NZ752696A - 19-nor C3,3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof - Google Patents

Abstract

Provided herein are 19-nor C3,3-disubstituted C2l-pyrazolyl steroids of Formula (I), and pharmaceutically accept-able salts thereof; wherein-, R1, R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are as defined herein. 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.

Description

-NOR C3,3-DISUBSTITUTED C21-N-PYRAZOLYL STEROIDS AND S OF USE THEREOF This application is a divisional application of New Zealand Patent Application No. 713303, filed on 17 April 2014, and is related to ational Patent Application No. , filed on 17 April 2014 and claims ty from International Patent Application No. , filed on 17 April 2013; each of which is incorporated herein by reference in its entirety.

Background of the Invention Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by s neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across al membranes. At rest, the neuronal ne ses a potential (or membrane voltage) of approximately -70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K+, Na+, C1-, organic anions) balance across the neuronal semipermeable membrane.

Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause ne depolarization (change of potential from - 70 mV to -50 mV). This effect is mediated by postsynaptic nic receptors which are stimulated by choline to increase ne permeability to Na+ ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.

In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by GABA, a neurotransmitter. GABA has a profound influence on overall brain bility because up to 40% of the neurons in the brain e GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to tate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to tory inputs (i.e., reduced neuron excitability). In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability (the level of arousal).

It is well-documented that the GRC is responsible for the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium®) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC.

Accumulated evidence has now indicated that in on to the benzodiazepine and barbiturate binding site, the GRC contains a distinct site for neuroactive steroids (Lan, N. C. et al., Neurochem. Res. 16:347-356 ).

Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are droxyreduced pregnan-ZO-one and 301—21-dihydroxy—5-reduced pregnan-ZO-one, metabolites of hormonal steroids terone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain bility was recognized in 1986 (Maj ewska, M. D. et al., Science 232: 1004-1007 (1986); Harrison, N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

The ovarian hormone progesterone and its lites have been demonstrated to have nd effects on brain excitability (Backstrom, T. et al., Acta . Gynecol. Scand. Suppl. 130: 19-24 (1985); Pfaff, D.W and McEwen, B. S., Science 219:808-814 ; Gyermek et al., JMed Chem. 11: 117 (1968); t, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987)). The levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well documented that the levels of progesterone and its metabolites decrease prior to the onset of menses. The monthly recurrence of certain physical symptoms prior to the onset of menses has also been well documented. These symptoms, which have become associated with premenstrual syndrome (PMS), include stress, y, and migraine headaches (Dalton, K, Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Subjects with PMS have a monthly ence of symptoms that are present in premenses and absent in postmenses.

In a similar fashion, a reduction in progesterone has also been temporally correlated with an increase in seizure frequency in female epileptics, i. e., catamenial epilepsy (Laidlaw, J ., Lancet, 1235-1237 (1956)). A more direct correlation has been observed with a reduction in progesterone lites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). In addition, for subjects with primary generalized petit mal epilepsy, the temporal incidence of seizures has been correlated with the incidence of the symptoms of premenstrual syndrome trom, T. et al., J.

Psychosom. Obstet. Gynaecol. 2:8-20 ). The steroid deoxycorticosterone has been found to be effective in treating subjects with epileptic spells correlated with their menstrual cycles (Aird, 3O RB. and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)), A syndrome also related to low progesterone levels is postnatal depression (PND). ately after birth, progesterone levels decrease dramatically leading to the onset of PND. The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe y and irritability. PND-associated depression is not amenable to treatment by classic antidepressants, and women experiencing PND show an increased nce of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).

Collectively, these observations imply a crucial role for progesterone and deoxycorticosterone and more specifically their lites in the homeostatic regulation of brain excitability, which is manifested as an increase in e activity or symptoms associated with catamenial epilepsy, PMS, and PND. The ation between reduced levels of progesterone and the symptoms ated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., JPsychosomObstet.

Gynaecol. 2:8-20 (1983)); Dalton, K, Premenstrual Syndrome and terone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy," in Advances in Epileptology.‘ XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279- 282, and Dalton, K, Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the aforementioned syndromes. For example, no dose-response relationship exists for progesterone in the ent of PMS (Maddocks et al., Obstet. Gynecol. 154: 573-581 (1986); Dennerstein et al., Brit. Med J 290: 1 6-1 7 (1986)).

New and improved neuroactive steroids are needed that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of lated diseases. The compounds, itions, and methods described herein are directed toward this end.

Summary of the Invention The present invention is based, in part, on the desire to provide novel 19-nor (i.e., C19 desmethyl) compounds, e.g, related to progesterone, deoxycorticosterone, and their metabolites, with good potency, cokinetic (PK) properties, oral ilability, formulatability, stability, safety, clearance and/or metabolism. One key feature of the compounds as described herein is disubstitution at the C3 position (eg, with one substituent being a 30: hydroxy moiety. The inventors envision titution at C-3 will eliminate the potential for oxidation of the hydroxy moiety to the ketone, prevent further lism, and reduce the ial for secondary elimination pathways, such as glucuronidation. The inventors further envision the overall effect of C3 disubstitution should be of improving the overall PK parameters and reducing potential toxicities and side s, which may allow, in certain embodiments, stration orally and/or chronically. Another key feature of the compounds as described herein is the presence of a hydrogen at the C19 position ("19-nor") rather than a methyl group. The inventors envision 19- nor compounds, as compared to their C19-methyl counterparts, will have improved physical properties, such as improved solubility. The inventors envision futher enhancement of solubility, for example, when the AB ring system is in the cis configuration.

Thus, in one , provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl ds of Formula (I): and pharmaceutically acceptable salts f; wherein: — represents a single or double bond; R1 is substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3_5 carbocyclyl; R2 is hydrogen, n, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3_6 carbocyclyl, or —ORA2, wherein RA2 is hydrogen or substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, or substituted or unsubstituted C3_6 carbocyclyl; R3a is hydrogen or —ORA3, wherein RA3 is hydrogen or substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C26 alkenyl, substituted or unsubstituted C2_6 alkynyl, or tuted or unsubstituted C3.6 carbocyclyl, and R3b is hydrogen; or R361 and R3b are joined to form an oxo (=0) group; each instance of R4&1 and R4b is independently hydrogen, substituted or unsubstituted C1_6 alkyl, or halogen, provided if the 2 between C5 and C6 is a single bond, then the hydrogen at C5 and R4a are each independently provided in the alpha or beta configuration, and R4b is ; each instance of R5, R6, and R7 is, ndently, hydrogen, n, -N02, -CN, -ORGA, - N(RGA)2, RGA, -C(=O)ORGA, -OC(=O)RGA, -OC(=O)ORGA, -C(=O)N(RGA)2, — N(RGA)C(=O)RGA, -OC(=O)N(RGA)2, -N(RGA)C(=O)ORGA, -N(RGA)C(=O)N(RGA)2, -SRGA, GA, e.g., RGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, — S(=O)2RGA, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C3_6 carbocylyl, or substituted or unsubstituted 3- to 6- membered heterocylyl; and each instance of RGA is independently hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted CM alkenyl, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C3_6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen ting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring. ds of Formula (I), sub—genera thereof, and pharmaceutically able salts thereof are collectively referred to herein as "compounds of the present invention." In another aspect, provided is a pharmaceutical composition comprising a compound of the t invention and a pharmaceutically acceptable excipient. In n embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the nd of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the t invention is provided in a lactically ive .

Compounds of the present invention as bed herein, act, in certain embodiments, as GABA modulators, e.g., effecting the GABAA receptor in either a positive or negative . As modulators of the excitability of the central nervous system (CNS), as mediated by their ability to modulate GABAA receptor, such compounds are expected to have CNS-activity.

Thus, in r aspect, provided are methods of ng a CNS—related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the t invention. In certain embodiments, the CNS—related disorder is selected from the group consisting of a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is stered chronically.

Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims.

Definitions Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below.

The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook ofChemistry and Physics, 75th Ed, inside cover, and specific functional groups are lly defined as described therein. Additionally, general principles of organic chemistry, as well as ic functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, ito, 1999; Smith and March, March ’s Advanced Organic try, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive c Transformations, VCH Publishers, Inc, New York, 1989; and Carruthers, Some Modern Methods ofOrganic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1 987.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and llization of chiral salts; or preferred isomers can be prepared by asymmetric ses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., edron 33:2725 (1977); Eliel, Stereochemistry ofCarbon Compounds (McGraw—Hill, NY, 1962); and Wilen, Tables ofResolvingAgents and Optical Resolutions p. 268 (EL. Eliel, Ed, Univ. of Notre Dame Press, Notre Dame, IN 1972).

The invention additionally encompasses compounds described herein as individual s ntially free of other isomers, and alternatively, as mixtures of various isomers.

When a range of values is listed, it is intended to encompass each value and sub—range within the range. For example "C1_6 alkyl" is intended to encompass, C1, C2, C3, C4, C5, C6, C1_6, C1_5, C1_4, C1—3, C1—2, C2—6, C2—5, C2—4, C2—3, C3—6, C3—5, C3—4, C44, C4—5, and C5—6 alkyl. 2O The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and ed scope of the present invention. When describing the invention, which may include compounds, pharmaceutical itions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise , the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein. The articles "a" and "an" may be used herein to refer to one or to more than one (i. e. at least one) of the tical s of the article. By way of e "an analogue" means one analogue or more than one analogue.

