19-nor c3,3-disubstituted c21-n-pyrazolyl steroids and methods for use thereof

Abstract

To provide 19-nor C3,3-disubstituted C21-N-pyrazolyl steroids, and methods for use thereof.SOLUTION: Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I), and pharmaceutically acceptable salts thereof. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and / or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, and tinnitus.SELECTED DRAWING: None

Description

[Background technology]

[0001] Background of the Invention Brain excitability, defined as the level of alertness of an animal on a continuum ranging from coma to seizures, is controlled by various neurotransmitters. Generally, neurotransmitters are involved in controlling the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of approximately -70 mV, with the interior of the cell being negative relative to the exterior. The electrical potential (voltage) is determined by the conductance of ions (K) across the neuronal semipermeable membrane. + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. Upon release into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV). This action is mediated by Na + It is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, which increases membrane permeability to ions. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0002] In the case of the GABA receptor complex (GRC), its effects on brain excitability are mediated by the neurotransmitter GABA. Because up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA exerts a profound influence on global brain excitability. GABA controls the excitability of individual neurons by regulating chloride ion conductance across neuronal membranes. By interacting with recognition sites on GRCs, GABA promotes the flow of chloride ions into the cell down the GRC's electrochemical gradient. Elevated intracellular levels of this anion cause hyperpolarization of the transmembrane potential, reducing the neuron's sensitivity to excitatory inputs (i.e., decreasing neuronal excitability). In other words, the higher the chloride ion concentration within a neuron, the lower the brain's excitability (level of arousal).

[0003] The GRC has been well documented to be involved in mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like or potentiate the actions of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZs), e.g., Valium®) exert their therapeutically beneficial effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now suggests that the GRC contains distinct sites for neuroactive steroids in addition to benzodiazepine and barbiturate binding sites (Lan, NC et al., Neurochem. Res. 16:347-356 (1991)).

[0004] Neuroactive steroids can be endogenously produced. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one (metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to change brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

[0005] The ovarian hormone progesterone and its metabolites have been shown to have profound effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff, D. .W and McEwen, B.S., Science 219:808-814 (1983); Gyermek et al., J Med Chem. 11:117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987)). Levels of progesterone and its metabolites fluctuate depending on the phase of the menstrual cycle. It is well documented that levels of progesterone and its metabolites decline before the onset of menstruation. It is also well documented that certain physical symptoms recur every month before the onset of menstruation. These symptoms, which occur with premenstrual syndrome (PMS), include stress, anxiety, and migraines (Dalton, K., Premenstrual Syndrome). Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984). Subjects with PMS experience recurring symptoms each month that appear before menstruation and disappear after menstruation.

[0006] In a similar manner, a decrease in progesterone correlates temporally with an increase in seizure frequency in female epileptic patients (i.e., catamenial 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 occurrence of seizures correlated with the occurrence of symptoms of premenstrual syndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating subjects with epileptic seizures correlated with the menstrual cycle (Aird, RB and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)).

[0007] Also associated with low progesterone levels is postpartum depression (PND). Immediately after birth, progesterone levels drop dramatically, leading to the onset of PND. PND symptoms range from mild depression to psychosis requiring hospitalization. PND is also accompanied by severe anxiety and irritability. PND-related depression is not amenable to treatment with conventional antidepressants, and women experiencing PND show a high incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)).

[0008] Taken together, these findings imply a critical role for progesterone and deoxycorticosterone and more specifically their metabolites in the homeostatic control of brain excitability, which manifests as increased seizure activity or symptoms associated with menstrual epilepsy, PMS, and PND. The correlation between low levels of progesterone and symptoms related to PMS, PND, and catamenial epilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy," Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279-282 and Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)). However, progesterone is not always effective in treating the above-mentioned syndromes. For example, there is no dose-response relationship for progesterone in the treatment of PMS (Maddo, cks et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).

[0009] There is a need for new and improved neurostimulatory steroids that act as modulators of brain excitability and as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are directed to this end. [Prior art documents] [Non-patent literature]

[0010]

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[0011] Summary of the Invention The present invention provides novel 19-nor (i.e., C19-desmethyl) compounds, e.g., pro- ... This invention is based, in part, on the desire to provide compounds related to progesterone, deoxycorticosterone, and their metabolites. One important feature of the compounds described herein is disubstitution at the C3 position (e.g., one substituent is a 3α hydroxy moiety). The inventors predict that disubstitution at C-3 will eliminate the possibility of oxidation of this hydroxy moiety to a ketone, preventing further metabolism and reducing the possibility of secondary elimination pathways such as glucuronidation. The inventors further predict that the overall effect of the C3 disubstitution will improve overall PK parameters and reduce potential toxicity and side effects, thereby enabling oral and / or chronic administration in certain embodiments. Another important feature of the compounds described herein is the presence of a hydrogen rather than a methyl group at the C19 position ("19-nor"). The inventors predict that the 19-nor compounds will have improved physical properties, such as improved solubility, compared to their C19-methyl counterparts. The inventors further predict that, for example, solubility will be increased when the AB ring system is in the cis configuration.

[0012] Thus, in one aspect, a compound of formula (I):

[0013] [ka]

[0014] Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids and pharmaceutically acceptable salts thereof; In formula (I): ----- represents a single or double bond; R 1 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, or -OR A2 where R A2 is hydrogen or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 3a is hydrogen or -OR A3 where R A3 is hydrogen or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b together form an oxo (=O) group; R 4a and R 4b Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or halogen, provided that the C5 and C6 ----- is a single bond, C5 hydrogen and R 4a and are each independently provided in the α or β configuration, and R 4b does not exist; R 5 , R 6 , and R 7 Each example is independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA, -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA )2, -SR GA , -S(O)R GA , e.g., -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl; and R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0015] The steroids of formula (I), subgenera thereof, and pharmaceutically acceptable salts thereof are collectively referred to herein as "compounds of the invention."

[0016] In another aspect, a pharmaceutical composition is provided that comprises a compound of the present invention and a pharmaceutically acceptable excipient.In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition.In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount.

[0017] The compounds of the invention as described herein may, in certain embodiments, be used to treat, for example, GABA A These compounds act as GABA modulators, affecting the GABA receptor in either a positive or negative manner. A They are predicted to have central nervous system (CNS) activity as regulators of CNS excitability as mediated by their ability to modulate receptors.

[0018] Thus, in another aspect, a method for treating a CNS-related disorder in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of the present invention. 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 disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, 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.

[0019] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description, examples, and claims.

[0020] definition chemical definition Definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are The functional groups are generally defined according to the table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described therein.In addition, the general rules of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0021] The compounds described herein may contain one or more asymmetric centers and therefore may exist as various isomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers may be isolated from mixtures 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. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon See, for example, "Compounds" (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., University 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 alternatively as mixtures of various isomers.

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

[0023] The following terms are intended to have the meanings presented below and are useful in understanding the specification and the intended scope of the invention. In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings, unless otherwise indicated. As described herein, it is also to be understood that any of the moieties defined below may be substituted with various substituents, and that each definition is intended to encompass substituted moieties within their scope as described below. Unless otherwise stated, the term "substituted" is defined as described below. It is further to be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue. do.

[0024] "Alkyl" means the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0025] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to divalent radicals of alkyl, alkenyl, and alkynyl groups, respectively. When a range or number of carbons 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 carbons in that linear divalent chain of carbons. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more groups as described herein.

[0026] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), and hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(C H3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), and substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-).

[0027] "Alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, an alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0028] "Alkenylene" refers to an alkenyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH-, -CH-CH=CH-). Exemplary substituted alkenylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), and substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0029] "Alkynyl" refers to an alkyl group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally A radical of a straight-chain or branched-chain hydrocarbon group ("C") having one or more than one carbon-carbon double bond (e.g., one, two, three, or four carbon-carbon double bonds), depending on 2~20In certain embodiments, alkynyl groups contain no double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or 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), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. 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, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0030] "Alkynylene" refers to a straight-chain alkynyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0031] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further comprises one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in its parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the 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 is a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 Al In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents (a "substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0032] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, further containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the 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 heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2~10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~4In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2~3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted with one or more substituents (a "substituted heteroalkenyl"). In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0033] The term "heteroalkynyl," as used herein, further includes one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are

[0033] An alkynyl group, as defined herein, is 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 the points of attachment). In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC"). 2~10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("heteroC 2~3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted with one or more substituents (a "substituted heteroalkynyl"). In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0034] As used herein, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl groups, respectively. When a range or number of carbons is 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 carbons in that linear divalent chain of carbons. "Alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups can be substituted or unsubstituted with one or more groups as described herein.

[0035] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" refers to a group in which an aryl ring, as defined above, is joined to one or more carbocyclyl groups.

[0023] The aryl group also includes ring systems fused with an aryl or heterocyclyl group, where the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[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] Representative examples of substituted aryl include:

[0038] [ka]

[0039] where R 56 and R 57 can be hydrogen, and R 56 and R57 At least one of the following is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O, or S). R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[0040] Other representative aryl groups having a fused heterocyclyl group include:

[0041] [ka]

[0042] where each W is C(R 66 )2, NR 66 , O, and S; and each Y is selected from carbonyl, NR 66, O, and S; and R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0043] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or with a carbocyclyl or heterocyclyl ring.

[0044] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0045] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in a cyclic arrangement) in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if valence 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 point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, wherein the point of attachment can be on either the aryl ring or the heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0046] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0047] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0048] Representative examples of heteroaryls include:

[0049] [ka]

[0050] wherein each Y is a carbonyl, N, NR 65 , O and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5- to 10-membered heteroaryl.

[0051] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0052] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ( "C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the above-mentioned 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), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. As the foregoing examples are illustrated, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclyl")), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0053] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0054] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, when valence allows. Heterocyclyl groups can be monocyclic ring systems ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can 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 to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0055] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0056] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0057] Particular examples of heterocyclyl groups are shown in the following illustrative examples:

[0058] [ka]

[0059] Here, each W is 67 , C(R 67 )2, NR 67 , O, and S; each Y is selected from NR 67 , O and S; R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10and aryl and 5- to 10-membered heteroaryl. 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 amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, 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. Substituents include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0060] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group are replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, especially 1 to 3, heteroatoms (e.g., alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl, etc.).

[0061] "Acyl" means -C(O)R 20 refers to the radical, where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to a group in which R 20 is an acyl group, which is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, and --C(O)-(CH2). t (C6~C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3~C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) (t is an integer from 0 to 4). 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0062] "Acylamino" means -NR 22 C(O)R 23 refers to the radical, where R 22 and each occurrence of R23 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, as defined herein, or R 22is an amino-protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. Certain exemplary "acylamino" groups are -NR 24 C(O)-C1-C8 alkyl, -NR 24 C(O)-(CH2) t (C6~C 10 aryl), -NR 24 C(O)-(CH2) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH2) t (C3~C 10 cycloalkyl) and -NR 24 C(O)-(CH2) t (4- to 10-membered heterocyclyl), where t is an integer from 0 to 4, and each R 24 independently represent H or C1-C8 alkyl. In certain embodiments, R 25 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; R 26 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy, or hydroxyl; with the proviso that R25 and R 26 At least one of is other than H.

[0063] "Acyloxy" means -OC(O)R 27 refers to the radical, where R 27 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 is C1-C8 alkyl substituted with halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl and heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0064] "Alkoxy" means -OR 29 refers to the group, where R 29is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0065] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 The "substituted alkoxy" group is a group having one or more substituents selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl) and -O-(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present can itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0066] "Amino" refers to the -NH2 radical.

[0067] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 cycloalkyl) or -(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0068] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl) and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent H or C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino encompasses both mono- and di-substituted amino groups.

[0069] "Azide" refers to the -N3 radical.

[0070] "Carbamoyl" or "amide" refers to the -C(O)NH2 radical.

[0071] "Substituted carbamoyl" or "substituted amide" refers to a group consisting of -C(O)N(R 62 )2 radical, where each R 62 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein R 62 At least one of R is not hydrogen. 62 is H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, aralkyl, 5-10 membered heteroaryl and heteroaralkyl; or C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R 62 is other than H.

[0072] Exemplary "substituted carbamoyl" groups include -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 membered heteroaryl), -C(O)NR 64 -(CH2) t (C3~C10 cycloalkyl) and -C(O)NR 64 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and each R 64 independently represent H or C1-C8 alkyl, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0073] "Carboxy" refers to the radical --C(O)OH.

[0074] "Cyano" refers to the -CN radical.

[0075] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is fluoro or chloro.

[0076] "Hydroxy" refers to the -OH radical.

[0077] "Nitro" refers to the -NO2 radical.

[0078] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0079] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0080] "Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl groups having from 3 to 10 carbon atoms, a single cyclic ring or multiple condensed rings (including fused and bridged ring systems), and at least one, and especially one to two, sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[0081] "Fused cycloalkenyl" refers to a cycloalkenyl having two ring carbon atoms in common with a second aliphatic or aromatic ring and having olefinic unsaturation positioned so as to impart aromaticity to the cycloalkenyl ring.

[0082] "Ethylene" refers to a substituted or unsubstituted --(CC)--.

[0083] "Ethenyl" refers to a substituted or unsubstituted --(C.dbd.C)--.

[0084] "Ethynyl" refers to -(C≡C)-.

[0085] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0086] "Thioketo" refers to the =S group.

[0087] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted (e.g., For example, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group. In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present in a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein, that result in the formation of stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and thereby form a stable moiety.

[0088] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -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(Rbb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd Is substituted with a group; Or the 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 radicals; R aa Each occurrence of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14aryl and 5- to 14-membered heteroaryl, or two R aa groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, Tetracyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bb groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R ddsubstituted with a group; R cc Each occurrence of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(Rff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(O)R ee , e.g., -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may be linked to form =O or =S; R ee Each occurrence of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heteroaryl, The aryl, heterocyclyl, and heteroaryl may independently be 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be linked to form =O or =S; where X - is the counter ion.

[0089] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2 Examples of such ions include sulfonate ions (e.g., methanesulfonate, 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, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0090] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc)2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5-14 membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined above.

[0091] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. It is not intended that the present invention be limited in any way by the exemplary recitation of substituents above.

[0092] Other definitions The term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with 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. 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 using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and methyl esters. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and methyl esters. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and methyl esters. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and methyl esters. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and methyl esters. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and methyl esters. + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0093] "Subjects" to which administration is contemplated include humans (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 monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0094] Disease, disorder, and condition are used interchangeably herein.

[0095] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a particular disease, disorder, or condition to lessen the severity of the disease, disorder, or condition or to delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0096] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health status, and condition of the subject.The effective amount includes therapeutic treatment and prophylactic treatment.

[0097] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0098] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula (I): [ka] or a pharmaceutically acceptable salt thereof; In formula (I): ----- represents a single or double bond; R 1 is a substituted or unsubstituted C 1~6 Alkyl (e.g., haloalkyl (e.g., -CHF2, -CH2F), -CH2OCH3, -CH2OCH2CH3), substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, or -OR A2 where R A2 is hydrogen or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 3a is hydrogen or -OR A3 where R A3 is hydrogen or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b together form an oxo (=O) group; R 4a and R 4b Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or halogen, provided that the C5 and C6 ----- is a single bond, C5 hydrogen and R 4a and are each independently provided in the α or β configuration, and R 4b does not exist; R 5 , R 6 , and R 7 Each example is independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA )2, -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl (e.g., haloalkyl), substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl or a substituted or unsubstituted 3- to 6-membered heterocyclyl; R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, bonded to oxygen an oxygen protecting group if attached to a nitrogen, a nitrogen protecting group if attached to a nitrogen, or two R GA the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring; and R 1 is a C optionally substituted with alkoxy or 1 to 2 halo groups (e.g., fluoro). 1~6 alkyl or R 5 , R 6 , and R 7 At least one of the groups is a halogen (e.g., —F, —Cl, —Br), —NO2, —CN, —OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, substituted or unsubstituted C 1~6 alkyl (e.g., -CH, -CHCH, haloalkyl (e.g., -CF)), where R GA is a substituted or unsubstituted C 1~2 is alkyl, The compound or a pharmaceutically acceptable salt thereof. (Item 2) R 1 is a C optionally substituted with alkoxy or 1 to 2 halo groups (e.g., fluoro). 1~6 alkyl, and R 5 , R 6 , and R 7 At least one of the groups is a halogen (e.g., —F, —Cl, —Br), —NO2, —CN, —OR GA , -N(R GA )2, -C(=O)R GA, -C(=O)OR GA , -SR GA , -S(O)R GA , e.g., -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, substituted or unsubstituted C 1~6 alkyl (e.g., -CH, -CHCH, haloalkyl (e.g., -CF)), where R GA is a substituted or unsubstituted C 1~2 The compound of formula (I) according to item 1, wherein the compound is alkyl. (Item 3) The compound has the formula (IA): [ka] The compound of formula (I) according to item 1, selected from the compounds (Item 4) The compound has the formula (IB): [ka] The compound of formula (I) according to item 1, selected from the compounds (Item 5) R 1 is unsubstituted C 1~6 The compound according to item 1, wherein the aryl group is alkyl. (Item 6) R 1 is an optionally alkoxy-substituted C 1~6 The compound according to item 1, wherein the aryl group is alkyl. (Item 7) R 1 is C optionally substituted with one or two halo (e.g., fluoro) 1~6 The compound according to item 1, wherein the aryl group is alkyl. (Item 8) R 1is -CH3, -CH2CH3, -CH2F, -CHF2, -CH2OCH2CH3, or -CH2OCH3. (Item 9) R 1 Item 9. The compound according to item 8, wherein is —CH3. (Item 10) R 2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. (Item 11) R 2 Item 11. The compound according to item 10, wherein is —CH3 or —OCH3. (Item 12) R 2 Item 12. The compound according to item 11, wherein is —OCH3. (Item 13) R 2 The compound according to item 1, wherein is hydrogen. (Item 14) R 3a and R 3b The compound according to item 1, wherein both and are hydrogen. (Item 15) ----- represents a single bond, and R 4a and R 4b and are both hydrogen, as described in item 1. Compound. (Item 16) ----- represents a single bond, and R 4a and R 4b and are both fluoro. The compound described. (Item 17) ----- represents a single bond, and R 4a is hydrogen, fluoro, -CH3, or -CF3 Item 1. The compound according to item 1, (Item 18) ----- represents a single bond, and R 4ais a substituted or unsubstituted C 1~6 Alkyl, or halogen, and R 4b The compound according to item 1, wherein is hydrogen. (Item 19) R 4a Item 19. The compound according to item 18, wherein is fluoro. (Item 20) R 5 , R 6 , and R 7 wherein at least one of is hydrogen. (Item 21) R 5 , R 6 , and R 7 wherein at least two of are hydrogen. (Item 22) R 5 , R 6 , and R 7 The compound according to item 1, wherein all of are hydrogen. (Item 23) R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, halogen, -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , or -S(=O)2N(R GA )2, where R GA is a substituted or unsubstituted C 1~2 The compound according to item 1, wherein the aryl group is alkyl. (Item 24) R 5 , R 6 , and R 7 24. The compound according to item 23, wherein at least one of is —CN. (Item 25) R 5 , R6 , R 7 At least one of the is -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , or -S(=O)2N(R GA )2, where R GA is a substituted or unsubstituted C 1~2 24. The compound according to item 23, wherein the alkyl is alkyl. (Item 26) R 5 , R 6 , R 7 At least one of the groups is -S(=O)2R GA 26. The compound according to item 25, wherein (Item 27) R GA 26. The compound according to item 25, wherein is —CH3. (Item 28) R 5 and R 7 The compound according to item 1, wherein is hydrogen. (Item 29) R 6 is a halogen (e.g., -F, -Cl, -Br), -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, substituted or unsubstituted C 1~6 alkyl (e.g., -CH, -CHCH, haloalkyl (e.g., -CF)), where R GA is a substituted or unsubstituted C 1~2 The compound according to item 1, wherein the aryl group is alkyl. (Item 30) R 6 -SR GA , -S(=O)R GA, -S(=O)2R GA , -S(=O)2OR GA , or -S(=O)2N(R GA )2, where R GA is a substituted or unsubstituted C 1~2 30. The compound according to item 29, wherein the alkyl is alkyl. (Item 31) R 6 is a halogen (e.g., -F, -Cl, -Br), -NO2, -CN, or a substituted or unsubstituted C 1~6 alkyl (e.g., -CH, -CHCH, haloalkyl (e.g., -CF)), where R GA is a substituted or unsubstituted C 1~2 30. The compound according to item 29, wherein the alkyl is alkyl. (Item 32) R 2 , R 3a , R 3b , R 4a , and R 4b is hydrogen. (Item 33) The compound according to Item 1. R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , and R 7 wherein at least three of are hydrogen. (Item 34) R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , and R 7 wherein at least four of are hydrogen. (Item 35) R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , and R 7wherein at least five of are hydrogen. (Item 36) R 6 is a halogen (e.g., -F, -Cl, -Br), -NO2, -CN, -C(=O)R GA , -C(=O)OR GA , -SR GA , -S(=O)R GA , -S(=O)2R GA , substituted or unsubstituted C 1~6 alkyl (e.g., -CH, -CHCH, haloalkyl (e.g., -CF)), where R GA is a substituted or unsubstituted C 1~2 36. The compound according to item 35, wherein the alkyl is alkyl. (Item 37) R 6 -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , or -S(=O)2N(R GA )2, where R GA is a substituted or unsubstituted C 1~2 37. The compound according to item 36, wherein the alkyl is alkyl. (Item 38) R 6 37. The compound according to item 36, wherein is —CN. (Item 39) R 1 is a substituted or unsubstituted C 1~6 37. The compound according to item 36, which is alkyl (e.g., haloalkyl (e.g., -CF3, -CHF2, -CH2F)) or alkoxy. (Item 40) The compound is: [ka] [ka] [ka] The compound according to item 1, selected from the group consisting of: (Item 41) The compound is: [ka] [ka] [ka] [ka] 3. The compound according to item 2, selected from the group consisting of: (Item 42) The compound is: [ka] [ka] 4. The compound according to item 3, selected from the group consisting of: (Item 43) A pharmaceutical composition comprising a compound according to any one of the preceding paragraphs or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 44) 20. A method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of items 1 to 19, or The method comprising administering a pharmaceutically acceptable salt. (Item 45) 45. The method of item 44, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus. (Item 46) 45. The method of claim 44, wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly. (Item 47) 45. The method of claim 44, wherein the compound is administered chronically. [Brief explanation of the drawings]

