Compositions and methods for treating CNS disorders

Abstract

Compositions and methods for treating CNS disorders are provided. [Solution] Formula (I): TIFF2023071871000280.tif5459 The present invention uses a neurostimulatory steroid represented by the formula: or a pharmaceutically acceptable salt thereof. The compound is believed to act as a GABA modulator. Also provided are pharmaceutical compositions containing the compound, as well as methods of use and treatment (e.g., for inducing sedation and / or anesthesia).

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 064,961, filed October 16, 2014, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] 2. Background of the Invention Brain excitability is defined as the level of alertness of an animal, which is a continuum ranging from coma to convulsions, and is controlled by various neurotransmitters. In general, neurotransmitters are involved in controlling the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of approximately -70 mV, with the inside of the cell being negative with respect to the outside of the cell. The electrical potential (voltage) is determined by the flow of ions (K + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV). This action is mediated by Na + It is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, which increases the membrane permeability to ions. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of the γ-aminobutyric acid (GABA) receptor complex (GRC), the effect on brain excitability is mediated by the neurotransmitter GABA. Since up to 40% of the neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on the excitability of the entire brain. GABA controls the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with recognition sites on the GRC, facilitating the flow of chloride ions intracellularly down the electrochemical gradient of the GRC. This intracellular increase in the level of anions causes hyperpolarization of the membrane potential across the membrane, reducing the sensitivity of the neuron to excitatory inputs (i.e., the excitability of the neuron is reduced). In other words, the higher the chloride ion concentration within the neuron, the lower the excitability and arousal levels of the brain.

[0004] The GRC has been well-documented to be involved in the mediation of anxiety, seizure activity, and sedation. Thus, GABA, and drugs that act like GABA or enhance the action of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®) produce their therapeutically useful effects by interacting with specific control sites on the GRC. Accumulating evidence now suggests that the GRC contains distinct sites for neurosteroids in addition to the benzodiazepine and barbiturate binding sites. See, for example, Lan, N.C. et al., Neurochem.Res. (1991) 16:347-356.

[0005] Neuroactive steroids are indeed produced endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α,21-dihydroxy-5-reduced pregnan-20-one (metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al., Science 232:1004-1007 (1986); Harrison, N.L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

[0006] Progesterone, an ovarian hormone, and its metabolites have been shown to have a profound effect on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff, D.W and McEwen, B.S., Science 219:808-814 (1983); Gyermek et al., J Med Chem. 11:117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987)). The levels of progesterone and its metabolites vary according to the stage of the menstrual cycle. It has been well established that the levels of progesterone and its metabolites decline prior to the onset of menstruation. It has also been well established that certain physical symptoms recur monthly prior to the onset of menstruation. These symptoms associated with premenstrual syndrome (PMS) include stress, anxiety, and migraine (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)). Subjects with PMS experience symptoms that appear premenstrually and disappear postmenstrually, recurring monthly.

[0007] Similarly, a decrease in progesterone has also been temporally correlated with an increase in seizure frequency in female epileptic patients (i.e., menstrual epilepsy) (Laidlaw, J., Lancet, 1235-1237 (1956)). A more direct correlation has been observed with a decrease in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). Furthermore, in the case of subjects with primary generalized petit mal epilepsy, the temporal incidence of seizures was correlated with the incidence of symptoms of premenstrual syndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating subjects with seizures correlated with the menstrual cycle (Aird, R.B. and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)).

[0008] Also, a syndrome associated with low progesterone levels is postpartum depression (PND). Immediately after childbirth, progesterone levels drop dramatically, leading to the onset of PND. The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also accompanied by severe anxiety and irritability. Depression associated with PND is not suitable for treatment with conventional antidepressants, and women experiencing PND exhibit a high incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)).

[0009] In summary, these findings suggest a crucial role for progesterone and deoxycorticosterone, and more specifically their metabolites, in the homeostatic control of brain excitability that manifests as increased seizure activity or symptoms associated with catamenial epilepsy, PMS, and PND. The correlation between low levels of progesterone and symptoms associated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8 - 20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy", Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279 - 282 and Dalton, K., Premen strual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)). However, progesterone is not always effective in treating the above - mentioned syndromes. For example, in the treatment of PMS, there is no dose - response relationship to progesterone (Maddocks et al., Obstet. Gynecol. 154:573 - 581 (1986); Dennerstein et al., Brit. Med J 290:16 - 17 (1986)).

[0010] There is a need for novel and improved neuroactive steroids that act as modulators of brain excitability and as agents for the prevention and treatment of CNS - related diseases. The compounds, compositions, and methods described herein are directed to this purpose.

PRIOR ART DOCUMENTS

NON - PATENT DOCUMENTS

[0011] [Non-Patent Document 1] Lan, N.C. et al., Neurochem.Res. 16:347-356 (1991) [Non-Patent Document 2] Majewska, M.D. et al., Science 232:1004-1007 (1986) [Non-Patent Document 3] Harrison, N.L. et al., J Pharmacol.Exp.Ther. 241:346-353 (1987) [Non-Patent Document 4] Backstrom, T. et al., Acta Obstet.Gynecol.Scand. Suppl. 130:19-24 (1985) [Non-Patent Document 5] Pfaff, D.W and McEwen, B.S., Science 219:808-814 (1983) [Non-Patent Document 6] Gyermek et al., J Med Chem. 11:117 (1968) [Non-Patent Document 7] Lambert, J. et al., Trends Pharmacol.Sci. 8:224-227 (1987) [Non-Patent Document 8] Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd Edition, Chicago Yearbook, Chicago (1984) [Non-Patent Document 9] Laidlaw, J., Lancet, 1235-1237 (1956) [Non-Patent Document 10] Rosciszewska et al., J.Neurol.Neurosurg.Psych. 49:47-51 (1986) [Non-Patent Document 11] Backstrom, T. et al., J.Psychosom.Obstet.Gynaecol. 2:8-20 (1983) [Non-Patent Document 12] Aird, R.B. and Gordan, G., J. Amer. Med. Soc. 145:715-719(1951) [Non-Patent Document 13] Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy", Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York(1984), pp.279-282 [Non-Patent Document 14] Maddocks et al., Obstet. Gynecol. 154:573-581(1986) [Non-Patent Document 15] Dennerstein et al., Brit. Med J 290:16-17(1986) [Summary of the Invention] [Means for Solving the Problems]

[0012] [Gist of the Invention] For example, C21-substituted neuroactive steroids designed to act as GABA modulators are provided herein. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for inducing anesthesia and / or sedation in a subject. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, spasm disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disorders, substance use disorders and / or withdrawal syndromes, or tinnitus) in a subject in need thereof (e.g., a subject having Rett syndrome, fragile X syndrome, or Angelman syndrome).

[0013] In one aspect, formula (I): [Chemical Formula] There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof; in formula (I): Ring A is a substituted or unsubstituted carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 1 is hydrogen, a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 2~6 alkenyl, or a substituted or unsubstituted C 3~6 carbocylyl; R 3-6 is hydrogen, a substituted or unsubstituted C 2 alkyl, a substituted or unsubstituted C 1~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted C 2~6 carbocylyl, or -OR 3~6 wherein R A2 is hydrogen or a substituted or unsubstituted C A2 alkyl, a substituted or unsubstituted C 1~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 2~6 carbocylyl; R 3~6 is hydrogen or -OR 3a wherein R A3 is hydrogen, a substituted or unsubstituted C A3 alkyl, a substituted or unsubstituted C 1~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 2~6 carbocylyl, and R 3~6 is hydrogen; or alternatively R 3b and R 3a together form an oxo (=O) group; R 3b is hydrogen, a substituted or unsubstituted C 4a alkyl, or -OR 1~6 wherein R A4 is hydrogen, a substituted or unsubstituted C A4 alkyl, a substituted or unsubstituted C 1~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 2~6Alkynyl, or substituted or unsubstituted C 3~6 is carbocyclic, and R 4b is hydrogen or substituted or unsubstituted C 1~6 alkyl; R 4a and R 4b together form an oxo (=O) group; or R 4a and R 4b together with the carbon atom to which they are attached form a ring (e.g., a 3- to 6-membered ring (e.g., a carbocyclic or heterocyclic ring)). R 7a is hydrogen or halogen; R 7b is hydrogen; R 5 is absent or is hydrogen; and

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0014] In one embodiment, A is, the ring A is a substituted or unsubstituted nitrogen-containing heterocyclic or nitrogen-containing heteroaryl. In one embodiment, A is attached via a nitrogen atom. In one embodiment, A is a monocyclic heteroaryl or heterocylcyl, e.g., a substituted monocyclic heteroaryl. In one embodiment, A is a bicyclic heteroaryl, e.g., a substituted bicyclic heteroaryl. Exemplary substituents are described herein.

[0015] In one embodiment, ring A is a substituted carbocyclic, heterocyclic, aryl, or heteroaryl, such as a substituted heterocyclic or heteroaryl. In some embodiments, the heterocyclic or heteroaryl is attached via a nitrogen atom. In one embodiment, A is a substituted heterocyclic attached via a nitrogen atom. In one embodiment, A is an unsubstituted heterocyclic attached via a nitrogen atom. In one embodiment, A is a substituted heteroaryl attached via a nitrogen atom. In one embodiment, A is an unsubstituted heteroaryl attached via a nitrogen atom.

[0016] In one embodiment, A is a substituted or unsubstituted imidazole or benzimidazole (e.g., a substituted imidazole or benzimidazole). In some embodiments, the imidazole or benzimidazole is attached via a nitrogen atom.

[0017] In one embodiment, A is substituted or unsubstituted and

Chemical formula

[0018] In one embodiment, A is substituted or unsubstituted and

Chemical formula

[0019] In one embodiment, A is substituted or unsubstituted and

Chemical formula

[0020] In one embodiment, R 1is hydrogen, methyl, ethyl, or propyl (e.g., methyl). In one embodiment, R 1 is unsubstituted C 1-3 alkyl. In one embodiment, R 1 is substituted C 1~6 alkyl (e.g., haloalkyl or alkoxyalkyl, e.g., methoxymethyl). In one embodiment, R 2 , R 3a , R 4a or R 4b at least one of which is not hydrogen. For example, in one embodiment, R 2 , R 3a , R 4a or R 4b at least two of which are not hydrogen.

[0021] In one embodiment, R 2 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 carbocyclic, or -OR A2 wherein R A2 is hydrogen or substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclic. In one embodiment, R 2 is -OR A2 wherein R A2 is hydrogen or substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclic, e.g., hydroxyl or alkoxy.

[0022] In one embodiment, R 3a is -OR A3 wherein R A3 is hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclic, and R 3b is hydrogen; or R 3a and R 3b together form an oxo (=O) group. In one embodiment, R 3a is -OR A3 wherein R A3 is hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclic, for example hydroxyl or alkoxy.

[0023] In one embodiment, R 4a is substituted or unsubstituted C 1~6 alkyl, or -OR A4 wherein R A4 is hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclic, and R 4b is hydrogen or substituted or unsubstituted C 1~6 alkyl; or R 4a and R 4b together form an oxo (=O) group.

[0024] In one embodiment, the compound is of formula (I-a):

Chemical formula

[0025] In one embodiment, the compound is of formula (I-b):

Chemical formula

[0026] In one embodiment, the compound is of formula (I-c1) or (I-c2):

Chemical formula

[0027] In one embodiment, formula (I-c1):

Chemical formula

[0028] In one embodiment, A is a carbon-bonded (e.g., A is linked via a carbon atom) substituted or unsubstituted 5- or 6-membered heteroaryl, or 6-membered aryl.

[0029] In one embodiment, ring A is a substituted or unsubstituted nitrogen-containing heterocyclyl or nitrogen-containing heteroaryl. In one embodiment, A is bonded via nitrogen. In one embodiment, A is a monocyclic heteroaryl or heterocyclyl, such as a substituted monocyclic heteroaryl. In one embodiment, A is a bicyclic heteroaryl, such as a substituted bicyclic heteroaryl. Exemplary substituents are described herein.

[0030] In one embodiment, R 1 is hydrogen. In one embodiment, R 1 is a substituted or unsubstituted C 1~6 alkyl, such as methyl.

[0031] In one embodiment, at least one of R 2 , R 3a , R 4a or R 4b is not hydrogen. For example, in one embodiment, at least two of R 2 , R 3a , R 4a or R 4b are not hydrogen.

[0032] In one embodiment, R 2 is a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 2~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, a substituted or unsubstituted C 3~6 carbocyclyl, or -OR A2 , where R A2 is hydrogen or a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 2~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 3~6 carbocyclyl. In one embodiment, R 2 is -OR A2 , where R A2is hydrogen or a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 2~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 3~6 carbocyclic, such as hydroxyl or alkoxy.

[0033] In one embodiment, R 3a is -OR A3 wherein R A3 is hydrogen, a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 2~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 3~6 carbocyclic, and R 3b is hydrogen; or R 3a and R 3b together form an oxo (=O) group. In one embodiment, R 3a is -OR A3 wherein R A3 is hydrogen, a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 2~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 3~6 carbocyclic, such as hydroxyl or alkoxy.

[0034] In one embodiment, R 4a is a substituted or unsubstituted C 1~6 alkyl, or -OR A4 wherein R A4 is hydrogen, a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 2~6 alkenyl, a substituted or unsubstituted C 2~6 alkynyl, or a substituted or unsubstituted C 3~6 carbocyclic, and R 4b is hydrogen or a substituted or unsubstituted C1~6 is alkyl; or R 4a and R 4b together form an oxo (=O) group.

[0035] In one embodiment, the compound is of formula (II):

Chemical formula

[0036] In one embodiment, the compound is of formula (II-a1) or (II-a2):

Chemical formula

[0037] In one embodiment, E is a ring containing at least one nitrogen atom.

[0038] In one embodiment, A is a ring containing at least one nitrogen atom.

[0039] In one embodiment, E is

Chemical formula

[0040] In one embodiment, E is

Chemical formula

Chemical formula

[0041] In one embodiment, E is a ring containing at least two nitrogen atoms. In one embodiment, E is a ring containing at least two nitrogen atoms, and R 1 is a substituted or unsubstituted C 2~6 alkyl. In one embodiment, E is a ring containing at least two nitrogen atoms, and R 2 , R 3a , R 4a or R 4b is at least one of which is not hydrogen.

[0042] In one embodiment, E is a ring containing at least three nitrogen atoms. In one embodiment, E is a ring containing four nitrogen atoms.

[0043] In one embodiment, R 1 is a substituted or unsubstituted C 2~6 alkyl.

[0044] In one embodiment, R 2 , R 3a , R 4a or R 4b is at least one of which is not hydrogen.

[0045] In one embodiment, E is a ring containing two, three or four nitrogen atoms.

[0046] In one embodiment, E is a ring selected from pyrazole, triazole, tetrazole, indazole, benzotriazole, triazolopyridine, triazolopyrazine, pyrazolopyrazine.

[0047] In one embodiment, A is a 6-membered heterocyclyl ring (e.g., a 6-membered heterocyclyl ring containing at least two heteroatoms).

[0048] In one embodiment, A is a 5- to 6-membered heterocyclyl ring, and n is 1 or 2.

[0049] In one embodiment, E is morpholine and n is 1 or 2.

[0050] In one embodiment, R 1 is hydrogen or unsubstituted C 1~6 alkyl. In one embodiment, R 1 is or methyl. In one embodiment, R 1 is substituted or unsubstituted C 2~6 alkyl.

[0051] In one embodiment, R 2 is hydrogen, -OR A2 wherein R A2 is hydrogen, or substituted or unsubstituted C 1~6 alkyl (e.g., methyl, ethyl).

[0052] In one embodiment, R 3a is -OR A3 wherein R A3 is hydrogen, or substituted or unsubstituted C 1~6 alkyl (e.g., methyl).

[0053] In one embodiment, R 3a and R 3b together form an oxo (=O) group.

[0054] In one embodiment, R 4a is hydrogen, or substituted or unsubstituted C 1~6 alkyl (e.g., methyl).

[0055] In one embodiment, R 4b is hydrogen, or substituted or unsubstituted C 1~6 alkyl (e.g., methyl).

[0056] In one embodiment, R 4a is hydrogen and R 4b is substituted or unsubstituted C 1~6It is alkyl (for example, methyl).

[0057] In one embodiment, R 5 is hydrogen.

[0058] In one embodiment, n is 0.

[0059] In one embodiment, n is 1, and R 6 is substituted or unsubstituted C1 ~6 alkyl, C 1~6 haloalkyl, halogen (for example, -F, -Br, -Cl), cyano, -OR A6 , -C(=O)OR A6 , -SR B6 , -S(=O)R B6 or S(=O)2R B6 wherein R A6 is hydrogen or substituted or unsubstituted C 1~6 alkyl (for example, methyl, ethyl), C 1~6 haloalkyl (for example, -CF3), and R B6 is substituted or unsubstituted C 1~6 alkyl.

[0060] In one embodiment, n is 1, and R 6 is halogen (for example, -F, -Br, -Cl) or cyano. In one embodiment, n is 1, and R 6 is substituted or unsubstituted C 1~6 alkyl (for example, methyl). In one embodiment, n is 1, and R 6 is C 1~6 haloalkyl, -OR A6 or -C(=O)OR A6 wherein R A6 is hydrogen or substituted or unsubstituted C 1~6 alkyl (for example, methyl, ethyl), C 1~6 haloalkyl (for example, -CF3). In one embodiment, n is 1, and R 6 is SRB6 、 -S(=O)R B6 、 or S(=O)₂R B6 wherein R B6 is a substituted or unsubstituted C 1~6 alkyl (e.g., methyl).

[0061] In one embodiment, n is 2, and R 6 is independently a substituted or unsubstituted C 1~6 alkyl, C 1~6 haloalkyl, halogen (e.g., -F, -Br, -Cl), cyano, -OR A6 、 -C(=O)OR A6 、 -SR B6 、 -S(=O)R B6 、 or S(=O)₂R B6 selected from, wherein R A6 is hydrogen or a substituted or unsubstituted C 1~6 alkyl (e.g., methyl, ethyl), C 1~6 haloalkyl (e.g., -CF₃), and R B6 is a substituted or unsubstituted C 1~6 alkyl.

[0062] In one embodiment, n is 2, and R 6 is independently selected from halogen (e.g., -F, -Br, -Cl). In one embodiment, n is 2, and one of R 6 is fluorine.

[0063] In one embodiment, n is 0, and R 1 is a substituted or unsubstituted C 2~6 alkyl.

[0064] In one embodiment, R 1 is a substituted or unsubstituted C 1~6 alkyl, and at least one of R 2 、 R 3a 、 R 4a or R 4b is not hydrogen.

[0065] In one embodiment, the compound is a compound of formula (II-a1), and E is a heteroaryl ring containing at least 3 nitrogen atoms.

[0066] In one embodiment, the compound is

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[0067] In one aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable excipient is provided. composition is provided.

[0068] In one aspect, a method of inducing sedation and / or anesthesia in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0069] In one aspect, a method of administering to a subject in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition is provided, wherein the subject experiences sedation and / or anesthesia within 2 hours of administration.

[0070] In one embodiment, the subject experiences sedation and / or anesthesia within 1 hour of administration.

[0071] In one embodiment, the subject experiences immediate sedation and / or anesthesia.

[0072] In one embodiment, the compound is administered by intravenous administration.

[0073] In one embodiment, the compound is administered chronically.

[0074] In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.

[0075] In one embodiment, the compound is administered in combination with another therapeutic agent.

[0076] In one aspect, there is provided a method for treating seizures in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0077] In one aspect, there is provided a method for treating epilepsy or a condition or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the status epilepticus is a convulsive status epilepticus (e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus) or a non-convulsive status epilepticus (e.g., generalized status epilepticus, complex partial status epilepticus).

[0078] In one aspect, there is provided a method for treating a disorder associated with GABA function in a subject in need of treatment for a disorder associated with GABA function, the method comprising administering to the subject a therapeutically effective amount of one of the compounds of formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition.

[0079] In one aspect, there is provided a method for treating a CNS-related disorder in a subject in need of treatment for a CNS-related disorder, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, the CNS-related disorder is a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a spastic disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disorder, a substance use disorder and / or withdrawal syndrome, or tinnitus.

[0081] In one embodiment, the subject is a subject having Rett syndrome, Fragile X syndrome, or Angelman syndrome. In one embodiment, the CNS-related disorder is a sleep disorder, an eating disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a spastic disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disorder, a substance use disorder and / or withdrawal syndrome, or tinnitus. In one embodiment, the CNS-related disorder is depression (e.g., postpartum depression). In one embodiment, the CNS-related disorder is tremor (e.g., essential tremor). In one embodiment, the CNS-related disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, cachexia).

[0082] In one embodiment, the compound is administered orally. In one embodiment, the compound is administered intramuscularly.

[0083] In one aspect, there is provided a kit comprising a solid composition comprising a compound of formula (I) and a sterile diluent.

[0084] The present invention also provides a pharmaceutical composition comprising a compound of the present invention, as well as methods of use and treatment (e.g., for inducing sedation and / or anesthesia, for treating CNS-related disorders). The steroids of formula (I), their subgenera, and their pharmaceutically acceptable salts are collectively referred to herein as "the compounds of the invention".

[0085] In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the invention is provided in a prophylactically effective amount.

[0086] The compounds of the invention as described herein, in certain embodiments, act, for example, as GABA A modulators that act in a positive or negative manner on the GABA A receptor. Such compounds are expected to have CNS activity as regulators of the excitability of the central nervous system (CNS) as mediated by their ability to modulate the GABA

[0087] Accordingly, in another aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In certain embodiments, the CNS-related disorder is selected from the group consisting of sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disorders, substance use disorders and / or withdrawal syndromes, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0088] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following detailed description, examples, and claims.

