NEGATIVE NMDA-MODULATING COMPOUNDS AND METHODS OF USE THEREOF Related Applications [0001] This application claims the benefit of and priority from U.S. Provisional Application Number 63/427,012, filed November 21, 2022, the entire contents of which are incorporated herein by reference. Background [0002] NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. NMDA receptors are expressed in the peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activating these receptors contributes to synaptic plasticity in some circumstances and excitotoxicity in others. These receptors are ligand-gated ion channels that admit Ca
2+ after binding of the glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function. Negative modulators may be useful as therapeutic agents with potential clinical uses in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (e.g., treatment resistant depression). [0003] There is a need for new compounds that are negative allosteric modulators of the NMDA receptor for the prevention and treatment of conditions associated with NMDA function. Compounds, compositions, and methods described herein are directed toward this end. Summary [0004] In one aspect, the disclosure provides a compound of Formula (I):
or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: 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 5-8 membered heteroaryl; each of R
15 and R
16 is independently hydrogen or substituted or unsubstituted C
1-6 alkyl; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl; R
18 is hydrogen or substituted or unsubstituted C
1-6 alkyl; R
19 is hydrogen or substituted or unsubstituted C
1-6 alkyl; R
20 is hydrogen, hydroxyl, substituted or unsubstituted C
1-6 alkyl, or substituted or unsubstituted C
3-6 carbocyclyl; R
20’ is hydrogen, hydroxyl, substituted or unsubstituted C
1-6 alkyl, or substituted or unsubstituted C
3-6 carbocyclyl; provided that R
20 and R
20’ are not both hydroxyl; and R
22 is 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 aryl; provided that when R
22 is -CH
3, R
3 is not -CH
3 or hydrogen. [0005] In some embodiments, the 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 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, C
6-10 aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 R
A;
each of R
15 and R
16 is independently hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
C; R
19 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
D; R
20 is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
E; R
20’ is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
F; provided that R
20 and R
20’ are not both hydroxyl; each instance of R
A, R
B, R
C, R
D, R
E, and R
F, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and C
1-6 alkoxy optionally substituted with 1-5 halo; R
22 is C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, or C
6-10 aryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, and C
2-6 alkynyl are independently optionally substituted with 1- 5 R
G and said C
3-6 carbocyclyl and C
6-10 aryl are independently optionally substituted with 1- 5 R
H; provided that when R
22 is -CH
3, R
3 is not -CH
3 or hydrogen; each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 R
G1; each instance of R
G1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1-6 alkoxy optionally substituted with 1-5 halo; and each instance of R
H, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1- 6 alkoxy optionally substituted with 1-5 halo. [0006] In some embodiments, the disclosure provides a compound of Formula (I-A) or (I- B):
acceptable salt, isotopic variant, or combination thereof. [0007] In some embodiments, the disclosure provides a compound of Formula (I-A-1) or (I-A-2):
acceptable salt, isotopic variant, or combination thereof. [0008] In some embodiments, the disclosure provides a compound of Formula (I-A-1-i) or (I-A-1-ii):
acceptable salt, isotopic variant, or combination thereof. [0009] In some embodiments, the disclosure provides a compound of Formula (I-A-2-i) or (I-A-2-ii):
acceptable salt, isotopic variant, or combination thereof. [0010] In some embodiments, the disclosure provides a compound of Formula (I-B-1) or (I-B-2):
salt, isotopic variant, or combination thereof. [0011] In some embodiments, the disclosure provides a compound of Formula (I-B-1-i) or (I-B-1-ii):
acceptable salt, isotopic variant, or combination thereof. [0012] In some embodiments, the disclosure provides a compound of Formula (I-B-2-i) or (I-B-2-ii):
acceptable salt, isotopic variant, or combination thereof. [0013] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein (i.e., (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2- ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), (I-B-2-ii)), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R
3 is substituted or unsubstituted C
1-6 alkyl or substituted or unsubstituted C
2-6 alkynyl; R
15 is hydrogen or substituted or unsubstituted C
1-6 alkyl and R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl; R
18 is substituted or unsubstituted C
1-6 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 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, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-5 R
A; R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is C
1-6 alkyl optionally substituted with 1-5 R
C; R
20 is hydrogen, hydroxyl, or C
1-6 alkyl optionally substituted with 1-5 R
E; and
R
20’ is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
F. [0015] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R
3 is substituted or unsubstituted C
1-6 alkyl; R
15 is hydrogen or substituted or unsubstituted C
1-6 alkyl and R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl; R
18 is -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and R
22 is substituted or unsubstituted C
1-6 alkyl or substituted or unsubstituted C
2-6 alkynyl. [0016] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R
3 is C
1-6 alkyl optionally substituted with 1-5 R
A; R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-5 R
G. [0017] In some embodiments, the disclosure provides a compound of any one of Formulae disclosed herein, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R
3 is C
1 alkyl substituted with 1-3 R
A; R
15 and R
16 are hydrogen; R
18 and R
19 are -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and
R
22 is C
1-6 alkyl optionally substituted with an unsubstituted C
1-6 alkoxy. In some embodiments, R
22 is -CH
3 or -CH
2OCH
3. [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 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkynyl, C
3-6 carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 R
A. In some embodiments, R
3 is -H, -CH
2F, - CHF
2, -CF
3, -CH
2OCH
3, -CH
2OH, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH(CH
3)
2, -C≡C-H, - C≡C-CH
3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently optionally substituted with 1-5 R
A. In some embodiments, R
3 is hydrogen. In some embodiments, R
3 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
3 is C
1-6 alkyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
1-6 alkyl substituted with 1-5 R
A. In some embodiments, R
3 is -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, or -CH
2OH. In some embodiments, R
3 is -CF
3. In some embodiments, R
3 is unsubstituted C
1-6 alkyl. In some embodiments, R
3 is -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, or -CH(CH
3)
2. In some embodiments, R
3 is -CH
3 or -CH
2CH
3. In some embodiments, R
3 is substituted or unsubstituted C
2-6 alkynyl. In some embodiments, R
3 is C
2-6 alkynyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is -C≡C-H or -C≡C-CH
3. In some embodiments, R
3 is substituted or unsubstituted C
3-6 carbocyclyl. In some embodiments, R
3 is C
3-6 carbocyclyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted cyclopropyl. In some embodiments, R
3 is substituted or unsubstituted 5-8 membered heteroaryl. In some embodiments, R
3 is 5-8 membered heteroaryl optionally substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted pyridyl. [0019] In some embodiments, R
15 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
15 is hydrogen or -CH
3. [0020] In some embodiments, R
16 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
16 is hydrogen or -CH
3. [0021] In some embodiments, R
15 and R
16 are hydrogen. In some embodiments, R
15 is - CH
3 and R
16 is hydrogen. In some embodiments, R
15 is hydrogen and R
16 is -CH
3. In some embodiments, R
15 and R
16 are -CH
3. In some embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl. In some embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B. In some
embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form an unsubstituted cyclopropyl. [0022] In some embodiments, R
18 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
18 is hydrogen, -CH
3, or -CH
2CH
3. In some embodiments, R
18 is -CH
3 or - CH
2CH
3. [0023] In some embodiments, R
19 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
19 is hydrogen or -CH
3. In some embodiments, R
19 is -CH
3. In some embodiments, R
19 is hydrogen. [0024] In some embodiments, R
18 and R
19 are hydrogen. In some embodiments, R
18 and R
19 are -CH
3. In some embodiments, R
18 is -CH
3 and R
19 is hydrogen. In some embodiments, R
18 is -CH
2CH
3 and R
19 is -CH
3. [0025] In some embodiments, R
20 is hydrogen, hydroxyl, or unsubstituted C
1-6 alkyl. In some embodiments, R
20 is hydrogen, hydroxyl, or -CH
3. [0026] In some embodiments, R
20’ is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
20’ is hydrogen or -CH
3. [0027] In some embodiments, R
20 and R
20’ are hydrogen. In some embodiments, R
20 and R
20’ are -CH
3. In some embodiments, R
20 is hydrogen and R
20’ is -CH
3. In some embodiments, R
20 is -CH
3 and R
20’ is hydrogen. In some embodiments, R
20 is hydroxyl and R
20’ is -CH
3. [0028] In some embodiments, R
22 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
22 is C
1-6 alkyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is substituted C
1-6 alkyl. In some embodiments, R
22 is C
1-6 alkyl substituted with 1-5 R
G. In some embodiments, R
22 is C
1-6 alkyl substituted with 1-3 R
G, wherein each instance of R
G is independently selected from the group consisting of: halo, hydroxyl, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl, wherein said C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 R
G1. In some embodiments, R
22 is -CH
2F, -CHF
2, -CF
3, -CH
2CH
2CH(CH
3)(CF
3), -CH
2OH, -CH
2OCH
3, - CH
2OCH
2CH
2OCH
3, -CH
2OCH(CH
3)
2, -CH
2OCF
3, -CH
2OCHF
2, -CH
3, -CH
2CH
3, - CH
2CH
2CH
2CH
3, -CH(CH
3)
2, -CH
2CH(CH
3)
2, -CH
2CH
2CH(CH
3)
2, -C(CH
3)
3, -CH=CH
2, - CH
2CH=CH
2, -CH=CHCH
3, -CH=C(CH
3)
2, -C≡C-H, -C≡C-CH
3, -C≡C-CF
3, unsubstituted cyclopropyl, unsubstituted cyclobutyl, bicyclo[1.1.1]pentanyl optionally substituted with 1-5 R
H, or phenyl optionally substituted with 1-5 R
H. In some embodiments, R
22 is -CH
2F, -
CHF
2, -CF
3, or -CH
2CH
2CH(CH
3)(CF
3). In some embodiments, R
22 is -CH
2OH, -CH
2OCH
3, -CH
2OCH
2CH
2OCH
3, -CH
2OCH(CH
3)
2, -CH
2OCF
3, or -CH
2OCHF
2. [0029] In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is 5-6 membered heteroaryl optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is a 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is a 5-6 membered nitrogen-containing heteroaryl containing 1-4 nitrogen atoms and optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is a 5-6 membered heteroaryl substituted with 1-3 R
G1, wherein each instance of R
G1 is independently selected from cyano, oxo, and C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with a C
3-6 carbocyclyl optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is 5-8 membered heterocyclyl optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is a 5-8 membered nitrogen-containing heterocyclyl optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is a 5-8 membered nitrogen-containing heterocyclyl containing 1 nitrogen atom and optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is an unsubstituted 5-8 membered heterocyclyl. [0030] In some embodiments, R
22 is unsubstituted C
1-6 alkyl. In some embodiments, R
22 is -CH
3, -CH
2CH
3, -CH
2CH
2CH
2CH
3, -CH(CH
3)
2, -CH
2CH(CH
3)
2, -CH
2CH
2CH(CH
3)
2, or - C(CH
3)
3. [0031] In some embodiments, R
22 is substituted or unsubstituted C
2-6 alkenyl. In some embodiments, R
22 is C
2-6 alkenyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is -CH=CH
2, -CH
2CH=CH
2, -CH=CHCH
3, or -CH=C(CH
3)
2. [0032] In some embodiments, R
22 is substituted or unsubstituted C
2-6 alkynyl. In some embodiments, R
22 is C
2-6 alkynyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is -C≡C-H, -C≡C-CH
3, or -C≡C-CF
3. [0033] In some embodiments, R
22 is substituted or unsubstituted C
3-6 carbocyclyl. In some embodiments, R
22 is C
3-6 carbocyclyl optionally substituted with 1-5 R
H. In some embodiments, R
22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl optionally substituted with 1-3 R
H. [0034] In some embodiments, R
22 is substituted or unsubstituted C
6-10 aryl. In some embodiments, R
22 is C
6-10 aryl optionally substituted with 1-5 R
H. In some embodiments, R
22
is unsubstituted phenyl. In some embodiments, R
22 is phenyl substituted with 1-3 R
H, wherein each instance of R
H is independently selected from the group consisting of: halo, cyano, and C
1-6 alkyl optionally substituted with 1-5 halo. [0035] In some embodiments, the compound of Formula (I) is any one compounds 1-118, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one compounds 1-118. In some embodiments, the compound of Formula (I) is any one of compounds 2, 7, 13, 14, 16, 18-21, 27, 29-32, 34-36, 38-40, 53-65, 67, 70, 73, 75, 77-79, 81-84, 86, 88, 90-93, 95, 97-98, 100- 101, 103-106, and 108, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one of compounds 2, 7, 13, 14, 16, 18-21, 27, 29-32, 34-36, 38-40, 53-65, 67, 70, 73, 75, 77-79, 81-84, 86, 88, 90-93, 95, 97-98, 100-101, 103-106, or 108. In some embodiments, the compound is a pharmaceutically acceptable salt of any one of compounds 2, 7, 13, 14, 16, 18-21, 27, 29-32, 34-36, 38-40, 53-65, 67, 70, 73, 75, 77-79, 81-84, 86, 88, 90-93, 95, 97-98, 100-101, 103- 106, or108. In some embodiments, the compound of Formula (I) is any one of compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100-101, or 104-106, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one of compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100-101, or 104-106. In some embodiments, the compound is a pharmaceutically acceptable salt of any one of compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100-101, or 104-106. [0036] In some embodiments, the compound provided herein is a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii). In some embodiments, the compound provided herein is a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I- B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii). In some embodiments, the compound provided herein is an isotopic variant of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2- i), and (I-B-2-ii). In some embodiments, the compound provided herein is an isotopic variant of a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1- ii), (I-B-2-i), and (I-B-2-ii).
[0037] In some embodiments, one or more hydrogen atoms are replaced by deuterium. In some embodiments, one or more hydrogen atoms are replaced by tritium. [0038] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I- A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to the disclosure, and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B- 1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of compound of any one of Formulae (I), (I-A), (I-B), (I-A- 1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I- B-2-i), and (I-B-2-ii), and a pharmaceutically acceptable carrier. In some embodiments, the disclosure provides a pharmaceutical composition comprising an isotopic variant of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I- A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii). In some embodiments, the disclosure provides a pharmaceutical composition comprising an isotopic variant of a pharmaceutically acceptable salt of a compound of any one of Formulae (I), (I- A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1- i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii). [0039] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I- A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure. [0040] In one aspect, the disclosure provides a method for effecting negative allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulae (I), (I-A), (I-B), (I-A- 1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I-B-1-ii), (I- B-2-i), and (I-B-2-ii)or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure.
[0041] In one aspect, the disclosure provides a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I- B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in treating a CNS-related condition in a subject. [0042] In one aspect, the disclosure provides a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I-B-1-i), (I- B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, for use in effecting negative allosteric modulation of an NMDA receptor. [0043] In one aspect, the disclosure provides a use of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I- B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for treating a CNS-related condition in a subject. [0044] In one aspect, the disclosure provides a use of a compound of any one of Formulae (I), (I-A), (I-B), (I-A-1), (I-A-2), (I-A-1-i), (I-A-1-ii), (I-A-2-i), (I-A-2-ii), (I-B-1), (I-B-2), (I- B-1-i), (I-B-1-ii), (I-B-2-i), and (I-B-2-ii) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition according to the disclosure, in the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor. [0045] In some embodiments, the CNS-related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus. In some embodiments, the CNS-related condition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychotic disorder, pain, a seizure disorder, drug induced dyskinesia (e.g., L-DOPA- induced dyskinesia (LID)), stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome (FXS), neuropsychiatric lupus, and tinnitus. Detailed Description
[0046] The present disclosure provides compounds that are NMDA receptor negative allosteric modulators. The compounds of the disclosure are useful as therapeutic agents for treating, for example, CNS-related conditions including, but not limited to an anxiety disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure disorder, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, neuropsychiatric lupus, and tinnitus. General Definitions [0047] The term “herein” means the entire application. [0048] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. Generally, nomenclature used in connection with the compounds, compositions, and methods described herein, are those well-known and commonly used in the art. [0049] It should be understood that any of the embodiments described herein, including those described under different aspects of the disclosure and different parts of the specification (including embodiments described only in the Examples), can be combined with one or more other embodiments of the disclosure, unless explicitly disclaimed or improper. Combinations of embodiments are not limited to those specific combinations claimed via the multiple dependent claims. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. [0050] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components). [0051] Throughout the specification, where compositions are described as having, including, or comprising (or variations thereof), specific components, it is contemplated that compositions also may consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising (or variations thereof), specific process steps, the processes also may consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of
steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions can be conducted simultaneously. [0052] The term “including” as used herein, means “including but not limited to.” “Including” and “including but not limited to” are used interchangeably. Thus, these terms will be understood to imply the inclusion of a stated integer (element or component) or group of integers (elements or components), but not the exclusion of any other integer (element or component) or group of integers (elements or components). [0053] As used herein, “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. [0054] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. [0055] The term “or” as used herein should be understood to mean “and/or,” unless the context clearly indicates otherwise. [0056] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range and including the endpoints, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential. [0057] All of the publications, patents, and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth
explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. Chemical Definitions [0058] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 102
nd Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 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] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), supercritical fluid chromatograph (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw– Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0060] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed
“diastereomers” and those that are non–superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- sequencing rules of Cahn, Ingold, and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (–)–isomers respectively). A chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. [0061] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. As used herein, the term “diastereomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers. [0062] The term “diastereomerically pure” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, of the diastereomer. Methods for determining diastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers,
such as high-performance liquid chromatography (HPLC) or supercritical fluid chromatograph (SFC). [0063] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R–position/center/carbon compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R– compound. In certain embodiments, the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound. In certain embodiments, the enantiomerically pure S–compound in such compositions can, for example, comprise, at least about 95% by weight S–compound and at most about 5% by weight R– compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier. [0064] Compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including
1H,
2H (D or deuterium), and
3H (T or tritium); C may be in any isotopic form, including
12C,
13C, and
14C; O may be in any isotopic form, including
16O and
18O; and the like. [0065] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C
1–6 alkyl” is intended to encompass, C
1, C
2, C
3, C
4, C5, C6, C
1–6, C1–5, C1–4, C1–3, C1–2, C
2–6, C2–5, C2–4, C2–3, C
3–6, C3–5, C3–4, C4–6, C4–5, and C
5–6 alkyl. [0066] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. It should also be understood that when described herein any of the moieties defined herein may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. [0067] “Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.
[0068] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C
1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C
1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C
1 alkyl”). Examples of C
1–6 alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C
4), tert–butyl (C
4), sec–butyl (C
4), iso–butyl (C
4), n–pentyl (C
5), 3–pentanyl (C
5), amyl (C
5), neopentyl (C
5), 3– methyl–2–butanyl (C
5), tertiary amyl (C
5), and n–hexyl (C
6). Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 4 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include Me (-CH
3), Et (-CH
2CH
3), iPr (-CH(CH
3)
2), nPr (-CH
2CH
2CH
3), n-Bu (-CH
2CH
2CH
2CH
3), or i-Bu (-CH
2CH(CH
3)
2). [0069] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to a divalent radical of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein. [0070] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH
2-), ethylene (-CH
2CH
2-), propylene (-CH
2CH
2CH
2-), butylene (-CH
2CH
2CH
2CH
2-), pentylene (-CH
2CH
2CH
2CH
2CH
2-), hexylene (-CH
2CH
2CH
2CH
2CH
2CH
2-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more halo, -NO
2, -OH, C
1-C
6 alkoxy, C
1-C
6 alkyl (e.g., methyl) groups, including but not limited to, substituted methylene (-CH(CH
3)-, (-C(CH
3)
2-), substituted ethylene (-CH(CH
3)CH
2-,-CH
2CH(CH
3)-, -C(CH
3)
2CH
2-,-CH
2C(CH
3)
2-), substituted propylene (-CH(CH
3)CH
2CH
2-, -CH
2CH(CH
3)CH
2-, -CH
2CH
2CH(CH
3)- , -C(CH
3)
2CH
2CH
2-, -CH
2C(CH
3)
2CH
2-, -CH
2CH
2C(CH
3)
2-), or C
1-C
6 cycloalkyl, and the
like. Alkylene abbreviations include, but are not limited to, -(CH(CH
3))–, –(CH(CH
2CH
3))–, –(CH(CH
2CH
2CH
3))–, –(CH(CH
2CH
2 CH
2CH
3))–, -(CH
2CH(CH
2CH
2 CH
2CH
3))–, -(CH
2CH
2CH(CH
2CH
2CH
2CH
3))–, –(CH(CH
3)CH
2)–, -(CH(CH
3)CH
2CH
2)–, -(CH(CH
3)CH
2CH
2CH
2)–, –( CH
2CH(CH
3)CH
2)–, -(CH
2CH(CH
3)CH
2CH
2)–, and -(CH
2CH
2CH(CH
3)CH
2CH
2)–. [0071] “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C2–20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C
2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C
2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C
2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C
2–4 alkenyl groups include ethenyl (C
2), 1–propenyl (C
3), 2–propenyl (C
3), 1– butenyl (C
4), 2–butenyl (C
4), butadienyl (C
4), and the like. Examples of C
2–6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C
5), pentadienyl (C
5), hexenyl (C
6), and the like. Additional examples of alkenyl include heptenyl (C
7), octenyl (C
8), octatrienyl (C
8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C
2–10 alkenyl. In certain embodiments, the alkenyl group is substituted C
2–10 alkenyl. [0072] “Alkenylene” refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (- CH=CH-) and propenylene (e.g., -CH=CHCH
2-, -CH
2-CH=CH-). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are
not limited to, substituted ethylene (-C(CH
3)=CH-, -CH=C(CH
3)-), substituted propylene (e.g., -C(CH
3)=CHCH
2-, -CH=C(CH
3)CH
2-, -CH=CHCH(CH
3)-, -CH=CHC(CH
3)
2-, - CH(CH
3)-CH=CH-,-C(CH
3)
2-CH=CH-, -CH
2-C(CH
3)=CH-, -CH
2-CH=C(CH
3)-), and the like. [0073] “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C2–20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C
2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C
2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C
2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C
2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C
2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4 alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C
3), 1–butynyl (C
4), 2–butynyl (C
4), and the like. Examples of C
2–6 alkenyl groups include the aforementioned C
2–4 alkynyl groups as well as pentynyl (C
5), hexynyl (C
6), and the like. Additional examples of alkynyl include heptynyl (C
7), octynyl (C
8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C
2–10 alkynyl. In certain embodiments, the alkynyl group is substituted C
2–10 alkynyl. [0074] “Alkynylene” refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. [0075] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur,
nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC
1–10 alkyl”). 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 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1–8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC
1–7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC
1–6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1–5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC1–4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1–3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1–2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC
2–6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC
1–10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC
1–10 alkyl. [0076] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2– 10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC
2–9 alkenyl”). In some embodiments,
a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC
2–6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC
2–5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms (“heteroC2–4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC
2–3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC
2–6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC
2–10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC
2–10 alkenyl. [0077] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–
10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC
2–8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2–7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC
2–6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2–5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms (“heteroC2–4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1
heteroatom (“heteroC
2–3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC
2–6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC
2–10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC
2–10 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 ^ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C
6–14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C
6 aryl”; e.g., phenyl). Aryl” also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C
6–14 aryl. In certain embodiments, the aryl group is substituted C
6–14 aryl. [0079] In certain embodiments, an aryl group is substituted with one or more of groups selected from halo, C
1-C
8 alkyl, C
1-C
8 haloalkyl, cyano, hydroxy, C
1-C
8 alkoxy, and amino. [0080] Examples of representative substituted aryls include the following
wherein one of R
56 and R
57 may be hydrogen and at least one of R
56 and R
57 is each independently selected from C
1-C
8 alkyl, C
1-C
8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C
1-C
8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR
58COR
59, NR
58SOR
59 NR
58SO
2R
59, COOalkyl, COOaryl, CONR
58R
59, CONR
58OR
59, NR
58R
59, SO
2NR
58R
59, S-alkyl, SOalkyl, SO
2alkyl, Saryl, SOaryl, SO
2aryl; or R
56 and R
57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R
60 and R
61 are independently hydrogen, C
1-C
8 alkyl, C1-C4 haloalkyl, C
3-C
10 cycloalkyl, 4-10 membered heterocyclyl, C
6-C
10 aryl, substituted C
6-C
10 aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl. [0081] “Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring. [0082] “Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. [0083] “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
[0084] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5–14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5–14 membered heteroaryl. [0085] Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. [0086] Examples of representative heteroaryls include the following:
wherein each Z is selected from carbonyl, N, NR
65, O, and S; and R
65 is independently hydrogen, C
1-C
8 alkyl, C
3-C
10 cycloalkyl, 4-10 membered heterocyclyl, C
6-C
10 aryl, and 5-10 membered heteroaryl. [0087] “Nitrogen-containing heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ^ electrons shared in a cyclic array) having ring carbon atoms and containing at least one nitrogen atom. Examples of nitrogen-containing heteroaryl groups included, but are not limited to, pyrrolyl, pyridinyl, pyridinonyl, pyridazinyl, and pyrimidinyl. [0088] “Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group. [0089] “Carbocyclyl” or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C
3–10 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C
3–8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C
3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C
3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C
5–10 carbocyclyl”). Exemplary C
3–6 carbocyclyl groups include, without limitation, cyclopropyl (C
3), cyclopropenyl (C
3), cyclobutyl (C
4), cyclobutenyl (C
4), cyclopentyl (C
5), cyclopentenyl (C
5), cyclohexyl (C
6), cyclohexenyl (C
6), cyclohexadienyl (C
6), and the like. Exemplary C
3–8 carbocyclyl groups include, without limitation, the aforementioned C
3–6 carbocyclyl groups as well as cycloheptyl (C
7), cycloheptenyl (C
7), cycloheptadienyl (C
7), cycloheptatrienyl (C
7), cyclooctyl (C
8), cyclooctenyl (C
8), bicyclo[2.2.1]heptanyl (C
7), bicyclo[2.2.2]octanyl (C
8),
and the like. Exemplary C
3–10 carbocyclyl groups include, without limitation, the aforementioned C
3–8 carbocyclyl groups as well as cyclononyl (C
9), cyclononenyl (C
9), cyclodecyl (C
10), cyclodecenyl (C
10), octahydro–1H–indenyl (C
9), decahydronaphthalenyl (C
10), spiro[4.5]decanyl (C
10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group includes either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C
3–10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C
3–10 carbocyclyl. [0090] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C
3–10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C
3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C
3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C
5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C
5–10 cycloalkyl”). Examples of C
5–6 cycloalkyl groups include cyclopentyl (C
5) and cyclohexyl (C
5). Examples of C
3–6 cycloalkyl groups include the aforementioned C
5–6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C
4). Examples of C
3–8 cycloalkyl groups include the aforementioned C
3–6 cycloalkyl groups as well as cycloheptyl (C
7) and cyclooctyl (C
8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C
3–10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C
3–10 cycloalkyl. [0091] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl. [0092] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0093] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation,
dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C
6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [0094] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [0095] “Acyl” refers to a radical -C(O)R
20, where 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 wherein R
20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH
3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH
2Ph), ––C(O)- C
1-C
8 alkyl, –C(O)-(CH
2)
t(C
6-C
10 aryl), –C(O)-(CH
2)
t(5-10 membered heteroaryl), –C(O)- (CH
2)
t(C
3-C
10 cycloalkyl), and –C(O)-(CH
2)
t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R
21 is C
1-C
8 alkyl, substituted with halo or hydroxy; orC
3-C
10 cycloalkyl, 4-10 membered heterocyclyl,C
6-C
10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C
1-
C
4 alkyl, halo, unsubstituted C
1-C
4 alkoxy, unsubstituted C
1-C
4 haloalkyl, unsubstituted C
1- C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. [0096] “Alkoxy” refers to the group –OR
29 where R
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 has 1 to 6 carbon atoms (“C
1–6 alkoxy”). In some embodiments, an alkoxy group has 1 to 5 carbon atoms (“C1–5 alkoxy”). In some embodiments, an alkoxy group has 1 to 4 carbon atoms (“C1–4 alkoxy”). In some embodiments, an alkoxy group has 1 to 3 carbon atoms (“C
1–3 alkoxy”). In some embodiments, an alkoxy group has 1 to 2 carbon atoms (“C
1– 2 alkoxy”). In some embodiments, an alkoxy group has 1 carbon atom (“C
1 alkoxy”). Examples of C
1-6 alkoxy groups include methoxy (C1), ethoxy(C2), n-propoxy (C3), isopropoxy (C3), 2-methoxyethoxy (C3), n-butoxy (C
4), tert-butoxy (C
4), sec-butoxy (C
4), n- pentoxy (C
5), n-hexoxy (C
6), and 1,2-dimethylbutoxy (C
6). Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms. [0097] In certain embodiments, R
29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C
6-C
10 aryl, aryloxy, carboxyl, cyano, C
3-C
10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl–S(O)-, alkyl– S(O)
2- and aryl-S(O)
2-. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, –O-(CH
2)t(C
6-C
10 aryl), –O-(CH
2)t(5-10 membered heteroaryl), –O-(CH
2)t(C
3-C
10 cycloalkyl), and –O-(CH
2)
t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1- C
4 haloalkyl, unsubstituted C
1-C
4 hydroxyalkyl, or unsubstituted C
1-C
4 haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are -OCF
3, -OCH
2CF
3, -OCH
2Ph, -OCH
2-cyclopropyl, -OCH
2CH
2OH, and -OCH
2CH
2NMe2. [0098] “Amino” refers to the radical -NH
2. [0099] “Substituted amino” refers to an amino group of the formula -N(R
38)
2 wherein 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, wherein at least one of R
38 is not a hydrogen. In certain embodiments, each R
38 is independently selected from hydrogen, C
1-C
8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C
6-C
10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3- C
10 cycloalkyl; or C
1-C
8 alkyl, substituted with halo or hydroxy; C
3-C
8 alkenyl, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH
2)t(C
6-C
10 aryl), -(CH
2)t(5-10 membered heteroaryl), -(CH
2)t(C
3-C
10 cycloalkyl), or -(CH
2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R
38 groups are joined to form an alkylene group. [0100] Exemplary “substituted amino” groups include, but are not limited to, –NR
39-C
1-C
8 alkyl, –NR
39-(CH
2)t(C
6-C
10 aryl), –NR
39-(CH
2)t(5-10 membered heteroaryl), –NR
39- (CH
2)t(C
3-C
10 cycloalkyl), and –NR
39-(CH
2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R
39 independently represents H or C
1-C
8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C
1-C
4 alkyl, halo, unsubstituted C
1- C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups. [0101] “Carboxy” refers to the radical -C(O)OH. [0102] “Cyano” refers to the radical -CN. [0103] “Halo” or ”halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [0104] “Hydroxyl” refers to the radical -OH. [0105] “Nitro” refers to the radical –NO
2. [0106] “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.
[0107] “Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like. [0108] “Nitrogen-containing heterocyclyl” group means a 5- to 8- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone. [0109] “Thioketo” refers to the group =S. [0110] “Imino” refers to the group =N-R
N, wherein R
N is hydrogen, alkyl, aryl, carbocyclyl, heteroaryl, or heterocyclyl, or any combination of selections therefrom. [0111] “Oxo” refers to the group =O. [0112] “Thiol” refers to the group -SH. [0113] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
[0114] Exemplary carbon atom substituents include, but are not limited to, halogen, –CN, –NO
2, –N3, –SO
2H, –SO
3H, –OH, –OR
aa, –ON(R
bb)
2, –N(R
bb)
2, –N(R
bb)
3 +X
–, –N(OR
cc)R
bb, –SH, –SR
aa, –SSR
cc, –C(=O)R
aa, –CO
2H, –CHO, –C(OR
cc)
2, –CO
2R
aa, –OC(=O)R
aa, –OCO
2R
aa, –C(=O)N(R
bb)
2, –OC(=O)N(R
bb)
2, –NR
bbC(=O)R
aa, –NR
bbCO
2R
aa, –NR
bbC(=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
bbC(=NR
bb)N(R
bb)
2, –C(=O)NR
bbSO
2R
aa, –NR
bbSO
2R
aa, –SO
2N(R
bb)
2, –SO
2R
aa, –SO
2OR
aa, –OSO
2R
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)
2R
aa, –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
bbP(=O)(OR
cc)
2, –NR
bbP(=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, 3–14 membered heterocyclyl, C
6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
dd groups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R
bb)
2, =NNR
bbC(=O)R
aa, =NNR
bbC(=O)OR
aa, =NNR
bbS(=O)
2R
aa, =NR
bb, or =NOR
cc; each instance of R
aa is, independently, selected from C
1–10 alkyl, C
1–10 perhaloalkyl, C
2–10 alkenyl, C
2–10 alkynyl, C
3–10 carbocyclyl, 3–14 membered heterocyclyl, C
6–14 aryl, and 5–14 membered heteroaryl, or two R
aa groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
dd groups; each instance of R
bb is, independently, selected from hydrogen, –OH, –OR
aa, –N(R
cc)
2, –CN, –C(=O)R
aa, –C(=O)N(R
cc)
2, –CO
2R
aa, –SO
2R
aa, –C(=NR
cc)OR
aa, –C(=NR
cc)N(R
cc)
2, –SO
2N(R
cc)
2, –SO
2R
cc, –SO
2OR
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, 3–14 membered heterocyclyl, C
6–14 aryl, and 5–14 membered heteroaryl, or two R
bb groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
dd groups;
each instance of R
cc is, independently, selected from hydrogen, C
1–10 alkyl, C
1–10 perhaloalkyl, C
2–10 alkenyl, C
2–10 alkynyl, C
3–10 carbocyclyl, 3–14 membered heterocyclyl, C
6–14 aryl, and 5–14 membered heteroaryl, or two R
cc groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
dd groups; each instance of R
dd is, independently, selected from halogen, –CN, –NO
2, –N
3, – SO
2H, –SO
3H, –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, –CO
2H, –CO
2R
ee, –OC(=O)R
ee, –OCO
2R
ee, –C(=O)N(R
ff)
2, – OC(=O)N(R
ff)
2, –NR
ffC(=O)R
ee, –NR
ffCO
2R
ee, –NR
ffC(=O)N(R
ff)
2, –C(=NR
ff)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
ffC(=NR
ff)N(R
ff)
2,–NR
ffSO
2R
ee, –SO
2N(R
ff)
2, –SO
2R
ee, –SO
2OR
ee, –OSO
2R
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, 5–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
gg groups, or two geminal R
dd substituents can be joined to form =O or =S; each instance of R
ee is, independently, selected from C
1–6 alkyl, C
1–6 perhaloalkyl, C
2– 6 alkenyl, C
2–6 alkynyl, C
3–10 carbocyclyl, C
6–10 aryl, 3–10 membered heterocyclyl, and 3–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
gg groups; each instance of R
ff is, independently, selected from 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 5–10 membered heteroaryl, or two R
ff groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
gg groups; and each instance of R
gg is, independently, halogen, –CN, –NO
2, –N3, –SO
2H, –SO
3H, –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
–, –NH
2(C
1–6 alkyl)
+X
–, –NH
3 +X
–, –N(OC
1–6 alkyl)(C
1–6 alkyl), –N(OH)(C
1–6 alkyl), –NH(OH), –SH, –SC
1–6 alkyl, –SS(C
1–6 alkyl), –C(=O)(C
1–6 alkyl), –CO
2H, –CO
2(C
1–6 alkyl), –OC(=O)(C
1–6 alkyl), –OCO
2(C
1–6 alkyl), –C(=O)NH
2, –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),
–NHCO
2(C
1–6 alkyl), –NHC(=O)N(C
1–6 alkyl)
2, –NHC(=O)NH(C
1–6 alkyl), – NHC(=O)NH
2, –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)NH
2, – OC(=NH)N(C
1–6 alkyl)
2, –OC(NH)NH(C
1–6 alkyl), –OC(NH)NH
2, –NHC(NH)N(C
1–6 alkyl)
2, –NHC(=NH)NH
2, –NHSO
2(C
1–6 alkyl), –SO
2N(C
1–6 alkyl)
2, –SO
2NH(C
1–6 alkyl), –SO
2NH
2,–SO
2C
1–6 alkyl, –SO
2OC
1–6 alkyl, –OSO
2C
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)NH
2, –C(=O)S(C
1–6 alkyl), –C(=S)SC
1–6 alkyl, – 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)(OC
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, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal R
gg substituents can be joined to form =O or =S; wherein X
– is a counterion. [0115] A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F
–, Cl
–, Br
–, I
–), NO
3 –, ClO
4 –, OH
–, H
2PO
4 –, HSO
4 –, SO
4 -2 sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like). [0116] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substitutuents include, but are not limited to, hydrogen, –OH, –OR
aa, –N(R
cc)
2, –CN, –C(=O)R
aa, –C(=O)N(R
cc)
2, –CO
2R
aa, –SO
2R
aa, –C(=NR
bb)R
aa, –C(=NR
cc)OR
aa, –C(=NR
cc)N(R
cc)
2, –SO
2N(R
cc)
2, –SO
2R
cc, –SO
2OR
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, 3–14 membered heterocyclyl, C
6–14 aryl, and 5–14 membered heteroaryl, or two R
cc groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R
dd groups, and wherein R
aa, R
bb, R
cc and R
dd are as defined above.
Other Definitions [0117] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [0118] “Pharmaceutically acceptable salt” refers to a salt of a compound disclosed herein that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non–toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3–(4–hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2–ethane–disulfonic acid, 2– hydroxyethanesulfonic acid, benzenesulfonic acid, 4–chlorobenzenesulfonic acid, 2– naphthalenesulfonic acid, 4–toluenesulfonic acid, camphorsulfonic acid, 4– methylbicyclo[2.2.2]–oct–2–ene–1–carboxylic acid, glucoheptonic acid, 3–phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N– methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter– ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1–79. [0119] “Pharmaceutically acceptable carrier” refers to compositions, carriers, diluents, and reagents which are pharmaceutically acceptable materials that are capable of administration to or upon a subject. A pharmaceutically acceptable carrier can be involved with carrying or
transporting the subject agents from one organ, or portion of the body, to another organ, or portion of the body. The carrier can be in the form of a solid, semi-solid or liquid diluent, cream or a capsule. The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. [0120] “Isotopic variant” refers to a compound disclosed herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof), wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as
2H,
3H,
13C,
14C,
15N,
17O,
18O,
32P,
33P,
33S,
34S,
35S,
18F, and
37Cl. Compounds disclosed herein which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure. Certain isotopic variants of the compounds of the present application, for example, those into which radioactive isotopes (e.g.,
3H and
14C) are incorporated, may be useful in drug and/or substrate distribution assays. Further, substitution with heavier isotopes (e.g.,
2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopic variants of compounds and pharmaceutically acceptable salts thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent. [0121] A “subject” to which administration is contemplated includes, but is not limited to, human subject (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein. [0122] Disease, disorder, and condition are used interchangeably herein. [0123] As used herein, the term “treat,” “treating” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition
in manner to improve or stabilize a subject's condition. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation, amelioration, reduction of the severity, or slowing the progression, of one or more symptoms or conditions associated with a condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Exemplary beneficial clinical results are described herein. [0124] As used herein, and unless otherwise specified, the term “prophylactic,” “prevention” and variations thereof, contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder, or condition. [0125] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment. [0126] The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” refer to an amount sufficient to treat a disease in a patient, e.g., effecting a beneficial and/or desirable alteration in the health of a patient suffering from a disease, treatment, healing, inhibition or amelioration of a physiological response or condition, delaying or minimizing one or more symptoms associated with the disease, disorder or condition etc. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, the nature and extent of disease, the therapeutics or combination of therapeutics selected for administration, and the mode of administration. The skilled worker can readily determine the effective amount for a given situation by routine experimentation. The terms “pharmaceutically effective amount,” “therapeutically effective amount,” or “therapeutically effective dose” also refer to the amount required to improve the clinical symptoms of a patient. A therapeutically effective amount of a compound also refers
to an amount of the therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. [0127] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. [0128] As used herein, and unless otherwise specified, “pharmacokinetics” can be defined as the study of bodily absorption, distribution, metabolism, and excretion of drugs. “Pharmacokinetics” can also be defined as the characteristic interactions of a drug and a body in terms of its absorption, distribution, metabolism, and excretion; or a branch of pharmacology concerned with the way drugs are taken into, move around, and are eliminated from, a body. [0129] “Administering” or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. In some embodiments, the administration includes both direct administration, including self- administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is administering the drug to the patient. When a method is part of a therapeutic regimen
involving more than one agent or treatment modality, the disclosure contemplates that the agents may be administered at the same or differing times and via the same or differing routes of administration. Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age of the subject, whether the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, the extent of the impairment, and the chemical and biological properties of the compound or agent (e.g. solubility, digestibility, bioavailability, stability and toxicity). [0130] As generally described herein, the disclosure provides compounds useful for preventing and/or treating a broad range of disorders, including, but not limited to, NMDA– mediated disorders. These compounds are expected to show improved in vivo potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, and/or safety as compared to other compounds. Compounds [0131] A compound, wherein the compound has the structure of Formula (I):
or a pharmaceutically acceptable salt, isotopic variant, or combination thereof (e.g., an isotopic variant of a pharmaceutically acceptable salt), wherein: 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 5-8 membered heteroaryl; each of R
15 and R
16 is independently hydrogen or substituted or unsubstituted C
1-6 alkyl; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl; R
18 is hydrogen or substituted or unsubstituted C
1-6 alkyl; R
19 is hydrogen or substituted or unsubstituted C
1-6 alkyl;
R
20 is hydrogen, hydroxyl, substituted or unsubstituted C
1-6 alkyl, or substituted or unsubstituted C
3-6 carbocyclyl; R
20’ is hydrogen, hydroxyl, substituted or unsubstituted C
1-6 alkyl, or substituted or unsubstituted C
3-6 carbocyclyl; provided that R
20 and R
20’ are not both hydroxyl; and R
22 is 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 aryl; provided that when R
22 is -CH
3, R
3 is not -CH
3 or hydrogen. [0132] In some embodiments, the compound of the 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 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, C
6-10 aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 R
A; each of R
15 and R
16 is independently hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
C; R
19 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
D; R
20 is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
E; R
20’ is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
F; provided that R
20 and R
20’ are not both hydroxyl; each instance of R
A, R
B, R
C, R
D, R
E, and R
F, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and C
1-6 alkoxy optionally substituted with 1-5 halo; R
22 is C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, or C
6-10 aryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, and C
2-6 alkynyl are independently optionally substituted with 1-5 R
G and said C
3-6 carbocyclyl and C
6-10 aryl are independently optionally substituted with 1-5 R
H; provided that when R
22 is -CH
3, R
3 is not -CH
3 or hydrogen;
each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 R
G1; each instance of R
G1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1-6 alkoxy optionally substituted with 1-5 halo; and each instance of R
H, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1- 6 alkoxy optionally substituted with 1-5 halo, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0133] In some embodiments, the compound of the disclosure is a compound of Formula (I-A) or (I-B):
or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0134] In some embodiments, the compound of the disclosure is a compound of Formula (I-A-1) or (I-A-2):
(I-A-1) (I-A-2), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0135] In some embodiments, the compound of the disclosure is a compound of Formula (I-A-1-i) or (I-A-1-ii):
or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0136] In some embodiments, the compound of the disclosure is a compound of Formula (I-A-2-i) or (I-A-2-ii): (
or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0137] In some embodiments, the compound of the disclosure is a compound of Formula (I-B-1) or (I-B-2):
or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0138] In some embodiments, the compound of the disclosure is a compound of Formula (I-B-1-i) or (I-B-1-ii):
or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0139] In some embodiments, the compound of the disclosure is a compound of Formula (I-B-2-i) or (I-B-2-ii):
or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0140] In some embodiments, the compound of Formula (I) is a compound wherein:
R
3 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-5 R
A; R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is C
1-6 alkyl optionally substituted with 1-5 R
C; R
20 is hydrogen, hydroxyl, or C
1-6 alkyl optionally substituted with 1-5 R
E; and R
20’ is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
F, 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 C
1-6 alkyl optionally substituted with 1-5 R
A; R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-5 R
G, 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 C
1 alkyl substituted with 1-5 R
A; R
15 and R
16 are hydrogen; R
18 and R
19 are -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and R
22 is C
1-6 alkyl optionally substituted with an unsubstituted C
1-6 alkoxy, 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 C1 alkyl substituted with 1-5 R
A; R
15 and R
16 are hydrogen; R
18 and R
19 are -CH
3;
R
20 is hydrogen; R
20’ is -CH
3; and R
22 is -CH
3 or -CH
2OCH
3, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. Groups R
3 and R
A – as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1-ii), (I-A- 2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii) [0144] In certain embodiments, 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 5-8 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 substituted or unsubstituted C
1-6 alkyl or substituted or unsubstituted C
2-6 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 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, C
6-10 aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 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 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, C
6-10 aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-3 R
A. 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 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkynyl, C
3-6 carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 R
A. In some embodiments, R
3 is hydrogen, C
1-6 alkyl, C
2-6 alkynyl, C
3-6 carbocyclyl, or 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkynyl, C
3-6 carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-3 R
A. In some embodiments, R
3 is substituted or unsubstituted C
1-6 alkyl or substituted or unsubstituted C
2-6 alkynyl. In some embodiments, R
3 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkenyl are independently optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkenyl are independently substituted with 1-5 R
A. In some
embodiments, R
3 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkenyl are independently optionally substituted with 1-3 R
A. In some embodiments, R
3 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkenyl are independently substituted with 1-3 R
A. In some embodiments, R
3 is -H, -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, -CH
2OH, -CH
3, - CH
2CH
3, -CH
2CH
2CH
3, -CH(CH
3)
2, -C≡C-H, -C≡C-CH
3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently optionally substituted with 1-5 R
A. In some embodiments, R
3 is -H, -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, -CH
2OH, -CH
3, -CH
2CH
3, - CH
2CH
2CH
3, -CH(CH
3)
2, -C≡C-H, -C≡C-CH
3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently substituted with 1-5 R
A. In some embodiments, R
3 is -H, -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, -CH
2OH, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, - CH(CH
3)
2, -C≡C-H, -C≡C-CH
3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently optionally substituted with 1-3 R
A. In some embodiments, R
3 is - H, -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, -CH
2OH, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH(CH
3)
2, - C≡C-H, -C≡C-CH
3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently substituted with 1-3 R
A. In some embodiments, R
3 is -H, -CH
2F, -CHF
2, - CF
3, -CH
2OCH
3, -CH
2OH, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH(CH
3)
2, -C≡C-H, -C≡C-CH
3, unsubstituted cyclopropyl, or unsubstituted pyridyl. [0146] In certain embodiments, R
3 is hydrogen. [0147] In certain embodiments, R
3 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
3 is C
1-6 alkyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
1-6 alkyl optionally substituted with 1-3 R
A. In some embodiments, R
3 is C
1-6 alkyl optionally substituted with 1 R
A. In some embodiments, R
3 is C1-3 alkyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C1-3 alkyl optionally substituted with 1- 3 R
A. In some embodiments, R
3 is methyl optionally substituted with 1-3 R
A. In some embodiments, R
3 is ethyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is n– propyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is isopropyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
1-6 alkyl substituted with 1-5 R
A. In some embodiments, R
3 is C
1-6 alkyl substituted with 1-3 R
A. In some embodiments, R
3 is C1- 6 alkyl substituted with 1 R
A. In some embodiments, R
3 is C1-3 alkyl substituted with 1-5 R
A. In some embodiments, R
3 is C
1-3 alkyl substituted with 1-3 R
A. In some embodiments, R
3 is methyl substituted with 1-3 R
A. In some embodiments, R
3 is ethyl substituted with 1-5 R
A. In some embodiments, R
3 is n–propyl substituted with 1-5 R
A. In some embodiments, R
3 is isopropyl substituted with 1-5 R
A.
[0148] In certain embodiments, R
3 is substituted C
1-6 alkyl. In certain embodiments, R
3 is C
1-6 alkyl substituted with 1-5 R
A. In certain embodiments, R
3 is C
1-6 alkyl substituted with 1-5 R
A. In some embodiments, R
3 is C
1-6 alkyl substituted with 1-3 R
A. In some embodiments, R
3 is substituted C
1-3 alkyl. In some embodiments, R
3 is C
1-3 alkyl substituted with 1-5 R
A. In some embodiments, R
3 is C1-3 alkyl substituted with 1-3 R
A. In some embodiments, R
3 is C1-3 alkyl substituted with 1 R
A. In certain embodiments, R
3 is methyl substituted with 1-3 R
A. In some embodiments, R
3 is methyl substituted with 1-3 R
A and each instance of R
A is independently halo, hydroxyl, or unsubstituted C
1-6 alkoxy. In some embodiments, R
3 is methyl substituted with 1-3 R
A and each instance of R
A is independently fluoro, hydroxyl, or -OCH
3. In some embodiments, R
3 is -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, or -CH
2OH. In some embodiments, R
3 is methyl substituted with 1-3 R
A and R
A is fluoro. In some embodiments, R
3 is -CH
2F, -CHF
2, or -CF
3. In some embodiments, R
3 is -CH
2F. In some embodiments, R
3 is -CHF
2. In some embodiments, R
3 is -CF
3. In some embodiments, R
3 is methyl substituted with 1-3 R
A and R
A is hydroxyl. In some embodiments, R
3 is - CH
2OH. In some embodiments, R
3 is methyl substituted with 1-3 R
A and R
A is -OCH
3. In some embodiments, R
3 is -CH
2OCH
3. In some embodiments, R
3 is ethyl substituted with 1-5 R
A. In some embodiments, R
3 is n–propyl substituted with 1-5 R
A. In some embodiments, R
3 is isopropyl substituted with 1-5 R
A. [0149] In certain embodiments, R
3 is unsubstituted C
1-6 alkyl. In some embodiments, R
3 is unsubstituted C
1-3 alkyl. In some embodiments, R
3 is -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, or - CH(CH
3)
2. In some embodiments, R
3 is -CH
3 or -CH
2CH
3. In some embodiments, R
3 is - CH
3. In some embodiments, R
3 is -CH
2CH
3. In some embodiments, R
3 is -CH
2CH
2CH
3. In some embodiments, R
3 is -CH(CH
3)
2. [0150] In certain embodiments, R
3 is substituted or unsubstituted C
2-6 alkynyl. In some embodiments, R
3 is C
2-6 alkynyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
2-6 alkynyl optionally substituted with 1-3 R
A. In some embodiments, R
3 is C
2-6 alkynyl optionally substituted with 1 R
A. In some embodiments, R
3 is unsubstituted C
2-6 alkynyl. In certain embodiments, R
3 is substituted or unsubstituted C2-3 alkynyl. In some embodiments, R
3 is C2-3 alkynyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
2-6 alkynyl substituted with 1-5 R
A. In some embodiments, R
3 is C
2-6 alkynyl substituted with 1-3 R
A. In some embodiments, R
3 is C
2-6 alkynyl substituted with 1 R
A. In some embodiments, R
3 is C2-3 alkynyl substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted C2-3 alkynyl. In some embodiments, R
3 is -C≡C-H or -C≡C-CH
3. In some embodiments, R
3 is ethynyl optionally substituted with 1 R
A. In some embodiments, R
3 is
ethynyl substituted with 1 R
A. In some embodiments, R
3 is -C≡C-H. In some embodiments, R
3 is propynyl optionally substituted with 1-3 R
A. In some embodiments, R
3 is propynyl substituted with 1-3 R
A. In some embodiments, R
3 is -C≡C-CH
3. [0151] In certain embodiments, R
3 is substituted or unsubstituted C
2-6 alkenyl. In some embodiments, R
3 is C
2-6 alkenyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
2-6 alkenyl optionally substituted with 1-3 R
A. In some embodiments, R
3 is C
2-6 alkenyl optionally substituted with 1 R
A. In some embodiments, R
3 is substituted C
2-6 alkenyl. In some embodiments, R
3 is C
2-6 alkenyl substituted with 1-5 R
A. In some embodiments, R
3 is C
2-6 alkenyl substituted with 1-3 R
A. In some embodiments, R
3 is C
2-6 alkenyl substituted with 1 R
A. In some embodiments, R
3 is unsubstituted C
2-6 alkenyl. In some embodiments, R
3 is substituted or unsubstituted C
2-4 alkenyl. In some embodiments, R
3 is C2-4 alkenyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C2-4 alkenyl substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted C2-4 alkenyl. In certain embodiments, R
3 is ethenyl optionally substituted with 1-3 R
A. In certain embodiments, R
3 is ethenyl substituted with 1-3 R
A. In certain embodiments, R
3 is unsubstituted ethenyl. In certain embodiments, R
3 is propenyl optionally substituted with 1-5 R
A. In certain embodiments, R
3 is propenyl substituted with 1-5 R
A. In certain embodiments, R
3 is unsubstituted propenyl. In certain embodiments, R
3 is butenyl optionally substituted with 1-5 R
A. In certain embodiments, R
3 is butenyl substituted with 1-5 R
A. In certain embodiments, R
3 is unsubstituted butenyl. [0152] In certain embodiments, R
3 is substituted or unsubstituted C
3-6 carbocyclyl. In some embodiments, R
3 is C
3-6 carbocyclyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
3-6 carbocyclyl optionally substituted with 1-3 R
A. In some embodiments, R
3 is C
3-6 carbocyclyl optionally substituted with 1 R
A. In some embodiments, R
3 is unsubstituted C
3-6 carbocyclyl. In some embodiments, R
3 is C3-4 carbocyclyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted C3-4 carbocyclyl. In some embodiments, R
3 is substituted C
3-6 carbocyclyl. In some embodiments, R
3 is C
3-6 carbocyclyl substituted with 1-5 R
A. In some embodiments, R
3 is C
3-6 carbocyclyl substituted with 1-3 R
A. In some embodiments, R
3 is C
3-6 carbocyclyl substituted with 1 R
A. In some embodiments, R
3 is C
3-4 carbocyclyl substituted with 1-5 R
A. In certain embodiments, R
3 is cyclopropyl or cyclobutyl, each of which is independently optionally substituted with 1-5 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 is independently substituted with 1-5 R
A. In certain embodiments, R
3 is cyclobutyl optionally substituted with
1-5 R
A. In certain embodiments, R
3 is cyclobutyl substituted with 1-5 R
A.In certain embodiments, R
3 is unsubstituted cyclobutyl. In certain embodiments, R
3 is cyclopropyl optionally substituted with 1-5 R
A. In certain embodiments, R
3 is cyclopropyl substituted with 1-5 R
A.In certain embodiments, R
3 is unsubstituted cyclopropyl. [0153] In certain embodiments, R
3 is substituted or unsubstituted 5-8 membered heteroaryl. In certain embodiments, R
3 is 5-8 membered heteroaryl optionally substituted with 1-5 R
A. In certain embodiments, R
3 is 5-8 membered heteroaryl optionally substituted with 1-3 R
A. In certain embodiments, R
3 is 5-8 membered heteroaryl optionally substituted with 1 R
A. In some embodiments, R
3 is substituted 5-8 membered heteroaryl. In certain embodiments, R
3 is 5-8 membered heteroaryl substituted with 1-5 R
A. In certain embodiments, R
3 is 5-8 membered heteroaryl substituted with 1-3 R
A. In certain embodiments, R
3 is 5-8 membered heteroaryl substituted with 1 R
A. In certain embodiments, R
3 is unsubstituted 5-8 membered heteroaryl. In certain embodiments, R
3 is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, R
3 is 5-6 membered heteroaryl optionally substituted with 1-5 R
A. In certain embodiments, R
3 is 5-6 membered heteroaryl substituted with 1-5 R
A.In certain embodiments, R
3 is unsubstituted 5-6 membered heteroaryl. In certain embodiments, R
3 is 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-5 R
A. In certain embodiments, R
3 is substituted 5-6 membered heteroaryl. In certain embodiments, R
3 is 5-6 membered heteroaryl substituted with 1-5 R
A. In certain embodiments, R
3 is 5-6 membered nitrogen-containing heteroaryl substituted with 1-5 R
A. In certain embodiments, R
3 is unsubstituted 5-6 membered nitrogen-containing heteroaryl. In certain embodiments, R
3 is 5-6 membered nitrogen-containing heteroaryl containing 1 nitrogen atom and optionally substituted with 1-5 R
A. In certain embodiments, R
3 is 5-6 membered nitrogen-containing heteroaryl containing 1 nitrogen atom and substituted with 1-5 R
A. In certain embodiments, R
3 is unsubstituted 5-6 membered nitrogen-containing heteroaryl containing 1 nitrogen atom. In some embodiments, R
3 is pyridyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is pyridyl substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted pyridyl. [0154] In certain embodiments, R
3 is substituted or unsubstituted C
6-10 aryl. In some embodiments, R
3 is C
6-10 aryl optionally substituted with 1-5 R
A. In some embodiments, R
3 is C
6-10 aryl optionally substituted with 1-3 R
A. In some embodiments, R
3 is C
6-10 aryl optionally substituted with 1 R
A. In certain embodiments, R
3 is substituted C
6-10 aryl. In some embodiments, R
3 is C
6-10 aryl substituted with 1-5 R
A. In some embodiments, R
3 is C6-
10 aryl substituted with 1-3 R
A. In some embodiments, R
3 is C
6-10 aryl substituted with 1 R
A.
In certain embodiments, R
3 is unsubstituted C
6-10 aryl. In some embodiments, R
3 is phenyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is phenyl substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted phenyl. In some embodiments, R
3 is naphthyl optionally substituted with 1-5 R
A. In some embodiments, R
3 is naphthyl substituted with 1-5 R
A. In some embodiments, R
3 is unsubstituted naphthyl. [0155] In certain embodiments, each instance of R
A, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and substituted or unsubstituted C
1-6 alkoxy. In certain embodiments, each instance of R
A, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
A, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
A, when present, is independently selected from the group consisting of halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
A, when present, is independently selected from the group consisting of halo, hydroxyl, and unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
A, when present, is independently selected from the group consisting of fluoro, hydroxyl, and unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
A, when present, is independently selected from the group consisting of fluoro, hydroxyl, and -OCH
3. In some embodiments, each instance of R
A, when present, is fluoro. In some embodiments, each instance of R
A, when present, is hydroxyl. In some embodiments, each instance of R
A, when present, is -OCH
3. Groups R
15, R
16, and R
B – as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1-ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B- 2-ii) [0156] In certain embodiments, R
15 is hydrogen or substituted or unsubstituted C
1-6 alkyl. In certain embodiments, R
15 is hydrogen. In certain embodiments, R
15 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B. In some embodiments, R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-3 R
B. In some embodiments, R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1 R
B. In some embodiments, R
15 is hydrogen or C
1-6 alkyl substituted with 1-5 R
B. In some embodiments, R
15 is hydrogen or C
1-6 alkyl substituted with 1-3 R
B. In some embodiments, R
15 is hydrogen or C
1-6 alkyl substituted with 1 R
B. In certain embodiments, R
15 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
15 is
hydrogen or unsubstituted C
1-3 alkyl. In some embodiments, R
15 is hydrogen or -CH
3. In some embodiments, R
15 is hydrogen. In some embodiments, R
15 is -CH
3. [0157] In certain embodiments, R
16 is hydrogen or substituted or unsubstituted C
1-6 alkyl. In certain embodiments, R
16 is hydrogen. In certain embodiments, R
16 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
16 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B. In some embodiments, R
16 is hydrogen or C
1-6 alkyl optionally substituted with 1-3 R
B. In some embodiments, R
16 is hydrogen or C
1-6 alkyl optionally substituted with 1 R
B. In some embodiments, R
16 is hydrogen or C
1-6 alkyl substituted with 1-5 R
B. In some embodiments, R
16 is hydrogen or C
1-6 alkyl substituted with 1-3 R
B. In some embodiments, R
16 is hydrogen or C
1-6 alkyl substituted with 1 R
B. In some embodiments, R
16 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
16 is hydrogen or unsubstituted C1-3 alkyl. In some embodiments, R
16 is hydrogen or -CH
3. In some embodiments, R
16 is hydrogen. [0158] In certain embodiments, each of R
15 and R
16 is independently hydrogen or substituted or unsubstituted C
1-6 alkyl; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl. In certain embodiments, each of R
15 and R
16 is independently hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B. In certain embodiments, each of R
15 and R
16 is independently hydrogen or C
1-6 alkyl substituted with 1- 5 R
B; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl substituted with 1-5 R
B. In some embodiments, R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B and R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B. In some embodiments, R
15 is hydrogen or C
1-6 alkyl substituted with 1-5 R
B and R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl substituted with 1-5 R
B. In certain embodiments, R
15 and R
16 are hydrogen. In certain embodiments, R
15 and R
16 are substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
15 and R
16 are C
1-6 alkyl optionally substituted with 1-5 R
B. In some embodiments, R
15 and R
16 are C
1-6 alkyl substituted with 1-5 R
B. In some embodiments, R
15 and R
16 are unsubstituted C
1-6 alkyl. In some embodiments, R
15 and R
16 are unsubstituted C1-3 alkyl. In some embodiments, R
15 and R
16 are -CH
3. In certain embodiments, R
15 is substituted or unsubstituted C
1-6 alkyl and R
16 is hydrogen. In some embodiments, R
15 is C
1-6 alkyl optionally substituted with 1-5 R
B and R
16 is hydrogen. In
some embodiments, R
15 is C
1-6 alkyl substituted with 1-5 R
B and R
16 is hydrogen. In some embodiments, R
15 is unsubstituted C
1-6 alkyl and R
16 is hydrogen. In some embodiments, R
15 is unsubstituted C1-3 alkyl and R
16 is hydrogen. In some embodiments, R
15 is -CH
3 and R
16 is hydrogen. In certain embodiments, R
15 is hydrogen and R
16 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
15 is hydrogen and R
16 is C
1-6 alkyl optionally substituted with 1-5 R
B. In some embodiments, R
15 is hydrogen and R
16 is C
1-6 alkyl substituted with 1-5 R
B. In some embodiments, R
15 is hydrogen and R
16 is unsubstituted C
1-6 alkyl. In some embodiments, R
15 is hydrogen and R
16 is unsubstituted C1-3 alkyl. In some embodiments, R
15 is hydrogen and R
16 is -CH
3. [0159] In certain embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B. In certain embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl substituted with 1-5 R
B. In some embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently optionally substituted with 1-5 R
B. In some embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is independently substituted with 1-5 R
B. In some embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a cyclopropyl optionally substituted with 1-5 R
B. In some embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form a cyclopropyl substituted with 1-5 R
B. In some embodiments, R
15 and R
16, taken together with the carbon atoms to which they are attached, form an unsubstituted cyclopropyl. [0160] In certain embodiments, each instance of R
B, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and substituted or unsubstituted C
1-6 alkoxy. In certain embodiments, each instance of R
B, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
B, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
B, when present, is independently selected from the group consisting of halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5
halo. In some embodiments, each instance of R
B, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of R
B, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH
3, and -OCF
3. Groups R
18, R
19, R
C, and R
D – as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1- ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii) [0161] In certain embodiments, R
18 is hydrogen or substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
18 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
C. In some embodiments, R
18 is hydrogen or C
1-6 alkyl substituted with 1-5 R
C. In some embodiments, R
18 is hydrogen or C
1-6 alkyl optionally substituted with 1-3 R
C. In some embodiments, R
18 is hydrogen or C
1-6 alkyl substituted with 1-3 R
C. In some embodiments, R
18 is hydrogen or C
1-6 alkyl optionally substituted with 1 R
C. In some embodiments, R
18 is hydrogen or C
1-6 alkyl substituted with 1 R
C. In some embodiments, R
18 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
18 is hydrogen or unsubstituted C1-3 alkyl. In some embodiments, R
18 is hydrogen, -CH
3, or -CH
2CH
3. [0162] In some embodiments, R
18 is hydrogen. [0163] In some embodiments, R
18 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
18 is substituted C
1-6 alkyl. In some embodiments, R
18 is C
1-6 alkyl optionally substituted with 1-5 R
C. In some embodiments, R
18 is C
1-6 alkyl substituted with 1-5 R
C. In some embodiments, R
18 is unsubstituted C
1-6 alkyl. In some embodiments, R
18 is unsubstituted C1-3 alkyl. In some embodiments, R
18 is -CH
3 or -CH
2CH
3. In some embodiments, R
18 is -CH
3. [0164] In certain embodiments, R
19 is hydrogen or substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
19 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
D. In some embodiments, R
19 is hydrogen or C
1-6 alkyl substituted with 1-5 R
D. In some embodiments, R
19 is hydrogen or C
1-6 alkyl optionally substituted with 1-3 R
D. In some embodiments, R
19 is hydrogen or C
1-6 alkyl substituted with 1-3 R
D. In some embodiments, R
19 is hydrogen or C
1-6 alkyl optionally substituted with 1 R
D. In some embodiments, R
19 is hydrogen or C
1-6 alkyl substituted with 1 R
D. In some embodiments, R
19 is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
19 is hydrogen or unsubstituted C
1-3 alkyl. In some embodiments, R
19 is hydrogen or -CH
3. [0165] In certain embodiments, R
19 is hydrogen.
[0166] In certain embodiments, R
19 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
19 is substituted C
1-6 alkyl. In some embodiments, R
19 is C
1-6 alkyl optionally substituted with 1-5 R
D. In some embodiments, R
19 is C
1-6 alkyl substituted with 1-5 R
D. In some embodiments, R
19 is unsubstituted C
1-6 alkyl. In some embodiments, R
19 is unsubstituted C1-3 alkyl. In some embodiments, R
19 is -CH
3. [0167] In certain embodiments, R
18 and R
19 are hydrogen. In some embodiments, R
18 and R
19 are substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
18 is C
1-6 alkyl optionally substituted with 1-5 R
C and R
19 is C
1-6 alkyl optionally substituted with 1-5 R
D. In some embodiments, R
18 is C
1-6 alkyl substituted with 1-5 R
C and R
19 is C
1-6 alkyl substituted with 1-5 R
D. In some embodiments, R
18 and R
19 are unsubstituted C
1-6 alkyl. In some embodiments, R
18 and R
19 are unsubstituted C
1-3 alkyl. In some embodiments, R
18 is - CH
2CH
3 and R
19 is -CH
3. In some embodiments, R
18 and R
19 are -CH
3. In some embodiments, R
18 is hydrogen and R
19 is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
18 is hydrogen and R
19 is C
1-6 alkyl optionally substituted with 1-5 R
D. In some embodiments, R
18 is hydrogen and R
19 is C
1-6 alkyl substituted with 1-5 R
D. In some embodiments, R
18 is hydrogen and R
19 is unsubstituted C
1-6 alkyl. In some embodiments, R
18 is hydrogen and R
19 is unsubstituted C
1-3 alkyl. In some embodiments, R
18 is hydrogen and R
19 is -CH
3. In some embodiments, R
18 is substituted or unsubstituted C
1-6 alkyl and R
19 is hydrogen. In some embodiments, R
18 is C
1-6 alkyl optionally substituted with 1-5 R
C and R
19 is hydrogen. In some embodiments, R
18 is C
1-6 alkyl substituted with 1-5 R
C and R
19 is hydrogen. In some embodiments, R
18 is unsubstituted C
1-6 alkyl and R
19 is hydrogen. In some embodiments, R
18 is unsubstituted C1-3 alkyl and R
19 is hydrogen. In some embodiments, R
18 is -CH
3 and R
19 is hydrogen. [0168] In certain embodiments, each instance of R
C, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and substituted or unsubstituted C
1-6 alkoxy. In certain embodiments, each instance of R
C, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
C, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
C, when present, is independently selected from the group consisting of halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
C, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5
fluoro. In some embodiments, each instance of R
C, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH
3, and -OCF
3. [0169] In certain embodiments, each instance of R
D, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and substituted or unsubstituted C
1-6 alkoxy. In certain embodiments, each instance of R
D, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
D, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
D, when present, is independently selected from the group consisting of halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
D, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of R
D, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH
3, and -OCF
3. Groups R
20, R
20’, R
E, and R
F – as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A-1- ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii) [0170] In certain embodiments, R
20 is hydrogen, hydroxyl, substituted or unsubstituted C
1-6 alkyl, or substituted or unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
20 is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
E. In certain embodiments, R
20 is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently substituted with 1-5 R
E. In certain embodiments, R
20 is hydrogen, hydroxyl, or C
1-6 alkyl optionally substituted with 1-5 R
E. In certain embodiments, R
20 is hydrogen, hydroxyl, or C
1-6 alkyl substituted with 1-5 R
E. In certain embodiments, R
20 is hydrogen, hydroxyl, or C
1-6 alkyl optionally substituted with 1-3 R
E. In certain embodiments, R
20 is hydrogen, hydroxyl, or C
1-6 alkyl substituted with 1-3 R
E. In certain embodiments, R
20 is hydrogen, hydroxyl, or unsubstituted C
1-6 alkyl. In certain embodiments, R
20 is hydrogen, hydroxyl, or unsubstituted C
1-3 alkyl. In certain embodiments, R
20 is hydrogen, hydroxyl, or -CH
3. [0171] In certain embodiments, R
20 is hydrogen. [0172] In certain embodiments, R
20 is hydroxyl.
