Neurostimulant steroids, compositions, and their use

Abstract

To provide neuroactive steroids for use in preventing and treating CNS-related conditions, compositions comprising the neuroactive steroids, and methods of treating CNS-related disorders.SOLUTION: Provided herein are 19-nor C3, 3-disubstituted steroids represented by formula (I), and compositions comprising the compound of formula (I). [In the formula, A represents an N-containing 5-membered heterocycle; R1 represents lower alkyl, or lower haloalkyl; R2 and R3 represent H, halo, or the like; and R4 represents a group such as halo, cyano, or lower alkyl.]SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related applications This application claims priority to International Application Number PCT / CN2014 / 078820 (filed May 29, 2014). The entire contents of this International Application are incorporated herein by reference. [Background technology]

[0002] Background of the Invention Brain excitability is defined as the range of animal arousal from coma to convulsions and is controlled by various neurotransmitters. Generally, neurotransmitters are involved in regulating the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70mV, and the inside of the cell is negative relative to the outside. The potential (voltage) is controlled by ions (K) across the neuronal semipermeable membrane. + kaNa + Cl - This is a result of the balance of organic anions. Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, excitatory chemical mediators such as acetylcholine cause membrane depolarization (a change in potential from -70mV to -50mV). This action is due to Na + This process is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine, an ion-permeability enhances membrane permeability. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of the GABA receptor complex (GRC), its effect on brain excitability is mediated by the neurotransmitter GABA. Since up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on overall brain excitability. GABA regulates the excitability of individual neurons by controlling the conductance of chloride ions across the neuronal membrane. By interacting with recognition sites on the GRC, GABA promotes the flow of chloride ions into the cell downwards along the GRC's electrochemical gradient. This increase in intracellular anion levels causes hyperpolarization of the membrane potential, reducing the neuron's sensitivity to excitatory input (i.e., decreasing neuronal excitability). In other words, the higher the chloride ion concentration within a neuron, the lower the brain's excitability (arousal level).

[0004] GRCs have been well-established to be involved in mediating anxiety, seizure activity, and sedation. Therefore, GABA, and drugs that act like GABA or enhance the effects of GABA (e.g., therapeutically beneficial barbiturates and benzodiazepines (BZs), e.g., Valium®), exert their therapeutically beneficial effects by interacting with specific regulatory sites on GRCs. Accumulated evidence now suggests that GRCs contain distinct sites for neurostimulant steroids in addition to benzodiazepine and barbiturate binding sites (Lan, NC et al., Neurochem. Res. 16:347-356 (1991)).

[0005] Neurostimulant steroids can occur endogenously. The most potent endogenous neurostimulant steroids are 3α-hydroxy-5-reduced pregnane-20-one and 3α-21-dihydroxy-5-reduced pregnane-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, MD et al., Science 232:1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-35). 3 (1987).

[0006] The ovarian hormone progesterone and its metabolites have been shown to have a significant effect on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Supplement 130:19-24 (1985); Pfaff, DW and McEwen, BS, 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 fluctuate according to the stage of the menstrual cycle. It is well-established that the levels of progesterone and its metabolites decrease before the onset of menstruation. It is also well-established that certain physical symptoms recur every month before the onset of menstruation. Symptoms associated with premenstrual syndrome (PMS) include stress, anxiety, and migraines (Dalton, K., Premenstrual Syndrome). Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984). Subjects with PMS experience a recurring episode of symptoms that appear before menstruation and disappear after menstruation each month.

[0007] In a similar manner, a decrease in progesterone also temporally correlates with an increase in seizure frequency in female epilepsy patients (i.e., menstrual epilepsy) (Laidlaw, J., Lancet, 1235-1237 (1956)). A more direct correlation was observed with a decrease in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). Furthermore, in subjects with primary generalized petit mal seizure epilepsy, the temporal frequency of seizures correlated with the frequency of premenstrual syndrome symptoms (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 epileptic seizures correlated with the menstrual cycle (Aird, RB and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)).

[0008] Another 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 who have experienced PND have a high incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).

[0009] In summary, these findings suggest a significant role for progesterone and deoxycorticosterone, and more specifically their metabolites, in regulating the homeostasis of brain excitability, manifesting as increased seizure activity or symptoms associated with menstrual epilepsy, PMS, and PND. The correlation between low levels of progesterone and symptoms associated with PMS, PND, and menstrual epilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)) has encouraged 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., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not always effective in treating the aforementioned syndromes. For example, there is no dose-response relationship to progesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).

[0010] Novel and improved neurostimulant steroids are needed that act as modulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders. The compounds, compositions, and methods described herein are intended for this purpose. [Prior art documents] [Non-patent literature]

[0011] [Non-licensed Document 1] Lan, NC, Neurochem. Res. 16: 347-356 (1991) [Non-licensed Document 2] Majewska, MD, Science 232:1004-1007(1986) [Non-licensed Document 3] Harrison, NL, J Pharmacol. Exp. Ther. 241:346-353 (1987) [Non-licensed Document 4] Backstrom, T., Acta Obstet. Gynecol. Scand. Supplement 130:19-24 (1985) [Non-licensed Document 5] Pfaff, DW McEwen, BS, Science 219:808-814(1983) [Non-licensed Document 6] Gyermekら,J Med Chem.11:117(1968) [Non-licensed Document 7] Lambert,J.ら,Trends Pharmacol.Sci.8:224-227(1987) [Non-licensed Document 8] Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd Edition, Chicago Yearbook, Chicago (1984) [Non-licensed Document 9] Laidlaw,J.,Lancet,1235-1237(1956) [Non-licensed Document 10] Rosciszewska, J. Neurol. Neurosurg. Psych. 49: 47-51 (1986) [Non-licensed Document 11] Backstrom, T., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983) [Non-licensed Document 12] Aird, RB 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) [Overview of the project] [Means for solving the problem]

[0012] Summary of the Invention The present invention is partly based on the desire to provide novel 19-nor (i.e., C19 desmethyl) compounds having excellent potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, safety, clearance, and / or metabolism, such as those related to progesterone, deoxycorticosterone, and their metabolites. One important feature of compounds such as those described herein is a disubstituted at the C3 position (e.g., one substituent is a 3α-hydroxyl moiety). The inventors anticipate that the C3 disubstituted eliminates the possibility of oxidation of this hydroxyl moiety to a ketone, preventing further metabolism and reducing the possibility of a second exclusion pathway such as glucuronidation. The inventors further anticipate that the overall effect of the C3 disubstituted should improve the overall PK parameters and reduce potential toxicity and side effects, thereby potentially allowing for oral and / or chronic administration in certain embodiments. Another important feature of the compounds described herein is the presence of a hydrogen atom instead of a methyl group at the C19 position ("19-nor"). The inventors anticipate that 19-nor compounds will have improved physical properties, such as improved solubility, compared to their C19-methyl counterparts. The inventors further anticipate that solubility will be increased, for example, when the AB ring system is in a cis configuration.

[0013] Therefore, in one aspect, in this specification, formula (I): [ka] 19-Nol-C3,3-disubstituted C21-triazoles and tetrazoles, as well as pharmaceutically acceptable salts thereof, are provided; in formula (I), A is group: [ka] Selected from, R 1is C1-C6 haloalkyl (CHF2, CH2F) or C1-C6 alkyl (e.g., CH3, CH2CH3, heteroalkyl, e.g., CH2OCH3, CH2OCH2CH3); R 2 and R 3 are independently selected from H, halo (e.g., F), C1-C6 alkyl (e.g., CH3) or alkoxy (e.g., OCH3, OCH2CH3); R 4 is halo (e.g., Cl, F), cyano, nitro, -S(O) x R a , -NR b R c , C1-C6 alkyl (e.g., CH3, CF3), C1-C6 alkoxy, -C(O)R a , -C(O)OR a , or -C(O)NR b R c ; R a is H or C1-C6 alkyl; R b and each of R c is independently H , -S(O) x R a , -C(O)R a , C1-C6 alkyl, or C1-C6 alkoxy, or R b and R c together with the atom to which they are attached form a ring; n is an integer from 0 to 2; and x is an integer from 0 to 2; where when A is (A-1) or (A-2), R 1 is selected from -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CBr3, -CHBr2, -CH2Br, or C1-C6 alkyl; or when A is (A-3) or (A-5), R 1 is -CH3, -CH2F, -CH2OCH3, or -CHF2, and when n is 0, at least one of R 2 and R 3 is not H.

[0014] Steroids of formula (I), their subgeneral genera, and their pharmaceutically acceptable salts are collectively referred to herein as "compounds of the present invention."

[0015] In another aspect, a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient is provided. In a particular embodiment, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In a particular embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a particular embodiment, the compound of the present invention is provided in a prophylactically effective amount.

[0016] The compounds of the present invention described herein, in certain embodiments, are, for example, GABA A They act as GABA regulators, either positively or negatively affecting the receptor. Such compounds act as GABA regulators. A It is expected to possess CNS activity, acting as a regulator of central nervous system (CNS) excitability mediated by its ability to modulate receptors.

[0017] Accordingly, in another context, a method is provided for treating a CNS-related disorder in a subject requiring treatment of such disorder, the method comprising the step of administering an effective amount of the compound of the present invention to the subject. In certain embodiments, the CNS-related disorder is selected from the group consisting of sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disorders, substance abuse 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.

[0018] Other purposes and advantages will become apparent to those skilled in the art by considering the following detailed description, examples and claims.

[0019] definition chemical definition

[0020] The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are identified according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are usually defined as they appear therein. Furthermore, general rules of organic chemistry, as well as specific functional parts and reactivity, 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 Un It is described in Iversity Press, Cambridge, 1987.

[0021] The compounds described herein may contain one or more chiral centers and therefore may exist in 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 concentrated in one or more stereoisomers). Isomers may be isolated from the mixture by methods known to those skilled in the art (including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts); or preferred isomers may be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon See Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by El Eliel, 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.

[0022] When a range of values ​​is enumerated, it is intended to include each value and subrange within that range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C4~6 , C 4~5 , and C 5~6 It is intended to include alkyl groups.

[0023] The following terms are intended to have the meanings presented below and are useful in understanding the intended scope of this specification and the invention. When describing the invention (which may encompass compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions), the following terms have the meanings below unless otherwise indicated, where they exist. It should also be understood that, where described herein, any of the parts defined below may be substituted with various substituents, and that each definition is intended to encompass the substituted parts within those ranges as described below. Unless otherwise stated, the term “substituted” is defined as described below. It should further be understood that, where used herein, the terms “group” and “radical” may be considered interchangeable. The articles “a” and “an” may be used herein to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, “an analogue” means one or more analogs.

[0024] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1~20 "Alkyl" refers to a group having 1 to 12 carbon atoms. In some embodiments, an alkyl group has 1 to 12 carbon atoms. 1~12 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1~10 Alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1~9 Alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1~8 Alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C").1~7 Alkyl). In some embodiments, the alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl"). 1~6 Alkyl). In some embodiments, there are 1 to 5 alkyl groups. Having carbon atoms ("C 1~5 Alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1~4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1~3 Alkyl). In some embodiments, the alkyl group has one to two carbon atoms ("C"). 1~2 Alkyl). In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 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-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and others. Unless otherwise specified, each alkyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkyl") or 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 It is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C 1~10It is an alkyl group. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0025] As used herein, “alkylene,” “alkenylene,” and “alkynylene” refer to the divalent radicals of an alkyl group, an alkenyl group, and an alkynyl group, respectively. When a range or number of carbon atoms is given for a particular “alkylene,” “alkenylene,” and “alkynylene” group, it is understood that the range or number refers to the range or number of carbon atoms in the divalent chain of the linear carbon atoms. The “alkylene,” “alkenylene,” and “alkynylene” groups may or may not be substituted with one or more groups as described herein.

[0026] "Alkylene" refers to an alkyl group in which two hydrogen atoms are removed to give a divalent radical, and which may or may not be substituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Examples of substituted alkylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), and substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-).

[0027] "Alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds). 2~20 An alkenyl group is a compound that, in certain embodiments, contains no triple bond at all. In some embodiments, the alkenyl group has 2 to 10 carbon atoms. do ("C 2~10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2~8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be located internally (e.g., 2-butenyl) or at the 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), and butadienyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Further examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified, each presence of an alkenyl group can be independently substituted as needed, 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 an unsubstituted C 2~10 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C 2~10 It is Alkenil.

[0028] An "alkenylene" is an alkenyl group in which two hydrogen atoms are removed to give a divalent radical, and which may or may not be substituted. Examples of unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Examples of substituted alkenylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted ethylenes (-C(CH3)=CH-, -CH=C(CH3)-) and substituted propylenes (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-).

[0029] "Alkynnyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds). 2~20This refers to an "alkynyl" group. In certain embodiments, the alkynyl group contains no double bonds at all. 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 9 carbon atoms ("C"). 2~9 ("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 7 carbon atoms ("C"). 2~7 ("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 a "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be located internally (e.g., 2-butynyl) or at the terminal (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), and 2-butynyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4Examples include alkynyl groups, such 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; for example, substituted with 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.

[0030] "Alkynylene" refers to a linear alkynyl group from which two hydrogens have been removed to give a divalent radical, which may or may not be substituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, and substituted or unsubstituted propynylene.

[0031] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in its parent chain, and this one or more heteroatoms are inserted between adjacent carbon atoms within its parent carbon chain, and / or one or more heteroatoms are inserted between a carbon atom and its parent molecule (i.e., between the points of attachment). In certain embodiments, a heteroalkyl group refers to a saturated group ("heteroC 1~10 alkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. In some embodiments, a heteroalkyl group refers to a saturated group ("heteroC 1~9is an “alkyl”). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1~8 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1~7 alkyl”). In some embodiments, the heteroalkyl group is a group having from 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1~6 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1~5 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC 1~4 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 3 carbon atoms and 1 heteroatom ((“heteroC 1~3 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 2 carbon atoms and 1 heteroatom ((“heteroC 1~2 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ((“heteroC1 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having from 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC 2~6 alkyl”). Unless otherwise specified, each example of the heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In certain embodiments, the heteroalkyl group is unsubstituted heteroC 1~10 alkyl. In certain embodiments, the heteroalkyl group is substituted heteroC1 ~10 alkyl.

[0032] The term “heteroalkenyl” means, as used herein, an alkenyl group as defined herein, further comprising one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms in its parent carbon chain, and / or one or more heteroatoms are inserted between a carbon atom and its parent molecule (i.e., between bonding sites). In certain embodiments, a heteroalkenyl group is a group having two to ten carbon atoms, at least one double bond, and one, two, three, or four heteroatoms ("hetero C 2~10 "Alkenyl" refers to a group. In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least 1 double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2~9 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 2 to 8 carbon atoms, at least 1 double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2~8 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 2 to 7 carbon atoms, at least 1 double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2~7 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("hetero C"). 2~6 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 2 to 5 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms ("hetero C"). 2~5 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 2 to 4 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms ("hetero C"). 2~4("Alkenyl"). In some embodiments, the heteroalkenyl group has 2 to 3 carbon atoms, at least 1 double bond, and 1 heteroatom ("hetero C"). 2~3 ("Alkenyl"). In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and one or two heteroatoms ("hetero C"). 2~6 (Alkenyl). Unless otherwise specified, each example of a heteroalkenyl group is either unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, the heteroalkenyl group is an unsubstituted hetero-C 2~10 It is an alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is Alkenil.

[0033] The term “heteroalkynyl” means, as used herein, an alkynyl group as defined herein, further comprising one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms in its parent carbon chain, and / or one or more heteroatoms are inserted between a carbon atom and its parent molecule (i.e., between bonding sites). In certain embodiments, a heteroalkynyl group is a group having two to ten carbon atoms, at least one triple bond, and one, two, three, or four heteroatoms ("hetero-C"). 2~10 "Alkynyl" refers to a heteroalkynyl group. In some embodiments, the heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2~9 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC"). 2~8("Alkynyl"). In some embodiments, the heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC"). 2~7 (Alkynyl). In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, or fewer It has at least one triple bond and one, two, or three heteroatoms ("hetero C"). 2~6 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and one or two heteroatoms ("heteroC"). 2~5 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and one or two heteroatoms ("heteroC"). 2~4 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 2 to 3 carbon atoms, at least 1 triple bond, and 1 heteroatom ("heteroC"). 2~3 ("Alkynyl"). In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and one or two heteroatoms ("heteroC"). 2~6 (Alkynyl). Unless otherwise specified, each example of a heteroalkynyl group is independently either unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). In certain embodiments, the heteroalkynyl group is an unsubstituted hetero-C 2~10 It is an alkynyl group. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkinyl.

[0034] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” refer to the divalent radicals of an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, and a heteroalkynyl group, respectively. When a range or number of carbon atoms is given for a particular “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene” group, it is understood that the range or number refers to the range or number of carbon atoms in the divalent chain of the linear carbon atoms. The “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may or may not be substituted with one or more groups as described herein.

[0035] "Aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided to the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement). 6~14 This refers to an aryl group. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, 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 an aryl ring, as defined above, is fused with one or more carbocyrillic or heterocyclyl groups, where the bonding radical or bond site is located on the aryl ring, and in such cases the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each presence of an aryl group is independently substituted as needed, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In a particular embodiment, The aryl group is an unsubstituted C 6~14 It is aryl. In certain embodiments, the aryl group is substituted C 6~14 It is Ariel.

[0036] 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.

[0037] Typical examples of substitution aryls include the following: [ka] Here, R 56 and R 57 One of them can be hydrogen, and R 56and R 57 At least one of them is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR. 58 COR 59 , NR 58 SOR 59 , NR 58 SO2R 59 COOalkyl, COOaryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59 Selected from S-alkyl, SOalkyl, SO2alkyl, S-aryl, SOaryl, SO2aryl; or R 56 and R 57 These can be linked together to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (including, as necessary, one or more heteroatoms selected from the group N, O, or S). 60 and R 61 These are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl substitution C6~C 10 These are aryl, 5-10 member heteroaryl, or substituted 5-10 member heteroaryl.

[0038] Other representative aryl groups that have condensed heterocyclyl groups include the following: [ka] These are listed, and here each W is C(R 66 )2, NR 66 Selected from , O, and S; and each Y is carbonyl, NR 66 , selected from O and S; and R 66These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 These are aryls and heteroaryls with 5 to 10 members.

[0039] A "condensed aryl" is an aryl ring in which two of its ring carbons are shared with a second aryl ring or heteroaryl ring, or with a carbocykyl ring or heterocycline ring.

[0040] "Aralkyl" is a subset of alkyl and aryl groups as defined herein, and means an optionally substituted alkyl group substituted with an optionally substituted aryl group.

[0041] A "heteroaryl" is a radical of a 5-10 member monocyclic or bicyclic 4n+2 aromatic ring system (for example, having 6 or 10 π electrons shared in the cyclic arrangement) in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each Heteroatoms are independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, where the valency allows. Heteroaryl bicyclic ring systems may 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 carbocyclyl or heterocyclyl groups, where the bond site is located on the heteroaryl ring, and in such cases, the number of ring members still points to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, where the bond site is located on the aryl ring or heteroaryl ring, and in such cases, the number of ring members points to the number of ring members in the fused (aryl / heteroaryl) ring system. One ring is a bicyclic heteroaryl group that does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), and the bond site can be located on either ring, i.e., on the ring containing a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0042] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each presence of a heteroaryl group is independently substituted as necessary, i.e., either unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0043] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, and benzotriazolyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinil, isoquinolinil, sinnolinil, quinoxalinil, phthalazinyl, and quinazolinil.

[0044] Typical examples of heteroaryls include: [ka] These are listed, where each Y is a carbonyl, N, or NR. 65 Selected from O and S; R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryls.

[0045] "Heteroaralkyl" is a subset of alkyl and heteroaryl groups as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted heteroaryl group.

[0046] A "carbocyclyl" or "carbocyclic" structure is a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3~10 A carbocyclyl group is a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms. 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 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 As for the carbocyclyl group, the above C 3~6Examples include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). 3~10 As for the carbocyclyl group, the above C 3~8 Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), OctaHydro-1H-indenyl(C9), De Cahydronaphthalenyl (C 10 ), spiro[4.5]decanil(C 10 Examples include, but are not limited to, the above. When the above examples are illustrated, in certain embodiments the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or include fused, bridging, or spirocyclic systems (e.g., bicyclic systems ("bicyclic carbocyclyl")) and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which a carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on the carbocyclyl ring, and in such cases the number of carbons still refers to the number of carbons in the carbocyclic system. Unless otherwise specified, each presence of a carbocyclyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments the carbocyclyl group may be unsubstituted C 3~10 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is carbocyclyl.

[0047] In some embodiments, "carbocyrill" is a monocyclic saturated carbocyrill group having 3 to 10 ring carbon atoms ("C 3~10It is a cycloalkyl group. 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 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above C 5~6 Examples include cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above C 3~6 Examples include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3~10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is a cycloalkyl group.

[0048] A "heterocyclyl" or "heterocyclic" is a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom 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 bond site can be a carbon or nitrogen atom, if the valency allows. A heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl"), a fused ring system, a bridging ring system, or a spiro-ring system (e.g., a bicyclic ring system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the bond site is located on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is located on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl is independently substituted as necessary, i.e., either 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.

[0049] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur.

[0050] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxyranil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanil. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanil, oxekanil, and thiokanil. Examples of five-membered heterocyclyl groups condensed to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranil, dihydrobenzothienyl, and benzoxazolinonil.Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0051] Specific examples of heterocyclyl groups are shown in the following illustrative examples: [ka] Here, each W is CR 67 , C(R 67 )2, NR 67 Selected from O and S; each Y is NR 67 Selected from O and S; R 67 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl and 5-10 membered heteroaryl groups. These heterocyclyl rings may be optionally substituted with one or more groups selected from acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amide), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl groups. Substituents include carbonyl or thiocarbonyl groups, which provide, for example, lactam derivatives and urea derivatives.

[0052] When "hetero" is used to describe a compound or a group present on a compound, it means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero may be applied to any of the hydrocarbyl groups described above (e.g., alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteralkenyl, etc.) having one to five, and in particular, one to three heteroatoms.

[0053] "Ashil" is -C(O)R 20 This refers to a radical, and here, R 20 This includes hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is R 20 The group other than hydrogen is the acyl group. 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, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 member heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t Examples include, but are not limited to, (4- to 10-membered heterocyclines) (where t is an integer from 0 to 4). In a particular embodiment, R 21 C1-C8 alkyl groups substituted with halo or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10Aryl, arylalkyl, 5-10 member heteroaryl or heteroarylalkyl (each of which is an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyalkyl) (It is substituted with droxy.)

[0054] "Acylamino" means -NR 22 C(O)R 23 This refers to a radical, and here, R 22 The presence of each of R23 is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl as defined herein, or R 22 This is an amino protecting group. Examples of "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. Specific example of "acylamino" groups are -NR 24 C(O)-C1~C8 alkyl, -NR 24 C(O)-(CH2) t (C6~C 10 Ariel), -NR 24 C(O)-(CH2) t (5-10 member heteroaryl), -NR 24 C(O)-(CH2) t (C3~C 10 Cycloalkyl) and -NR 24 C(O)-(CH2) t (4-10 member heterocyclyl), where t is an integer from 0 to 4, and each R 24 R independently represents H or C1-C8 alkyl. In a particular embodiment, R 25 C1-C8 alkyl groups substituted with H, halo, or hydroxyl; C3-C 10Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 member heteroaryl, or heteroarylalkyl, each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl; R 26 C1-C8 alkyl groups substituted with H, halo, or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 member heteroaryl or heteroarylalkyl, each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl; however, R 25 and R 26 At least one of them is not H.

[0055] "Acyloxy" is -OC(O)R 27 This refers to a radical, and here, R 27 R is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, as defined herein. Typical examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 These are C1-C8 alkyl groups substituted with halo or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10These are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.

[0056] "alkoxy" means -OR 29 It refers to the base, and here, R 29 These are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted carbocyclyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0057] In a particular embodiment, R 29 is amino, substituted amino, C6~C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10 One or more substituents selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, a group having 1 to 5 substituents, in particular 1 to 3 substituents, in particular 1 substituent. An example of a "substituted alkoxy" group is -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 member heteroaryl), -O-(CH2) t (C3~C 10Cycloalkyl) and -O-(CH2) t Examples include, but are not limited to, 4- to 10-membered heterocyclyl groups, where t is an integer from 0 to 4, and any existing aryl, heteroaryl, cycloalkyl, or heterocyclyl group may itself be substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0058] "Amino" refers to the -NH2 radical.

[0059] "Substituting amino acid" refers to the compound of the formula -N(R 38 ) refers to the amino group of 2, where R 38 R is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 38 At least one of them is not hydrogen. In a particular embodiment, each R 38 These are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C6-C 10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxyl; C3-C8 alkenyl substituted with halo or hydroxyl; C3-C8 alkynyl substituted with halo or hydroxyl, or -(CH2) t (C6~C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl) or -(CH2)t Selected from (4-10 member heterocyclyl), where t is an integer from 0 to 8, each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups link together to form an alkylene group.

[0060] Examples of "substituted amino" groups include -NR 39 -C1~C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3~C 10 Cycloalkyl) and -NR 39 -(CH2) t Examples include (4-10 member heterocyclyls), but are not limited to these, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 The terms "substituted amino" independently represent H or C1-C8 alkyl; any alkyl group present may be substituted by a halo, substituted or unsubstituted amino or hydroxyl group; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may be substituted by an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl group. To avoid misunderstanding, the term "substituted amino" is defined below. This includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups. Substituted aminos encompass both monosubstituted and disubstituted amino groups.

[0061] "Azide" refers to the -N3 radical.

[0062] "Carbamoyl" or "amide" refers to the -C(O)NH2 radical.

[0063] "Substituted carbamoyl" or "substituted amide" refers to -C(O)N(R 62 ) refers to a 2 radical, where each R 62 R is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 62 At least one of them is not hydrogen. In a particular embodiment, R 62 H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, aralkyl, 5-10 member heteroaryl and heteroaralkyl; or C1-C8 alkyl substituted with halo or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Selected from aryl, aralkyl, 5-10 member heteroaryl or heteroaralkyl, each of which is substituted with an 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 R 62 It is anything other than H.

[0064] An example of a "substituted carbamoyl" group is -C(O)NR 64 -C1~C8 alkyl, -C(O)NR 64 -(CH2) t (C6~C 10 Aryl), -C(O)N 64 -(CH2) t (5-10 member heteroaryl), -C(O)NR 64-(CH2) t (C3~C 10 Cycloalkyl) and -C(O)NR 64 -(CH2) t Examples include (4-10 member heterocyclyls), but are not limited to these, where t is an integer from 0 to 4, and each R 64 Each independently represents H or C1-C8 alkyl, and any existing aryl, heteroaryl, cycloalkyl or heterocyclyl group may itself be substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0065] "Carboxylate" refers to the -C(O)OH radical.

[0066] "Cyano" refers to the -CN radical.

[0067] "Halo" or "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I). In certain embodiments, the halo group is fluoro or chloro.

[0068] "Hydroxy" refers to the -OH radical.

[0069] "Nitro" refers to the -NO2 radical.

[0070] "Cycloalkylalkyl" refers to an alkyl radical in which an alkyl group is replaced by a cycloalkyl group. Typical cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and cycloheptylmethyl. Examples include, but are not limited to, methyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0071] A "heterocyclylalkyl" refers to an alkyl radical in which an alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, and morpholinylethyl.

[0072] A "cycloalkenyl" is a substituted or unsubstituted carbocyrillyl group having 3 to 10 carbon atoms, a single cyclic ring or multiple fused rings (including fused ring systems and bridging ring systems), and at least one, in particular, one to two olefin unsaturated moieties. Examples of such cycloalkenyl groups include monocyclic structures (e.g., cyclohexenyl, cyclopentenyl, cyclopropenyl, etc.).