[0089] Definition Chemical Definition The definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are specified according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside front cover), and specific functional groups are generally defined as described therein. Further, the general rules of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987. The compounds described herein may contain one or more asymmetric centers and thus may exist as various isomers, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers can be isolated from the mixture by methods known to those skilled in the art (including chiral high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), as well as the formation and crystallization of chiral salts); or the preferred isomers can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates

[0090] ​ 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, editor, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers and / or as mixtures of various isomers.

[0091] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, a compound of the "S" form is substantially free of the compound of the "R" form and thus has an "R" enantiomeric excess. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75 wt%, more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 91 wt%, more than 92 wt%, more than 93 wt%, more than 94 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, more than 98.5 wt%, more than 99 wt%, more than 99.2 wt%, more than 99.5 wt%, more than 99.6 wt%, more than 99.7 wt%, more than 99.8 wt% or more than 99.9 wt% enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0092] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound can contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition can contain, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound can contain, for example, about 90% excipient and about 10 % enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition can contain, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with a minor amount of excipient or carrier, or can be formulated without an excipient or carrier.

[0093] The compounds described herein can also contain one or more isotope substitutions. For example, H can be any isotopic form including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C can be any isotopic form including 12 C, 13 C, and 14 C; O can be any isotopic form including 16 O and 18 O; and so on.

[0094] The articles "a" and "an" can be used herein to refer to the grammatical object of the article being one or more (i.e., at least one). By way of example, "an analogue" means one analogue or more than one analogue.

[0095] When a range of values is recited, it is intended to include each value within that range and subranges thereof. For example, "C 1~6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 alkyl.

[0096] The following terms are intended to have the meanings presented below with respect thereto and are useful in understanding the specification and the intended scope of the invention.

[0097] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1~20 alkyl"). In some embodiments, the alkyl group has from 1 to 12 carbon atoms ("C 1~12 alkyl"). In some embodiments, the alkyl group has from 1 to 8 carbon atoms ("C 1~8 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C 1~6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C 1~5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C 1~4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C 1~3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C 1~2"alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl"). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1~10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1~10 alkyl and is such. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0098] "Alkenyl" refers to a radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds and no carbon-carbon triple bonds ("C 2~20 alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8"(alkenyl). In some embodiments, the alkenyl group has from 2 to 6 carbon atoms ("C 2~6 alkenyl). In some embodiments, the alkenyl group has from 2 to 5 carbon atoms ("C 2~5 alkenyl). In some embodiments, the alkenyl group has from 2 to 4 carbon atoms ("C 2~4 alkenyl). In some embodiments, the alkenyl group has from 2 to 3 carbon atoms ("C 2~3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. C 2~6 Examples of alkenyl groups include the above-described C 2~4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2~10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2~10 alkenyl.

[0099] "Alkynyl" refers to a radical of a straight-chain or branched-chain hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2~20refers to ") alkynyl". In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C 2~10 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2~8 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2~6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2~5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be present internally (e.g., 2-butynyl) or terminally (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. C 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 alkynyl groups, as well as pentynyl (C5), hexynyl (C6), etc. Further examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; e.g., 1 to 5 substituents, 1 to 3 substituents or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C 2~10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2~10 alkynyl.

[0100] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided in the aromatic ring system (「C 6~14 aryl」). In some embodiments, the aryl group has 6 ring carbon atoms (「C6 aryl」; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (「C 10 aryl」; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (「C 14 aryl」; e.g., anthracyl). "Aryl" also includes ring systems in which one or more aryl rings as defined above are condensed with one or more carbocyclic or heterocyclic groups, where the bonding radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms within the aryl ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of an aryl group is independently optionally substituted, i.e., unsubstituted (「unsubstituted aryl」) or substituted with one or more substituents (「substituted aryl」). In certain embodiments, the aryl group is unsubstituted C 6~14 aryl. In certain embodiments, the aryl group is substituted C 6~14 aryl.

[0101] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0102] Examples of representative substituted aryls include the following:

Chemical formula

[0103] Other representative aryl groups having a fused heterocyclyl group include the following:

Chemical formula

[0104] Unless otherwise stated, "halo" or "halogen" independently or as part of another substituent means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide" by itself or as part of another substituent means a fluoride, chloride, bromide, or iodide atom. In certain embodiments, the halo group is either fluorine or chlorine.

[0105] "Haloalkyl" and "haloalkoxy" can include alkyl and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups where halo is fluorine, respectively.

[0106] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. A heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, where the point of attachment is on the aryl ring or on the heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members within the fused (aryl / heteroaryl) ring system. For a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl).

[0107] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms provide an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms provide an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms provide an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl -yl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.

[0108] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0109] Examples of representative heteroaryls include the following formula: [Chemical Formula] are included, where each Y is carbonyl, N, NR65 , O and S; R 65 is independently hydrogen, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl.

[0110] "Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 carbocyclyl") and 0 heteroatoms in a non-aromatic ring system. In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl"). Exemplary C 3~6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3~8 carbocyclyl groups include the above-mentioned C 3~6 carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3~10 carbocyclyl groups include the above-mentioned C 3~8 carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10 ) cyclo decenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro [4.5] decanyl (C 10 ), etc., but are not limited thereto. When the foregoing examples are illustrated, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic") or includes a fused ring system, a bridged ring system or a spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclic")), and may be saturated or partially unsaturated. "Carbocyclic" also includes a ring system in which one or more aryl groups or heteroaryl groups are fused to a carbocyclic ring as defined above, where the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to refer to the number of carbons within the carbocyclic ring system. Unless otherwise specified, each occurrence of a carbocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclic") or substituted with one or more substituents ("substituted carbocyclic"). In certain embodiments, the carbocyclic group is unsubstituted C 3~10 carbocyclic. In certain embodiments, the carbocyclic group is substituted C 3~10 carbocyclic.

[0111] In some embodiments, "carbocyclic" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C 3~10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 cycloalkyl"). C 5~6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). C 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In certain embodiments, the cycloalkyl group is unsubstituted C 3~10 cycloalkyl. In certain embodiments, the cycloal kyl group is substituted C 3~10 cycloalkyl.

[0112] "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, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. The heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl") or a fused ring system, a bridged ring system, or a spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. The heterocyclyl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclic groups, where the point of attachment is on the carbocyclic or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl groups or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0113] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0114] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiirenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Two he Exemplary 6-membered heterocyclyl groups containing a heteroatom include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0115] Specific examples of the heterocyclyl group are shown in the following illustrative examples:

Chemical Structure

[0116] "Acyl" means -C(O)R 20 refers to a radical, 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 where R 20 is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 aryl), -C(O)-(CH2) t (5- to 10-membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) (t is an integer from 0 to 4 ), but are not limited thereto. In certain embodiments, R21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0117] "Acylamino" refers to a -NR 22 C(O)R 23 radical, where R 22 and the each presence of R23 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl as defined herein, or R 22 is an amino protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Specific exemplary "acylamino" groups are -NR 24 C(O)-C1-C8 alkyl, -NR 24 C(O)-(CH2) t (C6-C 10 aryl), -NR 24 C(O)-(CH2) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH2) t (C3-C 10 cycloalkyl) and -NR 24 C(O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4 and each R 24independently represents hydrogen or C1-C8 alkyl. In certain embodiments, R 25 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; R 26 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one of R 25 and R 26 is other than H.

[0118] "acyloxy" refers to a -OC(O)R 27 radical, where R 27 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certain embodiments, R 28 is C1-C8 alkyl substituted with halo or hydroxy; C3-C 10Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0119] "Alkoxy" refers to an -OR 29 group, where R 29 is substituted or un substituted 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. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0120] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2- and is a group having one or more substituents selected from the group consisting of, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t(5 to 10-membered heteroaryl), -O-(CH2) t (C3 to C 10 cycloalkyl) and -O-(CH2) t (4 to 10-membered heterocyclyl) are included, but not limited thereto, where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be unsubstituted C1 to C4 alkyl, halo, unsubstituted C1 to C4 alkoxy, unsubstituted C1 to C4 haloalkyl, unsubstituted C1 to C4 hydroxyalkyl or unsubstituted C1 to C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

[0121] "Amino" refers to the -NH2 radical.

[0122] "Substituted amino" refers to an amino group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, where at least one of R 38 is not hydrogen. In certain embodiments, each R 38 is independently hydrogen, C1 to C8 alkyl, C3 to C8 alkenyl, C3 to C8 alkynyl, C6 to C 10 aryl, 5 to 10-membered heteroaryl, 4 to 10-membered heterocyclyl or C3 to C 10 cycloalkyl; or C1 to C8 alkyl substituted with halo or hydroxy; C3 to C8 alkenyl substituted with halo or hydroxy; C3 to C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6 to C 10 aryl), -(CH2) t(5 to 10-membered heteroaryl), -(CH2) t (C3 to C 10 cycloalkyl) or -(CH2) t (4 to 10-membered heterocyclyl), where t is an integer from 0 to 8, each of which is unsubstituted C1 to C4 alkyl, halo, unsubstituted C1 to C4 alkoxy, unsubstituted C1 to C4 haloalkyl, unsubstituted C1 to C4 hydroxyalkyl or unsubstituted C1 to C4 haloalkoxy or hydroxy; or both R 38 groups are linked to form an alkylene group.

[0123] Exemplary "substituted amino" groups include -NR 39 -C1 to C8 alkyl, -NR 39 -(CH2) t (C6 to C 10 aryl), -NR 39 -(CH2) t (5 to 10-membered heteroaryl), -NR 39 -(CH2) t (C3 to C 10 cycloalkyl) and -NR 39 -(CH2) t (4 to 10-membered heterocyclyl), including but not limited to, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 is independently hydrogen or represents C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino or hydroxy; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. To avoid misunderstanding, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups as defined below. Substituted amino includes both mono-substituted amino groups and di-substituted amino groups.

[0124] "Azide" refers to the -N3 radical.

[0125] "Carbamoyl" or "amide" refers to the -C(O)NH2 radical.

[0126] "Substituted carbamoyl" or "substituted amide" refers to the -C(O)N(R 62 )2 radical, where each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, where at least one of R 62 is not hydrogen. In certain embodiments, R 62 is H, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl; or C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10Aryl, or a 5- to 10-membered heteroaryl, each of which is unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy substituted; provided that at least one R 62 is other than H.

[0127] "Carboxy" refers to the -C(O)OH radical.

[0128] "Cyano" refers to the -CN radical.

[0129] "Hydroxy" refers to the -OH radical.

[0130] "Nitro" refers to the -NO2 radical.

[0131] "Ethenyl" refers to substituted or unsubstituted -(C=C)-. "Ethylene" refers to substituted or unsubstituted -(C-C)-. "Ethynyl" refers to -(C≡C)-.

[0132] The "nitrogen-containing heterocyclyl" group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone and piperazone.

[0133] As defined herein, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted" means that, whether or not the term "optionally" precedes it, at least one hydrogen present on a given group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of that group, and when two or more positions in any given structure are substituted, those substituents may be the same or different at each position. The term "substituted" is intended to include substitution by all acceptable substituents of organic compounds, by any of the substituents described herein that form stable compounds. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent as described herein that satisfies the valence of the heteroatom and thus forms a stable moiety.

[0134] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb ), -N(R bb ), -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc, -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa )3, -OSi(R aa )3 - C(=S)N(R bb )2, -C(=O)SR aa , -C(=S)SR aa , -SC(=S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O)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 bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc )、C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclic, 3 - 14 membered heterocyclic, C 6~14 Aryl and 5 - 14 membered heteroaryl are included, but not limited thereto, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R aa each occurrence of which is independently selected from C 1~10 alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3 - 14 membered heterocyclic, C 6~14 aryl and 5 - 14 membered heteroaryl, or two R aa groups are linked to form a 3 - 14 membered heterocyclic or 5 - 14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, he Tetracyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R bb in each occurrence is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bb groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R cc in each occurrence is independently hydrogen, C 1~10 alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10Alkynyl, C 3~10 Carbocyclic, 3- to 14-membered heterocyclic, C 6~14 Selected from aryl and 5- to 14-membered heteroaryl, or two R cc Groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd Groups; R dd Each occurrence of which is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=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 ff C(=NR ff )N(R ff )2, -NR ff SO2Ree ,-SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3- to 10-membered heterocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, selected from, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; R ee each occurrence of which is independently selected from C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, C 6~10 aryl, 3- to 10-membered heterocyclic, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; R ff each occurrence of which is independently hydrogen, C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C2~6 alkynyl, C 3~10 carbocyclic, 3- to 10-membered heterocyclic, C 6~10 is selected from aryl and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups; Each occurrence of R gg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - 、-NH(C 1~6 alkyl)2 + X - 、-NH2(C 1~6 alkyl) + X - 、-NH3 + X - 、-N(OC 1~6 alkyl)(C 1~6 alkyl)、-N(OH)(C 1~6 alkyl)、-NH(OH)、-SH、-SC 1~6 alkyl、-SS(C 1~6 alkyl)、-C(=O)(C 1~6 alkyl)、-CO2H、-CO2(C 1~6 alkyl)、-OC(=O)(C 1~6 alkyl)、-OCO2(C 1~6 alkyl)、-C(=O)NH2、-C(=O)N(C 1~6 alkyl)2、-OC(=O)NH(C 1~6 alkyl)、-NHC(=O)(C 1~6 alkyl)、-N(C 1~6 alkyl)C(=O)(C 1~6 alkyl)、-NHCO2(C 1~6(alkyl), -NHC(=O)N(C 1~6 (alkyl)2, -NHC(=O)NH(C 1~6 (alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 (alkyl), -OC(=NH)(C 1~6 (alkyl), -OC(=NH)OC 1~6 alkyl, -C(=NH)N(C 1~6 (alkyl)2, -C(=NH)NH(C 1~6 (alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 (alkyl)2, -OC(NH)NH(C 1~6 (alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 (alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 (alkyl), -SO2N(C 1~6 (alkyl)2, -SO2NH(C 1~6 (alkyl), -SO2NH2, -SO2C 1~6 alkyl, -SO2OC 1~6 alkyl, -OSO2C 1~6 alkyl, -SOC 1~6 alkyl, -Si(C 1~6 (alkyl)3, -OSi(C 1~6 (alkyl)3-C(=S)N(C 1~6 (alkyl)2, C(=S)NH(C 1~6 (alkyl), C(=S)NH2, -C(=O)S(C 1~6 (alkyl), -C(=S)SC 1~6 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 carbocyclic, C 6~10Aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; wherein X - is a counterion.

[0135] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanolate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0136] When the valence allows, the nitrogen atom can be substituted or unsubstituted and can include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa, -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3 - to 14 - membered heterocyclic, C 6~14 aryl and 5 - to 14 - membered hetero aryl are included, but not limited to these, or two R cc groups bonded to the nitrogen atom are linked to form a 3 - to 14 - membered heterocyclic or 5 - to 14 - membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd are as defined above.

[0137] In certain embodiments, the substituent present on the nitrogen atom is an amino - protecting group (also referred to herein as a nitrogen - protecting group). Examples of amino - protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2ORcc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 alkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl, and 5- to 14-membered heteroaryl groups are included, but are not limited thereto, where each of alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and where R aa , R bb , R cc and R dd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0138] Exemplary amino protecting groups include amide groups (e.g., -C(=O)R aa )(including, but not limited to, formamide and acetamide); carbamate groups (e.g., -C(=O)OR aa )(including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz)); sulfonamide groups (e.g., -S(=O)2R aa )(including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM)), but are not limited thereto.

[0139] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Examples of oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, but are not limited thereto, where R aa , R bb , and R cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0140] Exemplary oxygen protecting groups include methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts), but are not limited thereto.

[0141] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Examples of sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2, but are not limited thereto, where R aa , R bb , and R cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0142] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. The present invention is not intended to be limited by the exemplary listing of substituents above in any way.

[0143] Other Definitions As used herein, the term "modulate" refers to the inhibition or potentiation of GABA receptor function. A "modulator" (e.g., a modulator compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of a GABA receptor.

[0144] "Pharmaceutically acceptable" means approved or approvable by a federal or state government regulatory agency, or corresponding agency of a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals (more specifically, humans).

[0145] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts and inorganic base addition salts or organic base addition salts. Specifically, such salts include: (1) those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, alkaline earth ion, or aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Examples of salts further include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic acids or inorganic acids, such as Examples include hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion for acidic functional groups. Such cations are exemplified by sodium cation, potassium cation, calcium cation, magnesium cation, ammonium cation, tetraalkylammonium cation, etc. See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0146] "Solvate" usually refers to the form of a compound associated with a solvent or water (also called "hydrate") by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, etc. The compounds of the present invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain examples, a solvate could be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both the solution phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0147] As used herein, the term "isotope variant" refers to a compound containing an unnatural proportion of isotopes in one or more of the atoms constituting such a compound. For example, an "isotope variant" of a compound can contain one or more non-radioactive isotopes, such as deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), etc. In such a compound with such isotope substitution, the following atoms can change if present, and as a result, for example, any hydrogen can be 2 H / D, any carbon can be 13 C, or any nitrogen can be 15It will be understood that it can be N, and the presence and arrangement of such atoms can be determined within the scope of the art. Similarly, the present invention may include, for example, the preparation of isotopic variants having radioisotopes in instances where the resulting compounds can be used for drug and / or substrate tissue distribution studies. Radioisotope tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose from the viewpoints of ease of incorporation and convenient detection means. Further, 11 C, 18 F, 15 O, and 13 N and other compounds substituted with positron-emitting isotopes can be prepared and will be useful in positron emission tomography (PET) studies for investigating substrate receptor occupancy. All isotopic variants of the compounds provided herein are intended to be encompassed within the scope of the present invention, whether radioactive or not.

[0148] "Stereoisomers": It should also be understood that compounds having the same molecular formula but differing in the nature of the atoms or the order of bonding or the arrangement of atoms in space are termed "isomers". Isomers that differ in the arrangement of atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of each other are termed "diastereomers", and those that are mirror images that cannot be superimposed on each other are termed "enantiomers". For example, if a compound has an asymmetric center, it is bonded to four different groups and a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are represented by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarization and are designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a "racemic mixture".

[0149] "Tautomers" refer to compounds with a specific compound structure in interchangeable forms, and compounds in which the displacement of hydrogen atoms and electrons fluctuates. Therefore, the two structures can be in equilibrium by the movement of π electrons and atoms (usually H). For example, enol and ketone are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or a base. Tautomers can be related to obtaining the optimal chemical reactivity and biological activity of the target compound.

[0150] "Subjects" for which administration is contemplated include humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or elderly adults)) and / or non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats and / or dogs), but are not limited thereto. 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.

[0151] Disease, disorder, and condition are used interchangeably herein.

[0152] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" are contemplated to be acts (a "therapeutic treatment") that are performed while a subject is suffering from a particular disease, disorder or condition and that reduce the severity of, or delay or slow the progression of, the disease, disorder or condition, and also acts (a "preventive treatment") that are performed before a subject begins to suffer from a particular disease, disorder or condition.

[0153] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, e.g., for treating CNS related disorders, and is sufficient to induce anesthesia or sedation. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. The effective amount encompasses both therapeutic and prophylactic treatments.

[0154] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with that disease, disorder or condition. A therapeutically effective amount of a compound means the amount of a therapeutic agent that provides a therapeutic benefit in the treatment of that disease, disorder or condition, either alone or in combination with other treatments. The term "therapeutically effective amount" can encompass an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0155] As used herein, 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 that disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means the amount of a therapeutic agent that provides a prophylactic benefit in the prevention of that disease, disorder or condition, either alone or in combination with other agents. The term "prophylactically effective amount" can encompass an amount that improves the overall prevention, or enhances the prophylactic efficacy of another prophylactic agent.

Mode for Carrying Out the Invention

[0156] Detailed Description of Specific Embodiments of the Present Invention As generally described herein, the present invention, for example, acts as a GABA modulator Provided are C21-substituted neurostimulatory steroids designed to be used. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for inducing anesthesia and / or sedation in a subject. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders.

[0157] Compound In one aspect, a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0158] In one aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2) and a pharmaceutically acceptable excipient.

[0159] In one aspect, there is provided a method of inducing sedation and / or anesthesia in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2), or a pharmaceutically acceptable salt thereof.

[0160] In one aspect, there is provided a method of administering to a subject in need thereof an effective amount of a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2)), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound, wherein the subject experiences sedation and / or anesthesia within 2 hours of administration.

[0161] In some embodiments, the subject experiences sedation and / or anesthesia within 1 hour of administration.

[0162] In some embodiments, the subject experiences sedation and / or anesthesia immediately.

[0163] In some embodiments, the compound is administered by intravenous administration.

[0164] In some embodiments, the compound is administered chronically.

[0165] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0166] In some embodiments, the compound is administered in combination with another therapeutic agent.

[0167] In one aspect, there is provided a method for treating seizures in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2), or a pharmaceutically acceptable salt thereof.

[0168] In one aspect, there is provided a method for treating epilepsy or a condition or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2)), or a pharmaceutically acceptable salt thereof.

[0169] In one aspect, in a subject in need of treatment of a disorder associated with GABA function There is provided a method for treating a disorder associated with GABA function, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2)), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of the compounds.

[0170] In one aspect, there is provided a method for treating a CNS-related disorder in a subject in need of treatment for a CNS-related disorder, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2)), or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disorder, a substance use disorder and / or withdrawal syndrome, or tinnitus. In some embodiments, the subject is a subject having Rett syndrome, fragile X syndrome, or Angelman syndrome.

[0171] In one aspect, there is provided a kit comprising a solid composition comprising a compound described herein (e.g., a compound of formula (I), (Ia), (Ib), (Ic-1), (Ic-2), (II), (II-a1), or (II-a2)) and a sterile diluent. Pharmaceutical composition

[0172] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0173] The pharmaceutical compositions provided herein can be administered by various routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration (e.g., nasal spray).