[0173] In certain embodiments, R
20 is substituted or unsubstituted C
1-6 alkyl. In certain embodiments, R
20 is substituted C
1-6 alkyl. In some embodiments, R
20 is C
1-6 alkyl optionally substituted with 1-5 R
F. In some embodiments, R
20 is C
1-6 alkyl substituted with 1-5 R
F. In some embodiments, R
20 is unsubstituted C
1-6 alkyl. In some embodiments, R
20 is unsubstituted C1-3 alkyl. In some embodiments, R
20 is -CH
3. [0174] In certain embodiments, R
20 is substituted or unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
20 is substituted C
3-6 carbocyclyl. In some embodiments, R
20 is C
3-6 carbocyclyl optionally substituted with 1-5 R
F. In some embodiments, R
20 is C
3-6 carbocyclyl substituted with 1-5 R
F. In some embodiments, R
20 is unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
20 is unsubstituted C
3-4 carbocyclyl. 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 carbocyclyl. In some embodiments, R
20’ is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
F. In some embodiments, R
20’ is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently substituted with 1-5 R
F. In some embodiments, R
20’ is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
F. In some embodiments, R
20’ is hydrogen or C
1-6 alkyl substituted with 1-5 R
F. In some embodiments, R
20’ is hydrogen or C1-
6 alkyl optionally substituted with 1-3 R
F. In some embodiments, R
20’ is hydrogen or C
1-6 alkyl o substituted with 1-3 R
F. In some embodiments, R
20’ is hydrogen or unsubstituted C
1-6 alkyl. In some embodiments, R
20’ is hydrogen or unsubstituted C1-3 alkyl. In some embodiments, R
20’ is hydrogen or -CH
3. [0176] In certain embodiments, R
20’ is hydrogen. [0177] In certain embodiments, R
20’ is hydroxyl. [0178] In certain embodiments, R
20’ is substituted or unsubstituted C
1-6 alkyl. In some embodiments, R
20’ is substituted C
1-6 alkyl. In some embodiments, R
20’ is C
1-6 alkyl optionally substituted with 1-5 R
F. In some embodiments, R
20’ is C
1-6 alkyl substituted with 1-5 R
F. In some embodiments, R
20’ is unsubstituted C
1-6 alkyl. In some embodiments, R
20’ is unsubstituted C
1-3 alkyl. In some embodiments, R
20’ is -CH
3. [0179] In certain embodiments, R
20’ is substituted or unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
20’ is substituted C
3-6 carbocyclyl. In some embodiments, R
20’ is C
3-6 carbocyclyl optionally substituted with 1-5 R
F. In some embodiments, R
20’ is C
3-6 carbocyclyl substituted with 1-5 R
F. In some embodiments, R
20’ is unsubstituted C
3-6
carbocyclyl. In certain embodiments, R
20’ is unsubstituted C
3-4 carbocyclyl. 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 alkyl. In some embodiments, R
20 is hydrogen, hydroxyl, or C
1-6 alkyl optionally substituted with 1-5 R
E and R
20’ is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
F. In some embodiments, R
20 is hydrogen, hydroxyl, or C
1-6 alkyl substituted with 1-5 R
E and R
20’ is hydrogen or C
1-6 alkyl substituted with 1-5 R
F. In some embodiments, R
20 is hydrogen and R
20’ is substituted C
1-6 alkyl. In some embodiments, R
20 is hydrogen and R
20’ is C
1-6 alkyl optionally substituted with 1-5 R
F. In some embodiments, R
20 is hydrogen and R
20’ is C
1-6 alkyl substituted with 1- 5 R
F. In some embodiments, R
20 is hydrogen and R
20’ is unsubstituted C
1-6 alkyl. In some embodiments, R
20 is hydrogen and R
20’ is unsubstituted C1-3 alkyl. In some embodiments, R
20 is hydrogen and R
20’ is -CH
3. In some embodiments, R
20 is substituted C
1-6 alkyl and R
20’ is hydrogen. In some embodiments, R
20 is C
1-6 alkyl optionally substituted with 1-5 R
E and R
20’ is hydrogen. In some embodiments, R
20 is C
1-6 alkyl substituted with 1-5 R
E and R
20’ is hydrogen. In some embodiments, R
20 is unsubstituted C
1-6 alkyl and R
20’ is hydrogen. In some embodiments, R
20 is unsubstituted C1-3 alkyl and R
20’ is hydrogen. In some embodiments, R
20 is -CH
3 and R
20’ is hydrogen. In some embodiments, R
20 is hydroxyl and R
20’ is substituted C
1-6 alkyl. In some embodiments, R
20 is hydroxyl and R
20’ is C
1-6 alkyl optionally substituted with 1-5 R
F. In some embodiments, R
20 is hydroxyl and R
20’ is C
1-6 alkyl substituted with 1-5 R
F. In some embodiments, R
20 is hydroxyl and R
20’ is unsubstituted C
1-6 alkyl. In certain embodiments, R
20 is hydroxyl and R
20’ is unsubstituted C
1-3 alkyl. In certain embodiments, R
20 is hydroxyl and R
20’ is -CH
3. In certain embodiments, R
20 is C
1-6 alkyl optionally substituted with 1-5 R
E and R
20’ is C
1-6 alkyl optionally substituted with 1-5 R
F. In certain embodiments, R
20 is C
1-6 alkyl substituted with 1-5 R
E and R
20’ is C
1-6 alkyl substituted with 1-5 R
F. In certain embodiments, R
20 and R
20’ are unsubstituted C
1-6 alkyl. In certain embodiments, R
20 and R
20’ are unsubstituted C1-3 alkyl. In certain embodiments, R
20 and R
20’ are -CH
3. In certain embodiments, R
20 and R
20’ are hydrogen. [0181] In certain embodiments, each instance of R
E, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and substituted or unsubstituted C
1-6 alkoxy. In certain embodiments, each instance of R
E, when present, is independently selected from the group consisting of
halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
E, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
E, when present, is independently selected from the group consisting of halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
E, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of R
E, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH
3, and -OCF
3. [0182] In certain embodiments, each instance of R
F, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and substituted or unsubstituted C
1-6 alkoxy. In certain embodiments, each instance of R
F, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and substituted or unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
F, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, nitro, amino, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
F, when present, is independently selected from the group consisting of halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
F, when present, is independently selected from the group consisting of fluoro, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 fluoro. In some embodiments, each instance of R
F, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH
3, and -OCF
3. Groups R
22, R
G, R
G1, and R
H – as they relate to Formulae (I), (I-A), (I-A-1), (I-A-1-i), (I-A- 1-ii), (I-A-2), (I-A-2-i), (I-A-2-ii), (I-B), (I-B-1), (I-B-1-1), (I-B-1-ii), (I-B-2), (I-B-2-i), and (I-B-2-ii) [0183] In certain embodiments, R
22 is 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 aryl. 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, wherein said C
1-6 alkyl, C
2-6 alkenyl, and C
2-6 alkynyl are independently optionally substituted with 1-5 R
G and said C
3-6 carbocyclyl and C
6-10 aryl are independently optionally substituted with 1-5 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, wherein said C
1-6 alkyl, C
2-6 alkenyl, and C
2-6 alkynyl are
independently substituted with 1-5 R
G and said C
3-6 carbocyclyl and C
6-10 aryl are independently substituted with 1-5 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, wherein said C
1-6 alkyl, C
2-6 alkenyl, and C
2-6 alkynyl are independently optionally substituted with 1-3 R
G and said C
3-6 carbocyclyl and C
6-10 aryl are independently optionally substituted with 1-3 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, wherein said C
1-6 alkyl, C
2-6 alkenyl, and C
2-6 alkynyl are independently substituted with 1-3 R
G and said C
3-6 carbocyclyl and C
6-10 aryl are independently substituted with 1-3 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. In some embodiments, R
22 is substituted or unsubstituted C
1-6 alkyl or substituted or unsubstituted C
2-6 alkynyl. In some embodiments, R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-5 R
G. In some embodiments, R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently substituted with 1-5 R
G. In some embodiments, R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-3 R
G. In some embodiments, R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently substituted with 1-3 R
G. In some embodiments, R
22 is C
1- 6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1 R
G. In some embodiments, R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently substituted with 1 R
G. In some embodiments, R
22 is unsubstituted C
1-6 alkyl or unsubstituted C
2-6 alkynyl. In some embodiments, R
22 is - CH
2F, -CHF
2, -CF
3, -CH
2CH
2CH(CH
3)(CF
3), -CH
2OH, -CH
2OCH
3, -CH
2OCH
2CH
2OCH
3, - CH
2OCH(CH
3)
2, -CH
2OCF
3, -CH
2OCHF
2, -CH
3, -CH
2CH
3, -CH
2CH
2CH
2CH
3, -CH(CH
3)
2, - CH
2CH(CH
3)
2, -CH
2CH
2CH(CH
3)
2, -C(CH
3)
3, -CH=CH
2, -CH
2CH=CH
2, -CH=CHCH
3, - CH=C(CH
3)
2, -C≡C-H, -C≡C-CH
3, -C≡C-CF
3, unsubstituted cyclopropyl, unsubstituted cyclobutyl, bicyclo[1.1.1]pentanyl optionally substituted with 1-5 R
H, or phenyl optionally substituted with 1-5 R
H. [0184] In certain embodiments, R
22 is substituted or unsubstituted C
1-6 alkyl. In certain embodiments, R
22 is C
1-6 alkyl optionally substituted with 1-5 R
G. In certain embodiments, R
22 is C
1-6 alkyl optionally substituted with 1-3 R
G. In certain embodiments, R
22 is C
1-6 alkyl optionally substituted with 1 R
G. In some embodiments, R
22 is methyl optionally substituted with 1-3 R
G. In some embodiments, R
22 is ethyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is n-propyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is isopropyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is n-butyl
optionally substituted with 1-5 R
G. In some embodiments, R
22 is isobutyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is sec-butyl optionally substituted with 1- 5 R
G. In some embodiments, R
22 is tert-butyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is n-pentyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is isopentyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is neopentyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is sec-pentyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is tert-pentyl optionally substituted with 1-5 R
G. [0185] In certain embodiments, R
22 is substituted C
1-6 alkyl. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1-5 R
G. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1-3 R
G. In certain embodiments, R
22 is unsubstituted C
1-6 alkyl. In some embodiments, R
22 is C
1-6 alkyl substituted with 1-3 R
G and each instance of R
G is independently selected from the group consisting of: halo, hydroxyl, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl, wherein said C
3-6 carbocyclyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1-3 R
G and each instance of R
G is independently selected from the group consisting of: halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with 1-3 R
G and R
G is halo. In some embodiments, R
22 is -CH
2F, - CHF
2, -CF
3, or -CH
2CH
2CH(CH
3)(CF
3). In some embodiments, R
22 is C
1-6 alkyl substituted with 1-3 R
G and each instance of R
G is independently hydroxyl or C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, R
22 is methyl substituted with 1-3 R
G and each instance of R
G is independently selected from the group consisting of: halo, hydroxyl, and C
1-6 alkoxy optionally substituted with 1-3 fluoro. In some embodiments, R
22 is methyl substituted with 1-3 R
G and R
G is halo. In some embodiments, R
22 is methyl substituted with 1-3 R
G and R
G is fluoro. In some embodiments, R
22 is -CH
2F, -CHF
2, or -CF
3. In some embodiments, R
22 is methyl substituted with 1-3 R
G and each instance of R
G is independently hydroxyl or C
1-6 alkoxy optionally substituted with 1-3 fluoro. In some embodiments, R
22 is - CH
2OH, -CH
2OCH
3, -CH
2OCH
2CH
2OCH
3, -CH
2OCH(CH
3)
2, -CH
2OCF
3, or -CH
2OCHF
2. [0186] In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is substituted or unsubstituted 5- 8 membered heteroaryl. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-8 membered heteroaryl optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-8 membered heteroaryl optionally substituted
with 1-3 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-8 membered heteroaryl optionally substituted with 1 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-6 membered heteroaryl optionally substituted with 1- 5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-6 membered nitrogen-containing heteroaryl optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-6 membered nitrogen-containing heteroaryl containing 1-4 nitrogen atoms and optionally substituted with 1-5 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is 5-6 membered heteroaryl substituted with 1-3 R
G1; and each instance of R
G1 is independently cyano, oxo or C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is pyrazolyl, tetrazolyl, or pyridinonyl, each of which is independently optionally substituted with 1-3 R
G1. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is pyrazolyl, tetrazolyl, or pyridonyl, each of which is independently optionally substituted with 1-3 R
G1; and each instance of R
G1 is independently cyano or C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is pyrazolyl optionally substituted with 1-3 R
G1; and each instance of R
G1 is independently cyano or C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is pyrazolyl substituted with 1-3 R
G1; and R
G1 is cyano. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is pyrazolyl substituted with 1 R
G1; and R
G1 is cyano. In some embodiments, R
22 is methyl substituted with 1 R
G; R
G is pyrazolyl substituted with 1 R
G1; and R
G1 is cyano. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is tetrazolyl optionally substituted with 1-3 R
G1; and R
G1 is independently cyano or C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is tetrazolyl optionally substituted with 1-3 R
G1; and R
G1 is C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is tetrazolyl substituted with 1-3 R
G1; and R
G1 is C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is tetrazolyl substituted with 1-3 R
G1; and R
G1 is unsubstituted C
1-6 alkyl. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is tetrazolyl substituted with 1-3 R
G1; and R
G1 -CH
3. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G; R
G is tetrazolyl substituted with 1 R
G1; and R
G1 -CH
3. In some embodiments, R
22 is methyl substituted with 1 R
G; R
G is tetrazolyl substituted 1 R
G1; and R
G1 -CH
3. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G1 and R
G1 is
unsubstituted pyridinonyl. In some embodiments, R
22 is methyl substituted with 1 R
G1 and R
G1 is unsubstituted pyridinonyl. [0187] In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is substituted or unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
22 is C
1-6 alkyl substituted 1 R
G and R
G is C
3-6 carbocyclyl optionally substituted with 1-5 R
G1. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is C
3-6 carbocyclyl optionally substituted with 1-3 R
G1. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is C
3-6 carbocyclyl substituted with 1-3 R
G1. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is unsubstituted C
3-4 carbocyclyl. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is unsubstituted cyclopropyl. In certain embodiments, R
22 is methyl substituted with 1 R
G and R
G is unsubstituted C3-4 carbocyclyl. In certain embodiments, R
22 is methyl substituted with 1 R
G and R
G is unsubstituted cyclopropyl. [0188] In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is substituted or unsubstituted 5-8 membered heterocyclyl. In some embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-8 membered heterocyclyl optionally substituted with 1-5 R
G1. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is 5-8 membered heterocyclyl optionally substituted with 1-3 R
G1. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is unsubstituted 5-8 membered heterocyclyl. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is unsubstituted 5-8 membered nitrogen-containing heterocyclyl. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is unsubstituted 5-8 membered nitrogen-containing heterocyclyl containing 1 nitrogen atom. In certain embodiments, R
22 is C
1-6 alkyl substituted with 1 R
G and R
G is unsubstituted pyrrolidinonyl. In certain embodiments, R
22 is C1-3 alkyl substituted with 1 R
G and R
G is unsubstituted pyrrolidinonyl. In certain embodiments, R
22 is methyl substituted with 1 R
G and R
G is unsubstituted pyrrolidinonyl. [0189] In certain embodiments, R
22 is unsubstituted C
1-6 alkyl. In some embodiments, R
22 is -CH
3, -CH
2CH
3, -CH
2CH
2CH
2CH
3, -CH(CH
3)
2, -CH
2CH(CH
3)
2, -CH
2CH
2CH(CH
3)
2, or - C(CH
3)
3. In some embodiments, R
22 is -CH
3, -CH
2CH
3, -CH
2CH
2CH
2CH
3, or -CH(CH
3)
2. In some embodiments, R
22 is -CH
3. In some embodiments, R
22 is -CH
2CH
3. In some embodiments, R
22 is -CH
2CH
2CH
2CH
3. In some embodiments, R
22 is -CH(CH
3)
2. In some embodiments, R
22 is -CH
2CH(CH
3)
2. In some embodiments, R
22 is -CH
2CH
2CH(CH
3)
2. In some embodiments, R
22 is -C(CH
3)
3.
[0190] In certain embodiments, R
22 is substituted or unsubstituted C
2-6 alkenyl. In some embodiments, R
22 is C
2-6 alkenyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is C
2-6 alkenyl optionally substituted with 1-3 R
G. In some embodiments, R
22 is C
2-6 alkenyl optionally substituted with 1 R
G. In some embodiments, R
22 is C
2-4 alkenyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is C2-4 alkenyl optionally substituted with 1-3 R
G. In certain embodiments, R
22 is C2-4 alkenyl optionally substituted with 1 R
G. In some embodiments, R
22 is C
2-6 alkenyl substituted with 1-5 R
G. In some embodiments, R
22 is C
2-6 alkenyl substituted with 1-3 R
G. In some embodiments, R
22 is C
2-6 alkenyl substituted with 1 R
G. In some embodiments, R
22 is C2-4 alkenyl substituted with 1-5 R
G. In some embodiments, R
22 is C
2-4 alkenyl substituted with 1-3 R
G. In certain embodiments, R
22 is C
2-4 alkenyl substituted with 1 R
G. In some embodiments, R
22 is unsubstituted C
2-6 alkenyl. In some embodiments, R
22 is unsubstituted C
2-6 alkenyl. In some embodiments, R
22 is unsubstituted C2-4 alkenyl. In some embodiments, R
22 is -CH=CH
2, - CH
2CH=CH
2, -CH=CHCH
3, or -CH=C(CH
3)
2. In some embodiments, R
22 is -CH=CH
2. In some embodiments, R
22 is -CH
2CH=CH
2. In some embodiments, R
22 is -CH=CHCH
3. In some embodiments, R
22 is -CH=C(CH
3)
2. [0191] In certain embodiments, R
22 is substituted or unsubstituted C
2-6 alkynyl. In some embodiments, R
22 is C
2-6 alkynyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is C
2-6 alkynyl optionally substituted with 1-3 R
G. In some embodiments, R
22 is C
2-6 alkynyl optionally substituted with 1 R
G. In some embodiments, R
22 is C
2-3 alkynyl optionally substituted with 1-5 R
G. In some embodiments, R
22 is C
2-3 alkynyl optionally substituted with 1-3 R
G. In some embodiments, R
22 is C
2-6 alkynyl substituted with 1-5 R
G. In some embodiments, R
22 is C
2-6 alkynyl substituted with 1-3 R
G. In some embodiments, R
22 is C
2-6 alkynyl substituted with 1 R
G. In some embodiments, R
22 is C
2-3 alkynyl substituted with 1-5 R
G. In some embodiments, R
22 is C2-3 alkynyl substituted with 1-3 R
G. In some embodiments, R
22 is -C≡C-H, -C≡C-CH
3, or -C≡C-CF
3. In some embodiments, R
22 is C
2-3 alkynyl substituted with 1-3 R
G. In some embodiments, R
22 is C
2-3 alkynyl substituted with 1-3 R
G and R
G is halo. In some embodiments, R
22 is C2-3 alkynyl substituted with 1-3 R
G and R
G is fluoro. In some embodiments, R
22 is -C≡C-CF
3. In some embodiments, R
22 is unsubstituted C
2-6 alkynyl. In some embodiments, R
22 is unsubstituted C
2-3 alkynyl. In some embodiments, R
22 is -C≡C-H or -C≡C-CH
3. [0192] In certain embodiments, R
22 is substituted or unsubstituted C
3-6 carbocyclyl. In certain embodiments, R
22 is C
3-6 carbocyclyl optionally substituted with 1-5 R
H. In some embodiments, R
22 is C
3-6 carbocyclyl optionally substituted with 1-3 R
H. In some
embodiments, R
22 is C
3-6 carbocyclyl optionally substituted with 1 R
H. In certain embodiments, R
22 is C
3-6 carbocyclyl substituted with 1-5 R
H. In certain embodiments, R
22 is a bicyclic C
3-6 carbocyclyl substituted with 1-5 R
H. In some embodiments, R
22 is a bicyclic C
3-6 carbocyclyl substituted with 1-3 R
H. In some embodiments, R
22 is a bicyclic C
3-6 carbocyclyl substituted with 1 R
H. In some embodiments, R
22 is unsubstituted C
3-6 carbocyclyl. In some embodiments, R
22 is cyclopropyl, cyclobutyl, or bicyclo[1.1.1]pentanyl, each of which is independently optionally substituted with 1-5 R
H. In some embodiments, R
22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl optionally substituted with 1-3 R
H. In some embodiments, R
22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl substituted with 1 R
H. In some embodiments, R
22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl substituted with 1 R
H, wherein R
H is -CH
3 or -CF
3. In some embodiments, R
22 is unsubstituted cyclopropyl. In some embodiments, R
22 is unsubstituted cyclobutyl. In some embodiments, R
22 is bicyclo[1.1.1]pentanyl optionally substituted with 1-3 R
H. In some embodiments, R
22 is bicyclo[1.1.1]pentanyl substituted with 1-3 R
H. In some embodiments, R
22 is bicyclo[1.1.1]pentanyl substituted with 1 R
H. In some embodiments, R
22 is bicyclo[1.1.1]pentanyl substituted with 1 R
H and R
H is -CH
3 or -CF
3. In some embodiments, R
22 is bicyclo[1.1.1]pentanyl substituted with 1 R
H and R
H is -CH
3. In some embodiments, R
22 is bicyclo[1.1.1]pentanyl substituted with 1 R
H and R
H is -CF
3. [0193] In certain embodiments, R
22 is substituted or unsubstituted C
6-10 aryl. In some embodiments, R
22 is C
6-10 aryl optionally substituted with 1-5 R
H. In some embodiments, R
22 is C
6-10 aryl substituted with 1-5 R
H. In some embodiments, R
22 is C
6-10 aryl optionally substituted with 1-3 R
H. In some embodiments, R
22 is C
6-10 aryl substituted with 1-3 R
H. In some embodiments, R
22 is phenyl optionally substituted with 1-5 R
H. In some embodiments, R
22 is phenyl substituted with 1-5 R
H. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H. In some embodiments, R
22 is phenyl substituted with 1-3 R
H. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H and each instance of R
H is independently selected from the group consisting of: halo, cyano, and C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is phenyl substituted with 1-3 R
H and each instance of R
H is independently selected from the group consisting of: halo, cyano, and C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H and each instance of R
H is independently selected from the group consisting of: halo, cyano, and C
1-6 alkyl optionally substituted with 1-5 fluoro. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H and each instance of R
H
is independently selected from the group consisting of: fluoro, cyano, and unsubstituted C
1-6 alkyl. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H and each instance of R
H is independently selected from the group consisting of: fluoro, cyano, and - CH
3. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H and R
H is fluoro. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H and R
H is - CH
3. In some embodiments, R
22 is phenyl optionally substituted with 1-3 R
H and R
H is cyano. In some embodiments, R
22 is unsubstituted C
6-10 aryl. In some embodiments, R
22 is unsubstituted phenyl. [0194] In certain embodiments, each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, substituted or unsubstituted C
1-6 alkoxy, substituted or unsubstituted C
3-6 carbocyclyl, substituted or unsubstituted C
6-10 aryl, substituted or unsubstituted 5-8 membered heteroaryl, and substituted or unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 R
G1. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C
3- 6 carbocyclyl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 R
G1. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, C
1-6 alkoxy optionally substituted with 1-5 halo, unsubstituted C
3-6 carbocyclyl, 5-8 membered heteroaryl optionally substituted with 1-5 R
G1, and unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, C
1-6 alkoxy optionally substituted with 1-3 halo, unsubstituted C
3-6 carbocyclyl, 5-8 membered heteroaryl optionally substituted with 1-3 R
G1, and unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, C
1-6 alkoxy optionally substituted with 1-3 halo, unsubstituted C
3-6 carbocyclyl, 5-8 membered heteroaryl optionally substituted with 1 R
G1, and unsubstituted 5-8 membered heterocyclyl. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of fluoro, hydroxyl, -OCH
3,
-OCH(CH
3)
2, -OCHF
2, -OCF
3, -OCH
2CH
2OCH
3, unsubstituted cyclopropyl, pyrazolyl, tetrazolyl, unsubstituted pyrrolidinonyl, and unsubstituted pyridinonyl, wherein said pyrazolyl and tetrazolyl are substituted with 1 R
G1. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of fluoro, hydroxyl, - OCH
3, -OCH(CH
3)
2, -OCHF
2, -OCF
3, -OCH
2CH
2OCH
3, unsubstituted cyclopropyl, pyrazolyl, tetrazolyl, unsubstituted pyrrolidinonyl, and unsubstituted pyridinonyl, wherein said pyrazolyl and tetrazolyl are substituted with 1 R
G1 and R
G1 is cyano or -CH
3. In some embodiments, each instance of R
G, when present, is independently selected from the group consisting of fluoro, -OCH
3, and pyrazolyl substituted with 1 R
G1, and R
G1 is cyano. [0195] In certain embodiments, each instance of R
G1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, substituted or unsubstituted C
1-6 alkyl, and substituted or unsubstituted C
1-6 alkoxy. In some embodiments, each instance of R
G1, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
G1, when present, is independently selected from the group consisting of halo, cyano, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
G1, when present, is independently selected from the group consisting of cyano and C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, each instance of R
G1, when present, is independently selected from the group consisting of cyano and unsubstituted C
1-6 alkyl. In some embodiments, each instance of R
G1, when present, is independently selected from the group consisting of cyano and -CH
3. In some embodiments, each instance of R
G1, when present, is cyano. In some embodiments, each instance of R
G1, when present, is -CH
3. [0196] In certain embodiments, each instance of R
H, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1-6 alkoxy optionally substituted with 1-5 halo. In some embodiments, each instance of R
H, when present, is independently selected from the group consisting of halo, cyano, and C
1-6 alkyl optionally substituted with 1-5 halo. In some embodiments, each instance of R
H, when present, is independently selected from the group consisting of fluoro, cyano, -CH
3, and -CF
3. In some embodiments, each instance of R
H, when present, is independently selected from the group consisting of fluoro, cyano, and -CH
3. In some embodiments, each instance of R
H, when present, is independently selected from the
group consisting of -CH
3 and -CF
3. In some embodiments, each instance of R
H, when present, is fluoro. In some embodiments, each instance of R
H, when present, is cyano. In some embodiments, each instance of R
H, when present, is -CH
3. In some embodiments, each instance of R
H, when present, is -CF
3. [0197] In some embodiments, the compound of Formula (I) is any one of the compounds in Table 1. Table 1
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 of Table 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. In some embodiments, the compound of Formula (I) is any one of Compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100- 101, or 104-106 of Table 1, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0199] It is to be understood that in any of the preceding embodiments, the compound may be in a non-salt form, or in the form of a pharmaceutically acceptable salt, an isotopic variant, or any chemically permissible combination thereof. For example, in some embodiments, the compound is in a non-salt form. In other embodiments, the compound is in the form of a pharmaceutically acceptable salt. In certain other embodiments, the compound is in the form of an isotopic variant. In certain other embodiments, the compound is in a non-salt form or in the form of an isotopic variant. In some embodiments, the compound is in a non-salt form or in the form of a pharmaceutically acceptable salt. In some embodiments, the compound is in the form of a pharmaceutically acceptable salt and an isotopic variant. Alternative Embodiments [0200] In some embodiments, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be
2H (D or deuterium) or
3H (T or tritium); carbon may be, for example,
11C,
13C, or
14C; oxygen may be, for example
18O; nitrogen may be, for example
15N, and the like. In other embodiments, a particular isotope (e.g.,
2H,
13C,
14C,
18O, or
15N) 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 an element that occupies a specific site of the compound. [0201] In certain embodiments, compounds described herein have one or more hydrogen atoms independently replaced by deuterium or tritium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by deuterium. In some embodiments, compounds described herein have one or more hydrogen atoms replaced by tritium. Pharmaceutical Compositions [0202] In another aspect, the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Formula (I)). [0203] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. [0204] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier. [0205] The present disclosure also relates to a compound described herein (e.g., a compound of Formula (I), or pharmaceutical composition thereof) for use as a pharmaceutical or a medicament. [0206] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. [0207] The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds provided herein are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration. [0208] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to
physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. [0209] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms (e.g., pills, tablets, capsules) may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [0210] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. [0211] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein. [0212] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[0213] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. [0214] The above-described components for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference. [0215] The compounds of this disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences. [0216] The present disclosure also relates to the pharmaceutically acceptable formulations of a compound described herein (e.g., a compound of Formula (I)). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α–, β– and γ– cyclodextrins consisting of 6, 7 and 8 ^–l ,4–linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β–cyclodextrin, e.g., for example, sulfobutyl ether β–cyclodextrin, also known as Captisol®. See, e.g., U.S.5,376,645. In certain embodiments, the formulation comprises hexapropyl- ^-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl- ^-cyclodextrin (10-50% in water). [0217] The present disclosure also relates to the pharmaceutically acceptable acid addition salt of a compound described herein (e.g., a compound of Formula (I)). The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
[0218] For the prevention and/or treatment of long-term conditions the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg. [0219] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses. [0220] When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition. [0221] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject, the disease or disorder to be treated and the particular mode of administration. As the skilled artisan will appreciate, specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease or disorder, the patient's disposition to the disease or disorder and the judgment of the treating physician. Methods of Treatment and Use [0222] Compounds of the present disclosure (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to be negative allosteric modulators of NMDA function, and therefore are useful for the treatment and prevention of, e.g., CNS–related conditions in a subject. [0223] In some embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), as described herein, are generally designed to penetrate the blood brain barrier (e.g., designed to be transported across the blood brain barrier). In certain embodiments, the compounds of the
present disclosure, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, may act as negative allosteric modulators (NAM) of NMDA, and inhibit NMDA receptor function. [0224] In one aspect, the disclosure provides a method for effecting negative allosteric modulation of an NMDA receptor in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. [0225] In one aspect, the disclosure provides a method for treating a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. [0226] In one aspect, the disclosure provides a method for treating a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. [0227] In one aspect, the disclosure provides a method for preventing a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. [0228] In one aspect, the disclosure provides a method for preventing a CNS-related condition in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or a pharmaceutical composition as disclosed herein. [0229] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in effecting negative allosteric modulation of an NMDA receptor in a subject. [0230] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject.
[0231] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in treating a CNS-related condition in a subject. [0232] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject. [0233] In one aspect, the disclosure provides a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for use in preventing a CNS-related condition in a subject. [0234] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor in a subject. [0235] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject. [0236] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a CNS-related condition in a subject. [0237] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing a disease, disorder or condition requiring negative allosteric NMDA modulation in a subject. [0238] In one aspect, the disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, or pharmaceutical composition as disclosed herein for the manufacture of a medicament for preventing a CNS-related condition in a subject. [0239] Exemplary CNS conditions related to negative allosteric modulation of NMDA receptors include, but are not limited to, adjustment disorders, stress or stress disorders (including post-traumatic stress disorder (PTSD)), anxiety disorders (including obsessive- compulsive disorder, posttraumatic stress disorder, social phobia, social anxiety disorder, and
generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactive disorder (ADHD)), eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), psychotic disorders, sleep disorders (including insomnia), substance abuse-related disorders and/or withdrawal syndromes (e.g., addiction to opiates, cocaine, and/or alcohol), personality disorders (including obsessive-compulsive personality disorder (OCD)), autism spectrum disorders (including those involving mutations to the Shank group of proteins (e.g., Shank3), Rett syndrome, Fragile X syndrome, and Angelman syndrome), addictive disorders, neurodevelopmental disorders (including Rett syndrome), pain (including neuropathic pain, injury-related pain syndromes, acute pain, and chronic pain; headaches, e.g., migraine headaches), seizures (including grand-mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and atonic seizures) and seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), vascular diseases (e.g., stroke, ischemia, vascular malformations), traumatic brain injury, movement disorders (including Huntington’s disease, Parkinson’s disease, and tremors), neuropsychiatric lupus, and tinnitus. [0240] In certain embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in the treatment or prevention of CNS-related conditions selected from adjustment disorders, anxiety disorders, cognitive disorders, mood disorders, personality disorders, neurodevelopmental disorders, pain, seizures and seizure disorders, stroke, traumatic brain injury, movement disorders, neuropsychiatric lupus, and tinnitus. In some embodiments, the CNS-related condition is a mood disorder selected from depression, post- partum depression, bipolar disorder, dysthymic disorder, and suicidality. In some embodiments, the CNS-related condition is a mood disorder selected from clinical depression, post-partum depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, and suicidal behavior. In some embodiments, the CNS-related condition is selected from a seizure, status epilepticus, Dravet’s disease, or Tuberous Sclerosis Complex. In some
embodiments, the CNS-related condition is a seizure selected from a grand-mal seizure, an absence seizure, a myoclonic seizure, a clonic seizure, a tonic seizure, and an atonic seizure. In some embodiments, the CNS-related condition is a movement disorder selected from Parkinson’s disease, Parkinsonism, dystonia, chorea, Huntington’s disease, ataxia, levodopa- induced dyskinesia, tremor, myoclonus and startle, tics and Tourette syndrome, restless leg syndrome, stiff person syndrome, and gait disorders. In some embodiments, the CNS-related condition is a tremor selected from a cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, and rubral tremor. In some embodiments, the CNS-related condition is Huntington’s disease. In some embodiments, the CNS-related condition is Parkinson’s disease. In some embodiments, the CNS is neuropsychiatric lupus. [0241] In certain embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in the treatment or prevention of a CNS-related condition, wherein the CNS-related condition is selected from the group consisting of: an anxiety disorder, a stress disorder, a cognitive disorder (including Alzheimer’s disease, mild cognitive impairment, and other forms of dementia (e.g., frontotemporal dementia)), a mood disorder (including depression (e.g., postpartum depression)), a personality disorder, an addictive disorder (including drug addiction (e.g., cocaine addiction)), a neurodevelopmental disorder, schizophrenia or other psychotic disorders (including schizoaffective disorder), pain (including acute and chronic pain; neuropathic pain, headaches, e.g., migraine headaches), a seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), drug induced dyskinesia (e.g., L- DOPA-induced dyskinesia (LID)), stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome (FXS), neuropsychiatric lupus, and tinnitus. [0242] In certain embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in the treatment or prevention of a CNS-related condition, wherein the CNS-related condition is selected from the group consisting of: a tremor, sleep disorders (e.g., insomnia), mood disorders (e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), eating disorders, stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD)), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), convulsive disorders (e.g., epilepsy (e.g.,
status epilepticus (SE)), seizures), neurodegenerative disease and disorders, disorders of memory and/or cognition (e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., anti-social personality disorder, obsessive compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monogenetic causes of autism such as synaptopathies, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain), traumatic brain injury (TBI), vascular diseases (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and/or withdrawal syndromes (e.g., addiction to opiates, cocaine, and/or alcohol), and tinnitus. [0243] In some embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in treating Parkinson’s Disease. In some embodiments, the compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful as adjunct treatment to L-DOPA for Parkinson’s Disease. The compounds described herein (e.g., a compound of Formula (I), and pharmaceutically acceptable salts, isotopic variants, and combinations thereof), are useful in treating L-DOPA-induced dyskinesia (LID) in a subject suffering from Parkinson’s Disease. [0244] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present disclosure, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. [0245] In yet another aspect, the present disclosure provides a combination of a compound of the present disclosure, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration. Movement Disorders [0246] Also described herein are methods for treating a movement disorder. As used herein, “movement disorders” refers to a variety of diseases and disorders that are 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 (defined particularly by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders. [0247] Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs). Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson’s disease, Parkinson’s disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor. [0248] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inherited degenerative disorder). [0249] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal postures or positions. Dystonic tremor may affect any muscle in the body. Dystonic tremors occurs irregularly and often can be relieved by complete rest. [0250] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. Tremor
frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset. [0251] Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occur in patients with essential tremor. [0252] Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson’s disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side. [0253] Physiological tremor can occur in normal individuals and have no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz. [0254] Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement. Patient with psychogenic tremor may have a conversion disorder or another psychiatric disease. [0255] Rubral tremor is characterized by coarse slow tremor which can be present at rest, at posture, and with intention. The tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes. [0256] Parkinson’s disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson’s disease, but is a symptom complex rather than a progressive neurodegenerative disease. [0257] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. [0258] Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face.
[0259] Huntington’s Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington’s disease can hinder walk, talk, and swallowing. [0260] Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements. [0261] Myoclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular. [0262] Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non- rhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example simple motor tics involve only a few muscles restricted to a specific body part. [0263] Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic. [0264] Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest. [0265] Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Stiff-legged gait with exaggerated lumbar hyperlordosis typically results. Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet. [0266] Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait. Mood disorders [0267] Also provided herein are methods for treating a mood disorder, for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive
disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior. [0268] Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living. [0269] Postnatal depression (PND) is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability. In some embodiments, the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., a refractory depression as described herein). [0270] In some embodiments, a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression. In an embodiment, a subject experiencing perinatal depression is at increased risk of experiencing PND. [0271] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. [0272] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failures to react to pleasurable stimuli, depressed mood more pronounced than that of grief or loss, excessive weight loss, or excessive guilt. [0273] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.
[0274] Catatonic depression refers to major depression involving disturbances of motor behavior and other symptoms. An individual may become mute and stuporose, and either is immobile or exhibits purposeless or bizarre movements. [0275] Seasonal affective disorder (SAD) refers to a type of seasonal depression wherein an individual has seasonal patterns of depressive episodes coming on in the fall or winter. [0276] Dysthymia refers to a condition related to unipolar depression, where the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e.g., at least 2 years). [0277] Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression. [0278] Depressive Personality Disorder (DPD) refers to a personality disorder with depressive features. [0279] Recurrent Brief Depression (RBD) refers to a condition in which individuals have depressive episodes about once per month, each episode lasting 2 weeks or less and typically less than 2-3 days. [0280] Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks. [0281] Bipolar disorder or manic depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced. During periods of depression there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder. [0282] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress. [0283] Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not ease depression symptoms for individuals with treatment-resistant depression. In some cases, individuals with treatment- resistant depression improve symptoms, but come back. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments,
including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and/or anxiolytic drugs, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation). [0284] Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide. Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide. The range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won’t be seen again. [0285] Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of depression, and relief of the same, may be ascertained by a physician or psychologist (e.g., by a mental state examination). Anxiety Disorders [0286] Provided herein are methods for treating anxiety disorders. Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders. [0287] Generalized anxiety disorder is a common chronic disorder characterized by long- lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults. [0288] In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said
attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis). [0289] Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions. [0290] The single largest category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid. [0291] Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience. Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression. Epilepsy [0292] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.
Epileptogenesis [0293] Epileptogenesis is a gradual process by which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptogenesis results from neuronal damage precipitated by the initial insult (e.g., status epilepticus). Status epilepticus (SE) [0294] Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered. Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more. [0295] Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non- convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non- convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus. Seizure [0296] A seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person’s body shakes rapidly and uncontrollably. During convulsions, the person’s muscles contract and relax repeatedly. [0297] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.
[0298] Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus. [0299] There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized convulsion, also called the grand-mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence. [0300] Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of "losing time." [0301] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects. [0302] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time. [0303] Tonic seizures are characterized by stiffening of the muscles. [0304] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall. [0305] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non- convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital
lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet Syndrome, Lennox-Gastaut Syndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 Female Pediatric Epilepsy. Examples [0306] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. [0307] The absolute configuration of an asymmetric center can be determined using methods known to one skilled in the art. In some embodiments, the absolute configuration of an asymmetric center in a compound can be elucidated from the X-ray single-crystal structure of the compound. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound obtained from the same or similar synthetic methodologies. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound coupled with a spectroscopic technique, e.g., NMR spectroscopy, e.g., 1H NMR spectroscopy or 19F NMR spectroscopy. Abbreviations [0308] MeOH: methanol; THF: tetrahydrofuran; Pd/C: palladium on carbon; CDCl3: deuterated chloroform; c-PrMgBr: cyclopropylmagnesium bromide; NH
4Cl: ammonium chloride; EtOAc: ethyl acetate; Na2SO
4: sodium sulfate; PE: petroleum ether; DMSO: dimethyl sulfoxide; TEA/Et3N: triethylamine; SO
3∙pyr: sulfur trioxide-pyridine complex; H
2O: water; NaHCO
3: sodium bicarbonate; CsF: cesium fluoride; TMSCF
3: trifluoromethyltrimethylsilane; TBAF: tetrabutylammonium fluoride; ACN/MeCN: acetonitrile; NH4HCO
3: ammonium bicarbonate; TFA: trifluoroacetic acid; EtMgBr: ethylmagnesium bromide; BHT: 2,6-di-t-butyl-4-methylphenoxide; MAD: methylaluminium bis(2,6-di-t-butyl-4-methylphenoxide); DCM: dichloromethane; Et
2O: diethyl ether; DMP: Dess-Martin periodinane; Ph3PMeBr/MePPh3Br: bromo(methyl)triphenylphosphorane; t- BuOK: potassium tert-butoxide; Na2S2O
3: sodium thiosulfate; O
3: ozone; Me2S/DMS: dimethyl sulfide; HBr: hydrobromic acid; TsOH: p-toluenesulfonic acid; Ph
3PEtBr/EtPPh
3Br:
bromo(ethyl)triphenylphosphorane; HCl: hydrochloric acid; NaBH
4: sodium borohydride; TBSCl: t-butyldimethylsilyl chloride; 9-BBN: 9-borabicyclo[3.3.1]nonane; NaOH: sodium hydroxide; H
2O
2: hydrogen peroxide; PCC: pyridinium chlorochromate; EtOH: ethanol; (tBuO)
3AlLiH/ LiAlH(OtBu)
3: lithium tri-(t-butoxy)aluminum hydride; NaH: sodium hydride; MeMgBr: methylmagnesium bromide; i-BuMgBr: isobutylmagnesium bromide; LAH/LiAlH4: lithium aluminum hydride; n-BuMgBr: n-butylmagnesium bromide; i- AmylMgBr: isoamylmagnesium bromide; CBS: Corey-Bakshi-Shibata catalyst; BH
3∙SMe
2/ BH3∙DMS: borane dimethylsulfide; CaCO
3: calcium carbonate; PhI(OAc)
2: (diacetoxyiodo)benzene; BnOH: benzyl alcohol; t-BuOH: tertbutanol; DME: dimethyl ether; TosMic: toluenesulfonylmethyl isocyanide; LDA: lithium diisopropyl amide; MeI: methyl iodide; DIBAL-H: diisobutylaluminum hydride; IPA/i-PrOH: isopropanol; PMBCl: p- methoxybenzyl chloride; AlMe3: trimethyl aluminum; DDQ: 2,3-dichloro-5,6- dicyanobenzoquinone; DMF: N,N-dimethylformamide; HMPA: hexamethylphosphoramide; LiHMDS: lithium bis(trimethylsilyl)amide; NaH
2PO
4: monosodium phosphate; K
2CO
3: potassium carbonate; NaBH4: sodium borohydride; m-CPBA: meta-chloroperoxybenzoic acid; NaOMe: sodium methoxide; n-PrMgBr: n-propylmagnesium bromide; BzCl: benzoyl chloride; PhMe: toluene; DMAP: 4-dimethylaminopyridine; i-PrMgCl: isopropylmagnesium chloride; t-BuMgCl: tertbutylmagnesium chloride; Cs2CO
3: cesium carbonate; DIPEA: N,N- diisopropylethylamine; TMSCF2Br: (bromodifluoromethyl)trimethylsilane; KOAc: potassium acetate; LiOH: lithium hydroxide; n-BuLi: n-butyllithium; TBDPSCl: tert- butylchlorophenylsilane; BnBr: benzylbromide; KHF
2: potassium bifluoride; DCE: 1,2- dichloroethane; t-BuLi: tert-butyl lithium; Me3SOI: trimethylsulfonium iodide; CD3OD: deuterated methanol (d4); Na2CO
3: sodium carbonate; BH3∙THF: borane tetrahydrofuran complex; Py: pyridine; 2-Me-THF: 2-methyltetrahydrofuran; AgOTf: silver trifluoromethanesulfonate/silver triflate; Selectfluor: chloromethyl-4-fluoro-1,4- diazoniabicyclo[2,.2.2]octane bis(tetrafluoroborate); NFSI: N-fluorobenzenefulonimide; NaOD: deuterated sodium hydroxide; AcOD: deuterated acetic acid; D
2O: deuterated water; Ac2O: acetic anhydride; BzOH: benzenol; CeCl3: cerium chloride; DEAD: diethyl azodicarboxylate; PPh3: triphenylphosphine; MeI: methyl iodide; TBSOTf: tert- butyldimethylsilyl trifluoromethansulfonate; NaBT
4: [
3H] tritium-labeled sodium borohydride; Me: methyl; Et: ethyl; i-Pr: iso-propyl; t-Bu: tertbutyl; Ph: phenyl; Bz: benzoyl; Ts: p-toluenesulfonyl; Bu: butyl; NBS: N-bromosuccinimide.
Materials and Methods [0309] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization. [0310] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 5
th Edition, John Wiley & Sons, New Jersey, 2014, and references cited therein. [0311] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or SFC. The following schemes are presented with details as to the preparation of representative compounds that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK. [0312]
1H-NMR reported herein (e.g., for the region between δ (ppm) of about 0.5 to about 4 ppm) will be understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integrations) of a compound. Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH
4HCO
3) (30 L water, 24 g NH
4HCO
3, 30 mL NH3.H
2O). Flow rate: 25 mL/min. [0313] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO
3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50mm, 3.5 μm at 45 C.
[0314] Exemplary general method for SFC: Column: CHIRALPAK® AD CSP (250 mm * 30 mm, 10 μm), Gradient: 45% B, A= NH3H
2O, B= MeOH, flow rate: 60 mL/min. For example, AD_3_EtOH_DEA_5_40_25ML would indicate: "Column: Chiralpak AD-3 150×4.6mm I.D., 3um Mobile phase: A: CO
2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5mL/min Column temp: 35
oC. [0315] Example 1: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-cyclopropyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (1)
[0316] Synthesis of 1.2 [0317] To a solution of 1.1 (100 g, 302 mmol) in MeOH (300 mL) and THF (300 mL) was added Pd/C (10 g, < 1% water). The solution was hydrogenated under 30 psi of hydrogen at 25 °C for 48 h. The mixture was filtered through a pad of Celite. The filter cake was washed with THF (3 x 300 mL) and the filtrate was concentrated under reduced pressure to give 1.2 (98 g).
1H NMR (400 MHz, CDCl
3) 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 x 50 mL), and the combined organic layers were washed with brine (50 mL, sat.), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 1.3 (2 g, 24%). 1.3:
1H NMR (400 MHz, CDCl
3) 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 addded TEA (886 mg, 8.76 mmol) and SO
3∙pyr (1.39 g, 8.76 mmol) at 25 °C and the resulting mixture was stirred at 30 °C for 16 h. This reaction was combined with another two (2) batches of reaction mixture obtained using similar protocols (1 g of 1.3 starting material), and the mixture was diluted with H
2O (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with NaHCO
3 (20 mL, sat. aq.), and H
2O (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~30% EtOAc in PE) to give 1.4 (550 mg).
1H NMR (400 MHz, CDCl3) δH 9.61-9.53 (m, 1H), 2.37-2.31 (m, 1H), 2.01-1.59 (m, 10H), 1.31-1.24 (m, 14H), 1.23 (s, 4H), 0.97 (s, 3H), 0.70 (s, 3H), 0.40-0.30 (m, 4H). [0322] Synthesis of 1 [0323] To a solution of 1.4 (700 mg, 1.87 mmol) in anhydrous THF (15 mL) was added CsF (709 mg, 4.67 mmol) at 0 °C. After stirring for 20 min, TMSCF
3 (663 mg, 4.67 mmol) was added at 0 °C and the mixture was stirred for 1 h. To the mixture was added TBAF∙3H
2O (2.36 g, 7.48 mmol) and the mixture was stirred at 50 °C for 1 h. The reaction mixture was poured into ice-water (20 mL) and stirred for 10 min and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, concentrated under reduced pressure and purified by silica gel chromatography (PE/EtOAc = 30/1 to 5/1) to afford 1 (150 mg).
[0324] Compound 1 (150 mg) was further purified by ELSD-HPLC ((column: DuraShell 150*25mm*5um), gradient: 60-90% B (water(10mM NH4HCO
3)-MeCN), B= MeCN), flow rate: 25 mL/min) to give 1 (16 mg, 11%).
1H NMR (400 MHz, CDCl3) δH 4.10-3.95 (m, 1H), 2.20-2.15 (m, 1H), 2.00-1.75 (m, 5H), 1.75-1.50 (m, 3H), 1.50-1.25 (m, 8H), 1.25-1.00 (m, 12H), 0.96 (s, 3H), 0.83 (s, 1H), 0.67 (s, 3H), 0.45-0.30 (m, 4H).
19F NMR (376.5 MHz, CDCl3) δF -72.20. LCMS (Mobile Phase: 1.5 mL/4 L TFA in water (solvent A) and 0.75 mL/4 L TFA in acetonitrile (solvent B), using the elution gradient 30%-90% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes at a flow rate of 0.8 mL/min; Column: Xtimate C182.1*30mm,3um; Wavelength: UV 220nm&254nm ; Column temperature: 50 °C; MS ionization: ESI; Detector: PDA&ELSD) MS ionization: ESI for C
26H
40F
3O [M+H-H
2O]
+ calcd.425, found 425, purity 100%. [0325] Example 2: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (2)
[0326] Synthesis of 2.1 [0327] To a solution of BHT (132 g, 599 mmol) in toluene (1.4 L) under nitrogen at 0 °C was added trimethylaluminum (2 M in toluene, 149 mL, 299 mmol) dropwise and the resulting mixture was stirred at 25 °C for 1 h to generate a solution of MAD. A solution of 1.2 (50 g, 150 mmol) in DCM (500 mL) was added to the MAD solution (0.213 M in toluene) dropwise at -70 °C under N2. After stirring at -70 °C for 1 h, EtMgBr (74.6 mL, 224 mmol, 3M in Et
2O) was added dropwise at -70 °C. The resulting solution was stirred at -70
°C for 1 h. The reaction mixture was quenched by addition of saturated aqueous citric acid (2 L) at 10 °C and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with saturated aqueous NH4Cl (2 x 500 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified from PE and further purified from MeCN (500 mL) to give 2.1 (32 g, 71%).
1H NMR (400 MHz, CDCl3) δH 3.73-3.55 (m, 1H), 3.44-3.30 (m, 1H), 2.1-1.62 (m, 6H), 1.57-1.31 (m, 14H), 1.28-1.04 (m, 11H), 1.03 (d, J = 6.8 Hz, 3H), 0.93 (s, 3H), 0.66 (s, 3H). [0328] Synthesis of 2.2 [0329] To a solution of 2.1 (8 g, 22 mmol) in DCM (80 mL) at 25 °C was added DMP (18.6 g, 44.0 mmol). After stirring at 25 °C for 30 min, the mixture was quenched with saturated aqueous NaHCO
3:Na
2S
2O
3 (v:v = 1:1, 80 mL) and the mixture was extracted with DCM (2 x 80 mL). The combined organic layers were washed with saturated aqueous NaHCO
3:Na2S2O
3 (v:v = 1:1, 80 mL) and brine (80 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 2.2 (4.3 g, 54.2 %).
1H NMR (400 MHz, CDCl3) δH 9.55 (d, J = 3.2 Hz, 1H), 2.42-2.26 (m, 1H), 1.94-1.79 (m, 4H), 1.76-1.48 (m, 8H), 1.47-1.21 (m, 14H), 1.11 (d, J = 6.4 Hz, 3H), 1.09-0.94 (m, 3H), 0.93 (s, 3H), 0.68 (s, 3H). [0330] Synthesis of 2 [0331] To a solution of 2.2 (5 g, 13.8 mmol) in THF (50 mL) was added CsF (628 mg, 4.14 mmol), and TMSCF
3 (4.89 g, 34.5 mmol). After stirring at 0 °C under N
2 for 1 h, TBAF (6.93 g, 22.0 mmol) was added. After stirring at 40 °C for another 2 h, the mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (2 x 50 mL). The layers were separated and the combined organic layer was washed with saturated aqueous NH
4Cl (2 x 40 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~30% EtOAc in PE). The resulting residue was further purified from MeCN (5 mL) to give 2 (172.6 mg, 43.1%).
1H NMR (400 MHz, CDCl
3) 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 purity 99%; MS ESI calcd. for C25H40F
3O1 [M-H
2O+H]
+ 413.3, found 413.3.
19F NMR (376.5 MHz, CDCl
3) δ
F -72.207.
[0332] Example 3: Synthesis of (5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-3H- cyclopenta[a]phenanthren-3-one (3)
[0333] Synthesis of 3.1 [0334] To a suspension of Ph
3PMeBr (53.5 g, 150 mmol) in anhydrous THF (300 mL) was added t-BuOK (16.8 g, 150 mmol) at 20 °C under N
2 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 at 20 °C for 2 h, the mixture was poured into 10% aqueous NH4Cl (600 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 200 mL), and the combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was dissolved in MeOH (500 mL), and water (500 mL) was added dropwise. A solid appeared which was collected by filtration and dried to give 3.1 (20 g).
1H NMR (400 MHz, CDCl
3) 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] Synthesis of 3.2 [0336] To a solution of 3.1 (20 g, 60.5 mmol) in DCM (600 mL) was added DMP (51.3 g, 121 mmol). After stirring at 20 °C for 30 min, the reaction mixture was quenched by addition of saturated aqueous NaHCO
3 (600 mL) until the aqueous layer reached a pH of ~9. Saturated aqueous Na2S2O
3 (600 mL) was added. After stirring at 20 °C for 10 min, the mixture was extracted with DCM (2 x 300 mL) and the combined organic layers were washed with saturated aqueous Na
2S
2O
3 (2 x 600 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 3.2 (19 g).
1H NMR (400 MHz, CDCl3) δH 9.59-9.55 (m, 1H), 4.62-4.53 (m, 2H), 2.56-2.46 (m, 1H), 2.41-2.29 (m, 1H), 2.18-1.78 (m, 8H), 1.71-1.60 (m, 1H), 1.53-1.37 (m, 5H), 1.36-1.23 (m, 3H), 1.21-1.05 (m, 7H), 1.04-0.95 (m, 1H), 0.94 (s, 3H), 0.71 (s, 3H). [0337] Synthesis of 3.3 [0338] To a solution of 3.2 (42.3g, 128 mmol) in THF (500 mL) was added TBAF (12.8 ml, 12.8 mmol, 1 M in THF) at 0 °C. After stirring at 0 °C for 10 min, TMSCF
3 (36.3g, 256 mmol) was added and the mixture was stirred at 25 °C for 1 h. Additional TBAF (40.3g, 128 mmol) was added and the mixture was stirred at 25 °C for 1 h. The mixture was quenched with water (300 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~12% EtOAc in PE) to give 3.3 (26.2g, 51%).
1H NMR (400 MHz, CDCl
3) δ
H 4.61-4.52 (m, 2H), 4.10-3.99 (m, 1H), 2.50 (t, J = 12Hz, 1H), 2.21-1.58 (m, 9H), 1.56-1.13 (m, 12H), 1.12-0.95 (m, 6H), 0.93 (s, 3H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -72.191. [0339] Synthesis of 3.4 [0340] To a solution of 3.3 (5 g, 12.5 mmol) in DCM (50 mL) and MeOH (50 mL) was added NaHCO
3 (5.25 g, 62.5 mmol). Ozone (1 atm) was passed through the solution at -70 °C. O
2 was then passed through the solution for 5 min. To the mixture was added Me2S (2.86 g, 46.2 mmol) at -70 °C in portions and the solution was warmed to 20 °C over 1 h and then stirred at 20 °C for 16 h. To the mixture was added 10% aqueous NH4Cl (300 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated unde reduced pressure. The residue was purified by flash silica gel chromatography (0~5% EtOAc in PE) to give 3.4 (4 g, 80%).
1H NMR (400 MHz, CDCl3) δH 4.05 (br s, 1H), 2.78-2.56 (m, 1H), 2.40-2.11 (m, 3H), 2.10-1.75 (m, 7H), 1.72-1.61 (m, 1H), 1.56-1.23 (m, 10H), 1.21-1.06
(m, 6H), 1.02 (s, 3H), 0.71 (s, 3H). LC-ELSD/MS purity 100%, MS ESI calcd. for C23H35F
3O
2 [M+H]
+ 401, found 401. [0341] Synthesis of 3 [0342] To a solution of BHT (1.36 g, 6.19 mmol) in toluene (10 mL) under nitrogen at 0 °C was added AlMe3 (1.54 mL, 3.09 mmol, 2 M in toluene) dropwise and the mixture was stirred at 25 °C for 1 h to generate a solution of MAD. To the MAD solution was added a solution of 3.4 (500 mg, 1.24 mmol) in DCM (10 mL) dropwise at -70 °C. After stirring at - 70 °C for 1 h under N2, MeMgBr (826 µL, 2.48 mmol, 3 M in Et2O) was added dropwise and the resulting solution was stirred for 2 h. The reaction mixture was poured into saturated aqueous citric acid (40 mL) at 10 °C and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc =5/1 to 3/1) and then further purified from DCM:n-hexane (1:2, 5 mL) at 60 °C for 20 min to give 3 (31.3 mg, 39%).
1H NMR (400 MHz, CDCl
3) 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 purity 100%, MS ESI calcd. for C
24H
38F
3O [M-H
2O+H]
+ 399.2, found 399.2.
[0343] Example 4: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-3-ethyl-13-methyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (4)
[0344] Synthesis of 4.2 [0345] To a suspension of 4.1 (100 g, 367 mmol) and Pd/C (10 g, 10% palladium on carbon, 50% water wet) in THF (1000 mL) was added hydrobromic acid (2 mL, 48% in water). The suspension was hydrogenated under 15 psi of hydrogen at 25 °C for 16 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 4.2 (95 g).
1H NMR (400MHz, CDCl3) δH
2.56 (t, J = 14.4 Hz, 1H), 2.45 (dd, J = 8.4, 19.2 Hz, 1H), 2.33-2.02 (m, 6H), 1.96-1.50 (m, 9H), 1.42-1.14 (m, 6H), 0.89 (s, 3H). [0346] Synthesis of 4.3 [0347] To a solution of 4.2 (95 g, 346 mmol) in MeOH (1000 mL) was added TsOH (5.95 g, 34.6 mmol) at 20 °C and the resulting mixture was stirred at 60 °C for 3 h. The mixture was quenched with TEA (3.67g) and the mixture was concentrated to a volume of 200 mL. EtOAc (300 mL) and water (300 mL) were added, the layers were separated, and the mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with
water (2 x 300 mL) and brine (2 x 300 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure to give 4.3 (120 g). [0348] Synthesis of 4.4 [0349] To a solution of bromo(ethyl)triphenylphosphorane (416 g, 1121 mmol) in THF (1000 mL) was added t-BuOK (125 g, 1121 mmol) at 20 °C. The mixture was warmed to 40 °C and stirred for 30 min under N2. A solution of 4.3 (120 g, 374 mmol) in THF (500 mL) was added, and the internal temperature of the resulting mixture was kept below 40 °C while stirring for 17 h. The mixture was quenched with a solution of NH4Cl (60 g, 10% aq.) and the organic phase was separated and concentrated under reduced pressure to give 4.4, which was then dissolved in MeOH (3000 mL). After stirring at 20 °C for 30 min, the mixture was treated with water (3000 mL) and stirred at 20 °C for 1 h and let stand for 17 h. The residue was collected and re-dissolved in DCM (1000 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 4.4 (110 g), which was purified by silica gel chromatography (0~0.5% EtOAc in PE) to give 4.4 (48.5 g, 44.4%).
1H NMR (CDCl
3 400MHz) δH 5.18-5.03 (m, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.44- 2.11 (m, 3H), 1.95-1.59 (m, 11H), 1.55-1.34 (m, 5H), 1.29-1.02 (m, 7H), 0.87 (s, 3H). [0350] Synthesis of 4.5 [0351] To a solution of 4.4 (47.5 g, 142 mmol) in THF (200 mL) was added aq. HCl (213 mL, 1 M) at 20 °C and the resulting mixture was stirred for 1 h. The mixture was combined with another batch of a reaction mixture obtained using similar conditions (1 g of 4.4 starting material). EtOAc (200 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with water (2 x 300 mL), saturated aqueous NaHCO
3 (200 mL), and brine (2 x 300 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure to give 4.5 (39.2 g).
1H NMR (CDCl3400MHz) δH 5.21-5.02 (m, 1H), 2.69-2.53 (m, 1H), 2.46-1.99 (m, 8H), 1.82- 1.47 (m, 11H), 1.41-1.05 (m, 6H), 0.91 (s, 3H). [0352] Synthesis of 4.6 [0353] To a solution of 4.5 (40 g, 139 mmol) in MeOH (400 mL) was added NaBH4 (9.45 g, 278 mmol) in portions and the resulting mixture was stirred at 10 °C for 40 min. The mixture was treated with water (500 mL) and DCM (2 x 300 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure to afford 4.6 (39 g). [0354] Synthesis of 4.7
[0355] To a solution of 4.6 (39 g, 135 mmol) in DCM (400 mL) was added imidazole (18.3 g, 270 mmol) and TBSCl (30.3 g, 202 mmol) at 10 °C and the resulting mixture was stirred for 12 h. The mixture was treated with water (500 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc = 100/1) to afford 4.7 (45 g, 83%). [0356] Synthesis of 4.8 [0357] To a solution of 4.7 (45 g, 111 mmol) in THF (400 mL) was added 9-BBN dimer (31.1 g, 127.65 mmol) and the resulting mixture was stirred at 50 °C for 2 h. After cooling to 0 °C, a solution of NaOH (222 mL, 1.11 mol, 5 M in H
2O) was added slowly. After the addition, H
2O
2 (125 g, 1.11 mol, 30%) was added slowly and the internal temperature of the reaction mixture was maintained below 15 °C during the course of the addition. The resulting solution was stirred at 10 °C for 2 h. The mixture was treated with water (500 mL), filtered, and the filtrate was extracted with EtOAc (2 x 400 mL). The combined organic layers were washed with saturated aqueous Na2S2O
3 (2 x 500 mL) and brine (500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to afford 4.8 (65 g). [0358] Synthesis of 4.9 [0359] To a solution of 4.8 (65 g, 154 mmol) and silica gel (50 g) in DCM (600 mL) was added PCC (49.4 g, 230 mmol) at 10 °C and the resulting mixture was stirred for 2 h. The mixture was filtered and the filtered cake was washed with DCM (2 x 200 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc = 50/1) to afford 4.9 (25 g, 38%). [0360] Synthesis of 4.10 [0361] Compound 4.9 (25 g, 59.7 mmol) was dissolved in TBAF (238 mL, 238 mmol, 1 M in THF) at 10 °C and the resulting mixture was stirred at 45 °C for 12 h. The mixture was treated with water (1000 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (2 x 300 mL) and brine (300 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc = 3/1) to afford 4.10 (13 g, 52%).
1H NMR (400 MHz, CDCl
3) δ
H 3.65-3.62 (m, 1H), 2.53 (t, J = 8Hz, 1H), 2.18-2.10 (m, 4H), 2.15-2.05 (m, 1H), 2.04-1.96 (m, 1H), 1.80-1.71 (m, 2H), 1.70-1.58 (m, 5H), 1.56-1.46 (m, 5H), 1.45-1.35 (m, 1H), 1.34-1.16 (m, 5H), 1.14-0.96 (m, 3H), 0.60 (s, 3H). [0362] Synthesis of 4.11
[0363] To a solution of 4.10 (3.5 g, 11.4 mmol) in DCM (50 mL) was added PCC (4.9 g, 22.8 mmol) at 25 °C and the resulting mixture was stirred for 2 h. The solution was filtered, and the filter cake was washed with DCM (2 x 50 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with (PE/EtOAc = 6/1) to afford 4.11 (2.8 g, 77%).
1H NMR (400 MHz, CDCl3) δH 2.65-2.50 (m, 2H), 2.25-2.01 (m, 9H), 1.80-1.55 (m, 7H), 1.54-1.44 (m, 3H), 1.43-1.20 (m, 6H), 0.65 (s, 3H). [0364] Synthesis of 4.12 [0365] To a solution of BHT (72.7 g, 329 mmol) in toluene (200 mL) under N2 at 0 °C was added trimethylaluminum (82.0 mL, 2 M in toluene, 164 mmol) dropwise and the resulting mixture was stirred at 25 °C for 1 h to generate a solution of MAD. To the MAD (78.8 g in toluene, 165 mmol) solution was added a solution of 4.11 (10 g, 33.0 mmol) in DCM (200 mL) dropwise at -70 °C and the resulting solution was stirred at -70 °C for 1 h under N2. EtMgBr (33 mL, 3M in ethyl ether, 99 mmol) was added dropwise at -70 °C and the mixture was stirred for 2 h. The reaction mixture was poured into citric acid (500 mL, sat. aq.) at 10 °C and extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (5~10% EtOAc in PE) to give 4.12 (9.0 g). 4.12 (9.0 g, 27.0 mmol) was further purified by flash silica gel chromatography (10~30% EtOAc in PE) to afford 4.12 (5.54 g, 61.7%).
1H NMR (400 MHz, CDCl
3) 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, 10H), 1.52-0.99 (m, 14H), 0.90-0.86 (t, J = 7.4 Hz, 3H), 0.68-0.57 (m, 3H). [0366] Synthesis of 4.13 [0367] To a solution of MePPh
3Br (17.6 g, 49.5 mmol) in THF (30 mL) was added t-BuOK (5.55 g, 49.5 mmol) at 25 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.4.12 (5.5 g, 16.5 mmol) in THF (20 mL) was added in portions to keep the internal temperature of the mixture below 50 °C during the course of the addition. After stirring at 50 °C for 2 h, the reaction mixture was poured into water (300 mL) at 25 °C and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with water (300 mL) and brine (200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0~10% EtOAc in PE) to give 4.13 (6.0 g, 60%).
1H NMR(400 MHz, CDCl3) δH 4.84 (s, 1H), 4.70 (s, 1H), 2.07- 2.00 (m, 1H), 1.86-1.79 (m, 2H), 1.77-1.73 (m, 5H), 1.71-1.64 (m, 3H), 1.64-1.56 (m, 4H),
1.48-1.42 (m, 3H), 1.37-1.31 (m, 3H), 1.27-1.24 (m, 2H), 1.20-1.14 (m, 2H), 1.10-0.97 (m, 3H), 0.91-0.84 (m, 5H), 0.57 (s, 3H). [0368] Synthesis of 4.14 [0369] To a solution of 14.13 (6.0 g, 18.1 mmol) in THF (100 mL) was added 9-BBN dimer (8.76 g, 36.2 mmol) and the resulting mixture was stirred at 50 °C under N2 for 2 h. The mixture was cooled to 0 °C and EtOH (10.3 mL, 181 mmol) and NaOH (54.2 mL, 5 M, 271 mmol) were added. H
2O
2 (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 Na2S2O
3 (500 mL), stirred for 30 min, then extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 4.14 (3.0 g). 4.14 (50 mg, 0.1434 mmol) was purified from MeCN (5 mL) at 25 °C to give 4.14 (29.9 mg, 59.9%).
