADHD)), eating disorders, mood disorders (including depression (e.g., postpartum depression)), bipolar disorder, mood disorders, dysthymic disorders, 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 (strong and tinnitus (TSC)), vascular disease (e.g., stroke, ischemia, vascular deformity), traumatic brain injury, movement disorders (including Huntington's disease, Parkinson's disease, and tremor), neuropsychiatric lupus, and tinnitus.

[0240] In certain embodiments, the compounds described herein (e.g., compounds of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations) are useful for the treatment or prevention of a CNS-related condition selected from adjustment disorder, anxiety disorder, cognitive disorder, mood disorder, personality disorder, neurodevelopmental disorder, 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, postpartum depression, bipolar disorder, dysthymic disorder, and suicidality. In some embodiments, the CNS-related condition referred to herein is a mood disorder selected from, for example, clinical depression, postpartum depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, mild depressive disorder, bipolar disorder or manic depression, depression caused by a chronic medical condition, treatment-resistant depression, treatment-refractory depression, suicidal tendencies, suicidal ideation, and suicidal behavior. In some embodiments, the CNS-related condition is selected from seizures, status epilepticus, Dravet's disease, or tuberous sclerosis complex. In some embodiments, the CNS-related condition is seizures selected from grand mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures. 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 movement disorders, tremor, myoclonus and startles, tics and Tourette's syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders. In some embodiments, the CNS-related condition is a tremor selected from cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's 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., compounds of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof) are useful for treating or preventing CNS-related conditions, including anxiety disorders, stress disorders, cognitive disorders (including Alzheimer's disease, mild cognitive impairment, and other forms of dementia (e.g., frontotemporal dementia)), mood disorders (including depression (e.g., postpartum depression)), personality disorders, addictive disorders (including drug addiction (e.g., cocaine addiction)), neurodevelopmental disorders, schizophrenia or other psychotic disorders (including schizoaffective disorder), pain (acute and chronic pain, neuropathic pain, headache), and the like. For example, migraine), seizure disorders (including monogenic forms of epilepsy such as status epilepticus and Dravet's disease, and tuberous sclerosis complex (TSC)), drug-induced dyskinesia (e.g., L-DOPA-induced dyskinesia (LID)), stroke, traumatic brain injury, adjustment disorder, autism spectrum disorder, fragile X syndrome (FXS), neuropsychiatric lupus, and tinnitus.

[0242] In certain embodiments, the compounds described herein (e.g., compounds of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof) are useful for treating or preventing a CNS-related condition, including but not limited to tremors, sleep disorders (e.g., insomnia), mood disorders (e.g., depression, dysthymic disorders (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), obsessive-compulsive disorders (e.g., obsessive-compulsive disorder (OCD)), integration disorders, and the like. Schizophrenia spectrum disorders (e.g., schizoaffective disorder), convulsive disorders (e.g., epilepsy (e.g., status epilepticus (SE)), seizures), neurodegenerative diseases and disorders, memory and / or cognitive disorders (e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewis body dementia, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism The condition is selected from the group consisting of autism with a genetic cause such as a synaptopathy, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, traumatic pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular deformity), 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., compounds of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof) are useful for treating Parkinson's disease. In some embodiments, the compounds described herein (e.g., compounds of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof) are useful as adjunctive treatments to L-DOPA for Parkinson's disease. The compounds described herein (e.g., compounds of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof) are useful for treating L-DOPA-induced dyskinesia (LID) in subjects suffering from Parkinson's disease.

[0244] In another aspect, there is provided a method of treating or preventing brain excitability in a subject susceptible to or suffering from 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, with another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or in combination with other agents. The administration of the combination can proceed by any technique apparent to one skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0246] Movement disorders Also described herein are methods for treating movement disorders.As used herein, "movement disorder" refers to various diseases and disorders associated with hyperkinetic movement disorders and related abnormalities in muscle control.Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette's syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

[0247] Tremor is the involuntary, sometimes rhythmic contraction and relaxation of muscles, which may involve vibration or spasms of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremors can be caused by genetic, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid and parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Lucy-Lewy, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (narcolepsy, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychiatric disorders. Clinical tremor can be classified into physiological tremor, intensified physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- and postural-specific tremor), dystonic tremor, Parkinson's tremor, cerebellar tremor, Holms tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor, or rubral tremor.

[0248] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after intentional movement.Cerebellar tremor is caused by lesions or damage to the cerebellum, such as tumors, stroke, or diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

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

[0250] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive or progress slowly, starting on one side of the body but affecting both sides within three years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor frequency may decrease with age, but severity may increase. Heightened emotions, stress, fever, physical fatigue, or hypoglycemia may trigger tremor and / or increase its severity. Symptoms generally progress over time and can be visible and persistent after onset.

[0251] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Cramps can be felt in the thighs and legs, and patients may sway uncontrollably when asked to stand in one place. Patients with essential tremor may experience orthostatic tremor.

[0252] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill-rolling" movement in the hands, and can also affect the jaw, lips, legs, and trunk. The onset of Parkinsonian tremor typically begins after the age of 60. Movements can begin in one limb or one side of the body and progress to involve the other side.

[0253] Physiological tremor can occur in normal individuals and has 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 thyroid overactivity and hypoglycemia. Tremor typically has a frequency of about 10 Hz.

[0254] Psychogenic or hysterical tremor can occur at rest, during postural maintenance, or during motor activity. Patients with psychogenic tremor may have conversion disorder or another psychiatric illness.

[0255] Rubral tremor is characterized by a coarse, slow tremor that can be present at rest, posturally, and at will. The tremor is associated with classic aberrant stroke, a condition affecting the red nucleus of the midbrain.

[0256] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms with Parkinson's disease, but is a group of conditions rather than a progressive neurodegenerative disease.

[0257] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, or tremor-like. Dystonia is often initiated or exacerbated by voluntary actions and is associated with overflow muscle activation.

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

[0259] Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0260] Ataxia refers to the complete loss of control over bodily movements and can affect fingers, hands, arms, legs, torso, speech, and eye movements.

[0261] Myoclonus and startle are responses to sudden, unexpected stimuli that can be auditory, tactile, visual, or vestibular.

[0262] Tics are involuntary movements that usually have sudden onset; they are brief, repetitive, but not rhythmic, typically mimic normal behavior, and often occur against a background of normal activity. Tics can be classified as motor or vocal; motor tics are associated with movement, and vocal tics are 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's syndrome is a childhood-onset, inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0264] Restless legs syndrome is a neurological sensorimotor disorder characterized by an overwhelming urge to move the legs while at rest.

[0265] Stiff-person syndrome is a progressive movement disorder characterized by involuntary, painful spasms and muscle stiffness, usually involving the lower back and legs. A stiff-legged gait with exaggerated lumbar hyperlordosis of the lower back is a typical outcome. Characteristic abnormalities in EMG recordings with serial motor unit activity of the paraaxial muscles are typically observed. Variants include "stiff limb syndrome," which produces focal stiffness typically affecting the distal legs and feet.

[0266] Gait disorders refer to abnormalities in the manner or style of walking due to neuromuscular, arthritic, or other physical changes. Gaits are classified according to the system responsible for the abnormal movement and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0267] Mood disorders Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, mild depressive disorder, bipolar disorder or manic depression, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior.

[0268] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have sleep problems, lose weight, and are generally agitated and irritable. Clinical depression affects an individual's emotions, thoughts, and behaviors and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble performing daily activities and feel that life is not worth living.

[0269] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after giving birth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying spells, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression described herein). In some embodiments, the PND is a treatment-refractory depression (e.g., a treatment-refractory depression described herein).

[0270] In some embodiments, subjects with PND also experienced depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, subjects who experience perinatal depression are at increased risk of experiencing PND.

[0271] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, marked weight gain, or increased appetite. Patients with AD may also have significant social impairments as a result of excessive sleep or sleepiness (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

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

[0273] Psychotic major depression (PMD) or psychotic depression refers to major depressive episodes, particularly of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0274] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become silent and stuporous, immobile, or exhibit aimless or bizarre movements.

[0275] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes occurring in the fall or winter.

[0276] Dysthymia refers to a condition related to unipolar depression that manifests with the same physical and cognitive problems, but which tend to be less severe and last longer (e.g., at least 2 years).