[0073] A "condensed cycloalkenyl" refers to a cycloalkenyl that has two ring carbon atoms common to a second aliphatic or aromatic ring, and has an olefin unsaturated ring positioned to confer aromaticity to the cycloalkenyl ring.

[0074] "Ethylene" refers to substituted or unsubstituted -(CC)- groups.

[0075] "Ethenyl" refers to a substituted or unsubstituted -(C=C)-.

[0076] "Ethynyl" refers to -(C≡C)-.

[0077] A "nitrogen-containing heterocyclyl" group refers to 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.

[0078] "Thioketo" refers to the S group.

[0079] Alkyl, alkenyl, alkynyl, carbocyrill, heterocyclyl, aryl, and heteroaryl groups as defined herein may be substituted as necessary (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyrill, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted" means, whether or not preceded by the term "as necessary," that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, produces a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions of that group, and when two or more positions in any given structure are substituted, the substituents are either the same or different at each position. The term “substituted” means all acceptable substituents of an organic compound, any substituents described herein that form a stable compound. Substitutions are intended to be included. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any preferred substituents, as described herein, that satisfy the bond valence of the heteroatom and consequently form a stable moiety.

[0080] Examples of carbon atom substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa , -SSR cc -C(=O)R aa -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 For example, -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14Examples include, but are not limited to, aryls and 5- to 14-membered heteroaryls. Here, each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Is it substituted by the base? Alternatively, two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb Or = NOR cc Replaced by the base; R aa Each of these beings is independent of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R bb Each of these entities exists independently as hydrogen, -OH, and -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, -SO2Rcc , -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R bb The groups are linked together to form a 3-14 member heterocyclyl or 5-14 member heteroaryl ring, where each alkyl Alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl compounds can be independently divided into 0, 1, 2, 3, 4, or 5 R compounds. dd Substituted with the base; R cc Each of these entities independently contains hydrogen and C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R dd Each of these entities 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 [[ID=�2]], -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(O)R ee , for example -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 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted by or two geminal R dd Substituents can link together to form either =O or =S; R ee Each of these beings is independent of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base; R ff Each of these entities independently contains hydrogen and C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups.gg Substituted with the base; R gg Each of these entities 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(C1 ~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 1~6Alkyl), -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 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 It is either an aryl, a 3-10 member heterocyclyl, a 5-10 member heteroaryl; or two geminal Rs. gg Substituents can link together to form =O or =S; where X - It is a counterion.

[0081] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Examples of counterions include halide ions (e.g., F -Cl - , Br - , I - ), NO3 - ClO4 - , OH - H2PO4 - HSO4 - SO4 -2 Examples include 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.).

[0082] Nitrogen atoms can be substituted or unsubstituted, wherever the bond valency allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, and -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, C1~10 Perhaloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryl and 5- to 14-membered heteroaryls, or two R atoms bonded to a nitrogen atom. cc The groups link together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc and R dd This is as defined above.

[0083] 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 in any way by the exemplary enumeration of substituents described above.

[0084] Other definitions The term "pharmaceutically acceptable salt" refers to a salt that, within reasonable limits of medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, and allergic reactions, and that is balanced by a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66, 1-19. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0085] The “subjects” to which the administration is intended include, but are not limited to, human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0086] Diseases, disorders, and conditions are used interchangeably in this specification.

[0087] As used herein, unless otherwise specified, the terms “treat,” “treating,” and “treatment” refer to actions taken while a subject is suffering from a particular disease, disorder, or condition. This refers to actions that reduce the severity of a disease, disorder, or condition, or that delay or slow the progression of the disease, disorder, or condition ("therapeutic actions"), and also refers to actions that are taken before the subject begins to develop a particular disease, disorder, or condition ("preventive actions").

[0088] Generally, the “effective dose” of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective dose of the compound in this invention may vary depending on factors such as the desired biological objective, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health status, and condition of the subject. The effective dose includes both therapeutic and prophylactic treatments.

[0089] Where used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide 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. “Therapeutic dose” of a compound means the amount of the therapeutic agent, alone or in combination with other treatments, that provides therapeutic benefit in the treatment of that disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0090] As used herein, unless otherwise specified, “preventive dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. The preventive dose of a compound means the amount of the therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of the disease, disorder, or condition. The term “preventive dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. [Brief explanation of the drawing]

[0091] [Figure 1] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 2] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 3]Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 4] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 5] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 6] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 7] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 8] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 9] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 10] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 11] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 12] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 13] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 14] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 15] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 16]Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 17] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 18] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 19] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 20] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 21] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Figure 22] Figures 1 to 22 illustrate typical 1H NMR spectra of exemplary compounds described herein. [Modes for carrying out the invention]

[0092] Detailed description of specific embodiments of the present invention As described herein, the present invention relates to formula (I): [ka] The formula provides 19-nor C3,3-disubstituted C21-triazole and C21-tetrazole neurostimulant steroids, or pharmaceutically acceptable salts thereof; in formula (I): A is group: [ka] Selected from; R 1 R is a C1-C6 haloalkyl (CHF2, CH2F) or C1-C6 alkyl (e.g., CH3, CH2CH3, CH2OCH3, CH2OCH2CH3); R2 and R 3 These are independently H, halo (e.g., F), C1-C6 alkyl (e.g., CH3) ) or selected from alkoxy (OCH3, OCH2CH3); R 4 These are halo (e.g., Cl, F), cyano, nitro, -S(O) x R a , -NR b R c , C1-C6 alkyl (e.g., CH3, CF3), C1-C6 alkoxy, -C(O)R a , -C(O)OR a -C(O)NR b R c And; R a is H or C1-C6 alkyl; R b and R c Each of these is independent of H, -S(O) x R a , -C(O)R a , C1-C6 alkyl, or C1-C6 alkoxy, or R b and R c These, together with the atoms to which they are bonded, form a ring (for example, R b and R c These, together with the atoms to which they are bonded, form 4- to 8-membered rings, such as heterocyclic rings, such as morpholine rings, pyrrolidine rings, and piperidine rings; n is an integer between 0 and 2; and x is an integer between 0 and 2.

[0093] In some embodiments, if A is (A-1) or (A-2), R 1 is selected from -CHF2, CH2F, -CCl3, -CHCl2, CH2Cl, -CBr3, CHBr2, CH2Br, or C1-C6 alkyl; or A is (A-3) or (A-5), and R 1 However, if n is -CH3, -CH2F, -CH2OCH3, or -CHF2, then R 2 and R 3 At least one of them is not H.

[0094] In some embodiments, if A is (A-1), (A-3), or (A-5), and n is 0, then R 2 and R 3 At least one of them is not H.

[0095] In some embodiments, if A is (A-1), (A-3), or (A-5), then R 2 and R 3 At least one of them is not H.

[0096] In some embodiments, if A is (A-1) or (A-2) and n is 0, then R 1 The C1-C6 alkyl group is selected from -CHF2, CH2F, -CCl3, -CHCl2, CH2Cl, -CBr3, CHBr2, CH2Br, or C1-C6 alkyl groups.

[0097] In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0098] In some embodiments, the compound of formula (I) is formula (Ia): [ka] It is selected from the following compounds.

[0099] In some embodiments, the compound of formula (I) is formula (Ib): [ka] It is selected from the following compounds.

[0100] In some embodiments, the compound of formula (I) is of formula (II): [ka] It is selected from the following compounds.

[0101] In some embodiments, n is 1, and R 4 is halo, cyano, -S(O) x R a , or C1-C6 alkyl. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is cyano. In some embodiments, R 4 is -S(O)2CH3. In some embodiments, A is group: [ka] Selected from.

[0102] In some embodiments, R 1 R is a C1-C6 alkyl group. In some embodiments, R 1 It is -CH3.

[0103] In some embodiments, R 2 and R 3 H is H.

[0104] In some embodiments, n is 1, and R 4 is halo, cyano, -S(O) x R a , or C1-C6 alkyl.

[0105] In some embodiments, R 4 It is -CH3.

[0106] In some embodiments, R 4 is -C(O)OR a In some embodiments, R a is H. In some embodiments, R a R is a C1-C6 alkyl group. In some embodiments, R a It is -CH2CH3.

[0107] In some embodiments, R 4 -C(O)NR b R c In some embodiments, R b and R c H is H.

[0108] In some embodiments, R 4 is cyano. In some embodiments, R 4 It is -S(O)2CH3.

[0109] In some embodiments, A is group: [ka] Selected from.

[0110] In some embodiments, this compound belongs to the group: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Selected from.

[0111] In one aspect, the Specified herein provides a pharmaceutical composition comprising a compound as described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0112] In one aspect, the present invention provides a method for treating a CNS-related disorder in a subject requiring treatment for the CNS-related disorder, the method comprising administering to the subject an effective amount of a compound as described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, an eating disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive impairment, a motor disorder, a personality disorder, autism spectrum disorder, pain, a traumatic brain injury, a vascular disorder, a substance abuse disorder and / or withdrawal syndrome, or tinnitus. In some embodiments, the CNS-related disorder is depression (e.g., postpartum depression). In some embodiments, the CNS-related disorder is tremor (e.g., essential tremor). In some embodiments, the CNS-related disorder is an eating disorder (e.g., anorexia nervosa, bulimia nervosa, binge eating disorder, cachexia).

[0113] In some embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In some embodiments, the compound is administered chronically.

[0114] In one aspect, this specification provides a method for inducing sedation and / or anesthesia in a subject, the method comprising the step of administering to the subject an effective amount of a compound of formula (I).

[0115] In one aspect, this specification provides a method for treating a seizure in a subject, the method comprising the step of administering to the subject an effective amount of the compound of formula (I).

[0116] In one aspect, this specification provides a method for treating epilepsy in a subject, the method comprising the step of administering to the subject an effective amount of a compound of formula (I).

[0117] In one aspect, this specification provides a method for treating a status epilepticus (SE) in a subject, the method comprising the step of administering to the subject an effective amount of a compound of formula (I). In some embodiments, the status epilepticus is a convulsive status epilepticus (e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, extremely refractory status epilepticus) or a non-convulsive status epilepticus (e.g., generalized status epilepticus, complicated partial status epilepticus).

[0118] In one aspect, this specification provides a method for treating a disorder in a subject requiring treatment of the disorder (for example, a disorder as described herein, e.g., a disorder related to 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 pharmaceutically acceptable composition.

[0119] Pharmaceutical composition In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition contains a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition contains a prophylactically effective amount of the active ingredient.

[0120] The pharmaceutical compositions provided herein may be administered by various routes, including, but not limited to, oral (enteral), parenteral (injection), rectal, transdermal, intradermal, intrathin, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal.

[0121] Typically, the compounds provided herein are administered in effective doses. The actual amount of compound administered is typically determined by a physician in light of the relevant circumstances, including the symptoms being treated, the chosen route of administration, the specific compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0122] When used to prevent the occurrence of CNS disorders, the compounds provided herein Typically, under the advice and supervision of a physician, the drug may be administered to subjects at risk of developing the symptoms at the dosage levels described above. Subjects at risk of developing specific symptoms generally include those with a family history of the symptoms or those identified by genetic testing or screening as particularly susceptible to developing the symptoms.

[0123] The pharmaceutical compositions provided herein are also administered chronically ("chronic administration"). Chronic administration means 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, or indefinitely, for example, over the remainder of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within the therapeutic window.

[0124] The pharmaceutical compositions of the present invention may be delivered using a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition may be given 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, intramuscular or subcutaneous bolus doses allow for the slow release of the active ingredient, while boluses delivered directly to a vein (e.g., by IV infusion) allow for faster delivery, which rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example by IV infusion, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in yet another embodiment, the pharmaceutical composition may be administered first as a bolus dose, followed by continuous infusion.

[0125] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, compositions are provided in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically discontinuous unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutically acceptable excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0126] For oral administration, a typical regimen involves 1 to 5 oral doses per day, particularly 2 to 4 doses, and usually 3 oral doses. When using these dosing patterns, each dose yields approximately 0.01 to approximately 20 mg / kg of the compound provided herein, with preferred doses yielding approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0127] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injectable doses, and are generally in the range of about 0.01% to about 20% by weight, preferably about 0.1% to about 20% by weight, preferably about 0.1% to about 10% by weight, and more preferably about 0.5% to about 15% by weight.

[0128] The dose levels of the injectable agent range from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of approximately 1 to 120 hours, particularly 24 to 96 hours. A preloading bolus of approximately 0.1 mg / kg to 10 mg / kg or more may also be administered to achieve an appropriate steady-state level. The maximum total dose is: For human patients weighing 40-80 kg, the intake is not expected to exceed approximately 2 g / day.

[0129] Liquid forms suitable for oral administration include buffers, suspensions, and pre-formulations (dispensing The solid form may contain a suitable aqueous or non-aqueous vehicle containing agents, colorants, fragrances, etc. The solid form may contain, for example, any of the following components or compounds of similar properties: 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); lubricants (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose, or saccharin); or flavorings (e.g., peppermint, methyl salicylate, or orange flavor).

[0130] 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 compound in such compositions is typically a trace component, often about 0.05–10% by weight, with the remainder being injectable excipients, etc.

[0131] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients. When formulated as an ointment, the active ingredients are typically miscible with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredients may 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 further ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0132] The compounds provided herein may also be administered by transdermal devices. Therefore, transdermal administration can be achieved using reservoir-type, porous membrane-type, or solid matrix-type patches.

[0133] The components described above for orally, injectably, or topically administered compositions are merely representative. Other materials and processing methods are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania (as incorporated herein by reference).

[0134] The compounds of the present invention may also be administered in sustained-release form or via sustained-release drug delivery systems. A description of typical sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0135] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, each comprising 6, 7, and 8α-1,4-linked glucose units, with optionally one or more substituents (including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution) on the linked sugar moiety. In certain embodiments, the cyclodextrin is sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0136] 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 those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.).

[0137] The following examples of formulations illustrate typical pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0138] Exemplary Formulation 1 - Tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of the active compound per tablet) using a tablet press.

[0139] Exemplary Formulation 2 - Capsules: The compound of the present invention can be mixed with a starch diluent in a dry powder in approximately a 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of the active compound per capsule).

[0140] Exemplary Formulation 3 - Liquid: The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg). The resulting mixture is passed through a No. 10 mesh US sieve and then mixed with a pre-prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89.50 mg). Sodium benzoate (10 mg), fragrance, and colorant are diluted with water and added while stirring. The total volume can then be increased to 5 mL by adding sufficient water.

[0141] Exemplary Formulation 4 - Tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of the active compound) using a tablet press.

[0142] Exemplary Formulation 5 - Injectable Formulation: The compound of the present invention may be dissolved or suspended in an injectable aqueous medium of sterile buffered saline at a concentration of approximately 5 mg / mL.

[0143] Exemplary Formulation 6 - Tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of the active compound per tablet) using a tablet press.

[0144] Exemplary Formulation 7 - Tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of the active compound per tablet) using a tablet press.

[0145] Exemplary Formulation 8 - Tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3 to 30 mg tablets (0.1 to 10 mg of the active compound per tablet) using a tablet press.

[0146] Exemplary Formulation 9 - Tablets: The compound of the present invention is used as a dry powder with a dry gelatin binder. The mixture can be mixed in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then pressed into 150-240 mg tablets (50-80 mg of the active compound per tablet) using a tablet press.

[0147] Exemplary Formulation 10 - Tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of the active compound per tablet) using a tablet press.

[0148] Instructions for use and handling As generally described herein, the present invention relates to neurostimulant steroids that can act as GABA modulators. In some embodiments, such compounds are expected to be useful as therapeutic agents for the treatment of disorders described herein (e.g., tremors (e.g., essential tremor); depression (e.g., postpartum depression)), and the process involves administering an effective amount of the compound or a composition of the present invention to the subject. In certain embodiments, the compound is administered by intravenous administration.

[0149] Previous studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) demonstrated that certain 3α-hydroxylated steroids are orders of magnitude more potent as GABA receptor complex (GRC) regulators than those previously 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)). Majewska et al. and Harrison et al. taught that 3α-hydroxylated-5-reduced steroids have considerably lower efficacy capabilities. In vitro and in vivo experimental data have demonstrated that high-titer steroids make them therapeutically useful in regulating brain excitability via GRCs (see, for example, Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(l):65-71 (1995)).

[0150] Various synthetic steroids have also been prepared as neurostimulant steroids. See, for example, U.S. Patent No. 5,232,917 (which discloses neurostimulant steroid compounds useful in treating, in a therapeutically beneficial manner, stress, anxiety, insomnia, paroxysmal disorders, and mood disorders (e.g., depression) that are susceptible to drugs effective against GRCs). Furthermore, while these steroids had previously been shown to interact at unique sites on the GRC distinct from other known interaction sites (e.g., barbiturates, benzodiazepines, and GABA), therapeutically beneficial effects on stress, anxiety, sleep, mood disorders, and paroxysmal disorders had also been previously induced (e.g., Gee, KW and Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders," Central Nervous System Disorders, edited by Horvell, Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG and Morselli, PL, "Psychopharmacology of GABAergic Drugs," Psychopharmacology: The Third Generation of Progress, edited by HYMeltzer, Raven Press, NY (1987), pp. 183-195; and Gee et al., European Journal of See Pharmacology, 136:419-423 (1987). These compounds have sustained effects. It is desirable in terms of time, potency, and oral activity (in addition to other forms of administration).

[0151] The compounds of the present invention, as described herein, can generally modulate GABA function and thus act as neurostimulant steroids for the treatment and prevention of CNS-related conditions in subjects. Modulation, as used herein, means inhibition or synergistic effect of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein are found to have therapeutic uses for the prevention and / or treatment of CNS symptoms in mammals, including human and non-human mammals. Accordingly, as stated herein, the present invention includes, and extends to, the listed treatment methods, as well as compounds for such methods, and the use of such compounds for preparing pharmaceuticals useful for such methods.

[0152] Exemplary CNS conditions associated with GABA regulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (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 impairments [e.g., attention deficit (e.g., attention-deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewis body type dementia)], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive impairments [e.g., attention deficit (e.g., attention-deficit hyperactivity disorder (ADHD))], dementia (e.g., Alzheimer's disease, Lewis body type dementia) This includes, but is not limited to, dementia, vascular dementia, motor 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, one-host causes of autism such as synaptic degeneration (e.g., Rett syndrome, fragile X syndrome, Angelman syndrome)), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disorders (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opioid preparations, cocaine, and / or alcohol)), and tinnitus.

[0153] In a separate context, combinations of the compounds of the present invention with other pharmacologically active agents are provided. The compounds provided herein may be administered as single activators or in combination with other agents. Combination administration may be carried out by any technique apparent to those skilled in the art (e.g., separate administrations, sequential administrations, simultaneous administrations, and alternating administrations).

[0154] In another context, a method is provided for treating or preventing brain excitation in a subject who is susceptible to or suffering from a condition related to brain excitation, the method comprising the step of administering to the subject an effective amount of the compound of the present invention.

[0155] In another context, a method is provided for treating or preventing tremors in a subject, the method comprising administering an effective amount of the compound of the present invention to a subject requiring such treatment. In a particular embodiment, the tremor is an essential tremor.

[0156] In another context, a method is provided for treating or preventing a mood disorder in a subject, the method comprising the step of administering an effective amount of the compound of the present invention to a subject in need of such treatment. In certain embodiments, the mood disorder is depression. In some embodiments, the mood disorder is postpartum depression.

[0157] In another context, methods to alleviate or prevent PMS or PND in subjects. A method is provided, which comprises the step of administering an effective amount of the compound of the present invention to a subject requiring such treatment.

[0158] In another context, a method is provided for treating or preventing stress or anxiety in a subject, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such treatment.

[0159] In another context, a method is provided for reducing or preventing insomnia in a subject, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such treatment.

[0160] In another context, a method is provided for inducing sleep and substantially maintaining the level of REM sleep observed in normal sleep, without inducing substantial rebound insomnia, the method comprising the step of administering an effective amount of the compound of the present invention.

[0161] In another context, a method is provided for treating cognitive enhancement or memory impairment by administering a therapeutically effective amount of the compound of the present invention to a subject. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0162] In another context, a method is provided for treating attention disorders by administering a therapeutically effective amount of the compound of the present invention to a subject. In a particular embodiment, this attention disorder is ADHD.

[0163] 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.

[0164] Anxiety disorder Anxiety disorder is a broad term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders.

[0165] Generalized anxiety disorder (GPD) is a generalized chronic disorder characterized by persistent anxiety that cannot be focused on any single object or situation. People suffering from GPD experience nonspecific, persistent fears and worries, and tend to worry excessively about ordinary things. GPD is the most common anxiety disorder affecting older adults.

[0166] In panic disorder, individuals suffer from short bursts of intense fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and shortness of breath. These panic attacks (defined by APA as sudden fear or discomfort that peaks in less than 10 minutes) can last for several hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent and unpredictable panic attacks, a diagnosis of phobic disorder also requires that the attacks have chronic consequences (either worry about the potential implications of the attack, persistent fear of future attacks, or significant behavioral changes related to the attack). Thus, individuals with phobic disorder experience symptoms even outside the scope of a particular panic episode. Often, unusual changes in heart rate are noticed by those suffering from panic, leading them to believe that their heart is somehow unwell or that they are about to experience another panic attack. In some cases, heightened perception of bodily functions (hypervigilance) occurs during panic attacks, and in these cases, some perceived physiological change is interpreted as a potentially life-threatening illness. To become (i.e., excessive hypochondria).

[0167] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder primarily characterized by recurrent obsessions (urgent, persistent, and disturbing thoughts or images) and compulsive behaviors (the urge to perform specific actions or rituals). OCD thought patterns can be linked to superstition insofar as they involve the person believing in causal relationships that do not actually exist. Often, the process is entirely illogical. For example, the compulsion to walk in a specific pattern may be used to alleviate an obsession with imminent danger. In many cases, this compulsion is not entirely inexplicable, but simply an urge to complete a neurotic-induced ritual. In a small number of cases, individuals with OCD may experience only obsessions without overt compulsions, and in even fewer, only compulsions.

[0168] One of the largest categories of anxiety disorders is phobias, which encompass all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate terrifying consequences from encountering their object of fear (which can range from animals, places, to bodily fluids).

[0169] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can arise from extreme situations (e.g., war, rape, hostage situations, or even major disasters). It can also result from prolonged (chronic) exposure to severe stressors (e.g., soldiers who can tolerate individual battles but cannot cope with continuous warfare). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0170] Eating disorders Eating disorders are characterized by disturbances in eating behavior and weight regulation and are associated with a wide range of adverse psychological, physical, and social consequences. Individuals with eating disorders may begin by eating less or more food, but at some point, their appetite may rapidly decrease or increase without control. Eating disorders may be characterized by significant distress or concern about weight or body shape, or by extreme efforts to control weight or food intake. Examples of eating disorders include anorexia nervosa, bulimia nervosa, binge eating disorder, cachexia, and their variations.

[0171] Individuals with anorexia nervosa typically perceive themselves as overweight, even when they are underweight. They may struggle with eating, food, and weight control. They typically weigh themselves repeatedly, carefully determine portion sizes, and eat only very small amounts of specific foods. They may engage in binge eating, followed by extreme dieting, excessive exercise, self-induced vomiting, or abuse of laxatives, diuretics, or enemas. Symptoms include extremely low body weight, severe dietary restriction, a cruel pursuit of thinness and reluctance to maintain a normal or healthy weight, a strong fear of weight gain, a distorted body image and self-esteem severely affected by perceptions of weight and body shape, or denial of the severity of underweight, or, in girls and women, menstrual deficiency. Other symptoms include thinning of the bones, brittle hair and nails, dry and yellowish skin, growth of fine hairs all over the body, moderate anemia, muscle wasting and weakness, severe constipation, low blood pressure or slow breathing and pulse, damage to the structure and function of the heart, brain damage, failure of multiple organs, decreased internal body temperature, lethargy, apathy, and infertility.

[0172] Individuals with bulimia nervosa typically experience recurrent, frequent episodes of eating large amounts of food and feel they lack control over these episodes. Later, compensatory behaviors for this bulimia may occur (e.g., forced vomiting, excessive use of laxatives or diuretics, fasting, excessive exercise, or a combination of these behaviors).

[0173] Unlike anorexia nervosa, people with bulimia nervosa typically maintain what is considered a healthy or normal weight, although some are slightly overweight. However, like those with anorexia nervosa, they typically fear gaining weight, desperately desire to lose weight, and are unhappy with their body size and shape. Bulimia behavior is usually carried out secretly because it is often accompanied by feelings of disgust or shame. This cycle of binge eating and purging can occur anywhere from a few times a week to many times a day. Other symptoms include a chronically ulcerated and painful throat, swollen salivary glands in the neck and jaw region, worn tooth enamel, teeth that become increasingly sensitive and prone to decay as a result of exposure to stomach acid, acid reflux and other gastrointestinal problems, bowel distress and irritation due to laxative abuse, severe dehydration due to fluid purging, and electrolyte imbalances (which can lead to heart attack or stroke).

[0174] 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 periods of binge eating. Individuals with binge eating disorder are often overweight or obese. Obese individuals with binge eating disorder are at higher risk of developing cardiovascular disease and hypertension. They also experience guilt, shame, and distress related to their binge eating, which can lead to further binge eating.

[0175] Cachexia, also known as a “wasting disease,” is a feeding-related problem experienced by many cancer patients. Individuals with cachexia may continue to eat normally, but their bodies may refuse to utilize the vitamins and nutrients they are taking orally, or they may lose their appetite and stop eating. When an individual experiences a loss of appetite and stops eating, they may be considered to have developed anorexia nervosa.

[0176] Neurodegenerative diseases and disorders The term "neurodegenerative disease" encompasses diseases and disorders that involve the progressive loss of 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 injuries; ataxia and seizures (including for treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign amnesia; hydrocephalus; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head trauma; coma; contusion injuries (e.g., spinal cord injury and head injury); dementia (including multiple stroke dementia and senile dementia); impaired consciousness; Down syndrome; drug-induced or medication-induced tremor-paralysis (e.g., acute siphonation, acute ataxia, tremor-paralysis, or tardive dyskinesia induced by psychotropic agents, neuroleptic malignant syndrome, or Drug-induced postural tremors; epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; intellectual disability; motor disorders including immobility and akinesia (rigidity) syndrome (brainstem nerve calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, post-encephalitis tremor palsy, etc.) Examples include progressive supranuclear palsy); disorders associated with muscle spasticity and spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiplegia, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as simple tics, complex tics, and symptomatic tics), myoclonus (generalized myoclonus and focal syloclonus) Examples include cyloclonus, tremors (e.g., resting tremor, postural tremor, and intention tremor), and ataxia (axial ataxia, dystonic writer's cramp, hemiplegic ataxia, paroxysmal ataxia, and focal ataxia (e.g., blepharospasm, oromandibular dystonia). Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic 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; tubular sclerosis, and neurodegeneration induced by viral infections (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and brain injury). Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and neurotoxic disorders after cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0177] epilepsy Epilepsy is a brain disorder characterized by recurrent seizures over a long period of time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonus (nyoclonic) epilepsy, epilepsy with grand mal seizures while awake, West syndrome, Lennox-Gastaut syndrome, and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in childhood.

[0178] Status epilepticus (SE) Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic 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, and extremely refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite first-line treatment, and second-line treatment is initiated. Refractory status epilepticus is characterized by persistent status epilepticus despite first-line and second-line treatment, and general anesthetics are generally administered. Extremely refractory status epilepticus is characterized by persistent status epilepticus despite first-line treatment, second-line treatment, and treatment with general anesthetics for 24 hours or more.

[0179] Nonconvulsive status epilepticus (NSE) can include, for example, focal NES, such as complex partial NES, simple partial NES, or micro NES; and generalized NES, such as late-onset absence NES, atypical absence NES, or typical absence NES.