1H NMR (400 MHz, CDCl3) δH 3.71-3.58 (m, 1H), 3.37-3.34 (m, 1H), 1.96 (td, J = 3.2, 12.4 Hz, 1H), 1.84-1.71 (m, 4H), 1.61-1.57 (m, 6H), 1.50-1.43 (m, 2H), 1.40-1.24 (m, 8H), 1.23-1.15 (m, 3H), 1.11- 0.98 (m, 8H), 0.88 (t, J = 7.4 Hz, 3H), 0.68 (s, 3H). LC-ELSD/MS: purity>99%, MS ESI calcd. for C23H39O [M-H
2O+H]
+ 331.3, found 331.3. [0370] Synthesis of 4.15 [0371] To a solution of 4.14 (1.0 g, 2.86 mmol) in DCM (10 mL) was added DMP (2.42 g, 5.72 mmol) dropwise and the resulting mixture was stirred at 15 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (30 mL) and saturated aqueous Na
2SO
4 (30 mL), then extracted with DCM (3 x 15 mL). The combined organic layers were washed with saturated aqueous Na2S2O
3 (2 x 10 mL) and brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified from PE (20 mL) at 15 °C to give 4.15 (1.1 g, 87%).
1H NMR (400 MHz, CDCl
3) δ
H 9.56-9.55 (d, J = 3.2 Hz, 1H), 2.36-2.33 (m, 1H), 1.94-1.78 (m, 5H), 1.76-1.72 (m, 2H), 1.70-1.55 (m, 8H), 1.45-1.30 (m, 8H), 1.12-1.10 (d, J = 5.2 Hz, 6H), 0.92-0.84 (m, 4H), 0.73-0.69 (m, 3H). [0372] Synthesis of 4 [0373] To a solution of 4.15 (1.0 g, 2.88 mmol) in THF (10 mL) was added CsF (874 mg, 5.76 mmol) at 10 °C under N2. TMSCF
3 (1.22 g, 8.63 mmol) was added dropwise at 10 °C and the mixture was stirred for 1 h. TBAF (2.25 g, 8.63 mmol) was added dropwise at 10 °C and stirred for 2 h. The mixture was poured into water (10 mL), stirred for 20 min, and then extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 4 (130 mg, 10.9%).
1H NMR (400 MHz, CDCl3) δ
H 4.08-3.97 (m, 1H), 2.14-2.12 (d, J = 6.4 Hz, 1H), 1.96-1.95
(m, 1H), 1.92-1.68 (m, 5H), 1.67-1.57 (m, 4H), 1.54 (s, 3H), 1.49-1.42 (m, 3H), 1.34-1.20 (m, 7H), 1.15-0.98 (m, 8H), 0.88-0.86 (t, J = 7.8 Hz, 3H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -72.207. LC-ELSD/MS: purity>99%, MS ESI calcd. for C24H37F
3O [M- H
2O+H]
+ 399.2, found 399.2. [0374] Example 5: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (5)
[0375] To a suspension of 3.4 (300 mg, 0.7490 mmol) in anhydrous THF (10 mL) under N2 was slowly added (tBuO)
3AlLiH (378 mg, 1.49 mmol) at 0 °C and the resulting mixture was stirred under N
2 for 2 h. The mixture was poured into 10% aqueous NH
4Cl (20 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 5/1 to 3/1) twice to afford 5 (11.8 mg, 11.8 %).
1H NMR (400 MHz, CDCl3) δH 4.08-3.98 (m, 1H), 3.70-3.55 (m, 1H), 2.12 (d, J = 6.0 Hz, 1H), 2.02-1.94 (m, 1H), 1.94-1.57 (m, 7H), 1.52-1.21 (m, 13H), 1.18-1.04 (m, 6H), 1.03-0.94 (m, 1H), 0.92 (s, 3H), 0.67 (s, 3H). LC- ELSD/MS purity 99%, MS ESI calcd. For C23H38F
3O
2 [M-H
2O+H]
+ 385, found 385. [0376] Example 6: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-(methoxymethyl)- 10,13-dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (6)
[0377] Synthesis of 6.1 [0378] To a solution of Me
3SI (607 mg, 2.98 mmol) in THF (10 mL) and DMSO (5 mL) was added NaH (119 mg, 60%, 2.98 mmol) at 0 °C in portions under N2, followed by addition of a solution of 3.4 (1 g, 2.49 mmol) in DMSO (5 mL). The reaction mixture was poured into ice-water (w/w = 1/1, 500 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 6.1 (1 g, 97.0 %).
1H NMR (400 MHz, CDCl
3) δ
H 4.09-3.97 (m, 1H), 2.62 (s, 1H), 2.58 (s, 1H), 2.42-2.31 (m, 1H), 2.03-1.49 (m, 14H), 1.32 (s, 7H), 1.10 (br d, J = 1.8 Hz, 6H), 0.99 (d, J = 8.0 Hz, 3H), 0.68 (d, J = 2.5 Hz, 3H).
19F NMR (376.5 MHz, CDCl3) δF -72.175. [0379] Synthesis of 6 [0380] To a mixture of sodium methoxide (777 mg, 14.4 mmol) in MeOH (20 mL) was slowly added 6.1 (1 g, 2.41 mmol) and the resulting mixture was stirred at 75 °C for 36 h. The reaction mixture was poured into ice-water (w/w = 1/1, 30 mL) and stirred for 20 min. The mixture was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 5/1 to 4/1). The resulting residue was further purified from DCM:n-hexane (2:1, 4 ml) at 60 °C for 20 min to give 6 (39.5 mg, 39.5%).
1H NMR (400 MHz, CDCl3) δH 4.09-3.97 (m, 1H), 3.45-3.30 (m, 5H), 2.56 (s, 1H), 2.23-2.15 (m, 1H), 2.01-1.76 (m, 5H), 1.71 (td, J = 3.2, 14.4 Hz, 1H), 1.63 (dd, J
= 4.8, 8.4 Hz, 1H), 1.55-1.19 (m, 13H), 1.18-1.04 (m, 6H), 1.02-0.95 (m, 1H), 0.93 (s, 3H), 0.66 (s, 3H). LC-ELSD/MS purity 100%, MS ESI calcd. for C24H36F
3O [M-CH
3OH- H
2O+H]
+ 397.3, found 397.3. [0381] Example 7: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol
[0382] A solution of MeMgBr (2.2 mL, 6.63 mmol, 3 M in Et
2O) in THF (2 mL) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into saturated aqueous NH4Cl (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 7 (50 mg).
1H NMR (400 MHz, CDCl3) δH 4.00-3.80 (m, 1H), 2.00-1.70 (m, 6H), 1.69-1.25 (m, 12H), 1.24-1.01 (m, 11H), 1.00-0.78 (m, 11H), 0.66 (s, 3H). LC-ELSD/MS purity >99%, MS ESI calcd. for C
25H
41 [M-2H
2O+H] 341, found 341. [0383] Example 8: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)-3- hydroxypentan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol
[0384] A solution of EtMgBr (2.2 mL, 6.63 mmol, 3 M in Et
2O) in THF (2 mL) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into saturated aqueous NH4Cl (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 8 (57.5 mg, 5.79 %).
1H NMR (400 MHz, CDCl
3) 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), 1.32-1.02 (m, 10H), 1.01-0.85 (m, 6H), 0.84-0.73 (m, 9H), 0.66 (s, 3H). LC-ELSD/MS purity >99%, MS ESI calcd. for C
26H
43 [M-2H
2O+H]
+ 355.4, found 355.4. [0385] Example 9: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)-3- hydroxy-5-methylhexan-2-yl)-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (9)
[0386] A solution of i-BuMgBr (3.31 mL, 2.0 M in THF, 6.63 mmol) in THF (2 mL) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into saturated aqueous NH4Cl (10 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE) to give 9 (60 mg, 6.5%).
1H NMR (400 MHz, CDCl
3) 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, 13H), 1.27-1.18 (m, 12H), 1.17-1.01 (m, 13H), 0.74-0.60 (m, 4H). LC-ELSD/MS purity >99%, MS ESI calcd. for C28H47 [M-2H
2O+H]
+ 383, found 383.
[0387] Example 10: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1R,2S)-1- cyclopropyl-1-hydroxypropan-2-yl)-3-ethyl-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (10)
[0388] Synthesis of 10.1 [0389] A solution of cyclopropylmagnesium bromide (22.0 mL, 11 mmol, 0.5 M in THF) was reacted with a solution of 2.2 (800 mg, 2.21 mmol) in THF (8 mL) at 0 °C and the resulting mixture was stirred for 0.5 h. The mixture was poured into saturated aqueous NH4Cl (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~35% EtOAc in PE) to give 10.1 (500 mg, 56.2%).
1H NMR (400 MHz, CDCl
3) 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] Synthesis of 10.2 [0391] To a solution of 10.1 (400 mg, 0.993 mmol) in DCM (5 mL) was added DMP (839 mg, 1.98 mmol) and the resulting mixture was stirred at 25 °C for 30 min. The mixture was quenched with saturated aqueous NaHCO
3:Na
2S
2O
3 (v:v = 1:1, 12 mL) and the mixture was extracted with DCM (2 x 12 mL). The combined organic layers were washed with saturated aqueous NaHCO
3:Na2S2O
3 (v:v = 1:1, 12 mL) and brine (12 mL), dried over anhydrous
Na
2SO
4, filtered, and concentrated to give 10.2 (450 mg).
1H NMR (400 MHz, CDCl
3) δ
H 2.64-2.53 (m, 1H), 2.00-1.77 (m, 5H), 1.74-1.52 (m, 7H), 1.48-1.24 (m, 10H), 1.17 (d, J = 6.8 Hz, 3H), 1.15-0.94 (m, 7H), 0.93 (s, 3H), 0.89-0.81 (m, 5H), 0.68 (s, 3H). [0392] Synthesis of 10 [0393] To a solution of 10.2 (450 mg, 1.12 mmol) in THF (5 mL) was added LiAlH4 (127 mg, 3.36 mmol) at 0 °C under N2 and the resulting mixture was stirred for 30 min. The mixture was poured into water (8 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3 x 8 mL), and the combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 10 (40 mg).10 (40 mg, 0.099 mmol) was dried in an oven at 80 °C to afford 10 (38.2 mg, 95.7 %).
1H NMR (400 MHz, CDCl
3) 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%, MS ESI calcd. for C27H43 [M-2H
2O+H]
+ 367, found 367. [0394] Example 11: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)- 3-hydroxyheptan-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3- ol (11)
[0395] A solution of 2.2 (1 g, 2.77 mmol) in THF (10 mL) was reacted with a solution of n- BuMgBr (6.47 mL, 16.2 mmol, 2.5 M in hexanes) at 0 °C and the resulting mixture was stirred for 15 min. The mixture was poured into H
2O (30 mL) and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~50% EtOAc in PE), further purified by flash silica gel chromatography (0~20% EtOAc in PE), and dried in an oven at 80 °C to give 11 (93.6 mg, 93.6%).
1H NMR (400 MHz, CDCl
3) 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 (m, 9H), 1.17-1.05 (m, 5H), 1.04-0.95 (m, 5H), 0.94-0.75 (m, 8H), 0.66 (s, 3H). LC-ELSD/MS purity >99%, MS ESI calcd. for C28H47 [M-2H
2O+H] 383, found 383. [0396] Example 12: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)- 3-hydroxy-6-methylheptan-2-yl)-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (12)
[0397] A solution of 2.2 (1 g, 2.77 mmol) in THF (10 mL) was reacted with isoamylmagnesium bromide (4.15 mL, 8.30 mmol, 2 M in Et
2O) at 0 °C under N
2 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 x 10 mL) and the combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 12 (12.2 mg, 1.02 %).
1H NMR (400 MHz, CDCl
3) 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), 1.27-1.03 (m, 10H), 1.02-0.95 (m, 7H), 0.94-0.78 (m, 9H), 0.66 (s, 3H). LC-ELSD/MS purity >99%, MS ESI calcd. for C29H49 [M-2H
2O+H]
+ 397, found 397. [0398] Example 13: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (13)
[0399] To a solution of 3.4 (400 mg, 0.9986 mmol) in THF (10 mL) was added CsF (302 mg, 1.99 mmol) at 10 °C under N
2, followed by addition of TMSCF
3 (425 mg, 2.99 mmol)
dropwise at 10 °C. After stirring at 10 °C for 1 h, TBAF (781 mg, 2.99 mmol, 1 M in THF) was added dropwise at 20 °C. After stirring at 20 °C for 2 h, the mixture was poured into water (10 mL) and stirred for 20 min. The mixture was extracted with EtOAc (2 x 20 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 13 (120 mg), which was purified by HPLC (column: C18 (250mm*50mm, 5um), gradient: 65-95% B (B=water (0.05%HCl)-MeCN), flow rate: 30mL/min) to give 13 (19 mg, 15.9%).
1H NMR (400 MHz, CDCl
3) 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).
19F NMR (376.5 MHz, CDCl3) δF -72.208, -78.789. [0400] Example 14: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-13-ethyl-3,10- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (14)
[0401] Synthesis of 14.2 [0402] To a solution of compound 14.1 (5.0 g, 15.9 mmol) in 3-picoline (50 mL) was added 5% Pd/C (0.5 g). The flask was evacuated and flushed with hydrogen and the reaction was stirred at 30 °C for 15 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% EtOAc in PE) to give 14.2 (3.2 g, 64 %).
1H NMR: (400 MHz, CDCl3) δH
2.69 (t, J = 13.6 Hz, 1H), 2.55 (t, J = 8.8 Hz, 1H), 2.34 (dt, J
1 =13.6, J
2 = 4.8 Hz, 1H), 2.25-2.00 (m, 8H), 1.95-1.80 (m, 2H), 1.75-1.63 (m, 2H), 1.58-1.63 (m, 7H), 1.28-1.08 (m, 4H), 1.02 (s, 3H), 0.63 (s, 3H). [0403] Synthesis of 14.3 [0404] To a solution of 14.2 (2 g, 6.31 mmol) in THF (20 mL) was added LiAlH(OtBu)
3 (1.76, 6.94 mmol) at -40 °C under N2 and stirred for 1 h. The mixture was poured into water (200 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 300 mL), and the combined organic layers were washed with saturated aqueous citric acid (300 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE) to give 14.3 (2.3 g).
1H NMR (400 MHz, CDCl3) δH
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 = 2.4 Hz, 2H), 0.61-0.58 (m, 3H). [0405] Synthesis of 14.4 [0406] To a solution of 14.3 (5.2 g, 16.3 mmol) in DCM (20 mL) was added TBSCl (3.67 g, 24.4 mmol) and imidazole (2.21 mg, 32.6 mmol) at 20 °C under N2 and the resulting mixture was stirred at 40 °C for 12 h. The reaction mixture was diluted with H
2O (20 mL) and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 14.4 (7.0 g, 99%).
1H NMR (400 MHz, CDCl
3) δ
H 3.64-3.56 (m, 1H), 2.52 (br t, J = 8.8 Hz, 1H), 2.15 (br d, J = 11.2 Hz, 1H), 2.11 (s, 3H), 2.03-1.95 (m, 1H), 1.87-1.73 (m, 3H), 1.69-1.63 (m, 2H), 1.49-1.34 (m, 9H), 1.27-1.13 (m, 6H), 0.90-0.89 (m, 12H), 0.58 (s, 3H), 0.06 (s, 6H). [0407] Synthesis of 14.5 [0408] To a solution of (R)-CBS (892 mg, 3.22 mmol) in toluene (50 mL) was added a solution of BH
3∙SMe
2 (3.22 mL, 32.2 mmol) and the resulting mixture was stirred at 0°C for 30 min under N2. To the mixture was added a solution of 14.4 (7 g, 16.1 mmol) in toluene (50 mL) dropwise at 0 °C and the mixture was stirred for 1 h. The mixture was quenched with the dropwise addition of MeOH (20 mL) and concentrated. The product was purified by silica gel chromatography (2~7% EtOAc in PE) to give 14.5 (4.02 g, 57.5%).
1H NMR (400 MHz, CDCl3) δH 3.69 (qd, J = 6.0, 12.8 Hz, 1H), 3.62-3.50 (m, 1H), 1.95-1.70 (m, 5H), 1.68-1.29 (m, 12H), 1.23-1.06 (m, 10H), 0.92-0.86 (m, 12H), 0.63 (s, 3H), 0.09-0.01 (m, 6H). [0409] Synthesis of 14.6 [0410] To a solution of 14.5 (2 g, 4.60 mmol) in cyclohexane (200 mL) was added CaCO
3 (1.37 g, 13.7 mmol), PhI(OAc)
2 (4.41 g, 13.7 mmol), and I2 (1.37 g, 9.20 mmol) at 25 °C under N
2. The mixture was heated to reflux (80 °C) by irradiating with an infrared lamp (250 W) for 30 min. The mixture was quenched with saturated aqueous Na2S2O
3 (200 mL), and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 14.6 (3 g). [0411] Synthesis of 14.7 [0412] To a solution of MePh3PBr (6.53 g, 18.3 mmol) in THF (30 mL) was added t-BuOK (2.05 g, 18.3 mmol) at 25 °C. The temperature was increased to 50 °C and the mixture 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 extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The mixture was combined with another batch of a reaction mixture obtained using similar conditions (3 g of 14.6 starting material). The residue was purified by silica gel chromatography (0~25% EtOAc in PE) to give 14.7 (6 g).
1H NMR (400 MHz, CDCl
3) δ
H 5.79-5.72 (dd, J = 11.2, 17.7 Hz, 1H), 5.30-5.27 (dd, J = 1.4, 11.3 Hz, 1H), 5.16-5.11 (dd, J = 1.6, 18.0 Hz, 1H), 3.91-3.77 (m, 1H), 3.64-3.49 (m, 1H), 2.36-2.32 (td, J = 3.2, 13.1 Hz, 1H), 1.88-1.66 (m, 7H), 1.57 (s, 3H), 1.49-1.26 (m, 10H), 1.12 -1.10 (d, J = 6.4 Hz, 5H), 0.97-0.86 (m, 10H), 0.81 (s, 3H), 0.05 (s, 6H). [0413] Synthesis of 14.8 [0414] To a solution of 14.7 (3.5 g, 7.83 mmol) in THF (50 mL) was added Pd/C (500 mg, 10% palladium on carbon, 50% water wet) and the solution was hydrogenated under 15 psi of hydrogen at 20 °C for 16 h. The mixture was filtered through a pad of Celite, and the filter cake was washed with THF (3 x 50 mL). The filtrate was concentrated under reduced pressure to give 14.8 (3.5 g).
1H NMR (400 MHz, CDCl
3) δ
H 3.82 (s, 1H), 3.63-3.52 (m, 1H), 2.11 (d, J = 12.4 Hz, 1H), 1.91-1.72 (m, 7H), 1.62-1.53 (m, 5H), 1.48-1.31 (m, 8H), 1.28-1.21 (m, 6H), 1.14-1.07 (m, 2H), 0.89 (s, 12H), 0.86-0.81 (m, 3H), 0.06 (s, 6H). [0415] Synthesis of 14.9 [0416] To a solution of 14.8 (300 mg, 0.672 mmol) in THF (10 mL) was added TBAF∙3H
2O (634 mg, 2.01 mmol) in one portion at 20 °C and the resulting mixture was stirred for 17 h. The mixture was poured into water (50 mL) and DCM (100 mL), and the layers were separated. The aqueous phase was extracted with DCM (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified from methanol (100 mL) at 20 °C to give 14.9 (190 mg, 85%). [0417] Synthesis of 14.10 [0418] To a solution of 14.9 (3.5 g, 10.4 mmol) in DCM (50 mL) was added DMP (13.2 g, 31.2 mmol) and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (100 mL) and saturated aqueous Na
2S
2O
3 (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with saturated aqueous Na2S2O
3 (2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 14.10, which was purified by flash silica gel chromatography (0~30% EtOAc in PE) to give 14.10 (1.9 g, 55.3%).
1H NMR
(400 MHz, CDCl
3) δ
H 2.75-2.63 (m, 1H), 2.48 (t, J = 8.8 Hz, 1H), 2.40-2.23 (m, 3H), 2.21 (s, 4H), 2.09-2.00 (m, 2H), 1.93-1.80 (m, 2H), 1.70-1.47 (m, 7H), 1.43-1.20 (m, 8H), 1.01 (s, 3H), 0.65 (t, J = 7.2 Hz, 3H). [0419] Synthesis of 14.11 [0420] To a MAD (6.53 g, 13.6 mmol) solution was added a solution of 14.10 (1.8 g, 5.44 mmol) in DCM (20 mL) dropwise slowly at -70 °C under N2. After stirring at -70 °C for 1 h under N
2, MeMgBr (3.6 mL, 10.8 mmol) was added dropwise slowly. After stirring for 2 h, the reaction mixture was poured slowly into saturated aqueous citric acid (100 mL) at 10 °C and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~30% EtOAc in PE) to give 14.11 (1.1 g, 58.5%).
1H NMR (400 MHz, CDCl3) δH
2.45 (t, J = 8.8 Hz, 1H), 2.35-2.25 (m, 1H), 2.24-2.16 (m, 4H), 2.03-1.79 (m, 2H), 1.74 (td, J = 3.2, 14.4 Hz, 1H), 1.66-1.59 (m, 3H), 1.56-1.35 (m, 8H), 1.32-1.21 (m, 9H), 1.10-1.00 (m, 3H), 0.93 (s, 3H), 0.62 (t, J = 7.5 Hz, 3H). LC-ELSD/MS purity > 99%, MS ESI calcd. for C23H37O [M-H
2O+H]
+ 329.3, found 329.3. [0421] Synthesis of 14.12 [0422] To a solution of MePh3PBr (1.53 g, 4.31 mmol) in THF (10 mL) was added t-BuOK (482 mg, 4.31 mmol) at 25 °C. The temperature was increased to 50 °C and the mixture was stirred for 1 h. A solution of 14.11 (0.5 g, 1.44 mmol) in THF (10 mL) was added to the reaction mixture at 50 °C and the mixture was stirred for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The mixture was combined with another batch of a reaction mixture obtained using similar conditions (1.53 g of 14.11 starting material). The residue was purified by flash silica gel chromatography (10~20% EtOAc in PE) to give 14.12 (890 mg).
1H NMR (400 MHz, CDCl
3) δ
H 4.80 (s, 1H), 4.77 (s, 1H), 2.22 (dd, J = 3.2, 9.2 Hz, 1H), 2.01-1.92 (m, 2H), 1.90-1.86 (m, 1H), 1.81 (s, 3H), 1.74 (td, J = 3.6, 14.2 Hz, 1H), 1.67- 1.60 (m, 2H), 1.56 (s, 3H), 1.43 (s, 3H), 1.38-1.35 (m, 1H), 1.26 (s, 4H), 1.23-1.12 (m, 5H), 1.06-0.99 (m, 3H), 0.93 (s, 3H), 0.90-0.82 (m, 3H), 0.74 (t, J = 7.2 Hz, 3H). LC-ELSD/MS purity >99%, MS ESI calcd. for C
24H
39 [M-H
2O+H]
+ 327.3 found 327.3. [0423] Synthesis of 14.13 [0424] To a solution of 14.12 (0.85 g, 2.46 mmol) in THF (20 mL) was added 9-BBN dimer (1.19 g, 4.92 mmol) in portions slowly under N
2. The reaction mixture was stirred at 50
°C under N
2 for 2 h. After cooling to 0 °C, the reaction mixture was quenched with EtOH (1.41 mL, 24.6 mmol) and NaOH (7.38 mL, 36.9 mmol, 5 M in H
2O) dropwise slowly under N2, followed by addition of H
2O
2 (3.69 mL, 36.9 mmol, 10 M in H
2O) dropwise slowly under N
2 at 15 °C. The mixture was stirred at 50 °C for 2 h, cooled, and poured into saturated aqueous Na2S2O
3 (100 mL) slowly and stirred for 30 min. The aqueous phase was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 14.13 (690 mg, 77.4%).
1H NMR (400 MHz, CDCl3) δH 3.68-3.60 (m, 1H), 3.42-3.31 (m, 1H), 2.25 (br d, J = 12.5 Hz, 1H), 2.01-1.62 (m, 6H), 1.56-1.48 (m, 3H), 1.45-1.34 (m, 7H), 1.33-1.14 (m, 9H), 1.10 (br d, J = 6.5 Hz, 8H), 0.96-0.87 (m, 6H). LC-ELSD/MS purity>99%, MS ESI calcd. for C
24H
41O [M-H
2O+H]
+ 345.3, found 345.3. [0425] Synthesis of 14.14 [0426] To a solution of 14.13 (580 mg, 1.59 mmol) in DCM (5 mL) was added DMP (1.34 g, 3.18 mmol) and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (100 mL) and saturated aqueous Na2S2O
3 (100 mL). The aqueous layer was extracted with DCM (2 x 100 mL) and the combined organic layers were washed with saturated aqueous Na
2S
2O
3 (2 x 100 mL) and brine (2 x 100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 14.14, which was purified from PE (50 mL) at 25 °C to give 14.14 (650 mg).
1H NMR (400 MHz, CDCl
3) δ
H 9.47 (d, J = 4.0 Hz, 1H), 2.42 (ddd, J = 4.0, 6.6, 10.4 Hz, 1H), 2.22 (dd, J = 3.2, 9.2 Hz, 1H), 2.03-1.68 (m, 6H), 1.63-1.53 (m, 5H), 1.43-1.40 (m, 3H), 1.26 (s, 5H), 1.20- 1.15 (m, 4H), 1.07 (dd, J = 3.6, 14.8 Hz, 7H), 0.95-0.86 (m, 7H). [0427] Synthesis of 14 [0428] To a solution of 14.14 (650 mg, 1.80 mmol) in THF (10 mL) was added CsF (546 mg, 3.60 mmol) at 10 °C under N2. TMSCF
3 (767 mg, 5.40 mmol) was added dropwise at 10 °C and the mixture was stirred for 1 h. TBAF (1.41 g, 8.63 mmol, 1 M in THF) was added dropwise at 20 °C and the mixture was stirred at 10 °C for 2 h. The mixture was poured into water (10 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 20 mL), and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 14 (105 mg, 13.5%).
1H NMR (400 MHz, CDCl
3) δ
H 4.13-4.05 (m, 1H), 2.28-2.19 (m, 2H), 2.06-1.69 (m, 5H), 1.58 (s, 7H), 1.46-1.34 (m, 9H), 1.25 (s, 4H), 1.17-1.02 (m, 9H), 0.92-0.82 (m, 4H).
19F NMR (376.5 MHz, CDCl3) δF -72.256. LC-ELSD/MS purity >99%, MS ESI calcd. for C25H40F
3O [M- H
2O+H]
+ 413.3, found 413.3.
[0429] Example 15: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-(hydroxymethyl)- 10,13-dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (15)
[0430] Synthesis of 15.1 [0431] Sodium metal (441 mg, 19.2 mmol) was slowly added to anhydrous BnOH (5 ml) in portions and the resulting mixture was stirred at 80 °C for 4 h. A solution of 6.1 (400 mg, 0.9648 mmol) was added in portions and the mixture was stirred at 80 °C under N2 for 16 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure. BnOH was removed by reduced pressure distillation. The residue was purified by silica gel chromatography (PE/EtOAc = 50/1 to 5/1). The resulting residue was further purified by SFC (column: C18 (250mm*50mm, 5um), gradient: 65-95% B (B=water (0.05%HCl)-ACN), flow rate: 30mL/min) to give 15.1 (40 mg, 15.0%).
1H NMR (400 MHz, CDCl3) δH 7.43-7.28 (m, 5H), 4.56 (s, 2H), 4.12-3.96 (m, 1H), 3.56-3.39 (m, 2H), 2.63 (s, 1H), 2.10-1.98 (m, 1H), 2.01-1.76 (m, 5H), 1.70-1.59 (m, 3H), 1.53-1.19 (m, 12H), 1.15-1.03 (m, 6H), 0.94-0.85 (m, 4H), 0.66 (s, 3H). [0432] Synthesis of 15 [0433] To a solution of 15.1 (20 mg, 0.07652 mmol) in MeOH (3 mL) was added Pd/C (dry, 10%, 20 mg) under N
2. The suspension was degassed under vacuum and purged with H
2 three times. After stirring at 25 °C under H
2 (15 psi) for 24 h, the reaction mixture was
filtered through a pad of Celite, washed with EtOAc (3 x 10 mL) and the filtrate concentrated. The residue was purified by silica gel chromatography (10~20% EtOAc in PE) to afford 15 (29 mg, 87.6%).
1H NMR (400 MHz, CDCl3) δH 4.12-3.94 (m, 1H), 3.66-3.56 (m, 2H), 2.23-2.19 (m, 1H), 1.98-1.68 (m, 8H), 1.52-1.33 (m, 9H), 1.28-0.89 (m, 15H), 0.67 (s, 3H).LC-ELSD/MS purity 99%, MS ESI calcd. for C24H35F
3O [M+H-2H
2O]+ 397.3, found 397.3.
19F NMR (376.5 MHz, CDCl3) δF -72.207. [0434] Example 16: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-isopropyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (16)
[0435] Synthesis of 16.1 [0436] A solution of isopropenylmagnesium bromide (90.0 mL, 45.0 mmol, 0.5 M in THF) was reacted with 1.2 (5 g, 15.0 mmol) at 0 °C under N2 and the resulting solution was stirred at 50 °C for 2 h. The mixture was slowly poured into ice-water (20 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and
concentrated to give 16.1a (1.2 g, 21.3%) and 16.1 (800 mg, 14.2%).
1H NMR (400 MHz, CDCl3) δH 5.01 (d, J = 4.8 Hz, 2H), 3.64 (d, J = 10.4 Hz, 1H), 3.36 (br s, 1H), 2.05-1.93 (m, 2H), 1.92-1.73 (m, 6H), 1.71-1.58 (m, 3H), 1.55-1.49 (m, 2H), 1.48-1.12 (m, 13H), 1.10-0.97 (m, 6H), 0.95-0.86 (m, 3H), 0.71-0.62 (m, 3H). [0437] Synthesis of 16.2 [0438] To a solution of 16.1 (800 mg, 0.7474 mmol) in THF (5 mL) was added 10% Pd/C (0.8 g, dry). The suspension was degassed under vacuum and purged with H
2 three times. After stirring under H
2 (15 psi) at 15 °C for 16 h, the reaction mixture was filtered through a pad of Celite and washed with MeOH (3 x 20 mL). The filtrate was concentrated to give 16.2 (650 mg).
1H NMR (400 MHz, CDCl
3) δ
H 3.64 (dd, J = 3.2, 10.4 Hz, 1H), 3.35 (dd, J = 7.2, 10.6 Hz, 1H), 2.11-1.93 (m, 2H), 1.88-1.74 (m, 3H), 1.71-1.63 (m, 2H), 1.56 (s, 6H), 1.50- 1.32 (m, 7H), 1.29-1.13 (m, 7H), 1.09-1.01 (m, 6H), 0.93 (s, 2H), 0.88 (d, J = 6.8 Hz, 4H), 0.66 (s, 3H). [0439] Synthesis of 16.3 [0440] To a suspension of 16.2 (450 mg, 0.398 mmol) in anhydrous DCM (5 mL) was added DMP (337 mg, 0.7964 mmol) at 20 °C under N2 and the resulting mixture was stirred for 30 min. The mixture was poured into a mixture of10% aqueous NaHCO
3 (20 mL) and saturated aqueous Na2S2O
3 (20 mL), stirred for 10 min, and extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), filtered, and concentrated to give 16.3 (300 mg). The residue was purified by silica gel chromatography (PE/EtOAc =2/1 to 1/2) to give 16.3 (300 mg, 67.1 %).
1H NMR (400 MHz, CDCl
3) δ
H 9.56 (d, J = 3.6 Hz, 1H), 2.35 (tdd, J = 3.6, 6.8, 10.2 Hz, 1H), 1.96-1.74 (m, 5H), 1.71-1.61 (m, 3H), 1.51-1.33 (m, 10H), 1.26 (t, J = 7.2 Hz, 5H), 1.11 (d, J = 6.8 Hz, 6H), 0.94 (s, 3H), 0.88 (d, J = 6.8 Hz, 5H), 0.69 (s, 3H). [0441] Synthesis of 16 [0442] To a solution of 16.3 (300 mg, 0.8008 mmol) in THF (10 mL) was added CsF (60.8 mg, 0.40 mmol) at 0 °C, and then TMSCF
3 (227 mg, 1.60 mmol) was added slowly. After stirring at 25 °C for 1 h, TBAF (1.26 g, 4.00 mmol, 1 M in THF) was added, and the mixture was stirred for 1 h. The mixture was quenched with 10% aqueous NH4Cl (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (400 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (15~20% EtOAc in PE) to give 16 (50 mg, 14.0%). 16 (40 mg, 0.045 mmol) was further purified from DCM:n-hexane (1:2, 5 mL) at 60 °C for 20 min to give 16 (17.8 mg, 89.4%).
1H NMR (400 MHz, CDCl
3) δ
H 4.14-
3.96 (m, 1H), 2.16 (d, J = 6.0 Hz, 1H), 2.10-1.95 (m, 2H), 1.94-1.72 (m, 4H), 1.71-1.59 (m, 3H), 1.53-1.28 (m, 9H), 1.26-0.98 (m, 11H), 0.93 (s, 3H), 0.88 (d, J = 6.8 Hz, 6H), 0.67 (s, 3H). LC-ELSD/MS purity 100%, MS ESI calcd. for C26H44F
3O
2 [M-H
2O+H]
+ 427, found 427. [0443] Example 17: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17S)-3,10,13-trimethyl-17- ((S)-4,4,4-trifluoro-3-hydroxy-2-methylbutan-2-yl)hexadecahydro-1H-
[0444] Synthesis of 17.2 [0445] To a solution of 17.1 (100 g, 315 mmol) in DCM (1 L) was added imidazole (32.1 g, 472 mmol) and TBSCl (52.2 g, 346 mmol) and the resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with water (2 x 1000 mL) and the DCM layer was separated. The organic layer was dried over anhydrous Na
2SO
4, filtered, and concentrated to give 17.2 (150 g, 95%).
1H NMR (400 MHz, CDCl3) δH 5.37-5.25 (m, 1H), 3.57-3.41 (m, 1H), 2.53 (t, J = 8.8 Hz, 1H), 2.32-2.15 (m, 3H), 2.12 (s, 3H), 2.07-1.96 (m, 2H), 1.82 (td, J = 3.6, 13.2 Hz, 1H), 1.73-1.59 (m, 4H), 1.50-1.42 (m, 3H), 1.29-1.04 (m, 3H), 1.00 (s, 3H), 0.91-0.91 (m, 3H), 0.90-0.86 (m, 9H), 0.63 (s, 3H), 0.06 (s, 6H). [0446] Synthesis of 17.3 [0447] To a mixture of t-BuOH (300 mL) and t-BuOK (38.9 g, 347 mmol) underN
2 was added 17.2 (30 g, 69.6 mmol) in DME (150 mL) and the mixture was stirred for 30 min. TosMic (27.0 g, 139 mmol) in DME (150 mL) was added and the mixture was stirred at 25 °C for 16 h. Water (100 mL) was added, the resulting mixture was stirred, and then extracted with EtOAc (2 x 1 L). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified from MeCN (500 mL) at 25 °C to give 17.3 (123 g, 56%).
1H NMR (400 MHz, CDCl
3) 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), 1.37-1.27 (m, 3H), 1.26-1.03 (m, 4H), 1.02-0.99 (m, 3H), 0.98-0.92 (m, 1H), 0.89 (s, 9H), 0.77-0.71 (m, 3H), 0.06 (s, 6H).
[0448] Synthesis of 17.4 [0449] A solution of 17.3 (20 g, 45.2 mmol) in THF (200 mL) was added to LDA (113 mL, 2 M, 226 mmol) and the resulting mixture was stirred at -70 °C under N2 for 1 h. Methyl iodide (32.0 g, 226 mmol) was added and the reaction mixture was stirred for 16 h. The mixture was warmed to 25 °C, quenched with ammonium chloride (200 mL, sat. aq.), and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated to give 17.4 (21 g).
1H NMR (400 MHz, CDCl
3) δ
H 5.31 (br d, J = 5.2 Hz, 1H), 3.54-3.41 (m, 1H), 2.65-2.37 (m, 1H), 2.31-2.13 (m, 2H), 2.08-1.88 (m, 3H), 1.83-1.64 (m, 5H), 1.59-1.49 (m, 5H), 1.44 (s, 3H), 1.34 (s, 2H), 1.31-1.16 (m, 3H), 1.06-0.98 (m, 5H), 0.95 (s, 3H), 0.89 (s, 9H), 0.05 (s, 6H). [0450] Synthesis of 17.5 [0451] To a solution of 17.4 (1 g, 2.19 mmol) in DCM (40 mL) was added DIBAL-H (1 M in toluene, 10.9 mL, 10.9 mmol) slowly at -70 °C and the resulting mixture was stirred for 30 min. The mixture was warmed to 25 °C and stirred for 1.5 h. The mixture was carefully poured into HCl (50 mL, 3 M in water) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous NaHCO
3 (2 x 100 mL), brine (2 x 100 mL), dried over Na
2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~15% EtOAc in PE) to give 17.5 (170 mg, 23%).
1H NMR (400 MHz, CDCl3) δH 9.64 (s, 1H), 5.39-5.28 (m, 1H), 3.54-3.48 (m, 1H), 2.35-2.16 (m, 2H), 2.02-1.80 (m, 4H), 1.78-1.62 (m, 4H), 1.53-1.34 (m, 6H), 1.21-1.14 (m, 1H), 1.10 (d, J = 6.8 Hz, 7H), 1.08-1.00 (m, 2H), 0.99 (s, 3H), 0.96-0.87 (m, 1H), 0.70 (s, 3H). [0452] Synthesis of 17.6 [0453] To a solution of 17.5 (170 mg, 0.493 mmol) in THF (10 mL) was added CsF (74.9 mg, 0.493 mmol) and TMSCF
3 (210 mg, 1.48 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 3 h. TBAF (4.93 mL, 1 M in THF) was added and the mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~20% of EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD(250mm*30mm,10um); Condition: 0.1%NH3H
2O IPA; Gradient: from 30% to 30% of B; Flow rate: 65 mL/min; Injections: 60) to give 17.6 (28.6 mg, 29%).
17.6:
1H NMR (400 MHz, CDCl
3) 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 = 6.4 Hz, 1H), 2.03-1.91 (m, 2H), 1.89-1.76 (m, 3H), 1.71- 1.61 (m, 3H), 1.53-1.35 (m, 7H), 1.14-1.04 (m, J = 1.8 Hz, 5H), 1.03-0.98 (m, 6H), 0.97-0.88 (m, 2H), 0.80 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -70.174. LC-ELSD/MS purity 99%, MS ESI calcd. for C24H36F
3O [M+H-H
2O]
+ 397.3, found 397.3. [0454] Synthesis of 17.7 [0455] To a solution of 17.6 (60 g, 144 mmol) in DCM (600 mL) was added TBSCl (32.5 g, 216 mmol) and imidazole (19.6 g, 288 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The reaction was quenched with water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure to give 17.7 (80 g).
1H NMR (400MHz, CDCl
3) 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), 1.17-1.07 (m, 4H), 1.03-0.97 (m, 5H), 0.96-0.87 (m, 15H), 0.86-0.76 (m, 4H), 0.09 (s, 3H), 0.05 (s, 6H).
19F NMR (376.5 MHz, CDCl
3) δ
F -69.943, -70.137. [0456] Synthesis of 17.8 [0457] To a solution of 17.7 (80 g, 151 mmol) in THF (1 L) was added NaH (12.0 g, 302 mmol, 60%) and the resulting mixture was stirred at 25 °C for 30 min. PMBCl (30.5 g, 196 mmol) was added under N2 and the mixture was stirred at 70 °C for 16 h. The mixture was slowly poured into 10% aqueous NH4Cl (600 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 17.8 (100 g). [0458] Synthesis of 17.9 [0459] To a solution of 17.8 (100 g) in THF (800 mL) was added TBAF (308 mL, 1 M in THF) at 25 °C and the resulting mixture was stirred at 60 °C for 16 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL), washed with water (2 x 800 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The product was purified by flash silica gel chromatography (20%~25% EtOAc in PE) to give 17.9 (59 g, 72%).
1H NMR (400MHz, CDCl3): δH 7.32-7.28 (m, 2H), 6.92-6.88 (m, 2H), 5.38-5.30 (m, 1H), 4.88-4.72 (m, 1H), 4.62 (s, 2H), 4.53-4.40 (m, 1H), 3.81 (s, 3H), 3.53-3.44 (m, 1H), 2.33-2.18 (m, 2H), 2.01-1.92 (m, 1H), 1.88-1.80 (m, 2H), 1.70-1.61 (m, 2H), 1.59-1.39 (m, 10H), 1.15-0.98 (m, 10H), 0.97-0.86 (m, 2H), 0.85-0.75 (m, 3H).
19F NMR (376.5 MHz, CDCl3) δF -66.801, -67.307.
[0460] Synthesis of 17.10 [0461] To a mixture of 17.9 (5 g, 9.35 mmol) in toluene (50 mL) and cyclohexanone (5 mL) was added aluminum isopropoxide (2.08 g, 10.2 mmol) at 25 °C under N2 and the resulting mixture was stirred at 100 °C for 16 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (5~10% of EtOAc in PE) to give 17.10 (3.5 g, 70%).
1H NMR (400 MHz, CDCl3) δH 7.28 (br d, J = 1.9 Hz, 2H), 6.88 (br d, J = 8.6 Hz, 2H), 5.73 (br s, 1H), 4.85-4.75 (m, 1H), 4.45 (dd, J = 2.4, 10.9 Hz, 1H), 3.86-3.83 (m, 1H), 3.80 (d, J = 3.6 Hz, 3H), 2.45- 2.26 (m, 4H), 1.95-1.88 (m, 3H), 1.79-1.67 (m, 6H), 1.51-1.36 (m, 5H), 1.20-1.15 (m, 5H), 1.08-1.00 (m, 5H), 0.86-0.77 (m, 4H). [0462] Synthesis of 17.11 [0463] To a solution of 17.10 (3.5 g, 6.57 mmol) in THF (50 mL) was added Pd/C (2 g, wet, 10%) at 25 °C. The mixture was degassed under vacuum and purged with H
2 several times. After stirring under H
2 (15 psi) at 25 °C for 16 h, the reaction mixture was filtered through a Celite pad to remove Pd/C and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5%~12% EtOAc in PE) to afford 17.11 (1.2 g, 34.1%).
1H NMR (400 MHz, CDCl3) δH 7.31-7.27 (m, 2H), 6.89 (dd, J = 2.4, 8.7 Hz, 2H), 4.89-4.74 (m, 1H), 4.46 (d, J = 10.8 Hz, 1H), 3.80 (d, J=3.0 Hz, 3H), 3.78 (s, 1H), 2.10-1.94 (m, 4H), 1.43 (s, 4H), 1.26 (br s, 5H), 1.21 (d, J = 6.0 Hz, 2H), 1.14 (br s, 4H), 1.07-1.00 (m, 6H), 0.88-0.84 (m, 7H), 0.79 (d, J = 18.8 Hz, 3H). [0464] Synthesis of 17.12 [0465] To a solution of BHT (1.5 g, 6.80 mmol) in toluene (5 mL) was added AlMe3 (2 M in toluene, 1.70 mL, 3.40 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 1 h. To the MAD solution was added 17.11 (500 mg, 0.935 mmol) in toluene (5 mL). After stirring at -70 °C for 1 h, MeMgBr (0.933 mL, 3M in ethyl ether) was added dropwise at -70 °C and the mixture was stirred for 3 h. The reaction was quenched with citric acid (30 mL, sat. aq.) at -70 °C and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~15% of EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD-H(250mm*30mm,5um); Condition: 0.1%NH3H
2O EtOH; Gradient: from 15% to 15% of B; Flow rate: 60 mL/min; Injections: 12) to give 17.12 (185 mg, 43%).
1H NMR (400 MHz, CDCl3) δH 7.29 (s, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.79 (d, J = 10.4 Hz, 1H), 4.47 (d, J = 10.4 Hz, 1H), 3.81 (s, 3H),
3.53 (q, J = 7.6 Hz, 1H), 2.01-1.67 (m, 6H), 1.60 (br d, J = 7.8 Hz, 5H), 1.45-1.35 (m, 7H), 1.24 (s, 4H), 1.19 (br d, J = 7.2 Hz, 3H), 1.10 (s, 3H), 1.04 (s, 5H), 0.93 (s, 3H), 0.77 (s, 3H). [0466] Synthesis of 17 [0467] To a solution of 17.12 (185 mg, 0.336 mmol) in DCM (5 mL) was added water (0.5 mL) and DDQ (152 mg, mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with NaHCO
3 (20 mL, sat. aq.) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (15~20% of EtOAc in PE) to give 17 (56.1 mg, 39%).
1H NMR (400 MHz, CDCl
3) δ
H 4.06 -3.90 (m, 1H), 2.12 (d, J=6.3 Hz, 1H), 1.99-1.58 (m, 8H), 1.55-1.34 (m, 9H), 1.30-1.25 (m, 6H), 1.15-0.98 (m, 10H), 0.94 (s, 3H), 0.76 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C25H40N3O [M+H-H
2O]
+ 413.3 found 413.3.
19F NMR (376.5 MHz, CDCl3) δF -70.182. [0468] Example 18: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17S)-3-ethyl-10,13- dimethyl-17-((S)-4,4,4-trifluoro-3-hydroxy-2-methylbutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (18)
[0469] Synthesis of 18.1 [0470] To a solution of BHT (1.5 g, 6.80 mmol) in toluene (5 mL) was added AlMe
3 (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, 3M in ethyl ether) was added dropwise at -70 °C and the mixture was stirred at -70 °C for 3 h. The reaction was quenched with citric acid (30 mL, sat. aq.) at -70 °C and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (10%~15% EtOAc in PE). The resulting residue was further purified by SFC (DAICEL CHIRALPAK AD-H(250mm*30mm,5um); Condition: 0.1%NH3H
2O EtOH; 20% of B; Flow rate: 60mL/min; Injections: 240) to give 18.1 (241 mg, 44%).18.1 (241 mg, 0.427 mmol) was further purified by SFC (DAICEL CHIRALPAK AD-H (250mm*30mm, 5um); Condition: 0.1%NH
3H
2O EtOH; 20% of B; Flow rate: 50 mL/min; Injections: 120) to give 18.1 (120 mg, 50%). 18.1: LC-ELSD/MS purity 99%, MS ESI calcd. for C34H51F
3O
3Na [M+Na]
+ 587.4 found 587.4. [0471] Synthesis of 18 [0472] To a solution of 18.1 (120 mg, 0.212 mmol) in DCM (5 mL) was added water (0.5 mL) and DDQ (96.4 mg, 0.425 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with NaHCO
3 (20 mL, sat. aq.) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (15~20% EtOAc in PE) to give 18 (80 mg), which was further purified from MeCN (2 mL) at 25 °C to give 18 (33.9 mg, 36%).
1H NMR (400 MHz, CDCl3) δH 4.02-3.94 (m, 1H), 2.09 (d, J = 6.4 Hz, 1H), 1.97-1.77 (m, 4H), 1.72-1.57 (m, 5H), 1.53-1.33 (m, 9H), 1.32-1.18 (m, 4H), 1.17-1.11 (m, 1H), 1.10-1.07 (m, 4H), 1.06-1.02 (m, 1H), 1.00 (s, 3H), 0.99-0.94 (m, 1H), 0.92 (s, 3H), 0.87 (t, J = 7.4 Hz, 3H), 0.76 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -70.174. LC-ELSD/MS purity 99%, MS ESI calcd. for C26H42F
3O [M+H-H
2O]
+ 427.3, found 427.3. [0473] Example 19: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethynyl-10,13- dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (19)
[0474] Synthesis of 19.1 [0475] To a solution of 3.3 (10 g, 28.1 mmol) in THF:DMF (112 mL, 3:1) was added NaH (2.98 g, 75 mmol，60% in mineral oil) at 25 °C under N2 and the resulting mixture was stirred for 10 min. PMBCl (5.85 g, 37.5 mmol) was added and the mixture was stirred at 68 °C for 30 min. The mixture was poured into 10% aqueous NH4Cl (120 mL) and stirred for 10 min and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated to give 19.1 (12 g).
1H NMR (400 MHz, CDCl3) δH 7.29 (br d, J = 2.4 Hz, 2H), 6.91-6.89 (m, 2H), 4.67-4.62 (m, 1H), 4.56 (br d, J = 6.4 Hz, 2H), 4.46 (s, 1H), 3.81 (s, 3H), 3.72-3.67 (m, 1H), 2.49 (br t, J=13.2 Hz, 1H), 2.07-1.94 (m, 3H), 1.89-1.78 (m, 4H), 1.45-1.37 (m, 5H), 1.26-1.19 (m, 5H), 1.10-1.04 (m, 6H), 0.92 (s, 3H), 0.89-0.82 (m, 3H), 0.60 (s, 3H). [0476] Synthesis of 19.2 [0477] To a solution of 19.1 (10 g, 19.2 mmol) in DCM (200 mL) and MeOH (110 mL) was added NaHCO
3 (8.05 g, 95.9 mmol). Ozone (1 atm) was passed through the mixture at -
70 °C for 30 min. O
2 was then passed through the solution for 5 min. Me
2S (3.56 g, 57.5 mmol) was slowly added in portions to the mixture at -70 °C, the solution was allowed to warm to 20 °C over 1 h and then was stirred for 16 h. The reaction mixture was quenched with 10% aqueous NH
4Cl (300 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with 10% aqueous NH4Cl (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~10% EtOAc in PE) to give 19.2 (3.94 g, 39.4%).
1H NMR (400 MHz, CDCl3) δH 7.27 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 11.6 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 3.81 (s, 3H), 3.76-3.63 (m, 1H), 2.74-2.57 (m, 1H), 2.40-2.25 (m, 1H), 2.20-2.10 (m, 1H), 2.08-1.95 (m, 3H), 1.89-1.70 (m, 4H), 1.54-1.19 (m, 10H), 1.18-1.03 (m, 7H), 1.01 (s, 3H), 0.63 (s, 3H). [0478] Synthesis of 19.3 [0479] A solution of ethynylmagnesium bromide (5.76 mL, 22.5 mmol, 1 M) in THF (20 mL) was reacted with a solution of 19.2 (1 g, 1.92 mmol) in THF (20 mL) at 50 °C under N
2. After stirring for 16 h, the mixture was slowly poured into 10% aqueous NH4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 19.3 (1.3 g), which was purified by SFC ( (Column:DAICEL CHIRALCEL OD(250mm*50mm,10um); Condition:0.1%NH3H
2O ETOH); Begin B: 55; End B: 55) to give the 19.3 (500 mg, 73.9%).
1H NMR (400MHz, CDCl
3) 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).
19F NMR (376.5MHz, CDCl3) δ -69.48. [0480] Synthesis of 19 [0481] To solution of 19.3 (500 mg, 0.914 mmol) in DCM (12 mL) was added DDQ (413 mg, 1.81 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The reaction mixture was poured into 10% aqueous NH
4Cl (50 mL) and stirred for 20 min. The aqueous phase was extracted with DCM (3 x 20 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~20% EtOAc in PE) to give 19 (140 mg, 35.9 %).
1H NMR (400MHz, CDCl
3) δ
H 4.09-3.97 (m, 1H), 2.48 (s, 1H), 2.19-2.09 (m, 1H), 2.06-1.90 (m, 4H), 1.90-1.79 (m, 3H), 1.77-1.63 (m, 4H), 1.47-1.19 (m, 11H), 1.14-1.01 (m, 6H), 0.97 (s, 3H), 0.67 (s, 3H). LC-ELSD/MS purity >99%, MS ESI calcd. for C25H36F
3O [M+H- H
2O]
+ 409.3, found 409.3.
19F NMR (376.5MHz, CDCl
3) δ -72.22.
[0482] Example 20: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-3- (prop-1-yn-1-yl)-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (20)
20 [0483] Synthesis of 20.1 [0484] To a solution of 3.4 (250 mg, 0.624 mmol) in THF (3 mL) was added (prop-1-yn-1- yl)magnesium bromide (6.24 mL, 3.12 mmol, 0.5 M in THF) at 50 °C under N2. After stirring at 50 °C for 10 min, the mixture was poured into ice-water (20 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 20.1, which was purified by silica gel chromatography (0~10% EtOAc in PE) to give 20.1 (150 mg, 54 %).
1H NMR (400 MHz, CDCl
3) δ
H 4.07-3.99 (m, 1H), 2.24-2.13 (m, 1H), 2.02-1.88 (m, 4H), 1.85 (s, 3H), 1.82-1.63 (m, 6H), 1.50-1.30 (m, 12H), 1.11-1.04 (m, 6H), 0.96 (s, 3H), 0.66 (s, 3H). [0485] Synthesis of 20 [0486] 20.1 (150 mg, 0.0340 mmol) was purified by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm,5 um), Condition: 0.1% NH3H
2O EtOH, Begin B: 25%, End B: 25%, FlowRate (ml/min) 60, Injections 50) to give 20 (18.8 mg, 12.6%).
1HNMR (400 MHz, CDCl
3) 4.08-3.97 (m, 1H), 2.24 (d, J = 5.2 Hz, 1H), 2.01 (s, 1H), 1.99-1.90 (m, 2H), 1.85 (s,
3H), 1.83-1.60 (m, 5H), 1.58-1.15 (m, 14H), 1.12-1.02 (m, 6H), 0.96 (s, 3H), 0.66 (s, 3H).
19F NMR (376 MHz, CDCl3) δF -72.209. LC-ELSD/MS 30-90AB_2min_E, purity>99%, MS ESI calcd. for C26H38F
3O [M-H
2O+H]
+ 423.3, found 423.3. [0487] Example 21: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-(difluoromethyl)- 10,13-dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (21)
[0488] Synthesis of 21.1 [0489] To a solution of 3.4 (1 g, 2.49 mmol), HMPA (489 mg, 2.73 mmol) and ((difluoromethyl)sulfonyl)benzene (2.38 g, 12.4 mmol) in anhydrous THF (15 mL) under N2 at -70 °C was added LiHMDS (12.4 mL, 12.4 mmol) dropwise. After stirring at -70 °C for 1 h and then at 25 °C for 10 h, the mixture was poured into water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE). The resulting residue was further purified by SFC to give 21.2 (100 mg, 50%).
1H NMR (400MHz, CDCl3) δH 7.99 (d, J = 7.6 Hz, 2H), 7.80-7.73 (m, 1H), 7.67- 7.58 (m, 2H), 4.10-4.00 (m, 1H), 2.67 (s, 1H), 2.23-2.12 (m, 2H), 1.93-1.80 (m, 7H), 1.71- 1.59 (m, 5H), 1.38-1.22 (m, 8H), 1.13-1.05 (m, 6H), 0.99 (s, 3H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -72.20, -109.77. [0490] Synthesis of 21 [0491] To a solution of 21.1 (100 mg, 0.169 mmol) and anhydrous NaH
2PO
4 (66.8 mg, 0.557 mmol) in anhydrous methanol (8 mL) at -20 °C under N2 was added Na/Hg amalgam
(338 mg) and the resulting mixture was stirred at -20 °C to 0 °C for 2 h. The mixture was diluted with EtOAc (30 mL) and filtered. The organic layer was washed with 10% aqueous NH4Cl (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (5~10% EtOAc in PE) to give 21 (43 mg, 56%).
1H NMR (400 MHz, CDCl3) δH 6.05-5.67 (m, 1H), 4.13-3.95 (m, 1H), 2.25-2.20 (m, 1H), 2.05-1.70 (m, 8H), 1.49-1.21 (m, 12H), 1.17-1.04 (m, 7H), 0.96 (s, 4H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -72.21, -135.75 (d, J = 124.25). LCMS purity 99%; MS ESI calcd. for C24H35F5O [M+H-H
2O]
+ 435.1, found 435.1. [0492] Example 22: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)- 3-hydroxyhex-5-en-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren- 3-ol (22)
[0493] A solution of (prop-2-en-1-yl)magnesium bromide (103 ml, 1 M in THF, 103 mmol) in THF (100 mL) under N
2 was reacted with a solution of 2.2 (15 g, 41.5 mmol) in THF (100 mL). After stirring at 25 °C for 2 h, the residue was slowly poured into a NH
4Cl solution (500 mL, sat. aq.). After stirring for 20 min, the aqueous phase was extracted with EtOAc (3 x 400 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (10~30% EtOAc in PE) to give 22 (4.8 g, 28.7%).22 (100 mg, 0.2483 mmol) was further purified from MeCN (5 mL) at 25 °C to give 22 (24.1 mg, 24.1%).
1H NMR (400 MHz, CDCl
3) δ
H 5.93-5.75 (m, 1H), 5.21-5.05 (m, 2H), 3.69 (d, J = 11.0 Hz, 1H), 2.24-2.20 (m, 1H), 2.01-1.65 (m, 7H), 1.64-1.51 (m, 7H), 1.50-1.31 (m, 7H), 1.30-1.03 (m, 9H), 0.93 (t, J = 3.2 Hz, 5H), 0.90-0.81 (m, 3H), 0.71-0.63 (m, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C
27H
42 [M-2H
2O+H] 367.3, found 367.3.
[0494] Example 23: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-10,13- dimethyl-17-((2R,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (23)
[0495] Synthesis of 23.2 [0496] To a solution of 23.1 (100 g, 302 mmol) in MeOH (300 mL) and THF (300 mL) was added Pd/C (10 g, < 1% water). The solution was hydrogenated under 30 psi of hydrogen at 25
°C for 48 h. The mixture was filtered through a pad of Celite. The filter cake was washed with THF (3 x 300 mL) and the filtrate was concentrated in vacuo to give 23.2 (98 g, 98%).
1H NMR (400 MHz, CDCl3) δH 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). [0497] Synthesis of 23.3 [0498] To a solution of BHT (132 g, 599 mmol) in toluene (1.4 L) under nitrogen at 0 °C was added trimethylaluminum (2 M in toluene, 149 mL, 299 mmol) dropwise and the resulting mixture was stirred at 25 °C for 1 h and used directly as a MAD solution. A solution of 23.2 (50 g, 150 mmol) in DCM (500 mL) was added to the MAD solution (0.213 M in toluene) dropwise at -70 °C under N
2. After stirring at -70 °C for 1 h, EtMgBr (74.6 mL, 224 mmol, 3M in Et2O) was added dropwise at -70 °C. The resulting solution was stirred at -70 °C for 1 h. The reaction mixture was quenched by aqueous citric acid (2 L) at 10 °C and the mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with saturated aqueous NH4Cl (2 x 500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified from PE to give 23.3 (50 g), which was further purified from MeCN (500 mL) to give 23.3 (32 g, 71%).
1H NMR (400 MHz, CDCl
3) 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, 14H), 1.28-1.04 (m, 11H), 1.03 (d, J = 6.8 Hz, 3H), 0.93 (s, 3H), 0.66 (s, 3H). [0499] Synthesis of 23.4 [0500] To a solution of 23.3 (5 g, 13.8 mmol) in THF (50 mL) was added CsF (628 mg, 4.14 mmol) and TMSCF
3 (4.89 g, 34.5 mmol). After stirring at 0 °C under N2 for 1 h, TBAF (6.93 g, 22.0 mmol) was added. After stirring at 40 °C for another 2 h, the mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated aqueous NH4Cl (2 x 40 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~30% EtOAc in PE) to give 23.4 (1 g), which was further purified from MeCN (5 mL) to give 23.4 (172.6 mg, 43.1%).
1H NMR (400 MHz, CDCl3) δH 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 purity 99%; MS ESI calcd. for C
25H
40F
3O
1 [M-H
2O+H]
+ 413.3, found 413.3.
19F NMR (376.5 MHz, CDCl3) δF -72.207. [0501] Synthesis of 23.5
[0502] To a solution of 23.4 (1 g, 2.32 mmol) in pyridine (5 mL) was added DMAP (28.3 mg, 0.232 mmol) and benzoyl chloride (978 mg, 6.96 mmol) at 25 °C under N2 and the resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with water (20 mL) and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to give 23.5, which 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: 30mL
.min
-1) to give 23.5 (200 mg, 13.5%).
1H NMR (400 MHz, CDCl3) δH 8.12-7.94 (m, 4H), 7.65-7.36 (m, 6H), 5.83- 5.70 (m, 1H), 2.28-1.58 (m, 12H), 1.28 (s, 11H), 1.13 (d, J = 6.8 Hz, 3H), 1.11-1.02 (m, 3H), 0.96 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H), 0.71 (s, 3H). [0503] Synthesis of 23 [0504] To a solution of 23.5 (200 mg, 0.313 mmol) in THF (1 mL), MeOH (1 mL) and H
2O (0.5 mL) was added NaOH (62.3 mg, 1.56 mmol) and the resulting mixture was stirred at 50 °C for 48 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (0~20% EtOAc in PE) to give 23 (99.5 mg, 74.2%).
1HNMR (400 MHz, CDCl
3) δ
H 4.34-4.19 (m, 1H), 1.99-1.78 (m, 6H), 1.67-1.40 (m, 13H), 1.33-1.01 (m, 9H), 0.97-0.92 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H), 0.67 (s, 3H).
19F NMR (400 MHz, CDCl3) δF - 75.40. LC-ELSD/MS 30-90AB_2min_E, purity>99%, MS ESI calcd. for C25H40F
3O [M- H
2O+H]
+ 413.2, found 413.2. [0505] Examples 24 & 25: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-10,13- dimethyl-17-((2S,3R,6R)-7,7,7-trifluoro-3-hydroxy-6-methylheptan-2- yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (24) and (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-10,13-dimethyl-17-((2S,3R,6S)-7,7,7-trifluoro-3- hydroxy-6-methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (25)
[0506] Synthesis of 24.1 [0507] To a solution of 22 (3.0 g, 7.45 mmol) in THF (50 mL) was added NaH (743 mg, 18.6 mmol, 60%) and the resulting mixture was stirred at 25 °C for 30 min. PMBCl (1.73 g 11.1 mmol) was added under N2 and the mixture was stirred at 70 °C for 16 h. The mixture was slowly poured into 10% aqueous NH4Cl (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (200mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~60% EtOAc in DCM) to give 24.1 (2.8 g, 71.9%).
1H NMR (400 MHz, CDCl
3) δ
H 7.29-7.26 (m, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.89 (m, 1H), 5.11-4.98 (m, 2H), 4.51 (d, J = 11.2 Hz, 1H), 4.33 (d, J = 11.2 Hz, 1H), 3.82-3.80 (m, 3H), 3.40 (td, J = 3.6,
8.8 Hz, 1H), 2.13 (d, J = 7.8 Hz, 1H), 1.99-1.86 (m, 3H), 1.72-1.60 (m, 7H), 1.48-1.36 (m, 7H), 1.31-1.23 (m, 6H), 1.13-1.06 (m, 3H), 0.96-0.93 (m, 6H), 0.91-0.87 (m, 5H), 0.68 (s, 3H). [0508] Synthesis of 24.2 [0509] To a solution of 24.1 (2.8 g, 5.35 mmol) in THF (20 mL) was added 9-BBN dimer (2.58 g, 10.7 mmol) in portions slowly under N2. After stirring at 50 °C under N2 for 2 h, the mixture was cooled to 0 °C and EtOH (3.07 mL, 53.5 mmol) and NaOH (16.0 mL, 5 M, 80.2 mmol) were added dropwise under N2. H
2O
2 (8.02 mL, 10 M, 80.2 mmol) was added dropwise under N2 at 15 °C and stirred at 50 °C for 2 h. The mixture was cooled, slowly poured into saturated aqueous Na
2S
2O
3 (100 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 24.2 (2.0 g, 69.2%).
1H NMR (400 MHz, CDCl3) δH 7.29-7.27 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.55 (d, J = 11.0 Hz, 1H), 4.27 (d, J = 11.0 Hz, 1H), 3.81 (s, 3H), 3.60 (s, 2H), 3.35 (d, J = 10.6 Hz, 1H), 2.01-1.92 (m, 3H), 1.90-1.75 (m, 3H), 1.74-1.67 (m, 3H), 1.63-1.55 (m, 9H), 1.49- 1.36 (m, 8H), 1.19-1.05 (m, 5H), 0.96-0.86 (m, 10H), 0.70 (s, 3H). [0510] Synthesis of 24.3 [0511] To a solution of 24.2 (2.0 g, 5.54 mmol) in DCM (20 mL) was added DMP (3.13 g, 11.0 mmol) dropwise under N2 and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with 10% aqueous NaHCO
3 (100 mL) and saturated aqueous Na
2S
2O
3 (1000 mL). The mixture was extracted with DCM (2 x 50 mL) and the combined organic layers were washed with saturated aqueous Na2S2O
3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified from PE (20 mL) at 25 °C to give 24.3 (2.0 g).
1H NMR (400 MHz, CDCl
3) δ
H 9.76-9.58 (m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.48 (d, J = 11.2 Hz, 1H), 4.18 (dd, J = 2.0, 11.2 Hz, 1H), 3.80 (s, 3H), 3.32-3.25 (m, 1H), 2.58-2.24 (m, 3H), 2.11-1.88 (m, 6H), 1.74-1.55 (m, 10H), 1.41 (dd, J = 5.2, 7.6 Hz, 5H), 1.30-1.12 (m, 7H), 1.01-0.85 (m, 9H), 0.69 (s, 3H). [0512] Synthesis of 24.4 [0513] To a solution of 24.3 (2.0 g, 3.71 mmol) in THF (10 mL) was added CsF (1.12 g, 7.42 mmol) at 10 °C under N
2. TMSCF
3 (1.57 mg, 11.1 mmol) was added dropwise at 10 °C and the mixture was stirred for 1 h. TBAF (2.90 g, 11.1 mmol) was added dropwise at 20 °C and the resulting mixture was stirred for 2 h. The mixture was poured into water (10 mL), stirred for 20 min, and extracted with EtOAc (2 x 20 mL). The combined organic layers were
washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 24.4 (2.5 g).
1H NMR (400 MHz, CDCl3) δH 7.26-7.21 (m, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.61-4.50 (m, 1H), 4.32-4.21 (m, 1H), 3.80 (s, 3H), 3.41-3.28 (m, 3H), 2.53 (s, 2H), 1.97-1.79 (m, 8H), 1.70-1.54 (m, 9H), 1.50-1.36 (m, 8H), 1.17-1.08 (m, 3H), 1.04-0.92 (m, 10H), 0.70 (s, 3H). [0514] Synthesis of 24.5 [0515] To a solution of 24.4 (2.5 g, 4.10 mmol) in DCM (20 mL) was added DMP (3.47 g, 8.20 mmol) dropwise under N2 and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with 10% aqueous NaHCO
3 (100 mL) and saturated aqueous Na2S2O
3 (500 mL) and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic layers were washed with saturated aqueous Na
2S
2O
3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified from PE (20 mL) at 25 °C to give 24.5 (2.5 g).
1H NMR (400 MHz, CDCl
3) δ
H 7.21 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.58-4.11 (m, 2H), 3.80 (s, 3H), 3.32-3.23 (m, 2H), 3.00-2.48 (m, 2H), 2.09-1.96 (m, 4H), 1.67-1.59 (m, 7H), 1.48-1.37 (m, 7H), 1.30-1.19 (m, 5H), 1.15-1.07 (m, 3H), 1.02-0.91 (m, 11H), 0.69 (d, J = 1.6 Hz, 3H). [0516] Synthesis of 24.6 [0517] To a solution of MePh3P (4.39 g, 12.3 mmol) in THF (10 mL) was added t-BuOK (1.37 mg, 12.3 mmol) at 25 °C and the resulting mixture was stirred at 50 °C for 1 h. A solution of 24.5 (2.5 g, 4.11 mmol) in THF (10 mL) was added at 50 °C and the resulting mixture was stirred for 16 h. The mixture was then poured into NH
4Cl (100 mL, sat. aq.) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (10~20% EtOAc in PE) to give 24.6 (700 mg, 28.2%).