[0277] Dual depression refers to a significant depressed mood (dysthymia) lasting at least two years and interrupted by periods of major depression.

[0278] Depressive personality disorder (DPD) refers to a personality disorder that has depressive features.

[0279] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, each lasting less than two weeks, typically less than two to three days.

[0280] Mild depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0281] Bipolar disorder or manic depression causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may feel or behave abnormally happy, active, or irritable. They often make poorly considered decisions with little consideration for the consequences. The need for sleep is usually reduced. During depressive periods, individuals may cry, make less eye contact with others, and have a negative outlook on life. The risk of suicide for people with the disorder is high, exceeding 6% over a 20-year period, and self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

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

[0283] Treatment-resistant depression refers to a state in which an individual has been treated for depression but their symptoms do not improve.For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve their symptoms, but then relapse.Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatment, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, and non-drug treatments (for example, psychotherapy, electroconvulsive therapy, vagus nerve stimulation therapy, and / or transcranial magnetic stimulation therapy).

[0284] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to attempt suicide. Suicidal ideation involves thoughts or an abnormal preoccupation with suicide. Suicidal ideation can range from, for example, momentary thoughts to extensive thinking, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to attempt it, withdrawing from social contacts, becoming preoccupied with death, feeling trapped or hopeless in a situation, increasing alcohol or drug use, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never see each other again.

[0285] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, despair, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, impaired mobility, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide, and attempted suicide. The presence, severity, frequency, and duration of symptoms may vary from case to case. The symptoms of depression and their alleviation can be confirmed by a doctor or psychologist (for example, by mental status examination).

[0286] Anxiety disorders Provided herein are methods for treating anxiety disorders. Anxiety disorders is an umbrella term that covers 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 illness characterized by long-term anxiety that is not focused on any one object or situation. People suffering from generalized anxiety experience persistent, nonspecific fear and worry and become excessively worried about everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0288] In panic disorder, individuals experience brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as a sudden onset of fear or discomfort that peaks in less than 10 minutes, but can last for several hours. They may be triggered by stress, fear, or exercise, although the specific cause is not always clear. In addition to recurring unexpected panic attacks, a diagnosis of panic disorder also requires the presence of chronic consequences, either worry about the potential impact of the attacks, ongoing fear of future attacks, or significant changes in behavior related to the attacks. Thus, individuals with panic disorder experience symptoms outside of specific panic episodes. Often, normal changes in heart rate are noticed by panic sufferers, leading them to believe there is something wrong with their heart or that another panic attack is imminent. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during panic attacks, and any perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

[0289] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized primarily by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). OCD thought patterns can be likened to superstition, insofar as they involve belief in nonexistent causal relationships. Often, this process is not entirely logical; for example, a compulsion to walk in a particular pattern may be used to alleviate obsessive thoughts of impending harm. Often, compulsions are simply a completely inexplicable urge to complete a tension-induced ritual. In a minority of cases, patients with OCD may experience only obsessions without any obvious compulsions, and a much smaller number experience only compulsions.

[0290] The single largest category of anxiety disorders is that of phobias, which includes all cases in which fear and anxiety are triggered by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering the phobic object, which can be anything from an animal to a place to a bodily fluid.

[0291] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to intense stressors, such as soldiers who endure individual battles but are unable to cope with sustained combat. Common symptoms include flashbacks, avoidance behaviors, and depression. epilepsy

[0292] Epilepsy is a brain disorder characterized by recurrent seizures over time, including, but not limited to, generalized epilepsy (e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with awakening grand mal seizures, West syndrome, Lennox-Gastaut syndrome), partial epilepsy (e.g., temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood). Epilepsy

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

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

[0295] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, minimal non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0296] Seizures A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A seizure is a rapid and uncontrollable shaking of a person's body. During a seizure, a person's muscles repeatedly contract and relax.

[0297] Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized and partial (also called focal or localized). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0298] Generalized seizures are caused by electrical impulses from the entire brain, while focal seizures are caused (at least initially) by electrical impulses in a smaller part of the brain. The part of the brain that produces the seizure is sometimes called the focus.

[0299] There are six types of generalized seizures. The most common, dramatic, and therefore best known is a generalized convulsion, also called a grand mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. Loss of consciousness is followed by 30-60 seconds of whole-body rigidity (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent jerking (the "clonic" phase), after which the patient enters deep sleep (the "postictal" or postictal phase). Injuries and accidents, such as tongue biting and urinary incontinence, can occur during a grand mal seizure.

[0300] Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. Affected people, most often children, typically stop their activities and stare blankly. These seizures begin and end suddenly and can occur several times a day. Affected people are usually unaware that they are having a seizure, but may be aware that they are "losing time."

[0301] Myoclonic seizures consist of sporadic jerking, usually on both sides of the body. Patients may describe the jerking as brief electric shocks. If severe, these seizures may cause objects to be dropped or thrown involuntarily.

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

[0303] Tonic seizures are characterized by muscle stiffness.

[0304] Cataplexy consists of a sudden generalized loss of muscle rigidity, especially in the arms and legs, often causing falls.

[0305] Seizures as referred to herein can include epileptic seizures; acute repetitive seizures; cluster seizures; persistent seizures; incessant 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; affective seizures; focal seizures; galactocele; generalized-onset seizures; infantile spasms; Jacksonian seizures; large bilateral myoclonic seizures; multifocal seizures; neonatal-onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; petit mal seizures, Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy. [Example]

[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 the scope thereof.

[0307] The absolute configuration of an asymmetric center can be determined using methods known to those 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 deduce the absolute configuration of a corresponding asymmetric center in another compound obtained from the same or similar synthetic methodology. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used in combination with spectroscopic techniques, such as NMR spectroscopy, for example, H NMR spectroscopy or F NMR spectroscopy, to infer the absolute configuration of a corresponding asymmetric center in another compound.

[0308] Abbreviation 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: methylaluminum 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 / EtPPh3B r: 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: Tri-(t-butoxy) lithium aluminum hydride, NaH: Sodium hydride , MeMgBr: methyl magnesium bromide, i-BuMgBr: isobutyl magnesium bromide, LAH / LiAlH4: lithium aluminum hydride, n-BuMgBr: n-butyl magnesium bromide, i-AmylMgBr: isoamyl magnesium bromide, CBS: Corey-Bakshi-Shibata catalyst, BH3·SMe2 / BH3·DMS: borane dimethyl sulfide, CaCO3: calcium carbonate, PhI(OAc)2: (diacetoxyiodo)benzene, BnOH: Benzyl alcohol, t-BuOH: tert-butanol, DME: dimethyl ether, TosMic: toluenesulfonylmethyl isocyanide, LDA: lithium diisopropylamide, MeI: methyl iodide, DIBAL-H: diisobutylaluminum hydride, IPA / i-PrOH: isopropanol, PMBCl: p-methoxybenzyl chloride, AlMe3: trimethylaluminum, 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-P rMgCl: isopropyl magnesium chloride, t-BuMgCl: tert-butyl magnesium 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: benzyl bromide, KHF2: potassium hydrogen fluoride, DCE: 1,2-Dichloroethane, t-BuLi: tert-butyllithium, 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-fluorobenzeneflutonimide, 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 trifluoromethanesulfonate, NaBT4: [, 3 H] tritiated sodium borohydride, Me: methyl, Et: ethyl, i-Pr: isopropyl, t-Bu: tert-butyl, Ph: phenyl, Bz: benzoyl, Ts: p-toluenesulfonyl, Bu: butyl, NBS: N-bromosuccinimide.

[0309] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents 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 selection 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," 5 th Edition, John Wiley & Sons, New Jersey, 2014 and the references cited therein.

[0311] The compounds provided herein can 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 regarding the preparation of representative compounds listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Examples of chiral columns available for use in the separation / purification of 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] As reported herein 1 It will be understood that H-NMR (e.g., for the region δ (ppm) from about 0.5 to about 4 ppm) is an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integration) of a compound. Exemplary general method for preparative HPLC: Column: Waters RBridge Preparative 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% to 95% B in 1.6 or 2 min, flow rate: 1.8 or 2 mL / min, column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 °C.

[0314] An 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 the following: "Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm Mobile phase: A: CO₂ B: Ethanol (0.05% DEA) Gradient: 5% to 40% B in 5 min, 40% for 2.5 min, then hold at 5% B for 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35°C."