[0180] The compositions described herein also include, prior to the onset of seizures, CNS disorders, e.g., traumatic brain injury; status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, extremely refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharge; and It can be administered as a preventative measure to subjects with periodic unilateral epileptic discharges.

[0181] seizure A seizure is a physical manifestation or change in behavior that follows an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” A convulsion is when a person’s body shakes rapidly and uncontrollably. During a convulsion, the person’s muscles repeatedly contract and relax.

[0182] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying seizure types helps physicians diagnose whether or not a patient has epilepsy.

[0183] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses from a relatively small area of ​​the brain. The part of the brain that causes a seizure is sometimes called a lesion.

[0184] There are six types of generalized seizures. The most common, dramatic, and therefore most well-known is the generalized convulsion (also called a grand mal seizure). In this type of seizure, the patient loses consciousness and usually collapses. Following this loss of consciousness, there is a period of generalized rigidity (called the "tonic" phase of the seizure) for 30–60 seconds, followed by a period of intense spasms ("clonic" phase) for 30–60 seconds, after which the patient falls into a deep sleep ("postictal" or after-seizure phase). During a grand mal seizure, injuries and accidents (e.g., biting the tongue and urinary incontinence) can occur.

[0185] Absence seizures cause brief periods of loss of consciousness (only a few seconds), with little to no symptoms. The patient (most frequently a child) typically stops their activity and stares blankly. These seizures begin and end suddenly and can occur several times a day. The patient is usually unaware that they are having a seizure unless they notice they are "losing time."

[0186] Myoclonic seizures consist of sporadic spasms, usually on both sides of the body. Patients sometimes describe these spasms as short electric shocks. In severe cases, these seizures can result in dropping or involuntarily throwing objects.

[0187] Clonic seizures are recurrent, rhythmic spasms that involve both sides of the body simultaneously.

[0188] Tonic seizures are characterized by muscle rigidity.

[0189] A toneacine episode consists of a sudden general decrease in muscle tone (especially in the arms and legs) and often leads to falls.

[0190] The seizures described herein may include epileptic seizures; acute recurrent seizures; cluster seizures; serial seizures; uninterrupted seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; astonic seizures; benign Rolandic seizures; febrile seizures; affective seizures; focal seizures; laughter seizures; generalized onset seizures; infantile spasms; Jackson's seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; microseizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

[0191] shaking Tremor is an involuntary, rhythmic contraction and relaxation of muscles, which may involve the vibration or twisting of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0192] Cerebellar tremor, or intention tremor, is a slow, broad tremor of the limbs that occurs after an intentional movement. Cerebellar tremors are caused by lesions or damage to the cerebellum, such as those resulting from tumors, strokes, or diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0193] Dystonic tremor occurs in individuals with dystonia, a movement disorder characterized by persistent, involuntary muscle contractions that result in twisting and repetitive movements, as well as / or painful abnormal postures or positions. Dystonic tremor can affect any muscle in the body. It occurs irregularly and can often be alleviated by complete rest.

[0194] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be moderate and non-progressive in some cases, and may start on one side of the body and progress slowly, but can affect both sides within three years. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of the tremor may decrease with age, but its severity may increase. Elevated emotions, stress, fever, physical fatigue, or hypoglycemia can trigger and / or increase the severity of tremors.

[0195] Orthostatic tremor is characterized by rapid (e.g., above 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. The spasms are felt in the thighs and legs, and the patient may tremble uncontrollably when required to stand upright. Orthostatic tremor can occur in patients with essential tremor.

[0196] Parkinsonian tremor is caused by damage to structures in the brain that control movement. It is often a prodromal symptom of Parkinson's disease and typically manifests as a “pill-making” behavior of the hands, which can also affect the chin, lips, legs, and trunk. Onset of Parkinsonian tremor typically begins in individuals older than 60 years of age. The movement may begin in one limb or one side of the body and progress to include the other.

[0197] Physiological tremors can occur in normal individuals and may have no clinical significance. They can be seen in all voluntary muscle groups. Physiological tremors can be triggered by certain drugs, alcohol withdrawal, or medical conditions (such as hyperthyroidism and hypoglycemia). Classically, these tremors have a frequency of approximately 10 Hz.

[0198] Psychogenic tremors or hysterical tremors can occur at rest or during postural or motor movements. Patients with psychogenic tremors may also have conversion disorder or another psychiatric disorder.

[0199] Rubral tremor is characterized by a coarse, slow tremor that may occur at rest, when changing position, or intentionally. This tremor is associated with a condition affecting the red nucleus of the midbrain (classic abnormal stroke).

[0200] Mood disorder Clinical depression includes major depressive disorder (MDD), severe depression, and unipolar depression. Also known as unipolar disorder and recurrent depression, it is a mental disorder characterized by pervasive, persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in activities that are usually pleasurable. Some people with clinical depression have difficulty sleeping, weight loss, and generally feel agitated and stimulate-responsive. Clinical depression affects the way an individual feels, thinks, and behaves, and can lead to a range of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0201] Postnatal depression (PND), also known as postpartum depression (PPD), is a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, screaming episodes, anxiety, and irritability. In some embodiments, this PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, this PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0202] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients with AD may also have significant social deficits as a result of excessive sleep or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived social rejection.

[0203] Melancholic depression is characterized by a loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasant stimuli, a depressed mood more pronounced than grief or loss, excessive weight loss, or excessive guilt.

[0204] Psychotic major depressive disorder (PMD), or psychotic depression, refers to an episode of major depression in which an individual experiences psychotic symptoms (e.g., delusions and hallucinations), particularly of a melancholic nature.

[0205] Catatonic depression is a form of major depression that includes disturbances in motor behavior and other symptoms. Individuals may be mute and confused, and may either be immobile or exhibit aimless or erratic movements.

[0206] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals experience a seasonal pattern of depressive episodes during the fall or winter.

[0207] Mood disorders are conditions associated with unipolar depression, characterized by the same physical and cognitive problems. They tend to be less severe and last longer (e.g., at least two years).

[0208] Double depression refers to a period of complete depression (dysthymia) lasting at least two years, separated by a major depressive episode.

[0209] Depressive personality disorder (DPD) is a personality disorder characterized by depressive features.

[0210] Recurrent short-term depression (RBD) is a condition in which an individual experiences approximately one depressive episode per month, with each episode lasting two weeks or less, typically less than two to three days.

[0211] Minor depressive disorder, or minor depression, is a type of depression characterized by the presence of at least two symptoms for two weeks.

[0212] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, including emotionally high moods (mania or hypomania) and low moods (depression). During manic periods, the individual may feel or be unusually happy, energetic, or stimulus-responsive. They often make poorly thought-out decisions with little regard for the consequences. The need for sleep is usually reduced. During depressive periods, they may scream, avoid eye contact with others, and have a negative outlook on life. The risk of suicide among people with this disorder is high, exceeding 6% over a 20-year period, while self-harm occurs in 30-40%. Other mental health problems (e.g., anxiety disorders and substance use disorders) are commonly associated with bipolar disorder.

[0213] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition (e.g., cancer or chronic pain, chemotherapy, chronic stress).

[0214] Treatment-resistant depression refers to a condition in which an individual has received treatment for depression but their symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the symptoms of depression in individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve but then relapse. Treatment-resistant depression occurs in depressed patients who are resistant to standard pharmacological treatments (such as tricyclic antidepressants, MAOIs, SSRIs, and double and triple reuptake inhibitors and / or anxiolytics) as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagal stimulation and / or transcranial magnetic stimulation).

[0215] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation is associated with thoughts about suicide or an abnormal preoccupation with suicide. The range of suicidal ideation varies greatly, for example, from fleeting thoughts to large-scale thoughts, detailed plans, role-playing, and attempted suicide. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contact, becoming obsessed with death, feeling trapped in a situation or despairing about a situation, increased alcohol or drug use, engaging in dangerous or self-destructive behavior, and saying goodbye as if never to see each other again.

[0216] Symptoms of depression include persistent anxiety or sadness, helplessness, despair, pessimism, worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in pleasant activities or hobbies, absence of positive thoughts or plans, excessive sleep, bulimia, loss of appetite, insomnia, self-injury, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Symptoms of depression, and their alleviation, may be confirmed by a physician or psychologist (e.g., by a mental state test).

[0217] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state characterized by amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, a reduced stress response, or a combination of all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects on its own, or sometimes from a combination of drugs (e.g., hypnotics, sedatives, paralyzing 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 otherwise experience.

[0218] Sedation is generally the reduction of nervousness or agitation through the administration of pharmacological agents to facilitate medical or diagnostic procedures.

[0219] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiety relief) to general anesthesia.

[0220] Minimal sedation is also known as anxiety relief. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are typically unaffected.

[0221] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness in which the patient intentionally responds to verbal commands, either alone or with light tactile stimulation. Typically, intervention to maintain the patient's airway is not required. Spontaneous ventilation is usually adequate. Cardiovascular function is usually maintained.

[0222] Deep sedation / analgesia is a drug-induced decrease in consciousness in which the patient cannot easily awaken but responds intentionally (rather than reflexively withdrawing from painful stimuli) after repeated or painful stimuli. Independent ventilatory function may be impaired, and the patient may require assistance to maintain their airway. Spontaneous ventilation may be insufficient. Cardiovascular function is usually maintained.

[0223] General anesthesia is drug-induced loss of consciousness in which the patient is unable to awaken even in response to painful stimuli. Because the ability to maintain independent ventilatory function is often impaired, assistance to maintain the patient's airway is frequently required. Positive pressure ventilation may be necessary due to reduced spontaneous ventilation or drug-induced neuromuscular dysfunction. Cardiovascular function may be impaired.

[0224] Sedation in the intensive care unit (ICU) allows for a reduced awareness of the patient's environment and decreased response to external stimuli. This can play a role in treating patients with critical illness and encompasses a wide range of symptom control, which varies from patient to patient and individual to individual throughout the course of the patient's illness. Heavy sedation in intensive care is used to facilitate endotracheal tube tolerance and ventilator synchronization (often accompanied by neuromuscular blocking agents).

[0225] In some embodiments, sedation (e.g., prolonged sedation, sustained sedation) is induced in the ICU and maintained over extended periods (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Prolonged sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0226] Sedation and analgesia during a procedure (also known as conscious sedation) is a technique that involves administering sedatives or dissociative agents, with or without analgesics, to enable a subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function. [Examples]

[0227] For the purpose of enabling a better understanding of the invention as described herein, the following examples are provided. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting their scope.

[0228] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures under typical or preferred process conditions (i.e.) The reaction conditions (such as reaction temperature, time, molar ratio of reactants, solvent, and pressure) are given, but it is understood that other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through conventional optimization.

[0229] Furthermore, as may be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable 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 TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, 2nd edition, Wiley, New York, 1991, and the references cited therein.

[0230] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail with respect to the preparation of representative triazoles and tetrazoles listed herein. The compounds provided herein may 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.

[0231] Reported herein 1 ¹H-NMR (for example, for an intermediate) may be a partial representation of the entire NMR spectrum of a compound (for example, a compound described herein). 1 1H NMR can exclude the δ(ppm) region between approximately 1 ppm and 2.5 ppm. (Total for representative examples) 1 A copy of the 1H-NMR spectrum is given in the figure.

[0232] General method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19 × 250 mm. Mobile phase: Acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min.

[0233] General method for analytical HPLC: Mobile phase: A: Water (10 mM NH4HCO3), B: Acetonitrile gradient: B 5% to 95% for 1.6 or 2 minutes; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 × 50 mm, 3.5 μm, 45C.

[0234] Synthesis procedure The compounds of the present invention may be prepared using suitable reagents, starting materials, and purification methods known to those skilled in the art, in accordance with methods reported in the art (Upasani et al., J.Med.Chem. 1997, 40:73-84; and Hogenkamp et al., J.Med.Chem. 1997, 40:61-72). In some embodiments, the compounds described herein may be prepared using the methods shown in general schemes 1 to 3, which involve nucleophilic substitution of 19-norpregnane bromide with a nucleophile. In specific embodiments... This nucleophile reacts with 19-norpregnane bromide in the presence of K2CO3 in THF.

[0235] Scheme 1 [ka]

[0236] Scheme 2 [ka]

[0237] Scheme 3 [ka]

[0238] Example 1. Synthesis of SA and SA intermediates [ka]

[0239] Synthesis of compound SA-B. Compound SA-A (50 g, 184 mmol) and palladium black (2.5 g) were hydrogenated with hydrogen at 10 atm in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL). After stirring at room temperature for 24 hours, the mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the crude compound. Recrystallization from acetone yielded compound SA-B (42.0 g, yield: 83.4%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24 (s, 3H), 2.18-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H), 1.53-1.37 (m, 7H), 1.29-1.13 (m, 3H), 1.13-0.90 (m, 2H), 0.89 (s, 3H).

[0240] Synthesis of compound SA-C. A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL of anhydrous toluene was added dropwise to a solution of methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide (MAD) (459.19 mmol, 3.0 eq, freshly prepared) under N2 at -78°C. After this addition was complete, the reaction mixture was stirred at -78°C for 1 hour. Then, 3.0 M MeMgBr (153.06 mL, 459.19 mmol) was slowly added dropwise to the above mixture under N2 at -78°C. Then, the reaction mixture was stirred at this temperature for 3 hours. TLC (petroleum ether / ethyl acetate = 3:1) indicated that the reaction was complete. Saturated aqueous solution NH4Cl was then slowly added dropwise to the mixture at -78°C. After this addition was complete, the mixture was filtered, the filter cake was washed with ethyl acetate, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated, and purified by flash chromatography on silica gel (petroleum ether / ethyl acetate 20:1 to 3:1) to obtain compound SA-C (40.2 g, yield: 90.4%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ2.47-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.96-1.74 (m, 6H), 1.70-1.62 (m, 1H), 1.54-1.47 (m, 3H), 1.45-1.37 (m, 4H), 1.35-1.23 (m, 8H), 1.22-1.10 (m, 2H), 1.10-1.01 (m, 1H), 0.87 (s, 3H).

[0241] Synthesis of compound SA-D. To a solution of PPh3EtBr (204.52 g, 550.89 mmol) in THF (500 mL), a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) was added at 0°C. After this addition was complete, the reaction mixture was stirred at 60°C for 1 hour, and then SA-C (40.0 g, 137.72 mmol) dissolved in THF (300 mL) was added dropwise at 60°C. The reaction mixture was heated at 60°C for 18 hours. The reaction mixture was cooled to room temperature, quenched with Sat.NH4Cl, and extracted with ELISA (3 × 500 mL). The combined organic layers were washed with brine, dried, and concentrated to obtain a crude product, which was purified by flash column chromatography (petroleum ether / ethyl acetate 50:1 to 10:1) to obtain compound SA-D (38.4 g, yield: 92%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H), 1.89-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.55-1.43 (m, 4H), 1.42-1.34 (m, 3H), 1.33-1.26 (m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).

[0242] Synthesis of compound SA-E. To a solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL), a solution of BH3.Me2S (126 mL, 1.26 mol) was added dropwise under ice bath. After this addition was complete, the reaction mixture was stirred at room temperature (14°C-20°C) for 3 hours. TLC (petroleum ether / ethyl acetate 3:1) indicated that the reaction was complete. The mixture was cooled to 0°C, and then 3.0 M aqueous NaOH (400 mL), followed by 30% aqueous H2O2 (30%, 300 mL), was added. The mixture was stirred at room temperature (14°C-20°C) for 2 hours, then filtered and extracted with SiO2 (3 × 500 mL). The combined organic layers were washed with saturated aqueous Na2S2O3 and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product (43 g, crude) as a colorless oil. This crude product was used in the next step without further purification.

[0243] Synthesis of compound SA-F. To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL), PCC (53.8 g, 268.32 mmol) was gradually added at 0°C. The reaction mixture was then stirred at room temperature (16°C to 22°C) for 3 hours. TLC (petroleum ether / ethyl acetate 3:1) indicated that the reaction was complete, so the reaction mixture was filtered and washed with DCM. The organic phase was washed with saturated aqueous Na2S2O3 and brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by flash column chromatography (petroleum ether / ethyl acetate 50:1 to 8:1) to obtain compound SA-F (25.0 g, yield: 62.5%, over two steps) as a white powder. 1 H NMR(SA-F):(400MHz,CDCl3)δ2.57-2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m, 10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).

[0244] Synthesis of compound SA. In a solution of SA-F (10 g, 31.4 mmol) and aq. HBr (5 drops, 48% in water) in 200 mL of MeOH, bromine (5.52 g, 34.54 mmol) was added. (mol) was added dropwise. The reaction mixture was stirred at 17°C for 1.5 hours. The resulting solution was quenched with saturated aqueous NaHCO3 at 0°C and extracted with Depositphotos (150 mL x 2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel eluting (PE:EA = 15:1 to 6:1) to obtain compound SA (9.5 g, yield: 76.14%) as an off-white solid. LC / MS: rt 5.4 min; m / z 379.0, 381.1, 396.1.

[0245] Example 2. Synthesis of compound SA-1. [ka] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL), 3H-1,2,4-triazole (32 mg, 0.46 mmol) and SA (36 mg, 0.09 mmol) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 5 mL of H2O and extracted with ELISA (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain the title compound as an off-white solid (11 mg, 31.3%). 1 HNMR(400MHz,CDCl3),δ(ppm), 7.67 (s, 1H), 7.64 (s, 1H), 5.27(AB,1H), 4.18(AB,1H) 2.65(1H, t), 1.27(s, CH3), 0.67(s, 3H).

[0246] Example 3. Synthesis of compound SA-2. [ka] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL), 1H-tetrazole (16 mg, 0.23 mmol) and SA (70 mg, 0.09 mmol) were added. This mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL of H2O and extracted with ELISA (2 × 10 mL). The combined organic layer was washed with brine. The solution was purified, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain the title compound as an off-white solid SA-2 (8 mg, 11.7%) and a by-product (10 mg, 14.0%). SA-2: 1 HNMR(500MHz,CDCl3),δ(ppm), 8.74 (s, 1H), 5.31(AB,1H),5.17(AB,1H), 2.65(1H, t), 1.28(s, CH3), 0.67(s, 3H).

[0247] Example 4. Synthesis of compound SA-3. [ka] To a suspension of SA (1 g, 2.52 mmol) in DMF (20 mL), K2CO3 (1.04 g, 7.55 mmol) and 4-methyl-2H-1,2,3-triazole (313.64 mg, 3.77 mmol) were added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into 5 mL of H2O and extracted with siRNA (30 mL). The combined organic layer was washed with brine (10 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to obtain the title compound SA-3 (269.2 mg, yield = 26.59%) as an off-white solid. 1HNMR(SA-3)(400MHz,CDCl3)δ7.42 (s, 1H), 5.14-5.13 (m, 2H), 2.57-2.56 (m, 1H), 2.33 (s, 3H), 2.01-2.00 (m, 2H), 1.81-1.70 (m, 6H), 1.45-1.39 (m, 7H), 1.27-1.24 (m, 9H), 1.01-1.00 (m, 3H), 0.70 (s, 3H).

[0248] Example 5. Synthesis of compounds SA-4 and SA-5. [ka] Compound SA (2.0 g, 5.03 mmol) was added to a solution of 4-methyl-2H-1,2,3-triazole (836.4 mg, 10.07 mmol) and K2CO3 (1.39 g, 10.07 mmol) in DMF (20 mL) under N2 conditions at room temperature (13-17 °C). The reaction mixture was stirred at room temperature (13-17 °C) for 4 hours. TLC indicated that the reaction was complete. The reaction mixture was then poured into water and extracted with RINKAN (50 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using silica gel to obtain 730 mg of a mixture of SA-4 / SA-5 and a by-product (500 mg, yield: 25%). This mixture was divided by SFC purification to obtain SA-4 (249.8 mg, yield: 12.5%). SA-5 (426.2 mg, yield: 21.3%) was obtained as an off-white solid. 1 H NMR(SA-4):(400MHz,CDCl3)δ7.49 (s, 1H), 5.14-5.02 (m, 2H), 2.67-2.63 (m, 1H), 2.21-2.16 (m, 4H), 2.11-2.08 (m, 1H), 1.88-1.75 (m, 6H), 1.65-1.55 (m, 1H), 1.51-1.37 (m, 7H), 1.33-1.22 (m, 8H), 1.14-1.08 (m, 3H), 0.69 (s, 3H). 1 H NMR(SA-5):(400MHz,CDCl3)δ7.35 (s, 1H), 5.20-5.04 (m, 2H), 2.65-2.61 (m, 1H), 2.38 (s, 3H), 2.25-2.17 (m, 1H), 2.09-2.05 (m, 1H), 1.88-1.63 (m, 7H), 1.50-1.28 (m, 15H), 1.15-1.06 (m, 3H), 0.67 (s, 3H).

[0249] Example 6. Synthesis of compounds SA-6 and SA-7. [ka] To a solution of compound SA (120 mg, 0.29 mmol) in THF (3 mL), K2CO3 (210 mg, 1.5 mmol) and 5-methyl-2H-tetrazole (126 mg, 1.5 mmol) were added. The resulting solution was stirred overnight at room temperature, at which point LC-MS analysis indicated that the reaction was complete. The reaction product was then diluted with  (20 mL), and the resulting solution was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain SA-6 (10 mg, 0.025 mmol, yield = 8%) and SA-7 (8 mg, 0.020 mmol, yield = 7%) as off-white solids. SA-6: 1H NMR(400MHz,CDCl3)δ5.16-5.03 (m, 2H), 2.66 (t, 1H), 2.46 (s, 3H), 2.25-2.10 (m, 1H), 2.08-2.02 (m, 1H), 1.90-1.70 (m, 7H), 1.68-1.02 (m, 18H),0.67 (s, 3H). LC-MS: rt=2.20 min; m / z=401.3 (M+H) + SA-7: 1 H NMR:(400MHz,CDCl3)δ5.40-5.30 (m, 2H), 2.62 (t, 1H), 2.55 (s, 3H), 2.30-2.00 (m, 2H), 1.90-1.56 (m, 7H), 1.50-1.02 (m, 18H), 0.70 (s, 3H). LC-MS: rt=2.30 min; m / z=401.2 (M+H) + .

[0250] Example 7. Synthesis of compound SA-8. [ka] To a solution of compound SA (150 mg, 0.377 mmol) and K2CO3 (104.3 mg, 0.755 mmol) in dry DMF (10 mL), 5-(trifluoromethyl)-1H-tetrazole (104.2 mg, 0.755 mmol) was added under N2 at room temperature (14-20°C). The reaction mixture was stirred at the same temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (PE:ethyl = 10:1 to 1:1) to obtain SA-8 (89.1 mg, yield: 51.9%) as a white powder. 1 H NMR(SA-8):(400MHz,CDCl3)δ5.51 (s, 2H), 2.69-2.65 (m, 1H), 2.26-2.18 (m, 1H), 2.09-2.05 (m, 1H), 1.87-1.77 (m, 6H), 1.69-1.62 (m, 1H), 1.55-1.43 (m, 7H), 1.37-1.26 (m, 8H), 1.19-1.09 (m, 3H), 0.72 (s, 3H).

[0251] Example 8. Synthesis of compound SA-9. [ka] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL), 3H-1,2,4-triazole (16 mg, 0.23 mmol) and SA (70 mg, 0.09 mmol) were added. This mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL of H2O and extracted with Â(2 × 10 mL) ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain the title compound as an off-white solid SA-9 (15 mg, 22%). SA-9: 1 HNMR(400MHz,CDCl3),δ(ppm), 7.76 (s, 1H), 7.64 (s, 1H), 5.27(AB,1H),5.14(AB,1H), 2.65(1H, t), 1.27(s, 3H), 0.67 (s, 3H).

[0252] Example 9. Synthesis of SC-SS and SC-SS intermediates [ka]

[0253] Synthesis of compounds SC-KK and SC-LL. To a stirred solution of trimethylsulfoxonium iodide (43 g, 210 mmol) in 200 mL of DMSO, NaH (60%, 8.4 g, 210 mmol) was added. After stirring at room temperature for 1 hour, a suspension of compound SC (30 g, 105 mmol) in 20 mL of DMSO was added dropwise. After 2.5 hours, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate (100 mL x 3). The combined ethyl acetate layers were then washed with brine (100 mL x 3), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1 to 15:1) to obtain compound SC-LL (14.7 g, 49 mmol, 47%).

[0254] Synthesis of compounds SC-MM and SC-NN. A mixture of reactants SA-KK and SA-LL (3.0 g, 10.0 mmol, 1:1) was mixed with dried (Bu)4NF, and the mixture was heated overnight at 100°C. The remaining mixture was poured into 50 mL of H2O and extracted with ELISA (2 × 50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 20:1) to obtain the product mixtures SC-MM and SC-NN (2.1 g, 6.5 mmol, 65%) as off-white solids.

[0255] Synthesis of compounds SC-OO and SC-PP. A solution of the reactant mixture SC-MM and SC-NN (2.1 g, 6.5 mmol) in anhydrous THF (30 mL) was mixed with BH3.THF (1.0 M, 13.0 mL, 13.0 mmol), and the solution was stirred overnight at 25°C. The reaction was then quenched by adding water (5 mL). 2 M NaOH solution (20 mL) was added, followed by 30% H2O2 (20 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification.

[0256] Synthesis of compounds SC-QQ and SC-RR. A crude reactant mixture of compounds SC-OO and SC-PP (2.2 g, 6.5 mmol, theoretical amount) was dissolved in dichloromethane (40 mL), to which pyridinium chloroformate (Pcc) was gradually added (2.8 g, 13.0 mmol). This solution was stirred overnight at 25°C. The mixture was then filtered through a short pad of silica gel, and the silica gel was washed with dichloromethane (3 × 50 mL). All filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15:1) to obtain product SC-QQ (910 mg, 2.7 mmol, yield = 41% (2 steps)) as an off-white solid, and product SC-RR (850 mg, 2.5 mmol, yield = 39% (2 steps)) as an off-white solid. Compound SC-QQ: 1 HNMR(500MHz, CDCl3)δ(ppm):4.17 (d, 2H), 2.53 (t, 1H), 2.17-2.13 (m, 2H), 2.11 (s, 3H), 2.03-2.00 (m, 1H), 0.62 (s, 3H). Compound SC-RR: 1 HNMR(500MHz, CDCl3)δ(ppm): 4.45 (AB×d, 1H), 4.39 (AB×d, 1H), 2.54 (t, 1H), 0.62 (s, 3H).

[0257] Synthesis of compound SF. To a solution of the reactant SC-RR (100 mg, 0.301 mmol) in methanol (10 mL), 48% hydrobromic acid (152 mg, 0.903 mmol) was added, followed by the addition of bromine (241 mg, 0.077 mL, 1.505 mmol). This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SF was used directly in the next step without further purification.

[0258] Example 10. Synthesis of compound SF-1. [ka] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 2H-tetrazole (28 mg, 0.4 mmol) and compound SF (83 mg, 0.2 mmol) were added. This mixture was stirred at room temperature for 15 hours, and the residue was then poured into 5 mL of H2O and extracted with RINKAN (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain SF-1 as an off-white solid (6 mg, 8%). SF-1: 1 HNMR(500MHz,CDCl3)δ(ppm):8.75 (s, 1H), 5.32 (AB, 1H), 5.19 (AB, 1H), 4.48 (AB×d, 1H), 4.38 (AB×d, 1H), 2.68 (t, 1H), 0.68 (s, 3H). LC-MS: rt=2.10 min, m / z=405.4[M+H] + .