1H NMR (400 MHz, CDCl3) δH 7.19 (t, J = 4.2 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 5.54 ( s, 1H), 5.13 (d, J = 2.8 Hz, 1H), 4.46 (d, J = 11.2 Hz, 1H), 4.17 (d, J = 11.2 Hz, 1H), 3.73 (s, 3H), 3.24 (s, 1H), 2.46-2.31 (m, 1H), 2.00-1.87 (m, 4H), 1.75-1.59 (m, 3H), 1.51-1.44 (m, 4H), 1.36 (d, J = 2.4 Hz, 3H), 1.27-1.21 (m, 4H), 1.10-0.99 (m, 5H), 0.91-0.85 (m, 6H), 0.83-0.77 (m, 10H), 0.63 (d, J = 1.6 Hz, 3H). [0518] Synthesis of 24.7 & 24.7a [0519] To a solution of 24.6 (300 mg, 0.4959 mmol) in THF (10 mL) was added dry Pd/C (0.1 g, 10 wt %). The suspension was degassed under vacuum and purged with H
2 three times. After stirring at 25 °C under H
2 (15 psi) for 4 h, the reaction mixture was filtered through a pad of Celite and washed with THF (3 x 100 mL). The filtrate was concentrated to
give a mixture of 24.7 & 24.7a (200 mg), which were separated by SFC (Column: Chiralcel OD-3150×4.6mm I.D., 3um Mobile phase: A: CO
2; B: MeOH (0.05% DEA) Gradient: 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min; Flow rate: 2.5 mL/min; Column temp.: 35℃; ABPR: 1500psi) to afford 24.7 (30 mg, 20.1%) and 24.7a (20 mg, 13.4%). 24.7:
1H NMR (400 MHz, CDCl3) δH 7.26 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.53 (s, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.80 (s, 3H), 3.26 (d, J = 10.4 Hz, 1H), 2.04 (s, 1H), 1.96-1.79 (m, 5H), 1.72-1.63 (m, 5H), 1.45-1.35 (m, 7H), 1.28-1.25 (m, 9H), 1.12-1.04 (m, 8H), 0.96-0.85 (m, 9H), 0.68 (s, 3H). 24.7a:
1H NMR (400 MHz, CDCl
3) δ
H 7.24 (s, 2H), 6.96-6.78 (m, 2H), 4.51 (d, J = 11.0 Hz, 1H), 4.25 (d, J = 11.0 Hz, 1H), 3.80 (s, 3H), 3.26 (d, J = 11.0 Hz, 1H), 2.59-2.17 (m, 1H), 2.08-1.78 (m, 5H), 1.74-1.63 (m, 2H), 1.57 (s, 6H), 1.50-1.36 (m, 8H), 1.32-1.18 (m, 7H), 1.07 (d, J = 6.8 Hz, 6H), 0.95-0.84 (m, 9H), 0.68 (s, 3H). [0520] Synthesis of 24 [0521] To a solution of 24.7 (30 mg, 0.04943 mmol) in DCM (10 mL) was added DDQ (22.4 mg, 0.09886 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The reaction mixture was quenched with NaHCO
3 (80 mL, sat. aq.) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~20% EtOAc in PE) to give 24 (4.6 mg, 19.1%).
1H NMR (400 MHz, CDCl
3) δ
H 3.68-3.57 (m, 1H), 2.25-2.12 (m, 1H), 2.04-1.93 (m, 2H), 1.89-1.78 (m, 2H), 1.72- 1.59 (m, 10H), 1.50-1.37 (m, 8H), 1.30-1.20 (m, 7H), 1.13 (d, J = 7.2 Hz, 4H), 1.08 (br d, J = 5.6 Hz, 3H), 0.94-0.91 (m, 4H), 0.90-0.85 (m, 4H), 0.66 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -73.086. LC-ELSD/MS purity 100%, MS ESI calcd. for C
29H
46F
3 [M-2H
2O+H]
+ 451.3, found 451.3. [0522] Synthesis of 25 [0523] To a solution of 24.7a (20 mg, 0.03295 mmol) in DCM (10 mL) was added DDQ (14.9 mg, 0.0659 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The reaction mixture was quenched with NaHCO
3 (80 mL, sat. aq.) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 25 (4.1 mg, 25.6%).
1H NMR (400 MHz, CDCl3) δH 3.68- 3.57 (m, 1H), 2.24-2.10 (m, 1H), 2.00-1.93 (m, 1H), 1.91-1.79 (m, 3H), 1.73-1.65 (m, 4H), 1.48-1.32 (m, 11H), 1.29-1.18 (m, 7H), 1.12 (d, J = 6.8 Hz, 4H), 1.09-1.04 (m, 3H), 0.94-
0.91 (m, 5H), 0.91-0.85 (m, 5H), 0.66 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -73.250. LC-ELSD/MS purity 100%, MS ESI calcd. for C29H46F
3 [M-2H
2O+H]
+ 451.3, found 451.3. [0524] Example 26: Synthesis of 1-((S)-2-hydroxy-3-((3R,5R,8R,9R,10S,13R,14S,17R)- 3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)- 1H-pyrazole-4-carbonitrile (26)
[0525] Synthesis of 26.2 [0526] To a suspension of NaH (2.75 g, 60%, 68.8 mmol) in THF (60 mL) was added (EtO)
2P(O)CH
2COOEt (15.4 g, 68.8 mmol) dropwise at 0 °C and the resulting mixture was stirred at 20 °C for 10 min. A solution of 26.1 (10 g, 34.4 mmol, preparation described in WO
2014/169833A1) in THF (20 mL) was added dropwise at 20 °C and the mixture was refluxed at 70 °C for 16 h. The mixture was then poured into NH4Cl (200 mL, 10% aq.) and extracted with EtOAc (200 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, concentrated, and purified by flash silica gel chromatography (0~20% EtOAc in PE) to give 26.2 (12 g, 97%). [0527] Synthesis of 26.3 [0528] To a solution of 26.2 (12 g, 33.2 mmol) in THF (150 mL) was added Pd/C (2 g, dry, 10%) under N2. The mixture was stirred under H
2 (40 psi) at 40 °C for 24 h. The mixture was filtered through a pad of Celite and washed with THF (3 x 50 mL). The combined filtrate was concentrated to give 26.3 (11.7 g, 97.5%).
1H NMR (400 MHz, CDCl
3) δ
H 4.11 (q, J = 6.8 Hz, 2H), 2.35 (dd, J = 5.2, 14.4 Hz, 1H), 2.10 (dd, J = 10.0, 14.8 Hz, 1H), 2.00-1.75 (m, 5H), 1.70-1.50 (m, 4H), 1.50-1.35 (m, 6H), 1.35-1.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H). [0529] Synthesis of 26.4 [0530] To a suspension of LiAlH4 (6.0 g, 158 mmol) in THF (120 mL) was added a solution of 26.3 (11.1 g, 30.6 mmol) in THF (30 mL) at 0 °C under N2 and the resulting mixture was stirred for 10 min. To the mixture was added water/THF (6 mL/200 mL) dropwise followed by NaOH (6 mL, 10% aq.) and water (18 mL). The mixture was filtered and the precipitate was washed with THF (3 x 100 mL). The combined filtrate was concentrated and the residue was purified from DCM (50 mL) to give 26.4 (9 g, 92%).
1H NMR (400 MHz, CDCl
3) δ
H 3.75-3.55 (m, 2H), 1.90-1.60 (m, 9H), 1.50-1.15 (m, 16H) 1.15- 0.90 (m, 6H), 0.59 (s, 3H). [0531] Synthesis of 26.5 [0532] To a solution of 26.4 (3 g, 9.3 mmol) in DCM (80 mL) was added DMP (7.92 g, 18.7 mmol) and the resulting mixture was stirred at 30 °C for 1 h. The mixture was washed with NaHCO
3 (160 mL, aq. sat.) and Na2S2O
3 (80 mL, aq. sat.) twice, dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by flash silica gel chromatography (10~30% EtOAc in PE) to give 26.5 (2.2 g, 74%).
1H NMR (400 MHz, CDCl
3) δ
H 9.76 (t, J = 2.4 Hz, 1H), 2.55-2.45 (m, 1H), 2.30-2.20 (m, 1H), 2.00-1.80 (m, 5H), 1.70-1.55 (m, 4H), 1.50-1.20 (m, 13H), 1.30-1.00 (m, 6H), 0.60 (s, 3H). [0533] Synthesis of 26.6
[0534] To a solution of 25.6 (4 g, 12.5 mmol) in THF (40 mL) was added MeMgBr (20.8 mL, 7.19 mmol, 3M) at 0 °C and the resulting mixture was stirred for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL), and the aqueous layer extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 26.6 (4 g).
1H NMR (400 MHz, CDCl3) δH 3.82-3.72 (m, 1H), 1.94-1.59 (m, 12H), 1.54-1.31 (m, 8H), 1.25-0.97 (m, 14H), 0.56 (s, 3H). [0535] Synthesis of 26.7 [0536] To a solution of 26.6 (4 g, 11.9 mmol) in DCM (50 mL) was added silica gel (8 g) and PCC (5.11 g, 23.8 mmol) at 20 °C and the resulting mixture was stirred for 1 h. The mixture was filtered, and the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated and the residue was purified by flash silica gel chromatography (0~40% EtOAc in PE) to give 26.7 (2.3 g, 58.2%).
1H NMR (400 MHz, CDCl3) δH
2.53-2.44 (m, 1H), 2.27- 2.18 (m, 1H), 2.14 (s, 3H), 1.82-1.74 (m, 3H), 1.69-1.57 (m, 7H), 1.48-1.38 (m, 5H), 1.34- 1.25 (m, 6H), 1.19-0.97 (m, 7H), 0.58 (s, 3H). [0537] Synthesis of 26.8 [0538] To a solution of 26.7 (200 mg, 0.60 mmol) and HBr (5.99 mg, 0.030 mmol, 40% aq.) in MeOH (10 mL) was added Br2 (105 mg, 0.66 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 2 h. The mixture was poured into saturated aqueous NaHCO
3 (20 mL), and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 26.8 (247 mg). [0539] Synthesis of 26.9 [0540] To a solution of 26.8 (240 mg, 0.58 mmol) in acetone (5 ml) was added K
2CO
3 (160 mg, 1.16 mmol) and 1H-pyrazole-4-carbonitrile (81.4 mg, 0.87 mmol) and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water and extracted with EtOAc (2 x 20 ml). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~40% EtOAc in PE) and further purified by prep-HPLC (Column: YMC Triart C18150
*25mm
*5um; Condition: water (10mM NH
4HCO
3)-ACN; Begin B: 70; End B: 100; Gradient Time(min): 9.5; 100% B Hold Time(min): 2) to give 26.9 (100 mg, 40 %).
1H NMR (400 MHz, CDCl3) δH 7.86 (s, 1H), 7.83 (s, 1H), 5.09-4.91 (m, 2H), 2.56 (dd, J = 4.0, 16.0 Hz, 1H), 2.28 (dd, J = 10.0, 16.0 Hz, 1H), 2.03-1.75 (m, 5H), 1.68-1.58 (m, 6H), 1.42-
0.93 (m, 17H), 0.59 (s, 3H). LCMS 30-90AB_2min_E, purity>99%, MS ESI calcd. for C26H36N3O [M-H
2O+H]
+ 406.3, found 406.3. [0541] Synthesis of 26 [0542] To a solution of 26.9 (540 mg, 1.27 mmol) in THF (10 mL) was added NaBH
4 (96.5 mg, 2.54 mmol) at 0 °C and the resulting mixture was stirred for 2 h. Acetone (30 mL) was added and the reaction mixture was stirred for 1 h. The mixture was poured into water (20 mL), diluted with EtOAc (10 mL), and washed with brine (10 mL). The organic layer was dried over anhydrous Na2SO
4, filtered, and concentrated. The resulting residue was purified by SFC ( (Column: DAICEL CHIRALPAK AD (250mm*30mm,10um); Condition: 0.1%NH
3H
2O EtOH); Begin B: 55%; End B: 55%) to give 26 (210 mg).
1H NMR (400 MHz, CDCl
3) δ
H 7.89 (s, 1H), 7.82 (s, 1H), 4.39-4.18 (m, 1H), 4.11-3.90 (m, 2H), 2.54-2.43 (m, 1H), 1.94-1.75 (m, 4H), 1.71-1.62 (m, 4H), 1.57-1.35 (m, 9H), 1.33-1.24 (m, 7H), 1.16-0.99 (m, 6H), 0.58 (s, 3H). LCMS 30-90AB_2min_E, purity>99%, MS ESI calcd. for C26H38N3O [M-H
2O+H]
+ 408.2, found 408.2. [0543] Example 27: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxyhex-4-yn-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-
[0544] Synthesis of 27.1
[0545] To a solution of 1.2 (20 g, 60.1 mmol) in THF (250 mL) was added CsF (4.56 g, 30.0 mmol) and TMSCF
3 (21.3 g, 150.0 mmol) at 0 °C under N2 and the resulting mixture was stirred at 25 °C for 30 min. TBAF (56.6 g, 180 mmol) was added and the mixture was stirred at 25 °C for 16 h. The mixture was quenched with 10% aqueous NH
4Cl (500 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with 10% aqueous NH4Cl (300 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified from MeCN (250 mL) at 50 °C to give 27.1 (12.1 g).
1H NMR (400 MHz, CDCl3) δH 3.68-3.60 (m, 1H), 3.41-3.31 (m, 1H), 2.12-1.58 (m, 10H), 1.55-1.16 (m, 13H), 1.14-1.01 (m, 6H), 0.96 (s, 3H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF - 78.775. LC-ELSD/MS purity >99%, MS ESI calcd. for C
23H
36F
3O [M+H-H
2O]
+ 385, found 385. [0546] Synthesis of 27.2 [0547] To a solution of 27.1 (12 g, 29.8 mmol) in DCM (300 mL) at 25 °C was added DMP (25.2 g, 59.6 mmol) and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with NaHCO
3 (250 mL, sat. aq.) and Na2S2O
3 (250 mL, sat. aq.) and extracted with DCM (2 x 150 mL). The combined organic layers were washed with NaHCO
3 (250 mL, sat. aq.) and Na
2S
2O
3 (250 mL, sat. aq.), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 27.2 (12 g).
1H NMR (400 MHz, CDCl3) δH 9.57 (d, J = 4.0Hz, 1H), 2.42-2.30 (m, 1H), 1.99-1.58 (m, 10H), 1.56-1.24 (m, 11H), 1.20-1.05 (m, 6H), 0.97 (s, 3H), 0.70 (s, 3H). [0548] Synthesis of 27 [0549] To a solution of (prop-1-yn-1-yl)magnesium bromide (8.94 mL, 4.47 mmol, 0.5 M in THF) was added a solution of 27.2 (600 mg, 1.49 mmol) in THF (10 mL) dropwise and the resulting mixture was stirred at 25 °C for 1 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 27 (190 mg, 28.9%).
1H NMR (400 MHz, CDCl3) δH 4.45-4.40 (m, 1H), 2.03-1.77 (m, 9H), 1.76-1.59 (m, 6H), 1.49-1.25 (m, 11H), 1.24-1.05 (m, 3H), 1.02 (d, J = 8.0Hz, 3H), 0.96 (s, 3H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.80. [0550] Example 28: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1R,2S)-1- cyclopropyl-1-hydroxypropan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (28)
[0551] To a solution of cyclopropylmagnesium bromide (147.9 mL, 0.5 M in hexane) was added 27.2 (600 mg, 1.49 mmol) dropwise under N2 at 0 °C and the resulting mixture was stirred at 50 °C for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 28 (40 mg, 6.06 %).
1H NMR (400 MHz, CDCl3) δH
2.97 (dd, J = 3.2, 9.2 Hz, 1H), 2.06-1.81 (m, 6H), 1.79-1.64 (m, 5H), 1.44-1.22 (m, 11H), 1.11-1.02 (m, 6H), 0.99-0.83 (m, 5H), 0.71-0.65 (m, 3H), 0.62-0.41 (m, 2H), 0.34 (qd, J = 4.8, 9.6 Hz, 1H), 0.27-0.14 (m, 1H). [0552] Example 29: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-4-fluoro-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (29)
[0553] Synthesis of 29.1 [0554] To a solution of 27.2 (1 g, 2.49 mmol), HMPA (489 mg, 2.73 mmol), and ((fluoromethyl)sulfonyl)benzene (433 mg, 2.49 mmol) in anhydrous THF (15 mL) under nitrogen at -70 °C was added LiHMDS (1 M in THF, 12.4 mL, 12.4 mmol) dropwise. After stirring at -70 °C for 1 h, followed by stirring at 25 °C for 10 h, the mixture was poured into water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 29.1 (400 mg).
1H NMR (400 MHz, CDCl3) δH 8.10-7.50 (m, 5H), 5.55-4.98 (m, 1H), 4.25-4.13 (m, 1H), 2.02-1.41 (m, 15H), 1.40-1.28 (m, 5H), 1.25-1.02 (m, 8H), 1.01-0.77 (m, 6H), 0.73-0.55 (m, 3H). [0555] Synthesis of 29 [0556] To a suspension of 29.1 (400 mg, 0.6959 mmol) and anhydrous NaH
2PO
4 (274 mg, 2.29 mmol) in anhydrous MeOH (8 mL) at -20 °C under N2 was added Na/Hg amalgam (1.40 g, 6.26 mmol) and the resulting mixture was stirred at -20 °C to 0 °C for 2 h. The mixture was diluted with EtOAc (30 mL) and filtered. The organic layer was washed with 10% aqueous NH4Cl (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified from PE and dried in an oven at 70 °C for 16 h to give 29 (95 mg, 32.6%).
1H NMR (400 MHz, CDCl3) δH 4.67-4.23 (m, 2H), 4.06-3.90 (m, 1H), 2.09-1.57 (m, 12H), 1.54-1.23 (m, 9H), 1.21-0.91 (m, 11H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.796, -232.454. LC-ELSD/MS purity 100%, MS ESI calcd. for C
24H
37F
4O [M+H-H
2O]
+ 417.3, found 417.3. [0557] Example 30: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-4,4- difluoro-3-hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (30)
[0558] Synthesis of 30.1 [0559] To a solution of 27.2 (1 g, 2.49 mmol), HMPA (489 mg, 2.73 mmol), and ((difluoromethyl)sulfonyl)benzene (2.38 g, 12.4 mmol) in anhydrous THF (20 mL) under nitrogen at -70 °C was added LiHMDS (1 M in THF, 12.4 mL, 12.4 mmol) dropwise. After stirring at -70 °C for 1 h, followed by stirring at 25 °C for 10 h, the mixture was poured into 10% aqueous NH4Cl (150 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE) to give 30.1 (200 mg, 13.6%).
1H NMR (400 MHz, CDCl3) δH 8.04-7.93 (m, 2H), 7.85-7.74 (m, 1H), 7.72-7.59 (m, 2H), 4.73-4.60 (m, 1H), 2.92-2.85 (m, 1H), 2.01-1.58 (m, 9H), 1.56-1.04 (m, 16H), 1.01-0.92 (m, 6H), 0.66 (s, 3H). [0560] Synthesis of 30 [0561] To a solution of 30.1 (200 mg, 0.337 mmol) and anhydrous Na2HPO
4 (248 mg, 1.11 mmol) in anhydrous MeOH (8 mL) at -20 °C under N
2 was added Na/Hg amalgam (452 mg) and the resulting mixture was stirred at -20 °C to 0 °C for 2 h. The mixture was quenched with 10% aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with 10% aqueous NH4Cl (60 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE) to give 30 (77.2 mg, 50.7%).
1H NMR (400 MHz, CDCl3) δH 5.91-5.57 (m, 1H), 3.88- 3.74 (m, 1H), 2.04-1.58 (m, 12H), 1.56-1.18 (m, 11H), 1.17-1.03 (m, 6H), 0.96 (s, 3H), 0.66 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.793, -124.552, -125.326, -127.453, -128.227. LC-ELSD/MS purity >99%, MS ESI calcd. for C
24H
36F
5O [M+H-H
2O]
+ 435, found 435.
[0562] Example 31: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-13-methyl-17- ((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (31)
[0563] Synthesis of 31.1 [0564] To a mixture of 4.5 (5 g, 17.4 mmol) and CsF (1.32 g, 8.70 mmol) in THF (50 mL) was added TMSCF
3 (6.17 g, 43.4 mmol) dropwise at 0 °C and the resulting mixture was stirred at 25 °C for 1 h. TBAF (52 mL, 1 M in THF, 52 mmol) was added and the mixture was stirred at 25 °C for 2 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried
over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 5/1~3/1) to give 31.1 (4.6 g). The product was purified from MeCN (3 mL) to give 31.1 (2.64 g, 40%).
1H NMR (400 MHz, CDCl3) δH 5.16-5.08 (m, 1H), 2.40-2.32 (m, 1H), 2.30-2.13 (m, 2H), 2.05-1.97 (m, 2H), 1.96-1.90 (m, 1H), 1.88-1.74 (m, 3H), 1.73-1.58 (m, 7H), 1.57-1.42 (m, 5H), 1.30-1.04 (m, 6H), 0.88 (s, 3H). [0565] Synthesis of 31.2 [0566] To a solution of 31.1 (1 g, 2.80 mmol) in THF (30 mL) was added 9-BBN dimer (2 g, 8.19 mmol) at 0 °C under N2 and the resulting solution was stirred at 65 °C for 1 h. After cooling the mixture to 0 °C, a solution of NaOH (6 mL, 5 M, 30 mmol) was added slowly. H
2O
2 (4 g, 35.2 mmol, 30% in water) was then slowly added to keep the internal temperature of the reaction mixture below 10 °C during the course of the addition. The mixture was then stirred at 60 °C under N2 for 1 h. The mixture was cooled to 30 °C and water (30 mL) was added. The reaction mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure to afford 31.2 (1.43 g). [0567] Synthesis of 31.3 [0568] To a solution of 31.2 (1.43 g, 3.81 mmol) in DCM (15 mL) was added DMP (3.23 g, 7.62 mmol) slowly at 25 °C and the resulting mixture was stirred for 1 h. The mixture was poured into saturated aqueous Na2S2O
3 (30 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc = 5/1~3/1) to give 31.3 (570 mg, 40%).
1H NMR (400 MHz, CDCl3) δH
2.57-2.51 (m, 1H), 2.20-2.09 (m, 5H), 2.05-1.93 (m, 3H), 1.89-1.56 (m, 8H), 1.55- 1.41 (m, 5H), 1.36-1.06 (m, 6H), 0.62 (s, 3H). [0569] Synthesis of 31.4 [0570] To a mixture of t-BuOK (2.46 g, 22.0 mmol) in THF (50 mL) was added MePPh3Br (7.85 g, 22.0 mmol) and the resulting mixture was stirred at 25 °C for 30 min. A solution of 31.3 (5.5 g, 14.7 mmol) in THF (50 mL) was added in portions and stirred for 1 h. The mixture was quenched with 10% aqueous NH4Cl (150 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~5% EtOAc in PE) to give 31.4 (4.5 g, 85.7%).
1H NMR (400 MHz, CDCl3) δH 4.85 (s, 1H), 4.70 (s, 1H), 2.11-1.80 (m, 8H), 1.78-1.56 (m, 7H), 1.54-1.41 (m, 5H), 1.33-1.00 (m, 8H), 0.58 (s, 3H). [0571] Synthesis of 31.5
[0572] To a solution of 31.4 (7 g, 18.8 mmol) in THF (150 mL) was added 9-BBN dimer (6.88 g, 28.2 mmol) at 0 °C under N2. After stirring at 25 °C for 16 h and cooling to 0 °C, a solution of NaOH (37.6 mL, 5 M, 188 mmol) was added slowly. H
2O
2 (21.3 g, 188 mmol, 30% in water) was slowly added to keep the internal temperature of the reaction mixture was below 10 °C during the course of the addition. Saturated aqueous Na2S2O
3 (300 mL) was carefully added and the mixture was stirred at 25 °C for 10 min. The mixture was diluted with water (500 mL) and filtered. The filter cake was washed with water (2 x 200 mL) and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified from MeCN (100 mL) to give 31.5 (5.5 g, 75.3%).
1H NMR (400 MHz, CDCl
3) δ
H 3.69-3.59 (m, 1H), 3.42-3.31 (m, 1H), 2.07-1.75 (m, 8H), 1.69-1.58 (m, 3H), 1.56-1.39 (m, 6H), 1.36-1.16 (m, 5H), 1.15-0.99 (m, 8H), 0.69 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF - 78.627. LC-ELSD/MS purity >99%, MS ESI calcd. for C22H34F
3O [M+H-H
2O]
+ 371, found 371. [0573] Synthesis of 31.6 [0574] To a solution of 31.5 (5.4 g, 13.8 mmol) in DCM (50 mL) at 25 °C was added DMP (11.7 g, 27.6 mmol) and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with NaHCO
3 (80 mL, sat. aq.) and Na2S2O
3 (80 mL, sat. aq.). The mixture was extracted with DCM (2 x 50 mL) and the combined organic layers were washed with NaHCO
3 (80 mL, sat. aq.) and Na
2S
2O
3 (80 mL, sat. aq.), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE) to give 31.6 (2.5 g). [0575] Synthesis of 31 [0576] To a solution of 31.6 (400 mg, 1.03 mmol) in THF (20 mL) was added CsF (78.2 mg, 0.515 mmol) at 10 °C under N2. TMSCF
3 (365 mg, 2.57 mmol) was added dropwise at 10 °C and the mixture was stirred for 1 h. TBAF (807 mg, 3.09 mmol) was added dropwise at 20 °C and the mixture was stirred for 2 h. The mixture was quenched with 10% aqueous NH4Cl (60 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 20 mL), and the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 31 (57.3 mg, 12.1%).
1H NMR (400 MHz, CDCl
3) δ
H 4.10-3.97 (m, 1H), 2.17-2.11 (m, 1H), 2.05-1.75 (m, 9H), 1.72-1.59 (m, 3H), 1.53-1.22 (m, 9H), 1.20-1.01 (m, 8H), 0.69 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -72.218, -78.648.
[0577] Example 32: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-methoxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-
[0578] Synthesis of 32.1 [0579] To a suspension of MePPh3Br (2.76 g, 7.74 mmol) in THF (20 mL) was added t- BuOK (868 mg, 7.74 mmol) at 25 °C under N
2 and the resulting mixture was stirred at 50 °C for 30 min.27.2 (1 g, 2.58 mmol) in THF (5 mL) was added in portions at 50 °C and the mixture was stirred for 1 h. The mixture was quenched at 15 °C with 10% aqueous NH4Cl (20 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers were concentrated under vacuum to give a residue, which was purified by silica gel chromatography (0~10% EtOAc in PE) to give 32.1 (0.9 g).
1H NMR (400 MHz, CDCl
3) δ
H 5.77-5.60 (m, 1H), 4.94-4.78 (m, 2H), 2.20-1.65 (m, 10H), 1.54-1.30 (m, 6H), 1.2 -0.91 (m, 15H), 0.68 (s, 3H). [0580] Synthesis of 32.2 [0581] To a solution of 32.1 (900 mg, 2.34 mmol) in DCM (20 mL) was added m-CPBA (949 mg, 85%, 4.68 mmol) at 25 °C and the resulting mixture was stirred for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (20 mL) at 25 °C. The organic layer was separated and washed with saturated aqueous NaHCO
3/Na2S2O
3 (1:1, 2 x 40 mL) and brine (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under vacuum to give
32.2 (900 mg).
1H NMR (400 MHz, CDCl
3) δ
H 2.87-2.60 (m, 3H), 2.12-1.68 (m, 14H), 1.49-1.28 (m, 11H), 1.16-1.10 (m, 2H), 0.98-0.94 (m, 4H), 0.64 (s, 3H). [0582] Synthesis of 32 [0583] To a solution of 32.2 (900 mg, 2.17 mmol) in MeOH (10 mL) was added sodium methoxide (3.51 g, 65.1 mmol) and the resulting mixture was stirred at 50 °C for 16 h. The mixture was quenched with 10% aqueous NH4Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NH
4Cl (10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc = 30/1 to 20/1). The resulting residue was further purified from MeCN (6 mL) to give 32 (18.8 mg, 53.8%).
1H NMR (400 MHz, CDCl
3) δ
H 3.94-3.82 (m, 1H), 3.49-3.37 (m, 4H), 3.33-3.18 (m, 1H), 2.36-2.25 (m, 1H), 2.12-1.63 (m, 11H), 1.50-1.19 (m, 9H), 1.16-0.89 (m, 11H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.789. LC- ELSD/MS purity 100%, MS ESI calcd. for C24H36F
3O [M+H-H
2O-CH
3OH]
+ 397.3, found 397.3. [0584] Example 33: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-(fluoromethyl)- 10,13-dimethyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (33)
[0585] Synthesis of 33.1 [0586] To a solution of 3.4 (800 mg, 2.15 mmol), HMPA (390 mg, 2.36 mmol), and ((fluoromethyl)sulfonyl)benzene (1.73 g, 10.7 mmol) in anhydrous THF (15 mL) under N2 at -70 °C was added LiHMDS (1 M in THF, 10.7 mL, 10.7 mmol) dropwise. The reaction mixture was stirred for 1 h at -70 °C and further stirred for 1 h at 25 °C. The mixture was
poured into saturated aqueous NHCl
4 (20 mL), stirred for 20 min and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE). The resulting residue was further purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); gradient: 50-50 % B (A= 0.1%NH3/H
2O, B=EtOH), flow rate: 70 mL/min) to give 33.1 (200 mg, 50.1%).
1H NMR (400MHz, CDCl3) δ
H 7.98-7.96 (m, 2H), 7.77-7.68 (m, 1H), 7.66-7.56 (m, 2H), 5.39-5.19 (m, 1H), 4.11-3.97 (m, 1H), 3.30 (s, 1H), 2.45-2.41 (m, 1H), 2.21-2.19 (m, 1H), 2.02-1.78 (m, 6H), 1.77-1.59 (m, 3H), 1.51-1.36 (m, 7H), 1.28-1.17 (m, 4H), 1.16-1.03 (m, 6H), 0.98 (s, 3H), 0.71-0.62 (m, 3H).
19F NMR (400 MHz, CDCl
3) δ
F -72.21, -187.00. [0587] Synthesis of 33 [0588] To a mixture of 33.1 (200 mg, 0.3479 mmol) and anhydrous NaH
2PO
4 (136 mg, 1.14 mmol) in anhydrous MeOH (20 mL) at 25 °C under N2 was added Na/Hg amalgam (777 mg 3.47 mmol) and the resulting mixture was stirred for 16 h. The mixture was poured into 10% aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH4Cl (20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 33 (117.3 mg, 77.4%).
1H NMR (400MHz, CDCl3) δH 4.53-4.30 (m, 2H), 4.09-3.99 (m, 1H), 2.21-2.07 (m, 2H), 2.02-1.80 (m, 5H), 1.79-1.72 (m, 1H), 1.63-1.61 (m, 2H), 1.53-1.29 (m, 9H), 1.28-1.20 (m, 3H), 1.18-1.05 (m, 7H), 0.95 (s, 3H), 0.67 (s, 3H).
19F NMR (400 MHz, CDCl3) δ
F -72.22, -233.67. LC-ELSD/MS purity >=99%, MS ESI calcd. For C24H38NaF4O
2 [M+Na]
+457.3, found 457.3. [0589] Example 34: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxypent-4-yn-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (34)
[0590] Ethynylmagnesiumbromide (74.4 mL, 37.2 mmol, 0.5 M in THF) was reacted with a solution of 27.2 (5 g, 12.4 mmol) in THF (50 mL) at 25 °C. After stirring at 60 °C for 10
min, the mixture was poured into saturated aqueous NH
4Cl (150 mL), and the aqueous phase was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to afford 34 (500 mg, 9.46%).
1H NMR (400 MHz, CDCl3) δH 4.45 (s, 1H), 2.43-2.40 (m, 1H), 2.05-1.80 (m, 7H), 1.75-1.54 (m, 6H), 1.43-1.20 (m, 10H), 1.15-1.03 (m, 6H), 0.96 (s, 3H), 0.68 (s, 3H). LC-ELSD/MS purity >99%, MS ESI calcd for C
25H
36F
3O [M-H
2O+H]
+ 409.3, found 409.3.
19F NMR (376.5 MHz, CDCl3) δF -78.774. [0591] Example 35: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-3- propyl-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (35)
[0592] Synthesis of 35.1 [0593] To a solution of BHT (1.68g, 7.66 mmol) in toluene (10 mL) under N
2 at 0 °C was added AlMe3 (1.91 mL, 2 M in toluene, 3.83 mmol) dropwise slowly. After stirring at 25 °C for 1 h, a solution of 3.4 (400 mg, 0.999 mmol) in DCM (5 mL) was added dropwise at -70 °C and stirred for 1 h under N
2. n-PrMgBr (2.49 mL, 4.99 mmol, 2 M in THF) was added dropwise at -70 °C and the resulting solution was stirred at -70 °C for 2 h. The reaction was quenched with NH4Cl (50 mL, sat. aq.) and extracted with EtOAc (2 x 30 mL). The combined organic layers were separated, dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~10% of EtOAc in PE) to give 35.1 (180 mg, 90.4%).
1H NMR (400 MHz, CDCl3) δH 4.11-3.96 (m, 1H), 2.14 (d, J = 6.4
Hz, 1H), 2.00-1.76 (m, 5H), 1.73-1.59 (m, 2H), 1.49-1.32 (m, 11H), 1.28-1.18 (m, 5H), 1.14- 1.04 (m, 6H), 0.99-0.83 (m, 9H), 0.68-0.64 (m, 3H). [0594] Synthesis of 35.2 [0595] To a solution of 35.1 (180 mg, 0.405 mmol) in pyridine (2 mL) was added DMAP (2.18 mg, 0.0405 mmol) and BzCl (170 mg, 1.21 mmol) at 25 °C and the resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was washed with water (20 mL) and the aqueous phase extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE). The resulting residue was further purified by prep-SFC (Column: DAICEL CHIRALPAK AD(250 mm*30 mm,10 um); Condition: 0.1%NH
3H
2O EtOH; Begin B: 20; End B: 20; ) to give 35.2 (100 mg, 33.4%). 35.2:
1H NMR (400 MHz, CDCl3) δH 8.14-8.02 (m, 2H), 7.64-7.57 (m, 1H), 7.51-7.44 (m, 2H), 5.57 (dq, J = 3.2, 7.8 Hz, 1H), 2.03-1.79 (m, 5H), 1.74-1.62 (m, 2H), 1.54-1.31 (m, 12H), 1.29-1.04 (m, 12H), 0.97-0.89 (m, 6H), 0.65 (s, 3H). [0596] Synthesis of 35 [0597] To a solution of 35.2 (100 mg, 0.182 mmol) in THF (10 mL), MeOH (3 mL) and H
2O (0.5 mL) at 25 °C was added NaOH (72.8 mg, 1.81 mmol) in one portion. After stirring at 25 °C for 1 h, the mixture poured into water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and purified from MeCN (10 mL) to give 35 (69.4 mg, 85.6%).
1H NMR (400 MHz, CDCl
3) δ
H 4.12-3.97 (m, 1H), 2.13 (d, J = 6.4 Hz, 1H), 2.00-1.78 (m, 5H), 1.73-1.56 (m, 2H), 1.52-1.27 (m, 14H), 1.26-1.00 (m, 11H), 0.94 (s, 6H), 0.67 (s, 3H). LC-ELSD/MS purity 100%, MS ESI calcd. For C26H42F
3O [M+H-H
2O]
+ 427, found 427. [0598] Example 36: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-methoxybutan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (36)
[0599] Synthesis of 36.1 [0600] To a suspension of MePPh3Br (2.76 g, 7.74 mmol) in THF (20 mL) was added t- BuOK (866 mg, 7.74 mmol) at 25 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.31.6 (1 g, 2.58 mmol) in THF (5 mL) was added in portions at 50 °C and stirred for 1 h. The reaction mixture was quenched with 10% aqueous NH4Cl (20 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 30 mL), and the combined organic layers were concentrated under vacuum to give a residue, which was purified by silica gel chromatography (0~10% EtOAc in PE) to give 36.1 (0.9 g).
1H NMR (400 MHz, CDCl3) δH 5.77-5.60 (m, 1H), 5.04-4.76 (m, 2H), 2.09-1.75 (m, 11H), 1.53- 1.40 (m, 5H), 1.14-0.82 (m, 13H), 0.72 (s, 3H). [0601] Synthesis of 36.2 [0602] To a solution of 36.1 (900 mg, 2.34 mmol) in DCM (20 mL) was added m-CPBA (949 mg, 85%, 4.68 mmol) at 25 °C and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (20 mL), and the organic layer was separated. The organic layer was then washed with saturated aqueous NaHCO
3/Na2S2O
3 (1:1, 2 x 20 mL) and brine (40 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum to give 36.2 (1.2 g).
1H NMR (400 MHz, CDCl
3) δ
H 2.92-2.37 (m, 3H), 2.14- 1.68 (m, 10H), 1.52-1.24 (m, 9H), 1.18-0.90 (m, 10H), 0.69-0.62 (m, 3H). [0603] Synthesis of 36 [0604] To a solution of 36.2 (900 mg, 2.24 mmol) in MeOH (20 mL) was added sodium methoxide (3.63 g, 67.2 mmol) and the resulting mixture was stirred at 50 ℃ for 16 h. The
mixture was quenched with 10% aqueous NH
4Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated aqueous NH4Cl (10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% of EtOAc in PE). The resulting residue was further purified from MeCN (10 mL) at 50 °C to give 36 (52.4 mg, 65.5%).
1H NMR (400 MHz, CDCl3) δH 3.95- 3.80 (m, 1H), 3.49-3.34 (m, 4H), 3.33-3.20 (m, 1H), 2.31(s, 1H), 2.08-1.58 (m, 12H), 1.53- 1.32 (m, 6H), 1.27-0.88 (m, 11H), 0.68 (s, 3H). LC-ELSD/MS purity 100%, MS ESI calcd. for C23H34F
3O [M+H-H
2O-CH
3OH]
+ 383.2, found 383.2.
19F NMR (376.5 MHz, CDCl3) δF - 78.654. [0605] Example 37: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-3- (pyridin-3-yl)-17-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (37)
[0606] Pyridin-3-ylmagnesium bromide (12 mL, 0.5 M in THF) was reacted with a solution of 3.4 (300 mg, 0.749 mmol) in THF (6 mL) at 25 °C under N2 and the resulting mixture was stirred for 1 h. The reaction mixture was slowly poured into 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH4Cl (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (1~15% EtOAc in PE). The resulting residue was further purified from MeCN (10 mL) at 60 °C to give 37 (61 mg, 61.1%).
1H NMR (400MHz, DMSO-d
6) δ
H 8.74-8.70 (m, 1H), 8.45-8.38 (m, 1H), 7.80-7.76 (m, 1H), 7.34-7.28 (m, 1H), 6.08-6.03 (m, 1H), 4.86 (s, 1H), 3.98-3.86 (m, 1H), 2.15-2.05 (m, 1H), 1.97-1.69 (m, 5H), 1.61-1.50 (m, 4H), 1.48-1.30 (m, 8H), 1.27-1.16 (m, 4H), 1.15-0.99 (m, 5H), 0.97 (s, 3H), 0.64 (s, 3H). LC-ELSD/MS purity 99%; MS ESI calcd. for C
28H
41F
3NO
2 [M+H]
+ 480, found 480.
19F NMR (376MHz, DMSO-d6) δ -70.395. [0607] Example 38: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxypentan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (38)
[0608] Ethylmagnesium bromide (1.24 mL, 3 M in Et
2O) was reacted with a solution of 27.2 (500 mg, 1.24 mmol) in THF (6 mL) at 50 °C under N2 and the resulting mixture was stirred at 50 °C for 1 h. The mixture was slowly poured into 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (2 x 10 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (1~15% EtOAc in PE) to give 38 (15.4 mg, 2.9%).
1H NMR (400 MHz, CDCl
3) δ
H 3.61-3.51 (m, 1H), 2.05-1.78 (m, 6H), 1.75-1.58 (m, 5H), 1.56- 1.26 (m, 8H), 1.25-1.16 (m, 5H), 1.15-1.00 (m, 4H), 0.99-0.85 (m, 9H), 0.66 (s, 3H). LC- ELSD/MS purity 99%; MS ESI calcd. For C25H40F
3O [M+H-H
2O]
+ 413, found 413.
19F NMR (376.5MHz, CDCl3) δF -78.59. [0609] Example 39: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (39)
[0610] Methylmagnesium bromide (1.24 mL, 3 M in Et
2O) was reacted with a solution of 27.2 (500 mg, 1.24 mmol) in THF (5 mL) at 50 °C under N
2 and the resulting mixture was stirred for 1 h. The mixture was slowly poured into 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (2 x 10 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (1~15% EtOAc in PE) to give 39 (44.1 mg, 8.54%).
1H
NMR (400MHz, CDCl
3) δ
H 3.96-3.81 (m, 1H), 2.01-.911 (m, 2H), 1.90-1.80 (m, 4H), 1.78- 1.61 (m, 6H), 1.60-1.49 (m, 4H), 1.47-1.31 (m, 3H), 1.30-1.23 (m, 3H), 1.22- 1.14 (m, 3H), 1.11-0.98 (m, 6H), 0.96 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.68 (s, 3H). LC-ELSD/MS purity 99%; MS ESI calcd. for C
24H
38F
3O [M+H-H
2O]
+, 399, found 399.
19F NMR (376MHz, CDCl3 ) δF -78.777. [0611] Example 40: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-10,13-dimethyl-17- ((2S,3S)-6,6,6-trifluoro-3-hydroxyhex-4-yn-2-yl)-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (40)
[0612] To a solution of 2-bromo-3,3,3-trifluoroprop-1-ene (650 mg, 3.72 mmol) in THF (20 mL) was added lithium diisopropylamide (1.86 mL, 2 M in THF/heptane/ethylbenzene, 3.72 mmol) dropwise at -70 °C under N2 and the resulting mixture was stirred at 0 °C for 30 min.27.2 (500 mg, 1.24 mmol) was added and the mixture was stirred at 25 °C for 16 h. The mixture was poured into saturated aqueous NH
4Cl (20 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 20 mL), and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 40 (150 mg, 24.4%).
1H NMR (400MHz, CDCl
3) δ
H 4.56 (s, 1H), 2.01-1.88 (m, 5H), 1.88-1.58 (m, 7H), 1.53-1.38 (m, 4H), 1.37-1.11 (m, 9H), 1.09-1.07 (m, 4H), 0.96 (s, 3H), 0.69 (s, 3H).
19F NMR (400 MHz, CDCl
3) δ
F -50.09, -78.78. [0613] Example 41: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxy-4-methylpentan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (41)
[0614] Synthesis of 41.1 [0615] To a solution of 27.2 (500 mg, 1.24 mmol) in THF (6 mL) was added isopropylmagnesium chloride (911 mg, 3.09 mL, 6.19 mmol, 2 M in THF) in one portion at 25 °C under N
2 and the resulting mixture was stirred for 1 h. The mixture was poured into saturated aqueous citric acid (10 mL) at 10 °C and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 41.1 (500 mg, 90.7%).
1H NMR (400 MHz, CDCl3) δH 3.20-3.10 (m, 1H), 2.02-1.81 (m, 6 H), 1.75-1.53 (m, 10 H), 1.51-1.29 (m, 8 H), 1.13-1.04 (m, 3 H), 1.03-0.98 (m, 3 H), 0.96 (s, 3 H), 0.90-0.85 (m, 3 H), 0.84-0.77 (m, 3 H), 0.67 (s, 3 H). [0616] Synthesis of 41.2 [0617] To a solution of 41.1 (500 mg, 1.12 mmol) in DCM (10 mL) was added DMP (712 mg, 1.68 mmol) at 25 °C and the resulting mixture was stirred for 30 min. The mixture was quenched with saturated aqueous NaHCO
3:Na
2S
2O
3 (20 mL, v:v = 1:1) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with saturated aqueous NaHCO
3: Na2S2O
3 (20 mL, v:v = 1:1), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 41.2 (270 mg, 55 %).
1H NMR (400 MHz, CDCl3) δH
2.73-2.62 (m, 2 H), 2.03 (s, 1 H), 1.98-1.80 (m, 4 H), 1.76-1.56 (m, 7 H), 1.44-1.22 (m, 8 H), 1.14-1.02 (m, 13 H), 0.96 (s, 3 H), 0.69 (s, 3 H).
19F
NMR (376.5 MHz, CDCl
3) δ
F -78.759. LC-ELSD/MS purity >=99%, MS ESI calcd. For C26H42F
3O
2 [M+H]
+ 443.3, found 443.3. [0618] Synthesis of 41 [0619] To a solution of 41.2 (230 mg, 0.52 mmol) in MeOH (10 mL) was added NaBH
4 (196 mg, 5.19 mmol) and the resulting mixture was stirred at 25 °C for 10 min. The mixture was quenched with 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 41 (61 mg, 26%).
1H NMR (400 MHz, CDCl3) δH 3.37 (t, J = 4.2 Hz, 1 H), 2.03-2.00 (m, 2 H), 1.98-1.57 (m, 11 H), 1.44-1.35 (m, 5 H), 1.34-1.01 (m, 9 H), 1.00- 0.94 (m, 9 H), 0.93-0.90 (m, 3 H), 0.67 (s, 3 H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.774. LC-ELSD/MS purity >=99%, MS ESI calcd. For C26H42F
3O [M-H
2O+H]
+ 427 found 427. [0620] Example 42: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4,4-dimethylpentan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (42)
[0621] Synthesis of 42.1 [0622] To a solution of 27.2 (500 mg, 1.24 mmol) in THF (6 mL) was added t-BuMgCl (3.64 mL, 6.19 mmol, 2 M in Et2O) in one portion at 25 °C under N2 and the resulting mixture was stirred for 1 h. The reaction mixture was poured into saturated aqueous citric acid (10 mL) at 10 °C and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by
silica gel chromatography (0~30% EtOAc in PE) to give 42.1 (500 mg).
1H NMR (400 MHz, CDCl3) δH 3.30 (s, 1H), 2.02-1.55 (m, 15H), 1.54-1.30 (m, 7H), 1.22-1.00 (m, 5H), 0.97-0.94 (m, 4H), 0.94-0.78 (m, 10H), 0.69 (s, 3H). [0623] Synthesis of 42.2 [0624] To a solution of 42.1 (500 mg, 1.09 mmol) in DCM (10 mL) was added DMP (691 mg, 1.63 mmol) at 25 °C and the resulting mixture was stirred for 30 min. The mixture was quenched with saturated aqueous NaHCO
3:Na
2S
2O
3 (20 mL, v:v = 1:1) and extracted with DCM (2 x 10 mL). The combined organic layers were washed with saturated aqueous NaHCO
3:Na2S2O
3 (20 mL, v:v = 1:1), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 42.2 (280 mg, 56%).
1H NMR (400 MHz, CDCl
3) δ
H 3.06-2.94 (m, 1H), 1.98-1.55 (m, 13H), 1.55-1.22 (m, 11H), 1.16-1.13 (m, 9H), 1.07-1.04 (m, 3H), 0.97 (s, 3H), 0.70 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.751. LC-ELSD/MS purity >99%, MS ESI calcd. For C
27H
44F
3O
2 [M+H]
+ 457.3, found 457.3. [0625] Synthesis of 42 [0626] To a solution of 42.2 (230 mg, 0.50 mmol) in THF (5 mL) was added LiAlH4 (57.3 mg, 1.51 mmol) and the resulting mixture was stirred at 25 °C for 15 min. The mixture was quenched with 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with 10% aqueous NH4Cl (10 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 42 (109.7 mg, 47%).
1H NMR (400 MHz, CDCl
3) δ
H 3.30-3.25 (m, 1H), 2.08-2.01 (m, 1H), 1.98-1.56 (m, 9H), 1.55-1.35 (m, 7H), 1.33-1.06 (m, 7H), 1.05-1.01 (m, 3H), 0.97-0.96 (m, 12H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.774. LC- ELSD/MS purity >99%, MS ESI calcd. For C
27H
44F
3O [M-H
2O+H]
+ 441.3, found 441.4. [0627] Example 43: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-(5-methyl-2H-tetrazol-2-yl)butan-2-yl)-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (43)
[0628] To a solution of 32.2 (500 mg, 1.20 mmol) in DMF (5 mL) was added 5-methyl-2H- 1,2,3,4-tetrazole (121 mg, 1.43 mmol) and Cs2CO
3 (1.16 g, 3.59 mmol). After stirring at 120 °C for 16 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated and purified by silica gel chromatography (0~20% MeOH in DCM) to give 43 (24.4 mg, 4.1%).
1H NMR (400MHz, CDCl3) δH 4.66-4.63 (m, 1H), 4.48-4.41 (m, 1H), 4.21-4.17 (m, 1H), 2.62 (d, J = 3.6 Hz, 1H), 2.56 (s, 3H), 2.04-1.81 (m, 7H), 1.79-1.59 (m, 5H), 1.56 (s, 5H), 1.47-1.45 (m, 1H), 1.44- 1.34 (m, 3H), 1.34-1.19 (m, 4H), 1.08-1.06 (d, J = 6.8 Hz, 3H), 0.97 (s, 3H), 0.71 (s, 3H).
19F NMR (400 MHz, CDCl3) δF -78.78. LC-ELSD/MS purity >99%, MS ESI calcd. For C
26H
42F
3N
4O
2 [M+H]
+ 499.3, found 499.3. [0629] Example 44: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1S,2S)-1-(4- fluorophenyl)-1-hydroxypropan-2-yl)-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (44)
[0630] A solution of (4-fluorophenyl)magnesium bromide (6.19 mL, 6.19 mmol, 1 M in THF) was reacted with a solution of 27.2 (500 mg, 1.24 mmol) in THF (20 mL). After stirring at 25 °C for 1 h, the mixture was quenched with 10% aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (30 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% of EtOAc in PE) to give 44 (100 mg, 16.2%).
1H NMR (400MHz, CDCl3) δH 7.32-7.27 (m, 2H), 7.01 (t, J = 8.8 Hz, 2H), 4.82 (s, 1H), 2.10- 1.98 (m, 1H), 1.95-1.77 (m, 6H), 1.74-1.57 (m, 5H), 1.53-1.15 (m, 7H), 1.15-1.08 (m, 2H) 1.08-0.97 (m, 3H), 0.94 (s, 3H), 0.87-0.85 (m, 5H), 0.72 (s, 3H).
19F NMR (400 MHz, CDCl3) δF -78.814, -115.547. LC-ELSD/MS purity >=99%, MS ESI calcd. For C29H39F4O [M-2H
2O+H]
+ 461.4, found 461.4. [0631] Example 45: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1S,2S)-1-(3- fluorophenyl)-1-hydroxypropan-2-yl)-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (45)
[0632] A solution of (3-fluorophenyl)magnesium bromide (6.19 mL, 6.19 mmol, 1 M in THF) was reacted with a solution of 27.2 (500 mg, 1.24 mmol) in THF (20 mL). After stirring at 25 °C for 1 h, the mixture was quenched with 10% aqueous NH
4Cl (30 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with 10% aqueous NH4Cl (30 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 45 (100 mg, 16.2 %).
1H NMR (400MHz, CDCl3) δH 7.34-7.29 (m, 1H), 7.12-6.95 (m, 3H), 4.85 (s, 1H), 2.12-2.02 (m, 1H), 1.97-1.81 (m, 5H), 1.75-1.65 (m, 5H), 1.64-1.59 (m, 1H), 1.52-1.40 (m, 2H), 1.38-1.22 (m, 6H), 1.21-1.11 (m, 1H), 1.11-1.01 (m, 3H), 1.00-0.95 (m, 3H), 0.91-0.86 (m, 5H), 0.72 (s, 3H).
19FNMR (400 MHz, CDCl
3) δ
F -78.81, -113.53. LC-ELSD/MS purity >=99%, MS ESI calcd. For C29H37F4 [M-2H
2O+H]
+ 461.2, found 461.2. [0633] Example 46: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1R,2S)-1- cyclobutyl-1-hydroxypropan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (46)
[0634] To a suspension of Mg (2.13 g, 29.6 mmol) and I2 (100 mg) in THF (15 mL) under N
2 at 25 °C was slowly added bromocyclobutane (2 g, 14.8 mmol) in THF (5 mL). After stirring at 40 °C for 1 h, that solution was reacted with a solution of 27.2 (1 g, 2.49 mmol) in THF (10 mL) was added at 0 °C. After stirring at 25 °C for 2 h, the mixture was poured into water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were
washed with brine (2 x 10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~35% EtOAc in PE) to give 44 (53.5 mg, 4.73%).
1H NMR δH.3.61-3.51 (m, 1H), 2.57-2.44 (m, 1H), 2.08 (s, 1H), 2.00-1.70 (m, 16H), 1.40-1.22 (m, 10H), 1.15-1.03 (m, 5H), 0.95 (s, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.65 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.749. LC-ELSD/MS purity 100%, MS ESI calcd. For C27H42F
3O [M+H-H
2O]
+ 439, found 439. [0635] Example 47: Synthesis of 1-((2S,3S)-2-hydroxy-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)-1H-
[0636] To a solution of 33.2 (0.2 g, 0.5338 mmol) in DMF (5 mL) was added 1H-pyrazole- 4-carbonitrile (108 mg, 1.60 mmol) and Cs
2CO
3 (521 mg, 1.60 mmol) and the resulting mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated to give a residue, which was purified by silica gel chromatography (0~20% EtOAc in PE) to give 47 (43.9 mg, 30%).
1H NMR (400MHz, CDCl
3) δ
H 7.90 (s, 1H), 7.82 (s, 1H), 4.23 (d, J = 13.3 Hz, 1H), 4.12-3.91 (m, 2H), 2.40 (d, J = 2.8 Hz, 1H), 2.07-1.59 (m, 12H), 1.48-1.09 (m, 13H), 1.03 (d, J = 6.8 Hz, 3H), 0.97 (s, 3H), 0.70 (s, 3H). LC-ELSD/MS purity 99%; MS ESI calcd. for C
28H
4F
3N
3O
2 [M+H]+ 508, found 508.
19F NMR (376.5MHz, CDCl
3) δ
F - 78.786. [0637] Example 48: Synthesis of 1-((2S,3S)-2-hydroxy-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)pyrrolidin- 2-one (48)
[0638] To a solution of pyrrolidin-2-one (410 mg, 4.82 mmol) in THF (5 mL) was added NaH (110 mg, 4.82 mmol) in portions at 0 °C and the resulting mixture was stirred for 10 min. A solution of 32.2 (1 g, 2.41 mmol) in THF (10 mL) was added and the mixture was stirred at 80 °C for 12 h. The mixture was treated with water (10 mL) dropwise and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and the residue purified by HPLC (column: C18 (250mm*50mm,5um), gradient: 65-95%B (B = water(0.05%HCl)-ACN), flow rate: 30 mL/min) to give 48 (31.7 mg, 2.64 %).
1H NMR (400 MHz, CDCl3) δH 3.91-3.75 (m, 1H), 3.57-3.38 (m, 3H), 3.32-3.18 (m, 1H), 3.11-3.01 (m, 1H), 2.50-2.35 (m, 2H), 2.11- 1.51 (m, 15H), 1.44-1.07 (m, 12H), 1.01-0.87 (m, 6H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.784. LC-ELSD/MS purity >99%, MS ESI calcd. For C28H45F
3NO
3 [M+H]
+ 500.3, found 500.3. [0639] Example 49: Synthesis of 1-((2S,3S)-2-hydroxy-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)-1H- pyrazole-3-carbonitrile (49)
[0640] To a solution of 32.2 (500 mg, 4.14 mmol) in DMF (6 mL) was added 1H-pyrazole- 4-carbonitrile (385 mg, 4.14 mmol) and Cs
2CO
3 (1.34 g, 4.14 mmol) at 25 °C and the resulting mixture was stirred at 120 °C for 3 h. The reaction mixture was diluted with water
(50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated, and the resulting residue was purified by silica gel chromatography (0~20% EtOAc in PE). The residue was further purified by Prep-HPLC ((column: Xbridge 150*30mm*10um), gradient: 75-95% B (A= water (10mM NH
4HCO
3), B = MeCN), flow rate: 25 mL/min) to give 49 (40 mg).
1H NMR (400 MHz, CDCl3) δH 7.54 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 4.30-3.96 (m, 3H), 2.30 (d, J = 3.2 Hz, 1H), 2.03-1.90 (m, 4H), 1.88-1.80 (m, 3H), 1.78-1.61 (m, 4H), 1.50-1.31 (m, 5H), 1.33-1.20 (m, 5H), 1.18-1.08 (m, 3H), 1.05-0.90 (m, 7H), 0.69 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.795. LC- ELSD/MS purity 99%; MS ESI calcd. For C28H41F
3N3O
2 [M+H]
+ 508.3, found 508.3. [0641] Example 50: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1S,2S)-1-(3,5- difluorophenyl)-1-hydroxypropan-2-yl)-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (50)
[0642] A solution of (3,5-difluorophenyl)magnesium bromide (1.86 mL, 2 M in PhMe) was reacted with a solution of 27.2 (500 mg, 1.24 mmol) in THF (6 mL) at 50 °C under N2. The mixture was stirred for 1 h and then was slowly poured into 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH4Cl (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (1~15% EtOAc in PE) to give 50 (11.9 mg, 1.86%).
1H NMR (400MHz, CDCl
3) δ
H 6.86 (d, J = 6.4 Hz, 2H), 6.76-6.64 (m, 1H), 4.80 (s, 1H), 2.08-1.98 (m, 1H), 1.94-1.85 (m, 4H), 1.80-1.61 (m, 5H), 1.54-1.40 (m, 4H), 1.34-1.21 (m, 6H), 1.09-0.92 (m, 7H), 0.90-0.79 (m, 5H), 0.71 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF - 78.804, -110.315. LC-ELSD/MS purity 100%; MS ESI calcd. for C
29H
38F
5O [M-H
2O+H]
+ 497.3, found 497.3. [0643] Example 51: Synthesis of 1-((2S,3S)-2-hydroxy-3- ((3R,5R,8R,9S,10S,13S,14S,17R)-3-hydroxy-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)pyridin- 2(1H)-one (51)
[0644] To a solution of 32.2 (400 mg, 0.9648 mmol) in DMF (5 mL) was added 1,2- dihydropyridin-2-one (109 mg, 1.15 mmol), Cs
2CO
3 (941 mg, 2.89 mmol) and DIPEA (373 mg, 2.89 mmol). After stirring at 120 °C for 16 h, the mixture was quenched with 10% aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with 10% aqueous NH4Cl (30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The resulting residue was purified by HPLC (column: Phenomenex Gemini-NX (80*30mm*3um), gradient: 62-92% B (A = water (10mM NH4HCO
3), B = ACN), flow rate: 30 mL/min) to give a mixture of 51 and NAM-102-034A (200 mg), which were separated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm,10 um), gradient: 40-40% B (A= 0.1%NH
3/H
2O, B = EtOH), flow rate: 70 mL/min) to give 51 (14.3 mg, 14.3%).
1H NMR (400MHz, CDCl3) δH 7.40-7.34 (m, 1H), 7.30-7.28 (m, 1H), 6.62-6.59 (m, 1H), 6.24-6.21 (m, 1H), 3.96 (s, 3H), 3.62-3.61 (m, 1H), 2.08-1.75 (m, 8H), 1.74-1.59 (m, 4H), 1.49-1.35 (m, 5H), 1.33-1.20 (m, 5H), 1.15-1.03 (m, 6H), 0.97 (s, 3H), 0.69 (s, 3H).
19F NMR (400 MHz, CDCl3) δF 78.75. LC-ELSD/MS purity >99%, MS ESI calcd. For C29H43F
3NO
3 [M+H]
+510.3, found 510.3. [0645] Example 52: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-isopropoxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (52)
[0646] NaH (858 mg, 21.5 mmol, 60% in kerosene) was added to i-PrOH (10 mL) at 25 °C and the resulting mixture was stirred at 80 °C for 1 h under N2.32.2 (600 mg, 1.44 mmol) was added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was treated with water (5 mL) and extracted with EtOAc (2 x 5 mL) and the combined organic layers were washed with water (2 x 5 mL) and brine (10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, purified by silica gel chromatography (0~50% EtOAc in PE), and further purified by HPLC (Column: Welch Xtimate C18150*25mm*5um; Condition: water (0.05%NH3H
2O+10mM NH4HCO
3)-ACN; Begin B: 75; End B: 100; Gradient Time(min): 12.5; 100% B Hold Time(min): 2; Flow Rate(ml/min): 30; Injections 4). The resulting residue was further purified by silica gel chromatography (0~20% EtOAc in PE) to give 52 (11.4 mg, 14.3%).
1H NMR (400 MHz, CDCl
3) δ
H 3.87-3.76 (m, 1H), 3.65-3.55 (m, 1H), 3.52-3.45 (m, 1H), 3.28-3.19 (m, 1H), 2.04-1.87 (m, 4H), 1.84-1.69 (m, 4H), 1.66-1.50 (m, 7H), 1.45-1.22 (m, 8H), 1.20-1.15 (m, 6H), 1.12-1.02 (m, 3H), 0.98-0.90 (m, 6H), 0.67 (s, 3H). LC-ELSD/MS purity >99%, MS ESI calcd for C
24H
36F
3O [M-C
3H
10O
2+H]
+ 397.3, found 397.3.
19F NMR (376.5 MHz, CDCl3) δF -78.775. [0647] Example 53: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxyhex-4-yn-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (53)
[0648] A solution of (prop-1-yn-1-yl)magnesium bromide (7.86 mL, 3.93 mmol, 0.5 M in THF) was reacted with a solution of 31.6 (315 mg, 0.79 mmol) in THF (3 mL) at 50 °C and the resulting mixture was stirred at 50 °C for 1 h. The mixture was poured into 10% aqueous NH
4Cl (3 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 53 (100.8 mg), which was further purified by silica gel chromatography (0~5% MeOH in DCM:PE (1:1)) to give 53 (45.7 mg, 13.6%).
1H NMR (400 MHz, CDCl
3) δ
H 4.45-4.35 (m, 1H), 2.03-1.76 (m, 11H), 1.67-1.39 (m, 10H), 1.33-1.20 (m, 4H), 1.16-1.00 (m, 8H), 0.69 (s, 3H). LC-ELSD/MS purity >99%,
MS ESI calcd. for C
25H
36F
3O [M+H-H
2O]
+ 409.3, found 409.3.
19F NMR (376.5 MHz, CDCl3) δF -78.646. [0649] Example 54: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-4- (difluoromethoxy)-3-hydroxybutan-2-yl)-10,13-dimethyl-3- (trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (54)
[0650] Synthesis of 54.1 [0651] To a solution of 32.2 (200 mg, 0.482 mmol) in THF (4 mL) and H
2O (1 mL) was added TsOH (16.6 mg, 0.0964 mmol) at 25 °C and the resulting mixture was stirred at 60 °C for 16 h. The mixture was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with water (2 x 5 mL) and brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 54.1 (200 mg).
1H NMR (400 MHz, CDCl3) δH 3.84-3.72 (m, 1H), 3.68-3.60 (m, 1H), 3.55-3.47 (m, 1H), 2.12-2.05 (m, 1H), 2.01-1.79 (m, 6H), 1.77- 1.61 (m, 5H), 1.50-1.22 (m, 11H), 1.16-1.01 (m, 4H), 1.00-0.88 (m, 6H), 0.67 (s, 3H). [0652] Synthesis of 54 [0653] To a solution of 54.1 (200 mg, 0.462 mmol) in DCM (5 mL) and water (5 mL) was added TMSCF
2Br (749 mg, 3.69 mmol) and KOAc (361 mg, 3.69 mmol) at 20 °C. After stirring at 20 °C for 48 h, the reaction mixture was diluted with water (40 mL) and DCM (40 mL). The organic phase was separated, washed with brine (40 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) twice to give 54 (13.5 mg, 6.78%).
1H NMR (400 MHz, CDCl
3) δ
H 6.50-6.05 (m, 1H),
3.97-3.87 (m, 2H), 3.78-3.69 (m, 1H), 2.06 (d, J = 2.8 Hz, 1H), 2.03-1.59 (m, 12H), 1.47- 1.34 (m, 5H), 1.30-1.04 (m, 8H), 1.00-0.93 (m, 6H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.795, -83.364, -83.778, -84.036, -84.460. LC-ELSD/MS purity 99%, MS ESI calcd for C
24H
36F
3O [M-HOCHF
2-H
2O+H]
+ 397.3, found 397.3. [0654] Example 55: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3S)- 3-hydroxypent-4-yn-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren- 3-ol (55)
[0655] To a solution of 2.2 (380 mg, 1.05 mmol) in THF (10 mL) was added ethynylmagnesium bromide (0.5 M in THF, 5 mL, 5.25 mmol) at 0 °C under N2 and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was slowly quenched with saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~25% EtOAc in PE). The resulting residue was further purified from MeCN (5 mL) and then lyophilized to give 55 (59.5 mg, 14.7%).
1H NMR (400 MHz, CDCl3) δH 4.45 (s, 1H), 2.42 (d, J = 2.0 Hz, 1H), 2.02-1.94 (m, 1H), 1.88 -1.57 (m, 8H), 1.50-1.17 (m, 15H), 1.14-0.96 (m, 7H), 0.93 (s, 3H), 0.87 (t, J = 7.6 Hz, 3H), 0.67 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C26H41O [M-H
2O+H]
+ 369.3, found 369.4. [0656] Example 56: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3S)- 3-hydroxyhex-4-yn-2-yl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren- 3-ol (56)
[0657] To a solution of 2.2 (500 mg, 1.38 mmol) in THF (10 mL) was added (prop-1-yn-1- yl)magnesium bromide (0.5 M in THF, 13.7 mL, 6.85 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was slowly quenched with saturated aqueous NH4Cl (10 mL). The resulting mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~25% EtOAc in PE). The resulting residue was further purified from MeCN (5 mL) at 70 °C to give 56 (11.6 mg, 2.1%).
1H NMR (400 MHz, CDCl3) δH 4.38- 4.43 (m, 1 H), 1.96-2.01 (m, 1 H), 1.87-1.91 (m, 1 H), 1.85-1.87 (m, 3 H), 1.77-1.85 (m, 2 H), 1.63-1.73 (m, 3 H), 1.57-1.63 (m, 4 H), 1.33-1.48 (m, 7 H), 1.19-1.30 (m, 6 H), 1.05-1.16 (m, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 0.95-1.00 (m, 1 H), 0.93 (s, 3 H), 0.87 (t, J = 7.6 Hz, 3 H), 0.66 (s, 3 H). LC-ELSD/MS purity 100%, MS ESI calcd. for C
27H
41 [M-2H
2O+H]
+ 365.4, found 365.4. [0658] Example 57: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (57)
[0659] A solution of 31.6 (200 mg, 0.51 mmol) in THF (3 mL) was reacted with MeMgBr (0.686 mL, 2.05 mmol, 3 M in Et
2O) at 0 °C and the resulting mixture was stirred for 12 h. The reaction mixture was quenched with 10% aqueous NH4Cl (10 mL) and extracted with
EtOAc (2 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (13%~ 15% EtOAc in PE). The resulting residue was further purified from CH
3CN (3 mL) to give 57 (8.8 mg, 4.2%).