[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)hexadecanehydro-1H-cyclopenta[a]phenanthren-3-ol (1) [ka]

[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 hours. The mixture was filtered through a pad of Celite. The filter cake was washed with THF (3×300 mL), and the filtrate was concentrated under reduced pressure to give 1.2 (98 g). 1 H NMR (400 MHz, CDCl3) δ H 3.69-3.60(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 × 50 mL), and the combined organic layers were washed with brine (50 mL, saturated), 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: 1 H NMR (400 MHz, CDCl3) δ H 3.70-3.56(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 added 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 two other (2) batches of the reaction mixture obtained using a similar protocol (1 g of 1.3 starting material), and the mixture was diluted with HO (30 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with NaHCO₃ (20 mL, saturated aqueous solution) and HO (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). 1 H NMR (400MHz, CDCl3)δ H9.61-9.53(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, TMSCF (663 mg, 4.67 mmol) was added at 0 °C, and the mixture was stirred for 1 h. TBAF·3H2O (2.36 g, 7.48 mmol) was added to the mixture, and the mixture was stirred at 50 °C for 1 h. The reaction mixture was poured into ice water (20 mL), stirred for 10 min, and the layers were separated. The aqueous phase was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with brine (2 × 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 give 1 (150 mg).

[0324] Compound 1 (150 mg) was further purified by ELSD-HPLC ((Column: DuraShell 150*25 mm*5 um), Gradient: 60-90% B (water (10 mM NH4HCO3)-MeCN), B = MeCN), Flow rate: 25 mL / min) to give 1 (16 mg, 11%). 1 H NMR (400MHz, CDCl3)δ H 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). 19 F NMR (376.5MHz, CDCl3)δ F-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), elution gradient 30% to 90% (solvent B) over 6 min, held at 80% for 0.5 min at a flow rate of 0.8 mL / min; column: Xtimate C18 2.1*30 mm, 3 μm; wavelength: UV 220 nm & 254 nm; column temperature: 50 °C; MS ionization: ESI; detector: PDA & ELSD) MS ionization: C 26 H 40 FO[M+H-HO] + Calculated ESI value of 425, found value of 425, purity 100%.

[0325] Example 2: Synthesis of (3R,5R,8R,9S,10S,13R,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) [ka]

[0326] 2.1 Synthesis

[0327] To a solution of BHT (132 g, 599 mmol) in toluene (1.4 L) under nitrogen, trimethylaluminum (2 M in toluene, 149 mL, 299 mmol) was added dropwise at 0 °C, and the resulting mixture was stirred at 25 °C for 1 h to give a MAD solution. A solution of 1.2 (50 g, 150 mmol) in DCM (500 mL) was added dropwise to the MAD solution (0.213 M in toluene) at −70 °C under N. After stirring at −70 °C for 1 h, EtMgBr (74.6 mL, 224 mmol, 3 M in EtO) was added dropwise at −70 °C. The resulting solution was stirred at −70 °C for 1 h. The reaction mixture was quenched by adding saturated aqueous citric acid (2 L) at 10 °C, and the mixture was extracted with EtOAc (2 × 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%). 1 H NMR (400 MHz, CDCl3) δ H 3.73-3.55(m,1H),3.44-3.30(m,1H),2.1-1.62(m,6H),1.57-1.31(m,14 H),1.28-1.04(m,11H),1.03(d,J=6.8Hz,3H),0.93(s,3H),0.66(s,3H).

[0328] 2.2 Synthesis

[0329] To a solution of 2.1 (8 g, 22 mmol) in DCM (80 mL) was added DMP (18.6 g, 44.0 mmol) at 25 °C. 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 × 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%). 1 H NMR (400MHz, CDCl3)δ H9.55(d,J=3.2Hz,1H),2.42-2.26(m,1H),1.94-1.79(m,4H),1.76-1.48(m,8H),1.4 7-1.21(m,14H),1.11(d,J=6.4Hz,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 TMSCF (4.89 g, 34.5 mmol). After stirring at 0 °C under N for 1 h, TBAF (6.93 g, 22.0 mmol) was added. After stirring at 40 °C for an additional 2 h, the mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (2 × 50 mL). The layers were separated, and the combined organic layer was washed with saturated aqueous NH4Cl (2 × 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%). 1 H NMR (400MHz, CDCl3)δ H 4.08-3.99(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 99% purity, C 25 H 40 F3O1[M-H2O+H] + MS ESI calculated value for 413.3, found value 413.3. 19 F NMR (376.5MHz, CDCl3)δ F -72.207.

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

[0333] 3.1 Synthesis

[0334] To a suspension of PhPMeBr (53.5 g, 150 mmol) in anhydrous THF (300 mL) was added t-BuOK (16.8 g, 150 mmol) at 20 °C under N2, and 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 for 2 h at 20 °C, the mixture was poured into 10% aqueous NH4Cl (600 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 × 200 mL), and the combined organic layers were washed with brine (2 × 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). 1 H NMR (400MHz, CDCl3)δ H 4.60-4.52(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] 3.2 Synthesis

[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 adding saturated aqueous NaHCO (600 mL) until the aqueous layer reached a pH of approximately 9. Saturated aqueous NaSO (600 mL) was added. After stirring at 20 °C for 10 min, the mixture was extracted with DCM (2 × 300 mL), and the combined organic layers were washed with saturated aqueous NaSO (2 × 600 mL), dried over anhydrous NaSO, filtered, and concentrated to give 3.2 (19 g). 1 H NMR (400MHz, CDCl3)δ H 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] 3.3 Synthesis

[0338] To a solution of 3.2 (42.3 g, 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, TMSCF (36.3 g, 256 mmol) was added, and the mixture was stirred at 25 °C for 1 h. Additional TBAF (40.3 mL, 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 × 500 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0–12% EtOAc in PE) to give 3.3 (26.2 g, 51%). 1 H NMR (400MHz, CDCl3)δ H4.61-4.52(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). 19 F NMR (376.5MHz, CDCl3)δ F -72.191.

[0339] 3.4 Synthesis

[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 bubbled through the solution at -70 °C. O2 was then bubbled through the solution for 5 min. Me2S (2.86 g, 46.2 mmol) was added portionwise to the mixture at -70 °C, and the solution was warmed to 20 °C over 1 h and then stirred at 20 °C for 16 h. 10% aqueous NH4Cl (300 mL) was added dropwise to the mixture, which was then extracted with DCM (2 × 100 mL). The combined organic layers were washed with 10% aqueous NH4Cl (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0–5% EtOAc in PE) to give 3.4 (4 g, 80%). 1 H NMR (400MHz, CDCl3)δ H 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,1 LC-ELSD / MS 100% purity, C 23 H 35 F3O2[M+H] + MS ESI calculated value 401, observed value 401.

[0341] Synthesis of 3

[0342] To a solution of BHT (1.36 g, 6.19 mmol) in toluene (10 mL) was added dropwise AlMe (1.54 mL, 3.09 mmol, 2 M in toluene) at 0 °C under nitrogen, and the mixture was stirred at 25 °C for 1 h to give a MAD solution. To the MAD solution was added dropwise a solution of 3.4 (500 mL, 1.24 mmol) in DCM (10 mL) at −70 °C. After stirring at −70 °C under N for 1 h, MeMgBr (826 μL, 2.48 mmol, 3 M in EtO) 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 × 40 mL). The combined organic layers were dried over anhydrous NaSO, 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%). 1 H NMR (400MHz, CDCl3)δ H 4.11-3.96(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: 100% purity, C 24 H 38 FO [M-HO+H] + MS ESI calculated value for 399.2, found value 399.2.

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

[0344] 4.2 Synthesis

[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 give 4.2 (95 g). 1 H NMR (400MHz, CDCl3)δ H 2.56(t,J=14.4Hz,1H),2.45(dd,J=8.4,19.2Hz,1H),2.33-2.02(m,6H),1.96-1.50(m,9H),1.42-1.14(m,6H),0.89(s,3H).

[0346] 4.3 Synthesis

[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 (3.67 g), 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 × 300 mL). The combined organic layers were washed with water (2 × 300 mL) and brine (2 × 300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4.3 (120 g).