[0259] Example 11. Synthesis of compounds SF-2 and SF-3. [ka] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 5-methyl-2H-tetrazole (33.6 mg, 0.4 mmol) and SF (85 mg, 0.2 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The residue mixture was poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to obtain SF-2 as an off-white solid (22 mg, 26%) and SF-3 as an off-white solid (38 mg, 45%). SF-2: 1 HNMR(500MHz,CDCl3)δ(ppm):5.15 (AB, 1H), 5.06 (AB, 1H), 4.48 (AB×d, 1H), 4.39 (AB×d, 1H), 2.68 (t, 1H), 2.47 (s, 3H), 0.69 (s, 3H). LC-MS: rt=2.09 min, m / z=419.3[M+H] + SF-3: 1 HNMR(500MHz,CDCl3)δ(ppm):5.35 (t, 2H), 4.48 (AB×d, 1H), 4.38 (AB×d, 1H), 2.63 (t, 1H), 2.56 (s, 3H), 2.25-2.18 (m, 2H), 2.10-2.04 (m, 1H), 0.72 (s, 3H). LC-MS: rt=2.20 min, m / z=419.1[M+H] + .

[0260] Example 12. Synthesis of compound SF-4. [ka] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 2H-1,2,3-triazole (28 mg, 0.4 mmol) and compound SF (85 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 15 hours, and the residue was poured into 5 mL of H2O and extracted with RINKAN (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain SF-4 as an off-white solid (12 mg, 15%). Compound SF-4: 1 HNMR(500MHz,CDCl3)δ(ppm):7.76 (d, 1H), 7.64 (d, 1H), 5.28 (AB, 1H), 5.14 (AB, 1H), 4.48 (AB×d, 1 H), 4.38 (AB×d, 1H), 2.66 (t, 1H), 2.25 (s, 1H), 2.23-2.20 (m, 1H), 2.11-2.08 (m, 1H), 0.68 (s, 3H). LC-MS: rt=2.05 min, m / z=404.3[M+H] + .

[0261] Example 13. Synthesis of SG and SG intermediates. [ka]

[0262] Synthesis of compounds SG-B1 and SG-B2. To a solution of compound SC (800 mg, 2.79 mmol) and PhSO2CF2H (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL), LHMDS (4 mL, 1 M in THF) was added dropwise under N2 at -78°C. After stirring at -78°C for 2 hours, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL), warmed to room temperature, and then extracted with Et2O (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a mixture of compounds SG-B1 and SG-B2 (700 mg). This mixture was further purified by chiral HPLC to obtain compound SG-B1 (200 mg, t = 4.31 min). 1 H NMR(400MHz,CDCl3),δ(ppm), 7.99-7.97 (d, 2H), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.08 (m, 1H), 0.88 (s, 3H); Compound SG-B2 (260mg, t=5.66min). 1 H NMR(400MHz,CDCl3),δ(ppm), 8.00--7.98 (d, 2H), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.09 (m, 1H), 0.88 (s, 3H).

[0263] Synthesis of compound SG-C. To a solution of compound SG-B2 (100 mg, 0.209 mmol) and anhydrous Na2HPO4 (100 mg) in anhydrous methanol (5 mL), Na / Hg amalgam (500 mg) was added under N2 at -20°C. After stirring at -20°C to 0°C for 1 hour, the methanol solution was decanted, and the solid residue was Et2O( The mixture was washed with 5 × 3 mL of brine. The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound SG-C (36 mg, 0.106 mmol, 51%). 1 H NMR (400MHz, CDCl3), δ(ppm), 6.02-5.88 (t, 1H), 5.17-5.15 (m, 1H), 0.88 (s, 3H).

[0264] Synthesis of compound SG-D. To a solution of compound SG-C (150 mg, 0.443 mmol) in dry THF (5 mL), a borane-tetrahydrofuran complex (1.0 M solution in 1.34 mL of THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (1 mL), followed by 30% aqueous H2O2 (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with RINKAN (3 × 10 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to obtain crude compound SG-D (210 mg). This crude product was used in the next step without further purification.

[0265] Synthesis of compound SG-E. Crude compound SG-D (210 mg) was dissolved in 10 mL of H2O-saturated dichloromethane (dichloromethane was shaken with several milliliters of H2O and then separated from the aqueous layer). Dess-Martin periodinate (380 mg, 0.896 mmol) was added to the solution. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to obtain compound SG-E (90 mg, 0.254 mmol, 57%) as an off-white solid. 1H NMR (400MHz, CDCl3), δ(ppm), 6.01-5.73 (t, 1H), 2.55-2.54 (m), 2.12 (s), 0.62 (s, 3H).

[0266] Synthesis of compound SG. Two drops of HBr (48%) were added to a solution of compound SG-E (80 mg, 0.226 mmol) in MeOH (5 mL), followed by the addition of bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water, then extracted with ethyl acetate (15 mL x 3), the combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain crude compound SG (95 mg). This crude product was used in the next step without further purification.

[0267] Example 14. Synthesis of compounds SG-1 and SG-2. [ka] A suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL) is supplemented with 2H-tetrazole (28 mg, 0.4 mmol) and 10 (86 mg, 0.2 mmol). The mixture was stirred at room temperature for 15 hours. The residue was poured into 5 mL of H2O and extracted with dimethyl(2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain SG-1 (12 mg, 14.2%) as an off-white solid and an off-white solid by-product (15 mg, 17.7%). SG-1: 1 HNMR(500MHz,CDCl3)δ(ppm):8.74 (s, 1H), 5.87 (t, 1H), 5.32 (AB, 1H, J=18.0Hz), 5.19 (AB, 1H), 2.68 (t, 1H, J=8.5Hz), 2.26-2.20 (m), 2.09-2.05 (m), 0.68 (s, 3H). LC-MS: rt=2.11 min, m / z=423.3[M+H] + .

[0268] Example 15. Synthesis of compounds SG-3 and SG-4. [ka] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 5-methyl-2H-tetrazole (28 mg, 0.4 mmol) and SG (86 mg, 0.2 mmol) were added. This mixture was stirred at room temperature for 15 hours. The residue mixture was poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to obtain SG-3 as an off-white solid (15 mg, 17%) and SG-4 as an off-white solid (30 mg, 34%). SG-3: 1 HNMR(500MHz,CDCl3)δ(ppm):5.87 (t, 1H), 5.15 (AB, 1H), 5.05 (AB, 1H), 2.67 (t, 1H), 2.47 (s, 3H), 2.22-2.20 (m, 1H) 2.09-2.07 (m, 1H), 0.69 (s, 3H). LC-MS: rt=2.14 min, m / z=437.1[M+H] + SG-4: 1 HNMR(500MHz,CDCl3)δ(ppm):5.87 (t, 1H), 5.35 (s, 2H), 2.63 (t, 1H), 2.56 (s, 3H), 0.72 (s, 3H). LC-MS:rt=2.24 min, m / z=437.0[M+H] + .

[0269] Example 16. Synthesis of compound SG-5. [ka] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL), 1H-1,2,3-triazole (50 mg, 0.72 mmol) and the reactant (100 mg, 0.23 mmol) were added. The mixture was stirred at room temperature for 15 hours, then the reaction mixture was poured into 10 mL of H2O and extracted with  (2 × 20 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by reverse-phase prep-HPLC to obtain the title compound SG-5 (15.4 mg, 0.0365 mmol, 22%). SG-5: 1 HNMR(400MHz,CDCl3)δ(ppm):7.75(s,1H), 7.64(s,1H), 5.87(t, 1H), 5.27 (AB, 1H), 5.14 (AB, 1H), 2.66 (t,1H), 0.69 (s, 3H).

[0270] Example 17. Synthesis of SE and SE intermediates. [ka] [ka]

[0271] Synthesis of compound SE-A. To a solution of EtMgBr (5 mmol, 1 M in THF) in THF (20 mL), a solution of compound SC (858 mg, 3 mmol) in dry THF (5 mL) was added via syringe pump over 30 minutes at 0°C. After stirring at 0°C for 5 hours, the reaction mixture was warmed and stirred overnight at room temperature. The reaction mixture was quenched with ice-cold water and extracted with RINKAN (15 mL x 3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was analyzed by flash column chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1). The compound SE-A ​​(900 mg) was obtained by further purification.

[0272] Synthesis of compound SE-B. A solution of compound SE-A ​​(200 mg, 0.66 mmol) in dry THF (5 mL) was mixed with borane-tetrahydrofuran complex (1.0 M solution in 2 mL of THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (1 mL), followed by 30% aqueous H2O2 (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with RINKAN (3 × 10 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to obtain compound SE-B (260 mg, crude). This crude product was used in the next step without further purification.

[0273] Synthesis of compound SE-C. Compound SE-B (260 mg, crude) was dissolved in 10 mL of dichloromethane, to which PCC (449 mg) was added. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with 10% aqueous NaCl (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 4:1 to 2:1) to obtain the title compound SE-C (15 mg) as an off-white solid. 1 H NMR (500MHz, CDCl3), δ(ppm), 2.49 (1H, t), 0.84(,t 3H), 0.59 (s, 3H).

[0274] Synthesis of compound SE. Two drops of HBr (48%) were added to a solution of compound SE-C (30 mg, 0.09 mmol) in MeOH (5 mL), followed by the addition of bromine (100 mg, 0.62 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water, then extracted with ethyl acetate (15 mL x 3), the combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain compound SE (36 mg crude). This crude product was used in the next step without further purification.

[0275] Example 18. Synthesis of compounds SE-1 and SE-2. [ka] To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (5 mL), 1H-tetrazole (40 mg, 0.46 mmol) and SM (100 mg, 0.243 mmol) were added. This mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL of H2O and extracted with Â(2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain the title compound as off-white solids SE-1 (9 mg, 9.2%) and SE-2 (15 mg, 15.6%). SE-1: 1 HNMR(400MHz,CDCl3)δ(ppm):8.75 (s, 1H), 5.32 (AB, 1H), 5.20 (AB, 1H), 2.67 (t, 1H), 1. 59 (q, 2H), 0.88 (t, 3H), 0.68 (s, 3H). LC-MS: rt=2.27min, m / z=383.4 (M + -H2O+ 1). SE-2: 1 HNMR(400MHz, CDCl3), δ(ppm):8.57 (s, 1H), 5.46 (s, 2H), 2.67 (t, 1H), 1.59 (q, 2H), 0.88 (t, 3H), ,0.71(s, 3H). LC-MS: rt=2.36min, m / z=383.4 (M + -H2O + 1).

[0276] Example 19. Synthesis of compounds SE-3 and SE-4. [ka]

[0277] To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (5 mL), 2H-1,2,3-triazole (36 mg, 0.52 mmol) and SE (100 mg, 0.25 mmol) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was then poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain the title compound as off-white solids SE-3 (9 mg, 9.3%) and SE-4 (10 mg, 10.3%). SE-3: 1 HNMR(500MHz,CDCl3)δ(ppm):7.75 (d, 1H), 7.64 (d, 1H), 5.27 (AB,1H),5.13 (AB, 1H), 2.67 (1H, t), 1.59(2H, q), 0.90(3H, t), 1.28 (s, 3H), 0.67 (s, 3H). LC-MS:rt=2.31min, m / z=400.4 (M + + 1). SE-4: 1 HNMR(500MHz,CDCl3)δ(ppm):7.68 (s, 2H), 5.25 (AB, 1H), 5.21(AB, 1H), 2.58 (t, 1H), 1.59 (2H, q), 0.90 (3H, t), 0.71 (s, 3H). LC-MS: rt=2.42min, m / z=400.4 (M + + 1).

[0278] Example 20. Synthesis of compounds SE-5 and SE-6. [ka]

[0279] A suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL) contains 5-methyl-2H-tetrazole (33.6 mg, 0.4 mmol) and compound SE (82 mg (0.2 mmol) was added. This mixture was stirred at room temperature for 15 hours, then the residue mixture was poured into 5 mL of H2O and extracted with dimethyl (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to obtain SE-5 as an off-white solid (11.1 mg, 13.5%) and SE-6 as an off-white solid (30.6 mg, 37.2%). SE-5: 1 HNMR(500MHz,CDCl3)δ(ppm):5.13 (AB, 1H), 5.07 (AB, 1H), 2.66 (t, 1H), 2.47 (s, 3H), 2.24-2.17 (m, 1H), 2.11-2.05 (m, 1H), 1.47 (q, 2H), 0.93 (t, 3H), 0.69 (s, 3H). LC-MS:rt=2.13 min, m / z=415.1[M+H] + SE-6: 1 HNMR(500MHz,CDCl3)δ(ppm):5.37 (AB, 1H), 5.33 (AB, 1H), 2.62 (t, 1H), 2.56 (s, 3H), 2.25-2.18 (m, 1H), 2.09-2.06 (m, 1H), 1.47 (q, 2H), 0.93 (t, 3H), 0.72 (s, 3H). LC-MS:rt=2.26 min, m / z = 415.3 [M + H] + .

[0280] Example 21. Synthesis of SM and SM intermediates. [ka]

[0281] Synthesis of compounds SA-DD and SA-EE. A compound mixture of SA-BB and SA-CC (5.0 g, 16.7 mmol) was dissolved in dry methanol (250 mL), and metallic sodium (1.2 g, 50.0 mmol) was added. The solution was refluxed for 16 hours. The methanol was then removed by evaporation, and the residue was dissolved in dichloromethane. The mixture was washed with H2O (3 × 50 mL) and brine (100 mL), dried over MgSiO4, filtered, and concentrated. The crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) and concentrated to obtain the product mixture SA-DD and SA-EE (4.6 g, 83%) as an off-white solid.

[0282] Synthesis of compounds SA-FF and SA-GG. A solution of the reactant mixture SA-DD and SA-EE (4.6 g, 13.9 mmol) in anhydrous THF (30 mL) is prepared by adding BH3.TH. F (1.0 M, 27.7 mL, 27.7 mmol) was added, and the solution was stirred overnight at 25°C. The reaction was then quenched by adding water (5 mL). 2 M NaOH solution (30 mL) was added, followed by 30% H₂O₂ (30 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification.

[0283] Synthesis of compounds SA-HH and SA-II. A crude reactant mixture, SA-FF and SA-GG (4.9 g, 13.9 mmol, theoretical amount), was dissolved in dichloromethane (40 mL) to which pyridinium chloroformate (PCC) was gradually added (6.0 g, 27.8 mmol). This solution was stirred overnight at 25°C, and the mixture was then filtered through a short pad of silica gel. The silica gel was washed with dichloromethane (3 × 50 mL). All filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15:1) to obtain product SA-HH (2.1 g, 6.03 mmol, yield = 43% (2 steps)) as an off-white solid, and product SA-II (2.2 g, 6.32 mmol, yield = 45% (2 steps)) as an off-white solid. Compound SA-HH: 1 HNMR(500MHz,CDCl3)δ(ppm):3.40 (s, 3H), 3.20 (s, 2H), 2.62-2.51 (m, 2H), 2.11 (s, 3H), 2.02-1.99 (m, 2H), 0.62 (s, 3H). Compound SA-II: 1 HNMR(500MHz,CDCl3)δ(ppm):3.42 (AB, 1H), 3.38 (AB, 1H), 3.40 (s, 3H), 2.65 (s, 1H), 2.54 (t, 1H), 2.16-2.14 (m, 1H), 2.11 (s, 3H), 2.02-1.98 (m, 1H), 0.61 (s, 3H).

[0284] Synthesis of compound SM. To a solution of reactant SA-II (100 mg, 0.301 mmol) in methanol (10 mL), 48% hydrobromic acid (152 mg, 0.903 mmol) was added, followed by the addition of bromine (241 mg, 0.077 mL, 1.51 mmol). This solution was heated at 25°C for 1.5 hours, then the mixture was poured into cold water (50 mL), and the resulting solid was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SM was used directly in the next step without further purification.

[0285] Example 22. Synthesis of compound SM-1. [ka] To a solution of compound SM (120 mg, 0.28 mmol) in THF (3 mL), K2CO3 (190 mg, 1.4 mmol) and 1H-tetrazole (100 mg, 1.4 mmol) were added. The resulting solution was stirred overnight at room temperature, and then the reaction product was diluted with SiO2 (20 mL). The resulting solution was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain SM-1 (12 mg, 10%) and an off-white solid by-product (14 mg, 12 %) was obtained. SM-1:1H NMR: (500MHz, CDCl3), δ (ppm), 8.74 (s, 1H), 5.32 (AB, 1H), 5.19 (AB, 1H), 3.42 (AB, 1H), 3.40 (S, 3H), 3.39 (AB, 1H), 2.68 (t, 1H), 2.66 (s, 1H), 0.67 (s, 3H). LC-MS:rt=2.19 min; m / z=399.2 (M-18) + .

[0286] Example 23. Synthesis of compounds SM-3 and SM-4. [ka] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 5-methyl-2H-tetrazole (33.6 mg, 0.4 mmol) and 10 (85 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 15 hours, then poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting mixture was purified by reverse-phase prep-HPLC to obtain SM-3 (8.6 mg, 10%) as an off-white solid and SM-3 (12 mg, 13.9%) as an off-white solid. 1 HNMR(500MHz,CDCl3)δ(ppm):5.15 (AB, 1H), 5.05 (AB, 1H), 3.42 (AB, 1H), 3.39 (AB, 1H), 3.40 (s, 3H), 2.67 (t, 1H), 2.64 (s, 1H), 2.47 (s, 3H), 2.21-2.17 (m, 1H), 2.08-2.05 (m, 1H), 0.68 (s, 3H). LC-MS: rt=2.14 min, m / z=431.2[M+H] + SM-4: 1 HNMR(500MHz,CDCl3)δ(ppm):5.37 (AB, 1H), 5.33 (AB, 1H), 3.42 (AB, 1H), 3.38 (AB, 1H), 3.40 (s, 3H), 2.63 (t, 1H), 2.56 (s, 3H), 0.71 (s, 3H). LC-MS: rt=2.25 min, m / z=431.2[M+H]+.

[0287] Example 24. Synthesis of compound SM-5. [ka] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 2H-1,2,3-triazole (28 mg, 0.4 mmol) and compound SM (85 mg, 0.2 mmol) were added. This mixture was stirred at room temperature for 15 hours, and the residue was then poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to obtain SM-5 as an off-white solid (25 mg, 30%). Compound SM-5: 1 HNMR(500MHz,CDCl3)δ(ppm):7.76 (s, 1H), 7.65 (s, 1H), 5.28 (AB, 1H), 5.14 (AB, 1H), 3.42 (AB, 1H), 3.39 (AB, 1H), 3.40 (s, 3H), 2.66 (t, 1H), 2.23-2.20 (m, 1H), 2.10-2.08 (m, 1H), 0.67 (s, 3H). LC-MS: rt=2.14 min, m / z=415.8[M+H] + .

[0288] Example 25. Synthesis of SO and SO intermediates. [ka]

[0289] Synthesis of compounds SO-C and SO-D. A compound mixture of SO-A and SO-B (5.0 g, 16.7 mmol) was dissolved in dry ethanol (250 mL), and Na (1.2 g, 50.0 mmol) was added. This solution was refluxed for 16 hours. The ethanol was removed by evaporation, and the residue was dissolved in dichloromethane, washed with H2O (3 × 50 mL) and brine (100 mL), dried over MgSiO4, filtered, and concentrated. This crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1), and concentrated to obtain the product mixture SO-C and SO-D (4.5 g, 78%) as an off-white solid.

[0290] Synthesis of compounds SO-E and SO-F. To a solution of the reactant mixture SO-C and SO-D (4.5 g, 13.0 mmol) in anhydrous THF (30 mL), BH3.THF (1.0 M, 27.7 mL, 27.7 mmol) was added, and the solution was stirred overnight at 25°C. Next, this reaction was quenched by adding water (5 mL). 2 M NaOH solution (30 mL) was added, followed by 30% H2O2 (30 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification.

[0291] Synthesis of compounds SO-G and SO-H. A crude reactant mixture of SO-E and SO-F (4.5 g, 13.0 mmol, theoretical amount) was dissolved in dichloromethane (40 mL), to which pyridinium chloroformate (PCC) was gradually added (5.7 g, 26.0 mmol). This solution was stirred overnight at 25°C. The mixture was then filtered through a short pad of silica gel, and the silica gel was washed with dichloromethane (3 × 50 mL). All filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 15:1) to obtain product SO-G (2.0 g, 5.5 mmol, yield = 42% (2 steps)) as an off-white solid, and product SO-H (1.8 g, 4.97 mmol, yield = 38% (2 steps)) as an off-white solid. SO-H: 1 HNMR(500MHz,CDCl3)δ(ppm):3.53 (q, 2H), 3.45 (AB, 1H), 3.41 (AB, 1H), 2.54 (t, 1H), 2.16-2.12 (m), 2.11 (s), 2.02-1.98 (m), 1.2 (t, 3H), 0.61 (s, 3H).

[0292] Synthesis of compound SO. To a solution of the reactant SO-H (100 mg, 0.301 mmol) in methanol (10 mL), 48% hydrobromic acid (152 mg, 0.903 mmol) was added, followed by the addition of bromine (241 mg, 0.077 mL, 1.505 mmol). This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SO was used directly in the next step without further purification.

[0293] Example 26. Synthesis of compounds SO-1 and SO-2. [ka] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 5-methyl-2H-tetrazole (33.6 mg, 0.4 mmol) and 10 (85 mg, 0.2 mmol) were added. This mixture was stirred at room temperature for 15 hours. The residue mixture was poured into 5 mL of H2O and extracted with Â(2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to obtain SO-1 as an off-white solid (9.6 mg, 10.8%) and SO-2 as an off-white solid (17.5 mg, 19.7%). SO-1: 1 HNMR(500MHz,CDCl3)δ(ppm):5.15 (AB, 1H), 5.05 (AB, 1H), 3.54 (q, 2H), 3.45 (AB, 1H), 3.41 (AB, 1H), 2.75 (s, 1H), 2.66 (t, 1H), 2.47 (s, 3H), 2.24-2.17 (m, 1H), 2.08-2.05 (m, 1H), 1.21 (t, 3H), 0.68 (s, 3H). LC-MS:rt=2.24 min, m / z = 445.3 [M + H] +SO-2: 1 HNMR(500MHz,CDCl3)δ(ppm):5.36 (AB, 1H), 5.35 (AB, 1H), 3.54 (q, 2H), 3.45 (AB, 1H), 3.41 (AB, 1H), 2.75 (s, 1H), 2.63 (t, 1H), 2.56 (s, 3H), 2.24-2.17 (m, 1H), 2.09-2.05 (m, 1H), 1.21 (t, 3H), 0.71 (s, 3H). LC-MS:rt=2.35 min, m / z=427.3[M-H2O+H] + .

[0294] Example 27. Synthesis of SL and SL intermediates. [ka]

[0295] Synthesis of compound SL-B. SA-A (10 g, 36.7 mmol) was added to 50 mL of acetyl chloride and 50 mL of acetic anhydride. This reaction mixture was heated to 120 °C for 5 hours and evaporated under reduced pressure to obtain crude SL-B as an off-white solid (10 g, yield 87%). 1 H NMR(400MHz, CDCl3), δ(ppm), 5.78 (s, 1H), 5.55 (s, 1H), 2.4(2H, dd), 2.13 (s, 3H), 0.90 (s, 3H).

[0296] Synthesis of compound SL-C. To a solution of SL-B (10 g, 31.8 mmol) in 200 mL of THF and 20 mL of H2O, mCPBA (11 g, 63.6 mmol) was added at 0°C and stirred at room temperature for 15 hours. The reaction mixture was extracted with 500 mL of siRNA, washed with 100 mL of saturated Na2SO3, 100 mL of saturated NaHCO3 and 100 mL of brine, evaporated under reduced pressure, and then purified by chromatography (PE:siRNA = 5:1) to obtain SL-C as an off-white solid (2.2 g, yield 24%). 1H NMR (400MHz, CDCl3), δ(ppm), 5.92 (s, 1H), 4.44 (s, 1H), 0.95 (s, 3H).

[0297] Synthesis of compound SL-D. 200 mg of Pd / C was added to a solution of SL-C (2 g, 6.94 mmol) in 50 mL of siRNA. This reaction mixture was hydrogenated in H2 at 1 atm for 15 hours. The reaction mixture was evaporated under reduced pressure and then purified by chromatography (PE:siRNA = 1:2) to obtain SL-D as an off-white solid (1 g, 50% yield). 1 H NMR (400MHz, CDCl3), δ(ppm), 3.83 (s, 1H), 0.93 (s, 3H).

[0298] Synthesis of compound SL-E. To a solution of SL-D (1 g, 3.4 mmol) in 100 mL of MeOH, 50 mg of TsOH was added and the mixture was heated to 60°C for 2 hours. This reaction mixture was extracted with 500 mL of siRNA, washed with 100 mL of saturated NaHCO3 and 100 mL of brine, and evaporated under reduced pressure to obtain SL-E as an off-white solid (1 g, 91% yield). 1 H NMR(400MHz,MeOD),δ(ppm), 3.80 (s, 1H), 3.20 (s, 3H), 3.15 (s, (3H), 0.89 (s, 3H) was obtained.

[0299] Synthesis of compound SL-F. To a solution of ethyltriphenylphosphonium bromide (10.67 g, 28.84 mmol) in 30 mL of THF, KOt-Bu (3.23 g, 28.80 mmol) was added. The reaction mixture was heated to 60°C for 1 hour, then SL-E (3.23 g, 9.6 mmol) was added to the mixture and stirred at 60°C for 15 hours. The reaction mixture was extracted with 500 mL of toluene, washed with brine, evaporated under reduced pressure, and then purified by chromatography (PE:toluene = 3:1) to obtain SL-F as an off-white solid (2.18 g, yield 65%). 1¹H NMR (400 MHz, d6-acetone), δ (ppm), 5.09-5.07 (m, 1H), 3.65 (s, 1H), 3.11 (s, 3H), 3.08 (s, 3H), 0.88 (s, 3H).

[0300] Synthesis of compound SL-G. SL-F (1 g, 2.9 mmol) was dissolved in 50 mL of THF, to which NaH (2 g, 5.8 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then, 1 mL of MeI was added to the mixture and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with 5 mL of H2O, extracted with 100 mL of siRNA, washed with brine, evaporated under reduced pressure, and then purified by chromatography (PE:siRNA = 10:1) to obtain SL-G as an off-white solid (577 mg, 55% yield). 1 1H NMR (400 MHz, d6-acetone), δ (ppm), 4.96-4.93 (m, 1H), 3.12 (s, 3H), 3.00 (s, 1H), 2.98 (s, 3H), 2.96 (s, 3H), 0.75 (s, 3H).

[0301] Synthesis of compound SL-H. To a solution of SL-G (1 g, 2.8 mmol) in 20 mL of THF, 2 mL of 2 M aqueous HCl was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 5 mL of H2O, extracted with 100 mL of siRNA, washed with brine, evaporated under reduced pressure, and then chromatographed (PE: siRNA = 1). Purified by a 0:1 ratio, SL-H was obtained as an off-white solid (750 mg, yield 83%). 1 H NMR(400MHz,CDCl3),δ(ppm), 5.15-5.11 (m, 1H), 3.32 (s, 3H), 3.14 (s, 1H), 0.92 (s, 3H).

[0302] Synthesis of compound SL-I. NaH (60%, 800 mg, 31.5 mmol) was added to a stirred solution of trimethylsulfonium iodide (6.4 g, 31.5 mmol) in 10 mL of DMSO. After stirring at room temperature for 1 hour, a suspension of SL-H (1 g, 3.2 mmol) in 5 mL of DMSO was added dropwise. After 15 hours, the reaction mixture was poured into ice-cold water, extracted with 300 mL of siRNA, washed with 100 mL of brine, dried, evaporated under reduced pressure, and then purified by chromatography (PE:siRNA = 10:1) to obtain SL-I and its isomers as off-white solids (793 mg, yield 76%).

[0303] Synthesis of compound SL-J. To a solution of SL-I and its isomer (150 mg, 0.45 mmol) in 10 mL of THF, LiAH4 (50 mg, 1.35 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 5 mL of H2O, extracted with 100 mL of siRNA, washed with brine, evaporated under reduced pressure, and then purified by chromatography (PE:EA = 3:1) to obtain SL-J as an off-white solid (72 mg, 48% yield). 1 H NMR (400MHz, CDCl3), δ(ppm), 5.11-5.10 (m, 1H), 3.33 (s, 3H), 3.12 (s, 1H), 1.22 (s, 3H), 0.89 (s, 3H).