1H NMR (400 MHz, CDCl
3) δ
H 3.96-3.88 (m, 1H), 2.07-1.90 (m, 4H), 1.88-1.77 (m, 3H), 1.74-1.62 (m, 4H), 1.51-1.40 (m, 4H), 1.37-1.31 (m, 1H), 1.28-1.18 (m, 3H), 1.15-1.06 (m, 6H), 1.03 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.62 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.64. LC-ELSD/MS purity 98%, MS ESI calcd. For C23H36F
3O [M-H
2O+H] 385.5, found 385.5. [0660] Example 58: Synthesis of (3R,5R,8S,9S,10S,13R,14S,17R)-17-((S)-2- hydroxypent-3-yn-1-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (58)
[0661] Synthesis of 58.2 [0662] To a solution of 58.1 (100 g, 344 mmol) in THF (1000 mL) was added CsF (10.4 g, 68.8 mmol) and TMSCF
3 (97.8 g, 688 mmol) at 0 °C under N2 and the resulting mixture was stirred at 25 °C for 30 min. TBAF∙3H
2O (229 g, 688 mmol) was added and the mixture was stirred at 25 °C for 1 h. The mixture was filtered and washed with EtOAc (2 x1000 mL) to give 58.2 (130 g), which was used directly in the next step without further purification. [0663] Synthesis of 58.3 [0664] To a solution of 58.2 (130 g, 360 mmol) in DCM (1000 mL) at 25 °C was added DMP (305 g, 720 mmol) and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (1000 mL) and saturated aqueous Na
2S
2O
3 (1000 mL). The mixture was extracted with DCM (2 x 1000 mL) and the combined organic layers were washed with saturated aqueous NaHCO
3 (1000 mL) and saturated aqueous Na2S2O
3 (1000 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 58.3 (130 g). [0665] Synthesis of 58.4 [0666] To a stirred solution of sodium hydride (6.6 g, 275 mmol, 60 % in oil) in THF (500 mL) was added ethyl-2-(diethoxyphosphanyl)acetate (65.4 g, 292 mmol) at 60 °C and the resulting mixture was stirred for 30 min under N2. A solution of 58.3 (30 g, 83.6 mmol) in THF (300 mL) was added and the mixture was stirred at 60 °C for 16 h. The mixture was cooled, poured into ice-water (300 mL), and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na
2SO
4,
filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) twice to give 58.4 (21 g, 58.7%).
1H NMR (400 MHz, CDCl3) δH 5.52 (t, J = 2.4 Hz, 1H), 4.18-4.13 (m, 2H), 2.89-2.76 (m, 2H), 2.01-1.69 (m, 9H), 1.56-1.39 (m, 7H), 1.28 (d, J = 2.8 Hz, 3H), 1.25 (s, 3H), 1.18-1.08 (m, 2H), 0.98 (s, 3H), 0.81 (s, 3H). [0667] Synthesis of 58.5 [0668] To a solution of 58.4 (5 g 11.6 mmol) in EtOH (50 mL) was added Pd/C (600 mg, wet, 10%) under N
2. The suspension was degassed under vacuum and purged with H
2 three times. The mixture was stirred at 30 °C for 16 h under H
2 (50 psi). The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give 58.5 (10 g).
1H NMR (400 MHz, CDCl
3) δ
H 4.11 (q, J = 6.8 Hz, 2H), 2.38-2.30 (m, 1H), 2.15-1.63 (m, 14H), 1.56-1.35 (m, 7H), 1.24 (s, 3H), 1.15-1.04 (m, 4H), 0.97 (s, 3H), 0.59 (s, 3H). [0669] Synthesis of 58.6 [0670] To a solution of 58.5 (2 g, 4.64 mmol) in THF (20 ml) was added LAH (170 mg, 4.64 mmol) at 0 °C under N2 and the resulting mixture was stirred at 25 °C for 1 h. H
2O (10 mL) was added to the reaction and the mixture was diluted with 1 M HCl to adjust to pH ~6.5. The mixture was extracted with EtOAc (20 mL x 2) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 58.6 (900 mg, 2.31 mmol).
1H NMR (400 MHz, CDCl3) δH 3.73-3.54 (m, 2H), 2.06-1.62 (m, 12H), 1.50-1.33 (m, 7H), 1.30-1.06 (m, 8H), 0.97 (s, 3H), 0.58 (s, 3H). [0671] Synthesis of 58.7 [0672] To a solution of 58.6 (900 mg, 2.31 mmol) in DCM (10 mL) was added DMP (3.91 g, 9.24 mmol) at 30 °C. To the suspension was added H
2O (4 mL, 1.54 mmol) at 30 °C and the mixture was heated to 40 °C. The reaction mixture was stirred at 40 °C for 1 h and the mixture was quenched with saturated aqueous NaHCO
3 (30 mL) at 10 °C. The organic layer was separated and then washed sequentially with saturated aqueous NaHCO
3/Na
2S
2O
3 (1:1, 25 mL x 2) and brine (30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum to give 58.7 (670 mg). [0673] Synthesis of 58.8 [0674] To a solution of 58.7 (670 mg, 1.73 mmol) in THF (7 mL) was added (prop-1-yn-1- yl)magnesium bromide (0.5 M in THF, 17.3 mL, 8.65 mmol) at 0 °C under N2 and the resulting mixture was stirred at 25 °C for 2 h. The reaction was slowly quenched with saturated aqueous NH
4Cl (12 mL). The resulting mixture was extracted with DCM (3 x 10
mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~25% EtOAc in PE) to give 58.8 (450 mg, 61%). [0675] Synthesis of 58.9 [0676] To a solution of 58.8 (445 mg, 1.04 mmol) in pyridine (2 mL) was added BzCl (174 mg, 1.24 mmol 1.2 eq.) at 25 °C under N2 and the resulting mixture was stirred for 2 h. The reaction mixture was quenched with HCl (2 M, 10 mL) and was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0~25% EtOAc in PE). The resulting residue was further purified by chiral SFC (Column: DAICEL CHIRALPAK AD (250mm*30mm,10um); Condition: 0.1%NH3H
2O IPA; Begin B 30%; End B 30%; FlowRate(ml/min): 70; Injections: 60) to give 58.9 (183 mg, 45.7%).
1H NMR (400 MHz, CDCl3) δH 8.10-8.03 (m, 2H), 7.59-7.41 (m, 3H), 5.68-5.54 (m, 1H), 2.04-1.95 (m, 2H), 1.94-1.83 (m, 11H), 1.81-1.59 (m, 7H), 1.47-1.32 (m, 5H), 1.18-1.02 (m, 4H), 0.99-0.95 (m, 3H), 0.65-0.57 (m, 3H). [0677] Synthesis of 58 [0678] To 58.9 (158 mg, 0.297 mmol) was added LiOH∙H
2O (49.5 mg, 1.18 mmol), H
2O (2 mL, 0.297 mmol) and THF (2 mL), and the resulting mixture was stirred at 25 °C for 2 h. H
2O (20 mL) was added and the mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 2:1). The product was dissolved in DCM (50 mL), and washed with HCl (1 M, 10 mL), saturated aqueous NaHCO
3 (20 mL), and brine (20 mL). The organic layer was dried over anhydrous Na
2SO
4, filtered, and concentrated to give 58 (26.6 mg, 20.9%).
1H NMR (400 MHz, CDCl3) δH δ 4.41-4.22 (m, 1H), 2.00-1.83 (m, 8H), 1.80-1.63 (m, 7H), 1.49-1.33 (m, 5H), 1.32-1.20 (m, 5H), 1.18-1.05 (m, 4H), 0.81 (s, 3H), 0.58 (s, 3H).
19F NMR (400 MHz, CDCl
3) δ
F -78.90. LC-ELSD/MS purity 100%, MS ESI calcd.for C
25H
36F
3O [M-H
2O+H] 409.4, found 409.4. [0679] Example 59: Synthesis of (3R,5R,8R,9R,10S,13R,14S,17R)-17-((S)-2- hydroxypent-3-yn-1-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (59)
[0680] Synthesis of 59.2 [0681] To a solution of 59.1 (100 g, 364 mmol) in THF (1000 mL) was added Pd/C (10 g, wet, 10%) and 48% aqueous HBr (1 mL). The reaction mixture was degassed under vacuum and purged with H
2 five times. The mixture was stirred at 25 °C for 48 h under H
2 (20 psi). The reaction mixture was filtered through a pad of Celite and washed with THF (5 x 200 mL). The combined filtrates were concentrated to give 59.2 (100 g).
1H NMR (400 MHz, CDCl
3) δ
H 3.68-3.60 (m, 1H), 2.56 (t, J = 14.0 Hz, 1H), 2.25-2.00 (m, 6H), 1.90-1.77 (m, 2H), 1.75-1.57 (m, 5H), 1.55-1.40 (m, 3H), 1.35-1.00 (m, 7H), 0.76 (s, 3H). [0682] Synthesis of 59.3 [0683] To a solution of 59.2 (100 g, 361 mmol) in THF (1 L) was added CsF (16.2 g, 72.2 mmol) at 0 °C and the resulting mixture was stirred for 10 min. TMSCF
3 (102 g, 722 mmol) was added and the mixture was stirred at 25 °C for 1 h. TBAF∙3H
2O (227 g, 722 mmol) was added and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (400 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 59.3 (120 g). [0684] Synthesis of 59.4 [0685] To a solution of 59.3 (60 g, 173 mmol) in DCM (500 mL) was added DMP (146 g, 346 mmol) and the reaction mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated aqueous NaHCO
3 (500 mL) and saturated aqueous Na
2S
2O
3 (500 mL). After stirring at 25 °C for 15 min, the organic layer was separated and washed with saturated aqueous NaHCO
3 (500 mL) and saturated aqueous Na2S2O
3 (500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 59.4 (70 g). [0686] Synthesis of 59.5 [0687] To a stirred solution of NaH (11.4 g, 478 mmol, 60 % in oil) in THF (400 mL) was added ethyl-2-(diethoxyphosphanyl)acetate (113 g, 507 mmol) at 60 °C and the resulting mixture was stirred for 30 min under N
2. A solution of 59.4 (50 g, 145 mmol) in THF (500 mL) was added and the reaction mixture was stirred at 60 °C for 10 h. The mixture was cooled, poured into ice-water (500 mL), and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 59.5 (20 g, 40.2%).
1H NMR (400 MHz, CDCl3) δH 5.52 (t, J = 2.0 Hz, 1H), 4.22-4.08 (m, 2H), 2.15-2.00 (m, 2H), 2.09-1.67 (m, 8H), 1.55-1.34 (m, 6H), 1.32- 1.23 (m, 6H), 1.20-1.16 (m, 5H), 0.82 (s, 3H).
[0688] Synthesis of 59.6 [0689] To a solution of 59.5 (20 g, 48.2 mmol) in THF (200 mL) was added Pd/C (2 g, wet, 10% purity) and the resulting mixture was stirred at 25 °C under H
2 (15 psi) for 16 h. The reaction mixture was filtered through a pad of Celite, and the filter cake was washed with EtOAc (3 x 200 mL). The combined filtrates were concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 59.6 (15.4 g, 33.9 mmol). [0690] Synthesis of 59.7 [0691] To a stirred solution of 59.6 (5.0 g, 12 mmol) in THF (50 mL) was added LAH (455 mg, 12 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (100 mL) and the mixture was extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL) and brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/ EtOAc = 2:1) to afford 59.7 (4.1 g, 90.8%).
1H NMR (400 MHz, CDCl
3) δ
H 3.74-3.55 (m, 2H), 2.09-1.77 (m, 6H), 1.76-1.57 (m, 6H), 1.56-1.31 (m, 7H), 1.29- 1.16 (m, 3H), 1.14-0.98 (m, 6H), 0.60 (s, 3H). [0692] Synthesis of 59.8 [0693] To a solution of 59.7 (1 g, 2.67 mmol) in DCM (10 mL) was added DMP (4.49 g, 10.6 mmol) at 25 °C. To the suspension was added H
2O (0.1 mL) at 30 °C and the reaction mixture was heated to 40 °C. The reaction mixture was stirred at 40 °C for 1 h. The mixture was the filtered, and the organic layer was washed with saturated aqueous NaHCO
3/Na
2S
2O
3 (1:1, 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0~50% EtOAc in PE) to give 59.8 (877 mg, 88%).
1H NMR (400 MHz, CDCl3) δH 10.16-9.52 (m, 1H), 2.53-2.44 (m, 1H), 2.32- 2.14 (m, 1H), 2.05-1.80 (m, 8H), 1.69-1.45 (m, 8H), 1.31-1.01 (m, 9H), 0.61 (s, 3H). [0694] Synthesis of 59.9 [0695] To a solution of 59.8 (877 mg, 2.35 mmol) in THF (10 ml) was added (prop-1-yn-1- yl)magnesium bromide (0.5 M in THF, 23.4 ml, 11.7 mmol) at 0 °C under N
2 and the resulting mixture was stirred at 25 °C for 2 h. The reaction was slowly quenched with saturated aqueous NH4Cl (10 mL) and extracted with DCM (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~25% EtOAc in PE) to give 59.9 (744 mg, 76.6%).
1H NMR (400 MHz, CDCl3) δH 4.36-4.25 (m, 1H), 1.96-1.73 (m, 10H), 1.73-1.52 (m, 10H), 1.50-1.48 (m, 5H), 1.18-1.01 (m, 6H), 0.60 (s, 3H). [0696] Synthesis of 59.10
[0697] To a solution of 59.9 (500 mg, 1.21 mmol) in pyridine (5 mL) was added BzCl (254 mg, 1.81 mmol) at 25 °C under N2 and the resulting mixture was stirred for 2 h. The reaction was quenched with HCl (2 M in water, 5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~25% EtOAc in PE). The resulting residue was further purified by chiral SFC (Column: DAICEL CHIRALPAK AD (250mm*30mm,10um), Condition: 0.1%NH
3H
2O IPA; Begin B: 30%; End B: 30%; FlowRate(ml/min): 70; Injections: 60) to give 59.10 (205 mg, 51.2%). [0698] Synthesis of 59 [0699] To a solution of 59.10 (205 mg, 0.396 mmol) in THF (2 mL) and H
2O (2 mL) was added LiOH∙H
2O (66.2 mg, 1.58 mmol) and the resulting mixture was stirred at 25 °C for 2 h. The mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc =2:1). The product was dissolved in DCM (50 mL), washed with HCl (10 M in water, 10 mL), 10% aqueous NaHCO
3 (10 mL), and brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 59 (84.9 mg, 53%).
1H NMR (400 MHz, CDCl3) δH 4.30-4.25 (m, 1H), 2.06-1.93 (m, 3H), 1.93-1.83 (m, 6H), 1.81-1.70 (m, 6H), 1.60-1.53 (m, 6H), 1.52-1.42 (m, 3H), 1.31-1.22 (m, 2H), 1.12-1.05 (m, 5H), 0.59 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.65. LC-ELSD/MS purity 99%, MS ESI calcd for C
24H
34F
3O [M-H
2O+H]
+ 395.3, found 395.3. [0700] Example 60: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-3-ethyl-17-((2S,3S)- 4-fluoro-3-hydroxybutan-2-yl)-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (60)
[0701] Synthesis of 60.1 [0702] To a mixture of MePPh3Br (6.21 g, 17.4 mmol) in THF (30 mL) was added t-BuOK (1.95 g, 17.4 mol) at 25 °C under N2 and the resulting mixture was stirred at 40 °C for 30 min.2.2 (2.1 g, 5.82 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The resulting mixture was then stirred at 50 °C for 2 h. The reaction mixture was slowly quenched with 10% aq. NH4Cl (20 mL). The resulting mixture was extracted with DCM (3 x 20 mL) and the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 60.1 (1.04 g, 50%).
1H NMR (400 MHz, CDCl
3) δ
H 5.75-5.54 (m, 1H), 4.99 -4.74(m, 2H), 1.97-1.81 (m, 3H), 1.74-1.65 (m, 2H), 1.65-1.50 (m, 4H), 1.49-1.44 (m, 3H), 1.41-1.32 (m, 4H), 1.29-1.09 (m, 8H), 1.08-1.05 (m, 1H), 1.04-1.00 (m, 4H), 1.00-0.95 (m, 1H), 0.94- 0.91 (m, 3H), 0.87 (t, J = 7.6 Hz, 3H), 0.66 (s, 3H). [0703] Synthesis of 60.2 [0704] To a solution of 60.1 (400 mg, 1.11 mmol) in DCM (10 ml) was added m-CPBA (80% purity, 570 mg, 3.33 mmol) at 25 °C, and the resulting mixture was stirred for 3 h. The reaction was slowly quenched with NaOH (5 mL). The resulting mixture was extracted with DCM (3 x 25 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to give 60.2 (940 mg).
1H NMR (400 MHz, CDCl
3) δ
H 2.83-2.37 (m, 3H), 1.99-1.78 (m, 4H), 1.72-1.55 (m, 5H), 1.54-
1.34 (m, 8H), 1.33-1.17 (m, 7H), 1.12-1.08 (m, 4H), 1.04-0.97 (m, 1H), 0.97-0.94 (m, 1H), 0.94-0.92 (m, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.66 (s, 3H). [0705] Synthesis of 60 [0706] To a solution of 60.2 (680 mg, 1.81 mmol) was added TBAF (36.2 mmol) in 12 mL THF [TBAF (36.2 mmol) in 12 mL THF was prepared from 1 M TBAF in THF (36.2 mL)], and the mixture was stirred at 100 ℃ for 12 h. The resulting mixture was poured into H
2O (20 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 2:1) to afford 60 (32.7 mg, 4.6%).
1H NMR (400 MHz, CDCl
3) δ
H 4.60-4.05 (m, 2H), 4.02-3.91(m, 1H), 2.00-1.75 (m, 5H), 1.70- 1.53 (m, 6H), 1.45-1.35 (m, 8H), 1.30-1.17 (m, 4H), 1.15-1.05 (m, 4H), 1.00-0.90 (m, 7H), 0.88 (t, J = 7.6 Hz, 3 H), 0.66 (s, 3 H).
19F NMR (376.5 MHz, CDCl3) δF -232.49. LC- ELSD/MS purity 97.73%, MS ESI calcd for C25H42FO [M-H
2O+H] 377.5, found 377.5. [0707] Example 61: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((2S,3S)-3-hydroxyhex-4-yn-2-yl)-6a-methyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (61)
[0708] Synthesis of 61.1 [0709] To a solution of t-BuOK (32.5 g, 290 mmol) in THF (500 mL) was added 59.4 (50 g, 145 mmol) at 25 °C under N2 and the resulting mixture was stirred at 25 °C for 10 min. Methyl benzenesulfinate (45.2 g, 290 mmol) was added and the mixture stirred at 30 °C for 0.5 h. The mixture was quenched with H
2O (500 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers were separated, dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 61.1 (107 g). [0710] Synthesis of 61.2 [0711] To a mixture of 61.1 (68 g, 145 mmol) in xylene (400 mL) was added Na2CO
3 (2.17 g, 1.37 mmol) in portions. After stirring at 125 °C under N
2 for 12 h, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to give 61.2 (11 g, 22.1%).
1H NMR: (400 MHz, CDCl3) δH 7.45 (dd, J = 1.2, 6.0 Hz, 1H), 5.97 (dd, J = 3.2, 5.6 Hz, 1H), 2.34-2.28 (m, 1H), 2.07-1.99 (m, 1H), 1.88-1.69 (m, 8H), 1.57-1.52 (m, 3H), 1.42-1.18 (m, 7H), 1.01 (s, 3H).
19F NMR (400 MHz, CDCl
3) δ
F -78.69. [0712] Synthesis of 61.3
[0713] To a stirred solution of trimethylsulfoxonium iodide (963 mg, 4.38 mmol) in DMSO (7 mL) was added t-BuOK (491 mg, 4.38 mmol) at 20 °C and the resulting mixture was stirred for 0.5 h under N2. To the mixture was added 61.2 (1 g, 2.92 mmol) and the mixture was stirred at 20 °C for 1 h. The reaction was quenched with water (30 mL) and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 61.3 (1 g, 48.1%).
1H NMR: (400 MHz, CDCl3) δH
2.09-1.90 (m, 5H), 1.86-1.70 (m, 10H), 1.58-1.43 (m, 4H), 1.35-1.29 (m, 3H), 1.15-1.07 (m, 2H), 0.97 (s, 3H).
19F NMR (400 MHz, CDCl3) δF -78.639. [0714] Synthesis of 61.4 [0715] To a solution of EtPPh
3Br (4.15 g, 11.2 mmol) in THF (30 mL) was added t-BuOK (1.25 g, 11.2 mmol) and the resulting mixture was stirred for 0.5 h at 45 °C under N2. A solution of 61.3 (1 g, 2.80 mmol) in THF (10 mL) was added at 45 °C and the reaction mixture was stirred for 12 h. The mixture was poured into saturated aqueous NH
4Cl (30 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 61.4 (900 mg, 87.3%). [0716] Synthesis of 61.5 [0717] To a solution of 61.4 (900 mg, 2.44 mmol) in THF (6 mL) was added 9-BBN dimer (1.18 g, 4.88 mmol) under N
2 and the resulting mixture was stirred at 20 °C under N
2 for 12 h. The mixture was cooled to 0 °C and EtOH (1.34g, 29.2 mmol) and NaOH (7.3 mL, 4M, 29.2 mmol) were added. H
2O
2 (5.5 g, 30% purity, 48.8 mmol) was added dropwise to keep the internal temperature of the reaction mixture below 15 °C during the course of the addition. The temperature was then increased to 80 °C and the reaction mixture was stirred for 1 h. The mixture was poured into saturated aqueous Na2S2O
3 (30 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 61.5 (700 mg, 74.2%).
1H NMR: (400 MHz, CDCl
3) δ
H 3.89-3.77 (m, 1H), 2.09-2.02 (m, 1H), 1.95-1.68 (m, 9H), 1.64-1.41 (m, 7H), 1.35-1.23 (m, 7H), 1.22-1.08 (m, 3H), 0.80- 0.76 (m, 1H), 0.75 (s, 3H), 0.26-0.17 (m, 1H).
19F NMR (400 MHz, CDCl3) δF -78.618. [0718] Synthesis of 61.6
[0719] To a solution of 61.5 (700 mg, 1.81 mmol) in DCM (10 mL) was added silica gel (700 mg) and PCC (780 mg, 3.62 mmol), and the resulting mixture was stirred at 25 °C for 1 h and then concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 61.6 (600 mg, 86.3%).
1H NMR: (400 MHz, CDCl
3) δ
H 2.78-2.68 (m, 1H), 2.26-2.15 (m, 3H), 2.11-1.68 (m, 11H), 1.53-1.04 (m, 11H), 0.92-0.82 (m, 1H), 0.72 (d, J = 6.0 Hz, 3H), 0.47-0.35 (m, 1H).
19F NMR (400 MHz, CDCl3) δF -78.631. [0720] Synthesis of 61.7 [0721] To a solution of PPh3MeBr (1.67 g, 4.68 mmol) in THF (10 mL) was added t-BuOK (525 mg, 4.68 mmol) at 20 °C under N2. The temperature was increased to 50 °C and the mixture was stirred for 0.5 h. A solution of 61.6 (600 mg, 1.56 mmol) in THF (5 mL) was added at 50 °C and the mixture was stirred for 16 h under N
2. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0~5% EtOAc in PE) to give 61.7 (500 mg, 83.8%).
1H NMR: (400 MHz, CDCl3) δH 5.10 (s, 1H), 4.87-4.82 (m, 1H), 2.42-2.37 (m, 1H), 2.02 (s, 1H), 1.96-1.67 (m, 12H), 1.65-1.44 (m, 6H), 1.36-1.28 (m, 2H), 1.24-1.06 (m, 4H), 0.71-0.66 (m, 1H), 0.65 (s, 3H), 0.30-0.21 (m, 1H).
19F NMR (400 MHz, CDCl3) δF -78.60. [0722] Synthesis of 61.8 [0723] To a solution of 61.7 (400 mg, 1.04 mmol) in THF (6 mL) was added 9-BBN dimer (503 mg, 2.08 mmol) under N
2, and the resulting mixture was stirred at 25 °C under N
2 for 12 h. EtOH (1.48 g, 32.2 mmol) and NaOH (4.16 mL, 20.8 mmol, 5 M in water) were added dropwise to keep the internal temperature of the reaction mixture below 15 °C during the course of the addition. H
2O
2 (2.35 g，20.8 mmol) was then added dropwise to keep the internal temperature of the reaction mixture below 15 °C during the course of the addition. The temperature was then increased to 70 °C and the mixture was stirred for 1 h. The mixture was cooled and poured into saturated aqueous Na2S2O
3 (20 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (10 mL) and the organic layer was washed with brine (20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~25% EtOAc in PE) to give 61.8 (320 mg, 76.9%).
1H NMR: (400 MHz, CDCl3) δH 3.85 (dd, J = 4.0, 10.4 Hz, 1H), 3.63 (dd, J = 6.0, 10.4 Hz, 1H), 2.08-2.02 (m, 1H), 1.95-1.65 (m, 10H), 1.57-1.42 (m, 6H), 1.33-1.06 (m, 8H), 1.01 (d, J
= 6.8 Hz, 3H), 0.77 (s, 3H), 0.66-0.59 (m, 1H), 0.17-0.08 (m, 1H).
19F NMR (400 MHz, CDCl3) δF -78.60. [0724] Synthesis of 61.9 [0725] To a solution of 61.8 (420 mg, 1.04 mmol) in DCM (10 mL) was added DMP (1.76 g, 4.16 mmol) at 20 °C under N2 and the resulting mixture was stirred for 10 min. The mixture was poured into saturated aqueous NaHCO
3 (50 mL), saturated aqueous Na2S2O
3 (50 mL) was then added, and the mixture was stirred for 10 min. The aqueous phase was extracted with DCM (3 x 20 mL) and the combined organic layers were washed with saturated aqueous Na2S2O
3 (2 x 30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to give 61.9 (180 mg, 43.4%).
1H NMR: (400 MHz, CDCl
3) δ
H 9.86-9.58 (m, 1H), 2.60-2.47 (m, 1H), 2.09-2.00 (m, 2H), 1.96-1.74 (m, 6H), 1.64-1.44 (m, 6H), 1.34-1.15 (m, 8H), 1.12 (d, J = 6.8 Hz, 3H), 1.02-0.83 (m, 1H), 0.81-0.75 (m, 3H), 0.73-0.65 (m, 1H), 0.24-0.14 (m, 1H).
19F NMR (400 MHz, CDCl
3) δ
F -78.618. [0726] Synthesis of 61 [0727] A solution of (prop-1-yn-1-yl)magnesium bromide (10 mL, 5 mmol, 0.5M in THF) was reacted with a solution of 61.9 (180 mg, 0.4516 mmol) in THF (2 mL) at 50 °C under N
2. After stirring at 50 °C for 0.5 h, the mixture was poured into saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) and further purified by silica gel chromatography (0~2% of acetone in DCM) to give 61 (23.4 mg, 11.9 %).
1H NMR: (400 MHz, CDCl3) δH 4.77 (s, 1H), 2.11-1.87 (m, 7H), 1.83-1.57 (m, 10H), 1.52-1.41 (m, 3H), 1.34-1.06 (m, 8H), 1.01 (d, J = 6.4 Hz, 3H), 0.77 (s, 3H), 0.66-0.59 (m, 1H), 0.15-0.07 (m, 1H).
19F NMR (400 MHz, CDCl3) δF -78.624. LC-ELSD/MS purity 100% MS ESI calcd. for C26H36F
3O [M-H
2O+H]
+ 421.2, found 421.2. [0728] Example 62: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-4-fluoro- 3-hydroxybutan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (62)
[0729] Synthesis of 62.1 [0730] To a suspension of MePPh
3Br (2.76 g, 7.74 mmol) in THF (20 mL) was added t- BuOK (866 mg, 7.74 mmol) at 25 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.31.6 (1 g, 2.58 mmol) in THF (5 mL) was added in portions at 50°C and stirred for 1 h. The reaction mixture was quenched with 10% aqueous NH
4Cl (20 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 30 mL), and the combined organic layers were concentrated under vacuum to give a residue, which was purified by silica gel chromatography (0~10% EtOAc in PE) to give 62.1 (0.9 g, 90.7%).
1H NMR (400 MHz, CDCl
3) δ
H 5.77-5.60 (m, 1H), 5.04-4.76 (m, 2H), 2.09-1.75 (m, 11H), 1.53-1.40 (m, 5H), 1.14-0.82 (m, 13H), 0.72 (s, 3H). [0731] Synthesis of 62.2 [0732] To a solution of 62.1 (900 mg, 2.34 mmol) in DCM (20 mL) was added m-CPBA (949 mg, 85%, 4.68 mmol) at 25 °C and the resulting mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (20 mL) and the organic layer was separated. The organic layer was washed with saturated aqueous NaHCO
3/Na
2S
2O
3 (1:1, 2 x 20 mL) and brine (40 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum to give 62.2 (1.2 g).
1H NMR (400 MHz, CDCl3) δH
2.92-2.37 (m, 3H), 2.14-1.68 (m, 10H), 1.52-1.24 (m, 9H), 1.18-0.90 (m, 10H), 0.69-0.62 (m, 3H). [0733] Synthesis of 62 [0734] 62.2 (1.3 g, 3.24 mmol) was added to TBAF (64.8 mmol, in 20 mL THF) [TBAF (64.8 mmol, in 20 mL THF) was prepared from 1 M TBAF in THF (64.8 mL)]. The mixture was heated to 100 °C and stirred for 12 h. The mixture was then poured into H
2O (100 mL)
and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 2:1). The resulting residue was further purified from CH
3CN (5 mL) to give 62 (16.4 mg, 1.2%).
1H NMR (400 MHz, CDCl
3) δ
H 4.60-4.25 (m, 2H), 4.05-3.97 (m, 1H), 2.15- 1.60 (m, 14H), 1.55-1.41 (m, 4H), 1.30-1.00 (m, 9H), 0.97 (d, J = 6.8 Hz, 3H), 0.69 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.66. LC- ELSD/MS purity 99%, MS ESI calcd. for C
23H
35F
4O [M+H-H
2O]
+ 403.3, found 403.3. [0735] Example 63: Synthesis of (3R,5R,8R,9R,10S,13R,14S,15R,17R)-17-((2S,3S)-3- hydroxyhex-4-yn-2-yl)-13,15-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (63)
[0736] Synthesis of 63.1 [0737] To a solution of MeMgBr (18.6 mL, 56.0 mmol, 3M) in THF (80 mL) was added CuI (7.99 g, 42.0 mmol) at 0 °C and the resulting mixture was stirred for 1 h.61.2 (5 g, 14.0 mmol) in THF (50 mL) was added at 0 °C and the mixture was stirred for 3 h. The mixture was then poured into saturated aqueous NH
4Cl (50 mL) and extracted with EtOAc (3 x 50
mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~18% EtOAc in PE) to give 63.1 (2.5 g, 48%). [0738] Synthesis of 63.2 [0739] To a suspension of EtPPh3Br (4.97 g, 13.4 mmol) in THF (25 mL) was added t- BuOK (1.5 mg, 13.4 mmol) at 25 °C under N2 and the resulting mixture was stirred at 40 °C for 30 min.63.1 (2.5 g, 6.71 mmol) in THF (5 mL) was added in portions to keep the internal temperature of the reaction mixture below 40 °C during the course of the addition. The resulting mixture was then stirred at 40 °C for 1 h. The reaction was quenched with 10% aqueous NH
4Cl (40 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography, (0~10% EtOAc in PE) to give 63.2 (1.5 g, 29.1%). [0740] Synthesis of 63.3 [0741] To a solution of 63.2 (1.2 g, 3.12 mmol) in THF (15 mL) was slowly added 9-BBN dimer (2.65 g, 21.8 mmol) in portions under N2. After stirring at 50 ℃ under N2 for 12 h, the mixture was cooled to 0 °C and EtOH (1.78mL, 31.2 mmol) was added. NaOH (9.36 mL, 5 M, 46.8 mmol) was then added dropwise under N2. H
2O
2 (5.8 g, 51.1 mmol) was subsequently added dropwise under N2 at 15 ℃. The mixture was warmed to 50 ℃ and stirred for 2 h. The mixture was cooled, poured into saturated aqueous Na
2S
2O
3 (100 mL) slowly and stirred for 30 min. The aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 63.3 (1.4 g). [0742] Synthesis of 63.4 [0743] To a solution of 63.3 (1.25 g, 3.10 mmol) in DCM (15 mL) was added DMP (3.94 g, 9.30 mmol) at 25 °C and the resulting mixture was stirred for 3 h. The mixture was quenched with saturated aqueous NaHCO
3:Na
2S
2O
3 (50 mL, v:v = 1:1) and extracted with DCM (2 x 20 mL). The combined organic layers were washed with saturated aqueous NaHCO
3:Na2S2O
3 (4 x 50 mL, v:v = 1:1), dried over anhydrous Na2SO
4, filtered, concentrated and purified by silica gel chromatography (15% EtOAc in PE) to give 63.4 (630 mg, 50.7%). [0744] Synthesis of 63.5 [0745] To a mixture of MePPh3Br (885 mg, 2.48 mmol) in THF (5 mL) was added t-BuOK (278 mg, 2.48 mmol) at 15 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.63.4 (500 mg, 1.24 mmol) in THF (5 mL) was added in portions to keep the internal
temperature of the reaction mixture below 50 °C during the course of the addition. The resulting mixture was stirred for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO
4, filtered, concentrated and purified by silica gel chromatography (3 % EtOAc in PE) to give 63.5 (478 mg, 48%).
1H NMR (400 MHz, CDCl
3) δ
H 4.84 (s, 1H), 4.71 (s, 1H), 2.18-2.05 (m, 2H), 2.03-1.85 (m, 5H), 1.76 (s, 3H), 1.67-1.15 (m, 14H), 1.00 (s, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.70 (s, 3H).
19F NMR (376 MHz, CDCl3) δF -78.96 (s). [0746] Synthesis of 63.6 [0747] To a solution of 63.5 (670 mg, 1.74 mmol) in THF (10 mL) was added 9-BBN dimer (631 mg, 2.61 mmol) at 20 °C and the resulting mixture was stirred for 16 h. The reaction mixture was sequentially treated with EtOH (1.00 mL, 17.4 mmol) at 25 °C, aqueous NaOH (3.47 mL, 5 M, 17.4 mmol) at 0 °C, and H
2O
2 (1.97 mL, 30%, 17.4 mmol) at 15 °C . After stirring at 50 °C for 1 h, the reaction mixture was quenched with saturated aqueous Na2S2O
3 (50 mL), stirred at 0 °C for 10 min and diluted with water (50 mL). The suspension was stirred at 25 °C for 1 h, filtered, washed with water (2 x 40 mL), dried under vacuum, and purified by silica gel chromatography, (0~1% acetone in DCM) to give 63.6 (400 mg, 57.1%).
1H NMR (400 MHz, CDCl3) δH 3.67-3.59 (m, 1H), 3.43-3.34 (m, 1H), 2.30-2.17 (m, 1H), 2.14-1.97 (m, 3H), 1.97-1.54 (m, 10H), 1.53-1.07 (m, 11H), 1.05 (d, J = 6.8 Hz, 3H), 1.02-0.94 (m, 1H), 0.91 (d, J = 7.2 Hz, 3H), 0.85 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F - 78.71 (s). [0748] Synthesis of 63.7 [0749] To a solution of 63.6 (350 mg, 0.8694 mmol) in DCM (5 mL) was added DMP (405 mg, 956 µmol) at 20 °C and the resulting mixture was stirred for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (20 mL) at 10 °C. The organic layer was separated, washed with saturated aqueous NaHCO
3/Na
2S
2O
3 (1:1, 2 x 20 mL) and brine (30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography, (0~15% EtOAc in PE) to give 63.7 (90 mg, 25.9%).
1H NMR (400 MHz, CDCl
3) δ
H 9.57 (d, J = 3.2 Hz, 1H), 2.41-1.55 (m, 16H), 1.51-1.47 (m, 2H), 1.29- 1.17 (m, 4H), 1.13 (d, J = 6.8 Hz, 3H), 1.09-0.99 (m, 3H), 0.92 (d, J = 7.2 Hz, 3H), 0.88 (s, 3H).
19F NMR (376 MHz, CDCl3) δF -78.73 (s). [0750] Synthesis of 63
[0751] A solution of 1-propynylmagnesium bromide (898 µL, 449 µmol, 0.5 M in THF) was reacted with a solution of 63.7 (90 mg, 0.2247 mmol) in THF (3 mL). After stirring at 15 °C for 1 h, the mixture was poured into saturated aqueous NH4Cl (80 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% of EtOAc in PE). The resulting residue was further purified from MeCN:water (1:1, 16 mL) to give 63 (10.7 mg, 35.6%).
1H NMR (400 MHz, CDCl
3) δ
H 4.44-4.37 (m, 1H), 2.29-2.17 (m, 1H), 2.14-1.88 (m, 5H), 1.86 (d, J = 2.4 Hz, 3H), 1.83-1.59 (m, 7H), 1.53-1.06 (m, 12H), 1.03 (d, J = 6.4 Hz, 3H), 1.01-0.94 (m, 1H), 0.91 (d, J = 7.2 Hz, 3H), 0.85 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -78.71 (s). LC-ELSD/MS purity 100% MS ESI calcd. for C
26H
38F
3O [M-H
2O+H]
+ 423.3, found 423.3. [0752] Example 64: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-5-methylhex-4-en-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (64)
[0753] To a solution of 27.2 (500 mg, 1.24 mmol) in THF (10 mL) was added (2-methylprop-1-en-1-yl)magnesium bromide (12.3 mL, 6.19 mmol, 0.5 M in THF) at 25 ℃ and the resulting mixture was stirred at 50 ℃ for 5 min. The mixture was quenched with 10% aqueous NH
4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (30 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to give 64 (22.9 mg, 4.04%).
1H NMR (400MHz, CDCl
3) δ
H 5.26 (s, 1H), 4.40 (s, 1H), 2.03-1.82 (m, 5H), 1.81-1.60 (m, 8H), 1.58-1.42 (m, 7H), 1.40-1.13 (m, 10H), 1.05- 0.94 (m, 8H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.811. LC-ELSD/MS purity >99%, MS ESI calcd for C27H44F
3O
2 [M+H]
+ 439.1, found 439.1. [0754] Example 65: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxypent-4-en-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (65)
[0755] A solution of ethenylmagnesium bromide (1.24 mL, 0.620 mmol, 0.5 M in THF) was reacted with a solution of 27.2 (50 mg, 0.124 mmol) in THF (2 ml) at 50 °C and the resulting mixture was stirred at 50 °C for 2 h. The reaction mixture was then combined with another batch of a mixture obtained using similar conditions (300 mg of 27.2 starting material). The combined mixture was quenched with 10% aqueous NH4Cl (30 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH = 33/1 to 20/1) to afford 65 (45.3 mg, 85.3%).
1H NMR (400MHz, CDCl
3) δ
H 6.047-5.59 (m, 1H), 5.36-5.05 (m, 2H), 4.26-4.08 (m, 1H), 2.05-1.86 (m, 5H) ,1.77-1.67 (m, 3H), 1.64-1.48 (m, 6H), 1.40-1.25 (m, 7H), 1.17-1.02 (m, 5H), 0.96 (s, 3H), 0.94-0.90 (m, 3H), 0.69 (s, 3H),
19F NMR (376.5 MHz, CDCl3) δF -78.784. LC-ELSD/MS purity >99%; MS ESI calcd for C25H38F
3O [M-H
2O+H]
+ 411.2, found 411.2. [0756] Example 66: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((1S,2S)-1- hydroxy-1-phenylpropan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (66)
[0757] A solution of phenylmagnesium bromide (1.16 mL, 2.32 mmol, 2 M in THF) was reacted with a solution of 31.6 (300 mg, 0.7761 mmol) in THF (10 mL) at 50 °C under N2 and the resulting mixture was stirred for 1 h. The mixture was slowly poured into 10% aqueous NH
4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH4Cl (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~15% EtOAc in PE). The resulting residue was further purified from MeCN (10 mL) at 25 °C for 30 min to give 66 (190.4 mg, 52.8%).
1H NMR (400 MHz, CDCl3) δH 7.36-7.29 (m, 4H), 7.25-7.21 (m, 1H), 4.94 (s, 1H), 2.15-2.05 (m, 1H), 1.97-1.90 (m, 2H), 1.86-1.77 (m, 3H), 1.71-1.59 (m, 10H), 1.49-1.40 (m, 3H), 1.30-1.01 (m, 8H), 0.75 (d, J = 6.4 Hz, 3H), 0.70 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.609. LC-ELSD/MS, purity 95%, MS ESI calcd. for C
28H
36F
3 [M- 2H
2O+H]
+ 429, found 429.3. [0758] Example 67: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((1R,2S)-1- cyclopropyl-1-hydroxypropan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H-
[0759] A solution of cyclopropylmagnesium bromide (7.76 mL, 0.5 M in hexane) was reacted with a solution of 31.6 (300 mg, 0.776 mmol) in THF (10 mL) under N
2 at 0 °C and the resulting mixture was warmed to 50 °C and stirred for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 67 (11 mg, 3.3%).
1H NMR (400 MHz, CDCl
3) δ
H 2.80-2.79 (m, 1H), 2.05-1.73 (m, 8H), 1.68-1.52 (m, 6H), 1.50-1.36 (m, 5H), 1.29-0.98 (m, 12H), 0.69 (s, 3H), 1.60-0.41 (m, 2H), 0.30 (m, 1H), 0.10 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -78.600. LC-ELSD/MS purity 99%, MS ESI calcd. For C25H38F
3O [M-H
2O+H]
+ 411.3, found 411.3.
[0760] Example 68: Synthesis of (2S,3S)-3-((3R,5R,8R,9R,10S,13S,14S,17R)-3- hydroxy-13-methyl-3-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren- 17-yl)butane-1,2-diol (68)
[0761] To 62.2 (300 mg, 0.749 mmol) in THF (4 mL) and H
2O (1 mL) at 25 °C was added TsOH (25.6 mg, 149 µmol) and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was treated with water (3 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with water (2 x 5 mL) and brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE). The resulting residue was further purified by silica gel chromatography (0~30% EtOAc in PE) to give 68 (90.8 mg, 29%).
1H NMR (400 MHz, CDCl3) δH 3.91-3.76 (m, 1H), 3.71-3.62 (m, 1H), 3.57-3.47 (m, 1H), 2.05-1.73 (m, 8H), 1.71- 1.65 (m, 2H), 1.59-1.33 (m, 9H), 1.28-1.01 (m, 9H), 0.95 (d, J = 7.2 Hz, 3H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F = -78.64. LC-ELSD/MS purity 99%, MS ESI calcd. For C
23H
37F
3O
3Na [M+Na]
+ 441.3, found 441.3. [0762] Example 69: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1S,2S)-1- hydroxy-1-phenylpropan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (69)
[0763] A solution of phenylmagnesium bromide (2.23 mL, 4.47 mmol, 2 M in THF) was reacted with a solution of 27.2 (600 mg, 1.49 mmol) in THF (10 mL) at 50 °C. After stirring
at 25 °C for 1 h, the mixture was poured into 10% aqueous NH
4Cl (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 69 (16.3 mg, 2.3%).
1H NMR (400MHz, CDCl3) δH 7.37-7.27 (m, 5H), 4.87-4.79 (m, 1H), 2.18-1.78 (m, 7H), 1.75-1.63 (m, 3H), 1.55- 1.39 (m, 4H), 1.36-0.96 (m, 11H), 0.96-0.91 (m, 4H), 0.97-0.85 (m, 3H), 0.76-0.68 (m, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.796. LCMS purity >99%, calcd. for C
29H
38F
3 [M- 2H
2O+H]
+ 443.2, found 443.2. [0764] Example 70: Synthesis of (2R,3R)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3- hydroxy-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butane-2,3-diol (70)
[0765] Synthesis of 70.2 [0766] To a solution of 1,3-dithiane (3.1 g, 25.8 mmol) in THF (30 mL) was added n-BuLi (10.9 mL, 2.5 M in hexane, 27.3 mmol) at -30 ℃. After stirring at -30 ℃ for 2 h, 70.1 (5 g,
12.9 mmol) in THF (70 mL) was added and the mixture was stirred at 20 ℃ for 16 h. The mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, concentrated under vacuum, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 70.2 (5.5 g, 84.2%).
1H NMR (400 MHz, CDCl3) δH 3.09-2.63 (m, 1H), 2.53 (t, J = 8.8 Hz, 1H), 2.20-2.10 (m, 4H), 2.07-1.52 (m, 16H), 1.52-1.36 (m, 6H), 1.36-1.10 (m, 7H), 0.97 (s, 3H), 0.61 (s, 3H). [0767] Synthesis of 70.3 [0768] To a suspension of 70.2 (5.5 g, 10.8 mmol) in MeCN (100 mL) and H
2O (20 mL) was added HgO (3.07 g, 14.2 mmol) and HgCl
2 (5.15 g, 19 mmol) at 20 °C and the resulting mixture was stirred at 90 °C for 12 h. The mixture was poured into water (200 mL), filtered, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 70.3 (4.3 g).
1H NMR (400 MHz, CDCl
3) δ
H 9.56 (s, 1H), 1.98-1.81 (m, 5H), 1.48-1.37 (m, 6H), 1.36- 1.21 (m, 11H), 1.15-1.02 (m, 5H), 0.98-0.86 (m, 4H), 0.77 (s, 3H). [0769] Synthesis of 70.4 [0770] To a suspension of 70.3 (500 mg, 1.2 mmol) in THF (5 mL) was added MeMgBr (1.59 mL, 3 M in Et2O, 4.8 mmol) at 25 °C and the resulting mixture was stirred for 12 h. The mixture was poured into water (20 mL), filtered, and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~45% EtOAc in PE) to give 70.4 (230 mg, 44.3%). [0771] Synthesis of 70.5 [0772] To a solution of 70.4 (230 mg, 0.532 mmol) in pyridine (10 mL) was added BzCl (0.492 mL, 4.25 mmol) at 0 ℃ and the resulting mixture was warmed to 50 ℃ and stirred for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE). The resulting residue was further purified by SFC (column: DAICEL CHIRALCEL OJ-H (250mm * 30 mm, 10 um), condition: 0.1% NH
3H
2O EtOH, Begin B: 40%, End B: 40%) to give 70.5 (30 mg, 10.6%). [0773] Synthesis of 70 [0774] To a solution of 70.5 (30 mg, 0.056 mmol) in MeOH (2 mL), THF (2 mL), and H
2O (1 mL) was added LiOH (66.8 mg, 2.79 mmol) at 25 ℃ and the resulting mixture was stirred
at 50 ℃ for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 70 (11.5 mg, 47.7%).
1H NMR (400 MHz, CDCl
3) δ
H 3.98 (q, J = 6.4 Hz, 1H), 2.29 (s, 1H), 2.06 (s, 1H), 2.01-1.61 (m, 13H), 1.48-1.19 (m, 10H), 1.15 (d, J = 6.4 Hz, 3H), 1.11-1.02 (m, 4H), 0.96 (s, 3H), 0.86 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δ
F -78.781. LC-ELSD/MS purity 99%, MS ESI calcd. for C
24H
36F
3O [M-2H
2O+H]
+ 397.1, found 397.1. [0775] Example 71: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3R)-4- cyclopropyl-3-hydroxybutan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (71)
[0776] Synthesis of 71.1 [0777] A solution of (prop-2-en-1-yl)magnesium bromide (5.16 mL, 1 M in THF, 5.16 mmol) was reacted with a solution of 31.6 (1 g, 2.58 mmol) in THF (5 mL) at 25 °C under N2. After stirring at 25 °C for 2 h, the mixture was slowly poured into saturated aqueous NH4Cl (50 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (2 x 30 mL), and the combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30%
EtOAc in PE) to give 71.1 (450 mg, 40.9%).
1H NMR (400 MHz, CDCl
3) δ
H 5.92-5.75 (m, 1H), 5.22-5.10 (m, 2H), 3.75-3.65 (m, 1H), 2.28-2.14 (m, 1H), 2.06-1.71 (m, 10H), 1.68-1.56 (m, 4H), 1.50-1.40 (m, 4H), 1.30-1.02 (m, 9H), 0.98-0.90 (m, 3H), 0.88-0.82 (m, 1H), 0.70 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.62. [0778] Synthesis of 71 [0779] To a solution of Et2Zn (6.71 mL, 1 M in hexane, 6.71 mmol) in DCM (10 mL) at 0 °C was added dropwise CF
3COOH (637 mg, 5.59 mmol) over a period of 0.5 h under N
2. CH
2I2 (1.79 g, 6.71 mmol) was added dropwise over a period of 15 min, then 71.1 (400 mg, 0.933 mmol) in DCM (10 mL) was added. After stirring at 0 °C for 1 h, the mixture was stirred at 20 °C for 12 h. The mixture was poured into saturated aqueous NH
4Cl (50 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 71 (53.1 mg, 12.8%).
1H NMR (400 MHz, CDCl
3) δ
H 3.85-3.75 (m, 1H), 2.06-1.87 (m, 4H), 1.87-1.63 (m, 8H), 1.48-1.38 (m, 4H), 1.36-1.12 (m, 7H), 1.09-1.01 (m, 6H), 0.89 (d, J = 6.4 Hz, 3H), 0.84-0.71 (m, 1H), 0.69 (s, 3H), 0.58-0.50 (m, 1H), 0.48-0.40 (m, 1H), 0.17-0.10 (m, 1H), 0.05-0.03 (m, 1H).
19F NMR (376.5 MHz, CDCl
3) δ
F -79.53. LC-ELSD/MS purity >97%, calcd. for C
26H
40F
3O [M- H
2O+H]
+ 425.1, found 425.1. [0780] Example 72: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-4,4- difluoro-3-hydroxybutan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (72)
[0781] Synthesis of 72.1 [0782] To a solution of 31.6 (500 mg, 1.29 mmol), HMPA (252 mg, 1.41 mmol), and difluoromethanesulfonylbenzene (1.23 g, 6.45 mmol) in anhydrous THF (20 mL) under nitrogen at -70 ℃ was added LiHMDS (1 M in THF, 6.45 mL, 6.45 mmol) dropwise. The mixture was stirred at -70 ℃ for 1 h then warmed to 25 ℃ and stirred for 10 h. The mixture was poured into 10% aqueous NH4Cl (150 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE). The resulting residue was further purified by HPLC (Column: Phenomenex Gemini-C18100*40 mm*3 um; Condition: water (TFA)-ACN; Begin B: 80%; End B%: 100; Gradient Time(min): 8; 100% B; Hold Time(min): 2; Flow Rate(mL/min): 60 Injections 2) to give 72.1 (50 mg, 6.7%).
1H NMR (400 MHz, CDCl
3) δ
H 8.00-7.98 (d, J = 7.6 Hz, 2H), 7.78-7.76 (m, 1H), 7.67-7.64 (m, 2H), 4.69-4.62 (m, 1H), 2.91 (s, 1H), 1.96-1.75 (m, 10H), 1.48-1.42 (m, 8H), 1.12-1.07 (m, 11H), 0.68 (s, 3H). [0783] Synthesis of 72 [0784] To a solution of 72.1 (50 mg, 0.08640 mmol) and anhydrous Na2HPO
4 (63.8 mg, 285 µmol) in anhydrous MeOH (8 mL) at -20 ℃ under N
2 was added Na/Hg amalgam (116 mg, 518 µmol). After stirring at -20 ℃ to 0 ℃ for 2 h, the mixture was poured into 10% aqueous NH4Cl (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH4Cl (20 mL), dried over anhydrous Na2SO
4,
filtered, concentrated, and purified by silica gel chromatography (0~25% EtOAc in PE). The resulting residue was further purified from MeCN (1 mL) at 25 ℃ to give 72 (26.4 mg, 53.7%).
1H NMR (400 MHz, CDCl3) δH 5.92-5.54 (m, 1H), 3.82-3.79 (d, J = 12.0 Hz, 1H), 2.06-1.75 (m, 10H), 1.68-1.59 (m, 3H), 1.54-1.28 (m, 7H), 1.26-1.19 (m, 2H), 1.15-1.01 (m, 8H), 0.69 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.655, -126.375. LC-MS purity >99%, calcd. for C20H
20F
3 [M-2H
2O-2F-3CH4+H]
+ 317.3, found 317.3. [0785] Example 73: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((1S,2S)-1- hydroxy-1-(p-tolyl)propan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (73)
[0786] (4-Methylphenyl)magnesium bromide (3.72 mL, 7.45 mmol) was reacted with a solution of 27.2 (600 mg, 1.49 mmol) in THF (10 mL) dropwise at 25 °C and the resulting mixture was stirred for 1 h. The mixture was poured into 10% aqueous NH
4Cl (300 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 73 (131 mg), which was further purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); Condition: 0.1%NH
3H
2O, flow rate: 70 mL/min) to give 73 (83 mg).73 was again purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); Condition: 0.1%NH
3H
2O, flow rate: 60 mL/min) to give 73 (13.5 mg, 1.8%).
1H NMR (400MHz, CDCl3) δ 7.24-7.09 (m, 4H), 4.85-4.73 (m, 1H), 2.34 (s, 3H), 2.14-1.76 (m, 7H), 1.75-1.59 (m, 5H), 1.51-1.16 (m, 10H), 1.15-0.98 (m, 3H), 0.96-0.85 (m, 7H), 0.71 (s, 3H).
19FNMR (376.5 MHz, CDCl
3) δ
F -78.814. LCMS purity >99%, calcd. for C
30H
40F
3 [M-2H
2O+H]
+ 457.1, found 457.1. [0787] Example 74: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((1S,2S)-1- hydroxy-1-(p-tolyl)propan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (74)
[0788] To a solution of 31.6 (500 mg, 1.29 mmol) in THF (20 mL) was added (4-methylphenyl)magnesium chloride (2 M in THF, 3.22 mL, 6.45 mmol) at 0 ℃ and the resulting mixture stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE). The resulting residue was further purified by SFC ((Column: Chiralpak AD-350* 4.6 mm I.D., 3 um); Mobile phase: A: CO
2; B: i-PrOH (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL /min; Column temp.: 35
oC; ABPR: 1500 psi) to give 74 (330 mg, 67%).
1H NMR: (400 MHz, CDCl
3) δ
H 7.20- 7.13 (m, 4H), 4.90 (s, 1H), 2.34 (s, 3H), 2.20-1.62 (m, 15H), 1.60-1.40 (m, 5H), 1.31-1.01(m, 7H), 0.75 (d, J = 6Hz, 3H), 0.69 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.58. LC- ELSD/MS purity 99%, MS ESI calcd. for C29H41F
3O [M-H
2O+H]
+ 461.3, found 461.1. [0789] Example 75: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R,Z)-3- hydroxyhex-4-en-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (75)
[0790] Synthesis 75.1 [0791] To a solution of 27 (1.3 g, 2.95 mmol) and imidazole (1g, 14.7 mmol) in DCM (15 mL) was added TBDPSCl (1.62 g, 5.90 mmol) in one portion at 0 ℃ under N
2 and the resulting mixture was stirred at 25 ℃ for 2 h. The residue was poured into 10% aqueous NH4Cl (100 mL) and stirred for 20 min and the aqueous phase was extracted with DCM (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 75.1 (1.2 g, 60%). [0792] Synthesis of 75.2 [0793] A mixture of 75.1 (1.2 g, 1.76 mmol), Pd/CsCO
3 (1.2g, 5% Pd, 1% water wet), quinoline (0.3 mL) in THF (1 mL), and EtOH (7 mL) was stirred under 15 psi of hydrogen at 20 ℃ for 3 h. The mixture was filtered through a pad of Celite and washed with THF (80 mL). The filtrate was concentrated to give 75.2 (1.0 g).
1H NMR (400 MHz, CDCl
3) δ
H 7.72- 7.64 (m, 4H), 7.43-7.31 (m, 6H), 5.64-5.59 (m, 1H), 5.20-5.12 (m, 1H), 4.45-4.43 (m, 1H), 1.94-1.60 (m, 7H), 1.59-1.43 (m, 3H), 1.41-1.28 (m, 8H), 1.26-1.10 (m, 6H), 1.08-1.00 (m, 13H), 0.99-0.85 (m, 6H), 0.59 (s, 3H). [0794] Synthesis of 75 [0795] To a solution of 75.2 (0.7 g, 1.02 mmol) in THF (10 mL) was added TBAF (5.1 mL, 5.1 mmol, 1 M in THF) and the resulting mixture was stirred at 25 ℃ for 16 h. The mixture was added dropwise to water (200 mL) and extracted with DCM (2 x 100 mL). The
combined organic layers were washed with water (200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give a residue, which was purified from MeCN (8 mL) to give 75 (84.3 mg, 18.6%).
1H NMR (400 MHz, CDCl3) δH 5.71-5.64 (m, 1H), 5.51-5.46 (m, 1H), 4.54-4.51 (m, 1H), 1.98-1.94 (m, 2H), 1.91-1.84 (m, 2H), 1.82-1.68 (m, 7H), 1.63-1.51 (m, 7H), 1.44-1.30 (m, 6H), 1.28-1.18 (m, 3H), 1.16-1.10 (m, 2H), 1.02-0.98 (m, 3H), 0.97-0.91 (m, 3H), 0.69-0.66 (m, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.777. LC-ELSD/MS purity >99%, MS ESI calcd. for C
25H
40F
3O [M+H-H
2O]
+ 425.3, found 425.3. [0796] Example 76: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-4-fluoro- 3-hydroxybutan-2-yl)-3-(fluoromethyl)-13-methylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (76)
[0797] Synthesis of 76.1 [0798] To a solution of 4.6 (18 g, 62.3 mmol) in DMF (100 mL) was added NaH (4.95 g, 124 mmol, 60% purity) at 0 °C in portions and the resulting mixture was stirred at 0 °C for 1 h. BnBr (21.2 g, 124 mmol) and HMPA (22.2 g, 124 mmol) were added and the mixture was stirred at 50 °C for 4 h. The mixture was quenched with H
2O (50 mL) and the resulting mixture was combined with another 3 batches of mixtures obtained using similar conditions. The combined mixtures were extracted with EtOAc (3 x 300 mL) and the combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous Na
2SO
4, filtered, and
concentrated. The residue was purified by silica gel chromatography (0~1% EtOAc in PE) to give 76.1 (100 g). [0799] Synthesis of 76.2 [0800] To a solution of 76.1 (25 g, 66.0 mmol) in THF (200 mL) was added 9-BBN dimer (31.9 g, 132 mmol) under N2 and the resulting mixture was stirred at 40 °C under N2 for 12 h. The mixture was cooled to 0 °C and EtOH (37.9 mL, 660 mmol) and NaOH (198 mL, 5M, 990 mmol) were added. H
2O
2 (99.0 mL, 10M, 990 mmol) was then added dropwise at 15 °C. After stirring at 40 °C for 1 h, the mixture was poured into Na2S2O
3 (300 mL, sat. aq.) and stirred for 30 min. The aqueous layer was extracted with EtOAc (2 x 300 mL) and the combined organic layers were washed with brine (400 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was combined with another 3 batches of reaction mixtures obtained using similar conditions and the combined mixtures were purified by silica gel chromatography (0~20% EtOAc in PE) to give 76.2 (44 g). [0801] Synthesis of 76.3 [0802] To a solution of 76.2 (32 g, 80.6 mmol) in DCM (300 mL) was added DMP (68.2 g, 161 mmol) at 25 °C and the resulting mixture was stirred for 1 h. The reaction mixture was combined with another 2 batches of reaction mixtures obtained using similar conditions. The combined mixtures were filtered, washed with saturated aqueous NaHCO
3/Na2S2O
3 (1:1, 2 x 500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum to give 76.3 (82 g). [0803] Synthesis of 76.4 [0804] To a mixture of MePPh3Br (73.5 g, 206 mmol) in THF (400 mL) was added t-BuOK (23.1 mg, 206 mmol) at 25 °C under N2 and the resulting mixture was warmed to 40 °C and stirred for 30 min.76.3 (41 g, 103 mmol) was added in portions to keep the internal temperature of the mixture below 50 °C during the course of the addition. After stirring at 40 °C for 2 h, the reaction was slowly quenched with 10% aqueous NH4Cl (200 mL). The resulting mixture was combined with another batch of a reaction mixture obtained using similar conditions. The combined mixtures were extracted with EtOAc (3 x 300 mL), washed with brine (500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 76.4 (76 g). [0805] Synthesis of 76.5 [0806] To a solution of 76.4 (19 g, 48.3 mmol) in THF (200 mL) was added 9-BBN dimer (23.3 g, 96.6 mmol) under N2 and the resulting mixture was stirred at 40 °C under N2 for 12 h. The mixture was cooled to 0 °C and EtOH (27.7 mL, 483 mmol) and NaOH (96.6 mL, 5M,
483 mmol) were added. H
2O
2 (48.3 mL, 10M, 483 mmol) was then added dropwise at 15 °C. After the mixture was stirred at 40 °C for 1 h, the mixture was poured into saturated aqueous Na2S2O
3 (200 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (2 x 300 mL) and the combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was combined with 3 batches of reaction mixtures obtained using similar conditions and the combined mixtures were purified by silica gel chromatography (0~15% EtOAc in PE) to give 76.5 (72 g). [0807] Synthesis of 76.6 [0808] To a solution of 76.5 (18 g, 43.8 mmol) in DCM (300 mL) was added DMP (37.1 g, 87.6 mmol) at 25 °C and the resulting mixture was stirred for 1 h. The reaction mixture was combined with another 3 batches of reaction mixtures obtained using similar conditions and the combined mixtures were washed with saturated aqueous NaHCO
3:Na2S2O
3 (1:1, 3 x 800 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum to give 76.6 (15 g, 84%), which was used in the next step without further purification. [0809] Synthesis of 76.7 [0810] To a mixture of MePPh3Br (26.2 g, 73.4 mmol) in THF (300 mL) was added t- BuOK (8.23 g, 73.4 mmol) at 25 °C under N
2 and the resulting mixture was stirred at 40 °C for 30 min.76.6 (15 g, 36.7 mmol) was added in portions to keep the internal temperature of the mixture below 50 °C during the course of the addition. After stirring at 40 °C for 2 h, the reaction was quenched with 10% aqueous NH
4Cl (200 mL) and combined with another 3 batches of reaction mixtures obtained under similar conditions. The combined mixtures were extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~5% EtOAc in PE) to give 76.7 (57 g).
1H NMR (400 MHz, CDCl3) δH 7.40-7.27 (m, 5H), 5.70-5.60 (m, 1H), 4.95-4.80 (m, 2H), 4.56 (s, 2H), 3.45-3.30 (m, 1H), 2.10-2.00 (m, 1H), 1.95-1.80 (m, 3H), 175-1.45 (m, 6H), 1.43-0.95 (m, 18H), 0.65 (s, 3H). [0811] Synthesis of 76.8 [0812] To a solution of 76.7 (57 g, 140 mmol) in DCM (800 mL) was added m-CPBA (47.8 g, 280 mmol) and the resulting mixture was stirred at 20 °C for 16 h. The mixture was diluted with DCM (200 mL), washed with saturated aqueous Na
2S
2O
3:NaHCO
3 (1:1, 2 x 800 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give a residue, which was purified by silica gel chromatography (0~10% EtOAc in PE) to give 76.8 (52 g, 88%).
1H NMR (400
MHz, CDCl
3) δ
H 7.38-7.27 (m, 5H), 4.56 (s, 2H), 3.43-3.32 (m, 1H), 2.88-2.39 (m, 3H), 2.00-1.59 (m, 10H), 1.53-1.16 (m, 9H), 1.15-0.93 (m, 9H), 0.71-0.59 (m, 3H). [0813] Synthesis of 76.9 [0814] A suspension of 76.8 (43.8 g, 103 mmol), KHF
2 (24.1 g, 309 mmol), and TBAF (618 mL, 618 mmol, 1 M in THF) was stirred at 100 °C for 16 h. The mixture was quenched with 10% aqueous NH4Cl (600 mL), extracted with EtOAc (2 x 400 mL), and the combined organic layers were washed with 10% aqueous NH
4Cl (50 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 76.9 (17.22 g, 37.8%). [0815] Synthesis of 76.10 [0816] To a solution of 76.9 (17.5 g, 39.5 mmol) in DCE (180 mL) was added imidazole (13.3 g, 197 mmol) and TBDPSCl (34.5 g, 126 mmol) at 55 °C and the resulting mixture was stirred for 16 h. The mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to afford 76.10 (30 g). [0817] Synthesis of 76.11 [0818] To a solution of 76.10 (4.5 g, 6.60 mmol) in MeOH (50 mL) was added Pd/C (1 g) under N2. After hydrogenation under 45 psi of hydrogen at 50 °C for 15 h, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give 76.11 (4 g). [0819] Synthesis of 76.12 [0820] To a solution of 76.11 (4 g, 18.4 mmol) in DCM (60 mL) was added DMP (5.72 g, 13.5 mmol) at 20 °C and the resulting mixture was stirred for 1 h. The reaction mixture was diluted with DCM (100 mL), quenched with saturated aqueous NaHCO
3 (100 mL) and saturated aqueous Na2S2O
3 (100 mL) and stirred at 25 °C for 5 min. The organic layer was separated, washed with saturated aqueous NaHCO
3 (100 mL) and saturated aqueous Na
2S
2O
3 (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give a residue, which was purified by silica gel chromatography (0~15% EtOAc in PE) to give 76.12 (900 mg, 22.6%).
1H NMR (400 MHz, CDCl
3) δ
H 7.79-7.57 (m, 4H), 7.50-7.30 (m, 6H), 4.40-4.13 (m, 2H), 3.95-3.82 (m, 1H), 2.70-2.57 (m, 1H), 2.35-1.98 (m, 6H), 1.82-1.43 (m, 11H), 1.37-0.77 (m, 19H), 0.65 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -221.808. [0821] Synthesis of 76.13
[0822] To a solution of 76.12 (900 mg, 1.52 mmol), HMPA (408 mg, 2.28 mmol), and PhSO
2CFH
2 (317 mg, 1.82 mmol) in THF (10 mL) was added LiHMDS (3.04 mL, 1 M in THF) dropwise at -70 °C under N2 and the resulting mixture was stirred at -25 °C for 12 h. The reaction mixture was quenched with saturated aqueous NH
4Cl (80 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to afford 76.13 (750 mg, 65.2%). [0823] Synthesis of 76.14 [0824] To a solution of 76.13 (750 mg, 0.982 mmol) and anhydrous Na2HPO
4 (388 mg, 3.24 mmol) in anhydrous MeOH (12 mL) at 25 °C under N
2 was added Na/Hg amalgam (1.09 g, 4.91 mmol). After stirring at 25 °C for 2 h, the mixture was quenched with 10% aqueous NH4Cl (80 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with 10% aqueous NH4Cl (60 mL), dried over anhydrous Na2SO
4, filtered, concentrated and purified by silica gel chromatography (0~15% EtOAc in PE). The resulting residue was further purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um), gradient: 25-25% B (A = 0.1%NH3/H
2O, B = EtOH), flow rate: 60 mL/min). The resulting residue was further purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 um), gradient: 20-20% B (A = 0.1%NH3/H
2O, B = EtOH), flow rate: 60 mL/min) to give 76.14 (110 mg, 18%).
1H NMR (400 MHz, CDCl3) δH 7.72-7.65 (m, 4H), 7.45-7.32 (m, 6H), 4.52-4.27 (m, 4H), 3.99-3.84 (m, 1H), 1.91-1.67 (m, 4H), 1.49-1.14 (m, 14H), 1.12-0.88 (m, 17H), 0.85-0.67 (m, 2H), 0.61-0.46 (m, 1H), 0.34 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -227.552, -233.548. [0825] Synthesis of 76 [0826] To a solution of 76.14 (110 mg, 0.176 mmol) in THF (5 mL) was added TBAF (3 mL, 3.00 mmol, 1 M in THF) and the resulting mixture was stirred at 50 °C for 2 h. The mixture was quenched with 10% aqueous NH4Cl (60 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (50 mL), dried over anhydrous Na2SO
4, filtered, concentrated, purified by silica gel chromatography (0~20% EtOAc in PE), and lyophilized to give 76 (29.2 mg, 43.1%).
1H NMR (400 MHz, CDCl3) δH 4.62-4.54 (m, 1H), 4.53-4.28 (m, 3H), 4.04-3.93 (m, 1H), 2.00-1.93 (m, 1H), 1.90-1.62 (m, 11H), 1.52-1.36 (m, 6H), 1.35-1.04 (m, 9H), 1.01-0.95 (m, 3H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -232.461, -233.527. LC-ELSD/MS purity >99%, MS ESI calcd. for C23H35F2 [M+H-2H
2O]
+ 349.3, found 349.3.