[0348] 4.4 Synthesis

[0349] To a suspension 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 heated 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 maintained below 40 °C with stirring for 17 h. The mixture was quenched with a solution of NHCl (60 g, 10% aqueous solution), 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 for 30 min at 20 °C, the mixture was treated with water (3000 mL), stirred at 20 °C for 1 h, and allowed to stand for 17 h. The residue was collected, redissolved in DCM (1000 mL), dried over anhydrous NaSO, 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%). 1 H NMR (CDCl3 400MHz)δ H 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] 4.5 Synthesis

[0351] To a solution of 4.4 (47.5 g, 142 mmol) in THF (200 mL) was added aqueous 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 reaction mixture (1 g of 4.4 starting material) obtained using similar conditions. EtOAc (200 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 200 mL), and the combined organic layers were washed with water (2 × 300 mL), saturated aqueous NaHCO (200 mL), and brine (2 × 300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4.5 (39.2 g). 1 H NMR (CDCl3 400MHz)δ H5.21-5.02(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] 4.6 Synthesis

[0353] To a solution of 4.5 (40 mg, 139 mmol) in MeOH (400 mL) was added NaBH (9.45 mg, 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 × 300 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4.6 (39 g).

[0354] 4.7 Synthesis

[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 mL, 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 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 100 / 1) to give 4.7 (45 g, 83%).

[0356] 4.8 Synthesis

[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 HO) was slowly added. After the addition, HO (125 g, 1.11 mol, 30%) was slowly added, maintaining the internal temperature of the reaction mixture below 15 °C during the addition process. 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 × 400 mL). The combined organic layers were washed with saturated aqueous NaSO (2 × 500 mL) and brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 4.8 (65 g).

[0358] 4.9 Synthesis

[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 filter cake was washed with DCM (2 × 200 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 50 / 1) to give 4.9 (25 g, 38%).

[0360] 4.10 Synthesis

[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 × 150 mL). The combined organic layers were washed with water (2 × 300 mL) and brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 4.10 (13 g, 52%). 1 H NMR (400MHz, CDCl3)δ H3.65-3.62(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,2 H),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] 4.11 Synthesis

[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 × 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 give 4.11 (2.8 g, 77%). 1 H NMR (400MHz, CDCl3)δ H 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] 4.12 Synthesis

[0365] To a solution of BHT (72.7 g, 329 mmol) in toluene (200 mL) was added trimethylaluminum (82.0 mL, 2 M in toluene, 164 mmol) dropwise at 0 °C under N2, and the resulting mixture was stirred at 25 °C for 1 h to give a MAD solution. To the MAD solution (78.8 g in toluene, 165 mmol) was added dropwise a solution of 4.11 (10 g, 33.0 mmol) in DCM (200 mL) at -70 °C, and the resulting solution was stirred at -70 °C under N2 for 1 h. EtMgBr (33 mL, 3 M 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, saturated aqueous solution) at 10 °C and extracted with DCM (3 × 400 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, 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 give 4.12 (5.54 g, 61.7%). 1 H NMR (400 MHz, CDCl3) δ H 2.57-2.51(m,1H),2.25-2.09(m,4H),2.06-1.97(m,1H),1.85-1.55(m,1 0H),1.52-0.99(m,14H),0.90-0.86(t,J=7.4Hz,3H),0.68-0.57(m,3H).

[0366] 4.13 Synthesis

[0367] To a solution of MePPhBr (17.6 g, 49.5 mmol) in THF (30 mL) was added t-BuOK (5.55 g, 49.5 mmol) under N at 25 °C, 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 portionwise to maintain the internal temperature of the mixture below 50 °C during 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 × 300 mL). The combined organic layers were washed with water (300 mL) and brine (200 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400 MHz, CDCl3) δ H 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] 4.14 Synthesis

[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 for 2 h under N. 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. HO (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 NaSO (500 mL), stirred for 30 min, and then extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400 MHz, CDCl3) δ H 3.71-3.58(m,1H),3.37-3.34(m,1H),1.96 (td,J=3.2,12.4Hz,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=7.4Hz,3H),0.68(s,3H).LC-ELSD / MS: Purity >99%, C 23 H 39 O [M-HO+H] + MS ESI calculated value for 331.3, found value 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 NaHCO (30 mL) and saturated aqueous NaSO (30 mL) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with saturated aqueous NaSO (2 × 10 mL) and brine (2 × 10 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400 MHz, CDCl3) δ H 9.56-9.55(d,J=3.2Hz,1H),2.36-2.33(m,1H),1.94-1.78(m,5H),1.76-1.72(m,2H),1.70-1.5 5(m,8H),1.45-1.30(m,8H),1.12-1.10(d,J=5.2Hz,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) under N at 10 °C. TMSCF (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 the mixture was stirred for 2 h. The mixture was poured into water (10 mL), stirred for 20 min, and then extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated to give 4 (130 mg, 10.9%). 1 H NMR (400 MHz, CDCl3) δ H4.08-3.97(m,1H),2.14-2.12(d,J=6.4Hz,1H),1.96-1.95(m,1H),1.92-1.68(m,5H),1.67-1.57(m,4H),1.5 4(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=7.8Hz,3H),0.67(s,3H). 19 F NMR (376.5 MHz, CDCl3) δ F -72.207. LC-ELSD / MS: Purity >99%, C 24 H 37 FO [M-HO+H] + MS ESI calculated value for 399.2, found value 399.2.

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

[0375] To a suspension of 3.4 (300 mg, 0.7490 mmol) in anhydrous THF (10 mL) under N was slowly added (tBuO)AlLiH (378 mg, 1.49 mmol) at 0 °C, and the resulting mixture was stirred under N for 2 h. The mixture was poured into 10% aqueous NHCl (20 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified twice by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 5 (11.8 mg, 11.8%). 1 H NMR (400 MHz, CDCl3) δ H4.08-3.98(m,1H),3.70-3.55(m,1H),2.12(d,J=6.0Hz,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 99% purity, C 23 H 38 F3O2[M-H2O+H] + MS ESI calculated value for 385, found value 385.

[0376] Example 6: Synthesis of (3R,5R,8R,9S,10S,13R,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) [ka]

[0377] 6.1 Synthesis

[0378] To a solution of MeSI (607 mg, 2.98 mmol) in THF (10 mL) and DMSO (5 mL) was added NaH (119 mg, 60%, 2.98 mmol) portionwise under N at 0 °C, followed by 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 × 50 mL), and the combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 6.1 (1 g, 97.0%). 1 H NMR (400 MHz, CDCl3) δ H4.09-3.97(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=1.8Hz,6H),0.99(d,J=8.0Hz,3H),0.68(d,J=2.5Hz,3H). 19 F NMR (376.5MHz, CDCl3)δ F -72.175.

[0379] Synthesis of 6

[0380] To a mixture of sodium methoxide (777 mg, 14.4 mmol) in MeOH (20 mL), 6.1 (1 g, 2.41 mmol) was slowly added, 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 × 20 mL), and the combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400 MHz, CDCl3) δ H 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=3.2,14.4Hz,1H),1.63(dd,J=4.8,8.4Hz,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 100% purity, C 24 H 36 F3O [M-CH3OH-H2O+H] + MS ESI calculated value for 397.3, found value 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 (7) [ka]

[0382] A solution of MeMgBr (2.2 mL, 6.63 mmol, 3 M in EtO) 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 × 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). 1 H NMR (400 MHz, CDCl3) δ H 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%, C 25 H 41 MS ESI calculated for [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 (8) [ka]

[0384] A solution of EtMgBr (2.2 mL, 6.63 mmol, 3 M in EtO) 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 × 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%). 1 H NMR (400 MHz, CDCl3) δ H 3.68-3.48(m,1H),2.00-1.80(m,3H),1.77-1.50(m,5H),1.49-1.33(m,9H),1.3 2-1.02(m,10H),1.01-0.85(m,6H),0.84-0.73(m,9H),0.66(s,3H).LC-ELSD / MS Purity >99%, C 26 H 43 [M-2H2O+H] + MS ESI calculated value for 355.4, found value 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) [ka]

[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), the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 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%). 1 H NMR (400 MHz, CDCl3) δ H 3.85-3.65(m,1H),2.05-1.85(m,2H),1.77-1.50(m,5H),1.49-1.28(m,13 H),1.27-1.18(m,12H),1.17-1.01(m,13H),0.74-0.60(m,4H).LC-ELSD / MS Purity >99%, C 28 H 47 [M-2H2O+H] + MS ESI calculated value for 383, found value 383.