[0304] Synthesis of compound SL-K. To a solution of SL-J (100 mg, 0.3 mmol) in dry THF (5 mL), borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (1 mL), followed by 30% aqueous H2O2 (1 mL). After stirring at room temperature for 1 hour, the mixture was extracted with RINKAN (3 × 100 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated to obtain SL-K as an off-white solid (100 mg, 91%). This crude product was used in the next step without further purification.

[0305] Synthesis of compound SL-L. To a solution of SL-K (100 mg, 0.29 mmol) in 20 mL of DCM, PCC (190 mg, 0.87 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 5 mL of H2O, extracted with 100 mL of Â, washed with brine, evaporated under reduced pressure, and then purified by chromatography (PE:Â=3:1) to obtain SL-L as an off-white solid (55 mg, 55% yield). 1 H NMR(400MHz,CDCl3),δ(ppm), 3.30 (s, 3H), 3.10 (s, 1H),2.5(1H,t,J=10Hz),2.1(s, 3H), 1.16 (s, 3H), 0.56 (s, 3H).

[0306] Synthesis of compound SL. Two drops of HBr (48%) were added to a solution of SL-L (40 mg, 0.11 mmol) in MeOH (5 mL), followed by the addition of bromine (150 mg, 0.33 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with RINKAN (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain the crude compound SL as an off-white solid (40 mg, yield 80%). This crude product was not further purified before proceeding to the next step. I used it.

[0307] Example 28. Synthesis of compounds SL-1 and SL-2. [ka] To a suspension of SL (40 mg, 0.09 mmol) in THF (5 mL), 1H-1,2,3-triazole (30 mg, 0.45 mmol) and K2CO3 (60 mg, 0.45 mmol) were added. This mixture was stirred at 25°C for 15 hours. The reaction mixture was purified by reverse-phase prep-HPLC to obtain SL-1 as an off-white solid (5 mg, yield 13%) and SL-2 as an off-white solid (5 mg, yield 13%). SL-1: 1 H NMR(400MHz,CDCl3),δ(ppm), 7.75 (s, 1H), 7.64 (s, 1H), 5.25-5.13 (m, 2H), 3.31 (s, 3H), 3.11 (s, 1H), 1.24 (s, 3H), 0.71 (s, 3H). SL-2: 1 H NMR (400MHz, CDCl3), δ(ppm), 7.68 (s, 2H), 5.27-5.19 (m, 2H), 3.31 (s, 3H), 3.11 (s, 1H), 1.21 (s, 3H), 0.75 (s, 3H).

[0308] Example 29. Synthesis of SH and SH intermediates. [ka]

[0309] Synthesis of compound SH-C. To a solution of compound SL-B (10 g, 31.8 mmol) in 200 mL of THF and 20 mL of H2O, m-CPBA (11 g, 63.6 mmol) was added at 0°C. After stirring at room temperature for 15 hours, the reaction mixture was diluted with 500 mL of RINKAN. The resulting solution was washed with 300 mL of sat.Na2SO3, 300 mL of sat.NaHCO3, and 300 mL of brine, and then evaporated under reduced pressure. The residue was purified by chromatography (PE:EA = 5:1) to obtain SH-C as an off-white solid (1.1 g, 3.8 mmol, yield 12%). 1 H NMR (500MHz, CDCl3), δ(ppm), 6.25 (s, 1H), 4.27 (dd, 1H), 0.93 (s, 3H).

[0310] Synthesis of compound SH-D. 200 mg of Pd / C was added to a solution of compound SH-C (2 g, 6.94 mmol) in 50 mL of siRNA. This reaction mixture was hydrogenated in H2 at 1 atm for 15 hours. The reaction mixture was evaporated under reduced pressure and then purified by chromatography (PE:EA = 1:2) to obtain SH-D as an off-white solid (1.5 g, 5.2 mmol, 75% yield). 1 H NMR (500MHz, CDCl3), δ(ppm), 3.97 (td, 1H), 0.88 (s, 3H).

[0311] Synthesis of compound SH-E. To a solution of compound SH-D (1 g, 3.4 mmol) in 100 mL of MeOH, 50 mg of TsOH was added. This solution was heated to 60°C for 2 hours. The reaction mixture was then diluted with 500 mL of acetone, washed with 100 mL of sat.NaHCO3 and 100 mL of brine, and evaporated under reduced pressure to obtain SH-E as an off-white solid (1 g, 91% yield).

[0312] Synthesis of compound SH-F. To a solution of ethyltriphenylphosphonium bromide (10.67 g, 28.84 mmol) in 30 mL of THF, KOt-Bu (3.23 g, 28.80 mmol) was added. This reaction was heated to 60°C for 1 hour, and then compound SH-E (3.23 g, 9.6 mmol) was added to the mixture. This solution was heated at 60°C for 15 hours. The reaction mixture was then diluted with 500 mL of siRNA. The resulting solution was washed with 100 mL of brine, evaporated under reduced pressure, and then purified by chromatography (PE:EA = 3:1) to obtain SH-F as an off-white solid (2 g, 5.74 mmol, yield 62%). 1 H NMR(500MHz, MeOD), δ(ppm), 5.15-5.12 (m, 1H), 3.80-3.78 (m, 1H), 3.21 (s, 3H), 3.15 (s, 3H), 1.67 (d, 3H), 0.95 (s, 3H).

[0313] Synthesis of compound SH-G. To a solution of compound SH-F (0.5 g, 1.43 mmol) in 10 mL of DCM, DAST (0.5 ml, 10 mmol) was added at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, then quenched with 5 L of sat.NaHCO3, extracted with 50 ml of DCM, washed with 100 ml of brine, dried over Na2SO4, concentrated under reduced pressure, and purified by chromatography (PE:EA = 30:1) to obtain SH-G as an off-white solid (175 mg, 0.5 mmol, yield 35%).

[0314] Synthesis of compound SH-H. Compound SH-G (350 mg, 1 mmol) was dissolved in 20 mL of THF, to which 2 M HCl (2 mL) was added. This solution was stirred at room temperature for 1 hour, and the reaction mixture was then extracted with 100 mL of siRNA, washed with 100 mL of brine, and evaporated under reduced pressure. The resulting residue was then purified by chromatography (PE:EA = 10:1) to obtain SH-H as an off-white solid (210 mg, 0.7 mmol, yield 60%). 1H NMR(500MHz,CDCl3),δ(ppm), 5.17-5.14 (m, 1H), 4.80-4.66 (m, 1H), 2.61-2.57 (m, 1H), 1.79 (d, 3H), 0.93 (s, 3H).

[0315] Synthesis of compound SH-I. NaH (60%, 400 mg, 16 mmol) was added to a stirred suspension of trimethylsulfonium iodide (3.2 g, 16 mmol) in 10 mL of DMSO. After stirring at room temperature for 1 hour, a suspension of compound SH-H (486 mg, 1.6 mmol) in 5 mL of DMSO was added dropwise. After 15 hours, the reaction mixture was poured into ice-cold water and extracted with 300 mL of phenylethylamine. The resulting solution was washed with 100 mL of brine, dried in (NaSO4), and evaporated under reduced pressure. The resulting residue was then purified by chromatography (PE:EA = 10:1) to obtain a mixture of SH-I and its C-3 isomer as an off-white solid (290 mg, 0.91 mmol, 58% yield).

[0316] Synthesis of compound SH-J. LiAH4 (100 mg, 2.7 mmol) was added to a solution of SH-I and its C-3 isomer (300 mg, 0.94 mmol) in 10 ml of THF. The suspension was stirred at room temperature for 1 hour. The reaction mixture was then quenched with 5 mL of H2O and extracted with 100 mL of siRNA. The resulting solution was washed with brine and evaporated under reduced pressure. The resulting residue was then purified by chromatography (PE:EA = 3:1) to obtain SH-J as an off-white solid (140 mg, 48% yield). 1 1H NMR (500MHz, CDCl3), δ (ppm), 5.15-5.12 (m, 1H), 4.72-4.60 (m, 1H), 1.70 (d, 3H), 1.27 (s, 3H), 0.92 (s, 3H).

[0317] Synthesis of compound SH-K. To a solution of compound SH-J (100 mg, 0.3 mmol) in dry THF (5 mL), borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (1 mL), followed by 30% aqueous H2O2 (1 mL). After stirring at room temperature for 1 hour, the mixture was extracted with RINKAN (3 × 100 mL). The combined organic extract was then washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated to obtain crude SH-K as an off-white solid (100 mg, 91%). This crude product was used in the next step without further purification.

[0318] Synthesis of compound SH-L. 20m of compound SH-K (100mg, 0.29 mmol). PCC (190 mg, 0.87 mmol) was added to the solution in DCLM, and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was then filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was then purified by chromatography (PE:EA = 3:1) to obtain SH-L as an off-white solid (53 mg, 53% yield). 1 H NMR(400MHz, CDCl3), δ(ppm), 4.71-4.57 (m, 1H), 2.54(1H, t), 2.15(s, 3H), 1.28 (s, 3H), 0.58 (s, 3H).

[0319] Synthesis of compound SH. Two drops of HBr (48%) were added to a solution of compound SH-L (40 mg, 0.11 mmol) in MeOH (5 mL), followed by the addition of bromine (150 mg, 0.33 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain crude compound SH as a yellow solid (40 mg, yield 80%). This crude product was used in the next step without further purification.

[0320] Example 30. Synthesis of compounds SH-1 and SH-2. [ka] To a suspension of compound SH (50 mg, 0.12 mmol) in THF (5 mL), 2H-1,2,3-triazole (120 mg, 1.8 mmol) and K2CO3 (200 mg, 1.2 mmol) were added. This mixture was stirred at 25°C for 15 hours. The reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain the crude product. This crude product was purified by reverse-phase prep-HPLC to obtain SH-1 as an off-white solid (12 mg, 0.03 mmol, yield 25%) and SH-2 as an off-white solid (5.7 mg, 0.014 mmol, yield 8.33%). SH-1: 1 H NMR(500MHz,CDCl3),δ(ppm), 7.76 (s, 1H), 7.65 (s, 1H), 5.29(1H,AB), 5.14(1H,AB), 4 .73-4.59 (m, 1H), 2.68 (1H, t), 1.30 (s, 3H), 0.67 (s, 3H). SH-2: 1 H NMR(500MHz,CDCl3),δ(ppm), 7.69 (s, 2H), 5.27(1H,AB), 5.23(1H,AB), 4.73-4.59 (m, 1H), 4.64-4.59 (m, 1H),2.60(1H,t),1.29 (s, 3H), 0.70 (s, 3H).

[0321] Example 31. Synthesis of SB and SB intermediates [ka]

[0322] Synthesis of compounds SB-B and SB-C. A small piece of lithium (7.63 g, 1.1 mol) was added to 2.7 L of concentrated ammonia in a three-necked flask at -70°C. As soon as all the lithium had dissolved, the blue solution was heated to -50°C. 19-Norandrosta-4-ene-3,17-dione SB-A (1.30 g, 110 mmol) and tert-BuOH (8.14 g, 110 mmol) in 800 ml of anhydrous tetrahydrofuran were added dropwise, and the mixture was stirred for 90 minutes until it turned bright yellow. Ammonium chloride (70 g) was added, and the excess ammonia was evaporated. The residue was extracted with 0.5 N HCl (500 mL) and dichloromethane (500 mL x 2). The combined organic layers were washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated to obtain a mixture of SB-B and SB-C (21 g, 70%), which was used directly in the next step without further purification. A solution of SB-B and SB-C (21 g, 76 mmol) in 50 mL of anhydrous dichloromethane was added to a suspension of pyridinium chloroformate (PCC) (32.8 g, 152 mmol) in 450 mL of dichloromethane. Room temperature After stirring for 2 hours, a 2N NaOH solution (500 mL) was added to the dark brown reaction mixture, and the mixture was stirred for a further 10 minutes. The resulting solution was extracted with dichloromethane, the combined organic layers were washed with 2N HCl and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1) to obtain the title compound SB-C (16.8 g, 80%) as an off-white solid. 1 H NMR (400MHz, CDCl3), δ(ppm), 3.65 (t, 1H, 1H), 0.77 (s, 3H). SB-C's 1 H NMR (400MHz, CDCl3), δ(ppm), 0.88 (s, 3H).

[0323] Synthesis of compound SB-D. Iodine (1.54 g, 6.1 mmol) was added to a solution of compound SB-C (16.8 g, 61.3 mmol) in methanol (250 mL). After stirring at 60 °C for 12 hours, the solvent was removed under reduced pressure. The crude product was dissolved in dichloromethane (200 mL), washed with saturated NaHCO3 (150 mL) and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography with basic alumina (petroleum ether / ethyl acetate = 100:1) to obtain compound SB-D (14 g, 43.8 mmol, 71%). 1 H NMR (400MHz, CDCl3), δ(ppm), 3.18 (s, 3H), 3.12 (s, 3H), 0.85 (s, 3H).

[0324] Synthesis of compound SB-E. Ethyl triphenylphosphonium bromide (26 g, 70 mmol) was slowly added at 0°C to a suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL). After stirring at 60°C for 3 hours, compound SB-D (7 g, 21.9 mmol) was added, and the mixture was stirred at 60°C for a further 2 hours. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride and extracted with RINKAN (2 × 500 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain crude compound SB-E (7.36 g, 100%). This crude product was used in the next step without further purification.

[0325] Synthesis of compound SB-F. A solution of crude compound SB-E (7.36 g, 21.9 mmol) in THF (50 mL) was acidified to pH=3 with 1N aqueous HCl. After stirring at room temperature for 12 hours, the reaction mixture was extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30:1 to 20:1) to obtain compound SB-F (4.8 g, 16.7 mmol, 76% from two steps). 1H NMR (400MHz, CDCl3), δ(ppm), 5.12-5.10 (m, 1H), 0.77 (s, 3H).

[0326] Synthesis of compound SB-G. To a solution of MeMgBr (28 mmol, 1 M in THF) in THF (50 mL), a solution of compound SB-F (4.8 g, 16.8 mmol) in dry THF (10 mL) was added via syringe pump over 30 minutes at 0°C. After stirring at 0°C for 5 hours, the reaction mixture was warmed and stirred overnight at room temperature. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1) to obtain compound SB-G (2.5 g, 8.28 mmol, 49%; Rf = 0.35, petroleum ether:ethyl acetate = 10:1). 1 H NMR(400MHz,CDCl3),δ(ppm), 5.05-5.03 (m, 1H), 1.21 (s, 3H), 0.90 (s, 3H).

[0327] Synthesis of compound SB-H. To a solution of compound SB-G (2 g, 6.62 mmol) in dry THF (50 mL), borane-tetrahydrofuran complex (20 mL; 1.0 M solution in THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (10 mL), followed by 30% aqueous H2O2 (12 mL). After stirring at room temperature for 1 hour, the mixture was extracted with RINKAN (3 × 100 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated to obtain crude compound SB-H (2 g, 100%). This crude product was used in the next step without further purification.

[0328] Synthesis of compound SB-I. Dess-Martin periodinate (5.5 g, 13 mmol) was added to a solution of crude compound SB-H (2 g, 6.62 mmol) in 60 mL of wet dichloromethane (dichloromethane was shaken with several milliliters of H2O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain compound SB-I (1 g, 3.14 mmol, 47% for two steps) as a white solid. 1 H NMR(400MHz,CDCl3),δ(ppm), 2.56 (t, 1H), 2.11 (s and m, 4H), 2.0 (dt, 1H), 1.8 (dm, 2H), 1.54 (m, 6 H) 1.43 (m, 1H), 1.34 (m, 2H),1.20 (m, 12H), 0.7 (m, 2H), 0.62(s, 3H).

[0329] Synthesis of compound SB. Five drops of HBr (48%) were added to a solution of compound SB-I (600 mg, 1.89 mmol) in MeOH (20 mL), followed by the addition of bromine (302 mg, 1.89 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over MgSO4, filtered, and concentrated to obtain crude compound SB (600 mg).

[0330] Example 32. Synthesis of compound SB-1. [ka] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL), 1,2,4-triazole (13 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with RINKAN (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse-phase prep-HPLC to obtain the title compound as an off-white solid (15 mg, 42%). SB-1: 1 HNMR (500 MHz, CDCl3), δ (ppm), 8.14 (s, 1H), 7.96 (s, 1H), 5.02 (AB, 1H), 4.93 (AB, J=18.0 Hz, 1H), 2.63 (t, 1H), 1.21 (s, CH3), 0.69 (s, 3H).

[0331] Example 33. Synthesis of compound SB-2. [ka]

[0332] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL), tetrazole (13 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This reaction mixture was purified by reverse-phase prep-HPLC to obtain SB-2 (7 mg, 19%) as an off-white solid and an off-white solid by-product (4 mg, 11%). SB-2: 1 HNMR(500MHz, CDCl3), δ(ppm), 8.58 (s, 1H), 5.49 (AB, 1H), 5.44 (AB, 1H), 2.63 (t, 1H), 1.21 (s, CH3), 0.72 (s, 3H).

[0333] Example 34. Synthesis of compounds SB-4 and SB-5. [ka] To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL), 5-methyl-1H-tetrazole (42.0 mg, 0.50 mmol) and compound SB (100 mg, 0.25 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with ELISA (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SB-4 as an off-white solid (10.1 mg, 0.025 mmol, 10.1%), and SB- Solution 5 was obtained as an off-white solid (21.3 mg, 0.053 mmol, 21.2%). SB-4: 1 HNMR(500MHz,CDCl3)δ(ppm):5.12 (AB, 1H), 5.06 (AB, 1H), 2.66 (t, 1H), 2.47 (s, 3H), 1.21 (s, CH3), 0.69 (s, 3H). LCMS:Rt=2.19 min. m / z=401.3[M+H] + SB-5: 1 HNMR(500MHz,CDCl3)δ(ppm):5.35 (AB, 1H), 5.34 (AB, 1H), 2.63 (t, 1H), 2.56 (s, 3H), 1.21 (s, CH3), 0.72 (s, 3H). LCMS:Rt=2.30 min. m / z=401.3[M+H] + .

[0334] Example 35. Synthesis of compound SB-6. [ka] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL), 1,2,3-1H-triazole (13 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with RINKAN (2 × 10 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This reaction mixture was purified by reverse-phase prep-HPLC to obtain SB-6 as an off-white solid (12 mg, 33%). SB-6: 1 HNMR(500MHz,CDCl3),δ(ppm), 7.76 (s, 1H), 7.64 (d, 1H), 5.26 (AB, 1H), 5.14 (AB, 1H), 2.59 (t, 1H), 1.21 (s, 3H), 0.68 (s, 3H).

[0335] Example 36. Synthesis of SD and SD intermediates. [ka]

[0336] Synthesis of compounds SD-B1 and SD-B2. To a solution of compound SC (1.3 g, 4.5 mmol) and PhSO2CH2F (790 mg, 4.5 mmol) in THF (25 mL) and HMPA (0.5 mL), LHMDS (5.5 mL, 1 M in THF) was added dropwise under N2 at -78°C. After stirring at -78°C for 2 hours, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL), warmed to room temperature, and then extracted with Et2O (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a mixture of compounds SD-B1 and SD-B2 (1.53 g). This mixture was further purified by chiral HPLC to obtain compound SD-B1-A (220 mg, t=3.41 min). 1H NMR(500MHz,CDCl3),δ(ppm), 7.99-7.97 (m, 2H), 7.75-7.74 (m, 1H), 7.62-7.55 (m, 2H), 5.13-5.09 (m, 1H), 4.86-4.78 (d, 1H), 0.88 (s, 3H);SD-B1-B (200mg,t=3.66min); 1 H NMR(500MHz,CDCl3),δ(ppm), 7.96-7.95 (m, 1H), 7.71-7.69 (m, 1H), 7.62-7.58 (m, 2H), 5.13-5.09 (m, 1H), 4.87-4.77 (d, 1H), 0.88 (s, 3H);SD-B2-A (235mg,t=4.9min). 1 H NMR(500MHz,CDCl3),δ(ppm), 7.99-7.97 (m, 1H), 7.72-7.70 (m, 1H), 7.62-7.59 (m, 2H), 5.29-5.20 (d, 1H), 4.88-4.78 (m,1H), 0.88 (s, 3H);SD-B2-B (220mg,t=5.2min). 1 H NMR(500MHz,CDCl3),δ(ppm), 7.99-7.97 (m, 2H), 7.72 (m, 1H), 7.62-7.59 (m, 2H), 5.30-5.20 (d, 1H), 5.09-5.08 (m,1H), 0.88 (s, 3H).

[0337] Synthesis of compound SD-C. To a solution of compound SD-B1-A (200 mg, 0.434 mmol) and anhydrous Na2HPO4 (100 mg) in anhydrous methanol (15 mL), Na / Hg amalgam (400 mg) was added under N2 at -20°C. After stirring at -20°C to 0°C for 1 hour, the methanol solution was decanted, and the solid residue was Et The mixture was washed with 2O (5 × 3 mL). The solvent of the combined organic phase was removed under reduced pressure, and 20 ml of brine was added, followed by extraction with Et2O. The combined ether phase was dried over MgSO4, and the ether was removed to obtain the crude product, which was further purified by silica gel chromatography (PE / EA = 10 / 1) to obtain 99 mg, 69% of the product. 1 H NMR (500MHz, CDCl3), δ(ppm), 5.12-5.10 (m, 1H,), 4.21-24.11 (d, 2H), 0.88 (s, 3H).

[0338] Synthesis of compound SD-D. To a solution of compound SD-C (95 mg, 0.296 mmol) in dry THF (5 mL), a borane-tetrahydrofuran complex (1.0 M solution in 1 mL of THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (1 mL), followed by 30% aqueous H2O2 (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with RINKAN (3 × 10 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to obtain compound SD-D (120 mg crude). This crude product was used in the next step without further purification.

[0339] Synthesis of compound SD-E. Compound SD-D (120 mg crude) was dissolved in 10 mL of wet dichloromethane (dichloromethane was shaken with several milliliters of H2O and then separated from the aqueous layer), and Dess-Martin periodinate (300 mg, 707 mmol) was added to the solution. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:5) to obtain compound SD-E (70 mg, 70% from two steps) as an off-white solid. 1H NMR (500MHz, CDCl3), δ(ppm), 4.21-4.11 (d, 2H), 2.19 (s, 3H), 0.62 (s, 3H).

[0340] Synthesis of compound SD. A solution of the reactant (200 mg, 0.594 mmol) in methanol (5 mL) was mixed with 48% hydrobromic acid (300 mg, 1.782 mmol), followed by the addition of bromine (475 mg, 0.152 mL, 2.97 mmol). This solution was heated at 25°C for 2 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 × 100 mL). The combined organic extract was washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0341] Example 37. Synthesis of compound SD-1. [ka]

[0342] To a suspension of K2CO3 (63 mg, 0.47 mmol) in THF (10 mL), 1,2,3-1H-triazole (11.4 mg, 0.47 mmol) and compound SD (100 mg, 0.23 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with siRNA (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SD-1 as an off-white solid (28.7 mg, 29.5%) and SGE-00921-01-A as an off-white solid (22.8 mg, 23.4%). SD-1: 1HNMR(500MHz, CDCl3), δ(ppm), 7.76 (d, 1H), 7.65 (d, 1H), 5.28 (AB, 1H), 5.14 (AB, 1H), 4.17 (d, 2H), 2.66 (t, 1H), 0.68 (s, 3H). LCMS:Rt=2.18 min. m / z=404.2[M+H] + .

[0343] Example 38. Synthesis of compounds SD-2 and SD-3. [ka] To a suspension of K2CO3 (63 mg, 0.47 mmol) in THF (10 mL), 5-methyl-1H-tetrazole (39.5 mg, 0.47 mmol) and compound SD (100 mg, 0.24 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SD-2 as an off-white solid (6.5 mg, 0.016 mmol, 6.7%) and SD-3 as an off-white solid (25.8 mg, 0.062 mmol, 25.8%). SD-2: 1 HNMR(500MHz,CDCl3)δ(ppm):5.12 (AB, 1H), 5.06 (AB, 1H), 4.17 (d, J=47.8 Hz, 2H), 2.67 (t, 1H), 2.47 (s, 3H), 0.69 (s, 3H). LCMS:Rt=2.11 min. m / z=419.3[M+H] + SD-3: 1 HNMR(500MHz,CDCl3)δ(ppm):5.35 (AB, 1H), 5.34 (AB, 1H), 4.17 (d, 2H), 2.63 (t, 1H), 2.56 (s, 3H), 0.72 (s, 3H). LCMS:Rt=2.21 min. m / z=419.3[M+H] + .

[0344] Example 39. Synthesis of compounds SD-4 and SD-5. [ka] To a solution of crude reaction material 11 (100 mg, 0.241 mmol) in anhydrous THF (5 mL), (140 mg, 1.2 mmol) was added, followed by the addition of potassium carbonate (85 mg, 1.2 mmol). This solution was heated at 60°C for 2 hours, then cooled to room temperature, and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase prep-HPLC to obtain product SD-4 (15 mg, 0.04 mmol, yield = 17%) and an off-white solid by-product (26 mg, 0.06 mmol, yield = 25%). SD-4: 1 HNMR(500MHz, CDCl3)δ(ppm): 8.75 (1H, s), 5.32 (1H, AB, J=18.5Hz), 5.18 (1H, AB), 4.17 (2H, d), 2.68 (1H, t), 0.68 (3H, s). LCMS:rt=2.14min, m / z=405[M+H] + .

[0345] Example 40. Synthesis of SP and SP intermediates. [ka]

[0346] Synthesis of compound SP-B. Ethyl magnesium bromide (3M in THF, 51.28mL) was added dropwise to a solution of reactant SC (4.4g, 15.38 mmol) in dry THF (50mL) at 0°C. The solution was then slowly warmed and stirred at ambient temperature for 15 hours. The reaction was quenched by adding Sat.NH4Cl solution (20mL), and the resulting solution was extracted with ethyl acetate (3×100mL). The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether: ethyl acetate = 10:1) to obtain product SP-B (3.15g, 10.00 mmol, 64.8%) as an off-white solid.

[0347] Synthesis of compound SP-C. To a solution of reactant SP-B (500 mg, 1.58 mmol) in anhydrous THF (10 mL), BH3.THF (1.0 M, 7.23 mL, 7.23 mmol) was added at room temperature, and the solution was stirred overnight at 25°C. The reaction was then quenched by adding water (5 mL), followed by the addition of 2 M NaOH solution (10 mL), and then 30% H2O2 (10 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with ethyl acetate (200 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SP-C was used directly in the next step without further purification.

[0348] Synthesis of compound SP-D. To a solution of the reactant SP-C (6.53 g, 19.67 mmol), cooled in an ice bath, in anhydrous DCM (100 mL), pyridinium chloroformate (8.48 g, 39.34 mol) was gradually added. This mixture was stirred overnight at ambient temperature. The solution was then diluted with DCM (50 mL) and filtered. The combined organic solution was washed with brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether: ethyl acetate = 10:1) to obtain product SP-D (2.5 g, 7.53 mmol, yield 39%) as an off-white solid. SP-D: 1 HNMR(500MHz,CDCl3)δ(ppm):2.54 (1H, t), 2.11 (3H,s), 1.42-1.45 (2H, q), 0.91 (3H, t), 0.62 (3H, s).

[0349] Synthesis of compound SP. To a solution of reactant SP-D (80 mg, 0.24 mmol) in methanol (5 mL), 48% hydrobromic acid (148 mg, 0.884 mmol) was added, followed by the addition of bromine (241 mg, 0.077 mL, 1.505 mmol). This solution was heated at 25°C for 1.5 hours, and then the mixture was poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (20 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SP was used directly in the next step without further purification.