[0827] Example 77: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R,E)-3- hydroxyhex-4-en-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (77)
[0828] Lithium (380 mg, 54.4 mmol) was added to fresh liquid ammonia (40 mL, 1.36 mmol) in portions at -70 °C. After stirring at -70 °C for 1 h, a solution of 27 (600 mg, 1.36 mmol) in dry THF (6 mL) and t-BuOH (2 mL, 2.72 mmol) was added to this mixture and the reaction mixture temperature was maintained below -60 °C during the course of the addition. After stirring at -70 °C for 1 h, NH
4Cl (500 mg) was added to reaction mixture and the mixture was warmed to room temperature and stirred for 16 h. H
2O (1 L) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (60 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 77 (90.6 mg, 20.9%).
1H NMR (400 MHz, CDCl3) δH 5.73-5.63 (m, 1H), 5.55-5.43 (m, 1H), 4.17-4.06 (m, 1H), 2.00- 1.82 (m, 4H), 1.76-1.67 (m, 7H), 1.64-1.48 (m, 6H), 1.44-1.20 (m, 9H), 1.12-0.99 (m, 4H), 0.96-0.92 (m, 5H), 0.68 (s, 3H),
19F NMR (376.5 MHz, CDCl
3) δ
F -78.784. LC-ELSD/MS purity > 99%; MS ESI calcd for C26H40F
3O [M-H
2O+H]
+ 425.3, found 425.3. [0829] Example 78: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3S)-4-fluoro- 3-hydroxybutan-2-yl)-3-(fluoromethyl)-10,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (78)
[0830] Synthesis of 78.1 [0831] To a solution of 1.2 (50.0 g, 150 mmol) in DCM (500 mL) was added imidazole (20.4 g, 300 mmol) and TBSCl (33.7g, 224 mmol) at 0 °C and the resulting mixture was stirred at 40 °C for 3 h. The mixture was poured into ice-water (600 mL) and stirred for 2 min. The aqueous phase was extracted with DCM (3 x 500 mL) and the combined organic layers were washed with brine (2 x 600 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to afford 78.1 (60 g, 89.6%).
1H NMR (400MHz, CDCl
3) δ
H 3.56 (dd, J = 3.2,
9.6 Hz, 1H), 3.25 (dd, J = 7.2, 9.6 Hz, 1H), 2.69 (t, J = 14.0 Hz, 1H), 2.44-2.07 (m, 2H), 2.06-1.97 (m, 3H), 1.92-1.42 (m, 8H), 1.40-1.03 (m, 10H), 1.01 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.68 (s, 3H), 0.02 (s, 6H). [0832] Synthesis of 78.2 [0833] To a solution of 78.1 (30.0 g, 67.1 mmol) in THF (300 mL) and MeOH (100 mL was added NaBH4 (7.59 g, 201 mmol) at 25 ℃ and the resulting mixture was stirred for 2 h. To the mixture was added 10% aqueous NH
4Cl (300 mL) and the mixture was subsequently extracted with EtOAc (800 mL). The organic phase was washed with brine (300 mL), dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo to give 78.2 (30 g, 99.6%).
1H NMR (400MHz, CDCl
3) δ
H 3.69-3.49 (m, 2H), 3.29-3.18 (m, 1H), 1.97 (d, J = 11.6 Hz, 1H), 1.83-1.60 (m, 5H), 1.59-1.32 (m, 9H), 1.30-1.01 (m, 10H), 0.91 (d, J = 2.0 Hz, 3H), 0.90- 0.81 (m, 12H), 0.65 (s, 3H), 0.02 (s, 6H). [0834] Synthesis of 78.3 [0835] To a solution of 78.2 (25.0 g, 55.7 mmol) and HMPA (19.8 g, 111 mmol) in THF (200 mL) was added NaH (4.43 g, 111 mmol, 60%) at 0 °C in portions. After stirring at 0 °C for 1 h, BnBr (40.3 g, 111 mmol) was added, and the resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with H
2O (800 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 78.3 (40.0 g).
1H NMR (400MHz, CDCl
3) δ
H 7.34-7.30 (m, 5H), 4.54 (s, 2H), 3.58 (dd, J = 3.2, 9.6 Hz, 1H), 3.42-3.30 (m, 1H), 3.23 (dd, J = 8.0, 9.6 Hz, 1H), 1.99-1.93 (m, 1H), 1.90-1.72 (m, 5H), 1.66-1.49 (m, 4H), 1.43-1.35 (m, 4H), 1.29-1.21 (m, 6H), 1.16-1.17 (m, 4 H), 0.98(d, J = 7.6 Hz, 3H), 0.95 (s, 3H), 0.90 (s, 9H), 0.65 (s, 3H), 0.03 (s, 6H). [0836] Synthesis of 78.4 [0837] To a solution of 78.3 (40.0 g, 74.2 mmol) in THF (400 mL) was added TBAF (371 mL, 1 M in THF, 371 mmol) at 25 °C and the resulting mixture was stirred for 12 h. The reaction mixture was quenched with saturated aqueous NH
4Cl (600 mL) and extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=12\1~4\1) to give 78.4 (28.0 g, 88.8 %). [0838] Synthesis of 78.5 [0839] To a solution of 789.4 (8.00 g, 18.8 mmol) in DCM (100 mL) was added DMP (23.9 g, 56.4 mmol) and the resulting mixture was stirred at 25 °C for 3 h. The mixture was quenched with saturated aqueous NaHCO
3 (50 mL) and saturated aqueous Na
2S
2O
3 (50 mL).
The mixture was extracted with DCM (2 x 50 mL) and the combined organic layers were washed with saturated aqueous Na2S2O
3 (2 x 50 mL) and brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE:EA = 20/1~1/8) to give 78.5 (12 g).
1H NMR (400MHz, CDCl
3) δ
H 9.55 (d, J = 3.2 Hz, 1H), 7.39-7.20 (m, 5H), 4.56 (s, 2H), 3.46-3.28 (m, 1H), 2.41-2.27 (m, 1H), 1.92-1.63 (m, 8H), 1.53-1.13 (m, 15H), 1.11 (d, J = 6.8 Hz, 3H), 0.92 (s, 3H), 0.68 (s, 3H). [0840] Synthesis of 78.6 [0841] To a suspension of MePPh3Br (31.6 g, 88.5 mmol) in THF (130 mL) was added t- BuOK (9.93 g, 15.8 mol) at 25 °C under N
2 and the resulting mixture was stirred at 50 °C for 1 h.78.5 (12.5 g, 29.5 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with 10% aqueous NH4Cl (100 m L) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were concentrated to give a residue, which was purified from MeOH:H
2O (1:1, 200 mL) at 25 °C to give 78.6 (12 g, 96.7%).
1H NMR (400MHz, CDCl
3) δ
H 7.27-7.22 (m, 5H), 5.62-5.51 (m, 1H), 4.83-4.69 (m, 2H), 4.46 (s, 2H), 3.33-3.23 (m, 1H), 2.00-1.70 (m, 6H), 1.63-1.36 (m, 6H), 1.30-1.24 (m, 3H),1.18-1.05 (m, 6H), 0.96-0.85 (m, 6H), 0.82 (s, 3H), 0.57 (s, 3H). [0842] Synthesis of 78.7 [0843] To a solution of 78.6 (12.0 g, 28.5 mmol) in DCM (130 mL) was added m-CPBA (15.2 g, 71.2 mmol) and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with Na2S2O
3 (300 mL, sat. aq.) and NaHCO
3 (300 mL, sat. aq.), diluted with DCM (200 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0~5% EtOAc in PE) to give 78.7 (7 g, 56.4 %).
1H NMR (400MHz, CDCl
3) δ
H 7.30-7.21 (m, 5H), 4.48 (s, 2H), 3.39-3.23 (m, 1H), 2.75-2.51 (m, 2H), 1.94-1.69 (m, 7H), 1.68-1.20 (m, 15H), 1.15-1.05 (m, 3H), 1.03 (s, 3H), 1.01-0.92 (m, 3H), 0.84 (s, 3H). [0844] Synthesis of 78.8 [0845] To a mixture of 78.7 (7.00 g, 16.0 mmol) and KHF
2 (534 mg, 6.84 mmol) in THF (6 mL) was added TBAF (70 mL, 1.0 M in THF) under N2 and the resulting mixture was stirred at 120 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with
brine (3 x 40 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0~10% of EA in PE) to give 78.8 (2.4 g, 32.8 %).
1H NMR (400MHz, CDCl3) δH 7.28-7.15 (m, 5H), 4.49 (s, 2H), 4.44- 4.19 (m, 2H), 3.97-3.85 (m, 1H), 3.35-3.24 (m, 1H), 1.81-1.67 (m, 5H), 1.61-1.54 (m, 2H), 1.45-0.96 (m, 19H), 0.91-0.87 (m, 2H), 0.84 (s, 3H), 0.57 (s, 3H)
19F NMR (377MHz, CDCl3) δF -226.48 (s), -232.46 (s). [0846] Synthesis of 78.9 [0847] To a solution of 78.8 (2.40 g, 5.25 mmol) in DCE (30 mL) was added imidazole (1.78 g, 26.2 mmol) and TBDPSCl (4.61 g, 16.8 mmol) at 25 °C. After stirring at 60 °C for 16 h, the mixture was poured into saturated aqueous NH
4Cl (80 mL) and extracted with DCM (3 x 80 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~6% EtOAc in PE) to afford 78.9 (4.0 g). [0848] Synthesis of 78.10 [0849] To a solution of 78.9 (4.20 g, 6.04 mmol) in THF (50 mL) was added wet Pd/C (1.50 g, 10 wt %) at 25 °C and the flask was purged with H
2 three times. The mixture was hydrogenated under 15 psi of hydrogen at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0~6 % EtOAc in PE) to give 78.10 (1.5 g, 41.0 %). [0850] Synthesis of 78.11 [0851] To a solution of 78.10 (900 mg, 1.48 mmol) in DCM (16 mL) was added DMP (1.37 g, 3.25 mmol) at 40 °C and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with saturated aqueous NaHCO
3 (60 mL) and saturated aqueous Na2S2O
3 (60 mL), and extracted with DCM (3 x 15 mL). The combined organic layers were washed with saturated aqueous NaHCO
3 (40 mL) and saturated aqueous Na2S2O
3 (40 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) and further purified by SFC ((Column: Chiralcel OD-350A 4.6 mm I.D., 3 um); Condition: A: CO
2; B: EtOH (0.05% DEA); Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min; Flow rate: 4 mL/min) to give 78.11 (400 mg, 40.2 %).
1H NMR (400MHz, CDCl
3) δ
H 7.73 (dd, J = 1.2, 7.6 Hz, 2H), 7.63 (dd, J = 1.6, 8.0 Hz, 2H), 7.47-7.34 (m, 6H), 4.38-4.13 (m, 2H), 3.93-3.83 (m, 1H), 2.73 (t, J = 14.0 Hz, 1H), 2.47-2.32 (m, 1H), 2.24-2.14 (m, 1H), 2.11-1.99 (m, 3H), 1.96-1.77 (m, 2H), 1.47-1.41 (m, 6H), 1.40-1.32 (m, 3H), 1.32-1.11 (m,
4H), 1.07 (s, 9H), 1.03 (d, J = 6.4 Hz, 3H), 1.01 (s, 3H), 0.98-0.90 (m, 3H), 0.63 (s, 3H).
19F NMR (377 MHz, CDCl3) δF -221.82 (s). [0852] Synthesis of 78.12 [0853] To a solution of 78.11 (280 mg, 0.46 mmol) and HMPA (121 mg, 0.70 mmol), was added ((fluoromethyl)sulfonyl)benzene (97.0 mg, 0.56 mmol) in anhydrous THF (6 mL) under nitrogen at -70 °C and LiHMDS (1 M in THF, 2.32 mL, 2.32 mmol) dropwise. After stirring at -70 °C for 1 h, the reaction mixture was warmed to 25 °C and stirred for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10 % EtOAc in PE) to give 78.12 (180 mg, 46.6 %).
1H NMR (400MHz, CDCl
3) δ
H 8.04-7.88 (m, 2H), 7.75-7.65 (m, 5H), 7.64-7.56 (m, 2H), 7.45-7.31 (m, 6H), 5.40-4.70 (m, 1H), 4.54-4.29 (m, 2H), 3.99-3.84 (m, 1H), 2.21-1.61 (m, 6H), 1.53-1.11 (m, 13H), 1.08 (s, 9H), 1.00-0.74 (m, 11H), 0.30-0.29 (m, 1H), 0.32 (s, 3H). [0854] Synthesis of 78.13 [0855] To a solution of 78.12 (180 mg, 0.637 mmol) and anhydrous NaH
2PO
4 (137 mg, 1.15 mmol) in anhydrous methanol (8 mL) was added Na/Hg amalgam (160 mg) at 25 °C under N2 and the resulting mixture was stirred for 16 h. To the mixture was added 10% NH4Cl (15 mL, sat. aq.) and the resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (10 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~10% EtOAc in PE). The residue was further purified by SFC ((Column: Chiralcel OD-350A 4.6 mm I.D., 3 um); Condition: A: CO
2; B: EtOH (0.05% DEA); Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min; Flow rate: 4 mL/min) to give 78.13 (60 mg, 40.8 %). [0856] Synthesis of 78 [0857] To a solution of 78.13 (50 mg, 0.0785 mmol) in THF (5 mL) was added TBAF (3 mL, 3.00 mmol, 1 M in THF) and the resulting mixture was stirred at 50 °C for 2 h. The mixture was quenched with 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) and lyophilized to give 78 (5.3 mg, 11.0 %).
1H NMR (400MHz, CDCl3) δH 4.61-4.28 (m, 4H), 4.03-3.93 (m, 1H), 2.24-2.01 (m, 2H), 1.98-1.72 (m, 6H), 1.53-1.32 (m, 9H), 1.28-1.04 (m, 9H), 0.96 (d, J = 7.2 Hz, 3H), 0.94 (s,
3H), 0.66 (s, 3H).
19F NMR (377MHz, CDCl
3) δ
F -232.51 (s), -233.67 (s). LC-ELSD/MS 30-90AB_2min_E, purity = 97.8%, MS ESI calcd. for C24H40F2O
2Na
+ [M+Na] 421.3, found 421.3. [0858] Example 79: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-6a- methyl-7-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (79)
[0859] To a solution of 61.9 (400 mg, 1.00 mmol) in THF (10 mL) was added CsF (568 mg, 4.00 mmol) at 25 °C under N2. TMSCF
3 (853 mg, 6.00 mmol) was added dropwise at 25 °C and the resulting mixture was stirred for 1 h. TBAF (8 mL, 1 M in THF, 4.36 mmol) was added and the mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (10 mL), washed with water (2 x 10 mL) and brine (6 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) and lyophilized to give 79 (23.9 mg, 59.8 %).
1H NMR (400MHz, CDCl3) δH 4.46-4.31 (m, 1H), 2.35 (d, J = 6.0 Hz, 1H), 2.21-1.98 (m, 3H), 1.95-1.63 (m, 10H), 1.61- 1.58 (m, 1H), 1.53-1.41 (m, 3H), 1.30-1.15 (m, 7H), 1.09-1.04 (m, 3H), 0.77 (s, 3H), 0.68 (q, J = 3.6 Hz, 1H), 0.17 (q, J = 8.0 Hz, 1H).
19F NMR (376 MHz, CDCl
3) δ
F -72.30 (s) -78.62 (s). [0860] Example 80: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (80)
[0861] Synthesis of 80.1 [0862] To a solution of 27.2 (5 g, 12.4 mmol) in THF (80 mL) was added TsOH (2.13 g, 12.4 mmol) at 25 °C under N2 and the resulting mixture was stirred for 12 h. The mixture was quenched with 10% aqueous NH4Cl (100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give a residue, which was purified by silica gel chromatography (0-15% of EtOAc in PE) and further purified by SFC ((Column: Chiralcel OD-350A 4.6 mm I.D., 3 um); Condition: A: CO
2; B: EtOH (0.05% DEA); Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min; Flow rate: 4 mL/min) to give 80.1 (4 g, 80.6%).. [0863] Synthesis of 80 [0864] 80.1 (3 g, 7.49 mmol) and methylmagnesium bromide (9.96 mL, 29.9 mmol, 3 M in ether) in THF (30 mL) were stirred at 25 °C under N2 for 12 h. The mixture was quenched with H
2O (15 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 80 (700 mg, 84.5%).
1H NMR (400 MHz, CDCl3) δH 4.08-4.07 (m, 1H), 2.0-1.85 (m, 5H), 1.84-1.65 (m, 4H), 1.56-1.54-1.42 (m, 7H), 1.40-1.35 (m, 2H), 1.34-1.28 (m, 4H), 1.14-1.12 (m, 7H), 0.96 (s, 3H), 0.83 (d, J = 6.4Hz, 3H), 0.65 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.779. LC- ELSD/MS purity >98%, MS ESI calcd. for C24H38F
3O [M+H-H
2O]
+ 399.3, found 399.2.
[0865] Example 81: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((1R,2S)-1-cyclopropyl-1-hydroxypropan-2-yl)-6a-methyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (81)
[0866] A solution of cyclopropylmagnesium bromide (10.0 mL, 5.0 mmol, 0.5 M in hexane) was reacted with a solution of 61.9 (400 mg, 1.00 mmol) in THF (10 mL) under N2 at 0 °C. The mixture was warmed to 50 °C and stirred for 1 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE). The resulting residue was further purified from MeCN (6 mL) and lyophilized to give 81 (3.1 mg, 8 %).
1H NMR (400MHz, CDCl3) δH 3.34 (m, 1H), 2.08-2.03 (m, 2H), 1.91-1.68 (m, 12H), 1.51-1.44 (m, 4H), 1.26- 1.24 (m, 4H), 1.14-1.07 (m, 4H), 1.04 (d, J = 6.8 Hz, 3H), 0.77 (s, 3H), 0.65-0.59 (m, 2H), 0.55-0.48 (m, 1H), 0.43-0.37 (m, 1H), 0.32-0.27 (m, 1H), 0.13-0.08 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.61. LC-ELSD/MS 30-90AB_2min_E, purity > 99%, MS ESI calcd. for C26H38F
3O [M-H
2O+H]
+ 423.3, found 423.3. [0867] Example 82: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((1R,2S)-1-cyclopropyl-1-hydroxypropan-2-yl)-2,6a- dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (82)
[0868] Synthesis of 82.1 [0869] To a solution of t-BuOK (38.3 g, 342 mmol) in THF (300 mL) was added 26.1 (40 g, 137 mmol) at 25 °C under N
2 and the resulting mixture was stirred for 10 min. Methyl benzenesulfinate (53.4 g, 342 mmol) was added and the mixture was stirred at 30 °C for 0.5 h. The mixture was quenched with H
2O (300 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were separated, dried over anhydrous Na
2SO
4, filtered, and concentrated to give 82.1 (56.8 g). [0870] Synthesis of 82.2 [0871] To a solution of 82.1 (56.8 g) in xylene (1000 mL) was added Na
2CO
3 (144 g, 11.36 mol) in portions and the resulting mixture was stirred at 140 °C under N
2 for 8 h. The mixture was filtered, concentrated, and the residue was purified by silica gel chromatography (0~17% EtOAc in PE) to give 82.2 (25 g, 64% yield over two steps).
1H NMR (400 MHz, CDCl
3) δ
H 7.54-7.49 (m, 1H), 6.02 (dd, J = 3.2, 6.0 Hz, 1H), 2.39-2.33 (m, 1H), 1.90-1.64 (m, 9H), 1.61-1.39 (m, 10H), 1.32-1.26 (s, 3H), 1.07 (s, 3H).
[0872] Synthesis of 82.3 [0873] To a stirred solution of Me3SOI (31.9 g, 145 mmol) in DMSO (500 mL) was added t-BuOK (17.9 g, 160 mmol) and the resulting mixture was stirred at 60 °C for 1 h under N2. 82.2 (21.0 g, 72.8 mmol) was added and the mixture was stirred at 20 °C for 2 h. The reaction was treated with water (200 mL) and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 82.3 (20 g, 90.9%).
1H NMR (400 MHz, CDCl3) δH
2.10-1.95 (m, 2H), 1.94-1.76 (m, 6H), 1.74-1.61 (m, 6H), 1.60-1.56 (m, 7H), 1.44-1.39 (m, 3H), 1.15- 1.04 (m, 3H), 1.01-0.92 (m, 3H). [0874] Synthesis of 82.4 [0875] To a stirred solution of EtPPh3Br (84.2 g, 227 mmol) in THF (500 mL) was added t- BuOK (25.4 g, 227 mmol) and the resulting mixture was stirred at 40-50 °C for 1 h under N2. 82.3 (23 g, 76.0 mmol) was added and the mixture was stirred at 40 °C for 3 h. The reaction mixture was quenched with 10% aqueous NH4Cl (300 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 50 mL), and the combined organic layers were concentrated to give a residue, which was purified from MeOH:H
2O (1:1, 800 mL) at reflux to give 82.4 (23 g, 96.2%).
1H NMR (400 MHz, CDCl3) δH 5.34 (q, J = 7.6 Hz, 1H), 2.15-2.09 (m, 1H), 1.86-1.81 (m, 5H), 1.72-1.63 (m, 10H), 1.41-1.39 (m, 3H), 1.35- 1.25 (m, 6H), 1.19-1.06 (m, 3H), 0.99 (s, 3H), 0.91-0.89 (m, 1H), 0.48-0.39 (m, 1H). [0876] Synthesis of 82.5 [0877] To a stirred solution of 82.4 (5.00 g, 15.8 mmol) in THF (50 mL) was added 9-BBN (11.4 g, 47.4 mmol) and the resulting mixture was stirred at 45 °C for 16 h under N2. To the mixture was added EtOH (70 mL) at 15 °C, followed by aqueous NaOH (47.4 mL, 5.0 M, 237 mmol) at 0 °C. Hydrogen peroxide (23.7 mL, 10 M, 237 mmol) was then added dropwise at 0 °C and the mixture was stirred at 78 °C for 1 h. The mixture was cooled to 15 °C and saturated aqueous Na
2S
2O
3 (200 mL) was added. The resulting precipitate was filtered and washed with water (3 x 50 mL) to give 82.5 (9 g). The product was purified from MeOH:water (1:1, 200 mL) at 25 °C to give 82.5 (11 g, 61.4% yield over 2 steps).
1H NMR (400 MHz, CDCl
3) δ
H 3.86-3.78 (m, 1H), 1.84-1.82 (m, 2H), 1.80-1.75 (m, 2H), 1.70-1.64 (m, 5H), 1.57-1.53 (m, 2H), 1.41-1.38 (m, 4H), 1.33-1.29 (m, 4H), 1.27-1.24 (m, 7H), 1.15- 0.95 (m, 5H), 0.74 (s, 3H), 0.23-0.16 (m, 1H). [0878] Synthesis of 82.6
[0879] To a solution of 82.5 (1.00 g, 3.00 mmol) in DCM (10 mL) was added DMP (5.08 g, 12.0 mmol) at 30 °C and the resulting mixture was stirred for 10 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (50 mL) at 0 °C and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 82.6 (1 g). [0880] Synthesis of 82.7 [0881] To a mixture of MePPh
3Br (5.40 g, 15.1 mmol) in THF (20 mL) was added t-BuOK (1.69 g, 15.1 mol) at 15 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.82.6 (1.00 g, 3.02 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 50 °C for 1 h. The mixture was quenched with 10% aqueous NH
4Cl (50 ml) at 15 °C and the organic layer was separated. The mixture was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified from MeOH:H
2O (1:1, 50 mL) at reflux to give 82.7 (0.8 g, 83.7%).
1H NMR (400 MHz, CDCl3) δH 5.10 (s, 1H), 4.84 (s, 1H), 2.39 (s, 1H), 2.06-2.03 (m, 2H), 1.86-1.82 (m, 2H), 1.76-1.72 (m, 4H), 1.48-1.35 (m, 4H), 1.32-1.22 (m, 12H), 1.19-1.09 (m, 3H), 0.95-0.80 (m, 2H), 0.64 (s, 3H), 0.29-0.19 (m, 1H). [0882] Synthesis of 82.8 [0883] To a stirred solution of 82.7 (800 mg, 2.43 mmol) in THF (20 mL) was added 9-BBN (2.35 g, 9.72 mmol) and the resulting mixture was stirred at 45 ℃ for 16 h. EtOH (30 mL) was added at 15 °C, followed by aqueous NaOH (9.72 mL, 5.0 M, 48.6 mmol) at 0 °C. Hydrogen peroxide (5 mL, 10 M, 48.6 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 78 °C for 1 h. The mixture was cooled to 15 °C and saturated aqueous Na
2S
2O
3 (50 mL) was added. The precipitate was filtered and washed with water (3 x 50 mL) to give 82.8, which was purified by silica gel chromatography (0~25% EtOAc in PE) to give 82.8. Compound 82.8 was further purified from IPA (5 mL) at 90 °C and then lyophilized to give 82.8 (18.6 mg, 12.0%).
1H NMR (400 MHz, CDCl
3) δ
H 3.89-3.81 (m, 1H), 3.66-3.58 (m, 1H), 1.87-1.66 (m, 8H), 1.62-1.57 (m, 2H), 1.44-1.35 (m, 5H), 1.31-1.24 (m, 7H), 1.21- 1.08 (m, 4H), 1.01 (d, J = 6.8 Hz, 3H), 0.76 (s, 3H), 0.64-0.60 (m, 1H), 0.14-0.08 (m, 1H). LC-ELSD/MS purity 96%, MS ESI calcd. for C
23H
37O [M-H
2O+H]
+ 329.2, found 329.2. [0884] Synthesis of 82.9 [0885] To a solution of 82.8 (500 mg, 1.44 mmol) in DCM (5 mL) was added DMP (3.04 g, 7.19 mmol) at 30 °C and the resulting mixture was stirred for 10 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (10 mL) and saturated aqueous Na
2S
2O
3 (10
mL) at 25 °C. The mixture was extracted with DCM (2 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 82.9 (740 mg, 2.15 mmol).
1H NMR (400 MHz, CDCl3) δH 9.82 (d, J = 2.8 Hz, 1H), 2.59-2.47 (m, 1H), 1.91-1.77 (m, 5H), 1.76-1.53 (m, 10H), 1.48-1.28 (m, 8H), 1.27 (s, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.79 (s, 3H), 0.72-0.64 (m, 1H), 0.22-0.12 (m, 1H). [0886] Synthesis of 82 [0887] A solution of cyclopropylmagnesium bromide (28.6 mL, 14.3 mmol, 0.5 M in hexane) was reacted with a solution of 82.9 (1.6 g, 3.59 mmol) in THF (20 mL) under N2 at 70 ℃ and the resulting mixture was stirred for 1 h. The mixture was poured into water (40 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 82, which was further purified from MeCN:H
2O (1:1, 20 mL) to give 82 (25.7 mg, 1%).
1H NMR (400 MHz, CDCl3) δH 3.34 (dd, J = 3.6, 8.8 Hz, 1H), 1.96-1.63 (m, 10H), 1.51-1.36 (m, 5H), 1.34-1.20 (m, 10H), 1.15-1.00 (m, 7H), 0.77 (s, 3H), 0.66-0.60 (m, 2H), 0.59-0.55 (m, 1H), 0.54-0.45 (m, 1H), 0.30-0.25 (m, 1H), 0.12-0.09 (m, 1H). LC-ELSD/MS purity>99%, MS ESI calcd. for C26H39 [M- 2H
2O+H]
+ 351.3, found 351.3. [0888] Example 83: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2,6a- dimethyl-7-((2S,3S)-4,4,4-trifluoro-3-hydroxybutan-2- yl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (83)
[0889] To a solution of 82.9 (1.48 g, 4.29 mmol) and CsF (1.30 g, 4.11 mmol) in THF (20 mL) was added TMSCF
3 (1.83 g, 12.87 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 15 °C for 3 h. TBAF (21.29 mL, 21.29 mmol, 1 M in THF) was added and the mixture was stirred at 15 °C for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (2 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, concentrated and purified by HPLC
(Column: Phenomenex C18150*25mm*10um; Condition: water (NH
4HCO
3)-ACN), Begin B: 53, End B: 83, Gradient Time (min): 5, 100%B. Hold Time (min): 2, Flow Rate (ml/min): 30) to afford 83 (121.3 mg, 8.1%).
1H NMR (400 MHz, CDCl3) δH 4.43-4.35 (m, 1H), 2.36 (d, J = 6.0 Hz, 1H), 2.07-1.98 (m, 1H), 1.60 (m, 10H), 1.47-13.6 (m, 4H), 1.32-1.25 (m, 8H), 1.23-1.11(m, 4H), 1.07-1.04 (m, 3H), 0.76 (s, 3H), 0.67-0.63 (m, 1H), 0.19-0.13 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -72.31. LCMS purity > 99%, MS ESI calcd. for C24H36F
3O [M-H
2O+H]
+ 397.2, found 397.2. [0890] Example 84: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-(methoxy-d3)butan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (84)
[0891] Na metal (2.28 g, 99.1 mmol) was added to CD
3OD (120 mL) at 20 ℃ and the resulting mixture was stirred for 2 h.62.2 (4.0 g, 9.98 mmol) in THF (30 mL) was added dropwise at 20 ℃ and the resulting mixture was warmed to 60 ℃ and stirred for 16 h. The mixture was poured into saturated aqueous NH
4Cl (200 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~25% EtOAc in PE). The resulting reside was further purified from MeCN:H
2O (2:1, 30 mL) to give 84 (589.4 mg, 58.9% yield).
1H NMR (400 MHz, CDCl3) δH 3.92-3.82 (m, 1H), 3.42 (dd, J = 2.4, 9.6 Hz, 1H), 3.26 (t, J = 9.6 Hz, 1H), 2.35 (d, J = 1.6 Hz, 1H), 2.09 (s, 1H), 2.05-1.65 (m, 9H), 1.54-1.32 (m, 6H), 1.24-1.03 (m, 8H), 0.94 (d, J = 6.8 Hz, 3H), 0.68 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -78.61. LC- ELSD/MS 30-90AB_7min_E, purity>99%, MS ESI calcd. for C
24H
40D
3F
3O
3N [M+NH
4]
+ 453.4, found 453.4. [0892] Example 85: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-3-ethyl-17-((2S,3S)- 3-hydroxy-4-methoxybutan-2-yl)-13-methylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (85)
[0893] Synthesis of 85.1 [0894] To a mixture of MePPh
3Br (12.3 g, 34.6 mmol) in 2-MeTHF (50 ml) was added t- BuOK (3.88 g, 34.6 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 50 °C for 30 min.4.15 (2 g, 5.77 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with 10% aqueous HCl (60 ml) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (60 mL) and the combined organic layers were concentrated to give a residue, which was purified by silica gel chromatography (0~10% EtOAc in PE) to give 85.1 (1 g, 50%). [0895] Synthesis of 85.2 [0896] To a mixture of 85.1 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA (997 mg, 5.80 mmol) under N
2 and the resulting mixture was stirred at 25 ℃ for 1 h. The mixture was quenched with NaOH (1 N in water, 50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated to give 85.2 (700 mg).
1H NMR (400 MHz, CDCl3) δH
2.79-2.72 (m, 1H), 2.60-2.2.61 (m,
1H), 2.60-2.50 (m, 1H), 1.98-1.75 (m, 6H), 1.69-1.61 (m, 6H), 1.53-1.40 (m, 4H), 1.09-0.99 (m, 9H), 0.98-0.91 (m, 1H), 0.88-0.75 (m, 7H), 0.70-0.60 (m, 3H). [0897] Synthesis of 85.3 [0898] To a solution of 85.2 (700 mg, 1.94 mmol) in MeOH (5 mL) was added sodium methoxide (1.04 g, 19.4 mmol) and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched with H
2O (10 mL) and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The product was purified by silica gel chromatography ( 0~5% DCM in MeOH) to give 85.3 (600 mg, 52.6% yield over 2 steps). [0899] Synthesis of 85.4 [0900] To a mixture of 85.3 (500 mg, 1.27 mmol), DMAP (154 mg, 1.27 mmol), and pyridine (0.41 mL, 5.08 mmol) in 2-Me-THF (5 mL) was added BzCl (0.45 mL, 3.81 mmol) and the resulting mixture was stirred at 25 °C for 16 h. The mixture was poured into water (10 mL) and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE). The resulting residue was further purified by SFC (Column: REGIS (R,R)WHELK- O1(250mm*25mm, 10 um),Condition: 0.1%NH3H
2O EtOH) to afford 85.4 (0.2 g, 40%).
1H NMR (400 MHz, CDCl3) δH 8.04 (d, J = 6.8 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 5.51-5.38 (m, 1H), 3.58 (dd, J = 10.4, 7.2 Hz, 1H), 3.505 (dd, J = 10.0, 6.4 Hz, 1H), 3.36 (s, 3H), 1.80-1.50 (m, 10H), 1.46-1.26 (m, 10H), 1.23-1.15 (m, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.08-0.95 (m, 5H), 0.85 (t, J = 7.6 Hz, 3H), 0.69 (s, 3H). [0901] Synthesis of 85 [0902] A mixture of 85.4 (200 mg, 0.04 mmol), LiOH·H
2O (168 mg, 4 mmol), THF (1.5 mL), MeOH (0.5 mL), and H
2O (0.5 mL) was stirred at 25 °C for 16 h. The aqueous phase was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by HPLC (Column: Phenomenex C18150*25mm*10um, Condition: water (NH4HCO
3)-ACN) to afford 85 (21 mg, 21%).
1H NMR (400 MHz, CDCl3) δH 3.90-3.83 (m, 1H), 3.50-3.35 (m, 4H), 3.33 (d, J = 9.6 Hz, 1H), 1.98-1.92 (m, 1H), 1.83-1.72 (m, 5H), 1.68-1.55 (m, 6H), 1.50-1.21 (m, 10H), 1.20-1.00 (m, 7H), 0.94 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H), 0.67 (s, 3H). LC-ELSD/MS 30-100AB_4min_ELSD, purity>99%, MS ESI calcd. for C25H41O [M-2H
2O+H]
+ 357.3, found 357.3.
[0903] Example 86: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((2S,3S)-3-hydroxy-4-methoxybutan-2-yl)-2,6a- dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (86)
[0904] Synthesis of 86.1 [0905] To a mixture of MePPh
3Br (9.52 g, 26.6 mmol) in THF (50 mL) was added t-BuOK (2.98 g, 26.6 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 50 °C for 30 min.82.9 (2 g, 5.33 mmol) was added in portions to keep the internal reaction mixture temperature below 50 °C during the course of the addition. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with 10% aqueous NH
4Cl (50 ml) at 15 °C and the organic layer separated. The mixture was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO
4, filtered, concentrated, and purified from MeOH:H
2O (1:1, 200 ml) at reflux to give 86.1 (1.9 g, 100%).
1H NMR (400 MHz, CDCl3) δH 5.94-5.85 (m, 1H), 5.00 (d, J = 17.2 Hz, 1H), 4.91 (dd, J = 2.0, 10.4 Hz, 1H), 2.29-2.22 (m, 1H), 2.00-1.88 (m, 1H), 1.78-1.62 (m, 8H), 1.59- 1.48 (m, 8H), 1.26 (s, 3H), 1.19-1.04 (m, 6H), 1.02 (d, J = 6.8 Hz, 3H), 0.77 (s, 3H), 0.61- 0.57 (m, 1H), 0.09-0.02 (m, 1H). [0906] Synthesis of 86.2 [0907] To a solution of 86.1 (1.6 g, 4.69 mmol) in DCM (20 mL) was added m-CPBA (1.61 g, 9.38 mmol) and the resulting mixture was stirred at 20 °C for 16 h. The mixture was diluted with DCM (20 mL) and washed with saturated aqueous Na2S2O
3/NaHCO
3 (1:1, 2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified
by silica gel chromatography (0~10% EtOAc in PE) to give 86.2 (1.03 g, 61%).
1H NMR (400 MHz, CDCl3) δH
2.88-2.85 (m, 1H), 2.83-2.79 (m, 1H), 2.73-2.67 (m, 1H), 2.00-1.97 (m, 1H), 1.87-1.78 (m, 6H), 1.73-1.64 (m, 10H), 1.45-1.39 (m, 6H), 1.27 (s, 3H), 1.09 (d, J = 6.4 Hz, 3H), 0.95-0.93 (m, 1H), 0.75-0.72 (m, 3H), 0.59-0.56 (m, 1H), 0.12-0.06 (m, 1H). [0908] Synthesis of 86 [0909] To a solution of 86.2 (200 mg, 557 µmol) in MeOH (5 ml) was added sodium methoxide (300 mg, 5.57 mmol) at 25 °C in portions and the resulting mixture was stirred at 65 °C for 16 h. The residue was poured into 10% aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by HPLC (Column: Phenomenex C18150*25mm*10um, Condition: water (NH
4HCO
3)-ACN, Begin B: 53, End B: 83, Gradient Time(min): 5, 100% B Hold Time(min): 2, Flow Rate(ml/min): 30) and lyophilized to give 86 (7.7 mg, 15.4%).
1H NMR (400 MHz, CDCl3) δH 4.24-4.18 (m, 1H), 3.59-3.53 (m, 1H), 3.42 (s, 3H), 3.39-3.36 (m, 1H), 1.98-1.91 (m, 1H), 1.84-1.66 (m, 8H), 1.44-1.36 (m, 4H), 1.33-1.20 (m, 10H), 1.17-1.04 (m, 5H), 0.92 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H), 0.66-0.62 (m, 1H), 0.16-0.09 (m, 1H). LC-ELSD/MS 30-100AB_4min_ELSD, purity 96.7%, MS ESI calcd. for C
25H
41O
2 [M-H
2O+H]
+ 373.3, found 373.3. [0910] Example 87: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-methoxybutan-2-yl)-3,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (87)
[0911] Synthesis of 87.1 [0912] To a solution of 4.2 (100 g, 364 mmol) in DCM (1000 mL) was added ethylene glycol (20.2 ml, 364 mmol), trimethyl orthoformate (60.5 ml, 364 mmol) and TsOH (6.92 g, 36.4 mmol), and the resulting mixture was stirred at 25 °C for 16 h. The mixture was poured into saturated aqueous NaHCO
3 (1000 mL) and extracted with DCM (3 x 1000 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 87.1 (107 g). [0913] Synthesis of 87.2 [0914] To a mixture of EtPPh3Br (162 g, 438 mmol) in THF (700 mL) was added t-BuOK (29 g, 258 mmol) at 20 °C under N
2 and the resulting mixture was stirred at 40 °C for 30 min. 87.1 (70 g, 219 mmol) was added in portions to keep the internal reaction mixture temperature below 40 °C during the course of the addition. The reaction mixture was stirred at 40 °C for 4 h and then quenched with 10% aqueous NH4Cl (500 mL) at 20 °C. The aqueous phase was extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated.
The residue was purified by silica gel chromatography (PE/EtOAc = 30/1 to 20/1) to give 87.2 (80 g). [0915] Synthesis of 87.3 [0916] To a solution of 87.2 (80 g, 242 mmol) in THF (800 mL) was added 9-BBN dimer (58.5 g, 242 mmol) in portions slowly under N2 and the resulting mixture was stirred at 50 °C for 3 h. The mixture was cooled to 0 °C and NaOH (724 ml, 5 M in water, 3.62 mol) was added dropwise under N
2. H
2O
2 (28.9 g, 846 mmol) was then added dropwise slowly under N2 at 0 °C. After stirring at 25 °C for 0.5 h, the mixture was cooled to 0 °C, slowly poured into saturated aqueous Na2S2O
3 (500 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc (3 x 1000 mL) and the combined organic layers were washed with brine (2 x 1000 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 87.3 (60 g). [0917] Synthesis of 87.4 [0918] To a solution of 87.3 (100 g, 286 mmol) in DCM (1000 mL) was added PCC (123 g, 572 mmol) and silica gel (132 g) at 25 °C and the resulting mixture was stirred for 3 h. The mixture was filtered through a pad of silica gel, which was washed with DCM (3000 mL). The filtrate was concentrated to give 87.4 (80 g). [0919] Synthesis of 87.5 [0920] To a solution of MePPh3Br (154 g, 432 mmol) in THF (500 mL) was added t-BuOK (29 g, 258 mmol) at 25 °C under N
2 and the resulting mixture was stirred at 40 °C for 30 min. 87.4 (50 g, 144 mmol) was added in portions to keep the internal temperature of the reaction mixture below 40 °C during the course of the addition. The reaction mixture was stirred at 40 °C for 16 h. The reaction mixture was quenched with 10% aqueous NH4Cl (500 mL) at 20 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with water (500 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 87.5 (50 g). [0921] Synthesis of 87.6 [0922] To a solution of 87.5 (50 g, 145 mmol) in THF (500 mL) was added 9-BBN dimer (52.5 g, 217 mmol) in portions slowly under N
2 and the resulting mixture was stirred at 25 °C for 12 h. The mixture was cooled to 0 °C and EtOH (66.7 g, 1.45 mol) and NaOH (290 mL, 5 M in water, 1.45 mol) were added dropwise under N2. H
2O
2 (145 mL, 10 M in water, 1.45 mmol) was added dropwise slowly under N2 at 25 °C. The mixture was warmed to 50 °C and stirred for 2 h. The mixture was cooled and slowly poured into saturated aqueous Na
2S
2O
3
(500 mL) and stirred for 30 min. The aqueous phase was extracted with EtOAc (2 x 500 mL) and the combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 87.6 (50 g). [0923] Synthesis of 87.7 [0924] To a solution of 87.6 (12 g, 31.8 mmol) in DCM (100 mL) was added DMP (26.9 g, 63.6 mmol) and the resulting mixture was stirred at 20 °C for 2 h. The residue was poured into saturated aqueous NaHCO
3/Na
2SO
3 (w/w = 1:1, 100 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 87.7 (12 g). [0925] Synthesis of 87.8 [0926] To a solution of MePPh3Br (47.5 g, 133 mmol) in THF (200 mL) was added t- BuOK (14.9 g, 133 mmol) at 25 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.87.7 (24 g, 66.5 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. After stirring at 50 °C for 16 h, the reaction mixture was quenched with saturated aqueous NH4Cl (200 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 300 mL), and the combined organic layers were concentrated and purified by silica gel chromatography (0~5% EtOAc in PE) to give 87.8 (14 g, 58.8%). [0927] Synthesis of 87.9 [0928] To a solution of 87.8 (14 g, 39 mmol) in DCM (150 mL) was added m-CPBA (15.7 g, 78 mmol) under N2 and the resulting mixture was stirred at 25 °C for 3 h. The mixture was poured into a mixture of saturated aqueous NaHCO
3 (100 mL) and saturated aqueous Na
2S
2O
3 (100 mL) and extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 87.9 (14.8 g). [0929] Synthesis of 87.10 [0930] To a solution of sodium methoxide (43.2 g, 800 mmol) in MeOH (500 mL) was added a solution of 87.9 (30 g, 80 mmol) in THF (100 mL) and the resulting mixture was stirred at 60 ℃ under N
2 for 16 h. The mixture was quenched with 10% aqueous NH
4Cl (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with 10% aqueous NH4Cl (500 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 87.10 (1.75 g, 5.4%).
1H NMR (400 MHz, CDCl
3) δ
H 3.94-3.93 (m, 4H), 3.88-3.86 (m, 1H), 3.40-3.38 (m, 4H),
3.30-3.23 (m, 1H), 2.00-1.92 (m, 3H), 1.87-1.82 (m, 3H), 1.49-1.45 (m, 6H), 1.41-1.37 (m, 5H), 1.15-1.10 (m, 4H), 1.07-1.02 (m, 5H), 0.96-0.92 (m, 3H), 0.67 (s, 3H). [0931] Synthesis of 87.11 [0932] To a solution of 87.10 (1.75 g, 4.3 mmol) in THF (40 mL) was added HCl (2 M in water, 10 mL) and the resulting mixture was stirred at 20 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated aqueous NaHCO
3 (50 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% of EtOAc in PE) to give 87.11 (0.56 g, 36.1%).
1H NMR (400 MHz, CDCl3) δH 3.91-3.85 (m, 1H), 3.40-3.38 (m, 4H), 3.30-3.24 (m, 1H), 2.61-2.57 (m, 1H), 2.23-2.15 (m, 7H), 2.03-1.99 (m, 1H), 1.73-1.64 (m, 7H), 1.51-1.47 (m, 3H), 1.16-1.12 (m, 7H), 0.98-0.94 (m, 3H), 0.72 (s, 3H). [0933] Synthesis 87 [0934] To a solution of BHT (0.907 g, 4.12 mmol) in toluene (10 mL) under N
2 at 0 ℃ was added AlMe3 (2 M in toluene, 1.03 mL, 2.06 mmol) dropwise. After stirring at 25 ℃ for 1 h, a solution of 87.11 (0.25 g, 5 mL in anhydrous DCM, 0.689 mmol) in anhydrous DCM was added dropwise at -70 ℃. After stirring at -70 ℃ for 1 h under N
2, MeMgBr (0.573 mL, 1.72 mmol, 3 M in Et2O) was added dropwise at -70 ℃ and the resulting solution was stirred for 1 h. The reaction mixture was then poured into saturated aqueous citric acid (20 mL) at 10 ℃, followed by the addition of ice water (50 mL), and the resulting mixture was stirred for 10 min. The suspension was filtered to give 87 (0.15 g), which was purified by silica gel chromatography (0~25% EtOAc in PE) to give 87 (38.6 mg, 14.8%).
1H NMR (400 MHz, CDCl3) δH 3.88-3.85 (m, 1H), 3.44-3.41 (m, 1H), 3.38-3.37 (m, 3H), 3.29-3.24 (m, 1H), 2.32- 2.24 (m, 1H), 2.00-1.93 (m, 2H), 1.92-1.86 (m, 2H), 1.82-1.70 (m, 3H), 1.63-1.56 (m, 3H), 1.47-1.42 (m, 3H), 1.29-1.18 (m, 6H), 1.14-1.07 (m, 2H), 0.95-0.93 (m, 3H), 0.87-0.75 (m, 4H), 0.72-0.64 (m, 4H), 0.64-0.62 (m, 3H). LC-ELSD/MS purity >99%, MS ESI calcd for C
24H
41O
2 [M+H-H
2O]
+ 361.3, found 361.2. [0935] Example 88: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-(2-methoxyethoxy)butan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (88)
[0936] To a solution of 2-methoxyethanol (300 mg, 3.94 mmol) was added NaH (191 mg, 7.95 mmol) at 0 °C dropwise and the resulting mixture was stirred at 25 °C for 0.5 h. To a solution of 36.2 (300 mg, 0.749 mmol) in 2-methoxyethanol (3 mL) was added the freshly prepared 2-methoxyethanol sodium (386 mg, 3.93 mmol) and the resulting mixture was stirred at 70 °C for 16 h. The mixture was cooled to 25 °C and poured into water (6 mL) and stirred for 20 min. The aqueous phase was extracted with DCM (3 x 3 mL) and the combined organic layers were washed with brine (2 x 3 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc = 3/1 to 1/1) and further purified by HPLC ((Column: Phenomenex C18150*25mm*10um); Condition: water( NH
4HCO
3)-ACN, flow rate: 30 mL/min) to give 88 (45.6 mg, 12.7%).
1H NMR (400 MHz, CDCl3) δH 3.91-3.87 (m, 1H), 3.71-3.66 (m, 1H), 3.63-3.58 (m, 1H), 3.57-3.51 (m, 3H), 3.39- 3.31 (m, 4H), 2.08 (s, 1H), 2.05-1.90 (m, 3H), 1.84-1.74 (m, 6H), 1.63-1.57 (m, 5H), 1.50- 1.36 (m, 4H), 1.20-1.02 (m, 8H), 0.95-0.93 (m, 3H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.62. LC-ELSD/MS purity >99%, MS ESI calcd. for C26H47F
3O
4N [M+NH4]
+ 494.3, found 494.3. [0937] Example 89: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2R,3S)-3- hydroxy-4-methoxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (89)
[0938] Synthesis of 89.1 [0939] To a solution of Me3SI (15.2 g, 74.8 mmol) in THF (250 mL) was added t-BuOK (8.37 g, 74.8 mmol) at 0 ℃ in portions under N2. To the reaction mixture was added 27.2 (15 g, 37.4 mmol) and the resulting mixture was stirred at 20 ℃ for 12 h. The mixture was poured into ice-water (w/w = 1/1, 300 mL) and stirred for 20 min. The mixture was extracted with EtOAc (2 × 200 mL), and the combined organic layers were washed with saturated aqueous NH
4Cl (150 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 89.1 (15 g).
[0940] Synthesis of 89.2 [0941] To a solution of 89.1 (15 g, 36.1 mmol) in MeOH (250 mL) was added sodium methoxide (13.6 g, 252 mmol) at 25 °C and the resulting mixture was stirred for 12 h at 50 °C. The reaction was quenched with saturated aqueous NH
4Cl (300 mL) and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 89.2 (16.3 g). [0942] Synthesis of 89.3 [0943] To a solution of 89.2 (15 g, 33.5 mmol) in DCM (200 mL) was added DMP (42.4 g, 100 mmol) at 20 °C and the resulting mixture was stirred at 20 °C for 3 h. The mixture was quenched with saturated aqueous NaHCO
3 and Na
2S
2O
3 (400 mL, v:v = 1:1) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCO
3 and Na2S2O
3 (100 mL, v:v = 1:1), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~3% EtOAc in PE) to give 89.3 (6.3 g, 42.6%). [0944] Synthesis of 89.4 [0945] To a solution of 89.3 (6.30 g, 13.7 mmol) in DCE (100 mL) was added 1H-imidazole (2.78 g, 41.0 mmol), tert-butyl(chloro)diphenylsilane (4.67 g, 27.4 mmol) at 50 °C. After stirring at 50 °C for 16 h, the mixture was quenched with H
2O (60 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were separated, dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~3% EtOAc in PE) and further purified by SFC (column: REGIS(S,S) WHELK -O1 (250mm*25mm, 10um); Condition: 0.1%NH3H
2O IPA); Begin B: 10; End B: 10; Gradient Time: 3,450; Flow Rate: 120mL/min) to give 89.4 (1.40 g, 22.3%). [0946] Synthesis of 89.5 [0947] To a solution of 89.4 (1.4 g, 2.41 mmol) in MeOH (20 mL) was added NaBH4 (500 mg, 13.2 mmol) and the resulting mixture was stirred at 25 °C for 10 min. The mixture was quenched with 10% aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with 10% aqueous NH4Cl (50 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~5% EtOAc in PE) to give 89.5 (312 mg, 22.4%). [0948] Synthesis of 89 [0949] To a solution 89.5 (150 mg, 0.258 mmol) in THF (5 mL) was added TBAF (324 mg, 1.03 mmol) in one portion at 40 °C under N
2. After stirring at 40 °C for 2 h, the reaction
mixture was poured into water (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, concentrated, purified by silica gel chromatography (0~15% of EtOAc in PE), and lyophilized to give 89 (7.6 mg, 99%).
1H NMR (400 MHz, CDCl
3) δ
H 4.06-4.97 (m, 1H), 3.54-3.36 (m, 4H), 3.50-3.22 (m, 1H), 2.09-1.85 (m, 6H), 1.82-1.68 (m, 6H), 1.45-1.36 (m, 5H), 1.33-1.23 (m, 6H), 1.12-1.05 (m, 3H), 0.96 (s, 3H), 0.89-0.83 (m, 3H), 0.68 (s, 3H).
19F NMR (400 MHz, CDCl3) δF - 78.787. LC-ELSD/MS purity 99%, MS ESI calcd for C
24H
36F
3O [M-CH
3OH-H
2O]
+ 397.3, found 397.2. [0950] Example 90: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2-ethyl- 7-((2S,3S)-4-fluoro-3-hydroxybutan-2-yl)-6a- methyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (90)
[0951] Synthesis of 90.2 [0952] To a solution of t-BuOK (16.4 g, 147 mmol) in THF (400 mL) was added 90.1 (22.5 g, 73.8 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 15 °C for 10 min. Methylbenzenesulfinate (22.9 g, 147 mmol) was added and the mixture was stirred at 30 °C for 0.5 h. The mixture was quenched with H
2O (500 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were separated, dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo to give 90.2 (35 g). [0953] Synthesis of 90.3 [0954] To a mixture of 90.2 (35 g, 81.6 mmol) in xylene (900 mL) was added Na2CO
3 (127 g, 1.2 mol) in portions. The reaction mixture was stirred at 140 °C for 16 h under N
2. The reaction mixture was concentrated under vacuum to give 90.3 (44 g). The product was combined with another batch of 90.3 obtained using similar conditions and the combined products were purified by silica gel chromatography (50~100% EtOAc in PE) to give 90.3 (44 g).
1H NMR (400 MHz, CDCl3) δH 7.54-7.50 (m, 1H), 6.06-5.99 (m, 1H), 2.41-2.33 (m,
1H), 1.90-1.80 (m, 4H), 1.75-1.52 (m, 8H), 1.47-1.24 (m, 9H), 1.07 (s, 3H), 0.89 (t, J = 7.6 Hz, 3H). [0955] Synthesis of 90.4 [0956] A stirred solution of trimethylsulfoxonium iodide (20.8 g, 94.9 mmol) and t-BuOK (11.6 g, 104 mmol) in DMSO (300 mL) was heated at 60 °C for 1 h under N2.90.3 (14.5 g, 47.9 mmol) was added and the resulting mixture was stirred at 25 °C for 1 h. The reaction was treated with water (300 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (200 mL), dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo to afford 90.4 (16 g). [0957] Synthesis of 90.5 [0958] To a mixture of EtPPh
3Br (112 g, 303 mmol) in THF (500 mL) was added t-BuOK (34 g, 303 mmol) at 15 °C under N2 and the resulting mixture was stirred at 40 °C for 30 min. 90.4 (16 g, 50.5 mmol) was added in portions to keep the internal temperature of the reaction mixture below 40 °C during the course of the addition. The resulting mixture was stirred for 1 h. The reaction mixture was quenched with 10% aqueous HCl (500 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (400 mL), and the combined organic layers were concentrated under vacuum to give 90.5 (17 g) which was combined with another batch of 90.5 obtained using similar conditions and the combined products were purified by silica gel chromatography (0~20% EtOAc in PE) to give 90.5 (15.84 g). [0959] Synthesis of 90.6 [0960] A solution of 90.5 (15 g, 45.6 mmol) and BH3∙THF (114 mL, 1 M in THF, 114 mmol) was stirred at 40 °C for 3 h. EtOH (125 mL) was added at 15 °C, followed by aqueous NaOH (140 mL, 5.0 M, 485 mmol) at 0 °C. Hydrogen peroxide (46.3 g, 30%) was added dropwise at 0 °C, the mixture was warmed to 15 °C, and saturated aqueous Na2S2O
3 (1000 mL) was added. The precipitate was filtered, and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 90.6 (13.5 g). [0961] Synthesis of 90.7 [0962] To a solution of 90.6 (14.3 g, 41.2 mmol) in DCM (150 mL) was added silica gel (15 g) and PCC (13.3 g, 61.8 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h and PE (150 mL) was added. The mixture was filtered through a pad of silica gel and eluted with DCM (200 mL). The filtrate was concentrated and the residue was purified by silica gel chromatography (8~15% EtOAc in PE) to give 90.7 (7 g, 50% yield over two steps).
1H
NMR (400 MHz, CDCl
3) δ
H 2.76-2.72 (m, 1H), 2.20 (s, 3H), 1.97-1.91 (m, 1H), 1.74-1.65 (m, 6H), 1.56-1.44 (m, 7H), 1.36-1.33 (m, 3H), 1.08-1.00 (m, 4H), 0.93-0.88 (m, 5H), 0.72 (s, 3H), 0.68-0.61 (m, 2H), 0.43-0.34 (m, 1H). [0963] Synthesis of 90.8 [0964] To a mixture of MePPh3Br (43.2 g, 121 mmol) in 2-Me-THF (70 mL) was added t- BuOK (13.5 g, 121 mol) at 15 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.90.7 (7 g, 20.3 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was then stirred at 50 °C for 1 h. The reaction mixture was quenched with 10% aqueous NH4Cl (200 mL) at 15 °C. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 80 mL). The combined organic layers were concentrated under vacuum, and the residue was purified by silica gel chromatography with EtOAc:PE (1:5) to give 90.8 (2.5 g, 35.9%).
1H NMR (400 MHz, CDCl3) δH 5.09 (s, 1H), 4.86-4.80 (m, 1H), 2.43-2.37 (m, 1H), 1.80-1.70 (m, 9H), 1.71-1.59 (m, 7H), 1.40-1.11 (m, 12H), 0.88 (t, J = 7.2 Hz, 3H), 0.64 (s, 3H), 0.28-0.19 (m, 1H). [0965] Synthesis of 90.9 [0966] To a solution of 90.8 (8 g, 23.3 mmol) in 2-Me-THF (300 mL) was added 9-BBN dimer (28 g, 116 mmol) at 15 °C and the resulting mixture was stirred at 45 °C for 16 h. EtOH (300 mL) was added at 15 °C and aqueous NaOH (93.2 mL, 5M, 466 mmol) was added at -10 °C, followed by the dropwise addition of H
2O
2 (52.6 g, 30%, 466 mmol). The mixture was stirred at 70 °C for 1 h. Saturated aqueous Na
2S
2O
3 (400 mL) was added to the mixture and the suspension was stirred at 15 °C for 16 h. The solid was filtered, washed with water (4 x 30 mL), and dried under vacuum. i-PrOH (20 mL) was added and the mixture was stirred at reflux. The mixture was cooled to give 90.9 (5 g, 59.23%).
1H NMR (400 MHz, CDCl3) δH 3.92-3.79 (m, 1H), 3.67-3.56 (m, 1H), 1.80-1.71 (m, 5H), 1.63 (m, 3H), 1.61-1.55 (m, 4H), 1.51-1.39 (m, 4H), 1.38-1.31 (m, 3H), 1.29-1.22 (m, 4H), 1.17 (m, 4H), 1.01 (d, J = 6.4 Hz, 3H), 0.91-0.86 (m, 3H), 0.76 (s, 3H), 0.65-0.59 (m, 1H), 0.15-0.07 (m, 1H). LC- ELSD/MS purity >99%, MS ESI calcd. for C24H39O [M-H
2O+H]
+ 343.3, found 343.3. [0967] Synthesis of 90.10 [0968] To a solution of 90.9 (4 g, 11.0 mmol) in DCM (40 mL) was added DMP (13 g, 30.6 mmol) at 25 °C and the resulting mixture was stirred for 40 min. The mixture was quenched with saturated aqueous NaHCO
3 (200 mL) at 10 °C. The organic phase was separated and washed with saturated aqueous NaHCO
3/Na2S2O
3 (1:1, 2 x 200 mL) and brine (200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated under vacuum to give 90.10 (4.75
g).
1H NMR (400 MHz, CDCl
3) δ
H 9.82 (d, J = 3.2 Hz, 1H), 2.59-2.45 (m, 1H), 2.25 (s, 1H), 1.90-1.80 (m, 1H), 1.79-1.65 (m, 7H), 1.62-1.55 (m, 5H), 1.50-1.36 (m, 5H), 1.31-1.17 (m, 6H), 1.11 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.78 (s, 3H), 0.71-0.65 (m, 1H), 0.22- 0.12 (m, 1H). [0969] Synthesis of 90.11 [0970] To a solution of MePPh3Br (23.7 g, 66.6 mmol) in THF (80 mL) was added t-BuOK (7.47 g, 66.6 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 50 °C for 30 min.90.10 (4 g, 11.1 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The resulting mixture was stirred for 1 h. The reaction mixture was quenched with 10% aqueous NH
4Cl (100 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers were concentrated under vacuum. The residue was purified from MeOH:H
2O (1:1, 200 mL) at reflux to give 90.11 (4 g).
1H NMR (400 MHz, CDCl
3) δ
H 5.96-5.83 (m, 1H), 5.05-4.96 (m, 1H), 4.93-4.87 (m, 1H), 2.32-2.21 (m, 1H), 1.79- 1.63 (m, 11H), 1.45-1.10 (m, 14H), 1.02 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.77 (s, 3H), 0.61-0.57 (m, 1H), 0.20-0.10 (m, 1H). [0971] Synthesis of 90.12 [0972] To a solution of 90.11 (4 g, 11.2 mmol) in DCM (40 mL) was added m-CPBA (3.83 g, 22.4 mmol) and the resulting mixture was stirred at 20 °C for 16 h. The mixture was diluted with DCM (20 mL), washed with saturated aqueous Na
2S
2O
3/NaHCO
3 (1:1, 2 x 40 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 90.12 (4.5 g). [0973] Synthesis of 90 [0974] To a mixture of 90.12 (500 mg) and KHF
2 (1.04g, 13.4mmol) was added TBAF (26.8mL, 26.8mmol) at 25 °C under N
2 and the resulting mixture was stirred at 120 °C for 16 h. The mixture was poured into ice-water (50mL) and the aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by prep-HPLC ((column: Phenomenex C18150*25mm*10um), gradient: 85-95%, Condition: water (NH4HCO
3)-CAN, flowrate: 30 mL/min) to give 90 (31.9 mg, 6.1%).
1H NMR (400 MHz, CDCl
3) δ
H 4.71-4.39 (m, 2H), 4.33-4.22 (m, 1H), 2.00-1.92 (m, 1H), 1.80-1.65 (m, 10H), 1.59-1.42 (m, 6H), 1.36-1.12 (m, 10H), 0.97-0.93 (m, 3H), 0.91-0.87 (m, 3H), 0.78-0.74 (m, 3H), 0.68-0.63 (m, 1H), 0.19-0.12 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -231.85. LC- ELSD/MS purity 99%; MS ESI calcd. for C25H40FO [M-H
2O+H]
+ 375.3, found 375.3.
[0975] Example 91: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2-ethyl- 7-((2S,3S)-3-hydroxy-4-methoxybutan-2-yl)-6a- methyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (91)
[0976] To a solution of 90.12 (500 mg, 1.34 mmol) in MeOH (5 mL) was added sodium methoxide (361 mg, 6.70 mmol) at 25 °C in portions and the resulting mixture was stirred at 65 °C for 10 h. The residue was poured into 10% aqueous NH4Cl (15 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE). The resulting residue was further purified by HPLC (Column: Phenomenex C18150*25mm*10um; Condition: water (NH4HCO
3)-MeCN) to afford 91 (35.4 mg, 5%).
1H NMR (400 MHz, CDCl
3) δ
H 4.27-4.14 (m, 1H), 3.62-3.52 (m, 1H), 3.47- 3.32 (m, 4H), 1.98-1.92 (m, 1H), 1.82-1.72 (m, 6H), 1.71-1.69 (m ,2H) 1.68-1.60 (m, 6H), 1.52-1.36 (m, 7H), 1.29-1.08 (m, 5H), 0.94-0.86 (m, 6H), 0.75 (s, 3H), 0.67-0.61 (m, 1H), 0.17-0.08 (m, 1H). LC-ELSD/MS purity >99 %, MS ESI calcd. for C
26H
43O
2 [M-H
2O+H]
+ 387.33, found 387.3. [0977] Example 92: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-3-(fluoromethyl)-17- ((2S,3S)-3-hydroxy-4-methoxybutan-2-yl)-13-methylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (92)
[0978] Synthesis of 92.1 [0979] To a solution of 87.11 (560 mg, 1.54 mmol), HMPA (413 mg, 2.31 mmol), and fluoromethanesulfonylbenzene (642 mg, 3.69 mmol) in THF (20 mL) was added LiHMDS (6.16 mL, 1 M in THF) dropwise at -70 ℃ under N
2. After stirring at -25 ℃ for 12 h, the reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~25% EtOAc in PE) twice to give 92.1 (129 mg, 15.6%). [0980] Synthesis of 92 [0981] To a solution of 92.1 (129 mg, 0.240 mmol) and anhydrous Na
2HPO
4 (189 mg, 1.58 mmol) in anhydrous MeOH (10 mL) at 25 ℃ under N
2 was added Na/Hg amalgam (1.07 g, 4.8 mmol). After stirring at 25 ℃ for 2 h, the mixture was quenched with 10% aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (10 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, purified by silica gel chromatography (0~20% EtOAc in PE), and separated by HPLC (Column: Phenomenex C18150*25mm*10um; Condition: water(TFA)-MeCN; Begin B: 40; End B: 70; FlowRate (ml/min): 30) to give 92 (1.5 mg, 1.6%).
1H NMR (400 MHz, CDCl3) δH 4.54-4.29 (m, 2H), 3.83-3.82 (m, 1H), 3.47-3.37 (m, 4H), 3.31-3.24 (m, 1H), 1.99- 1.83 (m, 4H), 1.68-1.56 (m, 5H), 1.50-1.34 (m, 7H), 1.33-1.17 (m, 4H), 1.15-1.00 (m, 7H), 0.97-0.91 (m, 3H), 0.67 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -233.532
. LC-ELSD/MS purity 100%, MS ESI calcd. For C
24H
41FO
3Na [M+Na]
+419.3, found 419.2.
[0982] Example 93: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-3-(difluoromethyl)- 17-((2S,3S)-3-hydroxy-4-methoxybutan-2-yl)-13-methylhexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (93)
[0983] Synthesis of 93.1 [0984] To a solution of 87.11 (650 mg, 1.86 mmol), HMPA (499 mg, 2.79 mmol), and PhSO
2CF
2H (857 mg, 4.46 mmol) in THF (10 mL) was added LiHMDS (7.44 mL, 1 M in THF, 7.44 mmol) dropwise at -70 ℃ under N2. The resulting mixture was stirred and warmed to 25 ℃ for 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~30% EtOAc in PE) to give 93.1 (120 mg, 48.1 %). [0985] Synthesis of 93 [0986] To a solution of 93.1 (120 mg, 0.2163 mmol) and anhydrous Na
2HPO
4 (170 mg, 1.42 mmol) in anhydrous MeOH (10 mL) at 25 ℃ under N2 was added Na/Hg amalgam (483 mg, 2.16 mmol) and the resulting mixture was stirred for 16 h. The mixture was quenched with 10% aqueous NH
4Cl (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH4Cl (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE). The residue was further purified by HPLC (Column: Phenomenex C18150*25mm*10um; Condition: water(TFA)-ACN; Begin B: 50; End B: 80; Flow Rate
(ml/min): 30) to afford 93 (8.1 mg, 9.05%).
1H NMR (400 MHz, CDCl
3) δ
H 6.05-5.70 (t, 1H), 3.91-3.85 (m, 1H), 3.45-3.41 (m, 1H), 3.40-3.33 (s, 3H), 3.31-3.24 (m, 1H), 2.00-1.94 (m, 1H), 1.92-1.89 (m, 1H), 1.88-1.85 (m, 2H), 1.79-1.77 (s, 5H), 1.65-1.59 (m, 3H), 1.56- 1.32 (m, 7H), 1.28-1.21 (m, 1H), 1.18-1.03 (m, 7H), 0.97-0.93 (m, 3H), 0.70-0.66 (s, 3H);
19F NMR (376.5 MHz, CDCl3) δF -135.545, 135.785. LC-ELSD/MS purity >99%, MS ESI calcd. for C24H40F2O
3Na [M+Na]
+ 437.3, found 437.3. [0987] Example 94: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-2-ethyl- 7-((2S,3R)-3-hydroxybutan-2-yl)-6a- methyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (94)
[0988] Synthesis of 94.1 [0989] To a solution of 90.10 (618 mg, 1.72 mmol) in 2-Me-THF (8 mL) was added MeMgBr (1.14 mL, 3 M in Et
2O, 3.44 mmol) at 0 °C under N
2 and the resulting mixture was stirred at 25 °C for 2 h. Saturated aqueous NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 94.1 (655 mg).