"Alkyl" refers to a radical of a straight—chain or branched saturated arbon group having from 1 to 20 carbon atoms ("C140 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C142 alkyl"). In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C1_10 alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1_9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1_g alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1_7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1_6 alkyl", also referred to herein as "lower ). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1_5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1_4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1_3 alkyl"). In some ments, an alkyl group has 1 to 2 carbon atoms ("C1_2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some ments, an alkyl group has 2 to 6 carbon atoms ("C2_6 alkyl"). Examples of C1_6 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). Additional examples of alkyl groups include n—heptyl (C7), n—octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e. g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain ments, the alkyl group is tituted C1_1o alkyl 2O (e.g., —CH3). In certain embodiments, the alkyl group is substituted C1_10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (- CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

As used herein, "alkylene,7) ccalkenylene," and "alkynylene," refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is ed for a particular ene,3) ccalkenylene," and "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. ene," "alkenylene," and "alkynylene" groups may be substituted or unsubstituted with one or more tuents as described .

"Alkylene" refers to an alkyl group wherein two hydrogens are removed to e a divalent 3O radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2—), ethylene (-CH2CH2-), ene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted ne groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,—CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted ene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, - CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

"Alkenyl" refers to a radical of a straight—chain or branched hydrocarbon group having from 2 to carbon atoms, one or more carbon—carbon double bonds (e. g., 1, 2, 3, or 4 carbon—carbon double , and optionally one or more —carbon triple bonds (e.g., 1, 2, 3, or 4 carbon— carbon triple bonds) ("C240 alkenyl"). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2_10 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2_9 alkenyl"). In some ments, an alkenyl group has 2 to 8 carbon atoms ("C2_g alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2_7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2_6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2_5 l"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2_4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2_3 alkenyl").

In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon—carbon double bonds can be internal (such as in 2—butenyl) or terminal (such as in 1— butenyl). es of C2_4 alkenyl groups include ethenyl (C2), 1—propenyl (C3), 2—propenyl (C3), 2O 1—butenyl (C4), 2—butenyl (C4), butadienyl (C4), and the like. Examples of C2_6 alkenyl groups include the entioned C2_4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cg), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally tuted, 116., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 tuents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C240 l. In certain embodiments, the alkenyl group is substituted €2-10 alkenyl. ylene" refers to an alkenyl group wherein two hydrogens are d to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., - CH=CHCH2-, -CH2-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)-), tuted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, - CHZCHCH(CH3)-, C(CH3)2-, 3)-CH=CH-,-C(CH3)2-CHZCH-, -CH2- C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

"Alkynyl" refers to a radical of a straight—chain or branched hydrocarbon group having from 2 to carbon atoms, one or more carbon—carbon triple bonds (e.g., l, 2, 3, or 4 carbon—carbon triple bonds), and optionally one or more carbon—carbon double bonds (e.g., l, 2, 3, or 4 carbon—carbon double bonds) ("C240 l"). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2_10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2_9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2_g alkynyl"), In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2_7 alkynyl"). In some ments, an alkynyl group has 2 to 6 carbon atoms ("C24, alkynyl"). In some embodiments, an alkynyl group has 2 to carbon atoms ("C2_5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2_4 alkynyl"). In some ments, an alkynyl group has 2 to 3 carbon atoms ("C2_3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 l"). The one or more carbon—carbon triple bonds can be internal (such as in 2—butynyl) or al (such as in 1— butynyl). Examples of C2_4 alkynyl groups include, without limitation, l (C2), l—propynyl (C3), 2—propynyl (C3), l—butynyl (C4), 2—butynyl (C4), and the like. Examples of C2_6 alkenyl groups include the aforementioned C2_4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and 2O the like. Additional examples of l include heptynyl (C7), octynyl (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, 1'.e., unsubstituted (an "unsubstituted alkynyl") or tuted (a "substituted alkynyl") with one or more substituents, e.g., for instance from 1 to 5 substituents, l to 3 substituents, or 1 substituent.

In certain embodiments, the alkynyl group is unsubstituted C240 alkynyl. In certain ments, the alkynyl group is substituted C240 alkynyl.

"Alkynylene" refers to a linear alkynyl group n two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted lene, substituted or unsubstituted propynylene, and the like. 3O The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., l, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, orus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i. 6., n the point of attachment. In certain ments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCHo alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms roC1_9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC1_g alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC1_7 alkyl"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC1_6 ). In some embodiments, a alkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC1_5 alkyl"). In some embodiments, a alkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms roC1_4 alkyl").

In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC1_3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC1_2 ). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl").

In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC2_6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl 2O group is independently unsubstituted (an "unsubstituted heteroalkyl") or tuted (a "substituted heteroalkyl") with one or more tuents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCHo alkyl. In certain embodiments, the heteroalkyl group is a substituted C1_1o alkyl.

The term "heteroalkenyl," as used herein, refers to an alkenyl group, as d herein, which further comprises one or more (e.g., l, 2, 3, or 4) heteroatoms (e. g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, 3O and 1, 2, 3, or 4 heteroatoms ("heteroCHo alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2_9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2_g alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2_7 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC2_6 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms roC2_5 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms ("heteroC2_4 alkenyl"). In some embodiments, a alkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("heteroC2_3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and l or 2 heteroatoms roC2_6 alkenyl"), Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more tuents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2_1o alkenyl. In certain embodiments, the heteroalkenyl group is a tuted heteroC2_1o alkenyl.

The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e. g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is ed between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a 2O alkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 atoms ("heteroCHo alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2_9 l"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2_g alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2_7 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC2_6 l"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2_5 alkynyl"). In some ments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms ("heteroC2_4 alkynyl"). In some embodiments, a alkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroC2_3 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and l or 2 heteroatoms ("heteroC2_6 l"). Unless otherwise specified, each instance of a heteroalkynyl group is ndently unsubstituted (an "unsubstituted heteroalkynyl") or tuted (a "substituted heteroalkynyl") with one or more tuents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2_1o alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2_1o alkynyl.

As used herein, "alkylene,7) ccalkenylene,)9 44alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene," refer to a divalent radical of an alkyl, alkenyl, alkynyl group, alkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular "alkylene,w 66alkenylene,79 nylene," "heteroalkylene," "heteroalkenylene," or "heteroalkynylene," group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain, "Alkylene," "alkenylene," ylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups may be substituted or unsubstituted with one or more substituents as described herein.

"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 7: electrons shared in a cyclic array) having 6—14 ring carbon atoms and zero heteroatoms ed in the aromatic ring system ("C6_14 . In some ments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl such as 1— naphthyl and 2—naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C14 aryl", e. g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, ne, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, hene, perylene, phenalene, phenanthrene, , pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently ally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is tituted C644 aryl. In certain embodiments, the aryl group is substituted C6_14 aryl.

In certain embodiments, an aryl group tuted with one or more of groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

Examples of representative substituted aryls include the following I} cc R57 and R57 R57 . wherein one of R56 and R57 may be hydrogen and at least one of R56 and R57 is each independently selected from C1-C8 alkyl, C1-C3 haloalkyl, 4-10 ed heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58C0R59, NngSOR59 NRSSSOgng, COOalkyl, COOaryl, CONRSSR", CONR580R59, NR58R59, sozNRSSR", S-alkyl, SOalkyl, SOgalkyl, Saryl, , SOgaryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, ally containing one or more heteroatoms selected from the group N, O, or S. R60 and R61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6—C10 aryl, substituted C6-C10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl .

Other representative aryl groups having a fused heterocyclyl group include the following: a?) £0 {r wherein each W is selected from C(R66)2, NR", 0, and S; and each Y is selected from yl, NR", 0 and S; and R66 is independently hydrogen, C1-C3 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 ed heteroaryl.

"Fused aryl" refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

"Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an ally substituted alkyl group substituted by an optionally substituted aryl group. oaryl" refers to a radical of a 5—1 0 membered monocyclic or bicyclic 4n+2 aromatic ring system (e. g., having 6 or 10 7t electrons shared in a cyclic array) having ring carbon atoms and 1—4 ring heteroatoms provided in the ic ring system, wherein each heteroatom is independently selected from en, oxygen and sulfur ("5—10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. aryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the aryl ring, as defined above, is fused with one or more yclyl or cyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. oaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of ment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.

Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, 1'.e., either the ring g a heteroatom (e.g., lyl) or the ring that does not contain a heteroatom (e.g., 5— indolyl).

In some embodiments, a heteroaryl group is a 5—1 0 ed aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5—1 0 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5—8 membered aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms ed in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5—8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5—6 membered aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5—6 ed heteroaryl"). In some embodiments, the 5—6 membered heteroaryl has 1—3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 membered heteroaryl has 1—2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5— 3O 6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is ndently optionally substituted, 126., tituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5—14 membered aryl. In n embodiments, the heteroaryl group is substituted 5—14 ed heteroaryl.

Exemplary 5—membered heteroaryl groups ning one heteroatom include, without tion, pyrrolyl, furanyl and thiophenyl. Exemplary 5—membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5—membered heteroaryl groups containing three heteroatoms e, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5—membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6— membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.