[0099] [Figure 1] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 2] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 3] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 4] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 5] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 6] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 7] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 8] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 9] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 10] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 11] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 12] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 13] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 14] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 15] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 16] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 17] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 18] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 19] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 20] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 21] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 22] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 23]1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 24] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 25] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 26] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 27] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 28] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 29] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 30] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 31] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 32] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 33] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 34] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 35] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 36]1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 37] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 38] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 39] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 40] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 41] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 42] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 43] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 44] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 45] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 46] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 47] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 48] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 49]1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 50] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 51] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. [Figure 52] 1-52 illustrate representative 1H NMR spectra of exemplary compounds described herein. DETAILED DESCRIPTION OF THE INVENTION

[0100] Detailed Description of Specific Embodiments of the Invention As described herein, the present invention provides a compound of formula (I):

[0101] [ka]

[0102] and pharmaceutically acceptable salts thereof; In formula (I): ----- represents a single or double bond; R 1 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, or -OR A2where R A2 is hydrogen or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 3a is hydrogen or -OR A3 where R A3 is hydrogen or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C for substitution 2~6 Alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b together form an oxo (=O) group; R 4a and R 4b Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or halogen, provided that the C5 and C6 ----- is a single bond, C5 hydrogen and R 4a and are each independently provided in the α or β configuration, and R 4b does not exist; R 5 , R 6 , and R 7 Each example is independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)ORGA , -N(R GA )C(=O)N(R GA )2, -SR GA , -S(O)R GA , e.g., -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl; and R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0103] In certain embodiments, R 1 is a C optionally substituted with alkoxy or 1 to 2 halo groups (e.g., fluoro). 1~6 alkyl, or R 5 , R 6 , and R 7 At least one of the groups is a halogen (e.g., —F, —Cl, —Br), —NO2, —CN, —OR GA , -N(R GA )2, -C(=O)RGA , -C(=O)OR GA , -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, substituted or unsubstituted C 1~6 alkyl (e.g., -CH, -CHCH, haloalkyl (e.g., -CF)), where R GA is a substituted or unsubstituted C 1~2 It is alkyl.

[0104] In certain embodiments, R 1 is a C optionally substituted with alkoxy or 1 to 2 halo groups (e.g., fluoro). 1~6 alkyl, and R 5 , R 6 , and R 7 At least one of the groups is a halogen (e.g., —F, —Cl, —Br), —NO2, —CN, —OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -SR GA , -S(=O)R GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, substituted or unsubstituted C 1~6 alkyl (e.g., -CH, -CHCH, haloalkyl (e.g., -CF)), where R GA is a substituted or unsubstituted C 1~2 It is alkyl.

[0105] Based on the above explanation, steroids of formula (I) include 3,3-disubstituted 19-nor neuroactive steroids in which the A / B ring system of the compound is cis (as given in formula (IA)), 3,3-disubstituted 19-nor neuroactive steroids in which the A / B ring system of the compound is trans (as given in formula (IB)), and 3,3-disubstituted 19-nor neuroactive steroids in which the B ring of the compound contains a C5-C6 double bond (as given in formula (IC)):

[0106] [ka]

[0107] [ka]

[0108] as well as pharmaceutically acceptable salts thereof.

[0109] base R 1 As generally defined herein, R 1 is a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 It is a carbocyclyl.

[0110] In certain embodiments, R 1 is a substituted or unsubstituted C 1~6 Alkyl, e.g., substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 An exemplary R is alkyl. 1 C 1~6Alkyl groups include substituted or unsubstituted 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), n-hexyl (C6), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups. 1~6 alkyl (e.g., -CF3, -CH2F, -CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups 1~6 Alkyl (e.g., -CH2Cl, -CHCl2), as well as C substituted with alkoxy groups 1~6 Examples of alkyl include, but are not limited to, alkyl (e.g., -CH2OCH3 and -CH2OCH2CH3). In certain embodiments, R 1 is the substituted C 1~6 alkyl, e.g., R 1 is haloalkyl, alkoxyalkyl, or aminoalkyl. In embodiments, R 1 is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.

[0111] In certain embodiments, R 1 is unsubstituted C 1~3 alkyl, e.g., R 1 is -CH3, -CH2CH3, or -CH2CH2CH3.

[0112] In certain embodiments, R 1 is a C substituted with one or more fluorine atoms1~6 alkyl. For example, R 1 is —CHF, —CHF, or —CF. In certain embodiments, R 1 is a C substituted with one or two fluorine atoms 1~6 alkyl. For example, R 1 is -CH2F or -CHF2.

[0113] In certain embodiments, R 1 -OR A1 C substituted with a group 1~6 alkyl, where R A1 is hydrogen, or substituted or unsubstituted alkyl. In certain embodiments, R 1 is -CH2OR A1 For example, where R A1 is hydrogen, -CH3, -CH2CH3, or -CH2CH2CH3, for example, R of formula -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH2CH2CH3 1 Provides the base.

[0114] In certain embodiments, R 1 is a substituted or unsubstituted C 2~6 alkenyl, for example, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 3~4 Alkenyl, substituted or unsubstituted C 4~5 Alkenyl, or substituted or unsubstituted C 5~6 alkenyl. In certain embodiments, R 1 is ethenyl (C2), propenyl (C3), or butenyl (C4), and is unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 1is ethenyl, propenyl, or butenyl, and is unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R 1 is ethenyl.

[0115] In certain embodiments, R 1 is a substituted or unsubstituted C 2~6 Alkynyl, for example, substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4 Alkynyl, substituted or unsubstituted C 4~5 Alkynyl, or substituted or unsubstituted C 5~6 In certain embodiments, R 1 is ethynyl, propynyl, or butynyl, and is unsubstituted or substituted with alkyl, halo, haloalkyl (e.g., CF), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R 1 is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. 1 is ethynyl (C2), propynyl (C3), or butynyl (C4), and is unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl. In certain embodiments, R 1 is ethynyl (C2), propynyl (C3), or butynyl (C4) and is substituted with phenyl. In certain embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amido. In certain embodiments, R 1is ethynyl (C2), propynyl (C3), or butynyl (C4), and is substituted or unsubstituted pyrrolyl, imidazolyl , pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

[0116] In certain embodiments, R 1 is ethynyl, propynyl, or butynyl, and is unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 1 is ethynyl or propynyl and is substituted with substituted or unsubstituted aryl. In certain embodiments, R 1 is ethynyl or propynyl and is substituted with phenyl, which is unsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. 1 is ethynyl or propynyl and is substituted with a substituted or unsubstituted carbocyclyl. 3a is ethynyl or propynyl, and is substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 is ethynyl or propynyl and is substituted with a substituted or unsubstituted heteroaryl. 1 is ethynyl or propynyl and is substituted with substituted or unsubstituted pyridinyl or pyrimidinyl. 1 is ethynyl or propynyl, and is substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. 1is ethynyl or propynyl and is substituted with a substituted or unsubstituted heterocyclyl. 1 is ethynyl or propynyl, and is substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In certain embodiments, R 1 is propynyl or butynyl and is substituted with hydroxyl or alkoxy. In certain embodiments, R 1 is propynyl or butynyl and is substituted with methoxy or ethoxy. 1 is ethynyl or propynyl and is substituted with chloro. In certain embodiments, R 1 is ethynyl or propynyl and is substituted with trifluoromethyl.

[0117] In certain embodiments, R 1 is a substituted or unsubstituted C 3~6 carbocyclyl, for example, substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 Carbocyclyl, or substituted or unsubstituted C 5~6 In certain embodiments, R 1 is a substituted or unsubstituted cyclopropyl, or a substituted or unsubstituted cyclobutyl.

[0118] base ----- , R 2 , R 3a , R 3b , R 4a , and R 4b As generally defined herein, R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 Carbocyclyl, or -OR A2 where RA2 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 It is a carbocyclyl.

[0119] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halogen, for example, fluoro, chloro, bromo, or iodo. In certain embodiments, R 2 is fluoro or chloro. In certain embodiments, R 2 is a substituted or unsubstituted C 1~6 alkyl, for example, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl , substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 For example, in some embodiments, R 2 is a halo (e.g., bromo, chloro, fluoro (i.e., a group R of the formula -CHF, -CHF, -CF) 2 Gives)) OR -OR A2 C substituted as needed 1~6 In certain embodiments, R A2 is -CH3, -CH2CH3, or -CH2CH2CH3, i.e., a group R of formula -OH, -OCH3, -OCH2CH3, or -OCH2CH2CH3 2 In certain embodiments, R 2 is a substituted or unsubstituted C 2~6 alkenyl, and in certain embodiments, R 2 is a substituted or unsubstituted C 2~6 Alkynyl, for example, substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4Alkynyl, substituted or unsubstituted C 4~5 Alkynyl, or substituted or unsubstituted C 5~6 In certain embodiments, R 2 is a substituted or unsubstituted C 3~6 carbocyclyl, for example, substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 Carbocyclyl, or substituted or unsubstituted C 5~6 In certain embodiments, R 2 is substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl. In certain embodiments, R 2 is -CH3, -CH2CH3, -CH2CH2CH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 HA-OR A2 In certain embodiments, R A2 is hydrogen. In certain embodiments, R A2 is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 In certain embodiments, R A2 is hydrogen, -CH3, -CH2CH3, or -CH2CH2CH3, i.e., a group R of formula -OH, -OCH3, -OCH2CH3, or -OCH2CH2CH3 2 In certain embodiments, R 2 is a non-hydrogen substituent in the alpha configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration.

[0120] As generally defined herein, R 3a is hydrogen or -OR A3where R A3 is hydrogen or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b together form an oxo (=O) group.

[0121] In certain embodiments, R 3a and R 3b Both are hydrogen.

[0122] In certain embodiments, R 3a and R 3b together form an oxo (=O) group.

[0123] In certain embodiments, R 3a HA-OR A3 and R 3b is hydrogen. R 3a -OR A3 In certain embodiments, R 3a is in the α or β configuration. 3a -OR A3 In certain embodiments, R 3a is in the α configuration. R 3a -OR A3 In certain embodiments, R 3a In certain embodiments, R A3 is hydrogen. In certain embodiments, R A3 is a substituted or unsubstituted C 1~6 Alkyl, e.g., substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6In certain embodiments, R A3 is hydrogen, -CH3, -CH2CH3, or -CH2CH2CH3, i.e., a group R of formula -OH, -OCH3, -OCH2CH3, or -OCH2CH2CH3 3a to provide.

[0124] As generally defined herein, R 4a and R 4b Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, or halogen, provided that the C5 and C6 ----- is a single bond, the hydrogen at C5 and R 4a and each independently may be in the α-configuration or is provided in the β configuration, and R 4b does not exist.

[0125] In certain embodiments, ----- is a single bond, and R 4a and R 4b At least one of In certain embodiments, at least one of the aryl groups is hydrogen. ----- is a single bond, and R 4a and R 4b At least one of the 1~6 Alkyl, e.g., substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 In certain embodiments, ----- is a single bond Yes, R 4a and R 4b At least one of is a C alkyl, for example, —CH or —CF. In certain embodiments, ----- is a single bond, and R 4a and R 4bAt least one of is halogen (eg, fluoro).

[0126] In certain embodiments, ----- is a single bond, and R 4a and R 4b Both are water In certain embodiments, ----- is a single bond, and R 4a and R 4b with Both are independently substituted or unsubstituted C 1~6 Alkyl, e.g., substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 In certain embodiments, ----- is a single bond, and R 4 a and R 4b and are both independently C alkyl, e.g., —CH or —CF. In certain embodiments, ----- is a single bond, and R 4a and R 4b Both The other is halogen (e.g., fluoro).

[0127] ----- In certain embodiments, R 4a is a non-hydrogen substituent in the α configuration do. ----- In certain embodiments, R 4a is a non-hydrogen substituent in the β configuration be.

[0128] In certain embodiments, ----- is a double bond, and R 4a is hydrogen. In the embodiment, ----- is a double bond, and R4a is substituted or unsubstituted C 1~6 alkyl, for example, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 In certain embodiments, ----- is a double bond, and R 4a is a C1 alkyl, e.g. For example, -CH3 or -CF3. In certain embodiments, ----- is a double bond , and R 4a is halogen (e.g., fluoro).

[0129] base R 5 , R 6 , and R 7 As generally defined herein, R 5 , R 6 , and R 7 Each example is independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA )2, -SR GA , -S(O)R GA (For example, -S(=O)R GA ), -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2RGA , -S(=O)2N(R GA )2, -N(R GA )S(=O)2R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 It is a carbocyclyl or a substituted or unsubstituted 3- to 6-membered heterocyclyl.

[0130] Additionally, as generally defined herein, R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group if attached to oxygen, a nitrogen protecting group if attached to nitrogen, or two R GA The groups, taken together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring. In certain embodiments, R GA Each instance of is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl (e.g., substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R GA Each example is hydrogen, -CH3, -CH2CH3, or substituted or unsubstituted phenyl.

[0131] In certain embodiments, R 5, R 6 , and R 7 At least one of R is hydrogen. 5 , R 6 , and R 7 At least two of R 5 , R 6 , and R 7 are all hydrogen to give an unsubstituted pyrazolyl.

[0132] In certain embodiments, R 5 , R 6 , R 7 At least one of R is a non-hydrogen substituent. 5 , R 6 , and R 7 "Non-hydrogen substituent" means R 5 , R 6 , and R 7 is not hydrogen, but halogen, -NO2, -CN, -CF3, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -SR GA , -S(O)R GA (For example, -S(=O)R GA ), -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA ;substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C2~6 Alkynyl, substituted or unsubstituted C 3~6 It means any one of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl.

[0133] In certain embodiments, R 5 , R 6 , R 7 At least one of R is halogen, e.g., fluoro, bromo, iodo, or chloro. 5 , R 6 , and R 7 In certain embodiments, one of R 5 is halogen, e.g., fluoro, bromo, iodo, or chloro. In certain embodiments, R 6 is halogen, e.g., fluoro, bromo, iodo, or chloro. In certain embodiments, R 7 is halogen, for example, fluoro, bromo, iodo, or chloro.

[0134] In certain embodiments, R 5 , R 6 , R 7 At least one of R is —NO. 5 , R 6 , and R 7 In certain embodiments, one of R 5 is —NO. In certain embodiments, R 6 is —NO. In certain embodiments, R 7 is -NO2.

[0135] In certain embodiments, R 5 , R 6 , and R 7 At least one of R is -CN. 5 , R 6 , and R 7 In certain embodiments, one of R5 is —CN. In certain embodiments, R 6 Ha-CN In certain embodiments, R 7 is -CN.

[0136] In certain embodiments, R 5 , R 6 , R 7 At least one of the is -OR GA For example, where R GA is hydrogen or substituted or unsubstituted C 1~6 alkyl (e.g., —CH or —CF). In certain embodiments, R 5 , R 6 , and R 7 One of them is -OR GA For example, —OH, —OCH, or —OCF. In certain embodiments, R 5 HA-OR GA For example, —OH, —OCH, or —OCF. In certain embodiments, R 6 HA-OR GA In certain embodiments, R 7 HA-OR GA and is, for example, —OH, —OCH3, or —OCF3.

[0137] In certain embodiments, R 5 , R 6 , R 7 At least one of the -N(R GA )2, where R GA is hydrogen or substituted or unsubstituted C 1~6 alkyl (e.g., —CH or —CF). In certain embodiments, R 5 , R 6 , and R 7 One of them is -N(R GA )2, for example, -NH2, -NHCH3, or -N(CH3)2. In certain embodiments, R 5 -N(R GA)2, for example, -NH2, -NHCH3, or -N(CH3)2. In certain embodiments, R 6 -N(R GA )2, for example, -NH2, -NHCH3, or -N(CH3)2. In certain embodiments, R 7 -N(R GA )2, for example, -NH2, -NHCH3, or -N(CH3)2.

[0138] In certain embodiments, R 5 , R 6 , and R 7 At least one of the groups is -C(=O)R GA , -C(=O)OR GA , or -C(=O)N(R GA )2, for example, where R GA is hydrogen or substituted or unsubstituted C 1~6 alkyl (e.g., —CH or —CF). In certain embodiments, R 5 , R 6 , and R 7 One of them is -C(=O)R GA For example, —CHO, —C(═O)CH, or —C(═O)CHCH. In certain embodiments, R 5 is -C(=O)R GA For example, —CHO, —C(═O)CH, or —C(═O)CHCH. In certain embodiments, R 6 is -C(=O)R GA For example, —CHO, —C(═O)CH, or —C(═O)CHCH. In certain embodiments, R 7 is -C(=O)R GA For example, —CHO, —C(═O)CH, or —C(═O)CHCH. In certain embodiments, R 5 , R 6 , and R 7 One of them is -C(=O)OR GAFor example, —C(═O)OH, —C(═O)OCH, or —C(═O)OCHCH. In certain embodiments, R 5 is -C(=O)OR GA For example, —C(═O)OH, —C(═O)OCH, or —C(═O)OCHCH. In certain embodiments, R 6 is -C(=O)OR GA For example, —C(═O)OH, —C(═O)OCH, or —C(═O)OCHCH. In certain embodiments, R 7 is -C(=O)OR GA For example, —C(═O)OH, —C(═O)OCH, or —C(═O)OCHCH. In certain embodiments, R 5 , R 6 , and R 7 One of them is -C(=O)N(R GA )2, for example, —C(═O)NH2, —C(═O)NHCH3, or —C(═O)N(CH3)2. In certain embodiments, R 5 is -C(=O)N(R GA )2, for example, —C(═O)NH2, —C(═O)NHCH3, or —C(═O)N(CH3)2. In certain embodiments, R 6 is -C(=O)N(R GA )2, for example, —C(═O)NH2, —C(═O)NHCH3, or —C(═O)N(CH3)2. In certain embodiments, R 7 is -C(=O)N(R GA )2, for example, —C(═O)NH2, —C(═O)NHCH3, or —C(═O)N(CH3)2.

[0139] In certain embodiments, R 5 , R 6 , R 7 At least one of the -OC(=O )R GA , -OC(=O)OR GA , or -OC(=O)N(R GA )2, for example, where R GAis hydrogen or substituted or unsubstituted C 1~6 alkyl (e.g., —CH or —CF). In certain embodiments, R 5 , R 6 , and R 7 One of them is -OC(=O)R GA For example, —OC(═O)CH. In certain embodiments, R 5 is -OC(=O)R GA For example, —OC(═O)CH. In certain embodiments, R 6 is -OC(=O)R GA For example, —OC(═O)CH. In certain embodiments, R 7 is -OC(=O)R GA For example, —OC(═O)CH. In certain embodiments, R 5 , R 6 , and R 7 One of them is -OC(=O)OR GA For example, —OC(═O)OCH. In certain embodiments, R 5 -OC(=O)OR GA For example, —OC(═O)OCH. In certain embodiments, R 6 -OC(=O)OR GA For example, —OC(═O)OCH. In certain embodiments, R 7 -OC(=O)OR GA For example, —OC(═O)OCH. In certain embodiments, R 5 , R 6 , and R 7 One of them is -OC(=O)N(R GA )2, for example, -OC(=O)NHCH3 or -OC(=O)N(CH3)2. In certain embodiments, R 5 is -OC(=O)N(R GA )2, for example, -OC(=O)NHCH3 or -OC(=O)N(CH3)2. In certain embodiments, R 6 is -OC(=O)N(R GA)2, for example, -OC(=O)NHCH3 or -OC(=O)N(CH3)2. In certain embodiments, R 7 is -OC(=O)N(R GA )2, for example, -OC(=O)NHCH3 or -OC(=O)N(CH3)2.