1H NMR (400 MHz, CDCl3) δH 4.29-4.21 (m, 1H), 1.80-1.64 (m, 10H), 1.62-1.57 (m, 5H), 1.48- 1.29 (m, 9H), 1.23-1.21 (m, 3H), 1.14-1.05 (m, 3H), 0.91-0.87 (m, 6H), 0.76-0.73 (m, 3H), 0.62-0.55 (m, 1H), 0.14-0.08 (m, 1H). [0990] Synthesis of 94.2
[0991] To a solution of 94.1 (500 mg, 1.33 mmol) in pyridine (20 mL) was added BzCl (933 mg, 6.64 mmol) and the resulting mixture was stirred at 60 °C for 24 h. Water (1 mL) was added and the mixture stirred at 25 °C for 4 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by Prep-TLC (PE:EtOAc = 3:1) and further purified by SFC (Column: Daicel ChiralPak IG (250*30mm, 10um); Condition: Heptane-(IPA:CAN = 4:1) (0.1%NH
3·H
2O); Begin B: 50%; End B: 50%; Gradient Time(min): 8.6; Flowrate (ml/min): 80) to afford 94.2 (38 mg, 17%). LC-ELSD/MS 30-100AB_1min_ELSD, purity 98.7%, MS ESI calcd. for C
25H
39 [M-BzOH-H
2O+H]
+ 339.3, found 339.3. [0992] Synthesis of 94 [0993] A mixture of 94.2 (32 mg, 66.8 µmol) and LiOH·H
2O (140 mg, 3.34 mmol) in THF (0.6 mL), MeOH (0.2 mL), and H
2O (0.2 mL) was stirred at 25 °C for 24 h. The mixture was diluted with H
2O (10mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by HPLC (Column: Phenomenex C18 150*25mm*10um; Condition: water (NH
4HCO
3)-ACN; Begin B: 58; End B: 88; Gradient Time (min): 8; 100% B Hold Time (min): 60; FlowRate (ml/min): 30) and lyophilized to give 94 (8.2 mg, 32%).
1H NMR (400 MHz, CDCl3) δH 4.19-4.26 (m, 1H), 1.83-1.72 (m, 6H), 1.72-1.55 (m, 8H), 1.46-1.23 (m, 10H), 1.13 (d, J = 6.4 Hz, 3H), 1.11-1.04 (m, 3H), 0.91- 0.87 (m, 6H), 0.76 (s, 3H), 0.65-0.61 (m, 1H), 0.13-0.08 (m, 1H). LC-ELSD/MS purity > 99%, MS ESI calcd. for C25H41O [M-H
2O+H]
+ 357.2, found 357.2. [0994] Example 95: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((2S,3S)-4-fluoro-3-hydroxybutan-2-yl)-2,6a- dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (95)
[0995] Synthesis of 95.1 [0996] To a mixture 86.2 (0.5 g, crude) and KHF
2 (1.07 g, 13.8 mmol) was added TBAF (27.7 mL, 27.7 mmol) at 25 °C under N
2 and the resulting mixture was stirred at 120 °C for 16 h. The mixture was poured into ice-water (50 mL) and the aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by Prep- HPLC (Column: Phenomenex C18150*25mm*10um) (water (NH
4HCO
3)-CAN 58%-88%)) to afford 95.1 (160 mg, 30%).
1H NMR (400 MHz, CDCl3) δH 4.58-4.49 (m, 1H), 4.45-4.25 (m, 2H), 1.91-1.67 (m, 9H), 1.66-1.32 (m, 10H), 1.27-1.04 (m, 9H), 0.90 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H), 0.63-0.57 (m, 1H), 0.16-0.07 (m, 1H).
19F NMR (376.5 MHz, CDCl
3) δ
F - 226.65. LC-ELSD/MS purity>99%, MS ESI calcd. for C24H38FO [M-H
2O+H]
+ 361.3, found 361.3. [0997] Synthesis of 95.2 [0998] To a solution of 95.1 (0.1 g, 0.26 mmol) in DCM was added DMP (335 mg, 0.79 mmol) at 20 °C and the resulting mixture was stirred at 40 °C for 1 h. The mixture was quenched with saturated aqueous NaHCO
3 (10 mL) at 10 °C. The organic phase was separated and washed with saturated aqueous NaHCO
3/Na
2SO
3 (1:1, 2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum to give 95.2 (100 mg). [0999] Synthesis of 95
[1000] To a solution of 95.2 (100 mg) in MeOH (2 mL) was added NaBH
4 (40 mg, 1.05 mmol) at 20 °C and the resulting mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl (10mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 95 (14.5 mg, 15%).
1H NMR (400 MHz, CDCl3) δH 4.71-4.40 (m, 2H), 4.33- 4.21 (m, 1H), 2.01-1.68 (m, 9H), 1.66-1.50 (m, 6H), 1.42-1.26 (m, 10H), 1.19-1.12 (m, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.76 (s, 3H), 0.70-0.62 (m, 1H), 0.20-0.11 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -231.86. LC-ELSD/MS purity>99%, MS ESI calcd. for C24H38FO [M- H
2O+H]
+ 361.3, found 361.2. [1001] Example 96: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-3-ethyl-17-((2S,3R)- 3-hydroxybutan-2-yl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (96)
[1002] Synthesis of 96.1 [1003] To a solution of 4.15 (800 mg) in 2-Me-THF (8 mL) was added MeMgBr (2.29 mL, 3 M, 6.89 mmol) at 0 °C under N
2 and the resulting mixture was stirred at 20 °C for 2 h. The mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 96.1 (571 mg).
1H NMR (400 MHz, CDCl3) δH 3.95-3.91(m, 1H), 1.84-1.73 (m, 10H), 1.50-1.42 (m, 10H), 1.17-1.11 (m, 8H), 0.91-0.86 (m, 10H), 0.66 (s, 3H).
[1004] Synthesis of 96.2 [1005] To a solution of 96.1 (571 mg) in DCM (6 mL) was added BzCl (441 mg, 3.14 mmol) and Et3N (635 mg, 6.28 mmol) at 20 °C and the resulting mixture was stirred for 32 h. The reaction mixture was quenched with saturated aqueous NH
4Cl (20 mL) and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~12% EtOAc in PE) to give 96.2 (120 mg).96.2 (120 mg) was further purified by SFC (Column: DAICEL CHIRALCEL OJ (250mm*30mm, 10um), gradient: 20-20% B (A = 0.1% NH3/H
2O, B = EtOH), flow rate: 70 mL/min) to give 96.2 (46.0 mg, 12%). LC-ELSD/MS purity 99%, MS ESI calcd. for C
24H
39 [M+H-H
2O- BzOH]
+ 327.3, found 327.3. [1006] Synthesis of 96 [1007] To a solution of 96.2 (46.0 mg, 98.5 µmol) in THF (0.25 mL) and MeOH (0.5 mL) was added a solution of LiOH·H
2O (82.6 mg, 1.97 mmol) in H
2O (0.25 mL) at 25 °C and the resulting mixture was stirred for 48 h. The reaction mixture was poured into water (10 mL) and the aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~22% EtOAc in PE) to give 96 (2.6 mg, 7%).
1H NMR (400 MHz, CDCl3) δH 3.96-3.85 (m, 1H), 2.00-1.94 (m, 1H), 1.84-1.58 (m, 10H), 1.51-1.45 (m, 6H), 1.44-1.32 (m, 5H), 1.20-1.00 (m, 10H), 0.92- 0.85 (m, 6H), 0.67 (s, 3H). LC-ELSD/MS purity 99%, MS ESI calcd. for C
24H
39 [M- 2H
2O+H]
+ 327.3, found 327.3. [1008] Example 97: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((2S,3R)-3-hydroxybutan-2-yl)-6a-methyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (97)
[1009] To a solution of BHT (2.08 g, 9.46 mmol) in toluene (4 mL) under nitrogen at 0 °C was added AlMe3 (2 M in toluene, 2.36 mL, 4.73 mmol) dropwise and the resulting mixture was stirred at 25 °C for 1 h. To the MAD (4.73 mmol in 4 mL toluene) solution was added a solution of 61.9 (200 mg, 0.473 mmol) in anhydrous DCM (2 mL) dropwise at -70 ℃. After stirring at -70 ℃ for 1 h under N2, MeMgBr (1.57 mL, 4.73 mmol, 3 M in Et2O) was added dropwise at -70 ℃ and the resulting solution was stirred at -70 ℃ for 2 h. The reaction mixture was poured into aqueous citric acid (20 mL, 15%) dropwise at 10 ℃ and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~40% EtOAc in PE) to give 97 (60.0 mg, 30%).
1H NMR (400 MHz, CDCl
3) δ
H 4.27-4.18 (m, 1H), 2.15-1.59 (m, 12H), 1.53-1.38 (m, 5H), 1.33-0.98 (m, 11H), 0.89 (d, J = 6.8 Hz, 3H), 0.77 (s, 3H), 0.66-0.60 (m, 1H), 0.16-0.07 (m, 1H).
19F NMR (376MHz, CDCl3) δF -78.61 (s). LC-ELSD/MS 30-90AB_2min_E, purity > 99%, MS ESI calcd. for C
24H
36F
3O [M-H
2O +H]
+ 397.3, found 397.3. [1010] Example 98: Synthesis of (2R,4aS,4bS,6aS,7R,7aS,8aR,8bS,8cR,10aR)-7- ((2S,3S)-3-hydroxy-4-methoxybutan-2-yl)-4a,6a-dimethyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (98)
[1011] Synthesis of 98.2
[1012] To a solution of 98.1 (30 g, 104 mmol) in THF (300 mL) was added CsF (15.7 g, 104 mmol) at 10 °C under N2. TMSCF
3 (44.3 g, 312 mmol) was added dropwise at 10 °C and the resulting mixture was stirred for 1 h. TBAF (49.2 g, 156 mmol) was added dropwise at 20 °C and the mixture was stirred for 2 h. The mixture was poured into water (300 mL) and stirred for 20 min and the aqueous phase was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~10% EtOAc in PE) to give 98.2 (35 g, 94 %).
1HNMR (400 MHz, CDCl3) δH
2.31-2.20 (m, 1H), 2.20-2.05 (m, 1H), 2.01-1.85 (m, 2H), 1.82-1.59 (m, 7H), 1.56-1.26 (m, 10H), 1.18-1.00 (m, 2H), 0.98 (s, 3H), 0.92 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -78.74 (s). [1013] Synthesis of 98.3 [1014] To a solution of t-BuOK (12.1 g, 108 mmol) in THF (200 mL) was added 98.2 (13 g) at 25 °C under N2 and the resulting mixture was stirred for 10 min. Methyl benzenesulfinate (16.8 g, 108 mmol) was added and the mixture was stirred at 30 °C for 0.5 h. The mixture was quenched with H
2O (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo to give 98.3 (21.8 g). [1015] Synthesis of 98.4 [1016] To a solution of 98.3 (38.8 g) in xylene (350 mL) was added Na2CO
3 (85 g, 802 mmol) in portions. After stirring at 140 °C under N
2 for 8 h, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 98.4 (4.8 g, 21% yield over 2 steps).
1H NMR (400 MHz, CDCl3) δH 7.52 (dd, J = 1.2, 5.8 Hz, 1H), 6.05 (dd, J = 3.2, 6.0 Hz, 1H), 2.39-2.35 (m, 1H), 1.99-1.91 (m, 4H), 1.86- 1.71 (m, 6H), 1.56-1.49 (m, 4H), 1.42-1.30 (m, 4H), 1.07 (s, 3H), 1.05 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.82. [1017] Synthesis of 98.5 [1018] A stirred solution of trimethylsulfoxonium iodide (11 g, 50.4 mmol) and t-BuOK (5.93 g, 52.9 mmol) in DMSO (200 mL) was heated at 60 °C for 1 h under N2.98.4 (9 g, 25.2 mmol) was added and the reaction mixture was stirred at 25 °C for 1 h. The reaction was treated with 10% aqueous NH
4Cl (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 98.5 (11 g).98.5 (200 mg) was purified by silica gel chromatography (0~30% EtOAc in PE) to give 98.5 (42 mg, 21.1% yield).
1H NMR (400 MHz, CDCl
3) δ
H 2.04-1.91 (m, 6H), 1.82-1.78 (m, 1H), 1.77-1.70 (m,
5H), 1.63-1.49 (m, 5H), 1.43-1.36 (m, 1H), 1.36-1.29 (m, 4H), 1.14-1.08 (m, 1H), 1.00 (s, 3H), 0.95 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.79. LC-ELSD/MS purity = 98%, MS ESI calcd. for C21H30F
3O
2 [M+H]
+ 371.2, found 371.2. [1019] Synthesis of 98.6 [1020] To a mixture of EtPPh3Br (32.9 g, 88.8 mmol) in THF (200 mL) was added t-BuOK (9.96 g, 88.8 mmol) at 20 °C under N2 and the resulting mixture was stirred at 20 °C for 30 min.98.5 (11 g, 29.6 mmol) was added in portions to keep the internal temperature of the reaction mixture below 40 °C during the course of the addition. The reaction mixture was stirred at 35 °C for 1 h, quenched with 10% aqueous NH4Cl (100 mL) at 10 °C, and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified from MeOH:H
2O (1:1, 150 mL) at reflux to give 98.6 (8.4 g). [1021] Synthesis of 98.7 [1022] To a stirred solution of 98.6 (8.4 g, 21.9mmol) in THF (200 mL) was added BH3·Me2S (6.5 mL, 10 M in Me2S, 65.6 mmol) at 15 °C and the resulting mixture was stirred at 40 °C under N2 for 1 h. EtOH (200 mL) was added at 15 °C, followed by aqueous NaOH (39.4 mL, 5.0 M, 197 mmol) at 0 °C. H
2O
2 (20.83 mL, 10 M in water, 208 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. To the mixture was added saturated aqueous Na2S2O
3 (100 mL) and the precipitate was filtered and washed with water (3 x 200 mL). The solution was concentrated to give 98.7 (9.6 g).98.7 (9.6 g) was purified from MeOH:H
2O (1:1, 30 mL) at reflux to give 98.7 (6 g, 68% yield over 2 steps).
1H NMR (400 MHz, CDCl3) δH 3.87-3.79 (m, 1H), 2.00-1.90 (m, 4H), 1.75-1.62 (m, 5H), 1.45-1.30 (m, 10H), 1.25-1.20 (m, 3H), 0.98 (s, 3H), 0.95-0.80 (m, 5H), 0.74 (s, 3H), 0.20- 0.10 (m, 1H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.76. [1023] Synthesis of 98.8 [1024] To a solution of 98.7 (5 g, 12.4 mmol) in DCM (100 mL) was added DMP (15.7 g, 37.2 mmol) at 30 ℃ and the resulting mixture was stirred for 10 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (100 mL) and saturated aqueous Na2S2O
3 (50 mL) at 0 ℃. The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 98.8 (6 g).98.8 (150 mg) was purified by silica gel chromatography (0~30% EtOAc in PE) to give 98.8 (42.7 mg, 28.6% yield).
1H NMR (400 MHz, CDCl3) δH 2.74 (d, J = 4.0 Hz, 1H), 2.22 (s, 3H), 2.07-1.91 (m, 5H), 1.83-1.63 (m, 6H), 1.52-1.40 (m, 3H), 1.39-1.23 (m, 7H), 0.99 (s, 3H), 0.90-0.87 (m, 1H), 0.72 (s, 3H), 0.46-0.38 (m, 1H).
19F
NMR (376.5 MHz, CDCl
3) δ
F -78.83. LC-ELSD/MS purity >99%, MS ESI calcd. for C23H34F
3O [M+H]
+ 399.2, found 399.2. [1025] Synthesis of 98.9 [1026] To a solution of MePPh
3Br (10.7 g, 30 mmol) in THF (100 mL) was added t-BuOK (3.36 g, 30 mmol) at 20 ℃ under N2 and the resulting mixture was stirred at 50 °C for 30 min.98.8 (4 g, 10 mmol) was added in portions to keep the internal temperature below 50 °C. The reaction mixture was stirred at 55 °C for 1 h. The reaction mixture was quenched with 10% aqueous NH4Cl (100 mL) at 10 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 98.9 (9.2 g).98.9 (9.2 g) was purified from MeOH:H
2O (1:1, 50mL) at reflux to give 98.9 (3.2 g, 80.8%). [1027] Synthesis of 98.10 [1028] To a stirred solution of 98.9 (3.3 g, 8.32 mmol) in THF (60 mL) was added 9-BBN dimer (10 g, 41.6 mmol) at 15 °C and the resulting mixture was stirred at 45 °C under N2 for 4 h. EtOH (200 mL) was added at 15 °C, followed by aqueous NaOH (49.8 mL, 5.0 M, 249 mmol) at 0 °C. H
2O
2 (28.47 mL, 10 M in water, 284 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at 20 °C for 16 h. The mixture was cooled to 15 °C and saturated aqueous Na2S2O
3 (100 mL) was added. The precipitate was filtered, washed with water (3 x 100 mL), and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified from MeOH:H
2O (1:1, 20 mL) at reflux to give 98.10. The product was further purified from i-PrOH (8 mL) at 90 °C, stirred for 0.5 h, cooled, and filtered to give 98.10 (582 mg, 17%).
1H NMR (400 MHz, CDCl
3) δ
H 3.88-3.79 (m, 1H), 3.67-3.58 (m, 1H), 2.10-1.85 (m, 4H), 1.80-1.50 (m, 10H), 1.45-1.35 (m, 1H), 1.34-1.02 (m, 9H), 1.01-1.92 (m, 6H), 0.75 (s, 3H), 0.70-0.60 (m, 1H), 0.16-0.09 (m, 1H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.76. [1029] Synthesis of 98.11 [1030] To a solution of 98.10 (500 mg, 1.20 mmol) in DCM (20 mL) was added DMP (1.52 g, 3.59 mmol) at 30 °C and the resulting mixture was stirred for 15 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (50 mL) and saturated aqueous Na
2S
2O
3 (25 mL) at 0 °C. The mixture was extracted with DCM (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 98.11 (690 mg).
[1031] Synthesis of 98.12 [1032] To a mixture of MePPh3Br (1.78 g, 5.00 mmol) in 2-Me-THF (8.00 mL) was added t-BuOK (562 mg, 5.00 mol) at 15 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.98.11 (690 mg, 1.67 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was then stirred at 50 °C for 1 h. The reaction mixture was quenched with 10% aqueous NH
4Cl (30 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 20 mL), and the combined organic layers were concentrated under vacuum. The residue was purified from MeOH:H
2O (1:1, 16 mL) to give 98.12 (270 mg, 54% yield over 2 steps).
1H NMR (400 MHz, CDCl
3) δ
H 5.97-5.81 (m, 1H), 5.05-4.88 (m, 2H), 2.31-2.20 (m, 1H), 2.08-1.87 (m, 5H), 1.78-1.73 (m, 2H), 1.69-1.64 (m, 4H), 1.46-1.28 (m, 7H), 1.24-1.12 (m, 4H), 1.02 (d, J = 6.4 Hz, 3H), 0.98 (s, 3H), 0.76 (s, 3H), 0.62-0.58 (m, 1H), 0.09-0.04 (m, 1H). [1033] Synthesis of 98.13 [1034] To a solution of 98.12 (240 mg, 0.584 mmol) in DCM (5 mL) was added m-CPBA (200 mg, 1.16 mmol) and the resulting mixture was stirred at 20 °C for 6 h. The mixture was diluted with DCM (20 mL) and washed with saturated aqueous Na
2S
2O
3:NaHCO
3 (1:1, 2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 98.13 (252 mg).
1H NMR (400 MHz, CDCl3) δH
2.89-2.85 (m, 1H), 2.84-2.79 (m, 1H), 2.72-2.69 (m, 1H), 1.98- 1.90 (m, 5H), 1.79-1.75 (m, 3H), 1.68-1.66 (m, 4H), 1.45-1.41 (m, 2H), 1.34-1.30 (m, 5H), 1.26-1.23 (m, 4H), 1.018-0.964 (m, 6H), 0.72 (s, 3H), 0.61-0.56 (m, 1H), 0.13-0.07 (m, 1H). [1035] Synthesis of 98.14 [1036] To a solution of 98.13 (250 mg, 0.586 mmol) in MeOH (5 ml) was added sodium methoxide (316 mg, 5.85 mmol) at 25 °C in portions and the resulting mixture was stirred at 65 °C for 5 h. The reaction mixture was poured into 10% aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by HPLC (Column: Phenomenex C18150*25mm*10um, Condition: water (NH4HCO
3)-ACN, 46%~76%, 8 min) to afford 98.14 (52.8 mg, 20%).
1H NMR (400 MHz, CDCl3) δH 4.30-4.19 (m, 1H), 3.49- 3.39 (m, 5H), 2.05-1.87 (m, 5H), 1.80-1.62 (m, 9H), 1.46-1.40 (m, 1H), 1.34-1.24 (m, 8H), 1.14-1.09 (m, 1H), 0.99 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.74 (s, 3H), 0.62-0.56 (m, 1H), 0.15-0.08 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -78.73. LC-ELSD/MS purity > 99%, MS ESI calcd. for C26H41F
3O
3Na [M+Na]
+ 481.2, found 481.2. [1037] Synthesis of 98.15
[1038] To a solution of 98.14 (24 mg, 0.052 mmol) in DCM (5 mL) was added DMP (77.7 mg, 0.156 mmol) at 30 °C and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (5 mL) and saturated aqueous Na
2S
2O
3 (3 mL) at 0 °C. The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 98.15 (60 mg). LC-ELSD/MS purity 81.1%, MS ESI calcd. for C
26H
39F
3O
3 [M+H]
+ 457.2, found 457.2. [1039] Synthesis of 98 [1040] To a solution of 98.15 (60 mg) in MeOH (5 mL) was added NaBH4 (100 mg, 2.62 mmol) at 0 °C and the resulting mixture was stirred at 20 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH
4Cl (10 mL) at 0 °C and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The product was combined with another batch of 98 obtained using similar conditions (60 mg of 98.15 starting material) and was purified by silica gel chromatography (0~30% EtOAc in PE) to give 98 (16 mg, 32%).
1H NMR (400 MHz, CDCl3) δH 4.23-4.17 (m, 1H), 3.59-3.52 (m, 1H), 3.42-3.34 (m, 4H), 2.02-1.89 (m, 5H), 1.81-1.61 (m, 8H), 1.46-1.25 (m, 7H), 1.23-1.06 (m, 4H), 0.98 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H), 0.68-0.63 (m, 1H), 0.17-0.10 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -78.78. LC-ELSD/MS purity>99%, MS ESI calcd. for C26H41F
3O
3 Na[M+Na]
+ 481.2, found 481.2. [1041] Example 99: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-(trifluoromethoxy)butan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (99)
[1042] Synthesis of 99.1 [1043] To a solution of 62.2 (3.4 g, 8.48 mmol) in THF (40 mL) and H
2O (10 mL) was added TsOH (1.73 g, 10.1 mmol) at 25 ℃ and the resulting mixture was stirred at 60 ℃ for 16 h. The reaction mixture was treated with saturated aqueous NaHCO
3 (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated aqueous NaHCO
3 (2 x 100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to afford 99.1 (4 g). [1044] Synthesis of 99.2 [1045] To a mixture of AgOTf (4.59 g, 17.9 mmol), Selectfluor (2.53 g, 7.16 mmol), NFSI (2.25 mg, 7.16 mmol), and CsF (3.25 g, 21.4 mmol) under N
2 was added 99.1 (1.5 g, 3.58 mmol), Benzotrifluoride (35 mL), toluene (10 mL), 2-fluoropyridine (1.73 g, 17.9 mmol), and TMSCF
3 (2.54 mg, 17.9 mmol). The mixture was stirred at 25 ℃ under N2 for 16 h, filtered, and concentrated. The residue was dissolved in pyridine (5 mL) and BzCl (82.6 mg, 0.588 mmol) was added. After stirring at 20 ℃ for 0.5 h, the mixture was quenched with 10%
aqueous NH
4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH4Cl (20 mL), dried over anhydrous Na2SO
4, filtered, purified by silica gel chromatography (0~5% EtOAc in PE) and further purified by SFC (Column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); Condition: Neu-EtOH; Begin B: 25; End B: 25; FlowRate (ml/min):70) to give 99.2 (106 mg). [1046] Synthesis of 99 [1047] To a solution of 99.2 (106 mg, 0.179 mmol) in THF:MeOH:H
2O (1:1:1, 7 mL) was added LiOH·H
2O (1.4 g, 35 mmol, 5 M in water) and the resulting mixture was stirred at 20 ℃ for 3 h. The reaction was quenched with 10% aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified from MeCN (10 mL) at 20 ℃ to give 99 (8.2 mg, 0.5%).
1H NMR (400 MHz, CDCl3) δH 4.02- 3.95 (m, 2H), 3.90-3.83 (m, 1H), 2.00-1.88 (m, 4H), 1.87-1.73 (m, 4H), 1.57-1.68 (m, 4H), 1.53-1.39 (m, 6H), 1.34-1.18 (m, 4H), 1.17-1.01 (m, 5H), 0.93 (d, J = 6.0Hz, 3H), 0.69 (s, 3H).
19F NMR (376 MHz, CDCl3) δF -60.654, -78.621. LC-ELSD/MS 30-100AB_4min_E, purity>99%, MS ESI calcd. For C24H35F6O
2 [M+H-H
2O]
+ 469.2, found 469.2. [1048] Example 100: Synthesis of (2R,4aS,4bS,6aS,7R,7aS,8aR,8bS,8cR,10aR)-7- ((2S,3R)-3-hydroxybutan-2-yl)-4a,6a-dimethyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (100)
[1049] To a solution of BHT (548 mg, 2.48 mmol) in toluene (1 mL) under nitrogen at 0 ℃ was added trimethylaluminum (2 M in toluene, 0.62 mL, 1.24 mmol) dropwise and the mixture was stirred at 25 ℃ for 1 h. To the MAD (595 mg, 1.24 mmol in 1 mL toluene) solution was added a solution of 98.11 (172 mg, 0.416 mmol) in anhydrous DCM (2 mL) dropwise at -70 ℃. After stirring at -70 ℃ for 1 h under N
2, MeMgBr (0.413 mL, 1.24 mmol, 3 M in Et
2O) was added dropwise at -70 ℃ and the resulting solution was stirred for 2 h. The reaction mixture was poured into citric acid (3 mL, 20% aq.) at 10 ℃ and extracted with
EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo. The product was purified by silica gel chromatography (0~30% EtOAc in PE) to give 100 (24.7 mg, 13.8%).
1H NMR (400 MHz, CDCl3) δH 4.17- 4.27 (m, 1H), 2.06-1.87 (m, 4H), 1.82-1.74 (m, 3H), 1.72-1.62 (m, 5H), 1.48-1.17 (m, 10H), 1.06-1.15 (m, 5H), 0.98 (s, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.76 (s, 3H), 0.67-0.62 (m, 1H), 0.18-0.08 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -78.77. LC-ELSD/MS purity >99%, MS ESI calcd. for C
25H
38F
3O [M-H
2O+H]
+ 411.2, found 411.2. [1050] Example 101: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-methoxybutan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-2,2,4,4-d4-3-ol (101)
[1051] Synthesis of 101.1 [1052] To a solution of 87.11 (600 mg, 1.65 mmol) in anhydrous THF (10 mL) was added NaOD (5 mL, 0.1 M in D
2O, 0.5 mmol) and CD
3OD (1 mL) at 20 ℃ under N
2 and the resulting mixture stirred at 50 ℃ for 16 h. The reaction mixture was adjusted to pH = 7 with AcOD (1 M in D2O). To the mixture was added NaCl (1.5 g) and PE (10 mL). The mixture was stirred for 5 min and the organic layer was separated. The aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo to give 101.1 (550 mg, 84.6 %, ~85% deuterated). Compound 101.1 was again subjected to the above conditions to give 101.1 (430 mg, 71.6 %,
94.6% deuterated). LC-ELSD/MS purity>99%, MS ESI calcd. for C
23H
35D
4O
3 [M+H]
+ 367.3, found 367.3. [1053] Synthesis of 101 [1054] To a solution of 101.1 (350 mg, 0.95 mmol) in anhydrous THF (4 mL) was added CsF (144 mg, 0.95 mmol) at 15 ℃ under N2. TMSCF
3 (0.4mL, 2.85 mmol) was added dropwise at 15 ℃ and the resulting mixture was stirred for 1 h under N2. TBAF (1.08 mL, 1 M in THF, 1.08 mmol) was added and the mixture was stirred at 20 ℃ for 1 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (10 mL). The organic layer was washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo. The residue was purified from CH
3CN: H
2O (1:1, 10 mL) at 80 ℃ to give 101 (48.0 mg, 0.34 mmol). The product was combined with another batch of 101 (20 mg) obtained using similar conditions and the combined products were lyophilized to give 101 (62.6 mg, 14.7%).
1H NMR (400 MHz, CDCl3) δH 3.92-3.83 (m, 1H), 3.47-3.35 (m, 4H), 3.27 (t, J = 8.8 Hz, 1H), 2.43-2.19 (m, 1H), 2.05-1.92 (m, 3H), 1.85-1.76 (m, 3H), 1.63-1.42 (m, 10H), 1.23-1.06 (m, 6H), 0.95 (d, J = 7.2 Hz, 3H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.69. LC-ELSD/MS purity>99%, MS ESI calcd. for C
24H
35D
4F
3O
3Na [M+Na]
+ 459.3, found 459.2 [1055] Example 102: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2R,3S)-4- fluoro-3-hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (102)
[1056] Synthesis of 102.1 [1057] To a solution of 27.2 (5 g, 12.4 mmol) in THF (80 mL) was added TsOH (2.13 g, 12.4 mmol) at 25 °C under N2 and the resulting mixture was stirred for 12 h. The mixture was quenched with 10% aqueous NH
4Cl (100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with 10% aqueous NH4Cl (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give a residue, which was purified by silica gel chromatography (0~15% EtOAc in PE) to give 102.1 (4 g). [1058] Synthesis of 102.2 [1059] To a solution of 102.1 (5.0 g, 12.9 mmol), HMPA (2.52 mg, 14.1 mmol), and ((difluoromethyl)sulfonyl)benzene (11.2 g, 64.5 mmol) in anhydrous THF (50 mL) under nitrogen was added LiHMDS (1 M in THF, 64.5 mL, 64.5 mmol) dropwise at -70 ℃. The mixture was stirred at -70 ℃ for 1 h, warmed to 25 ℃, and stirred for an additional 10 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 102.2 (6 g). [1060] Synthesis of 102 [1061] To a solution of 102.2 (100 mg, 0.1739 mmol) and anhydrous Na
2HPO
4 (68.7 mg, 0.573 mmol) in anhydrous MeOH (5 mL) under N2 was added Na/Hg amalgam (194 mg, 0.869 mmol) at 50 ℃ and the resulting mixture was stirred for 48 h. The mixture was quenched with 10% aqueous NH
4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 10% aqueous NH
4Cl (20 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~12% EtOAc in PE) to give a residue, which was further purified by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm,10um)); Condition: 0.1%NH
3H
2O IPA, flow rate: 70 mL/min) and lyophilized to give 102 (8.6 mg, 28.7%).
1H NMR (400MHz, CDCl3) δH 4.65- 4.30 (m, 2H), 4.13-4.07 (m, 1H), 2.01-1.88 (m, 4H), 1.86-1.74 (m, 4H), 1.69-1.57 (m, 4H), 1.46-1.37 (m, 5H), 1.35-1.30 (m, 2H), 1.29-1.20 (m, 4H), 1.171.07 (m, 3H), 0.96 (s, 3H), 0.89-0.87 (m, 3H), 0.69 (s, 3H).
19F NMR (400 MHz, CDCl3) δF -78.787, -232.643. [1062] Example 103: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((2S,3S)-4-fluoro-3-hydroxybutan-2-yl)-6a-methyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (103)
[1063] Synthesis 103.1 [1064] To a suspension of MePPh3Br (5.78 g, 22.5 mmol) in THF (25 mL) was added t- BuOK (2.52 g,22.5 mmol) at 25 °C under N
2 and the resulting mixture was stirred at 50 °C for 1 h.61.9 (900 mg, 2.25 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was then stirred for 1 h. The reaction mixture was cooled to 20 °C and quenched with 10% aqueous NH
4Cl (60 mL). The aqueous layer was extracted with EtOAc (3 x 200 mL) and the combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum. The residue was purified from MeOH:H
2O (1:1, 40 mL) to give 103.1 (800 mg).
1H NMR (400MHz, CDCl
3) δ
H 5.95-5.84 (m, 1H), 5.01 (dd, J = 1.2, 17.2 Hz, 1H), 4.91 (dd, J = 2.0, 10.6 Hz, 1H), 2.32-2.20 (m, 1H), 2.13-1.99 (m, 2H), 1.97-1.66 (m, 9H), 1.60-1.42 (m, 7H), 1.23-1.09 (m, 4H), 1.02 (d, J = 6.4 Hz, 3H), 0.94-0.81 (m, 1H), 0.78 (s, 3H), 0.63-0.57 (m, 1H), 0.12-0.01 (m, 1H). [1065] Synthesis of 103.2 [1066] To a solution of 103.1 (500 mg, 1.26 mmol) in DCM (20 mL) was added m-CPBA (434 mg, 2.52 mmol) and the resulting mixture was stirred at 20 ℃ for 16 h. The mixture was diluted with DCM (20 mL) and washed with saturated aqueous Na
2S
2O
3:NaHCO
3 (1:1, 50 mL x 2), dried over anhydrous Na2SO
4, filtered, and concentrated to give 103.2 (493 mg).
1H NMR (400 MHz, CDCl3) δH
2.89-2.69 (m, 3H), 2.04-2.03 (m, 1H), 1.96-1.85 (m, 3H), 1.84- 1.74 (m, 5H), 1.73-1.65 (m, 5H), 1.60-1.57 (m, 2H), 1.52-1.38 (m, 5H), 1.13-1.07 (m, 5H),
0.96-0.93 (m, 1H), 0.76-0.73 (m, 3H), 0.61-0.55 (m, 1H), 0.13-0.06 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -78.62. [1067] Synthesis of 103 [1068] To a solution of 103.2 (493 mg, 1.19 mmol) and KHF
2 (921 mg, 11.8 mmol) was added TBAF (23.7 mL, 1 M, 23.7 mmol) at 25 ℃ under N2 and the resulting mixture was stirred at 120 ℃ for 16 h. The mixture was poured into ice water (50 mL) and the aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to give 103 (18.9 mg, 3.47% yield over two step).
1H NMR (400 MHz, CDCl
3) δ
H 4.74-4.39 (m, 2H), 4.36-4.20 (m, 1H), 2.06-1.89 (m, 4H), 1.85-1.67 (m, 7H), 1.59-1.49 (m, 7H), 1.30-1.22 (m, 4H), 1.19-1.12 (m, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.77 (s, 3H), 0.70-0.63 (m, 1H), 0.24-0.12 (m, 1H).
19F NMR (376.5 MHz, CDCl3) δF -78.64, -231.77. LC-ELSD/MS purity >99%, MS ESI calcd for C
24H
36F
4O
2Na [M+Na]
+ 455.2 found, 455.2. [1069] Example 104: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((2S,3S)-3-hydroxy-4-methoxybutan-2-yl)-6a-methyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (104)
[1070] Sodium methoxide (445 mg, 8.24 mmol) was added to MeOH (6 mL) and the resulting mixture was stirred at 55 °C for 1 h. A solution of 103.2 (340 mg, 0.824 mmol) in MeOH (8 mL) was added to the solution in one portion and the resulting mixture was stirred at 55 °C for 16 h. The mixture was poured into saturated aqueous NH4Cl (20 mL) and the mixture was stirred for 30 min. The aqueous phase was extracted with DCM (3 x 30 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15 % EtOAc in PE) and further purified by SFC (Column: Daicel ChiralPak IG (250*30mm, 10um); Condition: Heptane-(IPA:CAN = 4:1) (0.1%NH
3·H
2O); Begin B: 50%; End B: 50%; Gradient Time(min): 8.6; Flowrate (ml/min): 80) to give 104 (200 mg, 54.6 %).
1H NMR (400 MHz, CDCl
3) δ
H 4.27-4.13 (m, 1H), 3.60-3.52 (m, 1H), 3.48-3.31 (m, 4H), 2.07-1.86 (m, 5H), 1.83-1.66 (m, 7H), 1.59-1.47 (m, 6H), 1.29-1.22 (m, 3H), 1.20-1.08 (m, 4H), 0.93 (d, J = 6.8 Hz, 3H), 0.76 (s, 3H), 0.68-0.62 (m, 1H), 0.19-0.08 (m, 1H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.62. LC-ELSD/MS purity >99%, MS ESI calcd for C
25H
40F
3O
3 [M+H]
+ 445.2, found 445.2. [1071] Example 105: Synthesis of (2R,4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10aR)-7- ((2S,3S)-3-hydroxy-4-(methoxy-d3)butan-2-yl)-6a-methyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (105)
[1072] A mixture of sodium (529 mg, 23.0 mmol) in CD
3OD (2 mL) was stirred at 20 ℃ for 10 min under N2. To the solution was added 103.2 (125 mg, 0.288 mmol) and the resulting mixture was stirred at 55 ℃ for 16 h. The mixture was poured into saturated aqueous NH
4Cl (10 mL) and stirred for 30 min. The aqueous phase was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in DCM) to give 105 (10.7 mg, yield: 8%, 95.2% deuterated).
1H NMR (400 MHz, CDCl3) δH 4.23-4.15 (m, 1H), 3.62-3.50 (m, 1H), 3.41-3.30 (m, 1H), 2.45-2.36 (m, 1H), 2.08-1.84 (m, 5H), 1.83-1.62 (m, 7H), 1.49-1.42 (m, 3H), 1.32- 1.02 (m, 9H), 0.91 (d, J = 6.8 Hz, 3H), 0.75 (s, 3H), 0.67-0.61 (m, 1H), 0.18-0.06 (m, 1H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.62. LC-ELSD/MS 30-100AB_4min_ELSD purity>99%, MS ESI calcd. for C25H37D3F
3O
3 [M+H]
+ 448.3, found 448.2. [1073] Example 106: Synthesis of (2R,4aS,4bR,6aS,7R,7aR,8aS,8bR,8cR,10aR)-7- ((2S,3S)-3-hydroxy-4-methoxybutan-2-yl)-6a-methyl-2- (trifluoromethyl)octadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (106)
[1074] Synthesis of 106.1 [1075] To a mixture of 61.2 (15.4 g, 44.9 mmol) and TEA (13.5 g, 134 mmol) in DCM (160 mL) was added Ac
2O (9.16 g, 89.8 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The mixture was quenched with saturated aqueous NaHCO
3 (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were separated, dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 106.1 (13 g, 75.5% yield).
1H NMR (400 MHz, CDCl3) δH 7.52 (dd, J =1.2, 6.0 Hz, 1H), 6.15-5.90 (m, 1H), 2.86-2.68 (m, 1H), 2.54- 2.30 (m, 2H), 2.05 (s, 4H), 1.94-1.60 (m, 10H), 1.54-1.42 (m, 2H), 1.35-1.25 (m, 3H), 1.08 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -76.91 (s).
[1076] Synthesis of 106.2 [1077] To a solution of 106.1 (13 g, 33.8 mmol) in THF (140 mL) and MeOH (26 mL) was added CeCl3∙7H
2O (12.5 g, 33.8 mmol) at 0 °C and the resulting mixture was stirred for 10 min. NaBH
4 (1.27 g, 33.8 mmol) was added and the mixture stirred at 0 °C for 1 h. Saturated aqueous NH4Cl (300 mL) and 20% aqueous citric acid (50 mL) were added and the mixture was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc = 20/1 to 3/1) to give 106.2 (12.0 g, 92.3% yield).
1H NMR (400 MHz, CDCl3) δH 6.02-5.83 (m, 1H), 5.75-5.50 (m, 1H), 4.34 (s, 1H), 2.87-2.67 (m, 1H), 2.47-2.31 (m, 1H), 2.04 (s, 3H), 2.01-1.85 (m, 4H), 1.81- 1.45 (m, 12H), 1.22-1.08 (m, 2H), 0.83 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -76.80 (s). [1078] Synthesis of 106.3 [1079] To a solution of 106.2 (10 g, 25.8 mmol) in THF (200 mL) was added Ph3P (13.5 g, 51.6 mmol) and benzoic acid (6.30 g, 51.6 mmol) at 25 °C. DEAD (8.98 g, 9.37 mL, 51.6 mmol) in THF (10 mL) was added dropwise at 25 °C and the resulting mixture was stirred for 2 h. The mixture was poured into H
2O (200 mL) and the aqueous layer was extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 20/1) to give 106.3 (12.5 g, 99.2%). [1080] Synthesis of 106.4 [1081] To a solution of 106.3 (12.5 g, 25.4 mmol) in THF (40 mL) and MeOH (150 mL) was added a solution of NaOH (10.1 g, 254 mmol) in water (50 mL) dropwise at 25 °C under N2 and the resulting mixture was stirred for 2 h. The mixture was poured into H
2O (150 mL) and the aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 20/1 to 6/1) to give 106.4 (4.4 g, 50.3% yield).
1H NMR (400 MHz, CDCl
3) δ
H 6.13 (d, J = 5.6 Hz, 1H), 6.02- 5.91 (m, 1H), 4.09 (d, J = 2.8 Hz, 1H), 2.46-2.31 (m, 1H), 2.13-1.98 (m, 2H), 1.97-1.91 (m, 1H), 1.84-1.72 (m, 5H), 1.65-1.58 (m, 2H), 1.54-1.44 (m, 3H), 1.36-1.16 (m, 5H), 0.83 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -78.63 (s). [1082] Synthesis of 106.5 [1083] To a solution of 106.4 (4.4 g, 12.7 mmol) in toluene (15 ml) was added diethylzinc (63.5 mL, 63.5 mmol, 1 M) and diiodomethane (5.12 mL, 63.5 mmol, 3.32 g/mL) at 0 °C, and the resulting mixture was stirred for 30 min. The mixture was warmed to 25 °C and
stirred for 16 h. The mixture was quenched with saturated aqueous NH
4Cl (100 mL) and 20% aqueous citric acid (30 mL) and stirred for 5 mins. The mixture was extracted with EtOAc (2 x 100 mL), and the combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 106.5 (4.5 g, 98.9%).
1H NMR (400 MHz, CDCl3) δH 3.90 (d, J = 5.6 Hz, 1H), 2.04-1.97 (m, 1H), 1.95-1.79 (m, 4H), 1.76-1.62 (m, 4H), 1.56-1.35 (m, 7H), 1.22-1.02 (m, 4H), 0.95-0.86 (m, 6H).
19F NMR (376 MHz, CDCl
3) δ
F - 78.65 (s). [1084] Synthesis of 106.6 [1085] To a solution of 106.5 (4.5 g, 12.5 mmol) in DCM (90 mL) was added DMP (10.6 g, 25.0 mmol) and the resulting mixture was stirred at 40 °C for 2 h. The mixture was quenched with saturated aqueous NaHCO
3 (80 mL) at 10 °C. The DCM phase was separated and washed with saturated aqueous NaHCO
3:Na2S2O
3 (1:1, 2 x 80 mL) and brine (80 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 106.6 (3.3 g, 74.1%).
1H NMR (400 MHz, CDCl3) δH
2.13-2.01 (m, 2H), 1.96-1.86 (m, 2H), 1.85-1.80 (m, 3H), 1.76-1.61 (m, 5H), 1.53- 1.30 (m, 5H), 1.30-1.16 (m, 3H), 1.14 (s, 3H), 1.13-1.05 (m, 1H), 0.94-0.89 (m, 1H), 0.88- 0.83 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.68 (s). LC-ELSD/MS 30- 90AB_2min_E, purity>99%, MS ESI calcd. for C20H
28F
3O
2 [M+H]
+ 357.2, found 357.2. [1086] Synthesis of 106.7 [1087] To a mixture of EtPPh
3Br (4.04g, 10.9 mmol) in THF (22 mL) was added t-BuOK (1.22 g, 10.9 mmol) at 15 °C under N2 and the resulting mixture was stirred at 40 °C for 60 min.106.6 (650 mg, 1.82 mmol) was added in portions to keep the internal temperature of the reaction mixture below 40 °C during the course of the addition. The reaction mixture was stirred at 65 °C for 16 h. The reaction mixture was quenched with 10% aqueous NH4Cl (40 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (50 mL), and the combined organic layers were concentrated under vacuum to give a residue, which was purified by silica gel chromatography (0~5% EtOAc in PE) to give 106.7 (650 mg, 97.0%).
1H NMR (400 MHz, CDCl3) δH 5.39-5.23 (m, 1H), 2.17-2.07 (m, 1H), 2.04-2.00 (m, 1H), 1.95-1.79 (m, 5H), 1.64 (dd, J = 1.2, 7.6 Hz, 3H), 1.60-1.44 (m, 8H), 1.22-1.12 (m, 5H), 1.09 (s, 3H), 1.04-0.94 (m, 2H), 0.87-0.71 (m, 1H), 0.46-0.24 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.63 (s). [1088] Synthesis of 106.8
[1089] To a solution of 106.7 (650 mg, 1.76 mmol) in THF (10 mL) was added BH
3∙Me
2S (1.58 mL, 10 M in Me2S, 15.8 mmol) and the mixture was stirred at 15 °C for 16 h. EtOH (5.05 mL, 88.0 mmol) was added dropwise followed by NaOH (17.5 mL, 88.0 mmol, 5 M in water) and H
2O
2 (8.79 mL, 10 M, 88.0 mmol). The mixture was stirred at 78 °C for 2 h, quenched with 10% aqueous Na2S2O
3 (50 mL), and extracted with EtOAc (2 x 50 mL). The organic layers were separated, dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo to give 106.8 (650 mg).
1H NMR (400 MHz, CDCl
3) δ
H 3.96-3.76 (m, 1H), 2.03-1.65 (m, 10H), 1.57-1.35 (m, 7H), 1.22 (d, J = 6.0 Hz, 3H), 1.16-1.02 (m, 6H), 0.92 (s, 3H), 0.86- 0.78 (m, 1H), 0.70-0.60 (m, 1H), 0.45-0.35 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.63 (s). [1090] Synthesis of 106.9 [1091] To a solution of 106.8 (210 mg, 0.543 mmol) in DCM (3 mL) was added DMP (457 mg, 1.08 mmol) and the resulting mixture was stirred at 40 °C for 0.5 h. The mixture was quenched with saturated aqueous NaHCO
3 (30 mL) at 10 °C and DCM (30 mL) was added. The organic phase was separated, washed with saturated aqueous NaHCO
3:Na2S2O
3 (1:1, 2 x 30 mL) and brine (30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 106.9 (150 mg, 72.1% yield).
1H NMR (400 MHz, CDCl3) δH
2.17-2.14 (m, 1H), 2.12 (s, 3H), 2.01-1.76 (m, 7H), 1.74-1.59 (m, 4H), 1.54-1.44 (m, 4H), 1.27-1.05 (m, 6H), 0.87 (s, 3H), 0.80-0.72 (m, 1H), 0.42-0.34 (m, 1H).
19F NMR (376 MHz, CDCl
3) δ
F -78.69 (s). LC-ELSD/MS 30- 90AB_2min_E, purity>99%, MS ESI calcd. for C
22H
32F
3O
2 [M+H]
+ 385.2, found 385.2. [1092] Synthesis of 106.10 [1093] To a mixture of PPh3MeBr (625 mg, 1.75 mmol) in THF (5 mL) was added t-BuOK (196 mg, 1.75 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 40 °C for 60 min.106.9 (135 mg, 0.351 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with 10% aqueous NH
4Cl (20 mL) at 15 °C and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated under vacuum to give a residue, which was purified by silica gel chromatography (0~10% EtOAc in PE) to give 106.10 (80 mg, 59.7% yield).
1H NMR (400 MHz, CDCl
3) δ
H 4.90 (s, 1H), 4.80 (s, 1H), 2.09-1.99 (m, 1H), 1.94-1.79 (m, 4H), 1.77 (s, 3H), 1.74-1.64 (m, 5H), 1.51-1.35 (m, 5H), 1.29-1.18 (m, 4H), 1.10-1.02 (m, 3H), 0.84 (s, 3H), 0.75-0.68 (m, 1H), 0.44-0.37 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.65 (s).
[1094] Synthesis of 106.11 [1095] To a solution of 106.10 (80 mg, 0.209 mmol) in THF (5 mL) was added 9-BBN dimer (2.08 mL, 1.04 mmol, 0.5 M) and the resulting mixture was stirred at 15 °C for 16 h. EtOH (0.36 mL, 6.27 mmol) was added dropwise followed by NaOH (1.25 mL, 5 M in water, 6.27 mmol) and H
2O
2 (0.627 mL, 10 M, 6.27 mmol). The mixture was stirred at 78 °C for 2 h, quenched with 10% aqueous Na2S2O
3 (20 mL), and extracted with EtOAc (2 x 10 mL). The combined organic layers were separated, dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 106.11 (50 mg, 59.7%).106.11 (50 mg, 0.124 mmol) was further purified from MeCN:H
2O (1:1, 20 mL) to give 106.11 (19.0 mg, 38.3% yield).
1H NMR (400 MHz, CDCl
3) δ
H 3.83 (dd, J = 3.6, 10.8 Hz, 1H), 3.54-3.46 (m, 1H), 2.06-2.00 (m, 1H), 1.94-1.87 (m, 1H), 1.85-1.66 (m, 7H), 1.58-1.44 (m, 7H), 1.26-1.04 (m, 6H), 1.00 (d, J = 6.8 Hz, 3H), 0.96 (s, 3H), 0.78-0.69 (m, 1H), 0.66-0.58 (m, 1H), 0.38-0.30 (m, 1H).
19F NMR (376 MHz, CDCl
3) δ
F -78.624. LC-ELSD/MS 30-90AB_2min_E, purity>99%, MS ESI calcd. for C23H34F
3O [M-H
2O+H]
+ 383.1, found 383.1. [1096] Synthesis of 106.12 [1097] To a solution of 106.11 (300 mg, 0.749 mmol) in DCM (3 mL) was added DMP (631 mg, 1.49 mmol) and the resulting mixture was stirred at 40 °C for 0.5 h. The mixture was quenched with saturated aqueous NaHCO
3 (30 mL) at 10 °C and DCM (30 mL) was added. The organic phase was separated and washed with saturated aqueous NaHCO
3:Na
2S
2O
3 (1:1, 2 x 30 mL) and brine (30 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 106.12 (330 mg).
1H NMR (400 MHz, CDCl3) δH 9.73 (d, J = 3.2 Hz, 1H), 2.57-2.40 (m, 1H), 1.97-1.62 (m, 11H), 1.59-1.42 (m, 8H), 1.22-1.16 (m, 3H), 1.10 (d, J = 6.8 Hz, 4H), 0.97 (s, 3H), 0.71-0.62 (m, 1H), 0.47-0.38 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.66. [1098] Synthesis of 106.13 [1099] To a mixture of MePPh3Br (589 mg, 1.65 mmol) in THF (3 mL) was added t-BuOK (185 mg, 1.65 mmol) at 25 °C under N2 and the resulting mixture was stirred for 30 min. 106.12 (330 mg, 0.828 mmol) was added in portions at 25 °C and the reaction mixture was stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH
4Cl (20 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (20 mL x 2), and the combined organic layers were concentrated under vacuum to give 106.13 (230 mg, 77% over two steps yield).
1H NMR (400 MHz, CDCl
3) δ
H 5.92-5.77 (m,
1H), 5.08-4.87 (m, 2H), 2.36-2.18 (m, 1H), 2.08-1.63 (m, 10H), 1.53-1.34 (m, 5H), 1.26-1.07 (m, 6H), 1.01 (d, J = 6.8 Hz, 4H), 0.96 (s, 3H), 0.82-0.78 (m, 1H), 0.69-0.59 (m, 1H), 0.36- 0.25 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.66. [1100] Synthesis of 106.14 [1101] To a solution of 106.13 (230 mg, 0.58 mmol) in DCM (3 mL) was added m-CPBA (198 mg, 1.16 mmol), and the resulting mixture was stirred at 20 °C for 16 h. The mixture was diluted with DCM (5 mL) and washed with saturated aqueous Na
2S
2O
3:NaHCO
3 (1:1, 10 mL x 2), dried over anhydrous Na2SO
4, filtered, and concentrated to give 106.14 (300 mg).
1H NMR (400 MHz, CDCl3) δH
2.99-2.87 (m, 1H), 2.82-2.53 (m, 2H), 2.04-1.79 (m, 8H), 1.58-1.44 (m, 9H), 1.32-1.16 (m, 7H), 1.06 (d, J = 6.4 Hz, 3H), 0.92 (s, 3H), 0.68-0.61 (m, 1H), 0.44-0.35 (m, 1H).
19F NMR (376 MHz, CDCl
3) δ
F -78.66. [1102] Synthesis of 106 [1103] To a solution of 106.14 (300 mg, 0.727 mmol) in MeOH (5 mL) was added sodium methoxide (196 mg, 3.63 mmol) at 25 °C in portions. The reaction mixture was stirred at 65 °C for 10 h and the mixture was poured into 10% aqueous NH4Cl (15 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~10% of EtOAc in PE) to give 106 (21.3 mg, 8.29% yield over two steps).
1H NMR (400 MHz, CDCl3) δH 4.20-4.10 (m, 1H), 3.51-3.46 (m, 1H), 3.42 (d, J = 2.0 Hz, 3H), 3.35-3.29 (m, 1H), 2.41 (br. s, 1H), 2.02-1.85 (m, 5H), 1.85-1.67 (m, 6H), 1.50-1.47 (m, 1H), 1.29-1.15 (m, 6H), 1.15-0.99 (m, 5H), 0.95 (s, 3H), 0.94-0.91 (m, 3H), 0.72-0.67 (m, 1H), 0.65-0.59 (m, 1H), 0.35-0.29 (m, 1H).
19F NMR (376 MHz, CDCl3) δF -78.68. ELSD/MS purity >99 %, MS ESI calcd. for C25H40F
3O
3 [M+H]
+ 445.2, found 445.2. [1104] Example 107: Synthesis of (3R,5R,8R,9R,10S,13R,14S,15S,17R)-17-((2S,3S)-3- hydroxy-4-methoxybutan-2-yl)-13,15-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (107)
[1105] Synthesis of 107.1 [1106] To a solution of t-BuOK (7.81 g, 69.6 mmol) in 2-Me-THF (200 mL) was added 63.1 (12.5 g, 34.8 mmol) in 2-Me-THF (100 mL) at 20 ℃ under N
2 and the resulting mixture was stirred for 10 min. Methyl benzenesulfinate (10.8 g, 69.6 mmol) was added and the mixture was stirred at 30 ℃ for 0.5 h. The mixture was quenched with saturated aqueous NH
4Cl (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo to give 107.1 (22 g).
1H NMR (400 MHz, CDCl3) δH 7.72-7.18 (m, 1H), 7.56-7.54 (m, 4H), 3.95 (d, J = 2.0 Hz, 1H), 2.82-2.77 (m, 1H), 1.97-1.73 (m, 9H), 1.53-1.47 (m, 4H), 1.43-1.28 (m, 7H), 1.18 (d, J = 7.6 Hz, 3H), 1.01 (s, 3H). [1107] Synthesis of 107.2 [1108] To a mixture of 107.1 (22 g, 45.5 mmol) in xylene (250 mL) was added Na
2CO
3 (48.1 g, 454 mmol) and the resulting mixture was stirred at 140 ℃ for 16 h under N
2. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 107.2 (7.6 g, 61% yield over 2 steps).
1H NMR (400 MHz, CDCl
3) δ
H 5.72 (s, 1H), 2.33 (d, J = 11.6 Hz, 1H), 2.16 (s, 3H), 1.99-1.92 (m, 2H), 1.88-1.65 (m, 10H), 1.51-1.26 (m, 7H), 1.09 (s, 3H). [1109] Synthesis of 107.3 [1110] Lithium (1.58 g, 225 mmol) was added to liquid ammonia (40 mL) in portions at -70 ℃. After stirring at -70 ℃ for 1 h, a solution of 107.2 (8.0 g, 22.4 mmol) in dry THF (70 mL) was added and the internal temperature of the reaction mixture was maintained below -60 ℃
during the course of the addition. The resulting mixture was stirred at -70 ℃ for 1 h. Ammonium chloride (10.0 g) was added to the reaction mixture at -60 ℃ under N2 and the mixture was warmed to room temperature and stirred for 16 h. H
2O (400 mL) was added, and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with aqueous HCl (1 M, 2 x 60 mL), saturated aqueous NaHCO
3 (100 mL), and brine (100 mL), and then dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum to give 107.3 (8.83 g).
1H NMR (400 MHz, CDCl
3) δ
H 3.70-3.60 (m, 1H), 1.96-1.90 (m, 2H), 1.83-1.74 (m, 7H), 1.70-1.66 (m, 2H), 1.60-1.54 (m, 5H), 1.48-1.42 (m, 3H), 1.17-1.09 (m, 5H), 1.04 (d, J = 6.4 Hz, 3H), 0.78 (s, 3H). [1111] Synthesis of 107.4 [1112] To a solution of 107.3 (8.83 g, 24.4 mmol) in DCM (200 mL) was added DMP (20.6 g, 48.8 mmol) at 30 ℃ and the resulting mixture was stirred for 15 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (150 mL) and saturated aqueous Na2S2O
3 (200 mL) at 0 ℃. The mixture was extracted with DCM (3 x 150 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~20% EtOAc in PE) to give 107.4 (6.6 g, 83%).107.4 (200 mg) was further purified by prep-HPLC (column: Phenomenex C18 150*25mm*10um; mobile phase: [water (NH4HCO
3)-MeCN)]; B%: 50%~80%, 8 min) to afford 107.4 (82.2 mg, 41%).
1H NMR (400 MHz, CDCl3) δH
2.79-2.69 (m, 1H), 2.20-2.13 (m, 1H), 2.03-1.91 (m, 3H), 1.82-1.69 (m, 7H), 1.67-1.56 (m, 3H), 1.51-1.43 (m, 3H), 1.35- 1.27 (m, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.14-1.06 (m, 2H), 0.93 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.77. LC-ELSD/MS purity>99%, MS ESI calcd. for C20H
28F
3O [M- H
2O+H]
+ 341.1 found 341.1. [1113] Synthesis of 107.5 [1114] To a mixture of EtPPh3Br (12.9 g, 35.0 mmol) in THF (100 mL) was added t-BuOK (3.92 g, 35.0 mmol) at 15 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.107.4 (6.3 g, 17.5 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 50 °C for 5 h and then stirred at 15 °C for 16 h. The reaction mixture was quenched with 10% aqueous NH
4Cl (100 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 100 mL), and the combined organic layers were concentrated under vacuum. The residue was purified from MeOH:H
2O (1:1, 100 mL) to give 107.5 (10 g).107.5 (10 g) was further purified by silica gel chromatography (0~3% EtOAc in PE) to give 107.5 (4.6 g, 70%).
1H NMR (400 MHz, CDCl
3) δ
H 5.11-5.00 (m, 1H),
2.73-2.57 (m, 1H), 2.26-2.17 (m, 1H), 1.93-1.69 (m, 10H), 1.64-1.48 (m, 10H), 1.46-1.41 (m, 1H), 1.07 (s, 3H), 1.03 (d, J = 6.0 Hz, 3H), 0.94 (s, 3H). [1115] Synthesis of 107.6 [1116] To a solution of 107.5 (4.6 g, 12.4 mmol) in THF (100 mL) was added BH
3·Me
2S (6.19 mL, 10 M in Me2S, 62.0 mmol) and the resulting mixture was stirred at 15 °C for 16 h. EtOH (14.2 g, 310 mmol) was added dropwise followed by NaOH (12.4 g, 310 mmol, 5 M in water) and H
2O
2 (35.8 g, 30%, 314 mmol), and the resulting mixture was stirred at 15 °C for 1 h. The mixture was quenched with saturated aqueous Na2S2SO
3 (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo to give 107.6 (6 g).
1H NMR (400 MHz, CDCl
3) δ
H 3.72- 3.68 (m, 1H), 2.32-2.28 (m, 1H), 2.00-1.93 (m, 4H), 1.85-1.76 (m, 9H), 1.57-1.53 (m, 4H), 1.45-1.40 (m, 5H), 1.06-1.02 (m, 5H), 0.83-0.77 (m, 3H), 0.72 (s, 3H). [1117] Synthesis of 107.7 [1118] To a solution of 107.6 (6 g, 15.4 mmol) in DCM (80 mL) was added DMP (19.5 g, 46.2 mmol) at 30 °C and the resulting mixture was stirred for 0.5 h. The mixture was quenched with saturated aqueous NaHCO
3 (250 mL) at 10 °C. The DCM phase was separated and washed with saturated aqueous NaHCO
3:Na
2S
2O
3 (1:1, 300 mL) and brine (100 mL), dried over anhydrous Na2SO
4, filtered, concentrated under vacuum, and purified by silica gel chromatography (0~9% EtOAc in PE) to give 107.7 (3.05 g, 63% over two step yield).
1H NMR (400 MHz, CDCl
3) δ
H 2.59-2.45 (m, 2H), 2.11 (s, 3H), 2.05-1.92 (m, 4H), 1.85-1.77 (m, 4H), 1.74-1.58 (m, 4H), 1.50-1.41 (m, 3H), 1.35-1.11 (m, 6H), 1.06 (d, J = 6.4 Hz, 3H), 0.95-0.90 (m, 1H), 0.68 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.71. LC- ELSD/MS purity>99%, MS ESI calcd. for C22H34F
3O
2 [M+H]
+ 387.2, found 387.1 [1119] Synthesis of 107.8 [1120] To a mixture of MePPh3Br (5.60 g, 15.7 mmol) in THF (30 mL) was added t-BuOK (1.76 g, 15.7 mmol) at 15 °C under N2 and the resulting mixture was stirred at 50 °C for 30 min.107.7 (3.05 g, 7.89 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the reaction. The reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with 10% aqueous NH4Cl (50 mL) at 15 °C and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 50 mL), and the combined organic layers were concentrated under vacuum. The residue was purified from MeOH:H
2O (1:1, 30 mL) to give 107.8 (3.4 g).
1H NMR (400 MHz, CDCl3) δH 4.85 (s, 1H), 4.67 (s, 1H), 2.14-2.09 (m, 1H), 2.03-1.78 (m, 7H), 1.74 (s,
3H), 1.69-1.53 (m, 6H), 1.48-1.41 (m, 2H), 1.29-1.17 (m, 6H), 1.14-1.08 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H), 0.90-0.84 (m, 1H), 0.63 (s, 3H). [1121] Synthesis of 107.9 [1122] To a solution of 107.8 (3.4 g, 8.84 mmol) in THF (30 mL) was added 9-BBN (8.54 g, 35.3 mmol) and the resulting mixture was stirred at 45 °C for 16 h. EtOH (9.76 g) was added, followed by aqueous NaOH (8.48 g, 5.0 M, 212 mmol) at 15 °C. H
2O
2 (24.73 g, 30%, 217 mmol) was added dropwise at 15 °C and the reaction mixture was stirred at 20 °C for 3 h. The mixture was cooled to 15 °C, saturated aqueous Na2S2O
3 (100 mL) was added, and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified from MeOH:H
2O (1.6:1, 26 mL) at 15 °C to give 107.9 (1.1 g).107.9(1.1 g) was further purified from i-PrOH (6 mL) at 80 °C to give 107.9 (150 mg). The mother liquor was concentrated under vacuum, and then again purified from i-PrOH (3 mL) at 80 °C to give 107.9 (430 mg, 12% over two steps).
1H NMR (400 MHz, CDCl
3) δ
H 3.62 (dd, J = 10.4, 3.2 Hz, 1H), 3.36 (dd, J = 10.4, 6.8 Hz, 1H), 2.01-1.73 (m, 8H), 1.71-1.58 (m, 4H), 1.53-1.47 (m, 3H), 1.46-1.07 (m, 10H), 1.05-1.02 (m, 6H), 0.83-0.77 (m, 1H), 0.73 (s, 3H)
19F NMR (376.5 MHz, CDCl
3) δ
F -78.67. LC-ELSD/MS purity>99%, MS ESI calcd. for C
23H
36F
3O [M- H
2O+H]
+ 385.4, found 385.4 [1123] Synthesis of 107.10 [1124] To a solution of 107.9 (500 mg, 1.24 mmol) in DCM (10 mL) was added DMP (1.57 g, 3.72 mmol) at 30 °C and the resulting mixture was stirred for 20 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (50 mL) and saturated Na2S2O
3 (25 mL) at 0 °C. The mixture was extracted with DCM (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 107.10 (520 mg).
1H NMR (400 MHz, CDCl3) δH 9.56 (d, J = 3.2 Hz, 1H), 2.37-2.29 (m, 1H), 2.04-1.78 (m, 9H), 1.68-1.55 (m, 6H), 1.49-1.22 (m, 8H), 1.11 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.0 Hz, 3H), 0.85-0.80 (m, 1H), 0.76 (s, 3H). [1125] Synthesis of 107.11 [1126] To a mixture of MePPh3Br (1.38 g, 3.87 mmol) in 2-Me-THF (8 mL) was added t- BuOK (434 mg, 3.87 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 50 °C for 30 min.107.10 (520 mg, 1.29 mmol) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 50°C for 1 h. The reaction mixture was quenched with saturated aqueous NH
4Cl (20 mL) at 15 °C and the organic layer was separated. The aqueous
layer was extracted with EtOAc (3 x 20 mL), and the combined organic layers were concentrated under vacuum. The residue was purified from MeOH:H
2O (1:1, 16 mL) to give 107.11 (500 mg).
1H NMR (400 MHz, CDCl3) δH 5.72-5.61 (m, 1H), 4.92-4.78 (m, 2H), 2.12-2.05 (m, 1H), 2.06-1.74 (m, 8H), 1.71-1.55 (m, 6H), 1.53-1.39 (m, 4H), 1.25-1.05 (m, 5H), 1.04-0.99 (m, 6H), 0.82-0.76 (m, 1H), 0.73 (s, 3H). [1127] Synthesis of 107.12 [1128] To a solution of 107.11 (500 mg, 1.25 mmol) in DCM (5 mL) was added m-CPBA (431 mg, 2.50 mmol) and the resulting mixture was stirred at 20 °C for 6 h. The mixture was diluted with DCM (20 mL) and washed with saturated aqueous Na2S2O
3:NaHCO
3 (1:1, 2 x 10 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~6% EtOAc in PE) to give 107.12 (233 mg, 48% three step yield). [1129] Synthesis of 107.13 [1130] To a solution of 107.12 (230 mg, 0.554 mmol) in MeOH (5 ml) was added sodium methoxide (360 mg, 6.66 mmol) in portions at 25 °C and the resulting mixture was stirred at 65 °C for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~13% EtOAc in PE) to give 107.13 (125.1 mg).
1H NMR (400 MHz, CDCl
3) δ
H 3.88-3.83 (m, 1H), 3.41-3.36 (m, 4H), 3.32-3.27 (m, 1H), 2.03-1.75 (m, 9H), 1.73- 1.57 (m, 7H), 1.51-1.40 (m, 5H), 1.30-1.18 (m, 4H), 1.04 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.87-0.82 (m, 1H), 0.72 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.62. LC- ELSD/MS purity 99%, MS ESI calcd. for C25H40F
3O
2 [M-H
2O+H]
+ 429.2, found 429.2. [1131] Synthesis of 107.14 [1132] To a solution of 107.13 (100 mg, 0.223 mmol) in DCM (3 mL) was added DMP (284 mg, 0.671 mmol) at 30 °C and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO
3 (20 mL) and saturated aqueous Na2S2O
3 (20 mL) at 0 °C. The mixture was extracted with DCM (3 x 10 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 107.14 (150 mg).