Exemplary 6—membered heteroaryl groups containing two heteroatoms include, without tion, pyridazinyl, dinyl, and pyrazinyl. Exemplary 6—membered heteroaryl groups ning three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.

Exemplary 7—membered heteroaryl groups containing one heteroatom e, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary cyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, iadiazolyl, indolizinyl, and purinyl. Exemplary 6,6— bicyclic heteroaryl groups include, without tion, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, inyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following: n each Y is selected from carbonyl, N, NR", 0, and S; and R65 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl. oaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally tuted heteroaryl group.

"Carbocyclyl" or "carbocyclic" refers to a radical of a non—aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("€3-10 carbocyclyl") and zero heteroatoms in the non— aromatic ring system. In some ments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3_g carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3_6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3_6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C540 carbocyclyl"). Exemplary C34, yclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), entenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.

Exemplary C3_g carbocyclyl groups include, without limitation, the aforementioned C3_6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), eptadienyl (C7), cycloheptatrienyl (C7), ctyl (Cg), cyclooctenyl (C3), bicyclo[2.2.l]heptanyl (C7), bicyclo[2.2.2]octanyl (C3), and the like. Exemplary C340 carbocyclyl groups include, without limitation, the aforementioned C3_s carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro—lH—indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic cyclic carbocyclyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. cyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to ate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently ally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the yclyl group is unsubstituted C3_1o carbocyclyl. In n embodiments, the carbocyclyl group is a substituted C3_10 carbocyclyl.

In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C3_10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3_g cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5_10 cycloalkyl"). Examples of C54 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3_6 cycloalkyl groups include the aforementioned C5_6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of (33.3 cycloalkyl groups include the aforementioned C3_6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (Cg). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain ments, the cycloalkyl group is unsubstituted C340 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C340 lkyl.

"Heterocyclyl" or "heterocyclic" refers to a radical of a 3— to lO—membered non—aromatic ring system having ring carbon atoms and l to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, , boron, phosphorus, and silicon ("3—10 membered heterocyclyl"). In heterocyclyl groups that n one or more nitrogen atoms, the point of attachment can be a carbon or en atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic cyclyl") or a fused, d or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring s wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or cyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cyclyl ring, and in such instances, the number of ring s ue to designate the number of ring s in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a ituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3—10 membered heterocyclyl. In certain embodiments, the cyclyl group is substituted 3—10 membered heterocyclyl.

In some ments, a heterocyclyl group is a 5—1 0 membered non—aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, , sulfur, boron, phosphorus, and silicon ("S—10 membered heterocyclyl"). In some embodiments, a cyclyl group is a 5—8 membered non—aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5—8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5—6 ed non—aromatic ring system having ring carbon atoms and 1— 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5—6 membered heterocyclyl"). In some embodiments, the 5—6 membered heterocyclyl has 1—3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 membered heterocyclyl has 1—2 ring heteroatoms selected from nitrogen, , and sulfur. In some embodiments, the 5—6 membered heterocyclyl has one ring heteroatom ed from nitrogen, oxygen, and sulfur. ary 3—membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, nyl. Exemplary 4—membered heterocyclyl groups containing one atom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5— membered cyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, othiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl—2,5—dione. ary S—membered heterocyclyl groups containing two atoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidinone. Exemplary 5—membered cyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6—membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6—membered heterocyclyl groups containing two heteroatoms e, without limitation, piperazinyl, morpholinyl, nyl, dioxanyl. Exemplary 6—membered cyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary ered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8— membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, nyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.

Exemplary 6-membered cyclyl groups fused to an aryl ring (also referred to herein as a 6,6- bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Particular es of heterocyclyl groups are shown in the following illustrative examples: 1? \C‘" 10Y) Y/X 15'? Y Y) Cd‘Y £1 TV"? +Yfi t@ (1% Y Y w \N Y Y kwY/A/ (:[WY>/ wherein each W is selected from CR67, C(R67)2, NR67, O, and S; and each Y is ed from NR67, O, and S; and R67 is independently hydrogen, C1-C3 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, y, azido, carboxyl, cyano, cycloalkyl, halogen, y, keto, nitro, thiol, -S-alkyl, —S-aryl, -S(O)-alkyl,— S(O)-aryl, —S(O)2-alkyl, and -S(O)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.

"Hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom, Hetero may be applied to any of the hydrocarbyl groups bed above such as alkyl, e. g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

"Acyl" refers to a radical —C(O)R20, where R20 is hydrogen, tuted or unsubstitued alkyl, substituted or titued alkenyl, tuted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or tuted or unsubstitued heteroaryl, as defined herein. "Alkanoyl" is an acyl group wherein R20 is a group other than hydrogen. Representative acyl groups e, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), exylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (- C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), —C(O)-C1-Cg alkyl, —C(O)-(CH2)I(C6-C10 aryl), — C(O)-(CH2)t(5-lO ed aryl), —C(O)-(CH2)[(C3-C10 cycloalkyl), and (CH2)t(4- membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R21 is C1- C8 alkyl, substituted with halo or hydroxy; or C3—C10 cycloalkyl, 4—10 membered heterocyclyl, C6- C10 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 tituted C1-C4 haloalkoxy or hydroxy.

"Acylamino" refers to a radical (O)R23, where each instance of R22 and R23 is independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or tituted heterocyclyl, tuted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R22 is an amino protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, lamino and carbonylamino. Particular exemplary "acylamino" groups are — 24C(O)-C1-Cg alkyl, — 24C(O)-(CH2)t(C6-C10 aryl), — 24C(O)- (CH2)t(5-10 membered heteroaryl), — 24C(O)—(CH2)t(C3-C10 cycloalkyl), and — 24C(O)- (CH2)t(4-10 ed heterocyclyl), wherein t is an integer from O to 4, and each R24 independently represents H or C1-C8 alkyl.In certain embodiments, R25 is H, C1-C8 alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 , tituted C1-C4 haloalkyl, tituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and R26 is H, C1- C8 alkyl, substituted with halo or y; C3—C10 cycloalkyl, 4—1 0 membered heterocyclyl, C6-C10 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; provided at least one of R25 and R26 is other than H.

"Acyloxy" refers to a radical —OC(O)R27, where R27 is hydrogen, substituted or unsubstitued alkyl, 3O substituted or unsubstitued alkenyl, substituted or titued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or tuted or unsubstitued heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, exylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certain ments, R28 is C1-C8 alkyl, tuted with halo or hydroxy; C3- C10 cycloalkyl, 4-10 membered cyclyl, C6—C10 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.

"Alkoxy" refers to the group —OR29 where R29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or titued carbocyclyl, tuted or unsubstituted cyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl. ular alkoxy groups are methoxy, ethoxy, n-propoxy, poxy, n- butoxy, tert-butoxy, sec-butoxy, n—pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, z'.e. with between 1 and 6 carbon atoms, Further particular alkoxy groups have between 1 and 4 carbon atoms.

In certain embodiments, R29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, S(O)—, aryl—S(O)-, alkyl—S(O)2- and aryl-S(O)2-. Exemplary ‘substituted ’ groups include, but are not limited to, —O-(CH2)I(C6-C10 aryl), —O-(CH2)t(5-1O membered heteroaryl), —O-(CH2)t(C3-C10 cycloalkyl), and —O-(CH2)t(4-l 0 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular ary ‘substituted ’ groups are - OCF3, -OCH2CF3, -OCH2Ph, -OCH2—cyclopropyl, -OCH2CH20H, and —OCH2CH2NMe2.

"Amino" refers to the radical -NH2.

"Substituted amino" refers to an amino group of the formula -N(R38)2 wherein R38 is hydrogen, tuted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued yclyl, substituted or unsubstituted heterocyclyl, substituted or tituted aryl, substituted or unsubstitued heteroaryl, or an amino protecting group, wherein at least one of R38 is not a hydrogen. In certain embodiments, each R38 is independently selected from hydrogen, C1-C8 alkyl, C3-C8 l, C3-C8 alkynyl, C6-C10 aryl, 5- membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl, or C1-C8 alkyl, substituted with halo or hydroxy; C3-C8 l, substituted with halo or hydroxy; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)[(C6-C10 aryl), -(CH2)[(5-10 membered heteroaryl), - (CH2)t(C3-C10 cycloalkyl), or [(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is tuted 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 R38 groups are joined to form an alkylene group.

Exemplary "substituted amino" groups include, but are not limited to, —NR39-C1-Cg alkyl, —NR39- (CH2)t(C6-C10 aryl), —NR39—(CH2)t(5-10 membered heteroaryl), —NR39-(CH2)t(C3-C10 cycloalkyl), and —NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from O to 4, for instance 1 or 2, each R39 independently represents H or C1-C3 alkyl; and any alkyl groups present, may themselves be substituted by halo, tuted or unsubstituted amino, or hydroxy; and any aryl, aryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 , unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1—C4 haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, ino, substituted ino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino . " refers to the radical -N3.

"Carbamoyl" or "amido" refers to the radical -C(O)NH2.