[0140] In certain embodiments, R 5 , R 6 , R 7 At least one of the -N(R GA )C(=O)R GA , -N(R GA )C(=O)OR GA , or -N(R GA )C(=O)N(R GA )2, for example, where R GA is hydrogen or substituted or unsubstituted C 1~6 alkyl (e.g., —CH or —CF). In certain embodiments, R 5 , R 6 , and R 7 One of them is -N(R GA )C(=O)R GA For example, —NHC(═O)CH. In certain embodiments, R 5 -N(R GA )C(=O)R GA For example, —NHC(═O)CH. In certain embodiments, R 6 -N(R GA )C(=O)R GA For example, —NHC(═O)CH. In certain embodiments, R 7 -N(R GA )C(=O)R GA For example, —NHC(═O)CH. In certain embodiments, R 5 , R 6 , and R 7 One of them is -N(R GA )C(=O)OR GA For example, —NHC(═O)OCH. In certain embodiments, R 5 -N(RGA )C(=O)OR GA For example, —NHC(═O)OCH. In certain embodiments, R 6 -N(R GA )C(=O)OR GA For example, —NHC(═O)OCH. In certain embodiments, R 7 -N(R GA )C(=O)OR GA For example, —NHC(═O)OCH. In certain embodiments, R 5 , R 6 , and R 7 One of them is -N(R GA )C(=O)N(R GA )2, for example, -NHC(=O)NH2 or -NHC(=O)N(CH3)2. In certain embodiments, R 5 -N(R GA )C(=O)N(R GA )2, for example, -NHC(=O)NH2 or -NHC(=O)N(CH3)2. In certain embodiments, R 6 -N(R GA )C(=O)N(R GA )2, for example, -NHC(=O)NH2 or -NHC(=O)N(CH3)2. In certain embodiments, R 7 -N(R GA )C(=O)N(R GA )2, for example, -NHC(=O)NH2 or -NHC(=O)N(CH3)2.

[0141] In certain embodiments, R 5 , R 6 , R 7 At least one of the is -SR GA , -S(O)R GA (For example, -S(=O)R GA ), -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N( RGA )S(=O)2R GA For example, where R GA is hydrogen, substituted or unsubstituted C 1~6 alkyl (e.g., —CH or —CF), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 5 , R 6 , and R 7 One of them is -SR GA (e.g., -SCH), or -S-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 , R 6 , and R 7 One of them is -S(O)R GA , e.g., -S(=O)R GA , for example, —S(═O)CH, —S(═O)CF, or —S(═O)-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 , R 6 , and R 7 One of them is -S(=O)2R GA , for example, —S(═O)2CH3, —S(═O)2CF3, or —S(═O)2-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 -SR GA , e.g., -SCH3, -SCF3; -S(O)R GA , e.g., -S(=O)R GA , for example, -S(=O)CH3, -S(=O)CF3; -S(=O)2R GA , for example, —S(═O)2CH3, —S(═O)2CF3, or —S(═O)2-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 -SR GA , e.g., -SCH3, -SCF3; -S(O)R GA , e.g., -S(=O)R GA, for example, -S(=O)CH3, -S(=O)CF3; -S(=O)2R GA , for example, —S(═O)2CH3, —S(═O)2CF3, or —S(═O)2-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 -SR GA , e.g., -SCH3, -SCF3; -S(O)R GA , e.g., -S(=O)R GA , for example, -S(=O)CH3, -S(=O)CF3; -S(=O)2R GA , for example, —S(═O)2CH3, —S(═O)2CF3, or —S(═O)2-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 , R 6 , and R 7 One of them is -S(=O)2OR GA In certain embodiments, R 5 is -S(=O)2OR GA , for example, —S(═O)2OCH3, —S(═O)2OCF3, or —S(═O)2Oaryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -S(=O)2OR GA , for example, —S(═O)2OCH3, —S(═O)2OCF3, or —S(═O)2Oaryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -S(=O)2OR GA , for example, —S(═O)2OCH3, —S(═O)2OCF3, or —S(═O)2Oaryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 , R 6 , and R 7 One of them is -OS(=O)2R GA In certain embodiments, R 5 is -OS(=O)2R GA, for example, —OS(═O)CH, —OS(═O)CF, or —OS(═O)-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -OS(=O)2R GA , for example, —OS(═O)CH, —OS(═O)CF, or —OS(═O)-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -OS(=O)2R GA , for example, —OS(═O)CH, —OS(═O)CF, or —OS(═O)-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 , R 6 , and R 7 One of them is -S(=O)2N(R GA )2. In certain embodiments, R 5 is -S(=O)2N(R GA )2, for example, -S(=O)2NHCH3, -S(=O)2NHCF3, or -S(=O)2-NH-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -S(=O)2N(R GA )2, for example, —S(═O)2NHCH3, —S(═O)2NHCF3, or —S(═O)2-NH-aryl; wherein aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -S(=O)2N(R GA )2, for example, -S(=O)2NHCH3, -S(=O)2NHCF3, or -S(=O)2-NH-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 , R 6 , and R 7 One of them is -N(R GA )S(=O)2R GAIn certain embodiments, R 5 is -N(R GA )S(=O)2R GA , for example, —NHS(═O)CH, —NHS(═O)CF, or —NHS(═O)-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -N(R GA )S(=O)2R GA , for example, —NHS(═O)CH, —NHS(═O)CF, or —NHS(═O)-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -N(R GA )S(=O)2R GA , for example, -NHS(=O)2CH3, -NHS(=O)2CF3, or -NHS(=O)2-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl.

[0142] In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~6 alkyl, for example, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl, or substituted or unsubstituted C 5~6 An exemplary C 1~6Alkyl groups include substituted or unsubstituted 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), tert-amyl (C5), n-hexyl (C6), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups. 1~6 alkyl (e.g., -CF3, -CH2F, -CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups 1~6 Alkyl (e.g., -CH2Cl, -CHCl2), as well as C substituted with alkoxy groups 1~6 Examples of alkyl include, but are not limited to, alkyl (e.g., -CH2OCH3 and -CH2OCH2CH3). In certain embodiments, R 5 , R 6 , R 7 At least one of the C 1~6 alkyl, e.g., R 5 , R 6 , R 7 At least one of R is haloalkyl, alkoxyalkyl, or aminoalkyl. 5 , R 6 , R 7 At least one of is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoroethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.

[0143] In certain embodiments, R 5 , R 6 , and R 7 At least one of the2~6 Alkenyl, for example, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 3~4 Alkenyl, substituted or unsubstituted C 4~5 Alkenyl, or substituted or unsubstituted C 5~6 alkenyl. In certain embodiments, R 5 , R 6 , R 7 At least one of R is ethenyl (C), propenyl (C), or butenyl (C) and is unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. 5 , R 6 , R 7 At least one of is ethenyl, propenyl, or butenyl and is unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. It has been replaced by .

[0144] In certain embodiments, R 5 , R 6 , and R 7 At least one of the 2~6 Alkynyl, for example, substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4 Alkynyl, substituted or unsubstituted C 4~5 Alkynyl, or substituted or unsubstituted C 5~6 In certain embodiments, R 5 , R 6 , R 7 At least one of is ethynyl, propynyl, or butynyl and is unsubstituted or substituted with alkyl, halo, haloalkyl (e.g., CF), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl.

[0145] In certain embodiments, R 5 , R 6 , and R 7 At least one of the 3~6 carbocyclyl, for example, substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 Carbocyclyl, or substituted or unsubstituted C 5~6 In certain embodiments, R 5 , R 6 , and R 7 At least one of is substituted or unsubstituted cyclopropyl, or substituted or unsubstituted cyclobutyl.

[0146] In certain embodiments, R 5 , R 6 , and R 7 At least one of is a substituted or unsubstituted 3- to 6-membered heterocyclyl, for example, a substituted or unsubstituted 3- to 4-membered heterocyclyl, a substituted or unsubstituted 4- to 5-membered heterocyclyl, or a substituted or unsubstituted 5- to 6-membered heterocyclyl.

[0147] In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 Alkyl (e.g., -CH3, -CF3).

[0148] R as a non-hydrogen substituent 5 , R 6 , and R 7 Exemplary combinations of are contemplated herein.

[0149] For example, in certain embodiments, the formula

[0150] [ka]

[0151] The C21-pyrazolyl has the formula:

[0152] [ka]

[0153] where R is a monosubstituted pyrazolyl ring of 5 , R 6 , and R 7 are respectively used in this specification. is a non-hydrogen substituent as defined by

[0154] In certain embodiments, the formula

[0155] [ka]

[0156] The C21-pyrazolyl has the formula:

[0157] [ka]

[0158] where R is a disubstituted pyrazolyl ring 5 , R 6 , and R 7 are each a non-hydrogen substituent as defined herein.

[0159] In certain embodiments, the formula

[0160] [ka]

[0161] The C21-pyrazolyl is a trisubstituted pyrazolyl ring, where R 5 , R 6 , and R 7 Each of is a non-hydrogen substituent as defined herein.

[0162] Various combinations of specific embodiments Various combinations of the specific embodiments are further contemplated herein.

[0163] For example, R 2 is hydrogen or a non-hydrogen alpha substituent, in certain embodiments of formula (I-A1), (I-B1), or (I-C1):

[0164] [ka]

[0165] In certain embodiments, a steroid of the formula R 1 is —CH, —CHCH, —CHF, —CHF, —CF, —CHOCH, or substituted or unsubstituted cyclopropyl. 2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 3a and R 3b and are both hydrogen. 3a and R 3b and combine to form =O (oxo). In certain embodiments where Ring B contains a C5-C6 double bond, R 4a is hydrogen, fluoro, —CH, or —CF. In certain embodiments where Ring B does not contain a C-C double bond, R 4a and R 4b and are both hydrogen. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R4b and are both -CH3 or -CF3. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both fluoro. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is disubstituted pyrazolyl. In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 , R 6 , and R 7 Each instance of is hydrogen.

[0166] R 2 is hydrogen or a non-hydrogen β-substituent, in certain embodiments of formula (I-A2), (I-B2), or (I-C2):

[0167] [ka]

[0168] In certain embodiments, a steroid of the formula R 1 is —CH, —CHCH, —CHF, —CHF, —CF, —CHOCH, or substituted or unsubstituted cyclopropyl. 2is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 3a and R 3b and are both hydrogen. 3a and R 3b and combine to form =O (oxo). In certain embodiments where Ring B contains a C5-C6 double bond, R 4a is hydrogen, fluoro, —CH, or —CF. In certain embodiments where Ring B does not contain a C-C double bond, R 4a and R 4b and are both hydrogen. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both -CH3 or -CF3. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both fluoro. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is disubstituted pyrazolyl. In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 , R 6 , and R 7 Each instance of is hydrogen.

[0169] R 3a is hydrogen or a non-hydrogen α-substituent, and R 3b is hydrogen, in certain embodiments of formula (I-A3), (I-B3), or (I-C3):

[0170] [ka]

[0171] In certain embodiments, a steroid of the formula R 1 is —CH, —CHCH, —CHF, —CHF, —CF, —CHOCH, or substituted or unsubstituted cyclopropyl. 2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 2 is a non-hydrogen substituent in the alpha configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments where Ring B contains a C5-C6 double bond, R 4a is hydrogen, fluoro, —CH, or —CF. In certain embodiments where Ring B does not contain a C-C double bond, R 4a and R 4b and are both hydrogen. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both -CH3 or -CF3. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both fluoro. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4bis hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is disubstituted pyrazolyl. In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 , R 6 , and R 7 Each instance of is hydrogen.

[0172] R 3a is hydrogen or a non-hydrogen β-substituent, and R 3b is hydrogen, in certain embodiments of formula (I-A4), (I-B4), or (I-C4):

[0173] [ka]

[0174] [ka]

[0175] In certain embodiments, a steroid of the formula R 1 is —CH, —CHCH, —CHF, —CHF, —CF, —CHOCH, or substituted or unsubstituted cyclopropyl. 2is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 2 is a non-hydrogen substituent in the alpha configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments where Ring B contains a C5-C6 double bond, R 4a is hydrogen, fluoro, —CH, or —CF. In certain embodiments where Ring B does not contain a C-C double bond, R 4a and R 4b and are both hydrogen. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both -CH3 or -CF3. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both fluoro. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is disubstituted pyrazolyl. In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 , R 6 , and R 7 Each instance of is hydrogen.

[0176] R3a and R 3b and taken together to form an oxo group,

[0177] [ka]

[0178] In certain embodiments, a steroid of the formula R 1 is —CH, —CHCH, —CHF, —CHF, —CF, —CHOCH, or substituted or unsubstituted cyclopropyl. 2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 2 is a non-hydrogen substituent in the alpha configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments where Ring B contains a C5-C6 double bond, R 4a is hydrogen, fluoro, —CH, or —CF. In certain embodiments where Ring B does not contain a C-C double bond, R 4a and R 4b and are both hydrogen. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both -CH3 or -CF3. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a and R 4b and are both fluoro. In certain embodiments where Ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is disubstituted pyrazolyl. In certain embodiments, R 5, R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 , R 6 , and R 7 Each instance of is hydrogen.

[0179] R 4a is a non-hydrogen substituent, in certain embodiments of formula (I-A6) or (I-B6):

[0180] [ka]

[0181] In certain embodiments, a steroid of the formula R 1 is —CH, —CHCH, —CHF, —CHF, —CF, —CHOCH, or substituted or unsubstituted cyclopropyl. 2 is -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -CH3, -CH2CH3, -CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 2 is a non-hydrogen substituent in the alpha configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments, R 3a and R 3b and are both hydrogen. 3a and R 3b and combine to form =O (oxo). 4ais fluoro, -CH3, or -CF3, and R 4b is hydrogen. In certain embodiments, R 4b is fluoro, -CH3, or -CF3, and R 4a is hydrogen. In certain embodiments, R 4a and R 4b and are both -CH or -CF. In certain embodiments, R 4a and R 4b and are both fluoro. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is disubstituted pyrazolyl. In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 , R 6 , and R 7 Each instance of is hydrogen.

[0182] R 4a is a non-hydrogen substituent, in certain embodiments of formula (I-A6) or (I-B6):

[0183] [ka]

[0184] In certain embodiments, a steroid of the formula R 1is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2OCH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is disubstituted pyrazolyl. In certain embodiments, R 5 , R 6 , and R 7 At least one of the 1~2 Alkyl (e.g., -CH3, -CF3), -CO2R GA , -C(=O)R GA , -CN, -NO2, or halogen, where R GA is a substituted or unsubstituted C 1~2 In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 , R 6 , and R 7 Each instance of is hydrogen.

[0185] In certain embodiments, the steroid of formula (I) is:

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] and pharmaceutically acceptable salts thereof.

[0191] In certain embodiments, the steroid of formula (I) is:

[0192] [ka]

[0193] [ka]

[0194] and pharmaceutically acceptable salts thereof.

[0195] In certain embodiments, the steroid of formula (I) is:

[0196] [ka]

[0197] [ka]

[0198] and pharmaceutically acceptable salts thereof.

[0199] In certain embodiments, the steroid of formula (I) is:

[0200] [ka]

[0201] [ka]

[0202] and pharmaceutically acceptable salts thereof.

[0203] In certain embodiments, the steroid of formula (I) is:

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] [ka]

[0208] [ka]

[0209] and pharmaceutically acceptable salts thereof.

[0210] In certain embodiments, the steroid of formula (I) is:

[0211] [ka]

[0212] [ka]

[0213] [ka]

[0214] and pharmaceutically acceptable salts thereof.

[0215] Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0216] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0217] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0218] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered to subjects at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0219] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof that can be continued for an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely, e.g., for 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, e.g., within the therapeutic window, for an extended period of time.

[0220] The pharmaceutical compositions of the present invention can also be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The configuration of the bolus dose can be: Depending on the systemic level of the active ingredient desired throughout the body, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV infusion) allows for a faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition can be administered initially as a bolus dose, followed by continuous infusion.

[0221] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0222] For oral administration, a typical regimen is 1 to 5 times, particularly 2 to 4 times, and typically 3 times per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0223] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injection doses, and generally range from about 0.01% to about 20% by weight, preferably from about 0.1% to about 20% by weight, preferably from about 0.1% to about 10% by weight, and more preferably from about 0.5% to about 15% by weight.

[0224] Injectable dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0225] Liquid forms suitable for oral administration include buffers, suspensions and dispensing preparations. The formulation may comprise a suitable aqueous or non-aqueous vehicle containing additives, colorants, flavoring agents, etc. Solid forms may contain, for example, any of the following ingredients, or compounds of a similar nature: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); fillers (e.g., starch or lactose); disintegrating agents (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring).

[0226] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. Conventionally, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0227] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s).When formulated as an ointment, active ingredient is typically mixed with a paraffin ointment base or a water-miscible ointment base.Alternatively, active ingredient can be formulated as a cream, for example, containing an oil-in-water cream base.Such transdermal formulations are well known in the art and generally contain additional ingredients that enhance the skin penetration or stability of active ingredient or formulation.All such known transdermal formulations and ingredients are included within the scope provided herein.

[0228] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0229] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0230] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0231] 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, consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0232] 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 pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0233] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with the present invention, although the present invention is not limited to the following pharmaceutical compositions.

[0234] Exemplary Formulation 1—Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.

[0235] Exemplary Formulation 2—Capsules: A compound of the invention is administered as a dry powder with a starch diluent. The mixture may be mixed in a 1:1 weight ratio and filled into 250 mg capsules (125 mg of active compound per capsule).

[0236] Exemplary Formulation 3 - Liquid: A compound of the invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended and passed through a No. 10 mesh US sieve, then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and color can be diluted with water and added with stirring. Sufficient water can then be added to bring the total volume to 5 mL.

[0237] Exemplary Formulation 4—Tablets: A compound of the invention can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0238] Exemplary Formulation 5—Injection: A compound of the invention can be dissolved or suspended in sterile buffered saline injectable aqueous medium to a concentration of approximately 5 mg / mL.

[0239] Exemplary Formulation 6—Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

[0240] Exemplary Formulation 7—Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

[0241] Exemplary Formulation 8—Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.

[0242] Exemplary Formulation 9—Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

[0243] Exemplary Formulation 10—Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

[0244] Methods of Use and Treatment As generally described herein, the present invention relates to C21-substituted neurostimulatory steroids designed to act, for example, as GABA modulators. In certain embodiments, such compounds are expected to be useful as therapeutic agents for inducing anesthesia and / or sedation in a subject. In some embodiments, such compounds are useful in treating CNS-related disorders (e.g., sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognition disorders, movement disorders, personality disorders, autism spectrum disorders, pain, etc.). The compounds are expected to be useful as therapeutic agents for the treatment of neuropathic pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, or tinnitus in subjects in need thereof (e.g., subjects with Rett syndrome, Fragile X syndrome, or Angelman syndrome).

[0245] Thus, in one aspect, the present invention provides a method of inducing anesthesia and / or sedation in a subject, comprising administering to the subject an effective amount of a compound of the present invention or a composition thereof. In certain embodiments, the compound is administered intravenously.

[0246] Previous studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) have demonstrated that certain 3α-hydroxylated steroids are orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than those reported by others (see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. and Harrison et al. taught that 3α-hydroxylated 5-reduced steroids are capable of only a significantly lower level of efficacy. In vitro and in vivo experimental data demonstrate the high potency of these steroids, making them therapeutically useful in modulating GRC-mediated brain excitability (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0247] Various synthetic steroids have also been prepared as neurostimulant steroids, see, for example, U.S. Patent No. 5,232,917 (disclosing neurostimulant steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders, and mood disorders (e.g., depression) in a therapeutically beneficial manner that are susceptible to agents effective against GRC). Furthermore, these steroids have previously been shown to interact at a unique site on the GRC that is distinct from other known interaction sites (e.g., barbiturates, benzodiazepines, and GABA), and therapeutically beneficial effects on stress, anxiety, sleep, mood disorders, and seizure disorders have previously been elicited (e.g., Gee, KW, and Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia, and Seizure Disorders," Central Nervous System Disorders, Horvell (ed.), Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG, and Morselli, PL, "Psychopharmacology of GABAergic Drugs," Psychopharmacology: The Third Generation of Progress, HY Meltzer (ed.), Raven Press, NY (1987), pp. 183-195; and Gee et al., European Journal of See Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency, and oral activity (in addition to other forms of administration).

[0248] The compounds of the present invention as described herein are generally designed to modulate GABA function, and thus act as neurostimulatory steroids for the treatment and prevention of CNS-related conditions in subjects. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Thus, the compounds and pharmaceutical compositions provided herein are intended to modulate the CNS in mammals, including humans and non-human mammals. They find use as therapeutics for the prevention and / or treatment of symptoms. Accordingly, as noted above, the present invention includes and extends within its scope the recited methods of treatment, as well as compounds for such methods and the use of such compounds to prepare medicaments useful for such methods.