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

[0388] 10.1 Synthesis

[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 × 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%). 1 H NMR (400 MHz, CDCl3) δ H 2.83-2.70(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] 10.2 Synthesis

[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 NaHCO:NaSO (v:v = 1:1, 12 mL), and the mixture was extracted with DCM (2 × 12 mL). The combined organic layers were washed with saturated aqueous NaHCO:NaSO (v:v = 1:1, 12 mL) and brine (12 mL), dried over anhydrous NaSO, filtered, and concentrated to give 10.2 (450 mg). 1 H NMR (400 MHz, CDCl3) δ H2.64-2.53(m,1H),2.00-1.77(m,5H),1.74-1.52(m,7H),1.48-1.24(m,10H),1.17 (d,J=6.8Hz,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 LiAlH (127 mg, 3.36 mmol) under N at 0 °C, 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 × 8 mL), and the combined organic layers were dried over anhydrous NaSO, 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 give 10 (38.2 mg, 95.7%). 1 H NMR (400 MHz, CDCl3) δ H 3.00-2.95(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%, C 27 H 43 [M-2H2O+H] + MS ESI calculated value 367, observed value 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) [ka]

[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 hexane) at 0 °C, and the resulting mixture was stirred for 15 min. The mixture was poured into HO (30 mL), and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0–50% EtOAc in PE) and further purified by flash silica gel chromatography (0–20% EtOAc in PE) and oven-dried at 80 °C to give 11 (93.6 mg, 93.6%). 1 H NMR (400 MHz, CDCl3) δ H 3.70-3.57(m,1H),2.15-1.76(m,4H),1.75-1.50(m,5H),1.49-1.28(m,10H),1.27-1.18( LC-ELSD / MS Purity >99%, C 28 H 47 MS ESI calculated for [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) [ka]

[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 EtO) at 0 °C under N, and 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 × 10 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0–30% EtOAc in PE) to give 12 (12.2 mg, 1.02%). 1 H NMR (400MHz, CDCl3)δ H 3.70-3.57(m,1H),2.20-1.76(m,4H),1.75-1.50(m,9H),1.49-1.28(m,9H),1.2 7-1.03(m,10H),1.02-0.95(m,7H),0.94-0.78(m,9H),0.66(s,3H).LC-ELSD / MS Purity >99%, C 29 H 49 [M-2H2O+H] + MS ESI calculated value for 397, found value 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) [ka]

[0399] To a solution of 3.4 (400 mg, 0.9986 mmol) in THF (10 mL) under N was added CsF (302 mg, 1.99 mmol) at 10 °C, followed by dropwise addition of TMSCF (425 mg, 2.99 mmol) 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 × 20 mL) and the combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered and concentrated to give 13 (120 mg), which was purified by HPLC (Column: C18 (250 mm * 50 mm, 5 um), Gradient: 65-95% B (B = water (0.05% HCl)-MeCN), Flow rate: 30 mL / min) to give 13 (19 mg, 15.9%). 1 H NMR (400MHz, CDCl3)δ H 4.15-3.93(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). 19 F NMR (376.5MHz, CDCl3)δ F -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) [ka] [ka]

[0401] 14.2 Synthesis

[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%). 1 H NMR: (400 MHz, CDCl3) δ H 2.69(t,J=13.6Hz,1H),2.55(t,J=8.8Hz,1H),2.34 (dt,J1=13.6,J 2= 4.8Hz,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] 14.3 Synthesis

[0404] To a solution of 14.2 (2 g, 6.31 mmol) in THF (20 mL) was added LiAlH(OtBu) (1.76, 6.94 mmol) under N at −40° C. 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 (3×300 mL), and the combined organic layers were washed with saturated aqueous citric acid (300 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by silica gel chromatography (0–25% EtOAc in PE) to give 14.3 (2.3 g). 1 H NMR (400MHz, CDCl3)δ H 3.71-3.55(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=2.4Hz,2H),0.61-0.58(m,3H).

[0405] 14.4 Synthesis

[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) under N at 20 °C, and the resulting mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with HO (20 mL), and the aqueous phase was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0–10% EtOAc in PE) to give 14.4 (7.0 g, 99%). 1 H NMR (400MHz, CDCl3)δ H 3.64-3.56(m,1H),2.52 (br t,J=8.8Hz,1H),2.15 (br d,J=11.2Hz,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] 14.5 Synthesis

[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 this 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 by 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%). 1 H NMR (400MHz, CDCl3)δ H3.69 (qd,J=6.0,12.8Hz,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] 14.6 Synthesis

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

[0411] 14.7 Synthesis

[0412] To a solution of MePhPBr (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 raised to 50 °C, and the mixture was stirred 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 was extracted with EtOAc (3 × 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 reaction mixture (3 g of 14.6 starting material) obtained using similar conditions. The residue was purified by silica gel chromatography (0–25% EtOAc in PE) to give 14.7 (6 g). 1 H NMR (400MHz, CDCl3)δ H5.79-5.72(dd,J=11.2,17.7Hz,1H),5.30-5.27(dd,J=1.4,11.3Hz,1H),5.16- 5.11(dd,J=1.6,18.0Hz,1H),3.91-3.77(m,1H),3.64-3.49(m,1H),2.36-2.32 (td,J=3.2,13.1Hz,1H),1.88-1.66(m,7H),1.57(s,3H),1.49-1.26(m,10H),1.12 -1.10(d,J=6.4Hz,5H),0.97-0.86(m,10H),0.81(s,3H),0.05(s,6H).

[0413] 14.8 Synthesis

[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 at 20 °C under 15 psi of hydrogen for 16 h. The mixture was filtered through a pad of silica gel, and the filter cake was washed with THF (3 × 50 mL). The filtrate was concentrated under reduced pressure to give 14.8 (3.5 g). 1 H NMR (400MHz, CDCl3)δ H 3.82(s,1H),3.63-3.52(m,1H),2.11(d,J=12.4Hz,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] 14.9 Synthesis

[0416] To a solution of 14.8 (300 g, 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 × 50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified from methanol (100 mL) at 20 °C to give 14.9 (190 mg, 85%).

[0417] 14.10 Synthesis

[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 NaHCO (100 mL) and saturated aqueous NaSO (100 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with saturated aqueous NaSO (2 × 100 mL) and brine (2 × 100 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400MHz, CDCl3)δ H 2.75-2.63(m,1H),2.48(t,J=8.8Hz,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=7.2Hz,3H).

[0419] 14.11 Synthesis

[0420] To a solution of MAD (6.53 g, 13.6 mmol) was added dropwise a solution of 14.10 (1.8 g, 5.44 mmol) in DCM (20 mL) at −70 °C under N. After stirring at −70 °C for 1 h under N, MeMgBr (3.6 mL, 10.8 mmol) was slowly added dropwise. After stirring for 2 h at 10 °C, the reaction mixture was poured into saturated aqueous citric acid (100 mL), and the aqueous phase was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400MHz, CDCl3)δ H 2.45(t,J=8.8Hz,1H),2.35-2.25(m,1H),2.24-2.16(m,4H),2.03-1.79(m,2H),1.74 (td,J=3.2,14.4Hz,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=7.5Hz,3H).LC-ELSD / MS Purity>99%,C 23 H 37 O [M-HO+H] + MS ESI calculated for 329.3, found 329.3.

[0421] 14.12 Synthesis

[0422] To a solution of MePhPBr (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 raised 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 × 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 the reaction mixture (1.53 g of 14.11 starting material) obtained using similar conditions. The residue was purified by flash silica gel chromatography (10–20% EtOAc in PE) to give 14.12 (890 mg). 1 H NMR (400MHz, CDCl3)δ H 4.80(s,1H),4.77(s,1H),2.22(dd,J=3.2,9.2Hz,1H),2.01-1.92(m,2H),1.90-1.86(m,1H),1.81(s,3H),1.74 (td,J=3.6,14.2Hz,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=7.2Hz,3H).LC-ELSD / MS Purity >99%, C 24 H 39 [M-H2O+H] + MS ESI calculated for 327.3, found 327.3.