"Substituted carbamoyl" or "substituted amido" refers to the radical —C(O)N(R62)2 wherein each R62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted cyclyl, substituted or unsubstituted aryl, substituted or unsubstitued heteroaryl, or an amino ting group, wherein at least one of R62 is not a hydrogen. In certain embodiments, R62 is selected from H, C1-C3 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, aralkyl, 5-10 ed heteroaryl, and heteroaralkyl; or C1-C3 alkyl substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is tuted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or y; provided that at least one R62 is other than H.

Exemplary ituted carbamoyl" groups include, but are not limited to, —C(O) NR64-C1-Cg alkyl, —C(O)NR64-(CH2)t(C6-C10 aryl), —C(O)N64-(CH2)[(5-1 0 membered heteroaryl), —C(O)NR64- (CH2)t(C3-C10 cycloalkyl), and —C(O)NR64-(CH2)t(4—1 0 membered heterocyclyl), wherein t is an r from 0 to 4, each R64 independently represents H or C1-C8 alkyl and any aryl, aryl, cycloalkyl or heterocyclyl groups present, may themselves 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 y.

"Carboxy" refers to the radical —C(O)OH.

"Cyano" refers to the l -CN.

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

"Hydroxy" refers to the radical -OH.

"Nitro" refers to the radical —N02.

"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, entylmethyl, exylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, exylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

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

"Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such lkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

"Fused cycloalkenyl" refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation d to impart aromaticity to the cycloalkenyl ring.

"Ethylene" refers to substituted or unsubstituted -.

"Ethenyl" refers to substituted or unsubstituted -.

"Ethynyl" refers to —(CEC)—. gen-containing heterocyclyl" group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e. g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e. g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, lidine, piperazine, and N—alkyl piperazines such as N-methyl zine. Particular examples include azetidine, piperidone and piperazone.

"Thioketo" refers to the group =S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e. g., ituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or stituted" aryl or "substituted" or "unsubstituted" heteroaryl . In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution s in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by ngement, cyclization, elimination, or other reaction.

Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or ent at each position. The term "substituted" is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents bed herein that results in the formation of a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen tuents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —N02, —N3, — SOZH, —so3H, —OH, —0Raa, —ON(Rbb)2, —N(Rbb)2, —N(Rbb);X—, —N(ORCC)Rbb, —SH, —SRaa, — SSRCC, —C(=0)Raa, —C02H, —CHO, —C(OR°°)2, —C02Raa, —0C(=0)Raa, —0C02Raa, —C(=O)N(Rbb)2, —OC(=O)N(Rbb)2, —NRbbC(=O)Raa, —NRbbC02Raa, —NRbbC(=O)N(Rbb)2, —C(=NRbb)Raa, — C(=NRbb)ORaa, —OC(=NRbb)Raa, —OC(=NRbb)ORaa, —C(=NRbb)N(Rbb)2, —OC(=NRbb)N(Rbb)2, — NRbbC(=NRbb)N(Rbb)2, —C(=O)NRbbSOzRaa, —NRbbSOzRaa, —SOzN(Rbb)2, —s02Raa, —s020Raa, — OSOgRaa, -S(O)Raa, e.g., aa, OS(—O)Raa, Si(Raa)3, —OSi(Raa)3 N(Rbb)2, — C(=O)SRaa, —C(=S)SRaa, —SC(=S)SRaa, —SC(=O)SRaa, —OC(=O)SRaa, —SC(=O)ORaa, —SC(=O)Raa, —P(=0)2Raa, —0P(=0)2Raa, —P(=0)(Raa)2, —0P(=0)(Raa)2, —OP(=O)(OR°°)2, —P(=O)2N(Rbb)2, — OP(=O)2N(Rbb)2, —P(=O)(NRbb)2, —OP(=O)(NRbb)2, —NRbbP(=O)(OR°°)2, —NRbbP(=O)(NRbb)2, — 2, —P(RCC)3, °)2, °)3, )2, —B(ORCC)2, —BRaa(ORC°), c1_10 alkyl, c1_10 perhaloalkyl, C240 alkenyl, C240 alkynyl, C3_10 carbocyclyl, 3—14 membered heterocyclyl, C6_14 aryl, and 5—14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with O, l, 2, 3, 4, or 5 Rdd groups, or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, = bbC(=O)Raa, =NNRbbC(=O)ORaa, = bbS(=0)2Raa, =NRbb, or =NORCC; 2O each instance of Ralal is, independently, selected from C1_1o alkyl, C1_1o perhaloalkyl, C240 alkenyl, C240 alkynyl, C3_10 carbocyclyl, 3—14 membered heterocyclyl, C6_14 aryl, and 5— 14 membered heteroaryl, or two R33 groups are joined to form a 3—14 membered heterocyclyl or 5—14 ed heteroaryl ring, wherein each alkyl, l, l, carbocyclyl, heterocyclyl, aryl, and heteroaryl is ndently substituted with 0, 1, 2, 3 4 7 7 or 5 Row1 groups; each instance of Rbb is, independently, selected from hydrogen, —OH, —ORaa, —N(R°C)2, — CN, —C(=O)Raa, —C(=O)N(RCC)2, —C02Raa, —SOzRaa, —C(=NRCC)ORaa, —C(=NRC°)N(RCC)2, — SO;N(R°°)2, —SOZR°°, CC, —SORaa, —C(=S)N(RCC)2, —C(=O)SRCC, —C(=S)SRc°, — P(=O)2Raa, (Raa)2, —P(=O)2N(RC°)2, —P(=O)(NRCC)2, C140 alkyl, C140 perhaloalkyl, C240 alkenyl, C240 alkynyl, C340 carbocyclyl, 3—14 membered heterocyclyl, C6_14 aryl, and 5—14 membered aryl, or two Rbb groups are joined to form a 3—14 membered heterocyclyl or 5—14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and aryl is independently substituted with O, 1, 2, 3, 4, or 5 Rdd groups; each instance of RCC is, ndently, selected from hydrogen, C1_1o alkyl, C1_1o oalkyl, C2_10 alkenyl, €2-10 alkynyl, €3-10 yclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 membered heteroaryl, or two Rcc groups are joined to form a 3—14 membered heterocyclyl or 5—14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently tuted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, CN, N02, N3, SOzH, so3H, —OH, —0Ree, —0N(Rff 2, —N(Rff 2, —N(Rff)2*x, —N(ORee)Rff, —SH, —SRee, —SSRee, — "e, —Co2H, ", )Ree, —OCO2Ree, —C(=0)N(Rff 2, —0C(=0)N(Rff 2, — NRffC(=O)Ree, —NRffCO2Ree, — ffC(=0)N(Rff 2, —C(=NRff)ORee, —OC(=NRfi)Ree, — OC(=NRff)ORee, —C(=NRff)N(Rff 2, —0C(=NR‘"f)N(Rff 2, — ffC(=NRff)N(Rff 2,— NRffSO2Ree, —so2N(Rff 2, —SO2R", —so20Ree, —oso2Rei -S(0)Ree, e. g.,—S(=O)Ree, — s1(Ree)3, —os1(Ree)3, —C(=S)N(Rff 2, —C(=O)SRee, SRee, —SC(=S)SRee, —P(=0)2Ree, —P(=O)(Ree)2, —OP(=O)(Ree)2, —OP(=O)(ORee)2, C1_6 alkyl, C1_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C340 carbocyclyl, 3—10 membered heterocyclyl, C640 aryl, 5—10 membered aryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, cyclyl, aryl, and 2O heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg , or two geminal Rdd substituents can be joined to form =0 or :8; each ce of R66 is, independently, selected from C1_6 alkyl, C1_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3_10 carbocyclyl, CHO aryl, 3—1 0 membered heterocyclyl, and 3—10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, yclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rff is, independently, selected from hydrogen, C1_6 alkyl, C1_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C340 carbocyclyl, 3—10 membered heterocyclyl, C540 aryl and —10 membered heteroaryl, or two Rff groups are joined to form a 3—14 membered heterocyclyl or 5—14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, 3O carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with O, 1, 2, 3, 4, or 5 Rgg groups; and each instance of Rgg is, independently, halogen, CN, N02, N3, SOzH, SO3H, —OH, — OC1_6 alkyl, —ON(C1_6 alkyl)2, —N(C1_6 alkyl)2, —N(C1_6 3l)C, _6 alkyl)2l}C, —NH2(C1_6 alkyl) 5C, —NH3*>C, —N(OC1_6 (C1_6 alkyl), —N(OH)(C1_6 alkyl), — NH(OH), —SH, —SC1_6 alkyl, —SS(C1_6 alkyl), —C(=O)(C1_6 alkyl), —C02H, —C02(C1_6 alkyl), —OC(=O)(C1_6 alkyl), —OC02(C14 alkyl), —C(=O)NH2, —C(=O)N(C1_6 alkyl)2, — OC(=O)NH(C1_6 alkyl), —NHC(=O)( CH5 alkyl), —N(C1_6 alkyl)C(=O)( C1_6 alkyl), — NHC02(C1_6 alkyl), —NHC(=O)N(C1_6 alkyl)2, —NHC(=O)NH(C1_6 , —NHC(=O)NH2, —C(=NH)O(C1_6 ,—OC(=NH)(C1_6 alkyl), —OC(=NH)OC1_6 alkyl, —C(=NH)N(C1_6 alkyl)2, —C(=NH)NH(C1_6 alkyl), —C(=NH)NH2, —OC(=NH)N(C1_6 alkyl)2, — OC(NH)NH(C1_6 alkyl), —OC(NH)NH2, —NHC(NH)N(C1_6 alkyl)2, —NHC(=NH)NH2, — NHS02(C1_6 alkyl), —SOZN(C1_6 alkyl)2, —SOzNH(C1_6 alkyl), —SOzNH2,—SOzC1_6 alkyl, — SOzOC1_6 alkyl, —0802C1_6 alkyl, —SOC1_6 alkyl, —Si(C1_6 alkyl)3, —OSi(C1_6 alkyl)3 — C(=S)N(C1_6 alkyl)2, C(=S)NH(C1_6 alkyl), H2, —C(=O)S(C1_6 alkyl), —C(=S)SC1_6 alkyl, )SC1_6 alkyl, —P(=O)2(C1_6 alkyl), —P(=O)(C1_6 alkyl)2, —OP(=O)(C1_6 alkyl)2, —OP(=O)(OC1_6 alkyl)2, C1_6 alkyl, C1_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C340 carbocyclyl, C6_1o aryl, 3—10 membered cyclyl, 5—10 membered heteroaryl, or two geminal Rgg substituents can be joined to form =0 or :8; wherein X‘ is a counterion.