[0249] Exemplary CNS conditions associated with GABA modulation 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 (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognition disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD))], dementia (e.g., Alzheimer's disease, Lewis body type dementia, dementia, vascular dementia], movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, a host of causes of autism such as synaptophathy (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 disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., opiate, cocaine, and / or alcohol addiction), and tinnitus.

[0250] In yet another aspect, the present invention provides a combination of the compound of the present invention with another pharmacologically active agent.The compound provided herein can be administered as a single active agent or can be administered in combination with other agents.The administration of the combination can proceed by any technique that is clear to those skilled in the art (for example, separate administration, sequential administration, simultaneous administration, and alternating administration).

[0251] In another aspect, there is provided a method of treating or preventing brain excitation in a subject susceptible to or afflicted with a condition associated with brain excitation, comprising administering to the subject an effective amount of a compound of the invention.

[0252] In yet another aspect, there is provided a method of treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof.

[0253] In yet another aspect, a method of reducing or preventing seizure activity in a subject is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.

[0254] In yet another aspect, there is provided a method of alleviating or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof.

[0255] In yet another aspect, there is provided a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, comprising administering an effective amount of a compound of the invention.

[0256] In yet another aspect, a method of alleviating or preventing PMS or PND in a subject The present invention provides a method for treating a rheumatoid arthritis, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

[0257] In yet another aspect, a method of treating or preventing a mood disorder in a subject is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In certain embodiments, the mood disorder is depression.

[0258] In yet another aspect, a method of inducing anesthesia in a subject is provided comprising administering to the subject an effective amount of a compound of the invention.

[0259] In yet another aspect, a method for treating cognitive enhancement or memory impairment is provided 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.

[0260] In yet another aspect, there is provided a method of treating an attention disorder by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0261] 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.

[0262] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects alone, or sometimes using a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the difficulty and pain they would otherwise experience.

[0263] Sedation is the reduction of irritability or agitation, typically through the administration of a pharmacological agent, to facilitate a medical or diagnostic procedure.

[0264] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0265] Minimal sedation is also known as anxiolysis. 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.

[0266] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness in which the patient responds purposefully to verbal commands, either alone or with light tactile stimulation. Interventions to maintain the patient's airway are usually not required. Spontaneous ventilation is typically adequate. Cardiovascular function is usually preserved.

[0267] Deep sedation / analgesia is a drug-induced decrease in consciousness from which the patient cannot be easily awakened but responds purposefully (rather than with a reflex withdrawal from a painful stimulus) after repeated or painful stimulation. Independent ventilatory function may be impaired, so the patient may require assistance to maintain the patient's airway. Spontaneous ventilation may be inadequate. Cardiac Cardiovascular function is usually preserved.

[0268] General anesthesia is a drug-induced loss of consciousness from which the patient cannot be aroused, even to painful stimuli. Assistance to maintain the patient's airway is often required because the ability to maintain independent ventilatory function is often impaired. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced neuromuscular depression. Cardiovascular function may be impaired.

[0269] Sedation in the intensive care unit (ICU) allows patients to become less aware of their environment and less responsive to external stimuli. This can play a role in the treatment of critically ill patients and encompasses a wide range of symptom control that varies from patient to patient and individual to individual throughout the course of their illness. Heavy sedation in intensive care is used to facilitate endotracheal tube tolerance and ventilator synchronization (often with neuromuscular blockers).

[0270] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced in an ICU and maintained for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0271] Procedural sedation and analgesia (also called conscious sedation) is the technique of administering sedatives or analgesics, with or without analgesics, to enable a subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function.

[0272] Anxiety disorders Anxiety disorder is an umbrella term that covers several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0273] Generalized anxiety disorder (GAD) is a common chronic disorder characterized by long-term anxiety that cannot be focused on any one object or situation. People suffering from GAD experience persistent, nonspecific fear and worry and become excessively worried about mundane events. GAD is the most common anxiety disorder affecting older adults.

[0274] In panic disorder, people suffer from brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as sudden onset of fear or discomfort that peaks in less than 10 minutes) can last for 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 attack's potential meaning, persistent fear of future attacks, or significant changes in behavior related to the attack). Thus, patients with phobic disorder experience symptoms even outside of a specific panic episode. Often, normal changes in heart rate are noticed by the panic sufferer, leading them to believe that something is wrong with their heart or that they are experiencing another panic attack. In some cases, a heightened perception of bodily functions (hypervigilance) occurs during a panic attack, in which any perceived physiological change is interpreted as a possible life-threatening illness (i.e., excessive hypochondria).

[0275] Obsessive-compulsive disorder is a type of anxiety disorder characterized by recurrent obsessions (distressing, persistent thoughts). OCD is primarily characterized by obsessions (intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). OCD thought patterns can be linked to superstition, insofar as they involve the person believing in nonexistent causal relationships. Often, the process is completely illogical. For example, a compulsion to walk in a particular pattern can be used to alleviate obsessive thoughts of imminent danger. And in many cases, the compulsion is not entirely inexplicable but is simply a nervously triggered urge to complete a ritual. In a minority of cases, OCD patients may only experience obsessions without overt compulsions, and even fewer experience only compulsions.

[0276] One of the largest categories of anxiety disorders is that of phobias, which encompasses all cases in which fear and anxiety are triggered by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering the object of their fear (which could be anything from an animal to a place to a bodily fluid).

[0277] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations (e.g., war, rape, hostage situations, or even serious misfortune). It can also result from prolonged (chronic) exposure to severe stressors (e.g., soldiers who tolerate individual combat but do not cope well with continuous war). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0278] Neurodegenerative Diseases and Disorders The term "neurodegenerative disease" encompasses diseases and disorders associated with the progressive loss of neuronal structure or function, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic damage; ataxia and seizures (including for the treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head injury; coma; contusion injury (e.g., spinal cord injury and head injury); dementia (including multi-infarct dementia and senile dementia); disorders of consciousness; Down's syndrome; drug-induced induced or drug-induced tremor tremors (e.g., psycholeptic-induced acute akathisia, acute ataxia, tremor tremors, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders, including akinesia and akinesia (rigidity) syndromes (including brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic tremor tremors, and progressive supranuclear palsy);Muscle spasticity and disorders associated with muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as simple tics, complex tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (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) Neuronal damage (including eye damage, ocular retinopathy or macular degeneration); neurotoxic disorders following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizures; Neurodegenerative diseases include, but are not limited to, status epilepticus; stroke; tinnitus; renal tubular sclerosis and viral infection-induced neurodegeneration (such as that caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy).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 neurotoxicity disorder after cardiac arrest.The method for treating or preventing neurodegenerative diseases also includes treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0279] epilepsy Epilepsy is a brain disorder characterized by repeated seizures over a long period of time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with awakening grand mal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0280] 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 very 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 and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite treatment with first-line therapy and second-line therapy is administered. Refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line and second-line therapy and general anesthetics are commonly administered. Super-refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line, second-line, and general anesthetics for 24 hours or more.

[0281] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, minimal non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0282] The compositions described herein can also be administered as prophylaxis to subjects with a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic discharges, prior to the onset of a seizure.

[0283] Seizures A seizure is a physical finding or change in behavior that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is when a person's body shakes rapidly and uncontrollably. During a convulsion, the person's muscles repeatedly contract and relax.

[0284] 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 the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0285] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses in a smaller part of the brain. The part of the brain that generates the seizure is sometimes called the focus.

[0286] There are six types of generalized seizures. The most common, dramatic, and therefore best known is a generalized convulsion (also called a grand mal seizure). In this type of seizure, the patient loses consciousness and usually collapses. This loss of consciousness is followed by 30-60 seconds of generalized rigidity (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent spasms (the "clonic" phase), after which the patient falls into a deep sleep (the "postictal" or after-seizure phase). During a grand mal seizure, impairments and accidents (e.g., tongue biting and urinary incontinence) can occur.

[0287] Absence attacks cause a brief loss of consciousness (only a few seconds) with few or no symptoms. The patient (most often a child) typically stops activity and stares blankly. These attacks begin and end abruptly and can occur several times a day. Patients are usually unaware they are having a attack, except that they may notice they are "losing time."

[0288] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe these jerks as brief electric shocks. When severe, these seizures can result in dropping or involuntary throwing of objects.

[0289] Clonic seizures are recurrent rhythmic spasms that involve both sides of the body simultaneously.

[0290] Tonic seizures are characterized by muscle stiffness.

[0291] Atonic seizures consist of a sudden loss of muscle tone throughout the body, especially in the arms and legs, often resulting in a fall.

[0292] The seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; continuous seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; galactocele; generalized onset seizures; infantile spasms; Jackson seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; petit mal seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. [Example]

[0293] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0294] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, but it is understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0295] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991, and the references cited therein.

[0296] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail for the preparation of representative pyrazoles listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. 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.

[0297] The compounds reported herein (e.g., for intermediates) 1 H-NMR can be a partial representation of the full NMR spectrum of a compound (e.g., a compound described herein). 1 1 H NMR can exclude the region δ (ppm) between about 1 ppm and about 2.5 ppm. 1A copy of the H-NMR spectrum is given in the figure.

[0298] 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.

[0299] General method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile. Gradient: 5% to 95% B in 1.6 or 2 min. Flow rate: 1.8 or 2 mL / min. Column: XBridge C18, 4.6 x 50 mm, 3.5 μm, 45°C.

[0300] Synthesis procedure The compounds of the present invention can be prepared according to methods reported in the art (Upasani et al., J. Med. Chem. 1997, 40:73-84; and Hogenkamp et al., J. Med. Chem. 1999, 40:74-75; and Hogenkamp et al., J. Med. Chem. 1999, 40:75-76; and Hogenkamp et al., J. Med. Chem. 1999, 40:76-77; and Hogenkamp et al., J. Med. Chem. 1999, 40:77-78; and Hogenkamp et al., J. Med. Chem. 1999, 40:78-79; and Hogenkamp et al., J. Med. Chem. 1999, 40:79-80; and Hogenkamp et al., 7, 40:61-72). In some embodiments, the compounds described herein can be prepared using the methods shown in General Schemes 1-4, which involve nucleophilic substitution of 19-norpregnane bromide with a nucleophile. In certain embodiments, the nucleophile reacts with 19-norpregnane bromide in the presence of K2CO3 in THF.

[0301] [ka]

[0302] [ka]

[0303] Example 1. Synthesis of SA and SA Intermediates

[0304] [ka]

[0305] Synthesis of Compound SA-B. Compound SA (50 g, 184 mmol) and palladium black (2.5 g) in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL) were hydrogenated at 10 atm of hydrogen. After stirring at room temperature for 24 hours, the mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain the crude compound. Recrystallization from acetone gave Compound SA-B (42.0 g, yield: 83.4%) as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 2.45-2.41 (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).

[0306] 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) at −78°C under N2. After the 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 added to the mixture at −78°C under N2. The reaction mixture was then stirred at this temperature for 3 hours. TLC (petroleum ether / ethyl acetate=3:1) showed that the reaction was complete. Saturated aqueous NH4Cl was then added dropwise slowly to the mixture at -78°C. After the addition was complete, the mixture was filtered, the filter cake was washed with EtOAc, and the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated, followed by precipitation onto silica gel. Purification by flash chromatography (petroleum ether / ethyl acetate 20:1 to 3:1) gave compound SA-C (40.2 g, yield: 90.4%) as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 2.47-2.41 (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).

[0307] Synthesis of Compound SA-D. To a solution of PPhEtBr (204.52 g, 550.89 mmol) in THF (500 mL) was added a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0 °C. After the addition was complete, the reaction mixture was stirred at 60 °C for 1 h, 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 h. The reaction mixture was cooled to room temperature and quenched with Sat. NH4Cl and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine, dried, and concentrated to give the crude product, which was purified by flash column chromatography (petroleum ether / ethyl acetate 50:1 to 10:1) to give compound SA-D (38.4 g, yield: 92%) as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 5.17-5.06 (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).

[0308] Synthesis of Compound SA-E. To a solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL) was added dropwise a solution of BH3.Me2S (126 mL, 1.26 mol) under ice bath. After the addition was complete, the reaction mixture was stirred at room temperature (14-20 °C) for 3 h. TLC (petroleum ether / ethyl acetate 3:1) showed the reaction was complete. The mixture was cooled to 0 °C, and 3.0 M aqueous NaOH (400 mL) was added, followed by 30% aqueous H2O2 (30%, 300 mL). The mixture was stirred at room temperature (14-20 °C) for 2 h, then filtered and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with saturated aqueous Na2S2O3, brine, dried over Na2SO4, and concentrated in vacuo to give the crude product (43 g, crude) as a colorless oil. The crude product was used in the next step without further purification.

[0309] Synthesis of Compound SA-F. To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL) was added PCC (53.8 g, 268.32 mmol) portionwise at 0 °C. The reaction mixture was then stirred at room temperature (16 °C to 22 °C) for 3 h. TLC (petroleum ether / ethyl acetate 3:1) indicated the reaction was complete, so the reaction mixture was filtered and washed with DCM. The organic phase was washed with saturated aqueous NaSO, brine, dried over NaSO, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate 50:1 to 8:1) to give Compound SA-F (25.0 g, yield: 62.5%, over two steps) as a white powder. 1 H NMR (SA-F):(400 MHz, CDCl3) δ 2.57-2.50 (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).

[0310] Synthesis of Compound SA. To 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 dropwise. The reaction mixture was stirred at 17 °C for 1.5 hours. The resulting solution was quenched with saturated aqueous NaHCO at 0 °C and extracted with EtOAc (150 mL × 2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel eluted with (PE:EA = 15:1 to 6:1) to give Compound SA (9.5 g, yield: 76.14%) as a white solid. LC / MS: rt 5.4 min; m / z 379.0, 381.1, 396.1.

[0311] Example 2. Synthesis of SB and SB intermediates

[0312] [ka]

[0313] [ka]

[0314] Synthesis of compounds SB-B and SB-C. Lithium chips (7.63 g, 1.1 mol) were added to 2.7 L of concentrated ammonia in a three-neck flask at -70 °C. Once dissolved, the blue solution was warmed to -50 °C. A solution of 19-norandrost-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 was added dropwise, and the reaction mixture was stirred for 90 minutes until it turned bright yellow. Ammonium chloride (70 g) was added, and excess ammonia was evaporated. The residue was extracted with 0.5 N HCl (500 mL) and dichloromethane (500 mL × 2). The combined organic layers were washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated to give 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. After stirring at room temperature for 2 hours, 2N NaOH solution (500 mL) was added to the dark brown reaction mixture and stirred for an additional 10 minutes. The resulting solution was extracted with dichloromethane, and the combined organic layers were washed with 2N HCl, 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 give the title compound SB-C (16.8 g, 80%) as a white solid. SB-B 1 H NMR (400 MHz, CDCl3), δ (ppm), 3.65 (t, 1H, 1H), 0.77 (s, 3H). SB-C's 1 H NMR (400 MHz, CDCl3), δ (ppm), 0.88 (s, 3H).

[0315] Synthesis of Compound SB-D. To a solution of Compound SB-C (16.8 g, 61.3 mmol) in methanol (250 mL) was added iodine (1.54 g, 6.1 mmol). After stirring at 60 °C for 12 hours, the solvent was removed under reduced pressure. The crude product was dissolved in dichloromethane (200 mL) and washed with saturated NaHCO (150 mL), brine, dried over NaSO, filtered, and concentrated. The residue was purified by chromatography on basic alumina (petroleum ether / ethyl acetate = 100:1) to give Compound SB-D (14 g, 43.8 mmol, 71%). 1 H NMR (400 MHz, CDCl3), δ (ppm), 3.18 (s, 3H), 3.12 (s, 3H), 0.85 (s, 3H).

[0316] Synthesis of Compound SB-E. To a suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL) was slowly added ethyltriphenylphosphonium bromide (26 g, 70 mmol) at 0 °C. After stirring at 60 °C for 3 h, Compound SB-D (7 g, 21.9 mmol) was added, and the mixture was stirred at 60 °C for an additional 2 h. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2 × 500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give crude Compound SB-E (7.36 g, 100%). This crude product was used in the next step without further purification.

[0317] 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 1 N aqueous HCl. After stirring at room temperature for 12 hours, the reaction mixture was extracted with ethyl acetate (250 mL × 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 give Compound SB-F (4.8 g, 16.7 mmol, 76% for two steps). 1H NMR (400 MHz, CDCl3), δ (ppm), 5.12-5.10 (m, 1H), 0.77 (s, 3H).

[0318] Synthesis of compound SB-G. MeMgBr (28 mmol, 1 M in THF) was dissolved in THF (50 To a solution of 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 at room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (150 mL × 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 give compound SB-G (2.5 g, 8.28 mmol, 49%; Rf = 0.35, petroleum ether / ethyl acetate = 10:1). 1 H NMR (400 MHz, CDCl3), δ (ppm), 5.05-5.03 (m, 1H), 1.21 (s, 3H), 0.90 (s, 3H).

[0319] Synthesis of Compound SB-H. To a solution of Compound SB-G (2 g, 6.62 mmol) in dry THF (50 mL) was added borane-tetrahydrofuran complex (20 mL; 1.0 M solution in 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 (10 mL) followed by 30% aqueous H2O2 (12 mL). After stirring at room temperature for 1 hour, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated to give crude Compound SB-H (2 g, 100%). This crude product was used in the next step without further purification.

[0320] Synthesis of Compound SB-I. To a solution of crude compound SB-H (2 g, 6.62 mmol) in 60 mL of wet dichloromethane (dichloromethane was shaken with a few milliliters of HO and then separated from the aqueous layer), Dess-Martin periodinate (5.5 g, 13 mmol) was added. After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with 10% aqueous NaSO (100 mL), brine (100 mL), dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give compound SB-I (1 g, 3.14 mmol, 47% for two steps) as a white solid. 1 H NMR (400 MHz, 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).

[0321] Synthesis of Compound SB. To a solution of Compound SB-I (600 mg, 1.89 mmol) in MeOH (20 mL), 5 drops of HBr (48%) were added, followed by 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 × 3). The combined organic layer was washed with brine (200 mL), dried over MgSO4, filtered, and concentrated to give crude Compound SB (600 mg).

[0322] Synthesis of Compound SB-J. A solution of Compound SB (600 mg, 1.5 mmol) in 10 mL of acetone was treated with CF3COOH (6.8 mL) and Et3N (9.5 mL). After refluxing for 30 minutes, CF3COONa salt (4.49 g, 33 mmol) was added in portions over 10 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, dried over MgSO4, filtered, and concentrated. The mixture was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 10:1 to 3:1) to give SB-J (300 mg, yield: 50% for two steps). 1 H NMR (400 MHz, CDCl3), δ (ppm), 4.23-4.13 (m, 2H), 2.48-2.44 (m), 0.64 (s, 3H).

[0323] Example 3. Synthesis of SA-V compound

[0324] [ka]

[0325] Synthesis of Compound SA-K. Compound SA-J (10 g, 36.7 mmol) was added to 50 mL of acetyl chloride and 50 mL of acetic anhydride. The reaction mixture was heated at 120° C. for 5 hours and evaporated under reduced pressure to give SA-K as a white solid (10 g, 87% yield). 1 H NMR (400 MHz, CDCl3), δ (ppm), 5.7 8 (s, 1H), 5.55 (s, 1H),2.4(2H,dd),2.13 (s, 3H), 0.90 (s, 3H).

[0326] Synthesis of Compound SA-L. To a solution of reactant SA-K (10 g, 31.8 mmol) in 200 mL of THF and 20 mL of HO was added mCPBA (11 g, 63.6 mmol) at 0 °C and stirred at room temperature for 15 hours. The reaction mixture was extracted with 500 mL of EtOAc, washed with 100 mL of saturated NaSO, 100 mL of saturated NaHCO, and 100 mL of brine, and evaporated under reduced pressure. The mixture was then purified by silica gel flash chromatography (petroleum ether / ethyl acetate = 5:1) to give SA-L-1 (2.2 g, 24% yield) as a white solid (eluted first) and SA-L (1.1 g, 12% yield) as a white solid (eluted second). SA-L-1:1H NMR (400 MHz, CDCl3), δ (ppm), 5.92 (s, 1H), 4.44 (s, 1H), 0.95 (s, 3H). SA-L:1H NMR (400 MHz, CDCl3), δ (ppm), 6.25 (s, 1H), 4.28-4.25 (m, 1H), 0.93 (s, 3H).

[0327] Synthesis of compound SA-M. To a solution of SA-L (2 g, 6.94 mmol) in 50 mL of EtOAc, 200 mg of Pd¥C was added. The reaction mixture was hydrogenated under 1 atm of H for 15 hours. The reaction mixture was evaporated under reduced pressure and then purified by chromatography (petroleum ether / ethyl acetate = 1:2) to give SA-M as a white solid (1.5 g, 75% yield). 1 H NMR (400 MHz, CDCl3), δ (ppm), 3.97 (td, 1H), 0.88 (s, 3H).