[0423] 14.13 Synthesis

[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) slowly in portions under N. The reaction mixture was stirred at 50 °C under N for 2 h. After cooling to 0 °C, the reaction mixture was quenched by the slow dropwise addition of EtOH (1.41 mL, 24.6 mmol) and NaOH (7.38 mL, 36.9 mmol, 5 M in HO) under N, followed by the slow addition of HO (3.69 mL, 36.9 mmol, 10 M in HO) at 15 °C under N. The mixture was stirred at 50 °C for 2 h, cooled, and slowly poured into saturated aqueous NaSO (100 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give 14.13 (690 mg, 77.4%). 1 H NMR (400MHz, CDCl3)δ H 3.68-3.60(m,1H),3.42-3.31(m,1H),2.25 (br d,J=12.5Hz,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=6.5Hz,8H),0.96-0.87(m,6H).LC-ELSD / MS purity >99%, C 24 H 41 O [M-HO+H] + MS ESI calculated for 345.3, found 345.3.

[0425] 14.14 Synthesis

[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 NaHCO (100 mL) and saturated aqueous NaSO (100 mL). The aqueous layer was extracted with DCM (2 × 100 mL), and the combined organic layers were washed with saturated aqueous NaSO (2 × 100 mL) and brine (2 × 100 mL), dried over anhydrous NaSO, 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). 1 H NMR (400MHz, CDCl3)δ H 9.47(d,J=4.0Hz,1H),2.42 (ddd,J=4.0,6.6,10.4Hz,1H),2.22(dd,J=3.2,9.2Hz,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=3.6,14.8Hz,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) under N at 10 °C. TMSCF (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 × 20 mL), and the combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated to give 14 (105 mg, 13.5%). 1 H NMR (400MHz, CDCl3)δ H4.13-4.05(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). 19 F NMR (376.5MHz, CDCl3)δ F -72.256. LC-ELSD / MS: Purity >99%, C 25 H 40 FO [M-HO+H] + MS ESI calculated value for 413.3, observed value 413.3.

[0429] Example 15: Synthesis of (3R,5R,8R,9S,10S,13R,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) [ka]

[0430] 15.1 Synthesis

[0431] Sodium metal (441 mg, 19.2 mmol) was slowly added portionwise to anhydrous BnOH (5 mL), and the resulting mixture was stirred at 80 °C for 4 h. A solution of 6.1 (400 mg, 0.9648 mmol) was added portionwise, and the mixture was stirred at 80 °C for 16 h under N2. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 × 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 distillation under reduced pressure. 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 (250 mm*50 mm, 5 um), gradient: 65-95% B (B = water (0.05% HCl)-ACN), flow rate: 30 mL / min) to give 15.1 (40 mg, 15.0%). 1H NMR (400MHz, CDCl3)δ H 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),2.0 1-1.76(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 N. The suspension was degassed under vacuum and purged with H three times. After stirring under H (15 psi) at 25 °C for 24 h, the reaction mixture was filtered through a pad of Celite, washed with EtOAc (3 × 10 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (10–20% EtOAc in PE) to give 15 (29 mg, 87.6%). 1 H NMR (400MHz, CDCl3)δ H 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.C 24 H 35 397.3 for F3O [M+H-2H2O]+, found 397.3. 19 F NMR (376.5MHz, CDCl3)δ F -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) [ka]

[0435] 16.1 Synthesis

[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 × 50 mL), and the combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 16.1a (1.2 g, 21.3%) and 16.1 (800 mg, 14.2%). 1 H NMR (400MHz, CDCl3)δ H 5.01(d,J=4.8Hz,2H),3.64(d,J=10.4Hz,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,2 H),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] 16.2 Synthesis

[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 H three times. After stirring under H (15 psi) at 15 °C for 16 h, the reaction mixture was filtered through a pad of Celite and washed with MeOH (3 × 20 mL). The filtrate was concentrated to give 16.2 (650 mg). 1 H NMR (400MHz, CDCl3)δ H 3.64(dd,J=3.2,10.4Hz,1H),3.35(dd,J=7.2,10.6Hz,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=6.8Hz,4H),0.66(s,3H).

[0439] 16.3 Synthesis

[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) under N at 20 °C, and the resulting mixture was stirred for 30 min. The mixture was poured into a mixture of 10% aqueous NaHCO (20 mL) and saturated aqueous NaSO (20 mL), stirred for 10 min, and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (2 × 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%). 1 H NMR (400MHz, CDCl3)δ H9.56(d,J=3.6Hz,1H),2.35 (tdd,J=3.6,6.8,10.2Hz,1H),1.96-1.74(m,5H),1.71-1.61(m,3H),1.51-1.33(m,10H),1. 26(t,J=7.2Hz,5H),1.11(d,J=6.8Hz,6H),0.94(s,3H),0.88(d,J=6.8Hz,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, followed by slow addition of TMSCF (227 mg, 1.60 mmol). After stirring at 25 °C for 1 h, TBAF (1.26 mL, 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 × 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%). 1 H NMR (400MHz, CDCl3)δ H 4.14-3.96(m,1H),2.16(d,J=6.0Hz,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=6.8Hz,6H),0.67(s,3H).LC-ELSD / MS 100% purity, C 26 H 44 F3O2[M-H2O+H] + MS ESI calculated value 427, observed value 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-methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (17) [ka]

[0444] 17.2 Synthesis

[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 mL, 346 mmol), and the resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (2 × 1000 mL), and the DCM layer was separated. The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give 17.2 (150 g, 95%). 1 H NMR (400MHz, CDCl3)δ H 5.37-5.25(m,1H),3.57-3.41(m,1H),2.53(t,J=8.8Hz,1H),2.32-2.15(m,3H),2.12(s,3H),2.07-1.96(m,2H),1.82 (td,J=3.6,13.2Hz,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] 17.3 Synthesis

[0447] 17.2 (30 g, 69.6 mmol) in DME (150 mL) was added to a mixture of t-BuOH (300 mL) and t-BuOK (38.9 g, 347 mmol) under N2, 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, and the resulting mixture was stirred and then extracted with EtOAc (2 × 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%). 1 H NMR (400MHz, CDCl3)δ H 5.38-5.23(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),1.3 7-1.27(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] 17.4 Synthesis

[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. for 1 h under N. Methyl iodide (32.0 g, 226 mmol) was then added, and the reaction mixture was stirred for 16 h. The mixture was warmed to 25° C., quenched with ammonium chloride (200 mL, saturated aqueous solution), and extracted with EtOAc (2×200 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 17.4 (21 g). 1 H NMR (400MHz, CDCl3)δ H5.31 (br d,J=5.2Hz,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] 17.5 Synthesis

[0451] To a solution of 17.4 (1 g, 2.19 mmol) in DCM (40 mL) was slowly added DIBAL-H (1 M in toluene, 10.9 mL, 10.9 mmol) at -70 °C, and the resulting mixture was stirred for 30 min. The mixture was heated 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 × 100 mL). The combined organic layers were washed with 10% aqueous NaHCO (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10% to 15% EtOAc in PE) to give 17.5 (170 mg, 23%). 1 H NMR (400MHz, CDCl3)δ H 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=6.8Hz,7H),1.08-1.00(m,2H),0.99(s,3H),0.96-0.87(m,1H),0.70(s,3H).

[0452] 17.6 Synthesis

[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 TMSCF (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 × 50 mL). The combined organic layers were washed with water (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10% to 20% EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm), conditions: 0.1% NH3HO IPA, gradient: 30% to 30% B, flow rate: 65 mL / min, injection: 60) to give 17.6 (28.6 mg, 29%). 17.6: 1 H NMR (400MHz, CDCl3)δ H 5.37-5.32(m,1H),4.09-3.92(m,1H),3.55-3.49(m,1H),2.36-2.16(m,2H),2.11(d,J=6.4Hz,1H),2.03-1.91(m,2H),1.89-1.7 6(m,3H),1.71-1.61(m,3H),1.53-1.35(m,7H),1.14-1.04(m,J=1.8Hz,5H),1.03-0.98(m,6H),0.97-0.88(m,2H),0.80(s,3H). 19 F NMR (376.5MHz, CDCl3)δ F -70.174. LC-ELSD / MS 99% purity, C 24 H 36 FO [M+H-HO] + MS ESI calculated value for 397.3, found value 397.3.

[0454] 17.7 Synthesis

[0455] To a solution of 17.6 (60 g, 144 mmol) in DCM (600 mL) was added TBSCl (32.5 mL, 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 × 500 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 17.7 (80 g). 1 H NMR (400MHz, CDCl3)δ H 5.38-5.25(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),1.1 7-1.07(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). 19 F NMR (376.5MHz, CDCl3)δ F -69.943, -70.137.