A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e. g., F‘, Cl‘, Br‘, 1—), NO3‘, C104: OH_, H2PO4‘, HSO4‘, SO4'2sulfonate ions (e.g., sulfonate, trifluoromethanesulfonate, p—toluenesulfonate, benzenesulfonate, lO—camphor sulfonate, naphthalene—2—sulfonate, naphthalene—l—sulfonic acid—S—sulfonate, ethan—l—sulfonic acid—2—sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, e, tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits, and e y, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —ORaa, —N(R°°)2, —CN, —C(=O)Raa, —C(=O)N(R°°)2, — cozRaa, —s02Raa, —C(=NRbb)Raa, —C(=NRCC)ORaa, CC)N(RCC)2, —SOgN(RCC)2, —SOzR°°, — SOZOR", —SORaa, —C(=S)N(R°°)2, —C(=O)SRC°, —C(=S)SRCC, —P(=O)2Raa, —P(=O)(Raa)2, — 3O N(R°°)2, —P(=O)(NRCC)2, C1_1o alkyl, C1_10 perhaloalkyl, C240 l, C240 alkynyl, C340 carbocyclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 ed aryl, or two RCC groups attached to a nitrogen atom are joined to form a 3—14 membered heterocyclyl or 5—14 membered aryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and aryl is independently substituted with 0, 1, 2, 3, 4, or 5 Raw1 , and wherein R", Rbb, RCC and Rdd are as d above.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above ary listing of substituents.

Other definitions The term aceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1—19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically able, nontoxic acid on salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, ic acid and perchloric acid or with organic acids such as 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 ceutically acceptable salts include e, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, lfate, heptanoate, ate, hydroiodide, 2— hydroxy—ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, te, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3—phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p—toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1_4alkyl)4 salts. Representative alkali or ne earth 3O metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic um, quaternary ammonium, and amine cations formed using counterions such as , hydroxide, ylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A "subject" to which administration is contemplated includes, but is not d to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (6.g, , child, adolescent) or adult t (e.g., young adult, middle—aged adult or senior ) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus s), , pigs, horses, sheep, goats, s, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a man animal. The terms "human," (Cpatient," and "subject" are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms "treat, 9) cctreating" and "treatment" contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the ssion of the disease, disorder or condition ("therapeutic treatment"), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition ("prophylactic ent").

In l, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such s as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject An effective amount asses therapeutic and prophylactic treatment.

As used herein, and 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 therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, er or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise ied, 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 ion, or prevent its recurrence. A prophylactically effective amount of a nd means an amount of a therapeutic agent, alone or in combination with other , which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

Brief Description of the Drawings FIGS. 1-52 depict representative 1H NMR spectra of exemplary compounds described herein.

Detailed Description of Certain Embodiments of the ion As bed herein, the present invention provides 19-nor C3,3-disubstituted C21-pyrazolyl neuroactive steroids of Formula (I): and pharmaceutically acceptable salts thereof; -_—-- represents a single or double bond; R1 is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, or substituted or unsubstituted C3_6 carbocyclyl; R2 is hydrogen, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 l, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C3_6 carbocyclyl, or —ORA2, wherein RA2 is hydrogen or substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted CM, alkenyl, substituted or unsubstituted C2-6 alkynyl, or tuted or unsubstituted C3.6 carbocyclyl; R3&1 is hydrogen or —ORA3, wherein RA3 is hydrogen or substituted or unsubstituted CH; alkyl, substituted or unsubstituted C26 alkenyl, substituted or unsubstituted C2_5 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, and R3b is hydrogen; or R3a and R3b are joined to form an oxo (=0) group; each instance of R4a and R4b is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen, provided if the -—-- between C5 and C6 is a single bond, then the en at C5 and R4a are each independently provided in the alpha or beta configuration, and R4b is absent; each instance of R5, R6, and R7 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, - N(RGA)2, -C(=O)RGA, -C(=O)ORGA, —OC(=O)RGA, )ORGA, -C(=O)N(RGA)2, — N(RGA)C(=O)RGA, -OC(=O)N(RGA)2, -N(RGA)C(=O)ORGA, -N(RGA)C(=O)N(RGA)2, -SRGA, -S(O)RGA, e.g.,-S(=O)RGA, -S(=O)2RGA, -S(=O)20RGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, — N(RGA)S(=O)2RGA, tuted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, substituted or tituted C3_6 carbocylyl, or substituted or unsubstituted 3- to 6- membered heterocylyl; and each instance of RGA is independently hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2.6 alkenyl, substituted or tituted C2-6 alkynyl, substituted or unsubstituted C3.6 carbocylyl, substituted or unsubstituted 3- to 6- ed heterocylyl, substituted or unsubstituted aryl, tuted or tituted heteroaryl, an oxygen protecting group when attached to , nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the ening atoms to form a substituted or unsubstituted cylyl or heteroaryl ring, In certain embodiments, R1 is C1_6 alkyl optionally substituted with alkoxy or one to two halo groups (e.g., fluoro), or at least one of R5, R6, and R7 is halogen (e.g., -F, -Cl, -Br), -N02, -CN, - ORGA, -N(RGA)2, -C(=O)RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)20RGA, — OS(=O)2RGA, -S(=O)2N(RGA)2, substituted or unsubstituted c1.6 alkyl (e.g., -CH3, -CH2CH3, haloalkyl, e.g., -CF3) wherein RGA is substituted or unsubstituted C1_2 alkyl.

In certain embodiments, R1 is CH; alkyl optionally tuted with alkoxy or one to two halo groups (e.g., fluoro), and at least one of R5, R6, and R7 is halogen (e.g., -F, -Cl, -Br), -N02, -CN, - ORGA, -N(RGA)2, RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)20RGA, - OS(=O)2RGA, —S(=O)2N(RGA)2, substituted or unsubstituted C1.6 alkyl (e.g, -CH3, -CH2CH3, haloalkyl, e. g., -CF3) n RGA is substituted or unsubstituted C1-2 alkyl, It is understood, based on the aforementioned description, that steroids of Formula (I) ass 3,3-disubstituted l9-nor neuroactive ds wherein the A/B ring system of the compound is cis (as provided in Formula (I-A), wherein the A/B ring system of the compound is trans (as ed in Formula (LB), and wherein the B ring of the compound comprises a C5-C6 double bond (as provided in Formula (I-C)): (1-3) (LC), and pharmaceutically acceptable salts thereof.

Group R1 As generally defined herein, R1 is substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, or substituted or unsubstituted C3_6 carbocyclyl.

In certain embodiments, R1 is substituted or unsubstituted C1_6 alkyl, e. g., substituted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_ 4alkyl, substituted or unsubstituted C4_5alky1, or substituted or unsubstituted C5_6alkyl. Exemplary R1 C1_6alkyl groups e, but are not d to, substituted or unsubstituted methyl (C1), ethyl (C2), yl (C3), isopropyl (C3), n—butyl (C4), tert—butyl (C4), tyl (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), C1_6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups (e.g., —CF3, —CH2F, —CHF2, difluoroethyl, and 2,2,2—trifluoro—1,l—dimethyl—ethyl), C1_6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups (e.g., —CH2C1, —CHC12), and C1_6 alkyl substituted with alkoxy groups (e.g., —CH20CH3 and —CH20CH2CH3). In certain ments, R1 is substituted CH; alkyl, e.g., R1 is haloalkyl, alkoxyalkyl, or aminoalkyl, In certain embodiments, R1 is Me, Et, n-Pr, n-Bu, i—Bu, fluoromethyl, chloromethyl, romethyl, trifluoromethyl, oroethyl, difluoroethyl, 2,2,2-trifluoro-l,l -dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.

In certain embodiments, R1 is unsubstituted C1_3 alkyl, e.g., R1 is —CH3, -CH2CH3, or — CH2CH2CH3.