[0328] Synthesis of compound SA-N. To a solution of SA-M (1 g, 3.4 mmol) in 100 mL of MeOH, 50 mg of TsOH was added and heated at 60° C. for 2 hours. The reaction mixture was extracted with 500 mL of EtOAc, washed with 100 mL of saturated NaHCO and 100 mL of brine solution, and evaporated under reduced pressure to give SA-N as a white solid (1 g, 91% yield).

[0329] Synthesis of compound SA-O. To a solution of ethyltriphenylphosphonium bromide (10.67 g, 28.84 mmol) in 30 mL of THF was added KOt-Bu (3.23 g, 28.80 mmol). The reaction was heated at 60° C. for 1 hour. SA-N (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 EtOAc, washed with brine solution, and evaporated under reduced pressure. Then, the mixture was purified by chromatography (petroleum ether / ethyl acetate=3:1) to give SA-O as a white solid (2 g, 62% yield). 1 H NMR (400 MHz, 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).

[0330] Synthesis of compound SA-P. To a solution of SA-O (0.5 g, 1.43 mmol) in 10 mL of DCM was added 0.5 mL of DAST at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes, then quenched with 5 mL of sat. NaHCO, extracted with 50 mL of DCM, washed with brine, dried, and concentrated under reduced pressure. The mixture was purified by chromatography (petroleum ether / ethyl acetate=30:1) to give SA-P as a white solid in 175 mg, 35% yield.

[0331] Synthesis of Compound SA-Q. To a solution of SA-P (350 mg, 1 mmol) in 20 mL of THF, 2 mL of 2 M HCl was added and stirred at room temperature for 1 hour. The mixture was quenched with 1 mL of H2O and extracted with 100 mL of EtOAc, washed with brine, and evaporated in vacuo, then purified by chromatography (petroleum ether / ethyl acetate=10:1) to give SA-Q as a white solid (210 mg, yield 60%). 1H NMR (400 MHz, 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).

[0332] Synthesis of Compound SA-R. To a stirred solution of trimethylsulfonium iodide (3.2 g, 16 mmol) in 10 mL of DMSO was added NaH (60%; 400 mg, 16 mmol). After stirring at room temperature for 1 hour, a suspension of SA-Q (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 (100 mL) and extracted with 300 mL of EtOAc, washed with 100 mL of brine solution, and evaporated under reduced pressure. Purification by chromatography (petroleum ether / ethyl acetate = 10:1) afforded SA-R and its isomer as a white solid (290 mg, 58% yield).

[0333] Synthesis of Compound SA-S. To a solution of SA-R and its isomer (300 mg, 0.94 mmol) in 10 mL of THF, LiAH (100 mg, 2.7 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was quenched with 5 mL of HO and extracted with 100 mL of EtOAc, washed with brine, and evaporated under reduced pressure. Then, the mixture was purified by chromatography (petroleum ether / ethyl acetate = 3:1) to give SA-S as a white solid (140 mg, 48% yield). 1 H NMR (400 MHz, CDCl3), δ (ppm) 5.15-5.12 (m, 1H), 4.72-4.60 (m, 1H), 1.70 (apparent d within m), 1.27 (apparent s within m), 0.92 (s, 3H).

[0334] Synthesis of Compound SA-T. To a solution of SA-S (100 mg, 0.3 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL; 1.0 M solution in 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 mL). After stirring at room temperature for 1 hour, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated to give SA-T as a white solid (100 mg, 91%). The crude product was used in the next step without further purification.

[0335] Synthesis of Compound SA-U. To a solution of SA-T (100 mg, 0.29 mmol) in 20 mL of DCM, PCC (190 mg, 0.87 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was quenched with 5 mL of HO and extracted with 100 mL of EtOAc, washed with brine, and evaporated under reduced pressure. Then, the mixture was purified by chromatography (petroleum ether / ethyl acetate = 3:1) to give SA-U as a white solid (53 mg, 53% yield). 1 H NMR (400 MHz, CDCl3), δ (ppm) 4.71-4.57 (m, 1H), 2.54(1H, t), 1.28 (apparent s within m), 0.58 (s, 3H).

[0336] Synthesis of Compound SA-V. To a solution of SA-U (40 mg, 0.11 mmol) in MeOH (5 mL), two drops of HBr (48%) were added, followed by bromine (150 mg, 0.33 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL). Washing, drying over MgSO, filtering and concentrating gave crude compound SA-V as a white solid (40 mg, 80% yield). This crude product was used in the next step without further purification.

[0337] Example 4. Synthesis of SB-W compound

[0338] [ka]

[0339] To a stirred solution of trimethylsulfonium iodide (8.1 g, 36.9 mmol) in 100 mL of DMSO was added NaH (60%; 1.26 g, 31.5 mmol). After stirring at room temperature for 1 hour, a suspension of compound SB-F (2.2 g, 7.2 mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred for an additional 2.5 hours, then poured into ice-cold water and extracted with ether (100 mL × 3). The combined ether layers were then washed with brine (100 mL × 3), dried over MgSO4, filtered, and concentrated to give crude product SB-S (2.2 g). This crude product was used in the next step without further purification.

[0340] Synthesis of Compound SB-T. Compound SB-S (2.2 g, 7.3 mmol) was dissolved in dry ethanol (250 mL), and Na (672 mg, 29.2 mmol) was added. The solution was stirred at reflux for 6 hours. The ethanol was removed by evaporation, and the residue was dissolved in dichloromethane and washed with HO (3 × 50 mL) and brine (100 mL), dried over MgSO, 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 give SB-T (1.8 g, 82%) as a white solid. 1 H NMR (500 MHz, CDCl3), δ (ppm), 5.03-5.01 (m, 1H), 3.43 (q, 2H), 3.13 (s, 2H), 0.80 (s, 3H).

[0341] Synthesis of Compound SB-U. To a solution of Compound SB-T (1.8 g, 5.2 mmol) in dry THF (50 mL) was added borane-tetrahydrofuran complex (20 mL of a 1.0 M solution in 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 (10 mL) followed by 30% aqueous H2O2 (12 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated to give Crude compound SB-U (1.8 g, 100%) was obtained, which was used in the next step without further purification.

[0342] Synthesis of Compound SB-V. To a solution of crude compound SB-U (1.8 g, 5.2 mmol) in 60 mL of HO-saturated dichloromethane (dichloromethane was shaken with a few milliliters of HO and then separated from the aqueous layer), Dess-Martin periodinate (4.4 g, 10.4 mmol) was added. After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with 10% aqueous NaSO (100 mL), brine (100 mL), dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give SB-V (1 g, 2.8 mmol, 56% for two steps) as a white solid. 1 H NMR (400 MHz, 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] + .

[0343] Synthesis of Compound SB-W. To a solution of compound SB-V (600 mg, 1.65 mmol) in MeOH (20 mL), 5 drops of HBr (48%) were added, followed by 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 × 3). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated to give crude compound SB-W (600 mg, 100%). The crude product was used in the next step without further purification. LCMS: Rt = 7.25 min. m / z = 463.1 [M + Na] + .

[0344] Example 5. Synthesis of SA-AA Compound

[0345] [ka]

[0346] Synthesis of Compound SA-X. To a solution of EtMgBr (5 mmol, 1 M in THF) in THF (20 mL) was added a solution of Compound SA-W (858 mg, 3 mmol) in dry THF (5 mL) via syringe pump over 30 minutes at 0° C. After stirring at 0° C. for 5 hours, the reaction mixture was warmed and stirred at room temperature overnight. The reaction mixture was added to ice-cold water. The mixture was quenched with HCl and extracted with EtOAc (15 mL × 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 give compound SA-X (900 mg).

[0347] Synthesis of Compound SA-Y. To a solution of Compound SA-X (200 mg, 0.66 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (2 mL of a 1.0 M solution in 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 EtOAc (3 x 10 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to give Compound SA-Y (260 mg, crude). The crude product was used in the next step without further purification.

[0348] Synthesis of Compound SA-Z. To a solution of Compound SA-Y (260 mg, crude) in 10 mL of dichloromethane was added PCC (449 mg). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with 10% aqueous NaCl (10 mL), 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 SA-Z (15 mg) as a white solid. 1 H NMR (500 MHz, CDCl3), δ (ppm), 2.49 (1H, t), 0.84(,t 3H), 0.59 (s, 3H).

[0349] Synthesis of Compound SA-AA. To a solution of Compound SA-Z (30 mg, 0.09 mmol) in MeOH (5 mL), two drops of HBr (48%) were added, 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 × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give Compound SA-AA (36 mg crude). This crude product was used in the next step without further purification.

[0350] Example 6. Synthesis of SA-JJ compound

[0351] [ka]

[0352] Synthesis of compounds SA-DD and SA-EE. Compound mixtures SA-BB and SA-CC. (5.0 g, 16.7 mmol) was dissolved in dry methanol (250 mL) and metallic Na (1.2 g, 50.0 mmol) was added, and the solution was refluxed for 16 h. Then, methanol was removed by evaporation, and the residue was dissolved in dichloromethane and washed with HO (3 × 50 mL) and brine (100 mL), dried over MgSO, 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 give the product mixture SA-DD and SA-EE (4.6 g, 83%) as a white solid.

[0353] Synthesis of Compounds SA-FF and SA-GG. To a solution of the reactant mixture SA-DD and SA-EE (4.6 g, 13.9 mmol) in anhydrous THF (30 mL) was added BH3.THF (1.0 M, 27.7 mL, 27.7 mmol). The solution was stirred at 25 °C overnight, and then the reaction was quenched by the addition of water (5 mL). 2 M NaOH solution (30 mL) was added, followed by 30% HO (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 in vacuo. The crude product mixture was used directly in the next step without further purification.

[0354] Synthesis of Compounds SA-HH and SA-II. To a solution of the crude reactant mixture SA-FF and SA-GG (4.9 g, 13.9 mmol, theoretical amount) in dichloromethane (40 mL) was added pyridinium chloroformate (PCC) (6.0 g, 27.8 mmol) in portions. The solution was stirred overnight at 25 °C, and then the mixture was 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 give product SA-HH (2.1 g, 6.03 mmol, yield = 43% (two steps)) as a white solid and product SA-II (2.2 g, 6.32 mmol, yield = 45% (two steps)) as a white solid. Compound SA-HH: 1 HNMR (500 MHz, 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 (500 MHz, 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).

[0355] Synthesis of Compound SA-JJ. To a solution of reactant SA-II (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol), followed by bromine (241 mg, 0.077 mL, 1.51 mmol). The solution was heated at 25° C. for 1.5 hours, and 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 extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SA-JJ was used directly in the next step without further purification.

[0356] Example 8. Synthesis of SB-R Compound

[0357] [ka]

[0358] Synthesis of Compound SB-K. To a solution of Compound SB-E (5 g, 15 mmol) in dry THF (20 mL) was added borane-tetrahydrofuran complex (30 mL of a 1.0 M solution in THF), and the reaction mixture was stirred at ambient temperature for 1 hour. 10% aqueous NaOH (56 mL) was then added slowly. The mixture was cooled in ice, and 30% aqueous H2O2 (67 mL) was added slowly. The mixture was stirred at ambient temperature for 1 hour and then extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were washed with 10% aqueous Na2S2O3 (100 mL), brine (100 mL), and dried over MgSO4. Filtration and removal of the solvent afforded 3.2 g of crude product for the next step reaction.

[0359] Synthesis of compound SB-L. To a solution of compound SB-K (3.2 g, 9 mmol) in THF (40 mL) was added 2 M HCl (3 mL). The 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 (petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain 2.2 g of the product as a white solid. Yield: 81.40%.

[0360] Synthesis of Compound SB-M. To a stirred solution of trimethylsulfonium iodide (6.43 g, 31.5 mmol) in 100 mL of DMSO, 60 wt% NaH (1.26 g, 31.5 mmol) was added. After stirring at room temperature (15 °C) for 1 hour, a solution of Compound SB-L (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 × 3). The combined ether layers were then washed with brine (100 mL × 3), dried (MgSO), filtered, and concentrated to give 1.6 g of crude product for the next step reaction.

[0361] Synthesis of Compound SB-N. Compound SB-M (1.6 g, 5 mmol) was dissolved in 60 mL of H2O-saturated CH2Cl2. (Using a separatory funnel, the CH2Cl2 was shaken with a few 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 The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 20:1 to 10:1) to give the title compound 1.2 g, 3.79 mmol, 75% as a white solid. 1 H NMR (400 MHz, CDCl3) δ (ppm): 2.63 (s, 1H), 2.59 (s, 1H), 2.12 (s, 3H), 0.63 (s, 3H).

[0362] Synthesis of SB-P and SB-Q. Compound SB-N (1.2 g, 3.8 mmol) was dissolved in dry methanol (250 mL), and Na (262 mg, 11.4 mmol) was added. The solution was refluxed for 16 h. Methanol was removed by evaporation, and the residue was dissolved in dichloromethane and washed with HO (3 × 50 mL) and brine (100 mL), dried over MgSO, filtered, and concentrated. The crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to give SB-P (300 mg, 25%) and SB-Q (300 mg, 25%) as white solids. SB-P: 1H NMR (400 MHz, CDCl) δ (ppm):3.39 (s, 3H), 3.19 (s, 2H), 2.54 (t, 1H), 0.61 (s, 3H). SB-Q:1H NMR (400 MHz, CDCl3) δ (ppm):3.39 (s, 5H),3.37 (s, 2H), 2.52 (t, 1H), 0.62 (s, 3H).

[0363] Synthesis of Compound SB-R. To a solution of reactant SB-P (190 mg, 0.545 mmol) in methanol (15 mL) was added 48% hydrobromic acid (275 mg, 1.635 mmol), followed by bromine (435 mg, 0.139 mL, 2.725 mmol). The solution was heated at 25° C. for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solution was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0364] Example 9. Synthesis of SB-FF Compound

[0365] [ka]

[0366] Synthesis of Compound SB-KK. To a solution of SA-K (68 g, 216.27 mmol) in 600 mL of CH3CN, select flour (90.22 g, 324.4 mmol) was added portionwise at -4 °C. The resulting reaction mixture was stirred at -4 °C for 3 hours. After the TLC showed 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 SB-KK (26.3 g, 41.8% yield) as a white solid. 1 H NMR (SB-KK) (400 MHz, 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).

[0367] Synthesis of Compound SB-X. To a solution of SB-KK (27 g, 92.98 mmol) in EtOAc (350 mL) was added at 20° C., and then Pd / C (2.7 g, 5%) was added to the mixture. The solution was stirred under hydrogen at 20° C. and 1 atm for 10 hours. After the LCMS showed 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 40:1 to 35:1 to 30:1 to 25:1 to 20:1 to 15:1 to 10:1 to 6:1) to obtain SB-X (15.6 g, 56.38%) as a white solid. 1 H NMR (SB-X) (400 MHz, 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).

[0368] Synthesis of compound SB-Y. SB-X (47 g, 160.75 mmol) was dissolved in MeOH (60 To a solution of SB-Y in 100 mL of HCl at 23° C., 2.35 g of TsOH was added. The solution was stirred at 60° C. for 1.5 hours. After the TLC showed that the reaction was complete, the mixture was filtered and concentrated to give SB-Y (35 g, 64.33%) as a white solid. 1 H NMR (SB-Y) (400 MHz, 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).

[0369] Synthesis of compound SB-Z. To a solution of ethyltriphenylphosphonium bromide (115.17 g, 310.23 mmol) in 150 mL of THF was added KOt-Bu (34.81 g, 310.23 mmol). The reaction mixture was heated at 60° C. for 1 hour, and SB-Y (35 g, 103.41 mmol) was added to the mixture, which was stirred at 60° C. for an additional 15 hours. The reaction mixture was cooled and extracted with 1500 mL of EtOAc, washed with brine, and concentrated to give SB-Z as a white solid (120 g, crude). 1 H NMR (SB-Z) (400 MHz, 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).

[0370] Synthesis of Compound SB-AA. To a solution of SB-Z (120 g, crude) in 600 mL of THF, 90 mL of 2 M aqueous HCl was added. The reaction mixture was stirred at 22 °C for 1 hour. After the TLC showed the reaction was complete, the reaction was quenched with aq. NaHCO3. The reaction mixture was extracted with 500 mL of EtOAc, 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 give SB-AA as a white solid (24 g, yield 76.23%). 1 H NMR (SB-AA) (400 MHz, 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).

[0371] Synthesis of Compound SB-BB. To a solution of MeSOI (78.07 g, 354.75 mmol) in 50 mL of THF was added a solution of t-BuOK (39.81 g, 354.75 mmol) in 50 mL of THF. The reaction mixture was stirred at 60° C. for 1.5 hours. Then, a solution of SB-AA (24 g, 78.83 mmol) in THF (300 mL) was added to the reaction. The reaction was stirred at 23° C. for 2.5 hours. After the TLC showed that the reaction was complete, the reaction was quenched with ice water. The reaction was extracted with 500 mL of EtOAc, washed with brine, and evaporated in vacuo to give SB-BB as a crude product (50 g). 1 H NMR (SB-BB) (400 MHz, 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).

[0372] Synthesis of Compound SB-CC. To a solution of SB-BB (50 g, crude) in 300 mL of THF, LiAlH4 (8.99 g, 236.49 mmol) was added at 0 °C. The reaction mixture was stirred at 23 °C for 1.5 hours. After the TLC showed the reaction was complete, the reaction was quenched with water. The reaction mixture was extracted with 1000 mL of EtOAc, 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 give SB-CC as a white solid (19 g, yield 75.19%). 1 H NMR (SB-CC) (400 MHz, 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).

[0373] Synthesis of Compound SB-DD. To a solution of SB-CC (19 g, 59.29 mmol) in dry THF (500 mL) was added C2H9BS (59.29 mL; 10 M solution in THF) at 0 °C. After stirring at room temperature for 2 h, 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 h, the mixture was filtered and extracted with EtOAc (300 mL). The combined organic layers were treated with aq. Na2S2O3, filtered, dried, and concentrated to give SB-DD as a crude material (21 g, crude). This crude product was used in the next step without further purification.

[0374] Synthesis of Compound SB-EE. To a solution of SB-DD (21 g, 59.29 mmol) in 200 mL of CHCl was added PCC (25.56 g, 118.58 mmol) at 0 °C and stirred at 22 °C for 2 h. The reaction mixture was filtered and extracted with 20 mL of CHCl, washed with aq. NaHCO, aq. NaSO, brine, and evaporated under reduced pressure. The residue was purified by chromatography (petroleum ether / ethyl acetate = 15:1 to 10:1 to 6:1) to give SB-EE as a white solid (12 g, yield 60.15%). 1 H NMR (SB-EE) (400 MHz, 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).

[0375] Synthesis of Compound SB-FF. 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 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 EtOAc, washed with brine, and evaporated under reduced pressure. The product was purified by column chromatography on silica gel eluted with (petroleum ether / ethyl acetate = 12:1, 10:1, 8:1, 6:1, 3:1) to give SB-FF as a white solid (12.3 g, 83.03% yield). 1 H NMR (SB-FF) (400 MHz, 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).

[0376] Example 12. Synthesis of SC-O compound

[0377] [ka]

[0378] Synthesis of compound SC-B. The pyridinium ion of reactant SC-A (10.0 g, 36.44 mmol) was To a solution of acetic anhydride (5.0 mL, 52.89 mmol) in ethanol (30 mL) was added. The mixture was stirred at 60 °C overnight. The solution was then poured into ice water (200 mL). The white precipitate was filtered and dissolved in ethyl acetate (300 mL). To remove residual pyridine, the resulting solution was washed with saturated CuSO4.5H2O solution (2 × 200 mL). The organic layer was further washed with brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 4:1) to give product SC-B (11.125 g, 35.16 mmol, yield = 96%) as a white solid. 1 HNMR (500 MHz, CDCl3) δ(ppm): 5.83 (1H, s), 4.62 (1H, dd), 2.05 (3H, s), 0.86 (3H, s).

[0379] Synthesis of Compound SC-C. To a solution of reactant SC-B (4.68 g, 14.79 mmol) in THF (150 mL) was added LiHMDS (1.0 M solution in THF, 17.74 mL, 17.74 mmol) at −78° C. The solution was stirred at −78° C. for 30 minutes. HMPA (3.09 mL, 17.74 mmol) was then added. The solution was stirred at −78° C. for an additional 30 minutes. Iodomethane (2.76 mL, 44.37 mmol) was then added. The solution was further stirred at −78° C. for 2 hours, then warmed to room temperature, and stirred for 1 hour. The 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. The solvent was removed in vacuo to give the crude product SC-C (4.50 g, 13.62 mmol, yield=92%) as a sticky oil, which was used in the next step without further purification. 1HNMR (500 MHz, CDCl3) δ(ppm):5.75 (1H, s), 4.62 (1H, t), 2.05 (3H, s), 1.10 (3H, d), 0.86 (3H, s).