[0350] Example 41. Synthesis of compounds SP-1 and SP-2. [ka] To a solution of the crude reaction product SP (500 mg, 1.2 mmol) in anhydrous THF (10 mL), 1,2,4-1H-triazole (500 mg, 6.0 mmol) was added, followed by the addition of potassium carbonate (1.02 g, 6 mmol). This solution was heated at 60°C for 2 hours, then cooled to room temperature, and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase prep-HPLC to obtain products SP-1 (105 mg, 0.26 mmol, yield = 22%) and SP-2 (62 mg, 0.15 mmol, yield = 13%) as off-white solids. SP-1: 1 HN MR(500MHz,CDCl3)δ(ppm):7.75(1H,s), 7.64(1H,s), 5.26(1H, AB), 5.14(1H, AB),2.66 (1H,t ), 0.91 (3H, t), 0.68 (3H, s). LCMS:rt=2.35min, m / z=400[M+H] + SP-2: 1 HNMR(500MHz,CDCl3)δ(ppm):7.68(2H, s), 5.25(1H, AB), 5.23(1H, AB, 2.59 (1H,t), 0.91 (3H, t), 0.70 (3H, s).LCMS:rt=2.49min, m / z=400[M+H] + .

[0351] Example 42. Synthesis of compound SP-3. [ka] To a solution of the crude reactant SP (247.5 mg, 0.603 mmol, theoretical amount) in THF (5 mL), tetrazole (84 mg, 1.202 mmol) was added, followed by potassium carbonate (166 mg, 1.202 mmol), and the mixture was heated at 50°C for 2 hours. The reaction mixture was then diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain the desired product SP-3 (14.4 mg, 0.0359 mmol, yield = 6.0% (2 steps)) as an off-white solid. Another desired product could not be obtained by prep-HPLC purification due to its very weak absorption (214 nm, 254 nm). SP-3: 1 HNMR(400MHz,CDCl3)δ(ppm):8.57 (1H, s), 5.46 (1H, AB), 5.45 (1H, AB), 2.65 (1H, t), 1.45 (2H, q), 0.91 (3H, t), 0.73 (3H, s). LCMS:rt=2.48 min, m / z=401.1[M+H] + .

[0352] Example 43. Synthesis of compounds SP-4 and SP-5. [ka] A suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL) contains 5-methyl-1H-tetrazole (42.0 mg, 0.50 mmol) and compound SP (10 (0 mg, 0.24 mmol) was added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with ELISA (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SP-4 as an off-white solid (15.2 mg, 0.037 mmol, 15.2%) and SP-5 as an off-white solid (13.3 mg, 0.032 mmol, 13.3%). SP-4: 1 HNMR(500MHz,CDCl3)δ(ppm):5.13 (AB, 1H), 5.05 (AB, 1H), 2.66 (t, 1H), 2.48 (s, 3H), 0.91(t, 1H), 0.69 (s, 3H). LCMS:Rt=2.30 min. m / z=415.3[M+H] + SP-5: 1 HNMR(400MHz,CDCl3)δ(ppm):5.36 (AB, 1H), 5.35 (AB, 1H), 2.63 (t, 1H), 2.58 (s, 3H), 0.91(t, 1H), 0.72 (s, 3H). LCMS:Rt=2.38 min. m / z=415.3[M+H] + .

[0353] Example 44. Synthesis of SI and SI intermediates. [ka]

[0354] Synthesis of compound SI-B. To a solution of compound SI-A (5 g, 15 mmol) in dry THF (20 mL), a borane-tetrahydrofuran complex (1.0 M solution in 30 mL of THF) was added. The reaction mixture was stirred at ambient temperature for 1 hour, and then 10% aqueous NaOH (56 mL) was slowly added. The mixture was cooled on ice, and then 30% aqueous H2O2 (67 mL) was slowly added. The mixture was stirred at ambient temperature for 1 hour, and then extracted with RINKAN (3 × 100 mL). The combined RINKAN extract was washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL) and dried over MgSO4. By filtration and removal of solvent, 3.2 g of the crude product for the next reaction was obtained.

[0355] Synthesis of compound SI-C. To a solution of compound SI-B (3.2 g, 9 mmol) in THF (40 mL), 2 M HCl (3 mL) was added. This reaction solution was stirred at room temperature for 12 hours, and then the solvent was removed under reduced pressure. The crude target compound was purified by silica gel chromatography (eluate: petroleum ether / ethyl acetate = 10:1 to 5:1). 2.2 g of the product was obtained as an off-white solid. Yield: 81.40%.

[0356] Synthesis of compound SI-D. A stirred solution of trimethylsulfonium iodide (6.43 g, 31.5 mmol) in 100 mL of DMSO was mixed with 60 wt% NaH (1.26 g, 31.5 mmol). After stirring at room temperature (15°C) for 1 hour, a solution of compound SI-C (2.2 g, 7.2 mmol) in 20 mL of DMSO was added dropwise. After 2.5 hours, the reaction mixture was poured into ice-cold water and extracted with ether (100 mL x 3). The combined ether layers were then washed with brine (100 mL x 3), dried, filtered, and concentrated to obtain 1.6 g of the crude product for the next reaction.

[0357] Synthesis of compound SI-E. Compound SI-D (1.6 g, 5 mmol) was dissolved in 60 mL of H2O-saturated CH2Cl2. (Using a separatory funnel, CH2Cl2 was shaken with several milliliters of H2O and then separated from the aqueous layer). DMP (4.2 g, 10 mmol) was added, and the resulting reaction mixture was vigorously stirred for 24 hours. This reaction solution was diluted with DCM (100 mL), washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluate: petroleum ether / ethyl acetate = 20:1 to 10:1) to obtain the title compound (1.2 g, 3.79 mmol, 75%) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ(ppm):2.63 (s, 1H), 2.59 (s, 1H), 2.12 (s, 3H), 0.63 (s, 3H).

[0358] Synthesis of compounds SI-F1 and SI-F2. [ka] SI-E (1.2 g, 3.8 mmol) was dissolved in dry methanol (250 mL), and Na (262 mg, 11.4 mmol) was added. This solution was refluxed for 16 hours. Methanol was removed by evaporation, and the residue was dissolved in dichloromethane, washed with H2O (3 × 50 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. This crude target compound was purified by silica gel chromatography (eluate: petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain SI-F1 (300 mg, 25%) and SI-F2 (300 mg, 25%) as off-white solids. SI-F1, 1H NMR (400MHz, CDCl3) δ (ppm): 3.39 (s, 3H), 3.19 (s, 2H), 2.54 (t, 1H), 2.11 (s, 3H), 0.61 (s, 3H). SI-F2, 1H NMR(400MHz,CDCl3)δ(ppm):3.39 (s, 5H),3.37 (s, 2H), 2.52 (t, 1H), 2.11 (s, 3H), 0.62 (s, 3H).

[0359] Synthesis of compound SI. A solution of SI-F1 (50 mg, 0.14 mmol) in MeOH was treated with 2 drops of HBr (48%), followed by 6 drops of bromine. This mixture was stirred at room temperature for 1 hour and then poured into ice water. This mixture was extracted with EA (50 mL) and sodium sulfate. Dried with thorium. Filtrated.

[0360] Example 45. Synthesis of SI-1. [ka] To a solution of the crude reactant (245.3 mg, 0.574 mmol, theoretical amount) in THF (5 mL), tetrazole (201 mg, 2.87 mmol) was added, followed by potassium carbonate (397 mg, 2.87 mmol). This mixture was heated overnight at 60°C. The solution was then diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain fractions 1 and 2. Fraction 2 was the pure product SI-1 as an off-white solid (27.5 mg, 0.066 mmol, overall yield of 2 steps = 11.5%). Fraction 1 was further purified by silica gel chromatography (eluate: petroleum ether / ethyl acetate = 1:4) to obtain an off-white solid by-product (8.2 mg, 0.0197 mmol, overall yield of 2 steps = 3.49%). SI-1: 1 HNMR(500MHz,CDCl3)δ(ppm):8.75 (1H, s), 5.32 (1H, AB), 5.21 (1H, AB), 3.39 (3H, s), 3.19 (2H, s), 2.67 (1H, t), 0.68 (3H, s). LC-MS:rt=2.19 min, m / z=417.3[M+H] + .

[0361] Example 46. Synthesis of compound SI-2. [ka] To a suspension of K2CO3 (248 mg, 1.8 mmol) in THF (50 mL), 1,2,3-1H-triazole (130 mg, 1.8 mmol) and compound SI (400 mg, 0.94 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 50 mL of H2O and extracted with ELISA (2 × 100 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This reaction mixture was purified by reverse-phase prep-HPLC to obtain SI-2 as an off-white solid (80 mg, 20%). SI-2:1 HNMR(500MHz,CDCl3),δ(ppm), 7.76 (d, 1H), 7.64 (d, 1H), 5.27 (AB, 1H), 5.13 (AB, 1H), 3.39 (s, 3H), 3.19 (s, 2H), 2.66 (t, 1H), 0.68 (s, 3H).

[0362] Example 47. Synthesis of compounds SI-3 and SI-4. [ka] To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL), 5-methyl-1H-tetrazole (42.0 mg, 0.50 mmol) and compound SI (100 mg, 0.23 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SI-3 as an off-white solid (12.6 mg, 0.029 mmol, 12.7%) and SI-4 as an off-white solid (22.3 mg, 0.052 mmol, 22.5%). SI-3: 1 HNMR(500MHz,CDCl3)δ(ppm):5.13 (AB, 1H), 5.05 (AB, 1H), 3.39 (s, 3H), 3.19 (s, 2H), 2.66 (t, 1H), 2.47 (s, 3H), 0.69 (s, 3H). LC-MS:Rt=2.14 min. m / z=431.3[M+H] + SI-4: 1 HNMR(500MHz,CDCl3)δ(ppm):5.35 (AB, 1H), 5.34 (AB, 1H), 3.39 (s, 3H), 3.19 (s, 2H), 2.63 (t, 1H), 2.56 (s, 3H), 0.72 (s, 3H). LC-MS:Rt=2.25 min. m / z=401.3[M+H] + .

[0363] Example 48. Synthesis of SQ and SQ intermediates. [ka]

[0364] Synthesis of compound SQ-B. NaH (60%; 1.26g, 31.5mmol) was added to a stirred solution of trimethylsulfonium iodide (8.1g, 36.9mmol) in 100mL of DMSO. After stirring at room temperature for 1 hour, a suspension of compound SC (2.2g, 7.2mmol) in DMSO (20mL) was added dropwise. This mixture was stirred for a further 2.5 hours, then poured into ice-cold water and extracted with ether (100mL x 3). The combined ether layers were then washed with brine (100mL x 3), dried over MgSO4, filtered, and concentrated to obtain the crude product SQ-B (2.2g). This crude product was used in the next step without further purification.

[0365] Synthesis of compound SQ-C. Compound SQ-B (2.2 g, 7.3 mmol) was dissolved in dry methanol (250 mL), and Na (672 mg, 29.2 mmol) was added. This solution was stirred under reflux for 6 hours. Methanol was removed by evaporation, and the residue was dissolved in dichloromethane, washed with H2O (3 × 50 mL) and brine (100 mL), dried over MgSiO4, filtered, and concentrated. This crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1), and concentrated to obtain SQ-C (1.8 g, 82%) as an off-white solid. 1 H NMR(500MHz,CDCl3),δ(ppm), 5.03-5.01 (m, 1H), 3.43 (q, 2H), 3.13 (s, 2H), 0.80 (s, 3H).

[0366] Synthesis of compound SQ-D. To a solution of compound SQ-C (1.8 g, 5.2 mmol) in dry THF (50 mL), a borane-tetrahydrofuran complex (1.0 M solution in 20 mL of THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (10 mL), followed by 30% aqueous H2O2 (12 mL). The mixture was stirred at room temperature for 1 hour and then extracted with RINKAN (3 × 100 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated to obtain crude compound SQ-D (1.8 g, 100%). This crude product was used in the next step without further purification.

[0367] Synthesis of SQ-E. Crude compound SQ-D (1.8 g, 5.2 mmol) was dissolved in 60 mL of H2O-saturated dichloromethane (dichloromethane was shaken with several milliliters of H2O and then separated from the aqueous layer). Dess-Martin periodinate (4.4 g, 10.4 mmol) was added to the solution. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain SQ-E (1 g, 2.8 mmol, 56% for two steps) as an off-white solid. 1 H NMR(400MHz, CDCl3), δ(ppm), 3.52 (q, 2H), 3.21 (s, 2H), 2.54 (t, 2H), 2.11 (s, 3H), 1.20 (t, 3H), 0.61 (s, 3H). LCMS:Rt=7.25min.m / z=345.1[M-17] + .

[0368] Synthesis of compound SQ. To a solution of compound SQ-E (600 mg, 1.65 mmol) in MeOH (20 mL), 5 drops of HBr (48%) were added, followed by the addition of bromine (264 mg, 1.65 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (100 mL x 3). The combined organic layer was then extracted using brine (200 mL). The compound was washed with (mL), dried over MgSO4, filtered, and concentrated to obtain the crude compound SQ (600 mg, 100%). This crude product was used in the next step without further purification. LCMS: Rt=7.25 min. m / z=463.1 [M+Na] + .

[0369] Example 49. Synthesis of compounds SQ-1 and SQ-2. [ka] To a suspension of K2CO3 (188 mg, 1.36 mmol) in THF (10 mL), 1,2,3-1H-triazole (94 mg, 1.36 mmol) and compound SQ (300 mg, 0.68 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with SiO2 (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SQ-1 as an off-white solid (81 mg, 0.19 mmol, 27.9%) and SQ-2 as an off-white solid (41 mg, 0.10 mmol, 14.7%). SQ-1: 1 HNMR(400MHz,CDCl3)δ(ppm):7.76 (s, 1H), 7.64 (s, 1H), 5.28 (AB, 1H), 5.14 (AB, 1H), 3.53 (q, 2H), 3.22 (s, 2H), 2.66 (t, 1H), 1.20 (t, 3H), 0.68 (s, 3H). LCMS:Rt=2.21 min. m / z=430.3[M+H] + SQ-2: 1HNMR(400MHz,CDCl3)δ(ppm):7.69 (s, 2H), 5.27 (AB, 1H), 5.22 (AB, 1H), 3.53 (q, 2H), 3.22 (s, 2H), 2.60 (t, 1H), 1.20 (t, 3H), 0.71 (s, 3H). LCMS:Rt=2.34 min. m / z=430.3[M+H] + .

[0370] Example 50. Synthesis of compounds SQ-3 and SQ-4. [ka] A suspension of K2CO3 (94 mg, 0.68 mmol) in THF (10 mL) contains 1, 2,3-1H-triazole (48 mg, 0.68 mmol) and compound SQ (150 mg, 0.34 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with Âr (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SQ-3 as an off-white solid (20.9 mg, 0.049 mmol, 14.4%) and SQ-4 as an off-white solid (15.2 mg, 0.035 mmol, 10.3%). SQ-3: 1 HNMR(400MHz,CDCl3)δ(ppm):8.57 (s, 1H), 5.46 (AB, 1H), 5.45 (AB, 1H), 3.53 (q, 2H), 3.22 (s, 2H), 2.66 (t, 1H), 1.21 (t, 3H), 0.72 (s, 3H). LCMS:Rt=2.35 min. m / z=431.4[M+H] + SQ-4: 1HNMR(400MHz,CDCl3)δ(ppm):8.74 (s, 1H), 5.32 (AB, J=18.0 Hz, 1H), 5.18 (AB, J=18.1 Hz, 1H), 3.52 (q, 2H), 3.22 (s, 2H), 2.68 (t, 1H), 1.20 (t, 3H), 0.68 (s, 3H). LCMS:Rt=2.22 min. m / z=431.4[M+H] + .

[0371] Example 51. Synthesis of compounds SQ-5 and SQ-6. [ka] To a suspension of K2CO3 (67 mg, 0.50 mmol) in THF (5 mL), 5-methyl-1H-tetrazole (42.0 mg, 0.50 mmol) and compound SQ (100 mg, 0.25 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with  (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SQ-5 as an off-white solid (8.5 mg, 0.019 mmol, 8.1%) and SQ-6 as an off-white solid (14.8 mg, 0.034 mmol, 13.2%). SQ-5: 1 HNMR(500MHz,CDCl3)δ(ppm):5.13 (AB, 1H), 5.06 (AB, 1H), 3.53 (q, 2H), 3.22 (s, 2H), 2.67 (t, 1H), 1.21 (t, 3H), 0.69 (s, 3H). LCMS:Rt=2.26 min. m / z=445.4[M+H] + SQ-6: 1HNMR(500MHz,CDCl3)δ(ppm):5.36 (AB, 1H), 5.35 (AB, 1H), 3.53 (q, 2H), 3.22 (s, 2H), 2.64 (t, 1H), 2.56 (s, 2H), 1.20 (t, 3H), 0.72 (s, 3H). LCMS:Rt=2.35 min. m / z=445.3[M+H] + .

[0372] Example 52. Synthesis of SV and SV intermediates. [ka]

[0373] Synthesis of compound SV-B. Selectflour (90.22 g, 324.4 mmol) was gradually added at -4°C to a solution of SL-B (68 g, 216.27 mmol) in 600 mL of CH3CN. The resulting reaction mixture was stirred at -4°C for 3 hours. After TLC indicated that the reaction was complete, the mixture was filtered and concentrated. The product was purified by column chromatography on silica gel eluted with (petroleum ether / ethyl acetate 20:1~15:1~10:1~8:1~6:1~5:1) to obtain SV-B (26.3 g, yield 41.8%) as an off-white solid. 1 H NMR(SV-B)(400MHz,CDCl3),δ(ppm), 6.02-5.94 (m, 1H,), 5.20-5.01 (m, 1H), 2.55-2.26 (m, 6H), 2.16-2.05 (m, 1H), 2.01-1.83 (m, 4H), 1.48-1.22 (m, 5H), 0.98-0.78 (m, 6H).

[0374] Synthesis of compound SB-X. SV-B (27 g, 92.98 mmol) was dissolved in  (350 mL) at 20°C, followed by the addition of Pd / C (2.7 g, 5%) to the mixture. This solution was stirred at 20°C under 1 atm hydrogen for 10 hours. After LC-MS indicated completion of the reaction, the mixture was filtered and concentrated. The product was purified by column chromatography using silica gel eluted with (petroleum ether / ethyl acetate 40:1~35:1~30:1~25:1~20:1~15:1~10:1~6:1) to obtain SB-X (15.6 g, 56.38%) as an off-white solid. 1 H NM R(SB-X)(400MHz,CDCl3),δ(ppm)=4.68-4.56 (m, 1H), 2.64-2.51 (m, 1H), 2.53-2.03 (m, 8H), 1.97-1.80 (m, 4H), 1.49-1.20 (m, 6H), 0.96-0.92 (m, 2H), 0.88-0.78 (m, 1H).

[0375] Synthesis of compound SB-Y. To a solution of SB-X (47 g, 160.75 mmol) in MeOH (600 mL), 2.35 g of TsOH was added at 23°C, and then this mixture was stirred at 60°C for 1.5 hours. After TLC indicated that the reaction was complete, the mixture was filtered and concentrated to obtain SB-Y (35 g, 64.33%) as an off-white solid. 1 H NMR(SB-Y)(400MHz,CDCl3),δ(ppm)=4.74-4.57 (m, 1H), 3.16 (s, 3H), 3.10 (s, 3H), 2.47-2.35 (m, 1H), 2.15-2.09 (m, 1H), 2.06-1.82 (m, 6H), 1.77-1.15 (m, 11H), 1.05-0.96 (m, 1H), 0.89 (s, 3H), 0.83-0.77 (m, 1H).

[0376] Synthesis of compound SB-Z. To a solution of ethyltriphenylphosphonium bromide (115.17 g, 310.23 mmol) in 150 mL of THF, KOt-Bu (34.81 g, 310.23 mmol) was added. This reaction mixture was heated to 60°C for 1 hour, and then SB-Y (35 g, 103.41 mmol) was added to the mixture and stirred at 60°C for a further 15 hours. This reaction mixture was cooled, extracted with 1500 mL of phenylethylamine, washed with brine, and concentrated to obtain SB-Z as an off-white solid (120 g, crude). 1 H NMR(SB-Z)(400MHz,CDCl3),δ(ppm)=5.13-5.07 (m, 1H), 4.67-4.54 (m, 1H), 3.14 (s, 3H), 3.09 (s, 3H), 2.42-2.15 (m, 3H), 1.92-1.79 (m, 3H), 1.67-1.61 (m, 4H), 1.57-1.50 (m, 2H), 1.45-1.15 (m, 10H), 1.01-0.94 (m, 1H), 0.92 (s, 3H), 0.90-0.84 (m, 1H).

[0377] Synthesis of compound SB-AA. SB-Z (120 g, crude) was dissolved in 600 mL of THF, to which 90 mL of 2 M aqueous HCl was added. The reaction mixture was stirred at 22°C for 1 hour. After TLC indicated completion of the reaction, the reaction was quenched with aq. NaHCO3. The reaction product was extracted with 500 mL of siRNA, washed with brine, and evaporated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether / ethyl acetate = 150:1, 125:1, 100:1, 80:1, 60:1, 50:1) to obtain SB-AA as an off-white solid (24 g, yield 76.23%). 1H NMR(SB-AA)(400MHz,CDCl3),δ(ppm)=5.13 (m, 1H), 4.65-4.48 (m, 1H), 2.62-2.42 (m, 1H), 2.44-2.07 (m, 8H), 1.92-1.80 (m, 1H), 1.72-1.55 (m, 8H), 1.36-1.08 (m, 6H), 0.92 (s, 3H), 0.83-0.73 (m, 1H).

[0378] Synthesis of compound SB-BB. A solution of Me3SOI (78.07 g, 354.75 mmol) in 50 mL of THF was added to a solution of t-BuOK (39.81 g, 354.75 mmol) in 50 mL of THF. This reaction mixture was stirred at 60°C for 1.5 hours. Next, a solution of SB-AA (24 g, 78.83 mmol) in THF (300 mL) was added to this reaction mixture. This reaction mixture was stirred at 23°C for 2.5 hours. After TLC indicated completion of the reaction, the reaction was quenched with ice water. This reaction mixture was then mixed in 500 ml. Extraction with HCl L, washing with brine, and evaporation under reduced pressure yielded SB-BB as the crude product (50 g). 1 H NMR(SB-BB)(400MHz,CDCl3),δ(ppm)=5.20-5.11 (m, 1H), 4.65-4.52 (m, 1H), 2.74-2.68 (m, 2H), 2.48-1.81 (m, 9H), 1.72-1.64 (m, 4H), 1.55-1.06 (m, 10H), 0.97-0.89 (m, 3H), 0.85-0.77 (m, 1H).

[0379] Synthesis of compound SB-CC. LiAlH4 (8.99 g, 236.49 mmol) was added at 0°C to a solution of SB-BB (50 g, crude) in 300 mL of THF. The reaction mixture was stirred at 23°C for 1.5 hours. After TLC indicated completion of the reaction, the reaction was quenched with water. The reaction product was extracted with 1000 mL of ethyl acetate, washed with brine, and evaporated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether / ethyl acetate = 100:1, 80:1, 60:1, 50:1, 40:1, 30:1) to obtain SB-CC as an off-white solid (19 g, yield 75.19%). 1 H NMR(SB-CC)(400MHz,CDCl3),δ(ppm)=5.17-5.07 (m, 1H), 4.66-4.48 (m, 1H), 2.41-2.32 (m, 1H), 2.28-2.15 (m, 2H), 2.09-2.05 (m, 1H), 1.88-1.75 (m, 2H), 1.68-1.64 (m, 3H), 1.40-1.31 (m, 1H), 1.25-1.13 (m, 9H), 0.89 (s, 3H), 0.81-0.72 (m, 1H).

[0380] Synthesis of compound SB-DD. To a solution of SB-CC (19 g, 59.29 mmol) in dry THF (500 mL), C2H9BS (59.29 mL; 10 M solution in THF) was added at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was cooled in an ice bath and then slowly quenched with 3 M aqueous NaOH (160 mL), followed by a 30% aqueous solution of H2O2 (100 mL). After stirring at 20°C for 1.5 hours, the mixture was filtered and extracted with siRNA (300 mL). The combined organic layer was treated with aq.Na2S2O3, extracted, dried, and concentrated to obtain SB-DD as a crude product (21 g, crude). This crude product was used in the next step without further purification.

[0381] Synthesis of compound SB-EE. To a solution of SB-DD (21 g, 59.29 mmol) in 200 mL of CH2Cl2, PCC (25.56 g, 118.58 mmol) was added at 0°C and the mixture was stirred at 22°C for 2 hours. The reaction mixture was filtered, extracted with 20 mL of CH2Cl2, washed with aq. NaHCO3, aq. Na2S2O3, and brine, and evaporated under reduced pressure. The residue was purified by chromatography (petroleum ether / ethyl acetate = 15:1~10:1~6:1) to obtain SB-EE as an off-white solid (12 g, yield 60.15%). 1 H NMR(SB-EE)(400MHz,CDCl3),δ(ppm)=4.65-4.46 (m, 1H), 2.55-2.51 (m, 1H), 2.22-2.09 (m, 4H), 2.06-1.97 (m, 32H), 1.88-1.77 (m, 2H), 1.69-1.54 (m, 5H), 1.48-1.30 (m, 3H), 1.28-1.05 (m, 11H), 0.83-0.72 (m, 1H), 0.63 (s, 3H).

[0382] Synthesis of compound SV. To a solution of SB-EE (12 g, 35.66 mmol) in 1500 mL of MeOH, HBr (5 drops) and Br2 (2.01 mL, 39.23 mmol) were added at 0°C. The reaction mixture was stirred at 16°C for 2 hours. The reaction mixture was quenched with aq. NaHCO3 and concentrated. The mixture was then extracted with 1000 mL of ethyl acetate, washed with brine, and evaporated under reduced pressure. The product was then (stone SV was purified by column chromatography using silica gel eluted with oil ether / ethyl acetate (12:1, 10:1, 8:1, 6:1, 3:1) to obtain SV as an off-white solid (12.3 g, yield 83.03%). 1 H NMR(SV)(400MHz,CDCl3),δ(ppm)=4.64-4.47 (m, 1H), 3.95-3.86 (m, 2H), 2.89-2.80 (m, 1H), 2.23-2.16 (m, 1H), 2.07-1.64 (m, 8H) 1.46-1.06 (m, 14H), 0.83-0.74 (m, 1H), 0.67 (s, 3H).

[0383] Example 53. Synthesis of compounds SV-1 and SV-2. [ka] To a suspension of SV (40 mg, 0.09 mmol) in THF (5 mL), 1H-1,2,3-triazole (30 mg, 0.45 mmol) and K2CO3 (60 mg, 0.45 mmol) were added. This mixture was stirred at 25°C for 15 hours. The solution was then diluted with ethyl acetate (100 mL), washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified by reverse-phase prep-HPLC to obtain SV-1 as an off-white solid (10 mg, 26% yield) and SV-2 as an off-white solid (10 mg, 26% yield). SV-1: 1 H NMR(400MHz,CDCl3),δ(ppm), 7.75 (s, 1H), 7.65 (s, 1H), 5.29-5.25 (1H,AB), 5.25-5.17 (1H,AB), 4.61-4.52 (d, 1H), 2.6(1H,t),1.18 (s, 3H), 0.63 (s, 3H). SV-2: 1 H NMR(400MHz, CDCl3), δ(ppm), 7.68 (s, 2H), 5.24-5.23 (m, 2H), 4.60-4.50 (d, 1H), 2.6(1H,t,), 1.25 (s, 3H), 0.74 (s, 3H).