In certain ments, R1 is C1-6 alkyl substituted with one or more fluorine atoms; e.g., R1 is — CH2F, -CHF2, or —CF3. In certain ments, R1 is C1_6 alkyl substituted with one or two ne atoms; e.g., R1 is —CH2F or -CHF2.

In certain ments, R1 is C14; alkyl substituted with one or more —ORAl groups, n RA1 is hydrogen or substituted or unsubstitued alkyl. In certain embodiments, R1 is —CH20RA1, e.g., wherein RA1 is hydrogen, —CH3, -CH2CH3, or —CH2CH2CH3, e.g, to provide a group R1 of formula —CH20H, H3, —CH20CH2CH3, or —CH20CH2CH2CH3.

In certain embodiments, R1 is substituted or unsubstituted C36 l, e.g., substituted or unsubstituted C2_3alkeny1, substituted or unsubstituted C3_4alkenyl, substituted or unsubstituted C4_ salkenyl, or substituted or unsubstituted C5_6alkenyl. In certain embodiments, R1 is ethenyl (C2), propenyl (C3), or butenyl (C4), tituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or yl. In certain embodiments, R1 is ethenyl, propenyl, or butenyl, unsubstituted or tuted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R1 is ethenyl.

In certain embodiments, R1 is substituted or unsubstituted C36 alkynyl, e. g., tuted or unsubstituted C2_3a1kynyl, substituted or unsubstituted C3_4alkynyl, substituted or tituted kyny1, or substituted or unsubstituted C5_6alkynyl. In certain embodiments, R1 is ethynyl, propynyl, or l, unsubstituted or substituted with alkyl, halo, haloalkyl (e. g., CF3), alkoxyalkyl, cycloalkyl (e.g, cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R1 is selected from the group consisting of oroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4), 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, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4) substituted with substituted 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 n embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4) substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, l,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

In certain embodiments, R1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In n embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted aryl. In certain embodiments, R1 is ethynyl or propynyl, substituted with phenyl unsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted carbocyclyl. In certain ments, R3&1 is ethynyl or propynyl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted heteroaryl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyridinyl, or pyrimidinyl. In certain embodiments, R1 is ethynyl or propynyl, tuted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, l, thiazolyl, isoxazoyl, 1,2,3-triazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In n embodiments, R1 is ethynyl or propynyl, tuted with tuted or unsubstituted heterocyclyl.

In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or mopholinyl. In certain embodiments, R1 is propynyl or butynyl, substituted with hydroxyl or alkoxy. In certain embodiments, R1 is propynyl or l, tuted with y or ethoxy. In n embodiments, R1 is ethynyl or propynyl, tuted with chloro. In certain embodiments, R1 is l or propynyl, substituted with trifluoromethyl.

In certain embodiments, R1 is substituted or unsubstituted C3_6 carbocyclyl, e.g., tuted or unsubstituted C3_4carbocyclyl, substituted or unsubstituted C4_5 carbocyclyl, or substituted or unsubstituted C5_6 carbocyclyl. In certain embodiments, R1 is substituted or unsubstituted ropyl or substituted or unsubstituted cyclobutyl.

Groups -—--, R2, R3", R317, R", and R45 As generally defined herein, R2 is hydrogen, halogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, or substituted or unsubstituted C3_6 carbocyclyl, or —ORA2, wherein RA2 is hydrogen, substituted or unsubstituted C1- 6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or tituted C2_6 alkynyl, or substituted or unsubstituted C3_6 carbocyclyl.

In certain ments, R2 is hydrogen. In certain embodiments, R2 is n, e. g., fluoro, chloro, bromo, or iodo. In certain embodiments, R2 is fluoro or chloro. In certain embodiments, R2 is substituted or unsubstituted ky1, e.g., tuted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4a1ky1, substituted or unsubstituted C4_ salkyl, or tuted or unsubstituted C5_6alkyl. For example, in some embodiments, R2 is C1- 6alkyl optionally tuted with halo (e.g., bromo, chloro, fluoro (i.e., to provide a group R2 of a -CH2F, -CHF2, -CF3)) or —ORA2. In certain embodiments, RAz is —CH3, -CH2CH3, or — CH2CH2CH3, z'.e., to provide a group R2 of formula —OH, —OCH3, H3, or —OCH2CH2CH3.

In certain embodiments, R2 is substituted or unsubstituted C26 alkenyl, In certain embodiments, R2 is substituted or unsubstituted C2_6 alkynyl, e.g., substituted or unsubstituted C2_3alkynyl, substituted or unsubstituted C3_4alkynyl, substituted or unsubstituted C4_5alkynyl, or substituted or unsubstituted C5_6alkynyl. In n embodiments, R2 is substituted or unsubstituted C3_6 carbocyclyl, e.g., substituted or unsubstituted C3_4carbocyclyl, substituted or unsubstituted C4_5 carbocyclyl, or substituted or unsubstituted C5_6 carbocyclyl. In certain embodiments, R2 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In certain ments, R2 is —CH3, -CH2CH3, —CH2CH2CH3, or substituted or unsubstituted cyclopropyl.

In certain embodiments, R2 is —ORA2. In certain embodiments, RA2 is hydrogen. In certain embodiments, RA2 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C1_6alkyl, substituted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_ 6alkyl. In certain embodiments, RA2 is en, —CH3, -CH2CH3, or —CH2CH2CH3, i.e., to provide a group R2 of a —OH, —OCH3, —OCH2CH3, or —OCH2CH2CH3. In certain embodiments, R2 is a non-hydrogen substituent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration.

As generally defined herein, R3&1 is hydrogen or —ORA3, wherein RA3 is hydrogen or substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or tituted C2_5 l, or substituted or unsubstituted C3-6 carbocylyl, and R31) is hydrogen; or R331 and R3b are 3O joined to form an oxo (=0) group.

In certain ments, both R3a and R3b are both hydrogen.

In certain embodiments, R3sz and R31) are joined to form an oxo (=0) group.

In n embodiments, R3a is —ORA3 and R31) is hydrogen. In certain embodiments, wherein R3a is —ORA3, R3a is in the alpha or beta configuration. In certain embodiments, wherein R3a is —ORA3, R321 is in the alpha configuration. In certain ments, wherein R3a is —ORA3, R3a is in the beta configuration. In certain embodiments, RA3 is hydrogen. In certain embodiments, RA3 is substituted or unsubstituted CH; alkyl, e.g., substituted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4a1kyl, substituted or unsubstituted C4- salkyl, or substituted or tituted C5_6alkyl. In certain embodiments, RA3 is hydrogen, —CH3, - CH2CH3, or —CH2CH2CH3, z'.e., to provide a group R38 of formula —OH, —OCH3, H3, or — OCH2CH2CH3.

As lly defined herein, each instance of R43 and R41) is independently hydrogen, substituted or unsubstituted C1_6 alkyl, or halogen, provided if the 2 between C5 and C6 is a single bond, then the hydrogen at C5 and R4a are each independently provided in the alpha or beta configuration, and R4b is absent.

In n embodiments, 2 is a single bond, at least one of R4a and R4b is hydrogen. In n embodiments, 2 is a single bond, at least one of R4a and R4b is substituted or tituted C1_6 alkyl, e. g., substituted or unsubstituted C1_2alkyl, tuted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_6alkyl. In certain embodiments, 2 is a single bond, at least one of R4a and R4b is C1 alkyl, e. g., -CH3 or -CF3. In n embodiments, 2 is a single bond, at least one of R4a and R4b is halogen, e. g., fluoro.

In certain ments, 2 is a single bond, and both of R4a and R4b are hydrogen. In certain embodiments, 2 is a single bond, and both of R42‘ and R4]) are independently substituted or unsubstituted C1-6 alkyl, e. g., substituted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, tuted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_6alkyl. In certain embodiments, 2 is a single bond, and both of R431 and R41) are independently C1 alkyl, e.g., —CH3 or -CF3. In certain embodiments, 2 is a single bond, and both of R4a and R4b are halogen, e.g., fluoro.

In certain embodiments, wherein 2 represents a single bond, R4a is a drogen substituent in the alpha configuration. In certain embodiments, wherein 2 represents a single bond, R4a is a non-hydrogen substituent in the beta configuration.

In certain embodiments, 2 is a double bond, and R43 is hydrogen. In certain embodiments, 2 is a double bond, and R42l is substituted or unsubstituted C1_6 alkyl, e.g., substituted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted kyl. In certain embodiments, 2 is a double bond, and R431 is C1 alkyl, e.g., -CH3 or -CF3. In certain embodiments, 2 is a double bond, and R431 is halogen, e. g., fluoro.

Groups R5, R6, and R7 As generally d herein, each instance of R5, R6, and R7 is, independently, hydrogen, halogen, -N02, -CN, -ORGA, -N(RGA)2, -C(=O)RGA, -C(=O)ORGA, )RGA, -OC(=O)ORGA, — C(=O)N(RGA)2, -N(RGA)C(=O)RGA, —0C(=0)N(RGA 2, -N(RGA)C(=O)ORGA, — N(RGA)C(=O)N(RGA)2, -SRGA, -S(O)RGA, e.g.,-S(=O)RGA, -S(=O)2RGA, -S(=O)20RGA, — OS(=O)2RGA, -S(=O)2N(RGA)2, -N(RGA)S(=O)2RGA, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C3_6 carbocylyl, or substituted or unsubstituted 3- to 6- membered heterocylyl.