[0380] Synthesis of Compounds SC-D and SC-E. To a solution of crude reactant SC-C (11.62 g, 35.16 mmol, theoretical amount) in methanol (100 mL) and water (20 mL) was added sodium hydroxide (2.81 g, 70.32 mmol). The solution was heated at 60 °C for 1 h. Most of the methanol solvent was then removed under reduced pressure. The remaining 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 (petroleum ether / ethyl acetate = 5:1) to give pure product SC-D (2.354 g, 8.162 mmol, yield = 23%) and pure product SC-E (5.306 g, 18.40 mmol, yield = 50%) as white solids. Compound SC-D: 1 HNMR (500 MHz, CDCl3) δ(ppm):5.81 (1H, s), 3.67 (1H, t), 1.11 (3H, d), 0.81 (3H,s).

[0381] Compound SC-E: 1 HNMR (500 MHz, CDCl3) δ(ppm):5.74 (1H, s), 3.67 (1H, t, J=8.5 Hz), 1.11 (3H, d), 0.81 (3H, s).

[0382] Synthesis of compound SC-F. Lithium (1.80 g, 260 mmol) was added to liquid ammonia (200 mL) at -78 °C. The liquid then turned deep blue. Then, a solution of reactant SC-D (3.0 g, 10.40 mmol) in t-BuOH (1.0 mL, 10.40 mmol) and THF (100 mL) was added to the 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 turned from deep blue to white. The mixture It was warmed to room temperature, and the ammonia was allowed to evaporate overnight in a hood. To the residue, water (300 mL) was added. The mixture was acidified to pH 6-7 with conc. HCl. Ethyl acetate (300 mL) was then added. The separated aqueous layer was further extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (300 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-F was used directly in the next step without further purification.

[0383] Synthesis of Compound SC-G. To a solution of crude reactant SC-F (1.749 g, 6.022 mmol) in dichloromethane (60 mL) was added pyridinium dichromate (PDC) (3.398 g, 9.033 mmol). The mixture was stirred at room temperature overnight. The solution was filtered through a short pad of Celite. The Celite was washed with CHCl (3 × 50 mL). The combined CHCl solution was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5:1) to give product SC-G (1.298 g, 4.50 mmol, yield = 75%) as a white solid. Compound SC-G: 1 HNMR (400 MHz, CDCl3) δ(ppm): 1.02 (3H, d), 0.91 (3H, s).

[0384] Synthesis of Compound SC-H. To a solution of reactant SC-G (1.948 g, 6.754 mmol) in anhydrous methanol (50 mL) was added p-toluenesulfonic acid monohydrate (128 mg, 0.6754 mmol). The solution was heated at 70 °C for 3 hours. The reaction was quenched by the addition of saturated Na2CO3 solution (10 mL). Most of the methanol solvent was removed under reduced pressure. The residue was then diluted with ethyl acetate (200 mL), and the resulting solution was washed with saturated Na2CO3 solution (2 × 100 mL). The combined aqueous layers were extracted with ethyl acetate (50 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10:1, with 0.1% NEt3) to give the product SC-H (652 mg, 1.949 mmol, yield = 29%) as a white solid. In addition, starting material (1.338 g) was also recovered. Therefore, the yield based on the recovered starting material is 92%. 1 H NMR (500 MHz, d6-acetone) δ(ppm): 3.079 (3H, s), 3.075 (3H, s), 2.38 (1H, dd), 1.98 (1H, dd), 0.91 (3H, d), 0.85 (3H, s).

[0385] Synthesis of Compound SC-I. To a solution of ethyltriphenylphosphonium bromide (8.795 g, 23.69 mmol) in anhydrous THF (20 mL) was added t-BuOK (2.658 g, 23.69 mmol). The solution turned reddish and was heated at 70° C. for 2 hours. Then, reactant SC-H (1.642 g, 4.909 mmol) was added in one portion. The solution was heated at 70° C. overnight. The reaction was quenched by the addition of 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 in vacuo. The crude product SC-I was used directly in the next step without further purification.

[0386] Synthesis of Compound SC-J. To the crude product SC-I (1.702 g, 4.909 mmol, theoretical amount) in THF (30 mL) was added 2 M HCl (3 mL). The solution was stirred at ambient temperature for 1 h. 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 layers were extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 100:3) to give the crude product SC-J (1.746 g) as a white solid. This was contaminated with some unresolved PPh3. It had been dyed. 1 Judging from the integration of the HNMR spectrum, the ratio of the desired product to PPh3 is 3:1, so the amount of the desired product SC-J is 1.354 g (4.506 mmol), and the yield is 92%. 1 H NMR (500 MHz, CDCl3) δ(ppm):5.13 (1H, qt), 1.66 (3H, dt), 1.02 (3H, d), 0.91 (3H, s).

[0387] Synthesis of Compound SC-K. To a solution of trimethylsulfoxonium iodide (5.213 g, 23.69 mmol) in anhydrous DMSO (30 mL) was added sodium hydride (60% wt, 948 mg, 23.69 mmol). The mixture was stirred at 25 °C for 1 hour. Then, a solution of the 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 at 25 °C overnight. The 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 with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-K was used directly in the next step without further purification.

[0388] Synthesis of Compound SC-L. To a solution of crude reactant SC-K (theoretical amount, 1.417 g, 4.506 mmol) in anhydrous THF (30 mL) was added lithium aluminum hydride (342 mg, 9.012 mmol) in portions. 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 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 in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 20:1) to give product SC-L (458 mg, 1.447 mmol, overall yield for two steps = 32%) as a white solid.

[0389] Synthesis of Compound SC-M. To a solution of reactant SC-L (458 mg, 1.447 mmol) in anhydrous THF (15 mL) was added BH3.THF (1.0 M, 7.23 mL, 7.23 mmol), and the solution was stirred at 25 °C overnight. The reaction was then quenched by the addition of water (5 mL). 2 M NaOH solution (10 mL) was added, followed by 30% HO (10 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 in vacuo. The crude product was used directly in the next step without further purification.

[0390] Synthesis of compound SC-N. To a solution of crude reactant SC-M (484 mg, 1.447 mmol, theoretical amount) in dichloromethane (40 mL) was added pyridinium dichromate (PDC) (1633 mg, 4.341 mmol) in portions. The solution was stirred at 25 °C overnight. 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 = 8:1) to give product SC-N (305 mg, 0.917 mmol, yield = 63% (two steps)) as a white solid. 1 H NMR (500 MHz, CDCl3) δ(ppm):2.54 (1H, t,), 2.12-2.19 (1H, m), 2.12 (3H, s 0.92 (3H, d), 0.61 (3H, s). 13 CNMR (100 MHz, 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, 2 4.22, 22.76, 15.14, 13.45.

[0391] Synthesis of compound SC-O. To a solution of reactant SC-N (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol), followed by bromine (241 mg, 0.077 mL, 1.505 mmol). The 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 extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-O was used directly in the next step without further purification.

[0392] Example 13. Synthesis of SC-Y compound

[0393] [ka]

[0394] Synthesis of Compound SC-P. Lithium (7.0 g, 1 mol) was added to NH (liquid, 2.0 L) at −78°C. After the liquid turned deep blue, a solution of Compound SC-A (27.0 g, 100 mmol) in t-BuOH (7.4 g, 100 mmol) and THF (20 mL) was added dropwise. The mixture was stirred at −78°C for 4 hours. Solid NH Cl (50 g) was then added to quench the reaction. The mixture turned from deep blue to white. The mixture was warmed to room temperature, and the ammonia was allowed to evaporate overnight. The residue was dissolved in 0.5 N aqueous HCl (50 mL) and extracted with dichloromethane (200 mL × 3). The combined organic layers were washed with saturated NaHCO (200 mL) and brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=4:1) to give the product SC-P (18.98 g, 68.7%) as a white solid. 1 H NMR (500 MHz, 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).

[0395] Synthesis of compound SC-Q. A 19.0 g sample of compound SC-P (68.84 mmol) ) was dissolved in 50 mL of THF at 0 °C. Then, 70 mL of MeMgBr in THF (3 M) was added dropwise over 30 min. The reaction was maintained at 0 °C for 8 h. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (200 mL × 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 = 5:1) to give product SC-Q (19.0 g, 94%) as a white solid. 1 H NMR (500 MHz, CDCl3) δ (ppm):5.78 (1H, br), 5.36 (1H, t), 3.67 (1H, t), 1.73 (3H, s), 0.77 (3H, s).

[0396] Synthesis of Compound SC-R. To a solution of compound SC-Q (19.0 g, 65.07 mmol) in dichloromethane (100 mL) was added pyridinium dichromate (PDC) (48.9 g, 130.14 mmol). The mixture was stirred at room temperature overnight. The solution was filtered through a short pad of Celite. The Celite was washed with CHCl (3 × 100 mL). The combined CHCl solution was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5:1) to give the product SC-R (10.0 g, 53%) as a white solid. 1 H NMR (500 MHz, CDCl3) δ (ppm):2.44 (1H, dd), 2.07 (1H, m), 1.21 (3H, s), 0.87 (3H, s).

[0397] Synthesis of Compound SC-S. A solution of Compound SC-R (5.0 g, 17.2 mmol) in anhydrous toluene (100 mL) was added to p-toluenesulfonic acid containing silica gel (80 g), and the mixture was stirred at less than 45° C. for 1 hour. Insoluble by-products were removed from the silica gel by elution with petroleum ether / ethyl acetate (10 / 1). The crude product SC-S (3.20 g, 11.75 mmol) was used in the next step without further purification.

[0398] Synthesis of Compound SC-T. To a solution of Compound SC-S (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 at room temperature overnight. The reaction mixture was then extracted with CHCl, and the combined organic layers were washed twice with NaHCO (100 mL) and brine, dried over NaSO, and concentrated. The crude product SC-T was used in the next step without further purification.

[0399] Synthesis of Compound SC-U. To a solution of compound SC-T (11.75 mmol) in methanol, HSO (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was then extracted with CHCl (200 mL × 3), and the combined organic layers were washed with NaHCO (100 mL) and brine, dried over NaSO, and concentrated. The residue was purified by chromatography (petroleum ether / ethyl acetate = 10:1) to give compound SC-U (3.30 g, 10.30 mmol, yield = 87% for two steps) as a white solid.

[0400] Synthesis of Compound SC-V. To a solution of ethyltriphenylphosphonium bromide (11.52 g, 31.0 mmol) in anhydrous THF (20 mL) was added t-BuOK (3.48 g, 31.0 mmol). The solution turned reddish and was heated at 70° C. for 3 hours. Compound SC-U (3.30 g, 10.30 mmol) was then added in one portion. The reaction solution was heated at 70° C. overnight and then quenched by the addition of water (10 mL). The mixture was diluted with EtOAc (200 mL), and the resulting solution was washed with brine (2×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-V (1.90 g) was used directly in the next step without further purification.

[0401] Synthesis of Compound SC-W. To a solution of compound SC-V (1.90 g, 5.72 mmol) in dry THF (20 mL) was added BH3-THF (18 mL of a 1.0 M solution in 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 (12 mL) followed by 30% H2O2 (20 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EA (100 mL x 3). The combined organic layers were washed with 10% aqueous Na2S2O3 (50 mL), brine, dried over Na2SO4, filtered, and concentrated to give crude compound SC-W (1.86 g, 5.31 mmol). The crude product was used in the next step without further purification.

[0402] Synthesis of Compound SC-X. To a solution of crude compound SC-W (1.86 g, 5.31 mmol) in dichloromethane (50 mL), pyridinium dichromate (PDC) (3.98 g, 10.62 mmol) was added in portions. The solution was stirred at 25 °C overnight. 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 = 10:1) to give product SC-X (1.20 g, 3.45 mmol, 65%) as a white solid. 1HNMR (500 MHz, CDCl3) δ(ppm):3.33 (3H, s), 3.04 (1H, s), 2.53 (1H, t), 2.12 (3H, s within m), 1.26 (3H, s within m), 0.62 (3H, s).

[0403] Synthesis of Compound SC-Y. To a solution of reactant SC-X (100 mg, 0.287 mmol) in methanol (10 mL) was added 48% HBr (152 mg, 0.903 mmol), followed by bromine (0.08 mL, 1.505 mmol). The 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 extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-Y was used directly in the next step without further purification.

[0404] Example 14. Synthesis of SC-EE compound

[0405] [ka]

[0406] Synthesis of Compounds SC-Z and SC-AA. To a solution of Compound SA-E (800 mg, 2.79 mmol) and PhSOCFH (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL) was added LHMDS (4 mL, 1 M in THF) dropwise under N at −78° C. After stirring at −78° C. for 2 h, the reaction mixture was quenched with saturated aqueous NHCl solution (10 mL) and warmed to room temperature, then extracted with EtO (20 mL × 3). The combined organic layer was 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 give a mixture of Compound SC-Z and SC-AA (700 mg). This mixture was further purified by chiral HPLC to give Compound SC-Z (200 mg, t = 4.31 min). 1 H NMR (400 MHz, 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 SC-AA (260mg,t=5.66min). 1 H NMR (400 MHz, 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).

[0407] Synthesis of Compound SC-BB. To a solution of compound SC-AA (100 mg, 0.209 mmol) and anhydrous NaHPO (100 mg) in anhydrous methanol (5 mL) was added Na / Hg amalgam (500 mg) under N 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 EtO (5 × 3 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound SC-BB (36 mg, 0.106 mmol, 51%). 1 H NMR (400 MHz, CDCl3), δ (ppm), 6.02-5.88 (t, 1H), 5.17-5.15 (m, 1H), 0.88 (s, 3H).

[0408] Synthesis of Compound SC-CC. To a solution of compound SC-BB (150 mg, 0.443 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.34 mL of a 1.0 M solution in 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 EtOAc (3 x 10 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to give crude compound SC-CC (210 mg). The crude product was used in the next step without further purification.

[0409] Synthesis of Compound SC-DD. To a solution of crude compound SC-CC (210 mg) in 10 mL of HO-saturated dichloromethane (dichloromethane was shaken with several milliliters of HO and then separated from the aqueous layer), Dess-Martin periodinate (380 mg, 0.896 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with 10% aqueous NaSO (10 mL), brine (10 mL), dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give compound SC-DD (90 mg, 0.254 mmol, 57%) as a white solid. 1 H NMR (400 MHz, CDCl3), δ (ppm), 6.01-5.73 (t, 1H), 2.55-2.54 (m, 1H), 2.12 (s, 3H), 0.62 (S, 3H).

[0410] Synthesis of compound SC-EE. To a solution of compound SC-DD (80 mg, 0.226 mmol) in MeOH (5 mL), two drops of HBr (48%) were added, 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 and then extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to obtain crude compound SC-EE (95 mg). This crude product was used in the next step without further purification.

[0411] Example 15. Synthesis of SC-II compound

[0412] [ka]

[0413] Synthesis of compound SC-FF. To a solution of reactant SB-F (4.4 g, 15.38 mmol) in dry THF (50 mL), ethylmagnesium bromide (3 M in THF, 51.28 mL) was added dropwise at 0 °C. The solution was then slowly warmed and stirred at ambient temperature for 15 h. Sat. NH4Cl solution (20 mL) was added to quench the reaction, and the resulting solution was extracted with ethyl acetate (3 × 100 mL). The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether:ethyl acetate = 10:1) to give the product SC-FF (3.15 g, 10.00 mmol, 64.8%) as a white solid.

[0414] Synthesis of Compound SC-GG. To a solution of reactant SC-FF (500 mg, 1.58 mmol) in anhydrous THF (10 mL) was added BH3.THF (1.0 M, 7.23 mL, 7.23 mmol) at room temperature, and the solution was stirred at 25 °C overnight. The reaction was then quenched by the addition of water (5 mL), 2 M NaOH solution (10 mL), followed by 30% HO (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 in vacuo. The crude product SC-GG was used directly in the next step without further purification.

[0415] Synthesis of compound SC-HH. To a solution of reactant SC-GG (6.53 g, 19.67 mmol) in anhydrous DCM (100 mL) cooled with an ice-water cooling bath, pyridinium chloroformate (8.48 g, 39.34 mol) was added portionwise. The mixture was stirred at ambient temperature overnight. 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 in vacuo. The residue was purified by flash chromatography (petroleum ether:ethyl acetate=10:1) to give product SC-HH (2.5 g, 7.53 mmol, 39% yield) as a white solid. 1 HNMR(500 MHz, 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).

[0416] Synthesis of Compound SC-II. To a solution of reactant SC-HH (80 mg, 0.24 mmol) in methanol (5 mL) was added 48% hydrobromic acid (148 mg, 0.884 mmol), followed by bromine (241 mg, 0.077 mL, 1.505 mmol). The 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 extracts were washed with brine (20 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-II was used directly in the next step without further purification.

[0417] Example 16. Synthesis of SC-SS compound

[0418] [ka]

[0419] Synthesis of compounds SC-MM and SC-NN. Dry (Bu)4NF was added to the reactant mixture SA-KK and SA-LL (3.0 g, 10.0 mmol, 1:1), and the mixture was then heated at 100 °C overnight. The remaining mixture was poured into 50 mL of HO and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 20:1) to give the product mixture SC-MM and SC-NN (2.1 g, 6.5 mmol, 65%) as a white solid.

[0420] Synthesis of compounds SC-OO and SC-PP. To a solution of the reactant mixture SC-MM and SC-NN (2.1 g, 6.5 mmol) in anhydrous THF (30 mL) was added BH3.THF (1.0 M, 13.0 mL, 13.0 mmol), and the solution was stirred at 25 °C overnight. The reaction was then quenched by the addition of water (5 mL). 2 M NaOH solution (20 mL) was added, followed by 30% HO (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 in vacuo. The crude product mixture was used directly in the next step without further purification.

[0421] Synthesis of Compounds SC-QQ and SC-RR. To a solution of the crude reactant mixture SC-OO and SC-PP (2.2 g, 6.5 mmol, theoretical amount) in dichloromethane (40 mL) was added pyridinium chloroformate (Pcc) in portions (2.8 g, 13.0 mmol). The solution was stirred at 25 °C overnight. 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 give the product SC-QQ (910 mg, 2.7 mmol, yield = 41% (two steps)) as a white solid and the product SC-RR (850 mg, 2.5 mmol, yield = 39% (two steps)) as a white solid. Compound SC-QQ: 1 HNMR (500 MHz, 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 (500 MHz, CDCl3) δ(ppm): 4.45 (AB×d, 1H), 4.39 (AB×d, 1H), 2.54 (t, 1H), 0.62 (s, 3H).

[0422] Synthesis of compound SC-SS. To a solution of reactant SC-RR (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol), followed by bromine (241 mg, 0.077 mL, 1.505 mmol). The 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 extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-SS was used directly in the next step without further purification.

[0423] Example 17. Synthesis of SA-ZZ compound

[0424] [ka]

[0425] Synthesis of Compounds SC-TT and SC-UU. To a solution of compound SB-F (1.3 g, 4.5 mmol) and PhSO2CH2F (790 mg, 4.5 mmol) in THF (25 mL) and HMPA (0.5 mL) was added LHMDS (5.5 mL, 1 M in THF) dropwise under N2 at -78 °C. After stirring at -78 °C for 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and warmed to room temperature, then extracted with Et2O (20 mL × 3). The combined organic layer was 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 give compounds SC-TT and SC-UU. A mixture (1.53 g) was obtained. This mixture was further purified by chiral HPLC to obtain compound SC-TT-1 (220 mg, t=3.41 min). 1 H NMR (500 MHz, 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);SC-TT-2 (200mg,t=3.66min); 1 H NMR (500 MHz, 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);SC-UU-1 (235mg,t=4.9min). 1H NMR (500 MHz, 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);SC-UU-2 (220mg,t=5.2min). 1 H NMR (500 MHz, CDCl), 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).

[0426] Synthesis of Compound SC-WW. To a solution of compound SC-TT-1 (200 mg, 0.434 mmol) and anhydrous NaHPO (100 mg) in anhydrous methanol (15 mL) was added Na / Hg amalgam (400 mg) under N at −20° C. After stirring at −20° C. to 0° C. for 1 h, the methanol solution was decanted, and the solid residue was washed with EtO (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 EtO. The combined ether phase was dried over MgSO and the ether was removed to give the crude product, which was further purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 99 mg, 69% product. 1 H NMR (500 MHz, CDCl3), δ (ppm), 5.12-5.10 (m, 1H,), 4.21-24.11 (d, 2H), 0.88 (s, 3H).

[0427] Synthesis of Compound SC-XX. To a solution of Compound SC-WW (95 mg, 0.296 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL of a 1.0 M solution in 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 EtOAc (3 x 10 mL). The combined organic layers were washed with 10% aqueous Na2S2O3 (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to give Compound SC-XX (120 mg crude). The crude product was used in the next step without further purification.

[0428] Synthesis of Compound SC-YY. To a solution of compound SC-XX (120 mg crude) in 10 mL of wet dichloromethane (dichloromethane was shaken with a few milliliters of HO and then separated from the aqueous layer), Dess-Martin periodinate (300 mg, 707 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with 10% aqueous NaSO (10 mL), brine (10 mL), dried over MgSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:5) to give compound SC-YY (70 mg, 70% for two steps) as a white solid. 1 H NMR (500 MHz, CDCl3), δ (ppm ), 4.21-4.11 (d, 2H), 2.19 (s, 3H), 0.62 (s, 3H).