[0174] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by the physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0175] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered at the dosage levels described above to subjects at risk of developing the condition, by and under the advice of a physician. Subjects at risk of developing a particular condition generally include those subjects having a family history of the condition, or those subjects identified by genetic testing or screening as being particularly susceptible to the development of the condition.

[0176] The pharmaceutical compositions provided herein are also administered chronically (“chronic administration”). Chronic administration refers to the administration of a compound or its pharmaceutical composition over a long period of time, for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely over the remaining period of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound, for example, within the therapeutic concentration range, in the blood over a long period of time. window)

[0177] The pharmaceutical composition of the present invention can further be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be administered as a bolus, for example, for the purpose of raising the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the active ingredient throughout the body. For example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV infusion) allows for a more rapid delivery, which rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide maintenance of a steady-state concentration of the active ingredient within the subject's body. Further, in still other embodiments, the pharmaceutical composition can be administered first as a bolus dose and then a continuous infusion can be carried out.

[0178] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, the compositions are provided in unit dosage forms that facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), and the remainder are various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0179] In the case of oral administration, oral administration 1 to 5 times a day, particularly 2 to 4 times, typically 3 times, is a representative regimen. When using these dosing patterns, each dose results in a compound provided herein of about 0.01 to about 20 mg / kg, and preferred doses each result in about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0180] Transdermal doses are generally selected to be similar to or provide lower blood levels than the levels achieved using injection doses and are generally in an amount in the range of about 0.01 wt% to about 20 wt%, preferably about 0.1 wt% to about 20 wt%, preferably about 0.1 wt% to about 10 wt%, and more preferably about 0.5 wt% to about 15 wt%.

[0181] Dosing levels for injections range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour and all are over about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve an appropriate steady state level. The maximum total dose is not expected to exceed about 5 g / day for a 40 - 80 kg human patient.

[0182] Liquid forms suitable for oral administration may contain a suitable aqueous or non - aqueous vehicle including buffers, suspending and dispensing agents, coloring agents, flavoring agents, etc. Solid forms may contain, for example, any of the following components or compounds of similar nature: binders (e.g., microcrystalline cellulose, tragacanth gum or gelatin); excipients (e.g., starch or lactose), disintegrants (e.g., alginic acid, Primogel or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate or orange flavor).

[0183] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As is conventional, the active compounds in such compositions are typically minor components, often in an amount of about 0.05 to 10% by weight, and the remainder is, for example, an injectable excipient.

[0184] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically admixed with a paraffin ointment base or a water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional components that enhance the skin penetration or stability of the active ingredient or the formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0185] The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be achieved using a reservoir-type or porous membrane-type or solid matrix type patch.

[0186] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials and processing techniques, etc., are shown in Remington’s Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8 (incorporated herein by reference).

[0187] The compounds of the present invention can also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0188] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0189] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient (e.g., a composition suitable for injection such as intravenous (IV) administration).

[0190] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersing aids or suspending aids, surfactants, isotonic agents, preservatives, lubricants, etc. that are suitable for the desired specific dosage form, e.g., suitable for injection. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington’s Pharmaceutical Sciences, 16th edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005).

[0191] For example, injectable preparations, such as sterile aqueous suspensions for injection, can be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile physiological saline or phosphate buffered saline, or Ringer's solution. are mentioned.

[0192] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrin, each consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, which may optionally contain one or more substituents on the sugar moieties to be linked, including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises heptapropyl-β-cyclodextrin. In a more specific embodiment, the composition comprises heptapropyl-β-cyclodextrin (10-50% in water).

[0193] Injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injectable medium prior to use.

[0194] In general, the compounds provided herein are administered in an effective amount. The actual amount of the compound administered will typically be determined by the physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, etc.

[0195] The composition is provided in unit dosage forms that facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid 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), and the remainder are various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0196] The compounds provided herein can be administered as a single active agent or in combination with other active agents. In one aspect, the invention provides combinations of the compounds of the invention with another pharmacologically active agent. Administration in combination can proceed by any technique that is apparent to one of ordinary skill in the art, such as separate administration, sequential administration, simultaneous administration, and alternating administration.

[0197] The description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, but one of ordinary skill in the art will understand that such compositions are generally suitable for administration to all kinds of animals. Modifications to render pharmaceutical compositions suitable for administration to humans suitable for administration to various animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or implement such modifications by routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st Edition, Lippincott Williams & Wilkins, 2005. Methods of Use and Treatment

[0198] As generally described herein, the invention acts, for example, as a GABA modulator Relates to C21-substituted neurostimulatory steroids designed to be kuyo. In certain embodiments, such compounds are predicted to be useful as therapeutic agents for inducing anesthesia and / or sedation in a subject. In some embodiments, such compounds are CNS-related disorders (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, spasm disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance use disorders and / or withdrawal syndromes, or tinnitus) in a subject in need thereof (e.g., a subject having Rett syndrome, fragile X syndrome, or Angelman syndrome). It is contemplated to be useful as a therapeutic agent for treating

[0199] Accordingly, in one aspect, the present invention provides a method for inducing anesthesia and / or sedation in a subject, the method comprising administering to the subject an effective amount of a compound or composition of the present invention. In certain embodiments, the compound is administered by intravenous administration.

[0200] Previous studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) have demonstrated that certain 3α-hydroxylated steroids are more potent by orders of magnitude than those reported by others (see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)) as regulators of the GABA receptor complex (GRC). Majewska et al. and Harrison et al. taught that 3α-hydroxylated-5-reduced steroids have only a rather low level of efficacy. Experimental data in vitro and in vivo have demonstrated that these high-titer steroids are therapeutically useful in the regulation of brain excitability via the GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(l):65-71 (1995)).

[0201] A variety of synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Patent No. 5,232,917 (which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders and mood disorders (e.g., depression) that are susceptible to agents effective against GRC in a therapeutically beneficial manner). Further, although these steroids have previously been shown to interact at unique sites on GRC that are different from other known interaction sites (e.g., barbiturates, benzodiazepines and GABA), therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizure disorders have also been previously induced (see, for example, Gee, K.W. and Yamamura, H.I., "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders", Central Nervous System Disorders, Horvell editor, Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K.G. and Morselli, P.L., "Psychopharmacology of GABAergic Drugs", Psychopharmacology: The Third Generation of Progress, H.Y. Meltzer editor, Raven Press, N.Y. (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency and oral activity (in addition to other dosage forms).

[0202] The compounds of the invention as described herein are generally designed to modulate GABA function and thus act as neuroactive steroids for the treatment and prevention of CNS-related conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as a treatment for the prevention and / or treatment of CNS disorders in mammals, including humans and non-human mammals. Accordingly, as described above, the present invention includes within its scope and extends to the recited methods of treatment, as well as compounds for such methods, and the use of such compounds for preparing medicaments useful for such methods.

[0203] Exemplary CNS conditions associated with GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression, mood-cycling disorders (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewy body type dementia, vascular dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorder (ASD) [e.g., autism, single-host causes of autism such as synaptophathy (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 use disorders and / or withdrawal syndromes [e.g., addiction to opiates, cocaine, and / or alcohol], and tinnitus, but are not limited thereto.

[0204] In yet another aspect, combinations of the compounds of the invention with other pharmacologically active agents are provided. The compounds provided herein can be administered as a single active agent or in combination with other agents. Administration in combination can proceed by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration).

[0205] In another aspect, there is provided a method of treating or preventing a condition associated with brain excitation in a subject who is susceptible to or suffering from a condition associated with brain excitation, the method comprising administering to the subject an effective amount of a compound of the present invention.

[0206] In yet another aspect, there is provided a method of treating or preventing stress or anxiety in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound or composition of the present invention.

[0207] In yet another aspect, there is provided a method of reducing or preventing seizure activity in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

[0208] In yet another aspect, there is provided a method of reducing or preventing insomnia in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound or composition of the present invention.

[0209] In yet another aspect, there is provided a method of inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, the method comprising administering an effective amount of a compound of the present invention.

[0210] In yet another aspect, there is provided a method of reducing or preventing PMS or PND in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

[0211] In yet another aspect, there is provided a method of treating or preventing mood disorders in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments, the mood disorder is depression.

[0212] In yet another aspect, a method of inducing anesthesia in a subject is provided, the method comprising administering to the subject an effective amount of a compound of the invention.

[0213] In yet another aspect, a method of treating cognitive enhancement or memory impairment is provided by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0214] In yet another aspect, a method of treating attention disorder is provided by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0215] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0216] Neurodegenerative diseases and disorders The compounds described herein can be used in the methods described herein for the treatment of disorders described herein, such as neurodegenerative diseases.

[0217] The term "neurodegenerative disease" encompasses diseases and disorders associated with the progressive loss of the structure or function of neurons, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and spasticity (including for treatment and prevention, and for prevention of seizures caused by schizophrenia or drugs used to treat schizophrenia); benign forgetfulness; cerebral edema; cerebellar ataxia (such as McLeod neuroacanthocytosis syndrome (MLS)); closed head injury; coma; injury due to contusion (e.g., spinal cord injury and head injury); dementia (such as multi-infarct dementia and senile dementia); disturbance of consciousness; Down syndrome; drug-induced or agent-induced parkinsonism (e.g., acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia induced by antipsychotics, neuroleptic malignant syndrome, or agent-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head injury); hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; dyskinesia induced by levodopa; mental retardation; movement disorders including akinesia and akinetic (rigid) syndromes (such as brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); disorders related to muscle spasm and muscle spasticity or weakness (such as chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham chorea, and syndrome Huntington's disease, dystonia (e.g., myoclonus dystonia), dyskinesia (including tics such as simple tics, complex tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal myoclonus (cyloclonus)), tremors (e.g., resting tremors, postural tremors, and intention tremors), and ataxia (including axial ataxia, dystonic writer's cramp, hemiplegic ataxia, episodic ataxia, and focal ataxia (e.g., blepharospasm, oromandibular dystonia, spastic dysphonia, and torticollis)); neuronal damage (including eye damage, retinopathy, or macular degeneration of the eye); stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxic disorders after cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tubulosclerosis, and neurodegeneration induced by viral infections (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and brain disorders), but not limited to these. Neurodegenerative diseases also include, but are not limited to, stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxic disorders after cardiac arrest. Methods of treating or preventing neurodegenerative diseases also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorders.

[0218] Mood disorders The compounds described herein can be used in the methods described herein for the treatment of disorders described herein, such as mood disorders.

[0219] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by persistent and pervasive low mood accompanied by low self-esteem and usually loss of interest or pleasure in normally enjoyable activities. People with clinical depression have sleep disturbances, weight loss, and generally feel agitation and nervousness. Clinical depression affects the way an individual feels, thinks, and behaves, and can cause various emotional and physical problems. Individuals with clinical depression may have difficulty performing their daily activities and may feel a lack of purpose in life.

[0220] Postpartum depression (PND), also referred to as postnatal depression (PPD), refers to one type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and nervousness. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0221] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD may also have excessive sleep or drowsiness (hypersomnia), heaviness in the limbs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0222] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, unresponsiveness to pleasurable stimuli, a mood that is more depressed than sad or bereaved, excessive weight loss, or excessive guilt.

[0223] Psychotic major depression (PMD) or psychotic depression refers to a particularly melancholic major depressive episode in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0224] Catatonic depression refers to major depression accompanied by motor behavioral disorders and other symptoms. An individual may become mute and comatose, and be bedridden or exhibit meaningless or strange behaviors.

[0225] Seasonal affective disorder (SAD) refers to one type of seasonal depression in which an individual has a seasonal pattern of depressive episodes occurring in the fall or winter.

[0226] Mood swings refer to symptoms associated with unipolar depression in which the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e.g., at least two years).

[0227] Double depression refers to a fairly depressed mood (mood swings) that lasts at least two years and is interrupted by periods of major depression.

[0228] Dysthymic personality disorder (DPD) refers to a personality disorder with depressive characteristics.

[0229] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes approximately once a month, each episode lasting two weeks or less and typically less than two to three days.

[0230] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0231] Bipolar disorder, also known as manic-depressive illness, causes extreme mood swings that include episodes of elevated mood (mania or hypomania) and depression. During a manic episode, an individual may feel or act abnormally happy, energetic, or irritable. They often make rash decisions without much consideration of the consequences. Usually, the need for sleep decreases. During a depressive episode, a person may cry, avoid eye contact with others, and develop a negative outlook on life. The risk of suicide in people with this disorder is high, over 6% over a period of 20 years or more, while self-harm occurs in 30 - 40%. Other mental health problems such as anxiety disorders and substance use disorders are commonly associated with bipolar disorder.

[0232] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, or chronic stress.

[0233] Treatment-resistant depression refers to symptoms in which an individual is being treated for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not relieve the depressive symptoms in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression may experience symptom improvement but then relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, as well as dual and triple uptake inhibitors and / or anxiolytics), and non-pharmacological treatments (such as psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0234] Suicide, suicidal thoughts, and suicidal acts refer to the tendency of an individual to commit suicide. Suicidal thoughts relate to thoughts of or abnormal preoccupation with suicide. The scope of suicidal thoughts can vary widely, for example, from momentary thoughts to extensive thoughts, detailed planning, role-playing, and incomplete attempts. Symptoms include conversations about suicide, acquisition of means of suicide, withdrawal from social contact, preoccupation with death, being caught up in emotions or despair about the situation, increased use of alcohol or drugs, risky or self-destructive behavior, and farewells as if one will never meet again.

[0235] Premenstrual dysphoric disorder (PMDD) refers to a severe exacerbation of premenstrual syndrome (PMS) that results in a disorder. PMDD typically causes extreme mood shifts that begin 7 - 10 days before the onset of a woman's period and continue for the first few days of the woman's period. Symptoms include sadness or despair, anxiety or tension, extreme irritability, and marked hypersensitivity or anger.

[0236] Symptoms of depression include persistent anxiety or feelings of sadness, weakness, despair, pessimism, worthlessness, lack of energy, restlessness, hypersensitivity, fatigue, loss of interest in enjoyable activities or hobbies, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicidal attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. The symptoms of depression, and their alleviation, can be confirmed by a physician or psychologist (e.g., by a mental state examination).

[0237] Anxiety disorder The compounds described herein can be used in the methods described herein for the treatment of disorders described herein, such as anxiety disorders.

[0238] Anxiety disorder is a general term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0239] Generalized anxiety disorder is a common chronic disorder characterized by persistent anxiety that cannot be focused on any one object or situation. People suffering from generalized anxiety experience nonspecific, persistent fears and worries and tend to worry excessively about ordinary situations. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0240] In panic disorder, a person suffers from intense fear and short-lived attacks of unease, often characterized by trembling, shaking, disorientation, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as sudden, reaching a peak in less than 10 minutes, fear or discomfort) can last for several hours and can be triggered by stress, fear, or even exercise, although the specific cause is not always clear. In addition to recurrent, unpredictable panic attacks, a diagnosis of panic disorder also requires that the attacks have chronic consequences (either worry about the potential meaning of the attack, persistent fear of future attacks, or significant changes in behavior related to the attack). Thus, patients with panic disorder experience symptoms even outside the scope of a particular panic episode. Often, normal changes in heart rate are noticed by people suffering from panic, leading them to think that something is wrong with their heart or that they are having another panic attack. In some cases, heightened awareness of bodily functions (hypervigilance) occurs during a panic attack, in which case any perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., hypochondria).

[0241] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder, mainly characterized by repetitive obsessive thoughts (intrusive, persistent, and unwanted thoughts or images) and compulsive behaviors (the urge to perform specific actions or rituals). OCD thought patterns can be associated with superstition insofar as the person believes in causal relationships that do not actually exist in reality. Often, the process is completely illogical. For example, the compulsive behavior of walking in a particular pattern can be used to relieve the obsessive thought of an impending danger. And in many cases, this compulsive behavior is not completely inexplicable, but simply the urge to complete a ritual induced by nervousness. In a minority of cases, OCD patients may only experience obsessive thoughts without obvious compulsive behaviors, and an even smaller number of patients may only experience compulsive behaviors.

[0242] One of the largest categories of anxiety disorders is phobias, which encompasses all cases in which fear and anxiety are triggered by specific stimuli or situations. Patients typically anticipate terrifying consequences from encountering the object of their fear, which can range from animals, places, to something related to body fluids.

[0243] Post-traumatic stress disorder (PTSD) is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can arise from extreme situations (such as war, rape, hostage situations, or even major disasters). It can also result from long-term (chronic) exposure to severe stressors (such as soldiers who can endure individual battles but cannot cope well with continuous warfare). Common symptoms include flashbacks, avoidance behaviors, and depression. Eating disorders

[0244] The compounds described herein can be used in the methods described herein, for example, in the treatment of disorders described herein such as eating disorders. Eating disorders are characterized by disorders of eating behavior and weight regulation and are associated with a wide range of harmful psychological, physical, and social consequences. Individuals with eating disorders begin to eat less or more food, but at some point, the urge to eat becomes uncontrollable and cycles down or up. Eating disorders can be characterized by severe distress or concern about weight or body size, or extreme efforts to control weight or food intake. Examples of eating disorders include anorexia nervosa, bulimia nervosa, binge eating disorder, cachexia, and their variants.

[0245] Individuals with anorexia nervosa typically consider themselves overweight even when underweight. Individuals with anorexia nervosa can become preoccupied with eating, food, and weight management. Individuals with anorexia nervosa typically weigh themselves repeatedly, portion their food carefully, and eat only very small amounts of certain foods. Individuals with anorexia nervosa may engage in binge eating followed by extreme dietary restriction, excessive exercise, self-induced vomiting, or abuse of laxatives, diuretics, or enemas. Symptoms include extreme low weight, strict food restriction, obsessive pursuit of thinness, and negativity about maintaining a normal or healthy weight, strong fear of weight gain, distorted body image, and self-esteem that is strongly influenced by perception of weight and body size, or denial of the severity of low weight, absence of menstruation among adolescent girls and women. Other symptoms include thinning of the bones, brittle hair and nails, yellowish dry skin, growth of fine body hair all over, mild anemia, muscle wasting, and weakness, severe constipation, low blood pressure or slow respiration and pulse, damage to the structure and function of the heart, brain damage, multiple organ failure, decreased body temperature, lethargy, fatigue, and infertility.

[0246] Individuals with bulimia nervosa typically have recurrent and frequent episodes of eating abnormally large amounts of food and feel a lack of control over these episodes. After such overeating, compensatory behaviors, such as forced vomiting, excessive use of laxatives or diuretics, fasting, excessive exercise, or combinations of these behaviors occur.

[0247] Unlike anorexia nervosa, people with bulimia nervosa usually maintain what is considered a healthy or normal weight, although some are slightly overweight. However, like people with anorexia nervosa, they typically fear weight gain, strongly desire weight loss, and are dissatisfied with their body size and shape. Usually, the binge-eating behavior is done secretly because it is often accompanied by feelings of revulsion or shame. The bingeing and purging cycles can occur anywhere from several times a week to several times a day. Other symptoms include a chronically inflamed and sore throat, swelling of the salivary glands in the neck and jaw area, erosion of tooth enamel, and teeth that become increasingly sensitive and decay as a result of exposure to stomach acid, acid reflux disorders, and other gastrointestinal problems , pain and irritation of the intestines due to laxative abuse, severe dehydration due to fluid purging, and electrolyte imbalances (which can lead to heart attacks or strokes).

[0248] Individuals with binge-eating disorder lose control over their eating. Unlike bulimia nervosa, compensatory behaviors, such as purging, excessive exercise, or fasting, do not occur after the binge-eating period. Individuals with binge-eating disorder are often overweight or obese. Obese individuals with binge-eating disorder are at high risk of developing cardiovascular disease and high blood pressure. They also experience guilt, shame, and distress about their binge-eating, which can lead to further binge-eating.

[0249] Cachexia is also known as "wasting disorder" and is an eating-related problem experienced by many cancer patients. Individuals with cachexia may be able to continue eating normally, but their bodies may reject the utilization of the vitamins and nutrients they consume, or they may lose their appetite and stop eating. When an individual experiences loss of appetite and stops eating, they may be considered to have developed anorexia nervosa.

[0250] Epilepsy The compounds described herein can be used in the methods described herein for the treatment of disorders described herein such as epilepsy, status epilepticus, or seizures as described in, for example, International Publication No. WO 2013 / 112605 and International Publication No. WO 2014 / 031792, the contents of which are hereby incorporated by reference in their entirety.

[0251] Epilepsy is a brain disorder characterized by recurrent seizures over a long period of time. Types of epilepsy can include, but are not limited to, generalized epilepsy such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy such as temporal lobe epilepsy, frontal lobe epilepsy, childhood benign focal epilepsy. Status epilepticus (SE)

[0252] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as 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 epilepticus seizures and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-line therapy, and second-line therapy is performed. Refractory status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-line and second-line therapies, and general anesthetics are commonly administered. Super-refractory status epilepticus is characterized by status epilepticus seizures that persist despite first-line therapy, second-line therapy, and treatment with general anesthetics for more than 24 hours.

[0253] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0254] The compositions described herein can also be administered as a prophylaxis to a subject having a CNS disorder, such as traumatic brain injury, status epilepticus, such as convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges, prior to the onset of seizures. seizure

[0255] A seizure is a behavioral or physical finding or change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion". A convulsion is when a human body shakes rapidly and uncontrollably. During a convulsion, the muscles of that human repeat contraction and relaxation.

[0256] Based on the type of behavior and brain activity, seizures are divided into two broad categories, namely, generalized and partial (also called focal or local). Classifying the type of seizure helps a physician diagnose whether a patient has epilepsy.

[0257] Generalized seizures are caused by electrical impulses from the whole brain, while partial seizures are caused by (at least initially) electrical impulses from a relatively small part of the brain. The part of the brain that causes a seizure is sometimes called a lesion.