Furthermore, as generally d herein, each ce of RGA is independently hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 l, substituted or tituted C3_6 carbocylyl, substituted or unsubstituted 3- to 6- ed heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, nitrogen ting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring. In n embodiments, each instance of RGA is independently hydrogen, substituted or unsubstituted C1_6 alkyl (e.g., substituted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted kyl, substituted or unsubstituted C4_5alkyl, or substituted or tituted C5_6alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted aryl. In certain embodiments, each instance of RGA is hydrogen, -CH3, —CH2CH3, or substituted or unsubstituted phenyl.

In certain embodiments, at least one of R5, R6, and R7 is hydrogen. In certain embodiments, at least two of R5, R6, and R7 are hydrogen. In certain embodiments, all of R5, R6, and R7 are hydrogen to provide an unsubstituted pyrazolyl, In certain embodiments, at least one of R5, R6, and R7 is a non-hydrogen substituent. As used , a R5, R6, and R7 "non-hydrogen substituent" means that R5, R6, and R7 are not en, but are any one of halogen, -N02, -CN, —CF3, -ORGA, -N(RGA)2, —C(=O)RGA, —C(=O)ORGA, - RGA, -OC(=O)ORGA, -C(=O)N(RGA)2, -N(RGA)C(=O)RGA, -OC(=O)N(RGA)2, — N(RGA)C(=O)ORGA, -SRGA, -S(O)RGA, e.g.,-S(=O)RGA, -S(=O)2RGA, -S(=O)20RGA, -OS(=O)2RGAu 2N(RGA)2, or —N(RGA)S(=O)2RGA; tuted or unsubstituted C1.6 alkyl, tuted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3_6 carbocylyl, or substituted or unsubstituted 3- to 6— membered heterocylyl.

In certain embodiments, at least one of R5, R6, and R7 is halogen, e. g., fluoro, bromo, iodo, or chloro. In certain embodiments, one of R5, R6, and R7 is halogen. In certain embodiments, R5 is halogen, e. g., fluoro, bromo, iodo, or chloro. In certain embodiments, R6 is halogen, e. g., fluoro, bromo, iodo, or chloro. In certain embodiments, R. . . 7 . . is halogen, e. g., fluoro, bromo, iodo, or chloro.

In n embodiments, at least one of R5, R6, and R7 is -N02. In certain embodiments, one of R5, R6, and R7 is -N02. In certain embodiments, R5 is -N02. In certain embodiments, R6 is -N02. In certain embodiments, R7 is -N02.

In certain embodiments, at least one of R5, R6, and R7 is —CN. In n embodiments, one of R5, R6, and R7 is —CN. In certain ments, R5 is —CN. In certain embodiments, R6 is —CN. In certain embodiments, R7 is —CN.

In certain embodiments, at least one of R5, R6, and R7 is -ORGA, e.g., n RGA is hydrogen or substituted or unsubstituted C1.6 alkyl (e.g., -CH3 or —CF3). In certain embodiments, one of R5, R6, and R7 is -ORGA, e.g., -OH, -OCH3, or —OCF3. In certain embodiments, R5 is -ORGA, e.g., -OH, - OCH3, or —OCF3, In certain embodiments, R6 is -ORGA. In certain ments, R7 is OK", e.g., -OH, -OCH3, or —OCF3, In certain embodiments, at least one of R5, R6, and R7 is —N(RGA)2, e. g., wherein RGA is hydrogen or substituted or unsubstituted CH; alkyl (e.g., —CH3 or —CF3). In certain embodiments, one of R5, R6, and R7 is )2, e. g., -NH2, -NHCH3, or —N(CH3)2V In certain embodiments, R5 is -N(RGA)2, e. g., -NH2, -NHCH3, or -N(CH3)2. In certain embodiments, R6 is )2, e.g., -NH2, -NHCH3, or -N(CH3)2. In n embodiments, R7 is -N(RGA)2, e.g., -NH2, , or )2.

In certain embodiments, at least one of R5, R6, and R7 is -C(=O)RGA, -C(=O)ORGA, or - C(=O)N(RGA)2, e.g., n RGA is hydrogen or substituted or unsubstituted C1_6 alkyl (e.g., -CH3 or —CF3). In certain embodiments, one of R5, R6, and R7 is -C(=O)RGA, e.g, -CHO, -C(=O)CH3, or -C(=O)CH2CH3. In certain embodiments, R5 is -C(=O)RGA, e. g., -CHO, —C(=O)CH3, or - C(=O)CH2CH3. In certain embodiments, R6 is -C(=O)RGA, e.g., -CHO, -C(=O)CH3, or - C(=O)CH2CH3. In certain embodiments, R7 is RGA, e.g., -CHO, -C(=O)CH3, or - C(=O)CH2CH3. In certain embodiments, one of R5, R6, and R7 is -C(=O)ORGA, e. g., -C(=O)OH, - C(=O)OCH3, or -C(=O)OCH2CH3, In certain embodiments, R5 is -C(=O)ORGA, e. g., -C(=O)OH, - CH3, or -C(=O)OCH2CH3, In certain ments, R6 is -C(=O)ORGA, e.g., -C(=O)OH, - C(=O)OCH3, or -C(=O)OCH2CH3. In certain embodiments, R7 is -C(=O)ORGA, e.g., -C(=O)OH, - C(=O)OCH3, or -C(=O)OCH2CH3. In certain embodiments, one of R5, R6, and R7 is - C(=O)N(RGA)2, e.g., -C(=O)NH2, -C(=O)NHCH3, or —C(=O)N(CH3)2. In certain embodiments, R5 is -C(=O)N(RGA)2, e.g., -C(=O)NH2, -C(=O)NHCH3, or -C(=O)N(CH3)2. In certain embodiments, R6 is -C(=O)N(RGA)2, e.g., -C(=O)NH2, -C(=O)NHCH3, or -C(=O)N(CH3)2. In certain embodiments, R7 is -C(=O)N(RGA)2, e.g., -C(=O)NH2, -C(=O)NHCH3, or -C(=O)N(CH3)2.

In certain embodiments, at least one of R5, R6, and R7 is )RGA, -OC(=O)ORGA, or - OC(=O)N(RGA)2, e.g., wherein RGA is hydrogen or substituted or unsubstituted C1_6 alkyl (e.g., - CH3 or —CF3). In certain embodiments, one of R5, R6, and R7 is -OC(=O)RGA, e.g., -OC(=O)CH3.

In certain embodiments, R5 is -OC(=O)RGA, e.g., -OC(=O)CH3_ In n embodiments, R6 is - OC(=O)RGA, e.g., -OC(=O)CH3, In certain embodiments, R7 is -OC(=O)RGA, e.g., -OC(=O)CH3.

In certain embodiments, one of R5, R6, and R7 is )ORGA, e.g., -OC(=O)OCH3_ In certain embodiments, R5 is -OC(=O)ORGA, e.g., —OC(=O)OCH3, In certain embodiments, R6 is - ORGA, e.g., -OC(=O)OCH3, In certain embodiments, R7 is -OC(=O)ORGA, e.g., - OC(=O)OCH3, In n embodiments, one of R5, R6, and R7 is -OC(=O)N(RGA)2, e.g., - OC(=O)I\HCH3 or -OC(=O)N(CH3)2, In n embodiments, R5 is -OC(=O)N(RGA)2, e.g., - 0C(=0)I\‘IICH3 or -OC(=O)N(CH3)2V In certain embodiments, R6 is -OC(=O)N(RGA)2, e. g., — OC(=O)1\HCH3 or -OC(=O)N(CH3)2V In certain embodiments, R7 is -OC(=O)N(RGA)2, e. g., — OC(=O)1\HCH3 or -OC(=O)N(CH3)2, In certain embodiments, at least one of R5, R6, and R7 is -N(RGA)C(=O)RGA, -N(RGA)C(=O)ORGA, or -N(RGA)C(=O)N(RGA)2, e.g., wherein RGA is hydrogen or substituted or unsubstituted C1_6 alkyl (e. g., -CH3 or —CF3). In certain embodiments, one of R5, R6, and R7 is -N(RGA)C(=O)RGA, e. g., - NHC(=O)CH3. In certain embodiments, R5 is -N(RGA)C(=O)RGA, In certain , e.g., -NHC(=O)CH3_ embodiments, R6 is -N(RGA)C(=O)RGA, e.g., —NHC(=O)CH3, In certain embodiments, R7 is - N(RGA)C(=O)RGA, e.g., -NHC(=O)CH3, In certain embodiments, one of R5, R6, and R7 is - N(RGA)C(=O)ORGA, e.g., -NHC(=O)OCH3, In certain embodiments, R5 is )C(=O)ORGA, e.g., -NHC(=O)OCH3, In n embodiments, R6 is -N(RGA)C(=O)ORGA, e.g., -NHC(=O)OCH3.