[0429] Synthesis of Compound SC-ZZ. To a solution of the reactant (200 mg, 0.594 mmol) in methanol (5 mL) was added 48% hydrobromic acid (300 mg, 1.782 mmol), followed by bromine (475 mg, 0.152 mL, 2.97 mmol). The 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 extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0430] Example 18. Synthesis of compounds SA-1 and SA-2

[0431] [ka]

[0432] To a suspension of KCO (50 mg, 0.36 mmol) in THF (5 mL) were added 5-(trifluoromethyl)-1H-pyrazole (80 mg, 0.59 mmol) and SA (100 mg, 0.25 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid, SA-1 (15 mg, 13.2%). SA-2 (5 mg, 4.4%). SA-1: 1 H NMR (500MHz, CDCl3), δ (ppm), 7.47 (d,1H),6.59 (d,1H), 4.99 (1H, AB), 4.95(1H, AB), 2.58 (1H, t), 1.00-2.20 (m, 24H),0.68 (s, 3H). SA-2: 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.57 (d,1H), 6.66 (d,1H), 5.03 (1H, AB), 4.93(1H, AB), 2.77 (1H, t), 1.00-2.2 (m, 24H), 0.9 (s, 3H).

[0433] Example 19. Synthesis of compound SA-3

[0434] [ka]

[0435] To a suspension of KCO (50 mg, 0.36 mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4-carboxylate (100 mg, 0.71 mmol) and SA (72 mg, 0.18 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (18 mg, 21.6%). 1 H NMR (500 MHz, CDCl3), δ (ppm) 7.93 (s, 1H), 7.91 (s, 1H), 4.97 (1H, AB), 4.86 (1H, AB), 4.28 (q, 2H), 2.60 (1H, t), 1.34 (t,3H), 1.00-2.25 (m, 24H), 0.67 (s,3H).

[0436] Example 20. Synthesis of compound SA-4

[0437] [ka]

[0438] To a suspension of KCO (50 mg, 0.36 mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol) and SA (50 mg, 0.12 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (9 mg, 17.4%). 1 H NMR (500 MHz, CDCl3), δ (ppm) 7.87 (1H, s), 7.82 (1H, s), 5.02 (1H, AB), 4.92 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, d×t), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H, m), 1.28 (3H , s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS:rt=2.24min,m / z=410.1[M+H] + .

[0439] Example 21. Synthesis of Compound SA-5

[0440] [ka]

[0441] To a suspension of KCO (50 mg, 0.36 mmol) in THF (5 mL) was added ethyl 1-(1H-pyrazol-5-yl)ethanone (100 mg, 0.91 mmol) and SA (50 mg, 0.12 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (37 mg, 65%): 1 H NMR (500 MHz, CDCl3), δ (ppm) 7.41 (d,1H), 6.85 (d,1H), 4.98 (1H, AB), 4.86 (1H, AB), 2.59 (t, 1H), 2.55 (s,3H), 1.00-2.25 (m, 24H), 0.69 (s,3H).

[0442] Example 22. Synthesis of compound SA-6

[0443] [ka]

[0444] To a solution of SA (350 mg, 0.88 mmol) and K2CO3 (243.5 mg, 1.76 mmol) in 10 mL of dry DMF was added 4-methyl-1H-pyrazole (144.6 mg, 1.76 mmol) at room temperature under N2. The reaction mixture was stirred at this temperature for 18 h. The reaction mixture was poured into water and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The mixture was purified by flash chromatography on a silica column (petroleum ether / ethyl acetate 10:1 to 2:1) to give SA-6 (230 mg, yield: 65.5%) as a white powder. Ta. 1 H NMR (400 MHz, CDCl3), δ (ppm), 7.35 (s, 1H), 7.18 (s, 1H), 4.92-4.79 (m, 2H), 2.59-2.55 (m, 1H), 2.23-2.15 (m, 1H), 2.10 (s, 3H), 2.07-2.03 (m, 1H), 1.88-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.49-1.22 (m, 16H), 1.13-1.05 (m, 3H), 0.68 (s, 3H). LCMS:rt=1.29min,m / z=399.2[M+H] + .

[0445] Example 23. Synthesis of compound SA-7

[0446] [ka]

[0447] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added 4-chloro-4H-pyrazole (21 mg, 0.21 mmol) and SA (36 mg, 0.09 mmol). The mixture was stirred at room temperature for 15 hours. The residual mixture was poured into 5 mL of HO and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (8 mg, 21%): 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.45 (s, 1H), 7.41 (s, 1H), 4.90 (AB, 1H), 4.81 (AB, 1H), 2.57 (t, 1H), 2.22-2.16 (m, 1H), 2.05-2.01 (m, 1H), 1.00-1.90 (m, 22H), 0.67 (s, 3H). LCMS:rt=2.52min,m / z=419.1[M+H]+.

[0448] Example 24. Synthesis of compound SA-8

[0449] [ka]

[0450] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added 4-nitro-4H-pyrazole (20 mg, 0.18 mmol) and SA (36 mg, 0.09 mmol). The mixture was stirred at room temperature for 15 hours. The resulting mixture was then cooled to 5°C. The mixture was poured into 1 mL of H2O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (12 mg, 31%): 1 H NMR (500 MHz, CDCl3), δ (ppm) 8.11 (s, 1H), 8.01 (s, 1H), 4.93 (AB, 1H), 4.83 (AB, 1H), 2.55 (t, 1H), 2.15-2.10 (m, 1H), 1.99-1.96 (m, 1H), 1.00-1.80 (m, 22H), 0.68 (s, 3H).

[0451] Example 25. Synthesis of Compound SA-9

[0452] [ka]

[0453] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added 4-bromo-4H-pyrazole (26 mg, 0.18 mmol) and SA (36 mg, 0.09 mmol). The mixture was stirred at room temperature for 15 hours. The residual mixture was poured into 5 mL of HO and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give SA-9 as a white solid (9 mg, 22%): 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.41 (s, 1H), 7.37 (s, 1H), 4.85 (AB, 1H), 4.77 (AB, 1H), 2.59 (t, 1H), 2.22-2.18 (m, 1H), 2.06-2.01 (m, 1H), 0.90-1.80 (m, 22H), 0.68 (s, 3H). 0.90-1.80 (m, 22H).

[0454] Example 26. Synthesis of compounds SA-10 and SA-11

[0455] [ka]

[0456] To a suspension of KCO (55 mg, 0.4 mmol) in THF (5 mL) was added 3-methyl-4H-pyrazole (33 mg, 0.4 mmol) and SA (79 mg, 0.2 mmol). ol) was added. The mixture was stirred at room temperature for 15 hours. The residual mixture was poured into 5 mL of H2O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give SA-10 as a white solid (9 mg, 11%) and SA-11 as a white solid (11 mg, 14%). Compound SA-10: 1H NMR (400 MHz, CDCl3), δ (ppm), 7.41 (d, 1H), 6.07 (s, 1H), 4.85 (s, 2H), 2.84-2.83 (m, 1H), 2.59 (t, 1H), 2.17 (s, 3H), 2.07-2.04 (m, 1H), 1.00-1.90 (m, 22H), 0.69 (s, 3H). Compound SA-11: 1 H NMR (400 MHz, CDCl3), δ (ppm), 7.28 (s, 1H), 6.09 (d, 1H), 4.84 (AB, 1H), 4.83 (AB, 1H), 2.56 (t, 1H), 2.27 (s, 3H), 2.22-2.14 (m, 1H), 2.05-2.02 (m, 1H), 1.00-1.90 (m, 22H), 0.67 (s, 3H), 1.00-1.90 (m, 22H).

[0457] Example 27. Synthesis of compound SA-12

[0458] [ka]

[0459] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added 3,5-dimethyl-4H-pyrazole (17 mg, 0.18 mmol) and SA (36 mg, 0.09 mmol). The mixture was stirred at room temperature for 15 hours. The residual mixture was poured into 5 mL of HO and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (11 mg, 30%): 1H NMR (500 MHz, CDCl3), δ (ppm), 5.86 (s, 1H), 4.79 (AB, 1H), 4.74 (AB, 1H), 2.57 (t, 1H), 2.21(s, 3H), 2.18-2.16 (m, 1H), 2.11(s, 3H), 2.05-2.02 (m, 1H), 0.90-1.80 (m, 22H), 0.68 (s, 3H).

[0460] Example 28. Synthesis of compound SA-13

[0461] [ka]

[0462] To a suspension of KCO (50 mg, 0.36 mmol) in THF (6 mL) was added 3H-pyrazole (16 mg, 0.23 mmol) and SA (36 mg, 0.09 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to give the title compound as a white solid (11 mg, 31.3%). 1 HNMR(400 MHz, CDCl3), δ (ppm), 7.56 (d,1H), 7.44 (d, 1H), 6.35 (s,1H), 4.95 (AB, 1H), 4.92 (AB,1H), 2.60 (1H, t), 1.00-2.25 (m, 24H), 0.68 (s, 3H).

[0463] Example 29. Synthesis of compound SA-14

[0464] [ka]

[0465] To a solution of the crude reactant (124.8 mg, 0.315 mmol, theoretical amount) in anhydrous THF (2.5 mL) was added 4-(trifluoromethyl)-1H-pyrazole (85.5 mg, 0.628 mmol), followed by potassium carbonate (86.8 mg, 0.628 mmol). The solution was heated at room temperature overnight, and then 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 in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give the product (69 mg, 0.152 mmol, yield = 48% (2 steps)) as a white solid. 1 HNMR(500 MHz, CDCl3) δ(ppm):7.72 (2H, s), 4.99 (1H, AB), 4.89 (1H, AB), 2.61 (1H, t), 2.2 (bq, 1H), 1.00-2.10 (23H, m), 0.69 (3H, s). 1.00-2.10 (24H, m). 19 FNMR (376 MHz, CDCl3) δ(ppm):-56.46. LCMS:rt=2.52min,m / z=453.2[M+H] + .

[0466] Example 30. Synthesis of compound SA-15

[0467] [ka]

[0468] To a solution of the crude reactant (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added 3,4-dimethyl-1H-pyrazole (120.7 mg, 1.256 mmol), followed by potassium carbonate (173.6 mg, 1.256 mmol). The solution was stirred at 25° C. overnight, and then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:3) to give the product (56 mg, 0.136 mmol, yield=22% (two steps)) as a white solid. 1 HNMR (400 MHz, CDCl3) δ(ppm):7.08 (1H, s), 4.77 (1H, AB), 4.76 (1H, AB), 2.55 (1H, t), 2.18 (3H, s), 1.00-2.20 (24H, m).0.67 (3H, s). LCMS:rt=2.41min,m / z=413.2[M+H] + .

[0469] Synthesis of 4-ethyl-1H-pyrazole

[0470] [ka]

[0471] Synthesis of 4-ethynyltrimethylsilane-1H-pyrazole. To a solution of the reactants (3.88 g, 20 mmol), Pd(dppf)Cl.CHCl (2.45 g, 3 mmol), and CuI (0.571 g, 3 mmol) in EtNH (30 mL) and THF (30 mL) was added ethynyltrimethylsilane (9.823 g, 14.1 mL, 100 mmol) under a N atmosphere, and the mixture was stirred at room temperature overnight. The black solution was then diluted with ethyl acetate (300 mL), and the resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 7.5:1) to give the product (1.90 g, 11.57 mmol, yield = 58%) as a brownish solid. 1 HNMR(500 MHz, DMSO-d6) δ(ppm):13.12 (1H, br), 8.07 (1H, s), 7.65 (1H, s), 0.19 (9H, s).

[0472] Synthesis of 4-ethynyl-1H-pyrazole. To a solution of the reactant (1.90 g, 11.57 mmol) in THF (20 mL) and water (4 mL) was added lithium hydroxide hydrate (970 mg, 23.14 mmol). The solution was stirred at room temperature overnight, and then most of the THF solvent was removed under reduced pressure. The solution was neutralized by the addition of acetic acid, and the resulting mixture was diluted with dichloromethane (200 mL) and brine (50 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 4:1) to give the product (828 mg, 8.99 mol, yield = 78%) as a light brown solid. 1 HNMR (500 MHz, DMSO-d6) δ(ppm): 13.11 (1H, br), 8.05 (1H, s), 7.65 (1H, s), 3.95 (1H, s).

[0473] Synthesis of 4-ethyl-1H-pyrazole. To a solution of the reactant (828 mg, 8.99 mmol) in ethanol (50 mL) was added 10 wt% Pd / C on carbon (165.6 mg, 0.16 mmol). The reaction mixture was hydrogenated overnight with a hydrogen balloon. A small amount of the sample solution was filtered, concentrated in vacuo, and 1 The reaction was characterized by HNMR and determined to be complete. The entire reaction mixture was filtered through Celite, and the Celite was washed with ethanol (20 mL). The combined filtrate was concentrated in vacuo. The residue was purified through a short pad of silica gel (petroleum ether / ethyl acetate = 3:1) to give the product (643 mg, 6.69 mmol, yield = 74%) as a pale yellow liquid. 1 HNMR (500 MHz, DMSO-d6) δ(ppm): 12.48 (1H, s), 7.39 (2H, s), 2.43 (2H, q, J=7.6 Hz), 1.13 (3H, t, J=7.6 Hz).

[0474] Example 31. Synthesis of compound SA-16

[0475] [ka]

[0476] To a solution of the crude reactant (249.5 mg, 0.629 mmol, theoretical amount) in anhydrous THF (5 mL) was added 4-ethyl-1H-pyrazole (120.7 mg, 1.256 mmol), followed by potassium carbonate (173.6 mg, 1.256 mmol). The solution was stirred at 25 °C overnight, and then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2 × 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2:3) to give the product (29.5 mg, 0.0714 mmol, yield = 11% (2 steps)) as a white solid. 1HNMR (400 MHz, CDCl3) δ(ppm):7.38 (1H, s), 7.18 (1H, s), 4.89 (1H, AB), 4.82 (1H, AB), 2.57 (1H, t), 2.51 (2H, q), 0.80-2.20 (24H, m), 0.68 (3H, s). LCMS:rt=2.34min,m / z=413.1[M+H] + .

[0477] Synthesis of 4-methylsulfonyl-1H-pyrazole

[0478] [ka]

[0479] Synthesis of 4-methylthio-1H-pyrazole. To a solution of 4-bromo-1H-pyrazole (200 mg, 1.361 mmol) in anhydrous THF (5 mL) was added n-BuLi (2.5 M, 1.8 mL, 4.5 mmol) at 0° C. The solution was stirred at room temperature for 1 hour. MeSSMe (128 mg, 0.12 mL, 1.361 mmol) was added at 0° C., and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (50 mL) and water (50 mL). The separated organic layer was washed with brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. Due to its odor, the crude product was used in the subsequent oxidation step without further purification.

[0480] Synthesis of 4-methylsulfonyl-1H-pyrazole. To a solution of the crude reactant (155.4 mg, 1.361 mmol, theoretical amount) in dichloromethane (2.7 mL) was added trifluoroacetic acid (0.1 mL) at 0 °C. 3-Chloroperbenzoic acid (m-CPBA, 85% wt, 863 mg, 4.25 mmol) was then added portionwise, and the solution was stirred at room temperature overnight. The solution was diluted with ethyl acetate (100 mL), and the resulting solution was washed with saturated Na2CO3 solution (3 × 50 mL), followed by brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate to ethyl acetate:methanol = 10:1) to give the product (51 mg, 0.349 mmol, yield = 26% (2 steps)) as a pale yellow thick oil. 1 HNMR (500 MHz, CDCl3) δ(ppm): 8.04 (2H, s), 3.14 (3H, s).

[0481] Example 32. Synthesis of compound SA-17 (a)

[0482] [ka]

[0483] To a solution of the crude reactant (124.8 mg, 0.315 mmol, theoretical amount) in anhydrous THF (2.5 mL) was added 4-(methylsulfonyl)-1H-pyrazole (51 mg, 0.349 mmol), followed by potassium carbonate (48 mg, 0.349 mmol). The solution was heated at 40° C. for 2 h, and then 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 in vacuo. The crude product was purified by reverse-phase prep-HPLC to give product SA-17 (4 mg, 0.00865 mmol, yield=2.8% (2 steps)) as a white solid. 1HNMR (400 MHz, CDCl3) δ(ppm):7.93 (1H, s), 7.87 (1H, s), 5.02 (1H, AB), 4.92 (1H, AB), 3.14 (3H, s), 2.63 (1H, t), 2.17-2.26 (1H, s), 2.04 (1H, d×t), 1.70-1.89 (6H, m), 1.56-1.69 (1H, m), 1.20-1.54 (12H, m), 1.27 (3H, s), 1.04-1.18 (3H, m), 0.68 (3H, s). LCMS:rt=2.35min,m / z=463.1[M+H] + .

[0484] (b)

[0485] [ka]

[0486] To a solution of SA (200 mg, 0.46 mmol) in 30 mL of DCM was added m-CPBA (236 mg, 1.16 mmol) at room temperature (15-19 °C). The reaction mixture was stirred at the same temperature for 6 h. TLC showed the reaction was complete. The reaction mixture was poured into saturated aqueous NaSO and extracted with DCM (50 mL × 2). The organic layer was washed with saturated aqueous NaSO (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / ethyl acetate 5 / 1-1 / 2) to give SA-17 (140.5 mg, yield: 65%) as a white solid. 1H NMR:(400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (s, 1H), 5.04-4.89 (m, 2H), 3.13 (s, 3H), 2.64-2.59 (m, 1H), 2.24-2.16 (m, 1H), 2.06-2.03 (m, 1H), 1.87-1.75 (m, 6H), 1.64-1.42 (m, 11H), 1.35-1.27 (m, 7H), 1.16-1.06 (m, 3H), 0.67 (s, 3H).

[0487] Example 33. Synthesis of compound SA-18

[0488] [ka]

[0489] To a mixture of SA (200 mg, 0.50 mmol) and K2CO3 (138.2 mg, 1.00 mmol) in 5 mL of dry DMF was added 4-(methylthio)-1H-pyrazole (114.2 mg, 1.00 mmol) at room temperature (25 °C) under N2. The reaction mixture was stirred at the same temperature for 18 h. The reaction mixture was poured into water and extracted with EtOAc (50 mL × 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / ethyl acetate 10 / 1 to 2 / 1) to give compound SA-18 (165 mg, yield: 76%) as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 7.53 (s, 1H), 7.42 (s, 1H), 4.94-4.80 (m, 2H), 2.60-2.56 (m, 1H), 2.34 (s, 3H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.87-1.58 (m, 12H, contained H2O), 1.49-1.27 (m, 14H), 1.15-1.07 (m, 2H), 0.67 (s, 3H). LCMS:rt=1.32min,m / z=431.2[M+H]+ .

[0490] Example 35. Synthesis of compound SA-20

[0491] [ka]

[0492] To a solution of SA (100.0 mg, 0.23 mmol) in 10 mL of DCM was added m-CPBA (51.86 mg, 0.26 mmol) at −78 °C. The reaction mixture was then stirred at −78 °C for 3 h. LCMS showed the reaction was complete. Saturated aqueous NaSO was then added to the mixture at −78 °C. The reaction was then warmed to room temperature (16 °C to 22 °C). The resulting mixture was extracted with EtOAc (50 mL × 2), washed with water (10 mL), brine (10 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 1 / 1 to EtOAc) to give SA-20 (90 mg, yield: 72.3%) as a white solid. 1 H NMR:(400 MHz, CDCl3) δ 7.82 (s, 1H), 7.81 (s, 1H), 5.05-4.88 (m, 2H), 2.89 (d, 3H), 2.64-2.59 (m, 1H), 2.25-2.17 (m, 1H), 2.06-2.03 (m, 1H), 1.87-1.74 (m, 6H), 1.65-1.58 (m, 2H, contained H2O), 1.48-1.40 (m, 7H), 1.33-1.28 (m, 8H), 1.15-1.07 (m, 3H), 0.68 (s, 3H). LCMS: rt=1.14min, m / z=429.2[M-H2O], 469.2[M+Na].

[0493] Example 36. Synthesis of compound SA-21

[0494] [ka]

[0495] To a suspension of compound SA (100 mg, 0.25 mmol) in THF (25 mL) was added 4-fluoro-1H-pyrazole (64.5 mg, 0.75 mmol) and K2CO3 (103 mg, 0.75 mmol). The mixture was stirred at 35 °C for 15 hours. The reaction mixture was then extracted with 50 mL of EtOAc, washed with 100 mL of HO and 100 mL of brine, and evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to give SA-21 as a white solid (19 mg, 0.05 mmol, 20% yield). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.37 (1H,d), 7.30 (1H,d), 4.85(1H,AB), 4.77(1H,AB), 2.57 (t,1H), 2.2 (bq, 1H), 2.1 (bd, 1H), 1.00-1.9 (22H, m), 0.67 (s, 3H). LCMS:Rt=2.31min,MS (ESI) m / z:403.4[M+H] + .