[0258] There are six types of generalized seizures. The most common and dramatic, and thus the most well-known, is the generalized convulsion (also called the grand mal). In this type of seizure, the patient loses consciousness and usually collapses. After this loss of consciousness, a general body stiffening (referred to as the "tonic" phase of the seizure) occurs for 30 to 60 seconds, followed by intense contractions (the "clonic" phase) for 30 to 60 seconds, after which the patient falls into a deep sleep (the "postictal" or after-seizure phase). During a grand mal seizure, injuries and accidents (such as biting the tongue and urinary incontinence) can occur.

[0259] Absence seizures cause a short loss of consciousness (only a few seconds) with little or no symptoms. The patient (most frequently a child) typically interrupts activity and stares blankly. These seizures start and end suddenly and can occur several times a day. The patient usually is not aware of having a seizure, except perhaps when they can "lose time."

[0260] Myoclonic seizures usually consist of sporadic contractions on both sides of the body. Patients sometimes describe these contractions as short electrical shocks. When severe, these seizures can result in dropping objects or involuntary throwing.

[0261] Clonic seizures are repetitive rhythmic contractions involving both sides of the body simultaneously.

[0262] Tonic seizures are characterized by muscle stiffening.

[0263] Atonic seizures consist of a sudden decrease in overall muscle tone (especially in the arms and legs), often resulting in a fall.

[0264] The seizures described herein are epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; seizures without interruption; persistent seizures; recurrent seizures; status epilepticus, for example, refractory convulsive status epilepticus, non-convulsive status epilepticus; refractory seizures; myoclonic seizures It can include seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; laughing seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or dissociative seizures.

[0265] Tremor The compounds described herein can be used in the methods described herein for the treatment of disorders described herein, such as tremor.

[0266] Tremor is an involuntary and sometimes rhythmic contraction and relaxation of muscles, with contraction and relaxation that may be accompanied by vibration or single contractions of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, torso, feet).

[0267] Cerebellar tremor or intention tremor is a slow and extensive tremor of the limbs that occurs after an intentional movement. Cerebellar tremor is caused by, for example, cerebellar lesions or cerebellar injury due to tumors, stroke, diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0268] Dystonic tremor occurs in individuals affected by dystonia (a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions). Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and can often be reduced by complete rest.

[0269] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be in part mild and non - progressive, and can start on one side of the body and be slowly progressive, but can affect both sides within 3 years. The hands are most frequently affected, but the head, voice, tongue, feet, and trunk can also be involved. The frequency of the tremor can decrease with a person's age, but the severity can increase. Emotional arousal, stress, fever, physical fatigue, or hypoglycemia can induce the tremor and / or increase its severity.

[0270] Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. Muscle cramps are felt in the thighs and legs, and patients may sway uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0271] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill - rolling" movement of the hand, and can also affect the jaw, lips, legs, and trunk. The onset of Parkinsonian tremor typically begins after the age of 60. The movement starts on one limb or one side of the body and can progress to include the opposite side.

[0272] Physiological tremor occurs in normal individuals and is not clinically particularly important. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions (including hyperthyroidism and hypoglycemia). The tremor classically has a frequency of about 10 Hz.

[0273] Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movements. Patients with psychogenic tremor may have a conversion disorder or another mental illness.

[0274] Truncal ataxia (rubral tremor) is characterized by slow, coarse tremors that may be present at rest, during posture, and with intention. This tremor is associated with conditions (classical and atypical strokes) that affect the red nucleus of the midbrain.

[0275] Anesthesia / Sedation The compounds described herein can be used in the methods described herein, for example, to induce anesthesia or sedation. Anesthesia is a pharmacologically induced reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects alone, or sometimes from a combination of drugs (e.g., hypnotics, sedatives, paralytic agents, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgical and other procedures without experiencing the difficulties and pain they would experience without anesthesia.

[0276] Sedation is generally a decrease in nervousness or agitation by the administration of a pharmacological agent to facilitate a medical or diagnostic procedure. Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiety relief) to general anesthesia.

[0277] Minimal sedation, also known as anxiety relief, is a drug-induced state in which patients respond normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are typically unaffected.

[0278] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness in which patients respond purposefully to verbal commands, either alone or accompanied by light tactile stimulation. Usually, intervention to maintain the patient's airway is not required. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.

[0279] Deep sedation / analgesia is a drug-induced decrease in consciousness in which the patient cannot be easily awakened but will respond purposefully (not by reflex withdrawal from a painful stimulus) after repeated or painful stimuli. Since independent eflon yla function may be impaired, this patient may require assistance to maintain the patient's airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

[0280] General anesthesia is a drug-induced loss of consciousness in which the patient is not even arousable to painful stimuli. Since the ability to maintain independent eflon yla function is often impaired, assistance to maintain the patient's airway is often required. Positive pressure ventilation may be needed due to decreased spontaneous ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.

[0281] Sedation in the intensive care unit (ICU) allows for a decrease in consciousness towards the patient's environment and a decrease in response to external stimuli. This can play a role in the treatment of patients with critical illnesses and encompasses a wide range of symptom control that varies from patient to patient and from individual to individual over the entire course of the patient's illness. Heavy sedation in intensive care is used to facilitate the tolerance of the endotracheal tube and synchronization of the ventilator (often with neuromuscular blocking agents).

[0282] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced in the ICU and maintained over an extended period (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks weeks, 3 weeks, 1 month, 2 months). Long-acting sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0283] Sedation and analgesia during procedures (also referred to as conscious sedation) is a technique of administering sedatives or dissociative agents, with or without analgesics, to enable a subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function. Equivalents and Scope

[0284] In the claims, the articles (e.g., "a", "an", and "the") can mean one or more than one unless the contrary is indicated or is not apparent from the context. Unless the contrary is indicated or is not apparent from the context, a claim or description that includes "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or process.

[0285] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the recited claims are introduced into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations found in any other claim that depends on the same base claim. If an element is presented as a list, for example, in the form of a Markush group, each subgroup of that element is also disclosed, and any element may be removed from that group. Generally, when the present invention or an aspect of the present invention is referred to as including a particular element and / or feature, a particular embodiment of the present invention or aspect thereof should be understood to consist of or consist essentially of such element and / or feature. For simplicity purposes, those embodiments are not explicitly shown herein in such words. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow the inclusion of further elements or steps. When a range is given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values expressed as a range may assume any specific value or sub-range within the range described in various embodiments of the present invention to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0286] This application refers to various issued patents, published patent applications, academic papers, and other publications (all of which are incorporated herein by reference). In the event of a conflict between any of the incorporated references and this specification, this specification shall govern. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments are considered to be known to one of ordinary skill in the art and may be excluded even if such exclusion is not explicitly shown herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, regardless of whether it relates to the existence of the prior art.

[0287] One of ordinary skill in the art will recognize or be able to ascertain many equivalents to the specific embodiments described herein using only routine experimentation. The scope of the embodiments described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. One of ordinary skill in the art will recognize that various changes and modifications can be made to this description without departing from the spirit or scope of the invention as defined in the following claims.

Examples

[0288] For the purpose of better understanding the invention described herein, the following examples are provided. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should in no way be construed as limiting their scope. Materials and Methods

[0289] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, but it is understood that other process conditions can also be used unless otherwise stated. The optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art through routine optimization.

[0290] ​Furthermore, as may be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. The selection of suitable protecting groups for specific functional groups, as well as the conditions suitable 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, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0291] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail with respect to the preparation of representative substituted biaryl amides listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0292] The stereochemistry assigned herein (e.g., the assignment of "R" or "S" to the C21 position of a steroid) can be assigned tentatively (e.g., randomly). For example, even if the C21 position is in the "S" configuration, this C21 position may be depicted in the "R" configuration.

[0293] reported herein (e.g., of intermediates)1 1H-NMR can be a partial representation of the total NMR spectrum of a compound (e.g., a compound described herein). For example, the reported 1 1H NMR can exclude the region of δ (ppm) between about 1 and about 2.5 ppm.

[0294] Exemplary general method for preparative HPLC: Column: Waters Rbridge p rep 10μm C18, 19×250 mm. Mobile phase: Acetonitrile, water (NH4HCO3) (30 L of water, 24 g of NH4HCO3, 30 mL of NH3.H2O). Flow rate: 25 mL / min

[0295] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile Gradient: 5% - 95% of B for 1.6 minutes or 2 minutes Flow rate: 1.8 or 2 mL / min; Column: Xbridge C18, 4.6×50 mm, 3.5μm, 45°C

[0296] Synthetic method Example 1. Synthesis of 1.

Chemical formula

[0297] Example 2. Synthesis of 2 and 3.

Chemical formula

[0298] Example 3. Synthesis of 4 and 5.

Chemical Structure

[0299] Step 2. Synthesis of A4. To a solution of A3 (4.2 g, 13.19 mmol) and 1H - imidazole (1.80 g, 26.37 mmol) in DMF (35 mL) was added TBSCl (3.98 g, 26.37 mmol). The mixture was stirred at 30 °C overnight. TLC indicated that the starting material had been completely consumed. The resulting mixture was added to brine (35 mL), and the resulting solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (25 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 100) to give A4 (5.2 g, 91%) as a white solid. L) was added, and the resulting solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (25 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 100) to give A4 (5.2 g, 91%) as a white solid. 1 1H NMR (A4): (400 MHz, CDCl3) δ 5.10 - 5.03 (m, 1H), 4.40 - 4.37 (m, 1H), 4.88 - 4.84 (m, 1H), 4.44 - 4.31 (m, 2H), 2.20 - 2.09 (m, 1H), 1.89 - 1.72 (m, 4H), 1.69 - 1.63 (m, 4H), 1.61 - 1.48 (m, 7H), 1.43 - 1.11 (m, 6H), 1.11 - 1.04 (m, 4H), 1.04 - 0.94 (m, 5H), 0.90 - 0.81 (m, 12H), 0.2 (s, 6H).

[0300] Step 3. Synthesis of A5. To a suspension of NaH (4.81 g, 120.16 mmol) in THF (50 mL) was added dropwise a solution of compound A4 (5.2 g, 12.02 mmol) in THF (20 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 30 minutes. Then, MeI (17.06 g, 120.16 mmol) was added dropwise. The mixture was stirred at 30 °C overnight. TLC (ethyl acetate / petroleum ether = 1 / 200) indicated that the reaction was complete. The reaction was quenched with aqueous NH4Cl solution (30 mL). The resulting solution was extracted with ethyl acetate (35 mL × 3), and the combined organic layers were dried and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 2) to afford A5 (4.7 g, 87.5%) as a white solid. 1 1H NMR (A5): (400 MHz, CDCl3) δ 5.11 - 5.02 (m, 1H), 3.99 - 3.96 (m, 1H), 3.23 - 3.17 (m, 1H), 3.28 (s, 3H), 2.73 - 2.67 (m, 1H), 2.46 - 2.32 (m, 1H), 2.23 - 2.11 (m, 1H), 1.88 - 1.74 (m, 2H), 1.71 - 1.64 (m, 4H), 1.63 - 1.61 (m, 4H), 1.51 - 1.33 (m, 5H), 1.22 - 1.08 (m, 5H), 1.04 (s, 3H), 0.96 (s, 3H), 0.94 - 0.88 (m, 11H), 0.87 - 0.78 (m, 2H), 0.2 (s, 6H).

[0301] Step 4. Synthesis of A6. A solution of A5 (4.7 g, 10.52 mmol) in THF (30 mL) was added dropwise to a solution of 9-BBN (210 mL, 0.5 M) in THF while stirring in an ice bath under a N2 atmosphere. The mixture was stirred at 60 °C overnight. The reaction was cooled in an ice bath and 10% aqueous NaOH solution (24 mL) was added dropwise, then 30% aqueous H2O2 solution (12 mL) was added dropwise, and the resulting solution was stirred at 15 °C for 3 hours. The mixture was quenched with saturated aqueous Na2S2O3 solution (50 mL). The resulting mixture was extracted with EtOAc (100×3 mL), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 50) to give A6 (2.5 g, 51%) as a white solid. 1 1H NMR (A6): (400 MHz, CDCl3) δ 3.97 - 3.93 (m, 1H), 3.89 - 3.81 (m, 1H), 3.75 - 3.64 (m, 1H), 3.64 - 3.61 (m, 1H), 3.21 (s, 3H), 2.34 - 2.27 (m, 1H), 0.96 - 0.92 (m, 4H), 0.87 (s, 9H), 0.81 (s, 3H), 0.78 - 0.72 (m, 1H), 0.2 (m, 6H).

[0302] Step 5. Synthesis of A7. Dess-Martin (1.28 g, 3.01 mmol) was added to a solution of A6 (2.5 g, 5.38 mmol) in dichloromethane (20 mL) under a N2 atmosphere. The mixture was stirred at 40 °C overnight. TLC indicated that the starting material had been completely consumed. The mixture was quenched with saturated aqueous Na2S2O3 solution (25 mL). The resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with saturated aqueous Na2S2O3 solution (25 mL×4), saturated aqueous NaHCO3 solution (20 mL), brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude A7 (2.7 g), which was used in the next step without further purification. 1 1H NMR (A7): (400 MHz, CDCl3) δ 3.98 - 3.93 (m, 1H), 3.71 - 3.68 (m, 1H), 3.21 (s, 3H), 2.54 - 2.36 (m, 4H), 2.21 - 2.06 (m, 5H), 1.96 - 1.31 (m, 20H), 1.30 - 1.06 (m, 8H), 1.02 - 0.91 (m, 4H), 0.92 - 0.84 (m, 10H), 0.83 - 0.72 (m, 5H), 0.2 (m, 6H).

[0303] Step 6. Synthesis of A8. To a solution of A7 (2.7 g, 5.83 mmol) in dichloromethane (30 mL) was added TFA (5 mL, 67.09 mmol) dropwise. The mixture was stirred at 15 °C for 1 h. TLC indicated the completion of the reaction. The mixture was quenched with saturated aqueous Na2HCO3 (25 mL). The resulting solution was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (45 mL × 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 3) to afford A8 (0.8 g, 34%) as a white solid. 1 1H NMR (A8): (400 MHz, CDCl3) δ 4.07 - 4.02 (m, 1H), 3.71 - 3.68 (m, 1H), 3.21 (s, 3H), 2.49 - 2.41 (m, 2H), 2.19 - 2.08 (m, 4H), 1.74 - 1.57 (m, 8H), 1.56 - 1.49 (m, 3H), 1.48 - 1.40 (m, 3H), 1.38 - 1.32 (m, 1H), 1.31 - 1.16 (m, 5H), 1.16 - 1.03 (m, 1H), 0.97 (s, 3H), 0.84 - 0.78 (m, 1H), 0.77 (s, 3H).

[0304] Step 7. Synthesis of A9. To a solution of A8 (0.7 g, 2.01 mmol) in MeOH (20 mL) was added aqueous HBr (5 drops, 40% in water). Then, Br2 (353.07 mg, 2.21 mmol) was added with stirring. The mixture was stirred at 15 °C for 3 h. TLC indicated that the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl (15 mL). The resulting solution was extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude A9 (1.0 g), which was used in the next step without further purification. 1 1H NMR (A9): (400 MHz, CDCl3) δ 4.08 - 4.04 (m, 1H), 3.91 (s, 2H), 3.71 - 3.68 (m, 1H), 3.28 - 3.19 (m, 3H), 2.77 - 2.71 (m, 1H), 2.51 - 2.35 (m, 2H), 2.34 - 2.24 (m, 1H), 2.22 - 2.11 (m, 1H), 1.83 - 1.68 (m, 7H), 1.67 - 1.48 (m, 10H), 1.47 - 1.38 (m, 2H), 1.21 - 1.10 (m, 4H), 0.98 (s, 3H), 0.77 - 0.86 (m, 4H).

[0305] Synthesis of Compounds 8.4 and 5. A solution of 1,2,3-triazole (824.10 mg, 11.93 mmol) in THF (15 mL) was added with LiHMDS (11.93 mL, 11.93 mmol, 1 M in THF) in an ice bath under a N2 atmosphere. The mixture was stirred at 0 °C for 30 minutes. Then, a solution of A9 (850 mg, 1.99 mmol) in THF (5 mL) was added, and the reaction was stirred at 15 °C for 4 hours. TLC indicated that the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl solution (15 mL). The resulting solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (15 mL × 4), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 3) to give 4 (77.5 mg, 9.4%) and 5 (57.4 mg, 7%) as yellow solids. 1 1H NMR (4): (400 MHz, CDCl3) δ 7.78 - 7.70 (m, 2H), 5.28 - 5.26 (m, 2H), 4.10 - 4.03 (m, 1H), 3.73 - 3.68 (m, 4H), 3.26 (s, 3H), 2.48 - 2.57 (m, 1H), 2.23 - 2.12 (m, 1H), 1.78 - 1.69 (m, 4H), 1.47 - 1.42 (m, 2H), 1.41 - 1.07 (m, 8H), 1.04 - 0.93 (m, 4H), 0.93 - 0.82 (m, 5H). 1 1H NMR (5): (400 MHz, CDCl3) δ 7.79 (s, 3H), 7.69 (s, 3H), 5.38 - 5.27 (d, J = 17.6Hz, 1H), 5.19 - 5.11 (d, J = 18Hz, 1H), 4.12 - 4.06 (m, 1H), 3.81 - 3.68 (m, 1H), 3.24 (s, 3H), 2.67 - 2.52 (m, 2H), 2.31 - 2.26 (m, 1H), 1.89 - 1.68 (m, 5H), 1.52 - 1.38 (m, 2H), 1.46 - 1.14 (m, 9H), 0.98 (s, 3H), 0.93 - 0.78 (m, 7H).

[0306] Example 4. Synthesis of 6 and 7.

Chemical formula

[0307] Step 2. Synthesis of A12. To a solution of compound A11 (2 g, 5.5 mmol) in DMF (20 mL) were added imidazole (1.12 g, 16.5 mmol) and TBSCl (1.65 g, 11 mmol). The solution was then heated to 30 °C and maintained at this temperature for 16 h. TLC and LCMS indicated that the reaction was complete. Brine and EtOAc were added to this solution and separated. The combined organic layers were washed with brine (1 00 mL×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with petroleum ether to give A12 (2.88 g, 99%) as a white solid. 1 1H NMR (A12): (400 MHz, CDCl3) δ 5.18 - 5.16 (m, 1H), 3.84 - 3.78 (m, 1H), 3.75 - 3.68 (m, 1H), 3.38 - 3.28 (m, 1H), 3.28 - 3.22 (m, 1H), 2.85 - 2.78 (m, 1H), 2.74 - 2.66 (m, 1H), 2.60 - 2.55 (m, 1H), 2.48 - 2.24 (m, 2H), 1.85 - 1.65 (m, 5H), 1.61 - 1.54 (m, 5H), 1.36 - 1.22 (m, 3H), 1.31 - 1.10 (m, 8H), 0.89 - 0.86 (m, 10H), 0.81 (s, 3H), 0.03 (s, 6H).

[0308] Step 3. Synthesis of A13. A solution of BH3 in THF (20 mmol, 20 mL, 1 M in THF) was added to a solution of A12 (1 g, 2.1 mmol) in THF (20 mL). The resulting solution was stirred at 45 °C for 20 h. The mixture was cooled in an ice bath and then saturated aqueous NaHCO3 solution was slowly added, followed by H2O2 (30%, 40 mL). The resulting suspension was stirred at 30 °C for 3 h. It was extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was concentrated. The residue was purified by flash chromatography eluting with petroleum ether:ethyl acetate = 8:1 to give A13 (800 mg, 77%) as a colorless solid. 1 1H NMR (A13): (400 MHz, CDCl3) δ 4.34 - 4.26 (m, 1H), 3.86 - 3.80 (m, 1H), 3.73 - 3.64 (m, 1H), 3.60 - 3.51 (m, 1H), 3.46 - 3.35 (m, 1H), 3.34 - 3.30 (m, 1H), 1.96 - 1.83 (m, 2H), 1.83 - 1.65 (m, 4H), 1.41 - 1.30 (m, 3H), 1.30 - 1.21 (m, 7H), 1.19 - 1.10 (m, 9H), 1.10 - 0.94 (m, 3H), 0.86 (s, 12H), 0.78 - 0.73 (m, 1H), 0.03 (s, 6H).

[0309] Step 4. Synthesis of A14. To a solution of A13 (600 mg, 1.2 mmol) in CH2Cl2 (25 mL) was added Dess-Martin reagent (1.55 g, 3.6 mmol). The mixture was stirred at 25 °C for 1 h. TLC indicated that the reaction was complete. The reaction was quenched by the addition of saturated aqueous Na2SO3 solution and separated. The organic layer was washed with saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried over anhydrous Na2SO4 and the solvent was concentrated to give crude A14 (690 mg) as a pale yellow oil. 11H NMR (A14) (400 MHz, CDCl3) δ 3.87 - 3.80 (m, 1H), 3.75 - 3.68 (m, 1H), 3.40 - 3.26 (m, 2H), 2.78 - 2.70 (m, 2H), 2.58 - 2.46 (m, 2H), 2.31 - 2.15 (m, 2H), 2.20 (s, 3H), 1.86 - 1.66 (m, 6H), 1.40 - 1.05 (m, 13H), 0.95 - 0.84 (m, 9H), 0.59 (s, 3H), 0.05 (s, 3H).