[0384] Example 54. Synthesis of compounds SV-3 and SV-4. [ka] A solution of SV (100 mg, 0.24 mmol) in 3 mL of DMF is mixed with 2H-tetrazole (33.73 mg, 0.48 mmol) and K2CO3 (99.82 mg, 0. 72 mmol) was added. The reaction mixture was stirred at 28°C for 2 hours. The resulting solution was quenched with water and extracted with SiO2 (50 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting (PE / EA = 12 / 1 to 2 / 1) to obtain SV-3 (16.1 mg, yield: 16.67%) and SV-4 (28.3 mg, yield: 29.17%) as off-white solids. 1 H NMR(SV-3):(400MHz,CDCl3)δ8.60 (s, 1H), 5.57-5.42 (m, 2H), 4.73-4.48 (m, 1H), 2.74-2.60 (m, 1H), 2.31-2.21 (m, 1H), 2.16-2.108(m, 1H), 1.97-1.89 (m, 1H), 1.86-1.60 (m, 7H), 1.55-1.11(m, 14H), 0.88-0.80 (m, 1H),0.77(s, 3H). 1 H NMR(SV-4):(400MHz,CDCl3)δ8.75 (s, 1 H), 5.36-5.16 (m, 2H), 4.66-4.47 (m, 1H), 2.73-2.62 (m, 1H), 2.30-2.18 (m, 1H), 2.09-1.74 (m, 6H), 1.67-1.60 (m, 3H), 1.38-1.16 (m, 11H), 0.88-0.75 (m, 1H), 0.70 (s, 3H).

[0385] Example 55. Synthesis of compounds SV-5 and SV-6. [ka] To a solution of SV (100 mg, 0.24 mmol) in 3 mL of DMF, 5-methyl-2H-tetrazole (40.48 mg, 0.48 mmol) and K2CO3 (99.82 mg, 0.72 mmol) were added. The reaction mixture was stirred at 21°C for 1 hour. The resulting solution was quenched with water and extracted with SiO2 (50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / SiO2 = 8 / 1 to 1 / 1) to obtain SV-5 (21.3 mg, yield: 21.14%) and SV-6 (27.1 mg, yield: 26.89%) as off-white solids. 1 H NMR(SV-5):(400MHz,CDCl3)δ5.43-5.31 (m, 2H), 4.68-4.49 (m, 1H), 2.69-2.62 (m, 1H), 2.59 (s, 3H), 2.31-2.20 (m, 1H), 2.14-2.09 (m, 1H), 1.95-1.88 (m, 1H), 1.85-1.60 (m, 8H), 1.46-1.20 (m, 12H), 1.02-0.93 (m, 1H), 0.89-0.80 (m, 1H), 0.77 (s, 3H). 1 H NMR(SV-6):(400MHz,CDCl3)δ5.21-5.05 (m, 2H), 4.69-4.50 (m, 1H), 2.73-2.63 (m, 1H), 2.50 (s, 3H), 2.30-2.19 (m, 1H), 2.13-2.01 (m, 2H), 1.98-1.57 (m, 9H), 1.45-1.14 (m, 12H),0.90-0.80 (m, 1H), 0.73 (s, 3H).

[0386] Example 56. Synthesis of compound SV-7. [ka] To a solution of SV (100 mg, 0.24 mmol) in 15 mL of DMF, 4-methyl-2H-1,2,3-triazole (40.01 mg, 0.48 mmol) and K2CO3 (99.82 mg, 0.72 mmol) were added. The reaction mixture was stirred at 28°C for 2 hours. The resulting solution was quenched with water and extracted with siRNA (50 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain SV-7 (20.6 mg, yield: 20.83%) as an off-white solid. 1 H NMR(SV-7):(400MHz,CDCl3)δ7.45 (s, 1 H), 5.23-5.10 (m, 2H), 4.68-4.49 (m, 1H), 2.64-2.57 (m, 1H), 2.35 (s, 3H), 2.30-2.18 (m, 1H), 2.14-2.00 (m, 2H), 1.93-1.58 (m, 8H), 1.46-1.09 (m, 13H), 0.86-0.76 (m, 1H), 0.75 (s, 3H).

[0387] Example 57. Synthesis of compounds SV-8 and SV-9. [ka] To a solution of SV (200 mg, 0.48 mmol) in 10 mL of DMF (5 mL), 4-methyl-2H-1,2,3-triazole (80.02 mg, 0.96 mmol) and K2CO3 (199.63 mg, 1.44 mmol) were added. The reaction mixture was stirred at 17°C for 2 hours. The resulting solution was quenched with water and extracted with  (50 mL). The organic layer was dried and concentrated. The residue was purified using silica gel to obtain 90 mg of a mixture of SV-8 / SV-9 and a by-product (60 mg). This mixture was divided by SFC purification to obtain SV-8 (38.8 mg, yield: 29.84%) and SV-9 (31.5 mg, yield: 23.3%) as off-white solids. 1H NMR(SV-8):(400MHz,CDCl3)δ7.347 (s, 1 H), 5.191-5.041 (q, J1=17.6 HMz, J2=42.4 HMz), 4.62-4.50 (m, 1H), 2.66-2.61 (m, 1H), 2.37 (s, 3H), 2.10-2.06 (m, 1H), 1.87-1.74 (m, 2H), 1.70-1.50 (m, 7H), 1.30-1.04 (m, 14H), 0.86-0.76 (m, 1H), 0.70 (s, 3H). 1 H NMR(SV-9):(400MHz,CDCl3)δ7.488 (s, 1 H), 5.08-5.07 (m, 2H), 4.63-4.50 (m, 1H), 2.68-2.63 (m, 1H), 2.22 (s, 3 H), 2.04-1.89 (m, 2H), 1.80-1.73 (m, 7H), 1.64-1.60 (m, 1H), 1.56-1.20 (m, 14H), 0.80-0.70 (m, 1H), 0.64 (s, 3H).

[0388] Example 58. Synthesis of SW and SW intermediates. [ka]

[0389] Synthesis of compound SW-B. SW-A (10 g, 36.7 mmol) was added to 50 mL of acetyl chloride and 50 mL of acetic anhydride. This reaction mixture was heated to 120 °C for 5 hours and evaporated under reduced pressure to obtain SW-B as an off-white solid (10 g, yield 87%). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.78 (s, 1H), 5.55 (s, 1H), 2.4 (dd, 2H), 2.13 (s, 3H), 0.90 (s, 3H).

[0390] Synthesis of compound SW-C. To a solution of SW-B (10 g, 31.8 mmol) in 200 mL of THF and 20 mL of H2O, mCPBA (11 g, 63.6 mmol) was added at 0°C. The mixture was added and stirred at room temperature for 15 hours. The reaction mixture was extracted with 500 mL of siRNA, washed with 100 mL of saturated Na2SO3, 100 mL of saturated NaHCO3, and 100 mL of brine, evaporated under reduced pressure, and then purified by chromatography (PE:siRNA = 5:1) to obtain SW-C as an off-white solid (2.2 g, yield 24%). 1 H NMR (400MHz, CDCl3), δ(ppm), 5.92 (s, 1H), 4.44 (s, 1H), 0.95 (s, 3H).

[0391] Synthesis of compound SW-D. 200 mg of Pd / C was added to a solution of SW-C (2 g, 6.94 mmol) in 50 mL of acetate. This reaction mixture was hydrogenated in H2 at 1 atm for 15 hours. The reaction mixture was then evaporated under reduced pressure and purified by chromatography (PE:acetate = 1:2) to obtain SW-D as an off-white solid (0.5 g, 25% yield). 1 H NMR (400MHz, CDCl3), δ (ppm), 3.84 (s, 1H), 2.62 (1H, t) 0.95 (s, 3H).

[0392] Synthesis of compound SW-E. To a solution of SW-D (1 g, 3.4 mmol) in 100 mL of MeOH, 50 mg of TsOH was added and the mixture was heated to 60°C for 2 hours. This reaction mixture was extracted with 500 mL of ethyl acetate, washed with 100 mL of saturated NaHCO3 and 100 mL of brine, and evaporated under reduced pressure to obtain SW-E as an off-white solid (1 g, 91% yield).

[0393] Synthesis of compound SW-F. To a solution of ethyltriphenylphosphonium bromide (10.67 g, 28.84 mmol) in 30 mL of THF, KOt-Bu (3.23 g, 28.80 mmol) was added. The reaction mixture was heated to 60°C for 1 hour. SW-E (3.23 g, 9.6 mmol) was added, and the resulting mixture was stirred at 60°C for 15 hours. The reaction mixture was then extracted with 500 mL of ethyltriphenylphosphonium bromide, washed with brine, and evaporated under reduced pressure. The resulting crude residue was purified by chromatography (PE:ethyltriphenylphosphonium = 3:1) to obtain SW-F as an off-white solid (2.17 g, yield 64%).

[0394] Synthesis of compound SW-G. To a solution of SW-F (1 g, 2.9 mmol) in 50 mL of THF, NaH (2 g, 5.8 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. Then, 1 mL of MeI was added to the mixture, and it was stirred overnight at room temperature. The reaction mixture was quenched with 5 mL of H2O, extracted with 100 mL of siRNA, washed with brine, and evaporated under reduced pressure. The resulting residue was purified by chromatography (PE:siRNA = 10:1) to obtain SW-G as an off-white solid (587 mg, 59% yield).

[0395] Synthesis of compound SW-H. SW-G (1 g, 2.8 mmol) was dissolved in 20 mL of THF, to which 2 M aqueous HCl (2 mL) was added. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with 5 mL of H2O, extracted with 100 mL of ethyl acetate, washed with brine, and evaporated under reduced pressure. The residue was purified by chromatography (PE:ethyl = 10:1) to obtain SW-H as an off-white solid (745 mg, yield 81%). 1 H NMR(400MHz,CDCl3),δ(ppm), 5.05-5.03 (m, 1H), 3.24 (s, 3H), 3.11 (s, 1H), 2.6(1H,t),0.87 (s, 3H).

[0396] Synthesis of compound SW-I. A stirring solution of trimethylsulfoxonium iodide (3.6 g, 16.5 mmol) in 5 mL of THF is mixed with potassium tert-butanolate (1.9 0 g, 16.5 mmol) was added. After stirring at 60°C for 1.5 hours, a suspension of SW-H (1 g, 3.3 mmol) in 10 mL of THF was added dropwise. After a further 3 hours, the reaction mixture was poured into ice-cold water, extracted with toluene (100 mL x 3), washed with brine (100 mL x 3), dried, filtered, and evaporated under reduced pressure to obtain SW-I as an off-white solid (800 mg, yield 73%). This crude product was used in the next step without further purification.

[0397] Synthesis of compound SW-J. To a solution of SW-I (150 mg, 0.45 mmol) in 10 mL of THF, LiAH4 (50 mg, 1.35 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with 5 mL of H2O, extracted with 100 mL of ethyl acetate, washed with brine, and evaporated under reduced pressure. The residue was purified by chromatography (PE:EA = 3:1) to obtain SW-J as an off-white solid (108 mg, yield 72%). 1 H NMR (400MHz, CDCl3), δ(ppm), 5.12-5.10 (m, 1H), 3.29 (s, 3H), 3.18 (s, 1H), 1.23 (s, 3H), 0.88 (s, 3H).

[0398] Synthesis of compound SW-K. To a solution of SW-J (100 mg, 0.3 mmol) in dry THF (5 mL), borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (1 mL), followed by 30% aqueous H2O2 (1 mL). After stirring at room temperature for 1 hour, the mixture was extracted with RINKAN (3 × 100 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated to obtain SW-K as an off-white solid (90 mg, 81%). This crude product was used in the next step without further purification.

[0399] Synthesis of compound SW-L. To a solution of SW-K (100 mg, 0.29 mmol) in 20 mL of DCM, PCC (190 mg, 0.87 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 5 mL of H2O, extracted with 100 mL of siRNA, washed with brine, evaporated under reduced pressure, and then purified by chromatography (PE:siRNA = 3:1) to obtain SW-L as an off-white solid (52 mg, 51% yield). 1 H NMR (400MHz, CDCl3), δ(ppm), 3.26 (s, 3H), 3.16 (s, 1H), 2.11 (s, 3H), 1.20 (s, 3H), 0.61 (s, 3H).

[0400] Synthesis of compound SW. Two drops of HBr (48%) were added to a solution of SW-L (40 mg, 0.11 mmol) in MeOH (5 mL), followed by the addition of bromine (150 mg, 0.33 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain the crude compound SW as an off-white solid (40 mg, yield 80%). This crude product was used in the next step without further purification.

[0401] Example 59. Synthesis of compounds SW-1 and SW-2. [ka] To a suspension of SW (40 mg, 0.09 mmol) in THF (5 mL), 1H-1,2,3-triazole (30 mg, 0.45 mmol) and K2CO3 (60 mg, 0.45 mmol) were added. This mixture was stirred at 25°C for 15 hours. The solution was then diluted with ethyl acetate (100 mL), washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The reaction mixture was purified by reverse-phase prep-HPLC to obtain SW-1 as an off-white solid (10 mg, 26% yield) and SW-2 as an off-white solid (8 mg, 20% yield). SW-1: 1 H NMR(400MHz,CDCl3),δ(ppm), 7.75 (s, 1H), 7.64 (s, 1H), 5.27-5.24 (1H,AB),5.17-5.13 (1H,AB), 3.28 (s, 3H), 3.17 (s, 1H),2.7(1H,t), 1.23 (s, 3H), 0.65 (s, 3H). SW-2: 1 H NMR(400MHz,CDCl3),δ(ppm), 7.68 (s, 2H), 5.28-5.25 (1H,AB), 5.23-5.20 (1H,AB), 3.28 (s, 3H), 3.17 (s, 1H), 2.6(1H,t), 1.24 (s, 3H), 0.75 (s, 3H).

[0402] Example 60. Synthesis of SZ and SZ intermediates. [ka] [ka]

[0403] Synthesis of compound SZ-B. To a solution of compound SZ-A (500 mg, 1.82 mmol) in THF (18 mL), LiHMDS (1.0 M solution in THF, 4.00 mL, 4.00 mmol) was added at -78°C. This solution was stirred at -78°C for 30 minutes. Next, HMPA (0.69 mL, 4.00 mmol) was added. This solution was stirred for a further 30 minutes at -78°C. Next, iodomethane (0.34 mL, 5.46 mmol) was added. This solution was stirred for a further 2 hours at -78°C, then warmed to room temperature and stirred for 1 hour. This reaction was quenched by adding water (2 mL). Most of the THF solvent was removed under reduced pressure. The residue was then diluted with ethyl acetate (100 mL), and the resulting solution was washed with brine (2 × 100 mL) and dried over magnesium sulfate. By removing the solvent under reduced pressure, the crude product SZ-B (350 mg, 67%) was obtained as a viscous oil. This crude product was used in the next step without further purification. SZ-B: 1 HNMR(500MHz, CDCl3)δ(ppm): 5.74 (1H, s), 3.67 (1H, t), 1.11 (3H, d), 0.81 (3H, s).

[0404] Synthesis of compound SZ-C. Lithium (687 mg, 99.0 mmol) was added to liquid ammonia (100 mL) at -78°C. The liquid turned deep blue. Next, a solution of reactant SZ-B (950 mg, 3.30 mmol) in t-BuOH (244 mg, 3.30 mmol) and THF (20 mL) was added to this Li-ammonia solution. The mixture was stirred at -78°C for 4 hours. Then, solid NH4Cl (7 g) was added to quench the reaction. The mixture changed from deep blue to white. The mixture was raised to room temperature, and the ammonia was evaporated overnight in a hood. Water (100 mL) was added to the residue. The mixture was acidified to pH 6-7 with concrete HCl. Then, ethyl acetate (100 mL) was added. The separated aqueous layer was further extracted with ethyl acetate (2 × 100 mL). The combined organic extracts were washed with brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SZ-C was used directly in the next step without further purification.

[0405] Synthesis of compound SZ-D. Crude compound SZ-C (980 mg, 3.40 mmol) was dissolved in dichloromethane (60 mL) and pyridinium dichromate (PDC) (2.56 g, 6.80 mmol) was added. This mixture was stirred overnight at room temperature. The solution was filtered through a short pad of Celite. The Celite was washed with CH2Cl2 (3 × 50 mL). The combined CH2Cl2 solution was concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / siRNA = 5:1) to obtain product SZ-D (680 mg, 69%) as an off-white solid. SZ-D: 1 HNMR(500MHz, CDCl3)δ(ppm): 1.02 (3H, d), 0.91 (3H, s).

[0406] Synthesis of compound SZ-E. To a solution of compound SZ-D (3.24 g, 11.24 mmol) in anhydrous methanol (100 mL), p-toluenesulfonic acid monohydrate (193 mg, 1.12 mmol) was added. This solution was heated at 70°C for 3 hours. This reaction was quenched by adding sat. Na2CO3 solution (10 mL). Most of the methanol solvent was removed under reduced pressure. The residue was then diluted with ethyl acetate (200 mL). The resulting solution was washed with saturated Na2CO3 solution (2 × 100 mL). The combined aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extract was washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / dimethyl=15:1, with 0.1% NET3 added) to obtain product SZ-E (1.76 g, 47%) as an off-white solid. Furthermore, the starting compound SZ-E (1.34 g) was also recovered. The yield based on the recovered starting material was 93%. SZ-E: 1 1H NMR (500 MHz, d6-acetone) δ (ppm): 3.080 (3H, s), 3.076 (3H, s), 2.37 (1H, dd), 1.98 (1H, dd), 0.91 (3H, d), 0.85 (3H, s).

[0407] Synthesis of compound SZ-F. t-BuOK (2.01 g, 17.96 mmol) was added to a suspension of ethyltriphenylphosphonium bromide (6.67 g, 17.96 mmol) in anhydrous THF (25 mL). When the solution turned red, it was heated at 70°C for 2 hours. Then, compound SZ-E (2.00 g, 5.99 mmol) was added all at once. This solution was heated at 70°C overnight. The reaction was quenched by adding water (10 mL). The mixture was diluted with ethyl acetate (200 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SZ-F was used directly in the next step without further purification.

[0408] Synthesis of compound SZ-G: Crude product SZ-F (2.25 g, 6.50 mmol, theoretical amount) in THF (50 mL) was mixed with 4 M HCl (2 mL). This solution was stirred at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate (300 mL), and the resulting solution was washed with saturated Na2CO3 solution (2 × 100 mL). The combined aqueous layer was extracted with ELISA (100 mL). The combined organic extract was washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ELISA = 20:1) to obtain the desired product SZ-G, 1.78 g (5.94 mmol, yield 91%). SZ-G: 1 HNMR(500MHz,CDCl3)δ(ppm):5.13 (1H, qt), 1.66 (3H, dt), 1.02 (3H, d), 0.91 (3H, s).

[0409] Synthesis of compound SZ-H: Sodium hydride (60% wt, 1.19 mg, 29.70 mmol) was added to a solution of trimethylsulfoxonium iodide (6.53 g, 29.70 mmol) in anhydrous DMSO (30 mL). The mixture was stirred at 25°C for 1 hour. Next, a solution of crude compound SZ-G (2.05 g, contaminated with some PPh3, theoretical amount, 1.78 g, 5.94 mmol) in anhydrous THF (10 mL) was added. This mixture was stirred overnight at 25°C. The reaction was quenched by adding water (5 mL). This mixture was diluted with ethyl acetate (300 mL), and the resulting solution was washed with water (2 × 100 mL), then washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SZ-H was used directly in the next step without further purification.

[0410] Synthesis of compound SZ-I: To a solution of the crude reactant SZ-H (theoretical amount, 1.21 g, 3.85 mmol) in anhydrous THF (30 mL), lithium aluminum hydride (731 mg, 19.25 mmol) was gradually added. This suspension was stirred at 25°C for 1 hour. The reaction was then quenched by adding Depositphotos (5 mL), followed by water (5 mL). The off-white solid was filtered and thoroughly washed with Depositphotos (5 × 100 mL). The combined filtrate was washed with brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / Depositphotos = 15:1) to obtain product SZ-I (560 mg, 1.78 mmol, total yield of 2 steps, 30%) as an off-white solid. SZ-I: 1 HNMR(500MHz,CDCl3)δ(ppm):5.11 (1H, qt), 2.05 (1H, s), 1.56 (3H, s), 1.17 (3H, s), 0.91(3H, d), 0.88 (3H, s).

[0411] Synthesis of compound SZ-J. To a solution of reactant SZ-I (320 mg, 1.013 mmol) in anhydrous THF (20 mL), BH3.THF (1.0 M, 5.07 mL, 5.065 mmol) was added. This solution was stirred overnight at 25°C, and the reaction was then quenched by adding water (4 mL). 2 M aqueous NaOH solution (8 mL) was added, followed by 30% H2O2 (8 mL). This mixture was stirred at room temperature for 1 hour. The mixture was diluted with RINKAN (200 mL), the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SZ-J was used directly in the next step without further purification.

[0412] Synthesis of compound SZ-K. Crude compound SZ-J (320 mg, 1.013 mmol) was dissolved in dichloromethane (30 mL) and pyridinium dichromate (PDC) was gradually added (1.14 mg, 3.039 mmol). This solution was stirred overnight at 25°C. The mixture was then filtered through a short pad of silica gel, and the silica gel was washed with dichloromethane (3 × 50 mL). All filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / siRNA = 6:1) to obtain product SZ-K (140 mg, 0.422 mmol, yield 42%, 2 steps) as an off-white solid. SZ-K: 1 HNMR(500MHz,CDCl3)δ(ppm):2.54 (1H, t), 2.12 (3H, s), 1.99 (1H, td), 1.82-1.86 (1H, m), 1.18 (3H, s), 0.92 (3H, d), 0.61 (3H, s). SZ-K: 13 CNMR(100MHz,CDCl3)δ(ppm):209.79, 71.09, 63.94, 55.87, 47.94, 47.78, 46.97, 44.35, 41.16, 40.20, 39.04, 37.93, 34.48, 33.13, 31.55, 30.91, 28.45, 25.80, 24.20, 22.73, 15.15, 13.43.

[0413] Synthesis of compound SZ. To a solution of compound SZ-K (100 mg, 0.301 mmol) in methanol (10 mL), 48% hydrobromic acid (152 mg, 0.903 mmol) was added, followed by the addition of bromine (241 mg, 0.077 mL, 1.505 mmol). This solution was heated at 25°C for 2 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SZ was used directly in the next step without further purification.

[0414] Example 61. Synthesis of compounds SZ-1 and SZ-2. [ka]

[0415] To a solution of crude compound SZ (80 mg, 0.195 mmol) in anhydrous THF (6 mL), 1,2,3-triazole (1,2,3-trizaole) (40.4 mg, 0.585 mmol) was added, followed by the addition of potassium carbonate (80.9 mg, 0.585 mmol). This solution was heated overnight at 50°C. The solution was then diluted with  (100 mL). The resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase prep-HPLC to obtain product SZ-1 (15 mg, 19%) and product SZ-2 (6 mg, 7.7%) as off-white solids. SZ-1: 1 HNMR(500MHz,CDCl3)δ(ppm):7.77 (1H, s), 7.65 (1H, s), 5.28 (1H, AB), 5.14 (1H, AB), 2.66 (1H, t), 1.18 (3H, s), 0.92 (3H, d), 0.68 (3H, s). SZ-2: 1 HNMR(500MHz,CDCl3)δ(ppm):7.69 (2H, s), 5.25 (1H, AB), 5.23 (1H, AB), 2.60 (1H, t), 1.18 (3H, s), 0.92 (3H, d), 0.71 (3H, s).

[0416] Example 62. Synthesis of SS and SS intermediates. [ka]

[0417] Synthesis of compounds SS-A1 and SS-A2. To a solution of compound SB-F (800 mg, 2.79 mmol) and PhSO2CF2H (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL), LHMDS (4 mL, 1 M in THF) was added dropwise under N2 at -78°C. After stirring at -78°C for 2 hours, the reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL), heated to room temperature, and then extracted with Et2O (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a mixture of compounds SS-A1 and SS-A2 (650 mg). This mixture was further purified by chiral HPLC to obtain compounds SS-A1 (250 mg, t=3.29 min) and SS-A2 (230 mg, t=3.89 min).

[0418] Synthesis of compound SS-B2. To a solution of compound SS-A2 (230 mg, 0.489 mmol) and anhydrous Na2HPO4 (150 mg) in anhydrous methanol (5 mL), Na / Hg amalgam (700 mg) was added under N2 at -20°C. After stirring at -20°C to 0°C for 1 hour, the methanol solution was decanted, and the solid residue was washed with Et2O (5 × 3 mL). The combined organic phase was removed under reduced pressure, and 20 ml of brine was added, followed by extraction with Et2O. The combined ether phase was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1) to obtain compound SS-B2 (120 mg, 73%). 1 H NMR(400MHz,CD3COCD3),δ(ppm), 6.02-5.88 (t, 1H), 5.13-5.08 (m, 1H), 0.92(s, 3H).

[0419] Synthesis of compound SS-C2. To a solution of compound SS-B2 (120 mg, 0.355 mmol) in dry THF (5 mL), borane-tetrahydrofuran complex (1.20 mL; 1.0 M solution in THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath, followed by 1 mL of 10% aqueous NaOH, and then a 30% aqueous solution of H2O2 ( The mixture was slowly quenched with 1.2 mL of phosphate solution. This mixture was stirred at room temperature for 1 hour, then extracted with toluene (3 × 10 mL). The combined organic layer was washed with 10% aqueous Na₂S₂O₃ (10 mL) and brine (10 mL), dried over MgSO₄, filtered, and concentrated to obtain compound SS-C2 (180 mg, crude). This crude product was used in the next step without further purification.

[0420] Synthesis of compound SS-D2. Dess-Martin periodinate (380 mg, 0.896 mmol) was added to a solution of compound SS-C2 (180 mg, crude) in 10 mL of wet dichloromethane (dichloromethane was shaken with several milliliters of H2O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:5) to obtain compound SS-D2 (70 mg, 55.7% from two steps) as an off-white solid. 1 H NMR (400MHz, CDCl3), δ(ppm), 5.90-5.61 (t, 1H), 2.48-2.43 (m, 1H), 2.10 (s, 3H), 0.55 (s, 3H).

[0421] Synthesis of compound SS. Two drops of HBr (48%) were added to a solution of compound SS-D2 (50 mg, 0.14 mmol) in MeOH (5 mL), followed by the addition of bromine (100 mg, 0.62 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain compound SS (72 mg, crude). This crude product was used in the next step without further purification.

[0422] Example 63. Synthesis of compound SS-1. [ka] To a suspension of K2CO3 (126 mg, 0.92 mmol) in THF (10 mL), 1,2,3-1H-triazole (22.4 mg, 0.92 mmol) and compound SS (200 mg, 0.46 mmol) were added. After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of H2O and extracted with ELISA (2 × 10 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to obtain SS-1 as an off-white solid (53.8 mg, 0.13 mmol, 27.7%). SS-1: 1 HNMR(400MHz,CDCl3)δ(ppm):7.76 (d, 1H), 7.64 (d, 1H), 5.82 (t, 1H), 5.25 (AB, 1H), 5.13 (AB, 1H), 2.65 (t, 1H), 0.69 (s, 3H). LCMS:Rt=2.01 min. m / z=422.3[M+H] + .

[0423] Example 64. Synthesis of SN and SN intermediates. [ka] [ka]

[0424] Synthesis of compound SN-B. To a solution of reactant SN-A (10.0 g, 36.44 mmol) in pyridine (30 mL), acetic anhydride (5.0 mL, 52.89 mmol) was added. This mixture was stirred overnight at 60°C. Then, this solution was poured into ice water (200 mL). The white precipitate was filtered and dissolved in ethyl acetate (300 mL). Residual pyridine... To remove the ions, the obtained solution was washed with sat.CuSO4.5H2O solution (2 × 200 mL). The organic layer was further washed with brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 4:1) to obtain product SN-B (11.125 g, 35.16 mmol, yield = 96%) as an off-white solid. SN-B: 1 HNMR(500MHz,CDCl3)δ(ppm):5.83 (1H, s), 4.62 (1H, dd), 2.05 (3H, s), 0.86 (3H, s).