1H NMR (400 MHz, CDCl
3) δ
H 4.08 (d, J = 17.2 Hz, 1H), 4.00 (d, J = 17.6 Hz, 1H), 3.42 (s, 3H), 2.62-2.51 (m, 1H), 2.04-1.76 (m, 8H), 1.73-1.58 (m, 5H), 1.52-1.41 (m, 3H), 1.37-1.16 (m, 7H), 1.10 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.85-0.80 (m, 1H), 0.74 (s, 3H). [1133] Synthesis of 107
[1134] To a solution of 107.14 (150 mg, 0.337 mmol) in MeOH (5 mL) was added NaBH
4 (110 mg, 2.89 mmol) at 0 °C and the resulting mixture was stirred at 20 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) at 0 °C and extracted with EtAOc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~9% EtOAc in DCM) to give 107 (7.6 mg, 5% three step yield).
1H NMR (400 MHz, CDCl
3) δ
H 3.86-3.81 (m, 1H), 3.46-3.40 (m, 4H), 3.25 (t, J = 9.6 Hz, 1H) 2.39-2.24 (br.s, 1H), 2.02-1.78 (m, 9H), 1.70-1.58 (m, 4H), 1.51-1.41 (m, 3H), 1.34-1.08 (m, 8H), 1.03 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.80-0.75 (m, 1H), 0.73 (s, 3H).
19F NMR (376.5 MHz, CDCl
3) δ
F -78.67. LC-ELSD/MS purity >99%, MS ESI calcd. for C
25H
40F
3O
2 [M-H
2O+H]+ 429.2, found 429.2. [1135] Example 108: Synthesis of (3R,5R,8R,9R,10S,13R,14S,15R,17R)-17-((2S,3S)-3- hydroxy-4-methoxybutan-2-yl)-13,15-dimethyl-3-(trifluoromethyl)hexadecahydro-1H-
[1136] Synthesis of 108.1 [1137] To a mixture of MePPh3Br (1.32 g, 3.72 mmol) in THF (10 mL) was added t-BuOK (417 mg, 3.72 mmol) at 15 °C under N
2 and the resulting mixture was stirred at 50 °C for 30 min.63.7 (500 mg, 1.24 mmol) in THF (2 mL) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was quenched with 10% aqueous NH4Cl (30 mL) at 15 °C and the organic layer was separated. The aqueous layer was
extracted with EtOAc (3 x 50 mL), and the combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0~5% EtOAc in PE) to give 108.1 (400 mg, 80%).
1H NMR (400 MHz, CDCl
3) δ
H 5.72-5.61 (m, 1H), 4.95-4.78 (m, 2H), 2.16-2.00 (m, 5H), 1.94-1.62 (m, 8H), 1.54-1.46 (m, 4H), 1.29-1.06 (m, 8H), 1.03 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 7.2 Hz, 3H), 0.85 (s, 3H). [1138] Synthesis of 108.2 [1139] To a solution of 108.1 (400 mg, 1.00 mmol) in DCM (10 mL) was added m-CPBA (517 mg, 3.00 mmol) at 0 °C and the resulting mixture was stirred at 20 °C for 5 h. The reaction mixture was washed with saturated aqueous Na
2S
2O
3:NaHCO
3 (1:1, 2 x 40 mL), then extracted with DCM (3 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 108.2 (400 mg, 96%).
1H NMR (400 MHz, CDCl3) δH
2.85-2.54 (m, 3H), 2.42-2.25 (m, 1H), 2.14-2.03 (m, 2H), 1.97-1.56 (m, 10H), 1.53-1.41 (m, 4H), 1.30-1.10 (m, 10H), 1.05-1.00 (m, 1H), 0.94-0.89 (m, 3H), 0.83-0.80 (m, 3H). [1140] Synthesis of 108 [1141] To a solution of 108.2 (500 mg, 1.20 mmol) in MeOH (16 mL) was added sodium methoxide (642 mg, 11.9 mmol) at 25 °C in portions and the resulting mixture was stirred at 65 °C for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~8% EtOAc in DCM) to give 108 (10.5 mg, 3%).
1H NMR (400 MHz, CDCl3) δH 3.88 (d, J = 9.4 Hz, 1H), 3.46-3.36 (m, 4H), 3.26 (t, J = 9.4 Hz, 1H), 2.32-2.02 (m, 4H), 2.00 (s, 1H), 1.94-1.80 (m, 6H), 1.70-1.62 (m, 2H), 1.52-1.48 (m, 3H), 1.29-1.03 (m, 10H), 0.95 (d, J = 7.2 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H), 0.84 (s, 3H).
19F NMR (376.5 MHz, CDCl3) δF -78.71. LC-ELSD/MS purity 97%, MS ESI calcd. for C24H36F
3O [M-MeOH- H
2O+H]
+ 397.3, found 397.1. [1142] Example 109: Synthesis of 1-((S)-3-hydroxy-4- ((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)-2-methylbutan-2-yl)-1H-pyrazole-4-carbonitrile (109)
[1143] Synthesis of 109.1 [1144] To a solution of 26.9 (200 mg, 0.47 mmol) in THF (2 mL) was added KOH (52.8 mg, 0.94 mmol) and MeI (134 mg, 0.94 mmol) at 25 °C and the resulting mixture was stirred for 2 h. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0~40% EtOAc in PE). The resulting residue was further purified by HPLC (Column: Phenomenex Gemini-NX 80*40mm*3um; Condition: water (0.05%NH3H
2O+10mM NH4HCO
3)-ACN; Begin B: 60; End B: 90) to afford 109.1 (18.5 mg, 18.5%).
1H NMR (400 MHz, CDCl
3) δ
H 7.98 (s, 1H), 7.88 (s, 1H), 2.13-2.21 (m, 1H), 1.77- 1.93 (m, 5H), 1.90-1.65 (m, 6H), 1.59-1.65 (m, 3H), 1.27-1.50 (m, 10H), 1.25 (s, 3H), 0.91- 1.17 (m, 8H), 0.43 (s, 3H). LC-ELSD/MS: purity 99%, MS ESI calcd. for C28H40N3O [M- H
2O+H]
+ 434.3, found 434.3. [1145] Synthesis of 109 [1146] To the mixture of 109.1 (160 mg, 0.3542 mmol) in MeOH (10 mL) was added NaBH
4 (26.9 mg 0.7084mol) at 0 °C and the resulting mixture was stirred for 2 h. Acetone (30 mL) was added, and the mixture was stirred for 1 h. The mixture was poured into water (20 mL), diluted with EtOAc (3 x 30 mL), and washed with brine (30 mL). The combined
organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by SFC ( (Column: DAICEL CHIRALPAK AD(250mm*30mm,10um); Condition:0.1%NH3H
2O IPA; Begin B: 55; End B: 55) to give 109 (38.3 mg, 23.9%).
1H NMR (400 MHz, CDCl
3) δ
H 7.94 (s, 1H), 7.82 (s, 1H), 3.80-3.64 (m, 1H), 2.49 (d, J = 6.4 Hz, 1H), 1.95-1.76 (m, 14H), 1.49-1.31 (m, 8H), 1.30-1.15 (m, 7H), 1.15-0.85 (m, 7H), 0.51 (s, 3H). LCMS 30-90AB_2min_E, purity≥99%, MS ESI calcd. for C28H44N3O
2 [M+H]
+ 454.3, found 454.3. [1147] Example 110: Synthesis of 1-((2S,3S)-3-hydroxy-4- ((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butan-2-yl)-1H-pyrazole-4-carbonitrile (110)
[1148] Synthesis of 110.1 [1149] To a solution of 26.9 (400 mg, 0.9442 mmol) in THF (10 mL) was added KOH (63.2 mg, 1.13 mmol) and MeI (200 mg, 1.41 mmol) at 25 °C and the resulting mixture was stirred for 2 h. The reaction mixture was treated with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0~60% EtOAc in PE). The resulting residue was further purified by SFC ((Column: DAICEL CHIRALPAK AD 250mm*30mm,10um); Condition: 0.1%NH3H
2O IPA; Begin B: 45; End B: 45) to give 110.1 (40 mg, 9.7%).
1H NMR (400
MHz, CDCl
3) δ
H 7.91 (s, 1H), 7.83 (s, 1H), 5.18-5.03 (m, 1H), 2.50-2.37 (m, 1H), 2.24-2.13 (m, 1H), 1.93-1.75 (m, 3H), 1.75-1.58 (m, 4H), 1.50-1.23 (m, 17H), 1.15-0.94 (m, 7H), 0.52 (s, 3H). LCMS 30-90AB_2min_E, purity 87%, MS ESI calcd. for C27H38N3O [M-H
2O+H]
+ 420.3, found 420.3. [1150] Synthesis of 110 [1151] To a solution of 110.1 (160 mg, 0.3656 mmol) in MeOH (10 mL) was added NaBH4 (27.7 mg 0.7312mol) at 0 °C and the resulting mixture was stirred for 2 h. Acetone (30 mL) was added and the mixture was stirred for 1 h. The mixture was poured into water (20 mL), diluted with EtOAc (10 mL), and washed with brine (10 mL). The organic phase was dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by SFC (Column: DAICEL CHIRALCEL OD-H (250mm*30mm,5um); Condition:0.1%NH
3H
2O MeOH; Begin B: 35; End B: 35) to give 110 (40 mg). Compound 110 (40 mg) was further purified by SFC (Column: DAICEL CHIRALPAK AD (250mm*30mm,10um); Condition:0.1%NH
3H
2O EtOH; Begin B: 55; End B: 55) to give 110 (12.2 mg, 7.6%).
1H NMR (400 MHz, CDCl3) δH 7.96-7.77 (m, 2H), 4.41-4.25 (m, 1H), 3.99-3.86 (m, 1H), 2.72- 2.57 (m, 1H), 1.94-1.75 (m, 4H), 1.71-1.57 (m, 5H), 1.54-1.27 (m, 14H), 1.26-0.93 (m, 10H), 0.56 (s, 3H). LCMS 30-90AB_2min_E, purity≥99%, MS ESI calcd. for C
27H
42N
3O
2 [M+H]
+ 440.4, found 440.4. [1152] Examples 111 & 112: Synthesis of 1-((2S,3S)-2-hydroxy-3- ((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)butyl)-1H-pyrazole-4-carbonitrile (111) and 1-((2S,3R)- 2-hydroxy-3-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro- 1H-cyclopenta[a]phenanthren-17-yl)butyl)-1H-pyrazole-4-carbonitrile (112)
[1153] Synthesis of 111.2 [1154] To a mixture of EtPPh3Br (15.6 g, 42.3 mmol) in THF (65 mL) was added t-BuOK (4.74 g, 42.3 mmol) at 25 °C under N2 and the resulting mixture was stirred at 40 °C for 1 h. 111.1 (4.5 g, 14.1 mmol) in THF (5 mL) was added in portions to keep the internal temperature of the reaction mixture below 50 °C during the course of the addition. The reaction mixture was stirred at 40 °C for 12 h and then was poured into water (100 mL) at 25 °C. The aqueous phase was extracted with EtOAc (2 x 100 mL), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0~10% EtOAc in PE) to give 111.2 (4 g, 85.8%).
1H NMR (400 MHz, CDCl
3) δ
H 5.35-5.21 (m, 1H), 2.04-1.97 (m, 1H), 1.90-1.72 (m, 5H), 1.71-1.53 (m, 12H), 1.49-1.34 (m, 6H), 1.33- 1.20 (m, 4H), 1.22-0.98 (m, 6H), 0.52 (s, 3H). [1155] Synthesis of 111.3 [1156] To a solution of 111.2 (4 g, 12.1 mmol) in THF (80 mL) was added BH
3 .Me
2S (3.63 mL, 36.3 mmol, 10 M in Me2S) and the resulting mixture was stirred at 15 °C for 20 h. EtOH (6.27 mL, 108 mmol) was added at 15 °C, followed by aqueous NaOH (21.6 mL, 5.0 M, 108 mmol) at 0 °C. H
2O
2 (10.8 mL, 10 M in water, 108 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 70 °C for 1 h and was cooled to 15 °C. Na2S2O
3 (100 mL, sat. aq.) was added and the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 111.3 (2.8 g).
1H NMR (400 MHz, CDCl
3) δ
H 4.13-4.05 (m, 1H), 3.95-3.86 (m, 1H), 2.00-1.90 (m, 1H), 1.72-1.54 (m, 7H), 1.48-1.34 (m, 9H), 1.25 (s, 6H), 1.06-1.00 (m, 8H), 0.91-0.89 (m, 2H), 0.85-0.81 (m, 2H), 0.69-0.67 (m, 3H). [1157] Synthesis of 111.4 [1158] To a solution of 111.3 (4.6 g, 13.1 mmol) in DCM (50 mL) was added DMP (11.1 g, 26.2 mmol) at 25 °C and the resulting mixture was stirred for 5 mins. The mixture was quenched with saturated aqueous NaHCO
3 (50 mL) and the organic phase was separated. The organic layer was washed with saturated aqueous NaHCO
3:Na2S2O
3 (1:1, 2 x 50 mL) and brine (50 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 111.4 (2.7 g, 59.6%).
1H NMR (400 MHz, CDCl3) δH
2.53-2.39 (m, 1H), 2.13-2.07 (m, 3H), 1.94-1.76 (m, 4H), 1.67- 1.56 (m, 8H), 1.51-1.27 (m, 8H), 1.26 (s, 3H), 1.24-1.17 (m, 1H), 1.14-1.09 (m, 3H), 1.05- 1.01 (m, 3H), 1.00-0.91 (m, 1H), 0.70-0.62 (m, 3H).
[1159] Synthesis of 111.5 [1160] To a solution of 111.4 (2.7 g, 7.79 mmol) in MeOH (30 mL) was added HBr (310 mg, 1.55 mmol, 40%) and Br2 (1.36 g, 8.56 mmol) dropwise at 25 °C and the resulting mixture was stirred for 4 h. NaHCO
3 (50 ml, sat. aq.) was added at 25 °C and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 111.5 (3.2 g).
1H NMR (400 MHz, CDCl
3) δ
H 4.07 (d, J = 4.0 Hz, 1H), 3.96 (s, 1H), 2.90-2.70 (m, 1H), 1.90-1.76 (m, 4H), 1.74-1.54 (m, 6H), 1.49-1.30 (m, 8H), 1.26-1.24 (m, 4H), 1.17 (d, J = 8.0 Hz, 2H), 1.13-1.08 (m, 3H), 1.08-0.84 (m, 4H), 0.72-0.64 (m, 3H). [1161] Synthesis of 111.6 & 111.6a [1162] To a solution of 111.5 (3.2 g, 7.52 mmol) in acetone (50 mL) was added 1H-pyrazole-4-carbonitrile (769 mg, 8.27 mmol) and K2CO
3 (3.10 mg, 22.5 mmol) and the resulting mixture was stirred at 25 °C for 4 h. The mixture was treated with water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE). The resulting residue was further purified by SFC (Column: DAICEL CHIRALCEL OD-H(250mm*30mm,5um); Mobile phase: A: CO
2 B: 0.1%NH3H
2O-EtOH; gradient: from 30% to 30% of B; FlowRate(ml/min): 50) to give 111.6 (1.05 g, 43.9%) and 111.6a (1.08 g, 45.1%). 111.6:
1H NMR (400 MHz, CDCl
3) δ
H 7.85 (s, 1H), 7.82 (s, 1H), 5.08 (d, J = 18.0 Hz, 1H), 4.95 (d, J = 17.6 Hz 1H), 2.66-2.56 (m, 1H), 1.93-1.88 (m, 1H), 1.87-1.61 (m, 9H), 1.56-1.35 (m, 9H), 1.26 (s, 3H), 1.21 (d, J = 8.0 Hz, 3H), 1.16-1.03 (m, 6H), 0.70 (s, 3H). LC- ELSD/MS: purity >99%; MS ESI calcd. for C27H38N3O [M-H
2O+H]
+ 420.3, found 420.3. 111.6a:
1H NMR (400 MHz, CDCl
3) δ
H 7.86 (s, 1H), 7.82 (s, 1H), 5.17-5.02 (m, 2H), 2.65- 2.55 (m, 1H), 1.94-1.76 (m, 5H), 1.71-1.44 (m, 11H), 1.41-1.29 (m, 7H), 1.15 (d, J = 8.0 Hz, 3H), 1.10-0.94 (m, 5H), 0.68 (s, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd. for C
27H
38N
3O [M-H
2O+H]
+ 420.3, found 420.3. [1163] Synthesis of 111 [1164] To a solution of 111.6600 mg, 1.37 mmol) in MeOH (10 mL) was added NaBH4 (104 mg, 2.74 mmol) and the resulting solution was stirred at 25 °C for 16 h. The reaction mixture was poured into saturated aqueous NH
4Cl (30 mL) and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 111 (230 mg, 38.2%).
1H NMR
(400 MHz, CDCl
3) δ
H 7.90 (s, 1H), 7.82 (s, 1H), 4.26-4.21 (m, 1H), 4.09-3.95 (m, 2H), 2.45 (br s, 1H), 2.01-1.93 (m, 1H), 1.91-1.77 (m, 5H), 1.69-1.58 (m, 4H), 1.52-1.28 (m, 9H), 1.27 (s, 3H), 1.26-1.05 (m, 7H), 1.03 (d, J = 7.6 Hz, 3H), 0.70 (s, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd. for C
27H
40N
3O [M-H
2O+H]
+ 422.3, found 422.3. [1165] Synthesis of 112 [1166] To a solution of 111.6a (600 mg, 1.37 mmol) in MeOH (10 mL) was added NaBH4 (104 mg, 2.74 mmol) and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into saturated aqueous NH4Cl (30 mL), and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~30% EtOAc in PE) to give 112 (140 mg, 23.2%).
1H NMR (400 MHz, CDCl3) δH 7.89 (s, 1H), 7.82 (s, 1H), 4.32-4.26 (m, 1H), 4.19-4.10 (m, 2H), 1.97 (d, J=4.0 Hz, 1H), 1.89-1.76 (m, 5H), 1.68-1.58 (m, 4H), 1.53-1.27 (m, 11H), 1.25 (s, 3H), 1.21-0.98 (m, 6H), 0.92 (d, J=8.0 Hz, 3H), 0.66 (s, 3H). LC-ELSD/MS: purity >99%; MS ESI calcd. for C27H40N3O [M-H
2O+H]
+ 422.3, found 422.3. [1167] Example 113: Synthesis of 4-((S)-1-hydroxy-2- ((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)ethyl)benzonitrile (113)
[1168] Synthesis of 113.1 [1169] To a solution of 25.3 (10 g, 27.5 mmol), and 2,6-lutidine (7.35 g, 68.7 mmol) in DCM (100 ml) was added TBSOTf (14.5 g, 55.0 mmol) at 0 °C and the resulting mixture was stirred at 40 °C for 16 h. The mixture was diluted with DCM (50 ml) and washed with water (100 ml). The organic phase was separated, dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 113.1 (8 g, 61%).
1H NMR (400 MHz, CDCl3) δH 4.15-4.10 (m, 2H), 2.43-2.32 (m,
1H), 2.22-2.00 (m, 1H), 1.98-1.53 (m, 9H), 1.48-1.25 (m, 3H), 1.24-1.19 (m, 12H), 1.16-0.98 (m, 6H), 0.86 (s, 9H), 0.59 (s, 3H), 0.07 (m, 6H). [1170] Synthesis of 113.2 [1171] To a suspension of 113.1 (7 g, 14.6 mmol) and MeNHOMe∙HCl (2.13 g, 21.9 mmol) in THF (70 mL) was added i-PrMgCl (2 M in THF, 29.2 mL, 58.4 mmol) at 0 °C under N2 and the resulting mixture was stirred at 20 °C for 10 min. To the mixture was added NH
4Cl (10% aq., 70 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo to give 113.2 (7.7 g).
1H NMR (400 MHz, CDCl3) δH 3.68 (s, 3H) 3.17 (s, 3H) 2.44-2.54 (m, 1H) 2.16-2.27 (m, 1H) 1.56-1.98 (m, 11H) 1.29-1.44 (m, 6H) 1.22 (s, 3H) 0.95-1.18 (m, 7H) 0.86 (s, 9H) 0.62 (s, 3H) 0.07 (s, 6H). [1172] Synthesis of 113.3 [1173] A solution of iPrMgCl∙LiCl (3.03 ml, 3.94 mmol, 1.3 M in THF) was added to 4- bromobenzonitrile (919 mg, 5.05 mmol) in THF (5 mL) slowly at 0 °C under N
2 and the resulting mixture was stirred at 20 °C for 2 h. To the mixture was added a solution of 113.2 (500 mg, 1.01 mmol) in THF (5 mL) dropwise and the mixture was stirred at -75 °C for 1 h and then at 20 °C for 1 h. The mixture was poured into saturated aqueous NH
4Cl (30 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) and then further purified from MeOH:H
2O (4:1, 10 mL) at 20 °C to give 113.3 (400 mg, 74%).
1H NMR (400 MHz, CDCl3) δH 8.02 (d, J = 8.00 Hz, 2H) 7.76 (d, J = 8.4 Hz, 2H) 3.08 (dd, J = 16.00, 3.20 Hz, 1H) 2.74 (dd, J = 15.60, 9.20 Hz, 1H) 1.58-1.99 (m, 9H) 1.23-1.47 (m, 9H) 1.22 (s, 3H) 0.99-1.17 (m, 6H) 0.85 (s, 9H) 0.68 (s, 3H) 0.07 (s, 6H). [1174] Synthesis of 113.4 [1175] To a suspension of 113.3 (1 g, 1.87 mmol) in anhydrous MeOH (10 mL) and THF (10 mL) was added NaBH
4 (35.5 mg, 0.94 mmol) slowly at 0 °C and the resulting mixture was stirred at 20 °C for 1 h. The mixture was slowly poured into H
2O (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na
2SO
4, filtered, concentrated, and purified by silica gel chromatography (0~15% EtOAc in PE) to give 113.4 (450 mg, 45%).
1H NMR (400 MHz, CDCl3) δH 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.80-4.70 (m, 1H), 1.88-1.56 (m, 11H), 1.53-1.28 (m, 8H), 1.21 (s, 3H), 1.18-0.87 (m, 8H), 0.85 (s, 9H), 0.61 (s, 3H), 0.05 (s, 6H).
[1176] Synthesis of 113 [1177] To a solution of 113.4 (150 mg, 0.28 mmol) in THF (2 mL) was added HCl (0.5 mL, 3 M in water, 1.50 mmol) at 25 °C and the resulting mixture was stirred at 60 °C for 24 h. The mixture was cooled to 25 °C, treated with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO
4, filtered, concentrated, and purified by silica gel chromatography (40~70% EtOAc in PE) to give 113 (48.7 mg, 41%).
1H NMR (400 MHz, CDCl
3) δ
H 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.83-4.65 (m, 1H), 2.00-1.65 (m, 12H), 1.47-1.27 (m, 8H), 1.24 (s, 3H), 1.22-0.79 (m, 8H), 0.59 (s, 3H). LC-ELSD/MS 30-90AB_2min_E, purity 99%, MS ESI calcd. for C
28H
36N [M-2H
2O+H]
+ 386.3, found 386.3. [1178] Example 114: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-2,2,4,4-d4-3-ol (114)
[1179] Synthesis of 114.1 [1180] To a solution of 1.2 (10.0 g, 30.0mmol) in DCM (100 mL) was added ethane-1,2- diol (16.6 mL, 300 mmol), trimethyl orthoformate (9.55 g, 90.0 mmol), and TsOH (114 mg, 600 µmol) at 20 ℃ and the resulting mixture was stirred for 18 h. The mixture was quenched with saturated aqueous NaHCO
3 (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 114.1 (12.0 g).
1H NMR (400 MHz, CDCl
3) δ
H 3.98-3.90 (m, 4H), 3.68-3.56 (m, 1H), 3.41-3.28 (m, 1H), 2.10-1.61 (m, 7H), 1.54-1.14 (m, 15H), 1.10- 1.00 (m, 6H), 0.95 (s, 3H), 0.68-0.66 (m, 3H). [1181] Synthesis of 114.2
[1182] To a solution of 114.1 (1.5 g, 3.98 mmol) in DCM (15 mL) was added DMP (2.53 g, 5.97 mmol) at 25 ℃ and the resulting mixture was stirred for 1 h. Saturated aqueous NaHCO
3 (10 mL) and saturated aqueous Na2S2O
3 (10 mL) were added, and the aqueous phase was extracted with DCM (2 x 10 mL). The combined organic layers were washed with saturated aqueous NaHCO
3:Na2S2O
3 (1:1, 2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 114.2 (1.5 g). [1183] Synthesis of 114.3 [1184] A solution of MeMgBr (4.00 mL, 12.0 mmol, 3 M in Et2O) in THF (5 mL) was reacted with a solution of 114.2 (1.5 g, 4.00 mmol) in THF (10 mL) at 0 ℃ and the resulting mixture was stirred at 25 ℃ for 1 h under N
2. The reaction mixture was poured into saturated aqueous NH
4Cl (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (15~25% EtOAc in PE) to give 114.3 (250 mg, 16.0%).
1H NMR (400 MHz, CDCl
3) δ
H 3.96-3.92 (m, 4H), 2.04-1.79 (m, 2H), 1.78-1.26 (m, 17H), 1.23-0.99 (m, 9H), 0.97-0.62 (m, 10H). [1185] Synthesis of 114.4 [1186] To a solution of 114.3 (250 mg, 0.6400 mmol) in THF (3 mL) was added HCl (0.6 mL, 1 M in water, 0.6 mmol) and the resulting mixture was stirred for 18 h at 25 ℃. The reaction mixture was poured into aqueous NaHCO
3 (10 mL, 1 M) and extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (30~60% EtOAc in PE) to give 114.4 (190 mg, 85.9%).
1H NMR (400 MHz, CDCl3) δH 3.99-3.86 (m, 1H), 2.80-2.58 (m, 1H), 2.44-2.10 (m, 3H), 2.03-1.70 (m, 5H), 1.49-1.30 (m, 9H), 1.27-1.18 (m, 3H), 1.18-1.13 (m, 2H), 1.12-1.05 (m, 3H), 1.03-1.00 (m, 5H), 0.94-0.89 (m, 3H), 0.72- 0.68 (m, 3H). [1187] Synthesis of 114.5 [1188] To a solution of 114.4 (190 mg, 0.5482 mmol) in pyridine (3 mL) was added benzoyl chloride (315 µL, 2.74 mmol) dropwise and the resulting mixture was stirred at 25 ℃ for 16 h. Water (0.2 mL) was added and the mixture was stirred at 25 ℃ for 3 h. Water (5 mL) was again added and the mixture was stirred at 25 ℃ for 10 min. The mixture was filtered, and the filter cake was washed with EtOAc (2 x 5 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated. The mixture was purified by silica gel chromatography (0~10% EtOAc in PE). The resulting residue was further purified by SFC (Column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); Condition:
0.1%NH
3H
2O EtOH; Begin B: 25%; End B: 25%; FlowRate (ml/min): 70; Injections: 60) to give 114.5 (40 mg, 40.2%).
1H NMR (400 MHz, CDCl3) δH 8.07-8.01 (m, 2H), 7.57-7.52 (m, 1H), 7.48-7.38 (m, 2H), 5.29-5.22 (m, 1H), 2.69 (t, J = 14.4 Hz, 1H), 2.39-2.28 (m, 1H), 2.21-2.13 (m, 1H), 2.09-1.99 (m, 3H), 1.97-1.78 (m, 4H), 1.72-1.62 (m, 1H), 1.50-1.09 (m, 16H), 1.07-1.04 (m, 3H), 1.02 (s, 3H), 0.71 (s, 3H). [1189] Synthesis of 114.6 [1190] To a solution of 114.5 (470 mg, 1.04 mmol) in THF (10mL) was added MeOH (5 mL), H
2O (0.5 mL), and LiOH (500 mg, 11.9 mmol), and the resulting mixture was stirred at 25 ºC for 16 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated. The mixture was purified by silica gel chromatography (7~20% EtOAc in PE) to give 114.6 (400 mg).
1H NMR (400 MHz, CDCl3) δH 3.96-3.86 (m, 1H), 2.69 (t, J = 14.0 Hz,1H), 2.41-2.27 (m, 1H), 2.20-2.13 (m, 1H), 2.07-1.99 (m, 3H), 1.94-1.50 (m, 7H), 1.46- 1.05 (m, 12H), 1.04-1.00 (m, 6H), 0.92 (d, J = 6.8 Hz, 3H), 0.71 (s, 3H). [1191] Synthesis of 114.7 [1192] To a solution of 114.6 (400 mg, 1.15 mmol) in THF (10 mL) was added NaOD (5 mL, 0.1 M in D
2O, 0.5 mmol) and CD
3OD (1 mL), and the resulting mixture was stirred at 25 ºC for 48 h. The reaction mixture was adjusted to pH = 7 with AcOD (0.1 M in D2O) and NaCl (1.5 g) was added. The mixture was stirred for 5 min and the organic layer was separated, dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo to give 114.7 (340 mg, 84.3%, ~95% deuterated).
1H NMR (400 MHz, CDCl
3) δ
H 4.00-3.80 (m, 1H), 2.08- 1.99 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.08 (m, 14H), 1.04-1.00 (m, 6H), 0.93 (d, J = 6.8 Hz, 3H), 0.71 (s, 3H). [1193] Synthesis of 114 [1194] To a solution of 114.7 (300 mg, 0.85 mmol) and CsF (1.29 g, 8.55 mmol) in THF (10 mL) was added TMSCF
3 (1.82 g, 12.8 mmol) at 0 ºC under N2 and the resulting mixture was stirred at 20 ºC for 2 h. TBAF (12.8 mL, 12.8 mmol, 1 M in THF) was added and the mixture was stirred at 20 ºC for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) and lyophilized to give 114 (48.9 mg, 98.5%).
1H NMR (400 MHz, CDCl3) δH 3.96-3.85 (m, 1H), 2.03-1.58 (m, 6H), 1.44-1.04 (m, 16H), 1.02 (d, J = 6.8 Hz, 3H), 0.96 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.68 (s, 3H).
19F NMR
(376 MHz, CDCl
3) δ
F -78.82. LC-ELSD/MS 30-90AB_2min_E, purity 100%; MS ESI calcd. for C24H34D4F
3O [M-H
2O+H]
+ 403.4, found 403.4. [1195] Example 115: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-4- fluoro-3-hydroxybutan-2-yl)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-2,2,4,4-d4-3-ol (115)
[1196] Synthesis of 115.1 [1197] To a solution of 87.8 (13 g, 36.2 mmol) in THF (130 mL) and MeOH (45 mL) was added HCl (15 mL, 6 M in water, 90.5 mmol) at 25 °C and the resulting mixture was stirred for 16 h. The mixture was poured into water (50 mL) and extracted with EtOAc (2 x 100
mL). The combined organic layers were washed with saturated aqueous NaHCO
3 (300 mL) and brine (300 mL), dried over anhydrous Na2SO
4, filtered, and concentrated to give 115.1 (9 g, 79 %).
1H NMR (400 MHz, CDCl3) δH 5.70-5.63 (m, 1H), 4.95-4.83 (m, 2H), 2.20-1.96 (m, 9H), 1.66-1.42 (m, 9H), 1.28-1.13 (m, 7H), 1.05-1.028 (m, 3H), 0.76-0.69 (m, 3H). [1198] Synthesis of 115.2 [1199] To a solution of 115.1 (9 g, 28.6 mmol) in anhydrous THF (90 mL) was added NaOD (48.4 mL, 0.1 M in D
2O, 0.5 mmol) and CD
3OD (40 mL) at 20 °C under N
2 and the resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was adjusted to pH = 7 with AcOD (1 M in D2O) and NaCl (10 g, solid) and PE (30 mL) were added. The mixture was stirred for 5 min and the organic layer was separated. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were dried over anhydrous Na
2SO
4, filtered, and concentrated in vacuo to give 115.2 (9 g, 81%, ~80% deuterated). Compound 115.2 was again subjected to the above conditions to give 115.2 (9 g, 98%, ~95% deuterated). MS ESI calcd. for C
22H
30D
4O [M +H]
+ 319.3, found 319.3. [1200] Synthesis of 115.3 [1201] To a solution of 115.2 (2 g, 6.28 mmol) in THF (20 mL) was added CsF (285 mg, 1.88 mmol) at 15 °C under N
2. TMSCF
3 (1.33 g, 9.42 mmol) was added dropwise at 15 °C, and the mixture was warmed to 25 °C and stirred for 1 h. TBAF (12.5 mL, 12.5 mmol, 1 M in THF) was added and the mixture was stirred for 2 h. The mixture was quenched with saturated aqueous NH
4Cl (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with saturated aqueous NH
4Cl (2 x 30 mL), dried over anhydrous Na2SO
4, filtered, and concentrated under reduced pressure to give 115.3 (2 g, 82%).
1H NMR (400 MHz, CDCl3) δH 5.70-5.63 (m, 1H), 4.95-4.82 (m, 2H), 2.15-1.93 (m, 6H), 1.63-1.45 (m, 8H), 1.32-1.15 (m, 7H), 1.04-1.02 (m, 4H), 0.7-0.68 (m, 3H).
19F NMR (376 MHz, CDCl3) δF -78.67. [1202] Synthesis of 115.4 [1203] To a solution of 115.3 (2 g, 5.12 mmol) in DCM (5 mL) was added m-CPBA (437 mg, 2.56 mmol) and the resulting mixture was stirred at 20 °C for 16 h. The mixture was diluted with DCM (5 mL), washed with saturated aqueous Na2S2O
3:NaHCO
3 (1:1, 2 x 20 mL), dried over anhydrous Na
2SO
4, filtered, and concentrated to give 115.4 (2 g, 96%). LC- ELSD/MS 30-100AB_3min_E, purity>82%, MS ESI calcd. for C
23H
30D
4F
3O [M-H
2O+H]
+ 387.2, found 387.2. [1204] Synthesis of 115.5
[1205] A suspension of 115.4 (2 g, 4.94 mmol) and KHF
2 (1.92 g, 24.7 mmol) in TBAF (49.4 mL, 49.4 mmol, 1 M in THF) was concentrated to remove the solvent. The mixture was heated and stirred at 100 °C for 16 h. The mixture was quenched with 10% aqueous NH4Cl (100 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~15% EtOAc in PE) to give 115.5 (200 mg, 9%).
1H NMR (400 MHz, CDCl
3) δ
H 4.49-4.40 (m, 1H), 4.37-4.28 (m, 1H), 4.04-3.94 (m, 1H), 2.02-1.74 (m, 8H), 1.64-1.48 (m, 8H), 1.17-1.05 (m, 7H), 0.98-0.91 (m, 3H), 0.69 (s, 3H). [1206] Synthesis of 115.6 [1207] To a solution of 115.5 (200 mg, 471 µmol) in DCE (5 mL) was added imidazole (127 mg, 1.88 mmol) and TBDPSCl (244 µL, 942 µmol) at 25 °C and the resulting mixture was stirred at 60 °C for 16 h. The mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was sequentially purified by silica gel chromatography (0~10% EtOAc in PE) and SFC (Column:DAICEL CHIRALPAK IG (250mm*30mm,10um); Condition: Neu-IPA; Begin: 20%; End: 20%) to give 115.6 (80 mg, 3%).
1H NMR (400 MHz, CDCl3) δH 7.72-7.67 (m, 4H), 7.44-7.35 (m, 6H), 4.50-4.34 (m, 2H), 3.98-3.87 (m, 1H), 2.10-1.68 (m, 5H), 1.67-1.49 (m, 5H), 1.47-1.29 (m, 8H), 1.12-1.05 (m, 12H), 0.95-0.81 (m, 3H), 0.60-0.50 (m, 1H), 0.36 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -78.62, 227.44. [1208] Synthesis of 115 [1209] To 115.6 (80 mg, 123 µmol) was added TBAF (1.20 mL, 1 M in THF) at 25 °C and the resulting mixture was stirred for 16 h under N
2. The reaction mixture was poured into H
2O (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO
4, filtered, and concentrated. The residue was purified by silica gel chromatography (0~20% EtOAc in PE) to give 115 (7.2 mg, 14.1%, 92.3% deuterated).
1H NMR (400 MHz, CDCl3) δH 4.60-4.30 (m, 2H), 4.03-3.94 (m, 1H), 2.01-1.95 (m, 2H), 1.84-1.78 (m, 3H), 1.67-1.59 (m, 5H), 1.55-1.46 (m, 3H), 1.45-1.36 (m, 3H), 1.10 (m, 6H), 0.97 (d, J = 7.2 Hz, 3H), 0.69 (s, 3H).
19F NMR (376 MHz, CDCl
3) δ
F -78.69, 232.41. LC- ELSD/MS 30-100AB_3min_E, purity>95%, MS ESI calcd. for C
23H
32D
4F
4O
2Na [M+Na]
+ 447.1, found 447.1.
[1210] Example 116: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17R)-17-((2S,3R)-3- hydroxybutan-2-yl-3-t)-10,13-dimethyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (116)
[1211] Synthesis of 116.2 [1212] To a suspension of 116.1 and silica gel in DCM was added PCC at 25 °C and the resulting mixture was stirred for 2 h. The mixture was filtered through a pad of silica gel and the filter cake was washed with DCM. The filtrate was concentrated to give 116.2. [1213] Synthesis of 116 [1214] A MeOH solution of NaBT
4 (50 µl, ~ 333 mCi, 80 Ci/mmol, 1.0 equiv.) at room temperature was added to an HPLC vial containing THF (50 µl) and 116.2 (4 mg, 2.3 equiv.). The reaction mixture was stirred at room temperature for 45 min and quenched with a saturated aqueous NH
4Cl solution (100 µl). The product was extracted with EtOAc (1 mL x 2) and the solvent was removed under a gentle flow of nitrogen. The crude reaction mixture was diluted with MeCN:H
2O (3:1, 1.0 mL). At this stage, 116 was purified using analytical HPLC (column: C18 (250mm*4.6mm, 3μm), isocratic: 25/75% B (B=Acetonitrile), flow rate: 1.2mL/min) to give 116, which was stored as an MeCN:H
2O (3:1) solution. [1215] Example 117: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-3- hydroxy-4-methoxybutan-2-yl-3-t)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (117)
[1216] Synthesis of 117.1 [1217] To a suspension of 36 and silica gel in DCM was added PCC at 25 °C and the resulting mixture was stirred for 2 h. The mixture was filtered through a pad of silica gel and the filter cake was washed with DCM. The filtrate was concentrated to give 117.1. [1218] Synthesis of 117 [1219] A MeOH solution of NaBT
4 (50 µl, ~ 333 mCi, 80 Ci/mmol, 1.0 equiv.) at room temperature was added to an HPLC vial containing THF (50 µl) and 117.1 (5 mg, 2.8 equiv.). The reaction mixture was stirred at room temperature for 45 min and quenched with a saturated aqueous NH
4Cl solution (100 µl). The product was extracted with EtOAc (1 mL x 2) and the solvent was removed under a gentle flow of nitrogen. The crude reaction mixture was diluted with MeCN:H
2O (3:1, 1.0 mL). At this stage, 117 was purified using analytical HPLC (column: C18 (250mm*4.6mm, 5μm), isocratic: 25/75% B (B=Acetonitrile), flow rate: 1.2mL/min) to give 117, which was stored as an MeCN:H
2O (3:1) solution. [1220] Example 118: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17R)-17-((2S,3S)-4- fluoro-3-hydroxybutan-2-yl-3-t)-13-methyl-3-(trifluoromethyl)hexadecahydro-1H- cyclopenta[a]phenanthren-3-ol (118)
[1221] Synthesis of 118.1 [1222] To a suspension of 62 and silica gel in DCM was added PCC at 25 °C and the resulting mixture was stirred for 2 h. The mixture was filtered through a pad of silica gel and the filter cake was washed with DCM. The filtrate was concentrated to give 118.1. [1223] Synthesis of 118 [1224] A MeOH solution of NaBT4 (50 µl, ~ 333 mCi, 80 Ci/mmol, 1.0 equiv.) at room temperature was added to an HPLC vial containing THF (50 µl) and 118.1 (5 mg, 2.9 equiv.). The reaction mixture was stirred at room temperature for 45 min and quenched with a saturated aqueous NH
4Cl solution (100 µl). The product was extracted with EtOAc (1 mL x 2) and the solvent was removed under a gentle flow of nitrogen. The crude reaction mixture was diluted with MeCN:H
2O (3:1, 1.0 mL), and 118 was stored as an MeCN:H
2O (3:1) solution. [1225] Example 119: Assay Methods and Biological Data [1226] Compounds of the present disclosure can be evaluated using various in vitro and in vivo assays described in the literature; examples of which are described below. [1227] The following examples are offered to illustrate the biological activity of the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting the scope thereof.
NMDA ModulationWhole-cell Patch Clamp of Mammalian Cells (Syncropatch 384i (Nanion Technologies)) [1228] Whole-cell patch clamp electrophysiology was used to investigate the effects of compounds on GluN1/GluN2A N-methyl-D-aspartate (NMDA) glutamate receptors expressed in mammalian cells. Cell Culture [1229] Human embryonic kidney (HEK293) cells expressing the recombinant human GluN1/GluN2A receptor under the control of a tetracycline-inducible expression system were used. Cells were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM) with 1% glutamine, 10% Tetracycline System Approved fetal bovine serum (FBS), and NMDA inhibitors. Cells were cultured in a humidified 5% CO
2 incubator at 37°C. Cells were induced with 50ng/ml tetracycline 18-24 hours prior to testing. A cocktail of channel blockers was added to the media to prevent cell death. [1230] Cells were 60-80% confluent at the time of harvest. Cells were detached from the flask TrypLE Enzyme Express (Thermo Fisher) at 37°C, and then cold extracellular solution was added to the flask, followed by incubation at 4°C and then trituration of the cells. The cell solution was then placed on a shaker on the Syncropatch platform at 10°C with a shake speed of a minimum 200rpm for at least 30 minutes prior to testing. Solutions [1231] Extracellular (EC) solution (in mM) – 140 NaCl, 4 KCl, 5 CaCl2, 10 HEPES, 5 Glucose, pH 7.4 with NaOH. All external solutions contained 0.2% DMSO and 0.01% Kolliphor® EL (C5135, Sigma) throughout the experiment. [1232] Intracellular (IC) solution (in mM) – 120 CsF, 10mM EGTA, 10 NaCl, 10 HEPES, 4 NaATP, 2 MgCl2, pH 7.2 with CsOH Plate Preparation [1233] First, the DMSO Master Plate was prepared, in which the DMSO stock of each test compound was serially diluted in 100% DMSO to 1000X the final assay concentration. Immediately prior to assay testing, the compounds were diluted 1:100 by transferring solutions from the DMSO Mast Plate to the Intermediate Plate pre-filled with EC solution using a Biomek FX automated liquid handling system. Compounds were then diluted further with extracellular solution into two pre-incubation plates – 1) compound from the Intermediate Plate was mixed with EC solution at a 1:5 dilution to create a 2X Compound Pre-Incubation Plate which was diluted a further 1:2 when added to the Syncropatch for the initial compound pre-incubation. And 2) compound from the Intermediate plate was mixed
with EC solution at a 1:10 Dilution to create the 1X Compound Pre-Incubation Plate, which was used for subsequent compound pre-incubations. Finally, a Compound + Agonist Plate was prepared by mixing compound from the 2X Compound Pre-Incubation Plate with 2X concentration of co-agonists in a 1:1 ratio. Voltage Protocol [1234] Each experiment sequentially included cell catching, sealing, whole-cell formation, liquid application, recording and data acquisition. Whole-cell patch clamp recordings were performed using multi-hole high resistance chips on the SyncroPatch 384i (Nanion Technologies). A steady-state voltage pulse at -80mV was applied throughout the assay and a 10 second recording window was triggered around 1 second prior to application of co- agonists. Currents were leak corrected and sampled at 5kHz. Application Protocol [1235] A fast application was used, in which 5μl co-agonist was rapidly applied at a speed of 30μl/s and then rapidly removed from the well. To test for modulator activity, the co- agonists glutamate (1 or 3μM) and glycine (100μM) were applied three times to show activation reproducibility, followed by 120 seconds pre-incubation of test compound alone. The test compound was then re-applied in the presence of co-agonists seven times. No washout periods were applied during the assay (total of ten applications). Analysis [1236] The voltage protocol generation data collection and analysis were performed on PatchControll384 and DataControll384. For each concentration tested, the fold peak amplitude increase was generated using the following equation: (Icomp/Icontrol)-1, where Icomp is the peak amplitude in the presence of the test compound and co-agonists from the fifth compound/co-agonist application, and Icontrol is the peak amplitude in the presence of agonist alone from the third co-agonist application. Test compounds were evaluated at 8 concentrations, with at least 2 replicate wells per concentration. The effect of all concentrations was then fitted with a four-parameter logistic curve fit using least squares regression and the IC50 and Emin were calculated. (GraphPad Prism). For compounds that were tested on multiple assays, the geometric mean of the IC50 and arithmetic mean of the Emin were calculated using the parameters derived from the curve fits on each individual assay. The results are shown in Table 2 below. Table 2:
For Table 2, "A" indicates an IC50 of 1 to 100 nM; "B" indicates an IC50 of greater than 100 nM up to 500 nM; "C" indicates an IC50 greater than 500 nM up to 1µM; "D" indicates an IC50 of greater than 1µM; "E" indicates an Emin of <0 to -15%; "F” indicates an Emin of <- 15% to -50%; and "G" indicates an Emin of <-50%. NUMBERED EMBODIMENTS [1237] Particular embodiments of the disclosure are set forth in the following numbered paragraphs: 1. A compound, wherein the compound has the structure of Formula (I):
or a pharmaceutically acceptable salt, isotopic variant, or a 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 5-8 membered heteroaryl; each of R
15 and R
16 is independently hydrogen or substituted or unsubstituted C
1-6 alkyl; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl; R
18 is hydrogen or substituted or unsubstituted C
1-6 alkyl; R
19 is hydrogen or substituted or unsubstituted C
1-6 alkyl;
R
20 is hydrogen, hydroxyl, substituted or unsubstituted C
1-6 alkyl, or substituted or unsubstituted C
3-6 carbocyclyl; R
20’ is hydrogen, hydroxyl, substituted or unsubstituted C
1-6 alkyl, or substituted or unsubstituted C
3-6 carbocyclyl; provided that R
20 and R
20’ are not both hydroxyl; and R
22 is 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 aryl; provided that when R
22 is -CH
3, R
3 is not -CH
3 or hydrogen. 2. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof according to paragraph 1, 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- 8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, C
6-10 aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 R
A; each of R
15 and R
16 is independently hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
C; R
19 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
D; R
20 is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
E; R
20’ is hydrogen, hydroxyl, C
1-6 alkyl, or C
3-6 carbocyclyl, wherein said C
1-6 alkyl and C
3-6 carbocyclyl are independently optionally substituted with 1-5 R
F; provided that R
20 and R
20’ are not both hydroxyl; each instance of R
A, R
B, R
C, R
D, R
E, and R
F, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C
6-10 aryl, and C
1-6 alkoxy optionally substituted with 1-5 halo; R
22 is C
1-6 alkyl, C
2-6 alkenyl, C
2-6 alkynyl, C
3-6 carbocyclyl, or C
6-10 aryl, wherein said C
1-6 alkyl, C
2-6 alkenyl, and C
2-6 alkynyl are independently optionally substituted with 1- 5 R
G and said C
3-6 carbocyclyl and C
6-10 aryl are independently optionally substituted with 1- 5 R
H; provided that when R
22 is -CH
3, R
3 is not -CH
3 or hydrogen;
each instance of R
G, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 R
G1; each instance of R
G1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1-6 alkoxy optionally substituted with 1-5 halo; and each instance of R
H, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C
1-6 alkyl optionally substituted with 1-5 halo, and C
1-6 alkoxy optionally substituted with 1-5 halo. 3. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 1 or 2, wherein the compound of Formula (I) is a compound of Formula (I-A) or (I-B):
4. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 3, wherein the compound of Formula (I-A) is a compound of Formula (I-A-1) or (I-A-2):
(I-A-1) (I-A-2). 5. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 4, wherein the compound of Formula (I-A-1) is a compound of Formula (I-A-1-i) or (I-A-1-ii):
6. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 4, wherein the compound of Formula (I-A-2) is a compound of Formula (I-A-2-i) or (I-A-2-ii):
7. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 3, wherein the compound of Formula (I-B) is a compound of Formula (I-B-1) or (I-B-2):
8. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 7, wherein the compound of Formula (I-B-1) is a compound of Formula (I-B-1-i) or (I-B-1-ii):
9. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 7, wherein the compound of Formula (I-B-2) is a compound of Formula (I-B-2-i) or (I-B-2-ii):
10. The compound according to paragraph 1 or 3, wherein:
R
3 is substituted or unsubstituted C
1-6 alkyl or substituted or unsubstituted C
2-6 alkynyl; R
15 is hydrogen or substituted or unsubstituted C
1-6 alkyl and R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl; R
18 is substituted or unsubstituted C
1-6 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. 11. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3, wherein: R
3 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-5 R
A; R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is C
1-6 alkyl optionally substituted with 1-5 R
C; R
20 is hydrogen, hydroxyl, or C
1-6 alkyl optionally substituted with 1-5 R
E; and R
20’ is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
F. 12. The compound according to any one of paragraphs 1, 3 and 10, wherein: R
3 is substituted or unsubstituted C
1-6 alkyl; R
15 is hydrogen or substituted or unsubstituted C
1-6 alkyl and R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl; R
18 is -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and R
22 is substituted or unsubstituted C
1-6 alkyl or substituted or unsubstituted C
2-6 alkynyl. 13. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3 and 10-11, wherein:
R
3 is C
1-6 alkyl optionally substituted with 1-5 R
A; R
15 is hydrogen or C
1-6 alkyl optionally substituted with 1-5 R
B; R
16 is hydrogen; or R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B; R
18 is -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and R
22 is C
1-6 alkyl or C
2-6 alkynyl, wherein said C
1-6 alkyl and C
2-6 alkynyl are independently optionally substituted with 1-5 R
G. 14. The compound according to any one of paragraphs 1 and 3-9, wherein 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. 15. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-9, wherein R
3 is hydrogen, C
1-6 alkyl, C
2-6 alkynyl, C
3-6 carbocyclyl, or 5-8 membered heteroaryl, wherein said C
1-6 alkyl, C
2-6 alkynyl, C
3-6 carbocyclyl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 R
A. 16. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 15, wherein R
3 is -H, -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, - CH
2OH, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH(CH
3)
2, -C≡C-H, -C≡C-CH
3, cyclopropyl, or pyridyl, wherein said cyclopropyl and pyridyl are independently optionally substituted with 1-5 R
A. 17. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 16 , wherein R
3 is hydrogen. 18. The compound according to any one of paragraphs 1, 3-10 and 14, wherein R
3 is substituted or unsubstituted C
1-6 alkyl. 19. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-10, and 14-15 and 18, wherein R
3 is C
1-6 alkyl optionally substituted with 1-5 R
A.
20. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 19, wherein R
3 is C
1-6 alkyl substituted with 1-5 R
A. 21. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 20, wherein R
3 is -CH
2F, -CHF
2, -CF
3, -CH
2OCH
3, or - CH
2OH. 22. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 21, wherein R
3 is -CF
3. 23. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 18 or 19, wherein R
3 is unsubstituted C
1-6 alkyl. 24. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 23, wherein R
3 is -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, or - CH(CH
3)
2. 25. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 24, wherein R
3 is -CH
3 or -CH
2CH
3. 26. The compound according to any one of paragraphs 1-10, wherein R
3 is substituted or unsubstituted C
2-6 alkynyl. 27. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-11, 14-15 and 26, wherein R
3 is C
2-6 alkynyl optionally substituted with 1-5 R
A. 28. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 27, wherein R
3 is -C≡C-H or -C≡C-CH
3. 29. The compound according to paragraphs 1-9 and 14, wherein R
3 is substituted or unsubstituted C
3-6 carbocyclyl. 30. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraphs 1-9, 14-15 and 29, wherein R
3 is C
3-6 carbocyclyl optionally substituted with 1-5 R
A.
31. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 30, wherein R
3 is unsubstituted cyclopropyl. 32. The compound according to paragraph 1-9, and 14, wherein R
3 is substituted or unsubstituted 5-8 membered heteroaryl. 33. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraphs 1-9, 14-15 and 32, wherein R
3 is 5-8 membered heteroaryl optionally substituted with 1-5 R
A. 34. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 33, wherein R
3 is unsubstituted pyridyl. 35. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-34, wherein R
15 is hydrogen or unsubstituted C
1-6 alkyl. 36. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 35, wherein R
15 is hydrogen or -CH
3. 37. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-36, wherein R
16 is hydrogen or unsubstituted C
1-6 alkyl. 38. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 37, wherein R
16 is hydrogen or -CH
3. 39. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-38, wherein R
15 and R
16 are hydrogen. 40. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-38, wherein R
15 is -CH
3 and R
16 is hydrogen. 41. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-9 and 14-38, wherein R
15 is hydrogen and R
16 is -CH
3.
42. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-9 and 14-38, wherein R
15 and R
16 are -CH
3. 43. The compound according to any one of paragraphs 1-34, wherein R
15 and R
16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C
3-6 carbocyclyl. 44. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-34 and 43, wherein R
15 and R
16, taken together with the carbon atoms to which they are attached, form a C
3-6 carbocyclyl optionally substituted with 1-5 R
B. 45. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 44, wherein R
15 and R
16, taken together with the carbon atoms to which they are attached, form an unsubstituted cyclopropyl. 46. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3 and 10-45, wherein R
18 is hydrogen or unsubstituted C
1-6 alkyl. 47. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 46, wherein R
18 is hydrogen, -CH
3, or -CH
2CH
3. 48. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 47, wherein R
18 is -CH
3 or -CH
2CH
3. 49. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-2 and 10-48, wherein R
19 is hydrogen or unsubstituted C
1-6 alkyl. 50. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 49, wherein R
19 is hydrogen or -CH
3. 51. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 50, wherein R
19 is -CH
3. 52. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 50, wherein R
19 is hydrogen.
53. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3, 14-47, 49-50, and 52, wherein R
18 and R
19 are hydrogen. 54. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3 and 10-51, wherein R
18 and R
19 are -CH
3. 55. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3, 10-50, and 52, wherein R
18 is -CH
3 and R
19 is hydrogen. 56. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3, 10-11, and 15-51, wherein R
18 is -CH
2CH
3 and R
19 is -CH
3. 57. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-56, wherein R
20 is hydrogen, hydroxyl, or unsubstituted C
1-6 alkyl. 58. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 57, wherein R
20 is hydrogen, hydroxyl, or -CH
3. 59. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-58, wherein R
20’ is hydrogen or unsubstituted C
1-6 alkyl. 60. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 59, wherein R
20’ is hydrogen or -CH
3. 61. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-60, wherein R
20 and R
20’ are hydrogen. 62. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-4, 7, 10-11, and 14-60, wherein R
20 and R
20’ are -CH
3.
63. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-4, 7, 10-11, and 14-60, wherein R
20 is hydrogen and R
20’ is -CH
3. 64. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-4, 7, 10-11, and 14-60, wherein R
20 is -CH
3 and R
20’ is hydrogen. 65. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-4, 7, 10-11, and 14-60, wherein R
20 is hydroxyl and R
20’ is -CH
3. 66. The compound according to any one of paragraphs 1-65, wherein R
22 is substituted or unsubstituted C
1-6 alkyl. 67. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-66, wherein R
22 is C
1-6 alkyl optionally substituted with 1-5 R
G. 68. The compound according to paragraph 66, wherein R
22 is substituted C
1-6 alkyl. 69. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 66-68, wherein R
22 is C
1-6 alkyl substituted with 1-5 R
G. 70. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 69, wherein R
22 is C
1-6 alkyl substituted with 1-3 R
G, wherein each instance of R
G is independently selected from the group consisting of: halo, hydroxyl, C
1-6 alkoxy optionally substituted with 1-5 halo, C
3-6 carbocyclyl, 5-8 membered heterocyclyl, and 5-8 membered heteroaryl, wherein said C
3-6 carbocyclyl, C
6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 R
G1. 71. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-66, wherein R
22 is -CH
2F, -CHF
2, -CF
3, - CH
2CH
2CH(CH
3)(CF
3), -CH
2OH, -CH
2OCH
3, -CH
2OCH
2CH
2OCH
3, -CH
2OCH(CH
3)
2, - CH
2OCF
3, -CH
2OCHF
2, -CH
3, -CH
2CH
3, -CH
2CH
2CH
2CH
3, -CH(CH
3)
2, -CH
2CH(CH
3)
2, - CH
2CH
2CH(CH
3)
2, -C(CH
3)
3, -CH=CH
2, -CH
2CH=CH
2, -CH=CHCH
3, -CH=C(CH
3)
2, -
C≡C-H, -C≡C-CH
3, -C≡C-CF
3, unsubstituted cyclopropyl, unsubstituted cyclobutyl, bicyclo[1.1.1]pentanyl optionally substituted with 1-5 R
H, or phenyl optionally substituted with 1-5 R
H. 72. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 71, wherein R
22 is -CH
2F, -CHF
2, -CF
3, or - CH
2CH
2CH(CH
3)(CF
3). 73. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 71, wherein R
22 is -CH
2OH, -CH
2OCH
3, - CH
2OCH
2CH
2OCH
3, -CH
2OCH(CH
3)
2, -CH
2OCF
3, or -CH
2OCHF
2. 74. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 71, wherein R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is 5-6 membered heteroaryl optionally substituted with 1-5 R
G1. 75. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 74, wherein the 5-6 membered heteroaryl is a 5-6 membered nitrogen-containing heteroaryl. 76. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 75, wherein the 5-6 membered nitrogen-containing heteroaryl contains 1-4 nitrogen atoms. 77. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 74-76, wherein the 5-6 membered heteroaryl is substituted with 1-3 R
G1, wherein each instance of R
G1 is independently selected from cyano, oxo, and C
1-6 alkyl optionally substituted with 1-5 halo. 78. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 57-70, wherein R
22 is C
1-6 alkyl substituted with a C
3-6 carbocyclyl optionally substituted with 1-5 R
G1. 79. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 57-70, wherein R
22 is C
1-6 alkyl substituted with 1 R
G, wherein R
G is 5-8 membered heterocyclyl optionally substituted with 1-5 R
G1.
80. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 79, wherein the 5-8 membered heterocyclyl is a 5-8 membered nitrogen-containing heterocyclyl. 81. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 80, wherein the 5-8 membered nitrogen-containing heterocyclyl contains 1 nitrogen atom. 82. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 79-81, wherein the 5-8 membered heterocyclyl is unsubstituted. 83. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 66 or 67, wherein R
22 is unsubstituted C
1-6 alkyl. 84. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 83, wherein R
22 is -CH
3, -CH
2CH
3, -CH
2CH
2CH
2CH
3, - CH(CH
3)
2, -CH
2CH(CH
3)
2, -CH
2CH
2CH(CH
3)
2, or -C(CH
3)
3. 85. The compound according to any one of paragraphs 1-11 and 14-65, wherein R
22 is substituted or unsubstituted C
2-6 alkenyl. 86. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-11, 14-65- and 85, wherein R
22 is C
2-6 alkenyl optionally substituted with 1-5 R
G. 87. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 86, wherein R
22 is -CH=CH
2, -CH
2CH=CH
2, -CH=CHCH
3, or -CH=C(CH
3)
2. 88. The compound according to any one of paragraphs 1-65, wherein R
22 is substituted or unsubstituted C
2-6 alkynyl. 89. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-65 and 88, wherein R
22 is C
2-6 alkynyl optionally substituted with 1-5 R
G.
90. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 89, wherein R
22 is -C≡C-H, -C≡C-CH
3, or -C≡C-CF
3. 91. The compound according to any one of paragraphs 1-11 and 14-65, wherein R
22 is substituted or unsubstituted C
3-6 carbocyclyl. 92. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-11 and 14-65 and 91, wherein R
22 is C
3-6 carbocyclyl optionally substituted with 1-5 R
H. 93. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 92, wherein R
22 is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or bicyclo[1.1.1]pentanyl optionally substituted with 1-3 R
H. 94. The compound according to any one of paragraphs 1-11 and 14-65, wherein R
22 is substituted or unsubstituted C
6-10 aryl. 95. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-11, 14-65 and 94, wherein R
22 is C
6-10 aryl optionally substituted with 1-5 R
H. 96. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 95, wherein R
22 is unsubstituted phenyl. 97. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 95, wherein R
22 is phenyl substituted with 1-3 R
H, wherein each instance of R
H is independently selected from the group consisting of: halo, cyano, and C
1-6 alkyl optionally substituted with 1-5 halo. 98. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-3, 11-15, 18-20, 35-39, 46-51, 57-60, and 66- 70, wherein: R
3 is C1 alkyl substituted with 1-3 R
A; R
15 and R
16 are hydrogen; R
18 and R
19 are -CH
3; R
20 is hydrogen; R
20’ is -CH
3; and
R
22 is C
1-6 alkyl optionally substituted with an unsubstituted C
1-6 alkoxy. 99. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 98, wherein R
22 is -CH
3 or -CH
2OCH
3. 100. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-99, wherein one or more hydrogen atoms are replaced by deuterium. 101. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-99, wherein one or more hydrogen atoms are replaced by tritium. 102. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 1, wherein the compound of Formula (I) is selected from the group consisting of any one compounds 1-101, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 103. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 102, wherein the compound of Formula (I) is selected from the group consisting 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, and 108, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 104. The compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to paragraph 102, wherein the compound of Formula (I) is selected from the group consisting of any one of compounds 7, 27, 32, 34, 36, 39, 40, 53, 55-57, 61, 63, 84, 95, 97-98, 100-101, and 104-106, or a pharmaceutically acceptable salt, isotopic variant, or combination thereof. 105. The compound according to any one of paragraphs 1-104. 106. The pharmaceutically acceptable salt of any one of paragraphs 1-104. 107. The isotopic variant of a compound according to any one of paragraphs 1-104. 108. The isotopic variant of a pharmaceutically acceptable salt of any one of paragraphs 1- 104.
109. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-108, and a pharmaceutically acceptable carrier. 110. A method for treating a CNS-related condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-108, or a pharmaceutical composition according to paragraph 109. 111. The method according to paragraph 110, wherein the CNS-related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus. 112. The method according to paragraph 110, wherein the CNS-related condition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychiatric disorder, pain, a seizure disorder, drug-induced dyskinesia, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome, neuropsychiatric lupus, and tinnitus. 113. A method for effecting negative allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-108, or a pharmaceutical composition according to paragraph 109. 114. A compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-108, or a pharmaceutical composition according to paragraph 109, for use in treating a CNS-related condition in a subject. 115. The compound, pharmaceutically acceptable salt, isotopic variant, combination thereof, or pharmaceutical composition for use according to paragraph 114, wherein the CNS-related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a
neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus. 116. The compound, pharmaceutically acceptable salt, isotopic variant, combination, or pharmaceutical composition for use according to paragraph 114, wherein the CNS-related condition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychiatric disorder, pain, a seizure disorder, drug-induced dyskinesia, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome, neuropsychiatric lupus, and tinnitus. 117. A compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-108, or a pharmaceutical composition according to paragraph 109, for use in effecting negative allosteric modulation of an NMDA receptor. 118. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-108, or a pharmaceutical composition according to paragraph 109, in the manufacture of a medicament for treating a CNS-related condition in a subject. 119. The use according to paragraph 118, wherein the CNS-related condition is selected from the group consisting of an adjustment disorder, an anxiety disorder, a cognitive disorder, a mood disorder, a personality disorder, a neurodevelopmental disorder, pain, a seizure or seizure disorder, stroke, traumatic brain injury, a movement disorder, neuropsychiatric lupus, and tinnitus. 120. The use according to paragraph 118, wherein the CNS-related condition is selected from the group consisting of an anxiety disorder, a stress disorder, a cognitive disorder, a mood disorder, a personality disorder, an addictive disorder, a neurodevelopmental disorder, schizophrenia or another psychiatric disorder, pain, a seizure disorder, drug-induced dyskinesia, stroke, traumatic brain injury, an adjustment disorder, an autism spectrum disorder, fragile X syndrome, neuropsychiatric lupus, and tinnitus. 121. Use of a compound or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, according to any one of paragraphs 1-108, or a pharmaceutical
composition according to paragraph 109, in the manufacture of a medicament for effecting negative allosteric modulation of an NMDA receptor.
or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: R3 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15 and R16 is independently hydrogen or substituted or unsubstituted C1-6 alkyl; or R15 and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl; R18 is hydrogen or substituted or unsubstituted C1-6 alkyl; R19 is hydrogen or substituted or unsubstituted C1-6 alkyl; R20 is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 carbocyclyl; R20’ is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 carbocyclyl; provided that R20 and R20’ are not both hydroxyl; and R22 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted C6-10 aryl; provided that when R22 is -CH3, R3 is not -CH3 or hydrogen. [0005] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic variant, or combination thereof, wherein: R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C6-10 aryl, or 5-8 membered heteroaryl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, C6-10 aryl, and 5-8 membered heteroaryl are independently optionally substituted with 1-5 RA;
each of R15 and R16 is independently hydrogen or C1-6 alkyl optionally substituted with 1-5 RB; or R15 and R16, taken together with the carbon atoms to which they are attached, form a C3-6 carbocyclyl optionally substituted with 1-5 RB; R18 is hydrogen or C1-6 alkyl optionally substituted with 1-5 RC; R19 is hydrogen or C1-6 alkyl optionally substituted with 1-5 RD; R20 is hydrogen, hydroxyl, C1-6 alkyl, or C3-6 carbocyclyl, wherein said C1-6 alkyl and C3-6 carbocyclyl are independently optionally substituted with 1-5 RE; R20’ is hydrogen, hydroxyl, C1-6 alkyl, or C3-6 carbocyclyl, wherein said C1-6 alkyl and C3-6 carbocyclyl are independently optionally substituted with 1-5 RF; provided that R20 and R20’ are not both hydroxyl; each instance of RA, RB, RC, RD, RE, and RF, when present, is independently selected from the group consisting of halo, hydroxyl, oxo, cyano, nitro, amino, imino, thiol, thioketo, C6-10 aryl, and C1-6 alkoxy optionally substituted with 1-5 halo; R22 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or C6-10 aryl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are independently optionally substituted with 1- 5 RG and said C3-6 carbocyclyl and C6-10 aryl are independently optionally substituted with 1- 5 RH; provided that when R22 is -CH3, R3 is not -CH3 or hydrogen; each instance of RG, when present, is independently selected from the group consisting of halo, hydroxyl, cyano, C1-6 alkoxy optionally substituted with 1-5 halo, C3-6 carbocyclyl, C6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl, wherein said C3-6 carbocyclyl, C6-10 aryl, 5-8 membered heteroaryl, and 5-8 membered heterocyclyl are independently optionally substituted with 1-5 RG1; each instance of RG1, when present, is independently selected from the group consisting of halo, cyano, oxo, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1-6 alkoxy optionally substituted with 1-5 halo; and each instance of RH, when present, is independently selected from the group consisting of halo, cyano, nitro, amino, C1-6 alkyl optionally substituted with 1-5 halo, and C1- 6 alkoxy optionally substituted with 1-5 halo. [0006] In some embodiments, the disclosure provides a compound of Formula (I-A) or (I- B):
or a pharmaceutically acceptable salt, isotopic variant, or a combination thereof, wherein: R3 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2- 6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, substituted or unsubstituted C6-10 aryl, or substituted or unsubstituted 5-8 membered heteroaryl; each of R15 and R16 is independently hydrogen or substituted or unsubstituted C1-6 alkyl; or R15 and R16, taken together with the carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 carbocyclyl; R18 is hydrogen or substituted or unsubstituted C1-6 alkyl; R19 is hydrogen or substituted or unsubstituted C1-6 alkyl; R20 is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 carbocyclyl; R20’ is hydrogen, hydroxyl, substituted or unsubstituted C1-6 alkyl, or substituted or unsubstituted C3-6 carbocyclyl; provided that R20 and R20’ are not both hydroxyl; and R22 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or substituted or unsubstituted C6-10 aryl; provided that when R22 is -CH3, R3 is not -CH3 or hydrogen. 
(I-A-1) (I-A-2). 
(I-A-1-i) (I-A-1-ii). 