[0310] Step 5. Synthesis of A15. TFA (2 mL) was added to a solution of A14 (600 mg, 1.20 mmol) in DCM (10 mL). The resulting solution was stirred at 25 °C for 3.5 h. TLC indicated that the reaction was complete. Then brine was added to this solution. The organic layer was washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in THF. Then an aqueous LiOH solution was added. The resulting solution was stirred at 25 °C for 16 h. TLC and LCMS indicated that the reaction was complete. The solvent was evaporated. The residue was washed with EtOAc and H2O. The organic layer was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give crude A15 (480 mg) as a pale yellow oil. 1 1H NMR (A15) (400 MHz, CDCl3) δ 3.96 - 3.88 (m, 1H), 3.78 - 3.70 (m, 1H), 3.42 - 3.34 (m, 2H), 2.76 - 2.68 (m, 2H), 2.60 - 2.45 (m, 2H), 2.30 - 2.18 (m, 1H), 2.12 (s, 3H), 1.92 - 1.73 (m, 8H), 1.61 - 1.50 (m, 2H), 1.38 - 1.25 (m, 9H), 1.25 - 1.14 (m, 10H), 0.93 (s, 3H), 0.59 (s, 3H).

[0311] Step 6. Synthesis of A16. To a solution of A15 (430 mg, 1.14 mmol) in MeOH (10 mL) was added HBr (0.08 mL) and Br2 (0.16 mL) in MeOH (1 mL). The resulting solution was stirred at 25 °C for 1.5 h. TLC indicated the completion of the reaction. The solvent was evaporated and the residue was extracted with DCM (50 mL×2). The organic layer was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give crude A16 (510 mg) as a pale yellow oil. 1 1H NMR (A16) (400 MHz, CDCl3) δ 3.96 - 3.88 (m, 1H), 3.78 - 3.74 (m, 2H), 3.76 - 3.68 (m, 1H), 3.39 - 3.33 (m, 2H), 3.12 - 3.06 (m, 1H), 2.66 - 2.60 (m, 1H), 2.51 - 2.44 (m, 2H), 2.25 - 2.18 (m, 1H), 1.98 - 1.76 (m, 7H), 1.41 - 1.24 (m, 6H), 1.23 - 1.12 (m, 8H), 0.63 (s, 3H).

[0312] Step 7. Synthesis of 6 and 7. To a dried flask were added 1,2,3 - triazole (450 mg, 6.74 mmol), K2CO3 (468 mg, 3.36 mmol) and DMF (5 mL). The resulting suspension was stirred at 33 °C for 30 min under N2. Then a solution of A16 (510 mg, 1.12 mmol) in DMF (5 mL) was added to the above suspension and it was stirred at 33 °C for an additional 4 h. LCMS indicated the completion of the reaction. This solution was quenched by the addition of saturated NH4Cl solution. It was extracted with EtOAc. The organic layer was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by pre - HPLC to give 6 (55 mg, 9.9%) as a colorless solid and 7 (67 mg, 12.1%) as a pale yellow solid. 1 ​1H NMR(6)(400 MHz, CDCl3) δ 7.71 (s, 2H), 5.21 - 5.20 (m, 2H), 3.95 - 3.90 (m, 1H), 3.80 - 3.70 (m, 1H), 3.42 - 3.33 (m, 2H), 2.78 - 2.70 (m, 2H), 2.63 - 2.58 (m, 1H), 2.40 - 2.35 (m, 1H), 1.90 - 1.70 (m, 7H), 1.43 - 1.25 (m, 7H), 1.24 - 1.13 (m, 8H), 0.69 (s, 3H). 1 1H NMR(7)(400 MHz, CDCl3) δ 7.79 (s, 1H), 7.65 (s, 1H), 5.26 - 5.10 (m, 2H), 3.98 - 3.90 (m, 1H), 3.80 - 3.70 (m, 1H), 3.40 - 3.35 (m, 2H), 2.85 - 2.80 (m, 1H), 2.75 - 2.65 (m, 1H), 2.60 - 2.45 (m, 2H), 2.31 - 2.20 (m, 1H), 1.98 - 1.78 (m, 7H), 1.46 - 1.25 (m, 7H), 1.24 - 1.13 (m, 7H), 0.68 (s, 3H).

[0313] Example 5. Synthesis of 8 and 9.

Chemical Structure

[0314] Step 2. Synthesis of A19. To a solution of A18 (17 g, 46.64 mmol) in CH3CN (1.5 L) was added TMSI (18.67 g, 93.28 mmol) dropwise under an N2 atmosphere in an ice bath. The mixture was stirred at 15 °C for 2 h. TLC (petroleum ether / ethyl acetate = 1 / 1) indicated that the starting material had been completely consumed. The reaction was quenched with Na2S2O3 (100 mL). The resulting mixture was extracted with EtOAc (45 mL × 3), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 3) to give A19 (5.5 g, 31%) as a yellow solid. 1 1H NMR (A19): (400 MHz, CDCl3) δ 4.74 - 4.61 (m, 1H), 4.39 - 4.36 (m, 1H), 4.35 - 3.31 (m, 1H), 4.22 - 4.15 (m, 2H), 3.29 - 3.22 (m, 1H), 3.16 - 3.05 (m, 1H), 2.77 - 2.58 (m, 1H), 2.54 - 2.36 (m, 3H), 2.38 - 2.13 (m, 8H), 1.15 (s, 3H), 0.88 (s, 3H).

[0315] Step 3. Synthesis of A20. To a solution of A19 (2.4 g, 6.89 mmol) and Et3N (2.09 mg, 20.66 mmol) in CH2Cl2 (70 mL) was added MsCl (11.05 g, 96.42 mmol) dropwise at 0 °C under an N2 atmosphere. The reaction mixture was stirred at 25 °C for 1 h. TLC (petroleum ether / ethyl acetate = 3 / 1) indicated that the reaction was complete. The reaction mixture was added dropwise to ice water (35 mL) at 0 °C with stirring. The resulting solution was extracted with CH2Cl2 (35 mL × 3). The combined organic layers were dried and concentrated to give A20 (1.6 g, 54%) as a white solid.

[0316] Step 4. Synthesis of A21 and A22. To a solution of A20 (1.4 g, 3.28 mmol) and 2H-1,2,3-triazole (1.13 g, 16.41 mmol) in DMF (25 mL) was added K2CO3 (2.27 g, 16.41 mmol). The reaction mixture was stirred at 30 °C overnight. TLC (petroleum ether / ethyl acetate = 1 / 2) indicated the completion of the reaction. The reaction mixture was added to brine (20 mL). The resulting solution was extracted with EtOAc (25 mL × 3). The combined organic layers were dried and concentrated to obtain a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 2 / 1 - 1 / 2) to give A21 (460 mg) and A22 (480 mg) as white solids.

[0317] Step 5-1. Synthesis of 8. To a solution of A21 (360 mg, 901.07 μmol) in THF (15 mL) was added K-selectride (1.08 mL, 1 M) at -78 °C under a N2 atmosphere. The reaction mixture was stirred at -78 °C for 2 h. TLC (DCM / MeOH = 20 / 1) indicated the completion of the reaction. The reaction was quenched with H2O2 (0.1 mL, 30%). The resulting solution was extracted with EtOAc (15 mL × 3), and the combined organic layers were washed with saturated aqueous Na2S2O4 solution (15 mL × 2) and brine (15 mL × 1). The mixture was dried and concentrated to obtain a crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 1) and further purified by SFC to give 8 (60.6 mg, 16.7%) as a white solid. 11H NMR (8): (400 MHz, CDCl3) δ 7.74 - 7.62 (m, 2H), 5.32 - 5.18 (m, 2H), 4.47 - 4.38 (m, 1H), 4.12 - 4.03 (m, 2H), 2.57 - 2.45 (m, 1H), 2.33 - 2.15 (m, 2H), 1.91 - 1.63 (m, 6H), 1.55 - 1.45 (m, 2H), 1.42 - 1.09 (m, 7H), 1.11 - 1.05 (m, 1H), 1.03 (s, 3H), 0.96 (s, 3H), 0.94 - 0.82 (m, 1H).

[0318] Synthesis of Project 5 - 2.9. To a solution of A22 (380 mg, 951.13 μmol) in THF (15 mL) was added K - selectride (1.14 mL, 1 M) at - 78 °C under a N2 atmosphere. The reaction mixture was stirred at - 78 °C for 2 h. TLC (DCM / MeOH = 20 / 1) indicated the completion of the reaction. The reaction was quenched with H2O2 (0.1 mL, 30%). The resulting solution was extracted with EtOAc (15 mL×3), and the combined organic layers were washed with saturated aqueous Na2S2O4 (15 mL×2) and brine (15 mL×1). The mixture was dried and concentrated to give a crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) and further purified by chiral SFC - HPLC to afford 9 (79.8 mg, 21%) as a white solid. 1 1H NMR (9): (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.68 (s, 1H), 5.31 - 5.25 (d, J = 17.6Hz, 1H), 5.20 - 5.14 (d, J = 17.6Hz, 1H), 4.48 - 4.45 (m, 1H), 4.12 - 4.03 (m, 1H), 2.65 - 2.53 (m, 2H), 2.32 - 2.15 (m, 1H), 1.92 - 1.71 (m, 5H), 1.68 - 1.59 (m, 4H), 1.54 - 1.42 (m, 1H), 1.41 - 1.15 (m, 4H), 1.13 - 1.05 (m, 1H), 1.04 (s, 3H), 0.94 - 0.85 (m, 4H).

[0319] Example 6. Synthesis of 10.

Chemical Structure

[0320] Step 2. Synthesis of A25. To a solution of 2,6-di-tert-butyl-4-methylphenol (A24, 120 g, 549 mmol) in toluene (400 mL) was added a solution of AlMe3 (137 mL, 274 mmol, 2 M) at room temperature, and at this point, methane gas was immediately evolved. The resulting mixture was stirred at room temperature for 1 hour. A solution of (5R,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one A24 (29.0 g, 91.7 mmol) in toluene (300 mL) was added at -78 °C under nitrogen. The reaction mixture was then stirred for 30 minutes, and then MeMgBr (91.3 mL, 274 mmol, 3.0 M) was added dropwise at -78 °C. The reaction mixture was stirred at this temperature for 3 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (300 mL) at -78 °C. The suspension was filtered, and the filter cake was washed with EtOAc (300 mL × 3). The combined organic phases were dried over Na2SO4 and evaporated to give a crude product. The crude product was purified by column chromatography on silica gel (PE:EtOAc = 10:1~6:1) to give 1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone A25 (6.0 g, 16.3%) as a pale yellow solid. 1 H NMR (A25) (400 MHz, CDCl3) δ 2.54 - 2.52 (m, 1H), 2.13 - 2.10 (m, 4H), 1.98 - 1.63 (m, 4H), 1.49 - 1.30 (m, 8H), 1.25 - 1.00 (m, 12H), 0.91 (s, 3H), 0.90 - 0.85 (m, 1H), 0.58 (s, 3H).

[0321] Step 3. Synthesis of A26. (3S,14S,17S)-3-Hydroxy-3,10,13 -To a stirred solution of trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone A25 (6.0 g, 18.04 mmol) in MeOH (100 mL) was added HBr (0.29 g, 3.61 mmol), and then Br2 (1.35 mL, 27.06 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. TLC indicated that the reaction was complete. The mixture was quenched with saturated aqueous NaHCO3 and adjusted to pH = 7. Then water (200 mL) was added and the solid was precipitated. The solid was filtered and washed with petroleum (100 mL × 2). The solid was collected and dried under reduced pressure. 2-Bromo-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone A26 (6.0 g) was obtained as a white solid. 1 1H NMR (A26) (400 MHz, CDCl3) δ 3.94 - 3.87 (m, 2H), 2.83 - 2.79 (m, 1H), 2.18 - 2.16 (m, 1H), 1.94 - 1.71 (m, 6H), 1.57 - 1.47 (m, 8H), 1.26 - 1.10 (m, 11H), 0.93 (s, 3H), 0.61 (s, 3H).

[0322] Step 4. Synthesis of 10. A mixture of 2-bromo-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (A26, 100 mg, 0.24 mmol) and K2CO3 (70 mg, 0.48 mmol) in 3 mL of acetone was added 1H-pyrazole-4-carbonitrile (30 mg, 0.36 mmol) at 25 °C. The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE / EtOAc = 5 / 1 - 2 / 1) to give 1-(2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (10, 25.5 mg, 25%) as a white solid. 1 H NMR (10) (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 5.03 - 4.87 (m, 2H), 2.25 - 2.15 (m, 1H), 2.10 - 1.80 (m, 3H), 1.75 - 1.71 (m, 3H), 1.54 - 1.35 (m, 8H), 1.33 - 0.95 (m, 10H), 0.94 (s, 3H), 0.64 (s, 3H). LCMS t R = 1.268 min (chromatography for 2 min), 10 - 80 AB, C 26 H 37 N3O2Na [M + Na] + The calculated value of MS ESI for 446, the measured value is 446.

[0323] Example 7. Synthesis of 11 and 12.

Chemical Structure

[0324] Example 8. Synthesis of 13.

Chemical Structure

[0325] Example 9. Synthesis of 14, 15, and 16.

Chemical Structure

[0326] Example 10. Synthesis of 17 and 18.

Chemical Structure

[0327] Example 11. Synthesis of 19 and 20.

Chemical Structure

[0328] Example 12. Synthesis of 21, 22, and 23.

Chemical Structure

[0329] Example 13. Synthesis of 24 and 25. [Chemical formula] According to Step 4 of Example 5, the title compound was prepared. 1 H NMR (24): (400 MHz, CDCl3) δ 7.48 (d, J = 1.6Hz, 1H), 6.72 (d, J = 2.4Hz, 1H), 5.04 - 4.89 (m, 2H), 2.60 (d, J = 4Hz, 1H), 2.58 - 1.72 (m, 8H), 1.58 - 1.42 (m, 8H), 1.31 - 1.07 (m, 10H), 0.95 (s, 3H), 0.65 (s, 3H). LCMS R t = 2.385 min (chromatography for 3 minutes), 10 - 80 AB, C 26 H 38 N3O2[M + H] + The MS ESI calculated value of is 424, the measured value is 406 [M + H - 18 + . 1 H NMR (25): (400 MHz, CDCl3) δ 7.50 (s, 1H), 6.72 (d, J = 2.4Hz, 1H) ​, 6.75 (s, 1H), 5.09 - 4.89 (m, 2H), 2.76 (d, J = 4Hz, 1H), 1.88 - 1.81 (m, 8H), 1.57 - 1.41 (m, 8H), 1.38 - 1.20 (m, 10H), 1.01 (d, J = 48Hz, 6H). LCMS R t = 2.415 min (3 - minute chromatography), 10 - 80 AB, C 26 H 37 N3O2[M + H] + The MS ESI calculated value of [M + H] is 424, the measured value is 446 [M + 23] + .

[0330] Example 14. Synthesis of 26 and 27.

Chemical Structure

[0331] Example 15. Synthesis of 28, 29, and 30.

Chemical Structure

[0332] Example 16. Synthesis of 31 and 32.

Chemical Structure

[0333] Example 17. Synthesis of 33 and 34.

Chemical Structure

[0334] Example 18. Synthesis of 35, 36, and 37.

Chemical Structure

[0335] Example 19. Synthesis of 38 and 39.

Chemical formula

[0336] Example 20. Synthesis of 40.

Chemical formula

[0337] Step 2. Synthesis of A29. To a solution of A28 (7.5 g, 23.6 mmol) in dry pyridine (70 mL) was added TsCl (6.79 g, 35.4 mmol) portionwise. The mixture was stirred at 40 °C for 6 h. When water was slowly added, a white solid precipitated. The white solid was filtered and washed with HCl (1 M) (200 mL × 3), then with water (200 mL × 3). The filtrate was dried under reduced pressure to give A29 (9.5 g) as a yellow solid.

[0338] Step 3. Synthesis of A30. To a stirred solution of collidine (100 mL) was added A29 (9.5 g, 20 mmol). The mixture was stirred at 130 °C for 4 h. After TLC indicated consumption of the starting material, the mixture was treated with H2SO4 (500 mL, 10%) to precipitate a solid. The solid was filtered and the residue was washed with H2SO4 (200 mL × 3) and concentrated to give A30 (6 g) as a yellow solid.

[0339] Step 4. Synthesis of A31. To a solution of A30 (6 g, 20 mmol) in CH2Cl2 (100 mL) was added m-CPBA (6.8 g, 39.6 mmol) portionwise at 0 °C. The mixture was stirred at 0 °C for 1 hour and then at 15 °C for 12 hours. The solution was washed successively with a saturated aqueous solution of Na2S2O3 (50 mL) and a saturated aqueous solution of Na2CO3 (200 mL), dried over NaSO4, filtered, and evaporated to dryness. Purification by flash column chromatography on silica gel (eluent: petroleum ether:ethyl acetate = 50:1) gave A31 (0.92 g) and a mixture (2.5 g) as white solids. 1 1H NMR (A31): (400 MHz, CDCl3) δ 3.19 - 3.11 (m, 2H), 2.58 - 2.50 (m, 1H), 2.11 (s, 3H), 2.08 - 1.82 (m, 3H), 1.70 - 1.08 (m, 17H), 0.90 - 0.82 (m, 1H), 0.78 (s, 3H), 0.72 - 0.63 (m, 1H), 0.59 (s, 3H).

[0340] Step 5. Synthesis of A32. To a solution of A31 (1 g, 3.16 mmol) in EtOH (20 mL) was added 12 drops of fuming sulfuric acid. The mixture was stirred at 19 °C for 3 hours, the reaction mixture was quenched with an aqueous NaHCO3 solution, and evaporated to low volume. The mixture was treated with water and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated to give A32 (0.95 g) as a white solid.

[0341] Step 6. Synthesis of A33. To a solution of A32 (0.95 g, 2.6 mmol) in MeOH (50 mL) were added aqueous HBr solution (0.2 mL, 48% in water) and Br2 (0.5 g, 3.14 mmol). The mixture was stirred at 19 °C for 2 h. Then the mixture was quenched with saturated aqueous NH4Cl solution (20 mL). The mixture was concentrated, water (50 mL) was added, and it was extracted with EtOAc (50 mL × 3). The organic phase was dried over Na2SO4 and concentrated to give the crude product. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 13:1) to give A33 (500 mg) as a white solid. 1 1H NMR: (400 MHz, CDCl3) δ 3.95 - 3.88 (m, 3H), 3.60 - 3.52 (m, 1H), 3.45 - 3.37 (m, 2H), 2.83 - 2.78 (m, 1H), 2.23 - 2.13 (m, 3H), 1.80 - 1.61 (m, 4H), 1.44 - 1.12 (m, 14H), 0.96 - 0.89 (m, 4H), 0.80 - 0.70 (m, 1H), 0.62 (s, 3H)

[0342] Step 7. Synthesis of 40. To a solution of K2CO3 (94 mg, 0.66 mmol) in DMF (8 mL) was added ethyl 1H - pyrazole - 3 - carboxylate (158 mg, 1.12 mmol). The mixture was stirred at 20 °C for 0.5 h under N2. Then to this mixture was added a solution of A33 (100 mg, 0.22 mmol) in DMF (4 mL), and the mixture was stirred at 20 °C for 3 h. The mixture was diluted with EtOAc (50 mL), washed with brine (50 mL × 3), and the organic layer was dried over anhydrous Na2SO4 and then concentrated to give the crude product. It was purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to give 40 (45 mg) as a yellow solid. 1 1H NMR (40): (400 MHz, CDCl3) δ 7.44 (d, J = 2 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 5.30 (s, 3H), 4.40 (dd, J = 7.6 Hz, J = 14.8 Hz, 2H), 3.96 - 3.91 (m, 1H), 3.60 - 3.53 (m, 1H), 3.47 - 3.38 (m, 2H), 2.60 - 2.52 (m, 1H), 2.21 - 2.11 (m, 1H), 2.07 - 2.00 (m, 1H), 1.90 - 1.61 (m, 6H), 1.52 - 1.15 (m, 17H), 1.03 - 0.92 (m, 4H), 0.82 - 0.72 (m, 1H), 0.66 (s, 3H)

[0343] Example 21. Synthesis of 42. [Chemical formula] Step 1. Synthesis of A34. To a solution of 2 (60 mg, 0.14 mmol) in CH2Cl2 (4 mL) was added Dess-Martin reagent (0.12 g, 0.28 mmol) at 0 °C. The reaction mixture was stirred at 30 °C for 1.5 h. After TLC indicated that the starting material was completely consumed, the mixture was quenched with a mixture of aqueous NaHCO3 and aqueous Na2S2O3 (5 mL). The mixture was extracted with CH2Cl2 (15 mL). The organic layer was washed with brine (8 mL × 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20 / 1 - 10 / 1) to give A34 (27.2 mg) as a white solid. 11H NMR (A34): (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.30 - 5.18 (m, 2H), 3.66 - 3.60 (m, 1H), 3.30 (s, 3H), 2.64 - 2.52 (m, 2H), 2.23 - 2.03 (m, 4H), 1.76 - 1.68 (m, 4H), 1.48 - 1.15 (m, 9H), 1.04 (s, 3H), 0.97 - 0.88 (m, 1H), 0.82 - 0.75 (m, 1H), 0.71 (s, 3H).

[0344] Synthesis of Project 2.42. To a stirred solution of MAD (182.2 mg, 0.56 mmol) in 5 mL of toluene was added dropwise a solution of A34 (0.1 g, 0.24 mmol) in toluene (15 mL) at -78 °C over 1 hour under nitrogen. After stirring at the same temperature for 0.5 hour, a solution of MeMgBr (0.52 mL, 1.4 mmol) was added dropwise at -78 °C. The reaction was warmed to -40 °C and stirred for 3 hours. After TLC indicated completion of the reaction, the reaction was poured into an aqueous NH4Cl solution and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by column chromatography on silica gel (PE / EA = 15 / 1 - 10 / 1) to give 42 (40 mg) as a white solid. 1 1H NMR (42): (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.31 - 5.16 (m, 2H), 3.31 (s, 3H), 3.06 - 2.98 (m, 1H), 2.59 - 2.55 (m, 1H), 2.22 - 1.95 (m, 3H), 1.45 - 1.11 (m, 16H), 1.04 - 0.94 (m, 1H), 0.92 (s, 3H), 0.83 - 0.874 (m, 1H), 0.70 (s, 3H)

[0345] Example 22. Synthesis of 43.