[0456] 17.8 Synthesis

[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 N and the mixture was stirred at 70 °C for 16 h. The mixture was slowly poured into 10% aqueous NH Cl (600 mL) and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na SO , filtered, and concentrated to give 17.8 (100 g).

[0458] 17.9 Synthesis

[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 × 800 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400MHz, CDCl3):δ H 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). 19 F NMR (376.5MHz, CDCl3)δ F -66.801, -67.307.

[0460] 17.10 Synthesis

[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 × 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% EtOAc in PE) to give 17.10 (3.5 g, 70%). 1 H NMR (400MHz, CDCl3)δ H7.28 (br d,J=1.9Hz,2H),6.88 (br d,J=8.6Hz,2H),5.73 (br s,1H),4.85-4.75(m,1H),4.45(dd,J=2.4,10.9Hz,1H),3.86-3.83(m,1H),3.80(d,J=3.6Hz,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] 17.11 Synthesis

[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 H several times. After stirring at 25 °C under H (15 psi) 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% to 12% EtOAc in PE) to give 17.11 (1.2 g, 34.1%). 1 H NMR (400MHz, CDCl3)δ H 7.31-7.27(m,2H),6.89(dd,J=2.4,8.7Hz,2H),4.89-4.74(m,1H),4.46(d,J=10. 8Hz,1H),3.80(d,J=3.0Hz,3H),3.78(s,1H),2.10-1.94(m,4H),1.43(s,4H),1.26 (br s,5H),1.21(d,J=6.0Hz,2H),1.14 (br s,4H),1.07-1.00(m,6H),0.88-0.84(m,7H),0.79(d,J=18.8Hz,3H).

[0464] 17.12 Synthesis

[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, 3 M 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, saturated aqueous solution) at -70 °C and extracted with EtOAc (3 × 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% to 15% EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 μm), conditions: 0.1% NH3H2O ​​EtOH, gradient: 15% to 15% B, flow rate: 60 mL / min, injection: 12) to give 17.12 (185 mg, 43%). 1 H NMR (400MHz, CDCl3)δ H 7.29(s,2H),6.89(d,J=8.4Hz,2H),4.79(d,J=10.4Hz,1H),4.47(d,J=10.4Hz,1H),3.81(s,3H),3.53(q,J=7.6Hz,1H),2.01-1.67(m,6H),1.60 (br d,J=7.8Hz,5H),1.45-1.35(m,7H),1.24(s,4H),1.19 (br d,J=7.2Hz,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 NaHCO (20 mL, saturated aqueous solution) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (15–20% EtOAc in PE) to give 17 (56.1 mg, 39%). 1 H NMR (400MHz, CDCl3)δ H 4.06 -3.90(m,1H),2.12(d,J=6.3Hz,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 99% purity, C 25 H 40 NO [M+H-H2O] + MS ESI calculated value 413.3 found value 413.3. 19 F NMR (376.5MHz, CDCl3)δ F -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) [ka]

[0469] 18.1 Synthesis

[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 1 h. 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, 3 M 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, saturated aqueous solution) at -70 °C and extracted with EtOAc (3 × 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 (250 mm * 30 mm, 5 μm), conditions: 0.1% NH3HO EtOH, 20% B, flow rate: 60 mL / min, injection: 240) to give 18.1 (241 mg, 44%). 18.1 (241 mg, 0.427 mmol) was further purified by SFC (DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 μm), conditions: 0.1% NH3HO EtOH, 20% B, flow rate: 50 mL / min, injection: 120) to give 18.1 (120 mg, 50%). 18.1:LC-ELSD / MS 99% purity, C 34 H 51 F3O3Na [M+Na] + MS ESI calculated value for 587.4, found value 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 NaHCO (20 mL, saturated aqueous solution) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, 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%). 1 H NMR (400MHz, CDCl3)δ H 4.02-3.94(m,1H),2.09(d,J=6.4Hz,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),1.17-1.1 1(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=7.4Hz,3H),0.76(s,3H). 19 F NMR (376.5MHz, CDCl3)δ F -70.174. LC-ELSD / MS 99% purity, C 26 H 42 FO [M+H-HO] + MS ESI calculated value for 427.3, found value 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) [ka]

[0474] 19.1 Synthesis

[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), 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). 1 H NMR (400MHz, CDCl3)δ H 7.29 (br d,J=2.4Hz,2H),6.91-6.89(m,2H),4.67-4.62(m,1H),4.56 (br d,J=6.4Hz,2H),4.46(s,1H),3.81(s,3H),3.72-3.67(m,1H),2.49 (br t,J=13.2Hz,1H),2.07-1.94(m,3H),1.89-1.78(m,4H),1.45-1.37(m,5H),1.2 6-1.19(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 NaHCO (8.05 g, 95.9 mmol). Ozone (1 atm) was passed through the mixture at −70° C. for 30 min. O was then passed through the solution for 5 min. MeS (3.56 g, 57.5 mmol) was slowly added portionwise to the mixture at −70° C., and the solution was warmed to 20° C. over 1 h and then stirred for 16 h. The reaction mixture was quenched with 10% aqueous NH Cl (300 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with 10% aqueous NH Cl (100 mL), dried over anhydrous Na SO , 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%). 1 H NMR (400MHz, CDCl3)δ H 7.27(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),4.65(d,J=11.6Hz,1H),4. 54(d,J=11.6Hz,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 N. After stirring for 16 h, the mixture was slowly poured into 10% aqueous NH4Cl (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with 10% aqueous NH4Cl (2 × 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 (250 mm * 50 mm, 10 um), conditions: 0.1% NH3HO ETOH), start B: 55, end B: 55) to give 19.3 (500 mg, 73.9%). 1 H NMR (400MHz, CDCl3)δ H 7.30-7.26(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). 19 F NMR (376.5MHz, CDCl3)δ-69.48.

[0480] Synthesis of 19 【...

Claims

1. A compound having the structure of formula (I): 【Chemistry 151】 or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R ３ is hydrogen, substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ２－６ Alkynyl, substituted or unsubstituted C ３－６ Carbocyclyl, substituted or unsubstituted C ６－１０ aryl, or substituted or unsubstituted 5- to 8-membered heteroaryl; R １５ and R １６ Each of the groups independently represents hydrogen or a substituted or unsubstituted C １－６ alkyl, or R １５ and R １６ together with the carbon atom to which they are attached, represent a substituted or unsubstituted C ３－６ forming a carbocyclyl, R １８ is hydrogen, or substituted or unsubstituted C １－６ is alkyl, R １９ is hydrogen, or substituted or unsubstituted C １－６ is alkyl, R ２０ is hydrogen, hydroxyl, substituted or unsubstituted C １－６ Alkyl, or substituted or unsubstituted C ３－６ is a carbocyclyl, R ２０’ is hydrogen, hydroxyl, substituted or unsubstituted C １－６ Alkyl, or substituted or unsubstituted C ３－６ is a carbocyclyl, However, R ２０ and R ２０’ are both not hydroxyl, and R ２２ is a substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkenyl, substituted or unsubstituted C ２－６ Alkynyl, substituted or unsubstituted C ３－６ Carbocyclyl, or substituted or unsubstituted C ６－１０ is aryl, However, R ２２ Ga-CH ３ If R ３ Ha-CH ３ or hydrogen, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof.