[0425] Synthesis of compound SN-C. To a solution of reactant SN-B (4.68 g, 14.79 mmol) in THF (150 mL), LiHMDS (1.0 M solution in THF, 17.74 mL, 17.74 mmol) was added at -78°C. This solution was stirred at -78°C for 30 minutes. Next, HMPA (3.09 mL, 17.74 mmol) was added. This solution was stirred for a further 30 minutes at -78°C. Next, iodomethane (2.76 mL, 44.37 mmol) was added. This solution was stirred further at -78°C for 2 hours, then warmed to room temperature and stirred for 1 hour. This reaction was quenched by the addition of water (10 mL). Most of the THF solvent was removed under reduced pressure. The residue was then diluted with ethyl acetate (300 mL), and the resulting solution was washed with brine (2 × 200 mL) and dried over magnesium sulfate. By removing the solvent under reduced pressure, the crude product SN-C (4.50 g, 13.62 mmol, yield = 92%) was obtained as a viscous oil. This crude product was used in the next step without further purification. SN-C: 1 HNMR(500MHz,CDCl3)δ(ppm):5.75 (1H, s), 4.62 (1H, t), 2.05 (3H, s), 1.10 (3H, d), 0.86 (3H, s).

[0426] Synthesis of compounds SN-D1 and SN-D2. Sodium hydroxide (2.81 g, 70.32 mmol) was added to a solution of the crude reactant SN-C (11.62 g, 35.16 mmol, theoretical amount) in methanol (100 mL) and water (20 mL). This solution was heated at 60°C for 1 hour. Most of the methanol solvent was removed under reduced pressure. The residual solution was acidified to pH 5-6 with 2 M HCl. The aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 5:1) to obtain pure product SN-D1 (2.354 g, 8.162 mmol, yield = 23%) and pure product SN-D2 (5.306 g, 18.40 mmol, yield = 50%) as off-white solids. SN-D1: 1 HNMR(500MHz, CDCl3)δ(ppm): 5.81 (1H, s), 3.67 (1H, t), 1.11 (3H, d), 0.81 (3H,s). SN-D2: 1 HNMR(500MHz,CDCl3)δ(ppm):5.74 (1H, s), 3.67 (1H, t), 1.11 (3H, d), 0.81 (3H, s).

[0427] Synthesis of compound SN-E. Lithium (1.80 g, 260 mmol) was added to liquid ammonia (200 mL) at -78°C. The liquid then turned deep blue. Next, the reactant SN-D1 (3.0 g, 10.40 mmol), in a solution of t-BuOH (1.0 mL, 10.40 mmol) and THF (100 mL), was added to this Li-ammonia solution. The mixture was stirred at -78°C for 4 hours. Then, solid NH4Cl (20 g) was added to quench the reaction. The mixture changed from deep blue to white. The mixture was raised to room temperature, and the ammonia was evaporated overnight in a hood. Water (300 mL) was added to the residue. The mixture was acidified to pH 6-7 with concrete HCl. Then, ethyl acetate (300 mL) was added. The separated aqueous layer was further extracted with ethyl acetate (2 × 100 mL). Combined organic extracts in brine (300mL) The product was washed, dried with magnesium sulfate, and concentrated under reduced pressure. The crude product SN-E was used directly in the next step without further purification.

[0428] Synthesis of compound SN-F. To a solution of the crude reactant SN-E (1.749 g, 6.022 mmol) in dichloromethane (60 mL), pyridinium dichromate (PDC) (3.398 g, 9.033 mmol) was added. This mixture was stirred overnight at room temperature. The solution was filtered through a short pad of Celite. The Celite was washed with CH2Cl2 (3 × 50 mL). The combined CH2Cl2 solution was concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 5:1) to obtain product SN-F (1.298 g, 4.50 mmol, yield = 75%) as an off-white solid. SN-F: 1 HNMR(400MHz, CDCl3)δ(ppm): 1.02 (3H, d), 0.91 (3H, s).

[0429] Synthesis of compound SN-G. To a solution of reactant SN-F (1.948 g, 6.754 mmol) in anhydrous methanol (50 mL), p-toluenesulfonic acid monohydrate (128 mg, 0.6754 mmol) was added. This solution was heated at 70°C for 3 hours. This reaction was quenched by adding sat.Na2CO3 solution (10 mL). Most of the methanol solvent was removed under reduced pressure. The residue was then diluted with ethyl acetate (200 mL). The resulting solution was washed with sat.Na2CO3 solution (2 × 100 mL). The combined aqueous layer was extracted with ethyl acetate (50 mL). The combined organic extract was washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 10:1, with 0.1% NEt3 added) to obtain product SN-G (652 mg, 1.949 mmol, yield = 29%) as an off-white solid. Furthermore, the starting material (1.338 g) was also recovered. The yield based on the recovered starting material was 92%. SN-G: 1 HNMR(500MHz,d6-acetone)δ(ppm):3.079 (3H, s), 3.075 (3H, s), 2.38 (1H, dd), 1.98 (1H, dd), 0.91 (3H, d, J=7.2 Hz), 0.85 (3H, s).

[0430] Synthesis of compound SN-H. t-BuOK (2.658 g, 23.69 mmol) was added to a solution of ethyltriphenylphosphonium bromide (8.795 g, 23.69 mmol) in anhydrous THF (20 mL). The solution then turned reddish and was heated at 70°C for 2 hours. Next, the reactant SN-G (1.642 g, 4.909 mmol) was added all at once. This solution was heated at 70°C overnight. The reaction was quenched by adding water (10 mL). The mixture was diluted with ethyl acetate (200 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SN-H was used directly in the next step without further purification.

[0431] Synthesis of compound SN-I. Crude product SN-H (1.702 g, 4.909 mmol, theoretical amount) in THF (30 mL) was mixed with 2 M HCl (3 mL). This solution was stirred at ambient temperature for 1 hour. The mixture was diluted with ethyl acetate (300 mL), and the resulting solution was washed with sat.Na2CO3 solution (2 × 100 mL). The combined aqueous layer was extracted with ethyl acetate (100 mL). The combined organic extract was washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 100:3) to obtain crude product SN-I (1.746 g) as an off-white solid. This was contaminated with some unseparable PPh3. 1 Based on the integration of the 1H NMR spectrum, the ratio of the desired product to PPh3 is 3:1. Therefore, the amount of the desired product SN-I is 1.354 g (4.506 mmol), and its yield is 92%. SN-I: 1 HNM R(500MHz, CDCl3)δ(ppm): 5.13 (1H, qt), 1.66 (3H, dt), 1.02 (3H, d), 0.91 (3H, s).

[0432] Synthesis of compound SN-J. Sodium hydride (60% wt, 948 mg, 23.69 mmol) was added to a solution of trimethylsulfoxonium iodide (5.213 g, 23.69 mmol) in anhydrous DMSO (30 mL). The mixture was stirred at 25°C for 1 hour. Then, a solution of crude reactant (1.746 g, contaminated with some residual PPh3, theoretical amount, 1.354 g, 4.506 mmol) in anhydrous THF (10 mL) was added. The mixture was stirred overnight at 25°C. This reaction was quenched by the addition of water (5 mL). The mixture was diluted with ethyl acetate (300 mL), and the resulting solution was washed with water (2 × 100 mL), then washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SN-J was used directly in the next step without further purification.

[0433] Synthesis of compound SN-K. To a solution of the crude reactant SN-J (theoretical amount, 1.417 g, 4.506 mmol) in anhydrous THF (30 mL), lithium aluminum hydride (342 mg, 9.012 mmol) was gradually added. The suspension was stirred at 25°C for 1 hour. The reaction was then quenched by adding ethyl acetate (5 mL), followed by water (5 mL). The off-white solid was filtered and thoroughly washed with ethyl acetate (5 × 100 mL). The combined filtrate was washed with brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 20:1) to obtain product SN-K (458 mg, 1.447 mmol, total yield of 2 steps = 32%) as an off-white solid.

[0434] Synthesis of compound SN-L. To a solution of reactant SN-K (458 mg, 1.447 mmol) in anhydrous THF (15 mL), BH3.THF (1.0 M, 7.23 mL, 7.23 mmol) was added, and the solution was stirred overnight at 25°C. The reaction was then quenched by adding water (5 mL). 2 M NaOH solution (10 mL) was added, followed by 30% H2O2 (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL), the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0435] Synthesis of compound SN-M. To a solution of crude reactant SN-L (484 mg, 1.447 mmol, theoretical amount) in dichloromethane (40 mL), pyridinium dichromate (PDC) was added gradually (1633 mg, 4.341 mmol). This solution was stirred overnight at 25°C. The mixture was then filtered through a short pad of silica gel, and the silica gel was washed with dichloromethane (3 × 50 mL). All filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether / ethyl acetate = 8:1) to obtain product SN-M (305 mg, 0.917 mmol, yield = 63% (2 steps)) as an off-white solid. SN-L: 1 HNMR(500MHz,CDCl3)δ(ppm):2.54 (1H, t0, 2.12-2.19 (1H, m), 2.12 (3H, s), 1.99 (1H, td), 1.80-1.86 (1H, m), 1.17 (3H, s), 0.92 (3H, d), 0.61 (3H, s): 13 CNMR(100MHz,CDCl3)δ(ppm):209.75, 71.09, 63.96, 55.89, 47.96, 47.80, 47.00, 44.35, 41.19, 40.22, 39.05, 37.95, 34.49, 33.14, 31.54, 30.92, 28.46, 25.82, 24.22, 22.76, 15.14, 13.45.

[0436] Synthesis of compound SN. To a solution of the reactant SN-M (100 mg, 0.301 mmol) in methanol (10 mL), 48% hydrobromic acid (152 mg, 0.903 mmol) was added, followed by the addition of bromine (241 mg, 0.077 mL, 1.505 mmol). This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SN was used directly in the next step without further purification.

[0437] Example 65. Synthesis of compounds SN-1 and SN-2. [ka] To a solution of the crude reaction product SN (124 mg, 0.301 mmol) in anhydrous THF (6 mL), 1,2,3-triazole (31 mg, 0.45 mmol) was added, followed by the addition of potassium carbonate (62 mg, 0.45 mmol). This solution was heated overnight at 50°C. Next, the solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase prep-HPLC to obtain product SN-1 (21 mg, 0.0526 mmol, yield = 17%) and product SN-2 (16 mg, 0.0400 mmol, yield = 13%) as off-white solids. SN-1:HNMR(400MHz,CDCl3)δ(ppm):7.76 (1H, s), 7.65 (1H, s), 5.20 (1H, AB), 5.14 (1H, AB), 2.66 (1H, t), 2.21 (1H, dd), 1.18 (3H, s), 0.92 (3H, d), 0.68 (3H, s). SN-2: 1 HNMR(500MHz,CDCl3)δ(ppm):7.69 (2H, s), 5.27 (1H, AB), 5.23 (1H, AB), 2.60 (1H, t), 2.20 (1H, dd), 1.17 (3H, s), 0.92 (3H, d), 0.71 (3H, s).

[0438] Example 66. Synthesis of SU and SU intermediates. [ka]

[0439] Synthesis of compound SU-B. Lithium (7.0 g, 1 mol) was added to NH3 (liquid, 2.0 L) at -78°C. After the liquid turned dark blue, compound SU-A (27.0 g, 100 mmol) was added dropwise in a solution of t-BuOH (7.4 g, 100 mmol) and THF (20 mL). The mixture was stirred at -78°C for 4 hours. The reaction was then quenched by adding solid NH4Cl (50 g). The mixture changed from deep blue to white. The mixture was heated to room temperature, and the ammonia was evaporated overnight. The residue was dissolved in 0.5 N aqueous HCl (50 mL) and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed with saturated NaHCO3 (200 mL) and brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / Â5=4:1) to obtain product SU-B (18.98 g, 68.7%) as an off-white solid. SU-B: 1 H NMR(500MHz,CDCl3)δ(ppm):3.66 (1H, t, J=8.0Hz), 2.29-2.27 (2H, m), 2.12-2.07 (2H, m), 1.83-1.81 (2H, m), 1.50 (1H, s), 0.77 (3H, s).

[0440] Synthesis of compound SU-C. A sample of compound SU-B (68.84 mmol) was dissolved in 50 mL of THF at 0°C. Then, 3 M MeMgBr in 70 mL of THF was added dropwise over 30 minutes. The reaction mixture was maintained at 0°C for 8 hours. The reaction mixture was quenched with ice-cold water and extracted with toluene (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was purified by flash column chromatography (PE / toluene = 5:1) to obtain product SU-C (19.0 g, 94%) as an off-white solid. SU-C: 1H NMR(500MHz,CDCl3)δ(ppm):5.78 (1H, br), 5.36 (1H, t), 3.67 (1H, t), 1.73 (3H, s), 0.77 (3H, s).

[0441] Synthesis of compound SU-D. Pyridinium dichromate (PDC) (48.9 g, 130.14 mmol) was added to a solution of compound SU-C (19.0 g, 65.07 mmol) in dichloromethane (100 mL). The mixture was stirred overnight at room temperature. This solution was filtered through a short pad of Celite. The Celite was washed with CH2Cl2 (3 × 100 mL). The combined CH2Cl2 solution was concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: PE / Â5 = 5:1) to obtain product SU-D (10.0 g, 53%) as an off-white solid. SU-D: 1 H NMR(500MHz, CDCl3)δ(ppm): 2.44 (1H, dd), 2.07 (1H, m), 1.21 (3H, s), 0.87 (3H, s).

[0442] Synthesis of compound SU-E: Compound SU-D (5.0 g, 17.2 mmol) was dissolved in anhydrous toluene (100 mL), to which p-toluenesulfonic acid (80 g) supported on silica gel was added, and the mixture was stirred at below 45°C for 1 hour. The insoluble by-product was removed from the silica gel by elution with PE / siRNA (10 / 1). The crude product SU-E (3.20 g, 11.75 mmol) was used in the next step without further purification.

[0443] Synthesis of compound SU-F: To a solution of compound SU-E (3.20 g, 11.75 mmol) in 10 mL of anhydrous dichloromethane, mCPBA (4.04 g, 23.50 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then extracted with CH2Cl2, the combined organic layers were washed twice with NaHCO3 (100 mL) and brine, dried over Na2SO4, and concentrated. The crude product SU-F was used in the next step without further purification.

[0444] Synthesis of compound SU-G. To a solution of compound SU-F (11.75 mmol) in methanol, H2SO4 (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was then extracted with CH2Cl2 (200 mL x 3), and the combined organic layer was washed with NaHCO3 (100 mL) and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (PE / Â=10:1) to obtain compound SU-G (3.30 g, 10.30 mmol, yield = 87% for two steps) as an off-white solid.

[0445] Synthesis of compound SU-H. t-BuOK (3.48 g, 31.0 mmol) was added to a solution of ethyltriphenylphosphonium bromide (11.52 g, 31.0 mmol) in anhydrous THF (20 mL). When the solution turned reddish, it was heated at 70°C for 3 hours. Then, compound SU-G (3.30 g, 10.30 mmol) was added all at once. This reaction solution was heated overnight at 70°C, and then quenched by adding water (10 mL). The mixture was diluted with ELISA (200 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SU-H (1.90 g) was used directly in the next step without further purification.

[0446] Synthesis of compound SU-I. To a solution of compound SU-H (1.90 g, 5.72 mmol) in dry THF (20 mL), BH3-THF (1.0 M solution in 18 mL of THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (12 mL), followed by 30% H2O2 (20 mL). This mixture was stirred at room temperature for 1 hour and then extracted with EA (100 mL x 3). The combined organic layer was washed with 10% aqueous Na2S2O3 (50 mL) and brine, and then Na2S The compound SU-I (1.86 g, 5.31 mmol) was dried over O4, filtered, and concentrated to obtain the crude compound SU-I. This crude product was used in the next step without further purification.

[0447] Synthesis of compound SU-J. Crude compound SU-I (1.86 g, 5.31 mmol) was dissolved in dichloromethane (50 mL) and pyridinium dichromate (PDC) was gradually added (3.98 g, 10.62 mmol). This solution was stirred overnight at 25°C. The mixture was then filtered through a short silica gel pad, and the silica gel was washed with dichloromethane (3 × 50 mL). All filtrates were combined and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: PE / Â=10:1) to obtain product SU-J (1.20 g, 3.45 mmol, 65%) as an off-white solid. SU-J: 1 HNMR(500MHz,CDCl3)δ(ppm):3.33 (3H, s), 3.04 (1H, s), 2.53 (1H, t), 2.12 (3H, s), 1.26 (3H, s), 0.62 (3H, s).

[0448] Synthesis of compound SU. To a solution of the reactant SU-J (100 mg, 0.287 mmol) in methanol (10 mL), 48% HBr (152 mg, 0.903 mmol) was added, followed by the addition of bromine (0.08 mL, 1.505 mmol). This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product SU was used directly in the next step without further purification.

[0449] Example 67. Synthesis of SU-1 and SU-2. [ka] To a solution of crude compound SU (100 mg, 0.243 mmol) in anhydrous THF (6 mL), 1,2,3-triazole (34 mg, 0.50 mmol) was added, followed by potassium carbonate (70 mg, 0.50 mmol). This solution was heated overnight at 50°C. Next, the solution was diluted with  (100 mL). The resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by reverse-phase prep-HPLC to obtain product SU-1 (35 mg, 0.084 mmol, yield = 34%) and product SU-2 (20 mg, 0.048 mmol, 20%) as off-white solids. SU-1: 1 H NMR(500MHz,CDCl3)δ(ppm):7.76 (1H, s), 7.65 (1H, s), 5.27 (1H, AB), 5.14 (1H, AB), 3.34 (3H, s), 3.04 (1H, s), 2.65 (1H, t), 1.24 (3H, s), 0.68 (3H, s). SU-2: 1 H NMR(500MHz,CDCl3)δ(ppm):7.68 (2H, s), 5.26 (1H, AB), 5.22 (1H, AB), 3.33 (3H, s), 3.04 (1H, s), 2.59 (1H, t), 1.24 (3H, s), 0.72 (3 H, s).

[0450] Example 68. Synthesis of SY and SY intermediates. [ka]

[0451] Synthesis of compound SY-B. Lithium (7.0 g, 1 mol) was added to NH3 (liquid, 2.0 L) at -78°C. After the liquid turned deep blue, the reactant SY-A (27.0 g, 100 mmol), in a solution of t-BuOH (7.4 g, 100 mmol) and THF (20 mL), was added dropwise. The mixture was stirred at -78°C for 4 hours, and then solid NH4Cl (50 g) was added to quench the reaction. The mixture then changed from deep blue to white. The mixture was raised to room temperature, and ammonia was evaporated overnight in a fume hood. The residue was dissolved in 0.5 N HCl (50 mL) and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed with saturated NaHCO3 (200 mL) and brine (200 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EA = 4:1) to obtain product SY-B (18.98 g, 68.76 mmol, yield = 68.7%) as an off-white solid. SY-B: 1 H NMR(500MHz,CDCl3)δ(ppm):3.66 (1H, t), 2.29-2.27 (2H, m), 2.12-2.07 (2H, m), 1.83-1.81 (2H, m), 1.50 (1H, s), 0.77 (3H, s).

[0452] Synthesis of compound SY-C. 19.0 g of compound SY-B (68.84 mmol) was dissolved in 50 mL of THF at 0°C. Then, 3 M MeMgBr in 70 mL of THF was added dropwise over 30 minutes, and the reaction mixture was maintained at 0°C for 8 hours. The reaction mixture was quenched with ice-cold water and extracted with EA (200 mL x 3). Combined organic The layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was purified by flash column chromatography (PE / EA=5:1) to obtain product SY-C (19.0 g, 65.07 mmol, yield=94%) as an off-white solid. SY-C: 1H NMR(500MHz,CDCl3)δ(ppm):5.78 (1H, br), 5.36 (1H, t), 3.67 (1H, t), 1.73 (3H, s), 0.77 (3H, s).

[0453] Synthesis of compound SY-D. To a solution of reactant SY-C (19.0 g, 65.07 mmol) in dichloromethane (100 mL), pyridinium dichromate (PDC) (48.9 g, 130.14 mmol) was added at room temperature, and the mixture was stirred overnight at room temperature. This solution was filtered through a short pad of Celite. The Celite was washed with CH2Cl2 (3 × 100 mL). The combined CH2Cl2 solution was concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: PE / EA = 5:1) to obtain product SY-D (10.0 g, 34.48 mmol, yield = 53%) as an off-white solid. SY-D: 1 H NMR(500MHz, CDCl3)δ(ppm): 2.44 (1H, dd), 2.07 (1H, m), 1.21 (3H, s), 0.87 (3H, s).

[0454] Synthesis of compound SY-E. To a solution of reactant SY-D (5.0 g, 17.2 mmol) in anhydrous toluene (100 mL), p-toluenesulfonic acid (80 g) supported on silica gel was quickly added, and the mixture was stirred at 45°C for 1 hour. The product was removed from the silica gel by elution with (PE / EA = 30:1). The crude product SY-E (3.20 g, 11.75 mmol) was used in the next step without further purification.

[0455] Synthesis of compound SY-F. To a solution of SY-E (3.20 g, 11.75 mmol) in 10 mL of anhydrous dichloromethane, mCPBA (4.04 g, 23.50 mmol) was added, and the reaction mixture was stirred overnight at room temperature. This solution was then extracted with CH2Cl2 (2 × 100 mL), and the combined organic layer was washed twice with NaHCO3 (100 mL) and brine, dried over Na2SO4, and concentrated. The crude product SY-E was used in the next step without further purification.

[0456] Synthesis of compound SY-G. To a solution of SY-F (900 mg, 3.12 mmol) in ethanol (50 mL), concentrated H2SO4 (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. As soon as TLC showed complete conversion, the solution was extracted with CH2Cl2 (200 mL x 3), the combined organic layer was washed with NaHCO3 (100 mL) and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography (PE / EA = 10:1) to obtain compound SY-G (600 mg, 1.80 mmol, yield = 57.6% for 2 steps) as an off-white solid.

[0457] Synthesis of compound SY-H. t-BuOK (500 mg, 4.48 mmol) was added to a solution of ethyltriphenylphosphonium bromide (1.99 g, 5.96 mmol) in anhydrous THF (10 mL). When the solution turned reddish, it was heated at 70°C for 3 hours. Then, the reactant SY-G (600 mg, 1.79 mmol) was added all at once. This solution was heated at 70°C overnight. The reaction was quenched by the addition of water (5 mL). The mixture was diluted with ethyl acetate (100 mL), and the resulting solution was washed with brine (2 × 50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluate: petroleum ether: ethyl acetate = 20:1) to obtain product SY-H (1.55 g, 4.48 mmol, 75.2%) as an off-white solid.

[0458] Synthesis of compound SY-I. To a solution of compound SY-H (1.20 g, 3.47 mmol) in dry THF (20 mL), BH3-THF (1.0 M solution in 18 mL of THF) was added. After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% aqueous NaOH (10 mL), followed by 30% H2O2 (15 mL). The mixture was stirred at room temperature for 1...

Claims

1. Equation (Ia): 【Chemistry 1a】 A compound or a pharmaceutically acceptable salt thereof, wherein A is group: 【Chemistry 1-2】 Selected from; R １ C １～６ Alkyl, C １～３ Substituted with alkoxy or fluoro as needed; R ２ is hydrogen, unsubstituted C １～３ Alkyl or unsubstituted C １～３ It is an alkoxy; R ４ is hydrogen, C １～３ alkyl optionally substituted with 1 to 3 halos, -CN, -C(O)OH, -C(O)NH ２ , or -C(O)O-C １～３ alkyl; and n is either 0 or 1, However, if A is (A-1) or (A-2), R １ is, -CHF ２ ien-CH ２ F, or C as needed １～３ C substituted with alkoxy １ ~C ６ It is alkyl, However, if A is (A-3) or (A-5) and R １ ga-CH ３ ien-CH ２ F, -CH ２ OCH ３ or -CHF ２ If n is 0, then R ２ It is something other than hydrogen, However, the compound or pharmaceutically acceptable salt of formula (Ia) is defined as formula: [Chemistry 1-3] Not a compound of or a pharmaceutically acceptable salt of, A compound or a pharmaceutically acceptable salt thereof.

2. R １ C １～６ Fluoroalkyl or C １～６ A compound or pharmaceutically acceptable salt according to claim 1, which is an alkoxyalkyl compound.

3. R １ R is methyl or ethyl, where R １ The methyl is C as needed. １～３ A compound or pharmaceutically acceptable salt according to claim 1, which is substituted with an alkoxy or one or two fluoropolymers.

4. R １ is, -CH ３ ien-CH ２ F, -CHF ２ ien-CH ２ CH ３ ien-CH ２ OCH ３ , or -CH ２ OCH ２ CH ３ The compound or pharmaceutically acceptable salt described in claim 3.

5. R １ is, -CH ３ The compound or pharmaceutically acceptable salt described in claim 4.

6. R ２ The compound or pharmaceutically acceptable salt according to any one of claims 1 to 5, wherein is hydrogen, methyl, or methoxy.

7. R ２ The compound or pharmaceutically acceptable salt according to claim 6, wherein is hydrogen.

8. A is group: 【Transformation 8】 A compound or pharmaceutically acceptable salt of the compound or pharmaceutically acceptable salt of claim 6, selected from the above.

9. R ４ These are hydrogen, methyl, -CN, -C(O)OH, -C(O)NH, which are optionally substituted with 1 to 3 halos. ２ , or -C(O)O-C １～３ The compound or pharmaceutically acceptable salt according to claim 8, wherein the compound is alkyl.

10. R ４ The compound or pharmaceutically acceptable salt according to claim 8, wherein is hydrogen, methyl, or -CN.

11. Compounds selected from the following: 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】

12. pharmaceutically acceptable salts of compounds selected from the following: 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, a compound according to claim 11 or a pharmaceutically acceptable salt according to claim 12, and a pharmaceutically acceptable excipient.

14. A composition for treating CNS-related disorders in human subjects, comprising an effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, the compound according to claim 11, or a pharmaceutically acceptable salt according to claim 12.

15. The composition according to claim 14, wherein the CNS-related disorder is a sleep disorder, eating disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disorder, substance abuse disorder or withdrawal syndrome, or tinnitus.

16. The composition according to claim 14, wherein the CNS-related disorder is depression, bipolar disorder, tremor, epilepsy, or an eating disorder.

17. The composition according to claim 16, wherein the depression is postpartum depression or major depressive disorder.

18. The composition according to claim 17, wherein the major depressive disorder is moderate major depressive disorder or severe major depressive disorder.

19. The composition according to claim 16, wherein the tremor is essential tremor or Parkinson's tremor.

20. The composition according to claim 16, wherein the CNS-related disorder is bipolar disorder.

21. The composition according to claim 16, wherein the eating disorder is anorexia nervosa, bulimia nervosa, binge eating disorder, or cachexia.

22. The composition according to claim 14, wherein the CNS-related disorder is status epilepticus, Lennox-Gastaut syndrome, tics associated with Tourette's syndrome, or tubular sclerosis.

23. The composition according to claim 22, wherein the status epilepticus state is either a convulsive status epilepticus state or a non-convulsive status epilepticus state.

24. The composition according to claim 14, wherein the composition is adapted for oral administration.

25. The composition according to claim 24, which is adapted for chronic administration.

26. A composition for inducing sedation and / or anesthesia in a human subject, comprising an effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, the compound according to claim 11, or a pharmaceutically acceptable salt according to claim 12.

27. The composition according to claim 26, wherein the composition is adapted for oral administration, subcutaneous administration, intravenous administration, or intramuscular administration.

28. The composition according to claim 27, which is adapted for chronic administration.

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