Chemical Structure

[0346] Example 23. Synthesis of 44, 45, and 46.

Chemical formula

[0347] Example 24. Synthesis of 47 and 48.

Chemical Structure

[0348] Example 25. Synthesis of 49 and 50.

Chemical Structure

[0349] Example 26. Synthesis of 51, 52, and 53.

Chemical Structure

[0350] Example 27. Synthesis of 54 and 55.

Chemical Structure

[0351] Example 28. Synthesis of 56, 57, 58, and 59.

Chemical Structure

[0352] Procedure 2.56 and 57 Synthesis. To a solution of A35 (120 mg, 300 μmol, 1.00 equiv) and KOH (33.6 mg, 600 μmol, 2 equiv) in THF (4.00 mL) was added CH3I (51 mg, 360 μmol, 1.2 equiv). The mixture was stirred at 25 °C for 3 h. TLC indicated disappearance of the material. The reaction was quenched with water and extracted with EA (2 × 20 mL). The combined organic phases were washed with brine and dried over Na2SO4, filtered, and concentrated to give the crude product. The residue was purified by prep-HPLC (0.5% HCl) to afford (R)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)propan-1-one (21 mg, 49.7 μmol) and (S)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)propan-1-one (30 mg, 72.5 μmol) as white solids. 1 1H NMR (56): (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.25 (q, J = 6.8 Hz, 1H), 2.23 - 2.14 (m, 1H), 2.10 - 2.00 (m, 1H), 1.90 - 1.75 (m, 3H), 1.58 - 1.50 (m, 5H), 1.49 - 1.25 (m, 8H), 1.24 - 1.07 (m, 9H), 1.04 - 1.00 (m, 3H), 0.95 (s, 3H), 0.64 (s, 3H). LCMS Rt = 0.945 min (1.5 min chromatography), C25H39N3O2 [M + H] + MS ESI calculated for 414, found 396 ([M + H - 18] 11H NMR (57): (400 MHz, CDCl3) δ 7.67 (s, 2H), 5.40 (q, J = 7.6 Hz, 1H), 2.65 - 2.63 (m, 1H), 2.14 - 2.12 (m, 2H), 1.95 - 1.66 (m, 5H), 1.60 - 1.49 (m, 3H), 1.55 - 1.25 (m, 10H), 1.42 - 1.00 (m, 10H), 0.95 (s, 3H), 0.67 (s, 3H). LCMS Rt = 0.927 min (1.5 - minute chromatograph y), C25H39N3O2 [M + H] + MS ESI calculated value for 414, measured value 396 ([M + H - 18] +

[0353] Step 3. Synthesis of 58 and 59. To a solution of A36 (130 mg, 325 μmol, 1.00 equivalent) and KOH (36.4 mg, 650 μmol, 2 equivalents) in THF (5.00 mL) was added CH3I (55.3 mg, 390 μmol, 1.2 equivalents). The mi xture was stirred at 25 °C for 3 hours. TLC indicated that the material had disappeared. The reaction was quenched with water and extracted with EA (2 × 30 mL); the combined organic phases were washed with brine and dried over Na2SO4, filtered, and concentrated to give the crude product. The residue was purified by Prep - HPLC (0.5% HCl) to give (R)-1 - ((3R,5R,8R,9S,10S,13S,14S,17S)-3 - hydroxy - 3,10,13 - trimethylhexadecahydro - 1H - cyclopenta[a]phenanthren - 17 - yl)-2-(1H - 1,2,3 - triazol - 1 - yl)propan - 1 - one (41.5 mg, 98.5 μmol) and (S)-1 - ((3R,5R,8R,9S,10S,13S,14S,17S)-3 - hydroxy - 3,10,13 - trimethylhexadecahydro - 1H - cyclopenta[a]phenanthren - 17 - yl)-2-(1H - 1,2,3 - triazol - 1 - yl)propan - 1 - one (24.5 mg, 58.5 μmol) as white solids. 11H NMR (58): (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.60 (s, 1H), 5.47 (q, J = 7.6 Hz, 1H), 2.56 - 2.51 (m, 1H), 2.15 - 2.00 (m, 1H), 1.90 - 1.75 (m, 3H), 1.66 - 1.64 (m, 3H), 1.60 - 1.54 (m, 2H), 1.50 - 1.39 (m, 9H), 1.25 - 1.00 (m, 11H), 0.94 (s, 3H), 0.66 (s, 3H). LCMS Rt = 1.054 min (chromatography for 2 minutes), C25H39N3O2 [M + H] + MS ESI calculated value for + is 414, measured value is 396 ([M + H - 18] 1 1H NMR (59): (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.74 (s, 1H), 5.64 (q, J = 7.2 Hz, 1H), 2.80 - 2.78 (m, 1H), 2.22 - 2.20 (m, 2H), 1.96 - 1.75 (m, 2H), 1.69 - 1.54 (m, 6H), 1.58 - 1.43 (m, 9H), 1.40 - 1.00 (m, 10H), 0.93 (s, 3H), 0.51 (s, 3H). LCMS Rt = 1.012 min (chromatography for 2 minutes), C25H39N3O2 [M + H] + MS ESI calculated value for + is 414, measured value is 396 ([M + H - 18]

[0354] Example 29. Synthesis of 60, 61, 62, and 63.

Chemical Structure

[0355] Synthesis of Steps 7.60 and 61. To a solution of A38 (95 mg, 211 μmol) and KOH (23.6 mg, 422 μmol) in THF (3.00 mL) was added CH3I (35.9 mg, 253 μmol). The mixture was stirred at 25 °C for 16 h. TLC indicated disappearance of the material. The reaction was then quenched with water and extracted with EA (2 × 20 mL); the combined organic phases were washed with brine and dried over Na2SO4, filtered, and concentrated to give the crude product. The residue was purified by prep-HPLC (0.5% HCl) to give (R)-2-(2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (9.4 mg, 20.0 μmol) and (S)-2-(2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (15.2 mg, 32.4 μmol) as white solids. 1 1H NMR (60): 400 MHz δ 7.88 (dd, J1 = 3.2 Hz, J2 = 6.8 Hz, 2H), 7.40 (dd, J1 = 3.2 Hz, J2 = 6.8 Hz, 2H), 5.74 - 5.68 (m, 1H), 2.74 - 2.69 (m, 1H), 2.25 - 2.1 (m, 1H), 2.00 - 1.75 (m, 8H), 1.60 - 1.29 (m, 10H), 1.28 - 1.25 (m, 8H), 1.25 - 1.00 (m, 2H), 0.97 (s, 3H), 0.73 (s, 3H). LCMS R t= 0.997 min (chromatography for 1.5 minutes), C29H41N3O2 [M+H] + MS ESi calculated value for + is 464, measured value is 446 ([M+H - 18] 1 1H NMR (600 MHz): δ 7.88 (dd, J1 = 2.8 Hz, J2 = 6.4 Hz, 2H), 7.42 (dd, J1 = 3.2 Hz, J2 = 6.4 Hz, 2H), 5.54 - 5.49 (m, 1H), 2.26 - 2.05 (m, 2H), 1.95 - 1.50 (m, 8H), 1.48 - 1.30 (m, 8H), 1.28 - 1.15 (m, 9H), 1.13 - 1.04 (m, 3H), 0.93 (s, 3H), 0.67 (s, 3H) LCMS R t = 1.006 min (chromatography for 1.5 minutes), C29H41N3O2 [M+H] + MS ESi calculated value for + is 464, measured value is 446 ([M+H - 18]

[0356] Step 7. Synthesis of 62 and 63. To a solution of A37 (290 mg, 644.4 μmol, 1.00 equivalent) and KOH (71.8 mg, 1280 μmol, 2 equivalents) in THF (6.00 mL) was added CH3I (109 mg, 772 μmol, 1.2 equivalents). The mixture was stirred at 25 °C for 3 hours. TLC indicated that the material had disappeared. The reaction was then quenched with water and extracted with EA (2 × 30 mL). The combined organic phases were washed with brine and dried over Na2SO4, filtered, and concentrated to give the crude product. The residue was purified by Prep-HPLC (0.5% HCl) to give (R)-2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pro Pan-1-one (41 mg, 84.7 μmol) and (S)-2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (47.5 mg, 100 μmol) were obtained as a white solid. 1 H NMR (62): 400 MHz δ 8.09 (d, J = 8.0 Hz, 1H), 7.57 - 7.55 (m, 1H), 7.49 - 7.47 (m, 1H), 7.39 - 7.37 (m, 1H), 5.81 - 5.79 (m, 1H), 2.72 - 2.68 (m, 1H), 2.01 - 1.75 (m, 8H), 1.65 - 1.55 (m, 2H), 1.50 - 1.25 (m, 8H), 1.24 - 1.00 (m, 11H), 0.93 (s, 3H), 0.61 (s, 3H). LCMS t R = 1.161 m in (2-minute chromatography), 30 - 90 AB, C29H41N3O2 [M + H] + MS ESI calculated value for 464, measured value 446 ([M + H - 18] 1 H NMR (63): 400 MHz δ 8.10 (d, J = 7.6 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.42 - 7.39 (m, 2H), 5.64 - 5.58 (m, 1H), 2.36 - 2.33 (m, 1H), 2.20 - 2.00 (m, 1H), 1.77 - 1.57 (m, 7H), 1.50 - 1.25 (m, 10H), 1.25 - 1.10 (m, 8H), 1.24 - 1.03 (m, 3H), 0.92 (s, 3H), 0.66 (s, 3H). LCMS R t = 1.186 m in (2-minute chromatography), C29H41N3O2 [M + H] + MS ESI calculated value for 464, measured value 446 ([M + H - 18]

[0357] Example 30. Synthesis of 64 and 65.

Chemical Structure

[0358] Example 31. Synthesis of 66 and 67.

Chemical Structure

[0359] According to Step 4 of Example 5, the title compound was prepared. 1 HNMR (66): (400 MHz, CDCl3) 7.94 (s,1H),7.66 - 7.62 (m, 1H), 7.29 ( s, 1H), 6.90 (t, J = 8Hz, 1H), 5.18 (s, 2H), 2.64 (s,1H), 2.13 - 2.00 (m,2H), 1.95 - 1.54 (m, 6H), 1.49 - 1.43 (m, 8H), 1.27 - 1.08 (m, 10H), 0.95 (s, 3H), 0.69 (s, 3H). LCMS R t = 0.949min (chromatography for 1.5 minutes), C 30 H 41 FN2O2[M + H] + The calculated value of MS ESI for 467, measured value 467. 1 HNMR (67): (400 MHz, CDCl3) δ 8.01 (s,1H),7.69 - 7.66 (m, 1H), 6.96 - 6.93 (m, 1H), 6.91 - 6.83 (m, 1H), 5.12 - 5.03 (m, 2H), 2.62 (t, J = 9.2, 1H), 2.17 - 1.95 (m,2H), 1.77 - 1.54 (m, 6H), 1.47 - 1.43 (m, 8H), 1.27 - 1.07 (m, 10H), 0.73 (s, 3H), 0.69 (s, 3H). LCMS R t = 1.151m in (chromatography for 2 minutes), C 29 H 39 FN2O2[M + H] + The calculated value of MS ESI for 467, measured value 467.

[0360] Example 32. Synthesis of 68 and 69.

Chemical Structure

[0361] Example 33. Synthesis of 70 and 71.

Chemical formula

[0362] Step 2. Synthesis of 71. To a solution of 70 (25 mg, 56.2 μmol) in 2 mL of CH2Cl2 was added m-CPBA (24.1 mg, 140 μmol) at 25 °C. The reaction mixture was stirred at the same temperature for 3 h. TLC (petroleum ether / ethyl acetate = 2:1, PMA) indicated completion of the reaction. The reaction mixture was poured into saturated aqueous Na2S2O3 and extracted with CH2Cl2 (10 mL×2). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 5 / 1~1 / 2) to give 71 (17.3 mg) as a white solid. 1 1H NMR (71): (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.87 (s, 1H), 5.04 - 4.89 (m, 2H), 3.13 (s, 3H), 2.62 (d, J = 9.2 Hz, 1H), 2.19 - 1.52 (m, 7H), 1.47 - 1.43 (m, 9H), 1.27 - 1.09 (m, 11H), 0.95 (s, 3H), 0.66 (s, 3H). LCMS R t = 1.265 min (2 - minute chromatography), chemical formula: C 26 H 40 N2O4S [M + H] + The calculated value of MS ESI for 477, measured value [M + H - 18]+ 459.

[0363] Example 34. Synthesis of 72 and 73.

Chemical Structure

[0364] Procedure 2. Synthesis of 72 and 73. To a solution of A39 (150 mg, 354 μmol, 1.00 equiv) and KOH (39.7 mg, 708 μmol, 2 equiv) in THF (4.00 mL) was added CH3I (60.1 mg, 424 μmol, 1.2 equiv). The mixture was stirred at 25 °C for 3 h. TLC indicated disappearance of the material. The reaction was quenched with water and extracted with EA (2 × 30 mL). The combined organic phases were washed with brine and dried over Na2SO4, filtered, and concentrated to give the crude product. The residue was purified by Prep-HPLC (0.5% HCl) to give 65 mg of the (P1 and P2, mixture) product. This mixed product was purified by SFC (0.2% NH4OH) to give 1-((R)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-oxopropan-2-yl)-1H-pyrazole-4-carbonitrile (20 mg, 45.5 μmol) and 1-((S)-1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-oxopropan-2-yl)-1H-pyrazole-4-carbo nitrile (35 mg, 79.9 μmol) as white solids. 1 1H NMR (72): 400 MHz δ 7.99 (s, 1H), 7.77 (s, 1H), 5.26 (q, J = 7.6 Hz, 1H), 2.71 - 2.62 (m, 1H), 2.18 - 2.16 (m, 2H), 2.00 - 1.72 (m, 2H), 1.70 - 1.65 (m, 6H), 1.52 - 1.41 (m, 10H), 1.43 - 1.02 (m, 11H), 0.94 (s, 3H), 0.55 (s, 3H). LCMS Rt = 1.122 min (2-minute chromatog raphy), C27H39N3O2 [M + H - 18] +The MS ESI calculated value is 420, and the measured value is 460 ([M + 23] 1 H NMR (73): 400 MHz δ 7.77 (s, 1H), 7.72 (s, 1H), 5.04 (q, J = 7.6 Hz, 1H), 2.49 - 2.47 (m, 1H), 2.07 - 2.00 (m, 1H), 1.92 - 1.88 (m, 3H), 1.67 - 1.62 (m, 6H), 1.60 - 1.40 (m, 8H), 1.27 - 1.06 (m, 11H), 0.94 (s, 3H), 0.65 (s, 3H). LCMS Rt = 1.132 min (chromatography for 2 minutes ), C27H39N3O2[M + H - 18] + The MS ESI calculated value is 420, and the measured value is 460 ([M + Na] + .

[0365] Example 35. Synthesis of 74, 75, and 76.

Chemical Structure

[0366] Example 36. Synthesis of 77 and 78.

Chemical Structure

[0367] Example 37. Synthesis of 79, 80, and 81.

Chemical Structure

[0368] Step 3. Synthesis of A43. To a solution of A42 (1.0 g, 3.15 mmol) in toluene (10 mL) ) To the solution in [the specific solvent or reaction medium], methylmagnesium bromide (9.45 mmol, 3.15 mL, 3 M in ether) was added at -70 °C. The mixture was stirred at this temperature for 2 hours. TLC (PE:EA = 3:1, PMA) indicated that the reaction was complete, and two major spots were observed. Saturated NH4Cl (20 mL) was added to the mixture, and then it was extracted with EtOAc (20 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to obtain a residue, which was purified by combi-flash (PE:EA = 100% - 60%) to give A43 (0.3 g) as a white solid. 1 H NMR (A43): (400 MHz, CDCl3) δ 2.52 (t, J = 8.8 Hz, 1H), 2.17 - 2.12 (m, 1H), 2.11 (s, 3H), 1.70 - 1.18 (m, 23H), 1.05 - 0.85 (m, 1H), 0.80 - 0.79 (m, 1H), 0.74 (s, 3H), 0.59 (s, 3H).

[0369] Step 4. Synthesis of A44. To a solution of A43 (0.3 g, 0.902 mmol) in MeOH (10 mL), 1 drop of HBr·Br2 (215 mg, 1.35 mmol) was added all at once. The reaction solution was stirred at 25 °C for 1 hour. TLC (PE:EA = 3:1, PMA) indicated that the reaction was complete, and a major spot was observed. The mixture was quenched to pH = 7 with saturated NaHCO3 solution, concentrated to obtain a residue, to which water (20 mL) was added, and then it was extracted with EtOAc (15 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give crude A44 (0.4 g) as a white solid. 1 H NMR (A44): (400 MHz, CDCl3) δ 3.94 - 3.87 (m, 2H), 2.81 (t, J = 8.8Hz, 1H), 2.18 - 2.11 (m, 1H), 1.95 - 1.85 (m, 1H), 1.80 - 1.10 (m, 22H), 1.00 - 0.75 (m, 2H), 0.74 (s, 3H), 0.62 (s, 3H).

[0370] Synthesis of 5.79. To a solution of A44 (400 mg, 0.97 mmol) in acetone (2 mL) was added 4H-pyrazole-4-carbonitrile (134 mg, 1.45 mmol), and then K2CO3 (267 mg, 1.94 mmol) was added. The resulting reaction mixture was stirred at 25 °C for 2 h. TLC (PE:EA = 3:1, PMA) indicated the completion of the reaction and the presence of the major spot. Water (4 mL) was added to this mixture, which was then extracted with EtOAc (2 mL×3). The combined organic phases were concentrated to give a residue, which was purified by combi-flash (PE:EA = 100%~50%) to afford 79 (0.4 g) as a white solid. 1 H NMR (79): (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 5.03 - 4.86 (m, 2H), 2.59 (t, J = 8.4Hz,1H), 2.25 - 2.10 (m, 1H), 2.05 - 1.95 (m, 1H), 1.80 - 1.15 (m, H), 1.05 - 0.76 (m, 4H), 0.75 (s, 3H), 0.65 (s, 3H). LCMS R t = 1.312 min (chromatography for 2 minutes), C26H38N3O2 [M + H] + The calculated value of MS ESI for [M + H - H2O] of C26H38N3O2 is 423, and the measured value is 406 + .

[0371] Synthesis of Compounds 6.80 and 81. To a solution of 79 (0.2 g, 0.472 mmol) in THF (5 mL) were added KOH (52.8 mg, 0.944 mmol) and MeI (80.3 mg, 0.566 mmol). The final reaction mixture was stirred at 25 °C for 1 h. TLC (PE:EA = 3:1) indicated the completion of the reaction. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (5 mL × 2). The combined organic phases were concentrated and then purified by prep-HPLC to give 1-((R)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-oxopropan-2-yl)-1H-pyrazole-4-carbonitrile (12 mg) and 1-((S)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-oxopropan-2-yl)-1H-pyrazole-4-carbonitrile (9 mg) as white solids. 1 1H NMR (80): (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.80 (s, 1H), 5.07 - 5.01 (m, 1H), 2.49 (t, J = 8.8 Hz, 1H), 2.15 - 1.80 (m, 2H), 1.75 - 1.15 (m, 25H), 0.95 - 0.85 (m, 1H), 0.84 - 0.75 (m, 1H), 0.74 (s, 3H), 0.65 (s, 3H). LCMS R t = 1.370 min (2-minute chromatography), C27H40N3O2 [M + H] + MS ESI calculated for 438, found 420 [M + H - H2O] + . 11H NMR (81): (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.77 (s, 1H), 5.30 - 5.24 (m, 1H), 2.73 (t, J = 8.8Hz, 1H), 2.17 - 2.14 (m, 2H), 1.75 - 1.15 (m, 25H), 1.00 - 0.90 (m, 1H), 0.85 - 0.75 (m, 1H), 0.74 (s, 3H), 0.55 (s, 3H). LCMS R t = 1.374 min (chromatography for 2 minutes), C27H40N3O2 [M + H] + The calculated value of MS ESI for + is 438, and the measured value is 420 [M + H - H2O] + .

[0372] Example 40. Synthesis of 89.

Chemical Structure

[0373] Example 41. Synthesis of 90, 91, 92, and 93.

Chemical Structure

[0374] Procedure 2. Synthesis of 90 and 91. To a solution of 90 (0.1 g, 0.25 mmol) in THF (5 mL) were added KOH (28 mg, 0.5 mmol) and MeI (42.5 mg, 0.3 mmol). The final reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the reaction was complete. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (5 mL × 2). The combined organic phases were concentrated and then purified by prep-HPLC to give (R)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)propan-1-one (92, 10.6 mg) and (S)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)propan-1-one (93, 12.5 mg) as white solids. 1 1H NMR (90): (400 MHz, CDCl3) δ 7.66 (s, 2H), 5.28 - 5.22 (m, 1H), 2.24 (t, J = 8.8 Hz, 1H), 2.14 - 1.95 (m, 3H), 1.85 - 1.70 (m, 3H), 1.65 - 0.75 (m, H), 0.71 (s, 3H), 0.64 (s, 3H). LCMS Rt = 1.381 min (Chromatography for 2 minutes), C25H39N3O2 [M + H] + MS ESI calculation of Calculated value 414, measured value 414. 11H NMR (91): (400 MHz, CDCl3) δ 7.66 (s, 2H), 5.43 - 5.37 (m, 1H), 2.65 (t, J = 8.8 Hz, 1H), 2.14 - 1.95 (m, 3H), 1.85 - 1.70 (m, 3H), 1.65 - 0.75 (m, 23H), 0.74 (s, 3H), 0.67 (s, 3H). LCMS Rt = 1.349 min (chromatography for 2 minutes), calculated MS ESI for C25H39N3O2 [M + H]+ 414, found 414.