2. R ３ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Carbocyclyl, C ６－１０ aryl, or 5- to 8-membered heteroaryl, １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Carbocyclyl, C ６－１０ Aryl and 5- to 8-membered heteroaryl independently represent 1 to 5 R Ａ optionally substituted with R １５ and R １６ each independently represents hydrogen or 1 to 5 R Ｂ C optionally substituted with １－６ alkyl, or R １５ and R １６ together with the carbon atoms to which they are attached, 1 to 5 R Ｂ C optionally substituted with ３－６ forming a carbocyclyl, R １８ is hydrogen or 1 to 5 R Ｃ C optionally substituted with １－６ is alkyl, R １９ is hydrogen or 1 to 5 R Ｄ C optionally substituted with １－６ is alkyl, R ２０ is hydrogen, hydroxyl, C １－６ Alkyl or C ３－６ carbocyclyl, １－６ Alkyl and C ３－６ Carbocyclyl independently has 1 to 5 R Ｅ optionally substituted with R ２０’ is hydrogen, hydroxyl, C １－６ Alkyl or C ３－６ carbocyclyl, １－６ Alkyl and C ３－６ Carbocyclyl independently has 1 to 5 R Ｆ optionally substituted with However, R ２０ and R ２０’ are both hydroxyl, R Ａ , R Ｂ , R Ｃ , R Ｄ , R Ｅ , and R Ｆ Each instance, when present, is independently selected from halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C ６－１０ aryl, and C optionally substituted with 1 to 5 halo １－６ alkoxy; R ２２ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Carbocyclyl or C ６－１０ aryl, １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ Alkynyl is independently selected from 1 to 5 R Ｇ and wherein said C ３－６ Carbocyclyl and C ６－１０ Aryl independently represents 1 to 5 R Ｈ optionally substituted with However, R ２２ Ga-CH ３ If R ３ Ha-CH ３ Or rather than hydrogen, R Ｇ Each instance, if present, is independently halo, hydroxyl, cyano, C optionally substituted with 1 to 5 halo. １－６ Alkoxy, C ３－６ Carbocyclyl, C ６－１０ aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl; ３－６ Carbocyclyl, C ６－１０ Aryl, 5- to 8-membered heteroaryl, and 5- to 8-membered heterocyclyl independently represent 1 to 5 R Ｇ１ optionally substituted with R Ｇ１ Each instance, if present, is independently halo, cyano, oxo, nitro, amino, C optionally substituted with 1 to 5 halo. １－６ C optionally substituted with alkyl and 1 to 5 halo １－６ alkoxy; and R Ｈ Each instance, if present, is independently halo, cyano, nitro, amino, C optionally substituted with 1 to 5 halo. １－６ C optionally substituted with alkyl and 1 to 5 halo １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, selected from the group consisting of alkoxy.

3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein the compound of formula (I) is a compound of formula (IA) or (IB): 【Chemistry 152】

4. 4. The compound of claim 3, wherein the compound of formula (IA) is a compound of formula (IA-1) or (IA-2), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 【Chemistry 153】

5. 5. The compound of claim 4, wherein the compound of formula (I-A-1) is a compound of formula (I-A-1-i) or (I-A-1-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 【Chemistry 154】

6. 5. The compound of claim 4, wherein the compound of formula (I-A-2) is a compound of formula (I-A-2-i) or (I-A-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 【Chemistry 155】

7. 4. The compound of claim 3, wherein the compound of formula (IB) is a compound of formula (IB-1) or (IB-2), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 【Chemistry 156】

8. 8. The compound of claim 7, wherein the compound of formula (IB-1) is a compound of formula (IB-1-i) or (IB-1-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 【Chemistry 157】

9. 8. The compound of claim 7, wherein the compound of formula (IB-2) is a compound of formula (IB-2-i) or (IB-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 【Chemistry 158】

10. R ３ is a substituted or unsubstituted C １－６ Alkyl, or substituted or unsubstituted C ２－６ is alkynyl, R １５ is hydrogen, or substituted or unsubstituted C １－６ alkyl, and R １６ is hydrogen, or R １５ and R １６ together with the carbon atom to which they are attached, represent a substituted or unsubstituted C ３－６ forming a carbocyclyl, R １８ is a substituted or unsubstituted C １－６ is alkyl, R ２０ is hydrogen, hydroxyl, or substituted or unsubstituted C １－６ alkyl, and R ２０’ is hydrogen, or substituted or unsubstituted C １－６ 4. The compound of claim 1 or 3, wherein the compound is alkyl.

11. R ３ is C １－６ Alkyl or C ２－６ alkynyl, １－６ Alkyl and C ２－６ Alkynyl is independently selected from 1 to 5 R Ａ optionally substituted with R １５ is hydrogen or 1 to 5 R Ｂ C optionally substituted with １－６ is alkyl, R １６ is hydrogen, or R １５ and R １６ together with the carbon atoms to which they are attached, 1 to 5 R Ｂ C optionally substituted with ３－６ forming a carbocyclyl, R １８ is 1 to 5 R Ｃ C optionally substituted with １－６ is alkyl, R ２０ is hydrogen, hydroxyl, or 1 to 5 R Ｅ C optionally substituted with １－６ alkyl, and R ２０’ is hydrogen or 1 to 5 R Ｆ C optionally substituted with １－６ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein R is alkyl.

12. R ３ is a substituted or unsubstituted C １－６ is alkyl, R １５ is hydrogen, or substituted or unsubstituted C １－６ alkyl, and R １６ is hydrogen, or R １５ and R １６ together with the carbon atom to which they are attached, represent a substituted or unsubstituted C ３－６ forming a carbocyclyl, R １８ is -CH ３ and R ２０ is hydrogen, R ２０’ is -CH ３ and R ２２ is a substituted or unsubstituted C １－６ Alkyl, or substituted or unsubstituted C ２－６ 11. The compound of any one of claims 1, 3 and 10, which is alkynyl.

13. R ３ is 1 to 5 R Ａ C optionally substituted with １－６ is alkyl, R １５ is hydrogen or 1 to 5 R Ｂ C optionally substituted with １－６ is alkyl, R １６ is hydrogen, or R １５ and R １６ together with the carbon atoms to which they are attached, 1 to 5 R Ｂ C optionally substituted with ３－６ forming a carbocyclyl, R １８ is -CH ３ and R ２０ is hydrogen, R ２０’ is -CH ３ and R ２２ is C １－６ Alkyl or C ２－６ alkynyl, １－６ Alkyl and C ２－６ Alkynyl is independently selected from 1 to 5 R Ｇ 12. The compound of any one of claims 1-3 and 10-11, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, optionally substituted with:

14. R ３ is hydrogen, substituted or unsubstituted C １－６ Alkyl, substituted or unsubstituted C ２－６ Alkynyl, substituted or unsubstituted C ３－６ The compound of any one of claims 1 and 3 to 9, which is carbocyclyl or substituted or unsubstituted 5-8 membered heteroaryl.

15. R ３ But hydrogen, C １－６ Alkyl, C ２－６ Alkynyl, C ３－６ carbocyclyl, or 5- to 8-membered heteroaryl, １－６ Alkyl, C ２－６ Alkynyl, C ３－６ Carbocyclyl and 5- to 8-membered heteroaryl independently have 1 to 5 R Ａ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, optionally substituted with:

16. R １５ is hydrogen or unsubstituted C １－６ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:

17. R １６ is hydrogen or unsubstituted C １－６ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:

18. R １５ and R １６ together with the carbon atoms to which they are attached, substituted or unsubstituted C ３－６ A compound according to any one of claims 1 to 15, which forms a carbocyclyl.

19. R １８ is hydrogen or unsubstituted C １－６ 19. The compound of any one of claims 1 to 3 and 10 to 18, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:

20. R １９ is hydrogen or unsubstituted C １－６ 20. The compound of any one of claims 1-2 and 10-19, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:

21. R ２０ is hydrogen, hydroxyl, or unsubstituted C １－６ 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:

22. R ２０’ is hydrogen or unsubstituted C １－６ 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:

23. R ２２ is substituted or unsubstituted C １－６ The compound of any one of claims 1 to 22, which is alkyl.

24. R ２２ is substituted or unsubstituted C ２－６ The compound of any one of claims 1 to 11 and 14 to 22, which is alkenyl.

25. R ２２ is substituted or unsubstituted C ２－６ The compound of any one of claims 1 to 22, which is alkynyl.

26. R ２２ is substituted or unsubstituted C ３－６ The compound of any one of claims 1 to 11 and 14 to 22, which is carbocyclyl.

27. R ２２ is substituted or unsubstituted C ６－１０ The compound according to any one of claims 1 to 11 and 14 to 22, which is aryl.

28. R ３ is 1 to 3 R Ａ C substituted with １ is alkyl, R １５ and R １６ is hydrogen, R １８ and R １９ is -CH ３ and R ２０ is hydrogen, R ２０’ is -CH ３ and R ２２ is unsubstituted C １－６ C optionally substituted with alkoxy １－６ 24. The compound of any one of claims 1 to 3, 11 to 15, 16 to 17, and 19 to 23, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein:

29. R ２２ But -CH ３ or -CH ２ OCH ３ 29. The compound of claim 28, wherein:

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

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

32. 32. A method of 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 claims 1 to 30, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition of claim 31.

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

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

35. 32. A method for 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 claims 1 to 30, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition of claim 31.

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

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

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

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

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

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

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

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

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