[0496] Example 37. Synthesis of compound SA-22

[0497] [ka]

[0498] To a suspension of Compound SA (100 mg, 0.25 mmol) in THF (25 mL) was added 1H-pyrazole-3-carbonitrile (70 mg, 0.75 mmol) and K2CO3 (103 mg, 0.75 mmol). The mixture was stirred at 35 °C for 15 h. The reaction mixture was then extracted with 50 mL of EtOAc and washed with 100 mL of HO and The resulting residue was purified by reverse-phase prep-HPLC to give SA-22 as a white solid (23 mg, 0.056 mmol, 24% yield).1 H NMR (500 MHz, CDCl3), δ (ppm), 7.48 (d, 1H), 6.73 (d, 1H), 5.03(1H,AB), 4.93(1H,AB), 2.60 (t,1H), 1.00-2.25 (24H, m), 0.68 (s, 3H). LCMS:Rt=2.38min,MS (ESI) m / z:410.2[M+H] + .

[0499] Example 38. Synthesis of compound SA-23

[0500] [ka]

[0501] To a suspension of KCO (55 mg, 0.4 mmol) in THF (5 mL) was added 1H-pyrazole (28 mg, 0.4 mmol) and compound SA-JJ (85 mg, 0.2 mmol). The mixture was stirred at room temperature for 15 hours, and then the residual mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give SA-23 as a white solid (29 mg, 35%). 1 HNMR(500 MHz, CDCl3) δ (ppm):7.55 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.88 (AB, 1H), 3.42-3.37 (m, 5H), 2.58 (t, 1H), 2.22-2.16 (m, 1H), 2.06-2.03 (m, 1H), 1.00-1.90 (m, 22H), 0.68 (s, 3H). LC-MS:rt=2.27min,m / z=415.3[M+H] + .

[0502] Example 39. Synthesis of compound SA-24

[0503] [ka]

[0504] To a solution of compound SA-JJ (120 mg, 0.28 mmol) in THF (3 mL) was added KCO (190 mg, 1.4 mmol) and 1H-pyrazole-4-carbonitrile (130 mg, 1.4 mmol). The resulting solution was stirred at room temperature overnight and then The reaction was diluted with EtOAc (20 mL). The resulting solution was washed with brine (10 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by prep-HPLC to afford SA-24 (30 mg, 24%) as a white solid. NMR:(500 MHz, CDCl3), δ (ppm), 7.86 (1H, s), 7.81 (1H, s), 5.0 (1H, AB), 4.88 (1H, AB), 3.39 (3H, s), 3.19 (2H, s), 2.59 (1H, t), 2.2 (m, 1H), 0.69 (3H, s), 0.60-2.1 (23H, m). LC-MS:rt=2.25min;m / z=440.4(M+H) + .

[0505] Example 40. Synthesis of compound SA-25

[0506] [ka]

[0507] To a suspension of SA-V (20 mg, 0.04 mmol) in THF (5 mL) was added pyrazole (30 mg, 0.45 mmol) and KCO (60 mg, 0.45 mmol). The mixture was stirred at 25 °C for 15 h. The reaction mixture was then purified by reverse-phase prep-HPLC to give SA-25 as a white solid (11 mg, 57% yield). 1H NMR (500 MHz, CDCl3), δ (ppm), 7.56 (s, 1H), 7.42 (s, 1H), 6.33 (s, 1H), 4.97(1H,AB), 4.89(1H,AB), 4.86-4.69 (m, 1H), 2.60 (1H, t), 1.00-2.20 (22H, m), 0.72 (s, 3H).

[0508] Example 42. Synthesis of compound SA-27

[0509] [ka]

[0510] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added 3H-pyrazole (16 mg, 0.23 mmol) and SC-EE (36 mg, 0.08 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (12 mg, 34.3%). 1 HNMR(500MHz,CDCl3)δ(ppm), 7.55(d,1H),7.42-7.41(d,1H), 6.34 (t,1H), 5.87 (t,1H), 4.97 (1H, AB), 4.88 (1H, AB), 2.55(t,1H), 0.69 (s, 3H), 1.10-2.25 (m, 24H), 0.69 (s, 3H).

[0511] Example 43. Synthesis of compound SA-28

[0512] [ka]

[0513] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added 1H-pyrazole-4-carbonitrile (20 mg, 0.23 mmol) and SC-EE (36 mg, 0.09 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to give the title compound as a white solid (22 mg, 61.6%). 1 HNMR(400 MHz, CDCl3), δ (ppm):7.86 (s, 1H), 7.81(s, 1H), 5.87 (t, 1H), 5.02 (AB, 1H), 4.90 (AB, 1H), 2.61 (t, 1H), 1.00-2.25 (m, 24H), 0.68 (s, 3H). LC-MS:rt=2.30min,m / z=446.2(M + +1).

[0514] Example 44. Synthesis of compound SA-29

[0515] [ka]

[0516] To a suspension of KCO (127 mg, 0.92 mmol) in THF (5 mL), 4-(methylsulfonyl)-1H-pyrazole (67 mg, 0.46 mmol) and reactant (200 mg, 0.46 mmol) were added, and the resulting mixture was stirred at room temperature for 15 hours. The mixture was then poured into 20 mL of HO and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound SA-29 as a white solid (46 mg, 0.0923 mmol, yield = 20%). 1HNMR (500 MHz, CDCl3) δ (ppm):7.93 (s, 1H), 7.87 (s, 1H), 5.87 (t, 1H), 5.02 (AB, 1H), 4.92 (AB, 1H), 3.14 (s, 3H), 2.63 (t, 1H), 2.25-2.17 (m, 1H), 2.08-2.04 (m, 1H), 1.00-2.00 (m, 22H), 0.69 (s, 3H). LC-MS:rt=2.10min,m / z=499.3[M+H] + .

[0517] Example 61. Synthesis of compound SA-30

[0518] [ka]

[0519] To a suspension of K2CO3 (25 mg, 0.18 mmol) in THF (5 mL) was added 1H-pyrazole-4-carbonitrile (20 mg, 0.21 mmol) and SA-AA (36 mg, 0.087 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was then poured into 5 mL of H2O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to give the title compound as a white solid. The compound was obtained (10 mg, 27.0%). 1 HNMR(400 MHz, CDCl3), δ (ppm):7.86(s, 1H), 7.81(s, 1H), 5.99 (AB, 1H), 5.85 (AB, 1H), 2.65 (t, 1H),1.59 (q, 2H), 0.88 (t, 3H), 1.00-2.25 (m, 24H), 0.89 (t, 3H), 0.68 (s, 3H). LC-MS:rt=2.45min,m / z=424.3(M + +1).

[0520] Example 45. Synthesis of compound SA-31

[0521] [ka]

[0522] To a suspension of KCO (55 mg, 0.4 mmol) in THF (5 mL) was added 1H-pyrazole (28 mg, 0.4 mmol) and compound SC-SS (83 mg, 0.2 mmol). The mixture was stirred at room temperature for 15 hours, and then the residual mixture was poured into 5 mL of H0 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give SA-31 as a white solid (7 mg, 9%). Compound SA-31: 1 HNMR (500 MHz, CDCl3) δ (ppm):7.55 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.88 (AB, 1H), 4.48 (AB×d, 1H), 4.38 (AB×d, 1H), 2.59 (t, 1H), 2.23-2.16 (m, 1H), 2.09-2.05 (m, 1H), 1.00-1.90 (22H, m), 0.68 (s, 3H). LC-MS:rt=2.15min,m / z=403.3[M+H] + .

[0523] Example 46. Synthesis of compound SA-32

[0524] [ka]

[0525] To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL), 1H-pyridinium chloride was added. To the mixture was added azolazole-4-carbonitrile (37 mg, 0.4 mmol) and compound SC-SS (83 mg, 0.2 mmol). The mixture was stirred at room temperature for 15 hours, and then the residual mixture was poured into 5 mL of H2O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residual mixture was purified by reverse-phase prep-HPLC to give SA-32 as a white solid (20 mg, 23%). Compound SA-32: 1 HNMR (500 MHz, CDCl3) δ (ppm):7.86 (s, 1H), 7.81 (s, 1H), 5.02 (AB, 1H), 4.91 (AB, 1H), 4.48 (AB×d, 1H), 4.38 (AB×d, 1H), 2.61 (t, 1H), 2.23 (s, 1H), 2.21-2.17 (m, 1H), 2.07-2.03 (m, 1H), 1.00-1.90 (m, 21H), 0.67 (s, 3H). LC-MS:rt=2.22min,m / z=428.3[M+H] + .

[0526] Example 47. Synthesis of compound SA-33

[0527] [ka]

[0528] To a suspension of KCO (119 mg, 0.86 mmol) in THF (5 mL), 4-(methylsulfonyl)-1H-pyrazole (63 mg, 0.43 mmol) and reactant SC-SS (180 mg, 0.43 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The residual mixture was poured into 20 mL of HO and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual mixture was purified by reverse-phase prep-HPLC to give the title compound SA-33 as a white solid (53 mg, 0.110 mmol, yield = 25.6%). 1HNMR (500 MHz, CDCl3) δ (ppm):7.93 (s, 1H), 7.87 (s, 1H), 5.02 (AB, 1H), 4.92 (AB, 1H,), 4.48 (AB×d), 4.39 (AB×d, 1H), 3.14 (s, 1H), 2.63 (t, 1H), 2.24-2.17 (m, 1H), 2.07-2.04 (m, 1H), 1.00-1.90 (m, 24H), 0.68 (s, 3H). LC-MS:rt=2.06min,m / z=481.2[M+H] + .

[0529] Example 49. Synthesis of compound SA-35

[0530] [ka]

[0531] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added 1H-pyrazole (20 mg, 0.23 mmol) and SA-AA (36 mg, 0.09 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase prep-HPLC to give SA-35 as a white solid (8 mg, 21.6%). 1 H NMR (400 MHz, CDCl3), δ (ppm), 7.53(1H,s), 7.41(1H,s) 6.33 (s,1H), 4.97(AB,1H), 4.88(AB,1H), 2.58(1H, t), 1.00-2.25 (24H, m), 0.88(3H, t), 0.68(s, 3H). LC-MS:rt=2.39min,m / z=399.4(M + +1).

[0532] Example 50. Synthesis of compound SB-1

[0533] [ka]

[0534] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added pyrazole (13 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol). After stirring at room temperature for 15 h, the reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse-phase prep-HPLC to give the following: 7.54 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.87 (AB, 1H), 2.58 (t, 1H), 0.90-2.25 (m, 21 H), 0.69 (s, 3H).

[0535] Example 51. Synthesis of compound SB-2

[0536] [ka]

[0537] To a solution of crude SB (124.8 mg, 0.314 mmol, theoretical amount) in anhydrous THF (3 mL) was added 4-cyanopyrazole (58.5 mg, 0.628 mmol), followed by potassium carbonate (86.8 mg, 0.628 mmol). The solution was heated at 50° C. for 2 h. The solution was then diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by reverse-phase prep-HPLC to give the desired product (34.6 mg, 0.0845 mmol, 27% overall yield for two steps) as a white solid. 1HNMR (400 MHz, CDCl3) δ(ppm):7.86 (1H, s), 7.82 (1H, s), 5.01 (1H, AB), 4.91 (1H, AB), 2.61 (1H, t), 2.16-2.26 (2H, m), 2.04 (1H, m), 1.00-1.90 (21H, m), 0.68 (3H, s). LCMS:rt=2.26min,m / z=410.2[M+H] + .

[0538] Example 52. Synthesis of compound SB-3

[0539] [ka]

[0540] To a solution of the crude reactant (374.3 mg, 0.942 mmol, theoretical amount) in anhydrous THF (7.5 mL) was added 4-methylsulfonyl-1H-pyrazole (110 mg, 0.754 mmol), followed by potassium carbonate (130 mg, 0.942 mmol). The solution was heated at 25° C. overnight, and then the solution was diluted with dichloromethane (200 mL). The resulting solution was washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography ( Purification with petroleum ether / ethyl acetate (1:3) gave the crude product, which was contaminated with 4-methylsulfonyl-1H-pyrazole. The crude product was then recrystallized from ethyl acetate to give the pure product (38.4 mg, 0.083 mmol, 8.8% yield over two steps) as a white solid. 1 HNMR (500 MHz, CDCl3) δ(ppm):7.92 (1H, s), 7.87 (1H, s), 5.02 (1H, AB), 4.91 (1H, AB), 3.14 (3H, s), 2.63 (1H, t), 0.9-2.25 (21H, m), 0.68 (3H, s). LCMS:rt=2.15min,m / z=463.3[M+H]+ .

[0541] Example 53. Synthesis of compound SB-4

[0542] [ka]

[0543] To a solution of the crude reactant (61.1 mg, 0.143 mmol, theoretical amount) in anhydrous THF (5 mL) was added 1H-pyrazole (97 mg, 1.43 mmol), followed by potassium carbonate (198 mg, 1.43 mmol). The solution was heated at 50° C. overnight. 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 in vacuo. The crude product was purified by reverse-phase prep-HPLC to give product SB-4 (7 mg, 0.0169 mmol, overall yield for two steps=12%) as a white solid. 1 HNMR (400 MHz, CDCl3) δ (ppm) 7.55 (1H, d), 7.42 (1H, d), 6.33 (1H, t), 4.97 (1H, AB), 4.88 (1H, AB), 3.39 (3H, s), 3.19 (2H, s), 2.59 (1H, t, J=8.9 Hz), 0.69 (3H, s), 0.60-2.25 (24H, m). LC-MS:rt=2.31min,m / z=415.3[M+H] + .

[0544] Example 54. Synthesis of compound SB-5

[0545] [ka]

[0546] To a solution of the crude reactant (122.6 mg, 0.287 mmol, theoretical amount) in anhydrous THF (3 mL) was added 4-cyanopyrazole (134 mg, 1.435 mmol), followed by potassium carbonate (198 mg, 1.435 mmol). The solution was heated at 60° C. overnight. The solution was then diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by reverse-phase prep-HPLC to give the desired product SB-5 (12.4 mg, 0.0282 mmol, overall yield for two steps=9.8%) and a by-product (4.2 mg, 0.00955 mmol, overall yield for two steps=3.3%) as a white solid. Compound SB-5 1 HNMR (400 MHz, CDCl3) δ(ppm):7.86 (s, 1H), 7.81 (s, 1H), 5.02 (AB, 1H), 4.90 (AB, 1H), 3.42 (AB, 1H), 3.40 (S, 3H), 3.39 (AB, 1H), 2.64 (s, 1H), 2.61 (t, 1H), 1.00-2.25 (m, 23H), 0.67 (s, 3H). LC-MS:rt=2.32min,m / z=440.2[M+H] + .

[0547] Example 55. Synthesis of compound SB-7

[0548] [ka]

[0549] To a solution of the crude reactant (368 mg, 0.861 mmol, theoretical amount) in anhydrous THF (7.5 mL) was added 4-methylsulfonyl-1H-pyrazole (126 mg, 0.861 mmol), followed by potassium carbonate (119 mg, 0.861 mmol). The solution was heated at 25° C. overnight, then diluted with dichloromethane (200 mL), and the resulting solution was washed with brine (2×50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:3) to give the crude product, which was contaminated with 4-methylsulfonyl-1H-pyrazole. The crude product was then recrystallized from ethyl acetate to give the pure product (50 mg, 0.101 mmol, 12% overall yield for two steps) as a white solid. 1 HNMR (500 MHz, CDCl3) δ(ppm):7.92 (1H, s), 7.87 (1H, s), 5.02 (1H, AB), 4.91 (1H, AB), 3.39 (3H, s), 3.19 (2H, s), 3.14 (3H, s), 2.63 (1H, t), 0.9-2.25 (21H, m), 0.68 (3H, s). LCMS:rt=2.13min,m / z=493.0[M+H] + .

[0550] Example 56. Synthesis of compound SB-8

[0551] [ka]

[0552] To a suspension of KCO (25 mg, 0.18 mmol) in THF (5 mL) was added pyrazole (13 mg, 0.18 mmol) and compound SB-W (36 mg, 0.09 mmol). After stirring at room temperature for 15 hours, the reaction mixture was poured into 5 mL of HO and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (15.6 mg, 0.073 mmol, 40.4%). 1 HNMR (500 MHz, CDCl3) δ (ppm):7.54 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.87 (AB, 1H), 3.52 (q, 2H), 3.21 (s, 2H), 2.59 (t, 1H), 0.69 (s, 3H), 0.69-2.25 (m, 24H). LCMS:Rt=2.35min.m / z=429.4[M+H] + .

[0553] Example 57. Synthesis of compound SB-9

[0554] [ka]

[0555] To a suspension of KCO (63 mg, 0.46 mmol) in THF (10 mL) were added 4-cyanopyrazole (43 mg, 0.46 mmol) and compound SB-W (100 mg, 0.23 mmol). After stirring at room temperature for 15 h, the reaction mixture was poured into 5 mL of HO and extracted with EtOAc (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 give SB-9 as a white solid (43.5 mg, 0.095 mmol, 41.7%). 1HNMR (500 MHz, CDCl3) δ (ppm7.86 (1H, s), 7.82 (1H, s), 5.01 (1H, AB), 4.91 (1H, AB), 3.53 ( 2H, q), 3.22 (2H, s), 2.61 (1H, t), 0.67 (3H, s), 0.67-2.25 (24H, m). LCMS:Rt=2.37min.m / z=454.4[M+H] + .

[0556] Example 58. Synthesis of compound SB-10

[0557] [ka]

[0558] To a suspension of SB-FF (40 mg, 0.09 mmol) in THF (5 mL) was added 1H-pyrazole (30 mg, 0.45 mmol) and KCO (60 mg, 0.45 mmol). The mixture was stirred at 25 °C for 15 h. The solution was then diluted with ethyl acetate (100 mL), and the resulting solution was washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The reaction mixture was purified by reverse-phase prep-HPLC to give SB-10 as a white solid (15 mg, 38% yield). 1 H NMR (400 MHz, CDCl3), δ (ppm), 7.55 (s, 1H), 7.41 (s, 1H), 6.33 (s, 1H), 4.99-4.95 (AB, 1H), 4.90-4.87 (AB, 1H), 4.55 (1H, d, 1H), 2.60 (t, 1H), 0.70-2.25 (m, 22H), 0.71 (s, 3H).

[0559] Example 59. Synthesis of compound SB-11

[0560] [ka]

[0561] To a solution of the crude reactant SB-FF (50.7 mg, 0.122 mmol, theoretical amount) in anhydrous THF (1.5 mL) was added 4-cyanopyrazole (22.7 mg, 0.244 mmol), followed by potassium carbonate (33.7 mg, 0.244 mmol). The solution was stirred overnight at 25° 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 cooled to room temperature. and concentrated in vacuo. The crude product was purified by reverse-phase prep-HPLC to give the desired product (14.2 mg, 0.0332 mmol, overall yield for two steps = 27%) as a white solid. 1 HNMR (400 MHz, CDCl3) δ(ppm):7.85 (s, 1H), 7.81 (s, 1H), 5.03-4.87 (m, 2H), 4.62-4.50 (m, 1H), 2.63-2.62 (m, 1H), 2.30-2.20 (m, 1H), 2.05-1.95 (m, 2H), 1.90-1.60 (m, 6H), 1.50-1.20 (m, 15H), 0.70 (s, 3H). 19 FNMR (376 MHz, CDCl3) δ(ppm):-193.13. LCMS:rt=2.13min,m / z=428.0[M+H] + .

[0562] Example 60. Synthesis of compound SB-12

[0563] [ka]

[0564] To a solution of SB-FF (85 mg, 0.20 mmol) in 2 mL of DMF, 4-methyl-1H-pyrazole (33.6 mg, 0.41 mmol) and KCO (84.84 mg, 0.61 mmol) were added. The reaction mixture was stirred at 28 °C for 1 h. The resulting solution was quenched with water (10 mL) and extracted with EtOAc (15 mL × 2). The combined organic layers were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with (petroleum ether / ethyl acetate = 12 / 1 to 2 / 1) to give SB-12 (23.1 mg, yield: 31.6%) as a white solid. 1 H NMR (SB-12):(400 MHz, CDCl3) δ 7.34 (s, 1H), 7.17 (s, 1H), 4.92-4.75 (m, 2H), 4.66-4.47 (m, 1H), 2.60-2.56 (m, 1H), 2.25-1.99 (m, 6H), 1.91-1.61 (m, 6H), 1.54-1.03 (m, 15H), 0.84-0.74 (m, 1H), 0.70 (s, 3H). LCMS:rt=1.23min,m / z=417.2[M+H] + .

[0565] Example 61. Synthesis of compound SB-13

[0566] [ka]

[0567] SB-FF (100 mg, 0.241 mmol), 1H-pyrazole-3-carbonitrile A mixture of SB-13 (45 mg, 0.48 mmol), K2CO3 (66 mg, 0.48 mmol), and DMF (3 mL) was stirred at room temperature for 2 h. TLC showed the reaction was com...

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【Claim 1】 Spasm.

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