[0375] Step 3. Synthesis of 92 and 93. To a solution of 91 (0.2 g, 0.5 mmol) in THF (5 mL) were added KOH (56 mg, 1.0 mmol) and MeI (85.1 mg, 0.6 mmol). The final reaction mixture was stirred at 25 °C for 1 h. LCMS indicated the completion of the reaction. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (5 mL × 2). The combined organic phases were concentrated and then purified by prep-HPLC to give (R)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)propan-1-one (92, 6.9 mg) and (S)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)propan-1-one (93, 1.5 mg) as white solids. 1 1H NMR (92): (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.60 (s, 1H), 5.48 - 5.46 (m, 1H), 2.57 (t, J = 8.8 Hz, 1H), 2.15 - 1.05 (m, 26H), 1.00 - 0.74 (m, 3H), 0.74 (s, 3H), 0.66 (s, 3H). LCMS Rt = 1.295 min (Chromatography for 2 minutes), C25H39N3O2 [M + H] + The calculated value of MS ESI for is 414, the measured value is 414. 1 H NMR (93): (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.75 (s, 1H), 5.68 - 5.64 (m, 1H), 2.78 (t, J = 8.8 Hz, 1H), 2.20 - 2.14 (m, 2H), 1.75 - 1.15 (m, 25H), 1.00 - 0.90 (m, 1H), 0.85 - 0.75 (m, 1H), 0.73 (s, 3H), 0.51 (s, 3H). LCMS Rt = 1.260 min (Chromatography for 2 minutes), C25H39N3O2 [M + H] + The calculated value of MS ESI for is 414, the measured value is 414.

[0376] Example 42. Synthesis of 96, 97, 98, 99, 100, 101, and 102.

Chemical Structure

[0377] Procedure 2. Synthesis of 98 and 99. To a solution of 96 (0.1 g, 0.22 mmol) in THF (5 mL) were added KOH (24.8 mg, 0.44 mmol) and MeI (37.7 mg, 0.266 mmol). The final reaction mixture was stirred at 25 °C for 1 h. LCMS indicated the completion of the reaction. Water (10 mL) was added to the reaction solution, which was then extracted with EtOAc (5 mL×2). The combined organic phases were concentrated and then purified by prep-HPLC to give ((R)-2-(2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (98, 8.6 mg) and (S)-2-(2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (99, 9.7 mg) as white solids. 1 1H NMR (98): (400 MHz, CDCl3) δ7.89 - 7.86 (m, 2H), 7.42 - 7.38 (m, 2H), 5.54 - 5.49 (m, 1H), 2.26 (t, J = 8.Hz, 1H), 2.20 - 2.05 (m, 2H), 1.85 - 1.75 (m, 3H), 1.75 - 0.78 (m, 24H), 0.69 (s, 3H), 0.67 (s, 3H). LC MS Rt = 1.493 min (chromatography for 2 min), calculated MS ESI for C29H42N3O2 [M + H]+ 464, found 446 [M + H - H2O] + . 1 1H NMR (99): (400 MHz, CDCl3) δ7.89 - 7.86 (m, 2H), 7.39 - 7.36 (m, 2H), 5.72 - 5.66 (m, 1H), 2.71 (t, J = 8.Hz, 1H), 2.19 - 2.05 (m, 2H), 2.00 - 1.90 (m, 3H), 1.75 - 0.78 (m, 24H), 0.75 (s, 3H), 0.70 (s, 3H). LC MS R t = 1.466 min (chromatography for 2 minutes), calculated MS ESI for C29H42N3O2[M + H]+ is 464, measured value is 464.

[0378] Step 3. Synthesis of 100, 101, and 102. To a solution of 97 (0.2 g, 0.44 mmol) in THF (5 mL) were added KOH (49.7 mg, 0.88 mmol) and MeI (126 mg, 0.88 mmol). The reaction mixture was stirred at 25 °C for 1 hour. LCMS indicated that the reaction was complete. H2O (10 mL) was added to this solution, and it was extracted with EtOAc (5 mL × 2). The combined organic phases were concentrated and then purified by prep-HPLC to obtain (R)-2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cycl openta[a]phenanthren-17-yl)propan-1-one (100, 3.8 mg), (S)-2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propan-1-one (101, 10.3 mg) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methylpropan-1-one (102, 24.7 mg) as white solids. 11H NMR (100): (400 MHz, CDCl3) δ 8.09 - 8.07 (m, 1H), 7.48 - 7.36 (m, 3H), 5.64 - 5.59 (m, 1H), 2.34 (t, J = 8.8 Hz, 1H), 2.15 - 1.75 (m, 2H), 1.74 - 1.70 (m, 3H), 1.70 - 0.75 (m, 24H), 0.71 (s, 3H), 0.66 (s, 3H). LCMS R t = 1.411 min (2 - minute chromatography), C29H42N3O2 [M + H] + MS ESI calculated value for [M + H] is 464, measured value is 464. 1 1H NMR (101): (400 MHz, CDCl3) δ 8.08 - 8.06 (m, 1H), 7.56 - 7.54 (m, 1H), 7.49 - 7.47 (m, 1H), 7.37 - 7.35 (m, 1H), 5.81 - 5.75 (m, 1H), 2.70 (t, J = 8.8 Hz, 1H), 2.15 - 1.95 (m, 2H), 1.95 - 1.85 (m, 3H), 1.70 - 0.75 (m, 24H), 0.73 (s, 3H), 0.61 (s, 3H). LCMS Rt = 1.391 min (2 - minute chromatography), C29H42N3O2 [M + H] + MS ESI calculated value for [M + H] is 464, measured value is 464. 1 1H NMR (102): (400 MHz, CDCl3) δ 8.09 - 8.07 (m, 1H), 7.43 - 7.34 (m, 3H), 2.32 (t, J = 8.8 Hz, 1H), 2.05 (s, 3H), 1.90 (s, 3H), 1.70 - 1.00 (m, 22H), 0.90 - 0.50 (m, 10H). LCMS Rt = 1.467 min (2 - minute chromatography), MS ESI calculated value for C30H44N3O2 [M + H]+ is 478, measured value is 478.

[0379] Example 43. Synthesis of 103. [Chemical formula] To a solution of 87 (50 mg, 0.1 mmol) in 10 mL of DCM, m-CPBA (18.9 mg, 0.11 mmol) was added at -78 °C. The reaction mixture was stirred at the same temperature for 3 hours. TLC (petroleum ether / ethyl acetate = 1:1, PMA) indicated the completion of the reaction. The reaction mixture was poured into saturated Na2S2O3 and extracted with CH2Cl2 (50 mL × 2). The organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EtOAc = 1:1.5) to obtain 103 (14 mg) as a white solid. 1 1H NMR: (103): 400 MHz δ 8.29 (s, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 5.61 - 5.51 (m, 2H), 2.78 (s, 3H), 2.68 (d, J = 8.8 Hz, 1H), 2.17 - 2.15 (m, 2H), 1.96 - 1.53 (m, 5H), 1.49 - 1.43 (m, 8H), 1.27 - 1.08 (m, 12H), 0.96 (s, 3H), 0.73 (s, 3H). LCMS R t = 0.877 m in (1.5-minute chromatography), C 29 H 41 N3O3S [M + H] + of MS ESI calculated value 512, measured value 494 [M + H - 18] + .

[0380] Example 44. Synthesis of 104. [Chemical formula] To a solution of 87 (50 mg, 100 mmol) in 10 mL of CH2Cl2, m-CPBA (43.1 mg, 250 mmol) was added at 25 °C. The reaction mixture was stirred at the same temperature for 3 h. TLC (petroleum ether / ethyl acetate = 1:1, PMA) indicated the completion of the reaction. The reaction mixture was poured into saturated Na2S2O3 and extracted with CH2Cl2 (50 mL × 2). The organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EtOAc = 1:1.5) to give 1-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-(methylsulfonyl)-2H-benzo[d][1,2,3]triazol-2-yl)ethanone (104, 8 mg) as a white solid. 1 H NMR: (104): 400 MHz δ 8.62 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.88 (t, J = 1.6 Hz, 1H), 5.64 - 5.55 (m, 2H), 3.12 (s, 3H), 2.68 (t, J = 8.8 Hz, 1H), 2.21 - 2.17 (m, 2H), 1.96 - 1.54 (m, 6H), 1.51 - 1.44 (m, 9H), 1.27 - 1.09 (m, 11H), 0.97 (s, 3H), 0.73 (s, 3H). LCMS R t = 0.913 m in (1.5-minute chromatography), C 29 H 41 N3O4S [M + H] + of MS ESI calculated value 528, measured value 510 [M + H - 18] + .

[0381] Example 45. Synthesis of 105 and 106.

Chemical formula

[0382] Example 47. Synthesis of 107 and 108.

Chemical Structure

[0383] Synthesis of A50: To a solution of (5S,8R,9S,10S,13S,14S)-10,13-dimethyldodecahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,4H)-dione (A49, 15.0 g, 52.0 mmol) in THF (200 mL) was added methylmagnesium bromide (156 mmol, 52 mL, 3 M in ether) at -70 °C. The mixture was stirred at -70 °C for 3 h, at which point TLC analysis (PE:EA = 3:1, PMA) indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl solution (300 mL), then concentrated, and the residue was extracted with DCM (500 mL × 3). The organic phase was dried, concentrated, and purified by combi-flash (PE:EA = 100% - 60%) to give (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-3,10,13-trimethyltetradecahydro-1H-cyclopenta[a]-phenanthren-17(2H)-one (A50, 6.5 g) as a white solid.

[0384] Synthesis of A51: To a solution of Ph3PEtBr (39.2 g, 106 mmol) in THF (50 mL) was added a slurry of t-BuOK (11.8 g, 106 mmol) in THF (50 mL) under N2. The mixture turned red and was stirred at 60 °C for 1 h, then (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-3,10,13-trimethyltetradecahydro-1H-cyclopenta[a]phenanthrene A solution of -17(2H)-one (A50, 6.5 g, 21.3 mmol) was added all at once. The reaction mixture was stirred at 60 °C for 16 h, at which point TLC analysis (PE:EA = 3:1, PMA) indicated that the reaction was complete. The reaction mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (100 mL × 3). The combined organic phases were dried, concentrated, and purified by combi-flash (PE:EA = 100% - 85%) to give (3R,5S,8R,9S,10S,13S,14S)-17-ethylidene-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (A51, 5.5 g) as a white solid. 1 H (400 MHz, CDCl3) δ 5.12 - 5.09 (m, 1H), 2.40 - 2.10 (m, 4H), 1.75 - 1.10 (m, 23H), 1.05 - 0.75 (m, 8H).

[0385] Synthesis of A52 A solution of BH3-Me2S (17.2 mL, 172 mmol) was added dropwise to a solution of (3R,5S,8R,9S,10S,13S,14S)-17-ethylidene-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (A51, 5.5 g, 17.3 mmol) in THF (100 mL) at 0 °C. The solution was stirred at 25 °C for 3 h. TLC (PE / EtOAc = 3 / 1) indicated that the reaction was complete. After cooling to 0 °C, a solution of NaOH (100 mL, 3 M) was added very slowly. After the addition was complete, H2O2 (100 mL, 30%) was added slowly while maintaining the internal temperature below 10 °C. The resulting solution was stirred at 25 °C for 2 h. The resulting solution was extracted with EtOAc (100 × 3). The combined organic solutions were washed with saturated aqueous Na2S2O3 (100 mL × 3), brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product (6 g) as a white solid. This crude product was used in the next step without further purification.

[0386] Synthesis of A53: To a solution of (3R,5S,8R,9S,10S,13S,14S,17S)-17-(1-hydroxyethyl)-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (A52, 6 g, 17.9 mmol) in DCM (50 mL) were added PCC (5.77 g, 26.8 mmol) and SiliaBond Thiol (6 g). The reaction mixture was stirred at 25 °C for 2 h, at which point TLC analysis (PE:EA = 3:1) indicated completion of the reaction. The mixture was concentrated and purified by combi-flash (PE:EA = 100% - 70%) to afford 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (A53, 4 g) as a white solid.

[0387] Synthesis of A54: To a solution of 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (A53, 4 g, 12 mmol) in MeOH (50 mL) was added 1 drop of HBr. Then Br2 (2.28 g, 14.3 mmol) was added all at once, and the reaction was stirred at 25 °C for 1 h until TLC analysis (PE:EA = 3:1, PMA) indicated completion of the reaction. The mixture was quenched with saturated NaHCO3 solution until the pH reached 7, and the reaction was concentrated and filtered to afford 2-bromo-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (A54, 4.5 g) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.91 - 3.90 (m, 2H), 2.85 - 2.75 (m, 1H), 2.25 - 1.80 (m, 2H), 1.75 - 1.10 (m, 20H), 1.05 - 0.63 (m, 10H).

[0388] Synthesis of 107 and 108. (2-Bromo-1-((3R,5S,8R,9S,10S ,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (A54, 0.2 g, 0.486 mmol) in acetone (2 mL) was added 4,5-difluoro-2H-benzo[d][1,2,3]triazole (75.3 mg, 0.486 mmol), and then K2CO3 (134 mg, 0.972 mmol) was added. The resulting reaction mixture was stirred at 25 °C for 16 h, at which point TLC indicated that the reaction was complete. The reaction was diluted with water (5 mL), then extracted with EtOAc (5 mL × 3), and the combined organic phases were concentrated to give a residue, which was purified by prep-HPLC to give 2-(4,5-difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (Compound 107, 51.9 mg) and 2-(4,5-difluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (Compound 108, 36.3 mg) as white solids. Compound 107: 1 1H NMR (400 MHz, CDCl3) δ 7.38-7.33 (m, 1H), 7.06-7.03 (m, 1H), 5.46-5.34 (m, 2H), 2.71 (t, J = 8.8Hz, 1H), 2.21-2.14 (m, 2H), 1.80-1.15 (m, 22H), 1.05-0.80 (m, 2H), 0.77 (s, 3H), 0.70 (s, 3H). LCMS:Rt=1.421min (chromatography for 2 minutes), C 28 H3 8F2N3O2[M+H] + The calculated MS ESI value is 486, and the measured value is 486. Compound 108: 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.62 (m, 1H), 7.31 - 7.25 (m, 1H), 5.57 - 5.47 (m, 2H), 2.66 (t, J = 8.8Hz, 1H), 2.30 - 2.14 (m, 2H), 1.80 - 1.15 (m, 22H), 1.05 - 0.73 (m, 8H). LCMS Rt = 1.475m in (chromatography for 2 minutes), C 28 H 38 F2N3O2[M+H] + The calculated MS ESI value is 486, and the measured value is 468[M + H - 18] + .

[0389] Example 48. Synthesis of 109 and 110.

Chemical Structure

[0390] Example 49. Synthesis of 111, 112, and 113.

Chemical Structure

[0391] Example 50. Synthesis of 114.

Chemical Structure

[0392] Example 51. Synthesis of 115, 116, and 117.

Chemical Structure

[0393] Example 52. Synthesis of 118.

Chemical Structure

[0394] Example 53. Synthesis of 119 and 120.

Chemical Structure

[0395] Example 54. Synthesis of 121.

Chemical Structure

[0396] Example 55. Synthesis of 124.

Chemical Structure

[0397] Example 56. Synthesis of 125, 126, and 127.

Chemical Structure

[0398] Example 57. Synthesis of 128.

Chem.

[0399] Example 58. Synthesis of 129.

Chem.

[0400] Example 59. Synthesis of 130.

Chemical Structure

[0401] Example 60. Synthesis of 131.

Chemical Structure

[0402] Example 62. Synthesis of 133.

Chemical Structure

[0403] Example 63. Synthesis of 134.

Chemical Structure

[0404] Example 64. Synthesis of 135 and 136.

Chemical formula

[0405] Example 65. Synthesis of 137.

Chemical formula

[0406] Example 66. Synthesis of 138.

Chemical formula

[0407] Example 67. Synthesis of 139.

Chemical formula

[0408] Process 2. Synthesis of AA3. In a flask, (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydrospiro[cyclopenta[a]phenanthrene-3,2'-oxirane]-17-ol (AA2, 23 g, 75.5 mmol To a solution of in MeOH (200 mL) was added MeONa (12.2 g, 226 mmol), and the reaction mixture was heated to 60 °C and stirred for 4 h. When TLC (PE:EtOAc = 3:1) indicated that the reaction was complete, the reaction was quenched with an aqueous NH4Cl solution (300 mL). The reaction product was extracted with EtOAc (200 mL × 2), washed with brine (200 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude product (3R,5S,8R,9S,10S,13S,14S,17S)-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol (AA3, 25 g) as a yellow solid, which was used directly in the next step without further purification. 1 1H NMR (CDCl3, 400 MHz): δδ = 3.78 - 3.63 (m, 1H), 3.40 (s, 3H), 3.20 (s, 2H), 2.09 - 2.02 (m, 3H), 1.89 - 1.32 (m, 26H), 1.29 - 0.75 (m, 14H).

[0409] Step 3. Synthesis of AA4. To a solution of (3R,5S,8R,9S,10S,13S,14S,17S)-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol (AA3, 25 g, 74.2 mmol) in dry DCM (200 mL) was added Dess-Martin reagent (47.0 g, 111 mmol) portionwise at 0 °C. The reaction mixture was stirred at 30 °C for 2 h. TLC (PE / EA = 3:1) indicated complete consumption of the starting material. The mixture was quenched with saturated NaHCO3 / Na2S2O3 = 1:3 (200 ml) and extracted with EtOAc (200 mL×2). The organic phase was washed with brine (200 mL), dried over Na2SO4, and the solvent was evaporated at 40 °C to give the crude product (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-17(2H)-one (AA4, 26 g), which was used directly in the next step without further purification. 1 1H NMR (CDCl3, 400 MHz): δ = 3.39 (s, 3H), 3.18 (s, 2H), 2.69 - 2.65 (m, 1H), 2.44 - 2.40 (m, 1H), 2.09 - 1.41 (m, 28H), 1.38 - 1.31 (m, 11H)

[0410] Step 4. Synthesis of AA5. To a suspension of EtPPh3Br (144 g, 388 mmol) in THF (500 mL) was added t-BuOK (43.5 g, 388 mmol). After stirring at 60 °C for 1 h, (3R,5S,8R,9S,10S,13S,14S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-17(2H)-one (AA4, 26 g, 77.7 mmol) was added portionwise at 60 °C. The reaction mixture was stirred at the same temperature for 8 h. TLC (PE / EtOAc = 3 / 1) indicated completion of the reaction and showed a major product with low polarity. The reaction mixture was quenched with an aqueous NH4Cl solution (500 mL) and extracted three times with EtOAc (500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (PE:EA = 10:1~6:1) to give (3R,5S,8R,9S,10S,13S,14S,Z)-17-ethylidene-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (AA5, 20 g) as a white solid. 1 1H NMR (CDCl3, 400 MHz): δδ = 5.12 - 5.10 (m, 1H), 3.39 (s, 3H), 3.18 (s, 2H), 2.40 - 2.12 (m, 3H), 1.66 - 1.16 (m, 25H), 1.10 - 0.70 (m, 9H)

[0411] Step 5. Synthesis of AA6. To a solution of (3R,5S,8R,9S,10S,13S,14S,Z)-17-ethylidene-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (AA5, 20 g, 57.7 mmol) in THF (200 mL) was added dropwise a solution of BH3-Me2S (57.6 mL, 10 M) at 0 °C. The solution was stirred at 25 °C for 8 h. TLC (PE : (EtOAc = 3:1) indicated that the reaction was almost complete, and a major product with high polarity was observed. After cooling to 0 °C, a solution of NaOH (230 mL, 3 M) was added very slowly. After the addition was complete, H2O2 (104 mL, 33%) was added slowly while maintaining the internal temperature below 10 °C. The resulting solution was stirred at 25 °C for 2 hours. The resulting solution was extracted with EtOAc (200 mL × 3). The combined organic solutions were washed with saturated Na2S2O3 (200 mL × 2), brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product (AA6, 25 g) as a yellow solid. This crude product was used in the next step without further purification.

[0412] Step 6. Synthesis of AA7. A mixture of (3R,5S,8R,9S,10S,13S,14S,17S)-17-((R)-1-hydroxyethyl)-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (AA6, 25 g, 68.5 mmol), PCC (21.9 g, 102 mmol), and silica gel (24 g, w / w = 1 / 1.1) in DCM (200 mL) was stirred at 25 °C for 2 hours. The color of this reaction mixture turned brown. TLC (PE / EtOAc = 3 / 1) indicated that the reaction was complete, and a major product with low polarity was observed. The solution was filtered, and the filter cake was washed with DCM (200 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EtOAc = 15 / 1 to 6 / 1 to obtain 1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (AA7, 16 g) as a white solid. 1HNMR (CDCl3, 400 MHz): δ δ = 3.41 (s, 3H), 3.40 (s, 2H), 2.58 - 2.53 (m, 1H), 2.18 - 2.13 (m, 4H), 2.03 - 1.99 (m, 2H), 1.71 - 1.30 (m, 23H), 1.10 - 10.70 (m, 6H), 0.67 (s, 3H)

[0413] Step 7. Synthesis of A55. To a solution of 1 - ((3R,5S,8R,9S,10S,13S,14S,17S) - 3 - hydroxy - 3 - (methoxymethyl) - 10,13 - dimethylhexadecahydro - 1H - cyclopenta[a]phenanthren - 17 - yl)ethanone (AA7, 15 g, 41.3 mmol) and a catalytic amount of HBr (167 mg, 40% in water) in MeOH (150 mL) was added dibromine (2.32 mL, 45.4 mmol) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. TLC (PE:EtOAc = 3:1) indicated the completion of the reaction. The reaction was quenched with saturated NaHCO3 and the pH was adjusted to 7 - 8. The reaction mixture was extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give the crude product 2 - bromo - 1 - ((3R,5S,8R,9S,10S,13S,14S,17S) - 3 - hydroxy - 3 - (methoxymethyl) - 10,13 - dimethylhexadecahydro - 1H - cyclopenta[a]phenanthren - 17 - yl)ethanone (A55, 16 g) as a yellow oil. 1 HNMR (CDCl3, 400 MHz): δ δ = 3.92 - 3.91 (m, 2H), 3.50 (s, 5H), 3.39 (S, 5H), 3.18 (s, 3H), 2.82 - 3.72 (m,, 1H), 2.30 - 2.10 (m, 1H), 1.72 - 1.12 (m, 34H), 1.08 - 0.70 (m, 9H), 0.67 (s, 3H).

[0414] Procedure 8.139 Synthesis. K2CO3 (125 mg, 906 μmol) was added to a solution of A55 (200 mg, 453 μmol) and 4-methyl-1H-pyrazole (48 mg, 588 μmol) in acetone (3 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 12 h, at which point TLC indicated that the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated to give the crude product (200 mg). The reaction mixture was purified by HPLC (column: Waters Xbridge Prep OBD C18 150× 30 5u, gradient: 44~74% B (A = 0.05% ammonia-ACN, B = acetonitrile), flow rate: 25 mL / min) to afford Compound 139 (53.6 mg) as a white solid. 1 1H NMR (chloroform-d, 400 MHz) δ = 7.34 (s, 1H), 7.17 (s, 1H), 4.77 - 4.91 (m, 2H), 3.39 (s, 3H), 3.18 (s, 2H), 2.57 (t, J = 8.8 Hz, 1H), 2.14 - 2.23 (m, 1H), 2.09 (s, 3H), 1.98 - 2.06 (m, 2H), 1.63 - 1.74 (m, 4H), 1.50 - 1.55 (m, 2H), 1.10 - 1.50 (m, 12H), 0.94 - 1.02 (m, 1H), 0.80 - 0.87 (m, 1H), 0.75 (s, 3H), 0.67 ppm (s, 3H). LCMS Rt = 2.848 min (4-minute chromatography), calculated MS ESI for C27H42N2O3[M+Na]+ 465.3, found 465.1 ([M+H-18]+).

[0415] Example 68. Synthesis of 140.

Chemical Structure

[0416] Example 69. Synthesis of 141.

Chemical Structure

[0417] Example 70. Synthesis of 142. [Chemical formula] According to Example 67, the title compound was prepared. Compound 141 (59.4 mg): 1 1H NMR (chloroform-d, 400 MHz) δ = 7.86 (s, 1H), 7.82 (s, 1H), 4.87 - 5.05 (m, 2H), 3.40 (s, 3H), 3.19 (s, 2H), 2.61 (t, J = 8.8 Hz, 1H), 2.16 - 2.26 (m, 1H), 2.01 - 2.08 (m, 2H), 1.66 - 1.77 (m, 4H), 1.14 - 1.55 (m, 14H), 0.94 - 1.04 (m, 1H), 0.82 - 0.89 (m, 1H), 0.76 (s, 3H), 0.66 (s, 3H). LCMS Rt = 2.827 min (chromatography for 4 minutes), MS ESI calculated value of C27H39N3O3[M+H]+ is 454.3, measured value is 454.2 ([M+H]+.

[0418] Example 71. Synthesis of 143. [Chemical formula] According to Step 4 of Example 5, the title compound was prepared. Compound 143: 1 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 1.0 Hz, 1H), 7.04 (d, J = 1.0 Hz, 1H), 5.00 - 4.81 (m, 2H), 2.69 - 2.57 (m, 1H), 2.29 - 1.02 (m, 27H), 0.99 - 0.89 (m, 3H), 0.69 (s, 3H). LCMS:R t = 1.367 min (chromatography for 2 minutes), C27H42N2O3 [M + H + Na] + The calculated value of MS ESI is 424, and the measured value is 424.

[0419] Example 73. Synthesis of 145.

Chemical Structure

[0420] Example 74. Synthesis of 146.

Chemical Structure

[0421] Example 75. Synthesis of 147.

Chem.

[0422] Example 76. Synthesis of 148.

Chem.

[0423] Example 77. Synthesis of 149. [Chemical formula] According to Step 7 of Example 47, the title compound was prepared. Compound 149: 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.05 (d, J = 6.8 Hz, 1H), 4.83 - 4.69 (m, 2H), 3.94 - 3.89 (m, 2H), 2.53 (t, J = 8.8 Hz, 1H), 2.17 - 1.99 (m, 2H), 1.67 - 1.18 (m, 24H), 0.78 - 0.77 (m, 3H) 0.73 (s, 3H), 0.64 (s, 3H). LCMS Rt = 1.334 min (chromatography for 2 minutes), C 27 H 42 N2O3[M + Na] + The calculated MS ESI value of 443, measured value 443.

[0424] Example 78. Synthesis of 150. [Chemical formula] According to Step 7 of Example 47, the title compound was prepared. Compound 149: 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.06 (s, 1H), 4.84 - 4.71 (m, 2H), 4.14 - 4.13 (m, 1H), 2.54 (t, J = 8.8 Hz, 1H), 2.18 - 2.00 (m, 2H), 1.69 - 1.50 (m, 24H), 1.36 - 1.19 (m, 22H), 0.79 - 0.78 (m, 2H) 0.74 (s, 3H), 0.65 (s, 3H). LCMS Rt = 0.957 min (chromatography for 1.5 minutes), C 28 H 44 N2O3[M + Na] + The calculated MS ESI value of 479, measured value 479.

[0425] Example 79. Synthesis of 151, 152, and 153.

Chemical formula

[0426] Synthesis of Compound 152: To a solution of Compound 151 (400 mg, 0.901 mmol) in MeOH (5 mL) was added Pd / C (wet, 10%, 40 mg). After degassing three times with H2, the reaction mixture was stirred at 25 °C for 6 hours in H2 (15 psi). When TLC (PE:EA) indicated that the starting material had been consumed, the reaction mixture was filtered to remove Pd / C and the filtrate was concentrated to obtain 2-(4 - amino - 1H - pyrazol - 1 - yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3 - hydroxy - 3,10,13 - trimethylhexadecahydro - 1H - cyclopenta[a]phenanthren - 17 - yl)ethanone (200 mg). Compound 152: 1 H NMR (400 MHz, CDCl3) δ 7.20 (s, 1H), 7.01 (s, 1H), 4.83 - 4.70 (m, 2H), 2.54 (t, J = 8.8 Hz, 1H), 2.18 - 2.00 (m, 2H), 1.69 - 1.50 (m, 4H), 1.40 - 1.20(m, 15H), 0.79 - 0.78 (m, 2H) 0.75 (s, 3H), 0.65 (s, 3H). LCMS Rt = 0.754min(1.5 minutes of chromatography), C 25 H 39 N3O2[M + Na] + The calculated value of MS ESI for 436, the measured value is 436.

[0427] Synthesis of Compound 153: To a solution of 2-(4-amino-1H-pyrazol-1-yl)-1-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanone (150 mg, 0.362 mmol) in DCM (2 mL), acetic anhydride (44.3 mg, 0.434 mmol) was added, and then TEA (0.15 mL, 0.362 mmol) was added. The resulting reaction mixture was stirred at 25 °C for 12 h. LCMS indicated that the starting material was completely consumed. Water (10 mL) was added to this mixture, and then it was extracted with EtOAc (8 mL × 3). The combined organic phases were concentrated to give a residue, which was purified by prep-HPLC to give N-(1-(2-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazol-4-yl)acetamide (13 mg). Compound 153: 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.42 (s, 1H), 7.09 (s, 1H), 4.91 - 4.78 (m, 2H), 2.54 (t, J = 8.4 Hz, 1H), 2.19 - 2.01 (m, 5H), 1.67 - 1.51 (m, 5H), 1.40 - 1.17(m, 19H), 0.97 - 0.79 (m, 3H), 0.75 (s, 3H), 0.66 (s, 3H). LCMS Rt = 1.205 min (chromatography for 2 minutes), C 27 H 41 N3O3[M + H] + The calculated MS ESI value of is 456, and the measured value is 456.

[0428] Example 80. Synthesis of 154.

Chemical Structure

[0429] Example 81. Synthesis of 155.

Chemical Structure

[0430] Synthesis of A57. To a solution of A56 in THF (30 mL) was added a solution of BH3-Me2S (7.01 mL, 70.01 mmol) dropwise at 0 °C. The solution was stirred at 25 °C for 12 h, and at this point, TLC (PE:EA = 3:1) indicated that the reaction was complete. After cooling to 0 °C, a solution of NaOH (23.3 mL, 3 M, 70.01 mmol) was slowly added while maintaining the temperature below 10 °C, and then H2O2 (8.06 g, 33% w / w in water, 70.1 mmol) was added. The resulting solution was stirred at 25 °C for 2 h and then extracted with EtOAc (40 mL × 3). The combined organic phases were washed with saturated aqueous Na2S2O3 (20 mL × 2), brine (30 mL), dried over Na2SO4, and concentrated to give A57 as a white solid. This crude product was used in the next step without further purification.

[0431] Synthesis of A58. A mixture of A57, PCC (2.32 g, 10 mmol), and silica gel (2.5 g) in DCM (30 mL) was stirred at 25 °C for 1 h. Thereafter, TLC (PE:EA = 3:1) indicated that the reaction was complete. The solution was concentrated under reduced pressure to obtain the crude product, which was purified by chromatography on silica gel (PE:EA = 5:1) to give A58 (1.05 g) as a yellow solid.

[0432] Synthesis of A59. Bromine (138 mg, 865 μmol) was added dropwise to a solution of A58 (200 mg, 577 μmol) and concentrated HBr (9.7 mg, 57.6 μmol) in MeOH (5 mL). The reaction mixture was stirred at 25 °C for 8 h and then heated to 50 °C over 8 h. At this point, TLC (PE:EA = 3:1) indicated that the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3 (4 mL), and the pH was adjusted to 7 - 8. The solution was extracted with EtOAc (8 mL × 3), and the combined organic phases were dried over Na2SO4 and concentrated to give A59 (210 mg).

[0433] Synthesis of 155. Potassium carbonate (243 mg, 1.76 mmol) and morpholine (255 mg, 2.93 mmol) were added to a solution of A59 (250 mg, 587 μmol) in acetone (6 mL) at 25 °C, and the mixture was stirred at 50 °C for 8 h. TLC (PE:EA = 1:1) analysis indicated that the reaction was complete. At this point, the mixture was extracted with water (8 mL) and EA (12 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated to give 155 (220 mg, crude) as a yellow solid. The crude solid was purified by preparative HPLC (0.05% HCl - ACN) to give 155 (42.0 mg) as a white solid. 1 H NMR (400 MHz, Methanol - d4) δ 3.80 - 3.60 (m, 4H), 3.28 - 3.17 (m, 1H), 2.81 - 2.48 (m, 4H), 2.18 - ...

Claims

1. as follows: 【Chemical Formula 1】 【Chemical Formula 2】 【Chemical Formula 3】 【Chemical Formula 4】 【Chemical Formula 5】 【Chemical Formula 6】 【Chemical Formula 7】 【Chemical Formula 8】 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical Formula 11】 【Chemical Formula 12】 【Chemical Formula 13】 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical Formula 16】 【Chemical Formula 17】 【Chemical Formula 18】 【Chemical Formula 19】 【Chemical Formula 20】 【Chemical Formula 21】 【Chemical Formula 22】 【Chemical Formula 23】 【Chemical Formula 24】 【Chemical Formula 25】 【Chemical Formula 26】 【Chemical Formula 27】 【Chemical Formula 28】 【Chemical Formula 29】 【Chemical Formula 30】 【Chemical Formula 31】 [Chemical Formula 32] [Chemical Formula 33] [Chemical Formula 34] [Chemical Formula 35] [Chemical Formula 36] [Chemical Formula 37] [Chemical Formula 38] [Chemical Formula 39] [Chemical Formula 40] [Chemical Formula 41] [Chemical Formula 42] [Chemical Formula 43] [Chemical Formula 44] [Chemical Formula 45] [Chemical Formula 46] [Chemical Formula 47] A compound selected from the following:

2. The compound is as follows: [Chemical Formula 48] [Chemical Formula 49] [Chemical Formula 50] [Chemical Formula 51] [Chemical Formula 52] [Chemical Formula 53] [Chemical Formula 54] [Chemical Formula 55] [Chemical Formula 56] [Chemical Formula 57] [Chemical Formula 58] [Chemical Formula 59] [Chemical Formula 60] 【Chemical Formula 61】 【Chemical Formula 62】 【Chemical Formula 63】 【Chemical Formula 64】 【Chemical Formula 65】 【Chemical Formula 66】 【Chemical Formula 67】 【Chemical Formula 68】 【Chemical Formula 69】 【Chemical Formula 70】 【Chemical Formula 71】 【Chemical Formula 72】 【Chemical Formula 73】 【Chemical Formula 74】 【Chemical Formula 75】 【Chemical Formula 76】 【Chemical Formula 77】 【Chemical Formula 78】 【Chemical Formula 79】 【Chemical Formula 80】 【Chemical Formula 81】 【Chemical Formula 82】 【Chemical Formula 83】 【Chemical Formula 84】 The compound according to claim 1, selected from the following:

3. The compound is as follows: 【Chemical Formula 85】 【Chemical Formula 86】 【Chemical Formula 87】 【Chemical Formula 88】 【Chemical 89】 【Chemical 90】 【Chemical 91】 【Chemical 92】 【Chemical 93】 【Chemical 94】 【Chemical 95】 【Chemical 96】 【Chemical 97】 【Chemical 98】 【Chemical 99】 【Chemical 100】 【Chemical 101】 【Chemical 102】 【Chemical 103】 【Chemical 104】 【Chemical 105】 【Chemical 106】 【Chemical 107】 【Chemical 108】 【Chemical 109】 【Chemical 110】 【Chemical 111】 【Chemical 112】 【Chemical 113】 The compound according to claim 2, selected from the following:

4. The compound is as follows: 【Chemical 114】 【Chemical 115】 【Chemical 116】 【Chemical 117】 【Chemical Formula 118】 【Chemical Formula 119】 【Chemical Formula 120】 【Chemical Formula 121】 【Chemical Formula 122】 The compound according to claim 3, selected from the following:

5. as follows: 【Chemical Formula 123】 【Chemical Formula 124】 【Chemical Formula 125】 【Chemical Formula 126】 【Chemical Formula 127】 【Chemical Formula 128】 【Chemical Formula 129】 【Chemical Formula 130】 【Chemical Formula 131】 【Chemical Formula 132】 【Chemical Formula 133】 【Chemical Formula 134】 【Chemical Formula 135】 【Chemical Formula 136】 【Chemical Formula 137】 【Chemical Formula 138】 【Chemical Formula 139】 【Chemical Formula 140】 【Chemical Formula 141】 【Chemical Formula 142】 【Chemical Formula 143】 【Chemical Formula 144】 【Chemical Formula 145】 【Chemical 146】 【Chemical 147】 【Chemical 148】 【Chemical 149】 【Chemical 150】 【Chemical 151】 【Chemical 152】 【Chemical 153】 【Chemical 154】 【Chemical 155】 【Chemical 156】 【Chemical 157】 【Chemical 158】 【Chemical 159】 【Chemical 160】 【Chemical 161】 【Chemical 162】 【Chemical 163】 【Chemical 164】 【Chemical 165】 【Chemical 166】 【Chemical 167】 【Chemical 168】 【Chemical 169】 A pharmaceutically acceptable salt of a compound selected from the following:

6. The salt is as follows: 【Chemical 170】 【Chemical 171】 【Chemical 172】 【Chemical 173】 【Chemical 174】 【Chemical 175】 【Chemical 176】 【Chemical 177】 【Chemical 178】 【Chemical 179】 【Chemical 180】 【Chemical 181】 【Chemical 182】 【Chemical 183】 【Chemical 184】 【Chemical 185】 【Chemical 186】 【Chemical 187】 【Chemical 188】 【Chemical 189】 【Chemical 190】 【Chemical 191】 【Chemical 192】 【Chemical 193】 【Chemical 194】 【Chemical 195】 【Chemical 196】 【Chemical 197】 【Chemical 198】 【Chemical 199】 【Chemical 200】 【Chemical 201】 【Chemical 202】 【Chemical 203】 【Chemical 204】 【Chemical 205】 【Chemical 206】 The pharmaceutically acceptable salt according to claim 5, which is selected from pharmaceutically acceptable salts of compounds selected from

7. The salt is as follows: 【Chemical 207】 【Chemical 208】 【Chemical 209】 【Chemical 210】 【Chemical 211】 【Chemical 212】 【Chemical 213】 【Chemical 214】 【Chemical 215】 【Chemical 216】 【Chemical 217】 【Chemical 218】 【Chemical 219】 【Chemical 220】 【Chemical 221】 【Chemical 222】 【Chemical 223】 【Chemical 224】 【Chemical 225】 【Chemical 226】 【Chemical 227】 【Chemical 228】 【Chemical 229】 【Chemical 230】 【Chemical 231】 【Chemical 232】 【Chemical 233】 【Chemical 234】 【Chemical 235】 The pharmaceutically acceptable salt according to claim 5, selected from pharmaceutically acceptable salts of compounds selected from

8. The salt is as follows: 【Chemical 236】 【Chemical 237】 【Chemical 238】 【Chemical 239】 【Chemical 240】 【Chemical 241】 【Chemical 242】 【Chemical 243】 【Chemical 244】 The pharmaceutically acceptable salt according to claim 5, selected from pharmaceutically acceptable salts of compounds selected from

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to any one of claims 5 to 8 and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition for inducing sedation and / or anesthesia in a subject, comprising the compound according to any one of claims 1 to 4.

12. A pharmaceutical composition for inducing sedation and / or anesthesia in a subject, the pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8.

13. A pharmaceutical composition for treating seizures in a subject, the pharmaceutical composition comprising a compound according to any one of claims 1 to 4.

14. A pharmaceutical composition for treating seizures in a subject, the pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8.

15. A pharmaceutical composition for treating epilepsy or status epilepticus in a subject, the pharmaceutical composition comprising a compound according to any one of claims 1 to 4.

16. A pharmaceutical composition for treating epilepsy or status epilepticus in a subject, the pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8.

17. A pharmaceutical composition for treating tremors in a subject, the pharmaceutical composition comprising a compound according to any one of claims 1 to 4.

18. A pharmaceutical composition for treating tremors in a subject, the pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8.

19. The pharmaceutical composition according to claim 17 or claim 18, wherein the tremor is essential tremor or parkinsonian tremor.

20. The pharmaceutical composition according to claim 19, wherein the tremor is essential tremor.

21. A pharmaceutical composition for treating depression in a subject, the pharmaceutical composition comprising a compound according to any one of claims 1 to 4.

22. A pharmaceutical composition for treating depression in a subject, comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8.

23. The pharmaceutical composition according to claim 21 or claim 22, wherein the depression is postpartum depression.

24. The pharmaceutical composition according to claim 21 or claim 22, wherein the depression is major depressive disorder.

25. The pharmaceutical composition according to claim 24, wherein the major depressive disorder is severe major depressive disorder or moderate major depressive disorder.

26. A pharmaceutical composition for treating depression in a subject and for treating eating disorders in a subject, wherein the eating disorder is selected from anorexia nervosa, bulimia nervosa, binge eating disorder and cachexia, and comprising a compound according to any one of claims 1 to 4.

27. A pharmaceutical composition for treating eating disorders in a subject, wherein the eating disorder is selected from anorexia nervosa, bulimia nervosa, binge eating disorder and cachexia, and comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8.

28. A pharmaceutical composition for treating Angelman syndrome in a subject, comprising a compound according to any one of claims 1 to 4.

29. A pharmaceutical composition for treating Angelman syndrome in a subject, comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8.

30. A pharmaceutical composition for treating a disorder related to GABA function in a subject in need of treatment for a disorder related to GABA function, comprising the compound according to any one of claims 1 to 4, wherein the disorder is selected from the group consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, spasm disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder (ASD), pain, traumatic brain injury (TBI), vascular disease, substance use disorder and / or withdrawal syndrome, and tinnitus.

31. A pharmaceutical composition for treating a disorder related to GABA function in a subject in need of treatment for a disorder related to GABA function, comprising a pharmaceutically acceptable salt according to any one of claims 5 to 8, wherein the disorder is selected from the group consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, spasm disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder (ASD), pain, traumatic brain injury (TBI), vascular disease, substance use disorder and / or withdrawal syndrome, and tinnitus.

32. The pharmaceutical composition according to any one of claims 9 to 31, wherein the pharmaceutical composition is adapted to be orally administered.

33. The pharmaceutical composition according to claim 32, wherein the pharmaceutical composition is adapted to be administered as a tablet.

34. The pharmaceutical composition according to claim 33, wherein the tablet comprises 0.1% to 50% of the compound or pharmaceutically acceptable salt by weight of the tablet.

35. The pharmaceutical composition according to any one of claims 9 to 34, wherein the pharmaceutical composition is adapted to be administered 1 to 5 times a day.

36. The pharmaceutical composition according to any one of claims 9 to 35, wherein each dosage of the pharmaceutical composition provides 0.01 mg to 20 mg of the compound or a pharmaceutically acceptable salt per kilogram of body weight.

37. The pharmaceutical composition according to any one of claims 9 to 36, wherein the pharmaceutical composition is adapted to be administered chronically.

38. The pharmaceutical composition according to any one of claims 9 to 37, wherein the pharmaceutical composition is adapted to be administered for a period of at least three months.

39. The pharmaceutical composition according to any one of claims 9 to 38, wherein the pharmaceutical composition is adapted to be administered in combination with another therapeutic agent.

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