In certain embodiments, R7 is -N(RGA)C(=O)ORGA, e.g., -NHC(=O)OCH3, In certain embodiments, one of R5, R6, and R7 is -N(RGA)C(=O)N(RGA)2, e.g., -NHC(=O)NH2 or -NHC(=O)N(CH3)2. In certain ments, R5 is —N(RGA)C(=O)N(RGA)2, e.g., - ’HC(=O)I\;H2 or O)N(CH3)2. In certain ments, R6 is -N(RGA)C(=O)N(RGA)2, e.g., - ’HC(=O)I\;H2 or O)N(CH3)2. In certain embodiments, R7 is -N(RGA)C(=O)N(RGA)2, e.g., — ’HC(=O)I\’H2 or -NHC(=O)N(CH3)2.

In certain embodiments, at least one of R5, R6, and R7 is —SRGA, -S(O)RGA, e.g.,-S(=O)RGA, - S(=O)2RGA, -S(=O)20RGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, or -N(RGA)S(=O)2RGA, e. g., wherein RGA is hydrogen, tuted or unsubstituted C1_6 alkyl (e. g., -CH3 or —CF3), tuted or tituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, one of R5, R6, and R7 is -SRGA, e. g., -SCH3, or -S-Ary1, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R5, R6, and R7 is -S(O)RGA, e.g.,-S(=O)RGA, e. g., - S(=O)CH3, -S(=O)CF3, or -S(=O)-Ary1, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In n embodiments, one of R5, R6, and R7 is -S(=O)2RGA, e.g., -S(=O)2CH3, - S(=O)2CF3, or -S(=O)2-Ary1, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In n embodiments, R5 is -SRGA, e.g., —SCH3, -SCF3; -S(O)RGA, e.g.,-S(=O)RGA, e.g., -S(=O)CH3, -S(=O)CF3; -S(=O)2RGA, e.g., -S(=O)2CH3, -S(=O)2CF3, or -S(=O)2-Ary1, wherein Aryl is substituted or tituted aryl or heteroaryl. In certain embodiments, R6 is —SRGA, e.g., -SCH3, - scra, -S(O)RGA, e.g.,-S(=O)RGA, e.g., -S(=O)CH3, -S(=O)CF3; -S(=O)2RGA, e.g., -S(=O)2CH3, — S(=O)2CF3, or -S(=O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R7 is -SRGA, e.g., -SCH3, -SCF3; -S(O)RGA, e.g.,-S(=O)RGA, e.g., -S(=O)CH3, -S(=O)CF3; -S(=O)2RGA, e.g., —S(=O)2CH3, —S(=O)2CF3, or -S(=O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R5, R6, and R7 is - S(=O)20RGA. In certain embodiments, R5 is -S(=O)20RGA, e. g., 20CH3, 20CF3, or - S(=O)20Ary1, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R6 is -S(=O)20RGA, e.g., —S(=O)20CH3, 20CF3, or -S(=O)20Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R7 is -S(=O)20RGA, e. g., -S(=O)20CH3, -S(=O)20CF3, or -S(=O)20Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R5, R6, and R7 is -OS(=O)2RGA. In certain embodiments, R5 is -OS(=O)2RGA, e.g., -OS(=O)2CH3, )2CF3, or -OS(=O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R6 is )2RGA, e. g., -OS(=O)2CH5, -OS(=O)2CF5, or -OS(=O)2-Aryl, wherein Aryl is tuted or unsubstituted aryl or heteroaryl. In certain embodiments, R7 is -OS(=O)2RGA, e. g., )2CH3, -OS(=O)2CF3, or -OS(=O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, one of R5, R6, and R7 is -S(=O)2N(RGA)2. In certain embodiments, R5 is - S(=O)2N(RGA)2, e.g., -S(=O)2NHCH5, -S(=O)2NHCF3, or 2-NH-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R6 is -S(=O)2N(RGA)2, e. g., -S(=O)2NHCH5, -S(=O)2NHCF5, or -S(=O)2-NH-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R7 is —S(=O)2N(RGA)2, e.g., -S(=O)2NHCH3, - S(=O)2NHCF3, or -S(=O)2-NH-Aryl, wherein Aryl is tuted or unsubstituted aryl or heteroaryl. In n embodiments, one of R5, R6, and R7 is -N(RGA)S(=O)2RGA. In certain embodiments, R5 is -N(RGA)S(=O)2RGA, e.g., -NHS(=O)2CH3, -NHS(=O)2CF3, or -NHS(=O)2-Aryl, wherein Aryl is substituted or tituted aryl or heteroaryl. In certain embodiments, R6 is - N(RGA)S(=O)2RGA, e.g., -NHS(=O)2CH3, —NHS(=O)2CF3, or -NHS(=O)2-Aryl, wherein Aryl is substituted or tituted aryl or heteroaryl. In certain embodiments, R7 is -N(RGA)S(=O)2RGA, e.g., -NHS(=O)2CH5, O)2CF3, or —NHS(=O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl.

In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C1_6 alkyl, e.g., substituted or unsubstituted C1_2alkyl, substituted or unsubstituted kyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_ . Exemplary C1_6alkyl groups include, but are not limited to, 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), l (C6), C1_6 alkyl substituted with l, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 3O more fluoro groups (e.g., —CF5, —CH2F, —CHF; oethyl, and 2,2,2—trifluoro—l,l—dimethyl— ethyl), C1_6 alkyl substituted with l, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups (e. g., —CH2Cl, —CHC12), and C1_6 alkyl substituted with alkoxy groups (e.g., —CH20CH3 and —CH20CH2CH3). In certain embodiments, at least one of R5, R6, and R7 is substituted C1_6 alkyl, e.g., at least one of R5, R6, and R7 is haloalkyl, alkoxyalkyl, or aminoalkyl. In certain embodiments, at least one of R5, R6, and R7 is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2—trifluoro-l,l-dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.

In certain embodiments, at least one of R5, R6, and R7 is tuted or unsubstituted C2-6 alkenyl, e.g., substituted or unsubstituted C2_3alkenyl, substituted or unsubstituted C3_4alkenyl, substituted or unsubstituted C4_5alkenyl, or substituted or unsubstituted C5_6alkenyl. In certain embodiments, at least one of R5, R6, and R7 is ethenyl (C2), propenyl (C3), or butenyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, at least one of R5, R6, and R7 is ethenyl, yl, or butenyl, unsubstituted or tuted with alkyl, halo, kyl, alkoxyalkyl, or hydroxy.

In n embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C2_6 alkynyl, e.g., substituted or unsubstituted C2_3alkynyl, substituted or unsubstituted C3_4alkynyl, substituted or tituted kynyl, or substituted or unsubstituted C5_6alkynyl. In certain embodiments, at least one of R5, R6, and R7 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (e. g., CF3), alkoxyalkyl, cycloalkyl (e. g., cyclopropyl or cyclobutyl), or hydroxyl.

In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C3_6 carbocyclyl, e.g., substituted or unsubstituted CHcarbocyclyl, substituted or unsubstituted C4_5 carbocyclyl, or substituted or unsubstituted C54 carbocyclyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl, In certain embodiments, at least one of R5, R6, and R7 is tuted or unsubstituted 3- to 6- membered heterocylyl, e. g., substituted or unsubstituted 3-4 membered heterocylyl, substituted or unsubstituted 4-5 ed heterocylyl, or substituted or unsubstituted 5-6 membered cylyl.

In certain embodiments, at least one of R5, R6, and R7 is substituted or tituted C1_2 alkyl (e. g., —CH3, -CF3), -C02RGA, -C(=O)RGA, -CN, -N02, or halogen, wherein RGA is tuted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3).

Exemplary combinations of R5, R6, and R7 as drogen substituents are contemplated herein.

N | P' R7 For example, in certain embodiments, the C21-pyrazolyl of formula W is a mono- tuted pyrazolyl ring of formula: N/ I N/ I N/ I \ \ \ P‘ 1" IN R7 "I‘M (i—a) "M (i—b) or "m , (i-c), wherein R5, R6, and R7 are each non—hydrogen substituents as defined herein.

N | IN R7 In certain embodiments, the C21-pyrazolyl of formula "9°"- is a di-substituted pyrazolyl ring of formula: R5 R5 R6 R6 / | / / N\ N\ | N\ | [N E" R7 l" R7 "5"" (ii-a), "5%! (ii-b), or "MI , wherein R5, R6, and R7 are each non-hydrogen substituents as defined herein.

N | F‘ R7 In certain embodiments, the C21-pyrazolyl of formula W is a tri-substituted pyrazolyl ring wherein each of R5, R6, and R7 are non-hydrogen substituents as defined herein, s Combinations ofCertain Embodiments Various combinations of certain ments are futher contemplated herein.

For example, in certain embodiments, wherein R2 is hydrogen or a non-hydrogen alpha substituent, provided is a steroid of Formula (I-Al), , or (I-Cl): (I-Bl), (LCD, or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CHgF, -CHF2, —CF3, —CH20CH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, —CH2CH3, 2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R361 and R31) are both en. In certain embodiments, R321 and R3b are joined to form =O (oxo). In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R461 is hydrogen, fluoro, -CH3, or - CF3. In certain embodiments, n Ring B does not comprises a C5-C6 double bond, both of R431 and R4b are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4b are —CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R43 and R41) are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, R4a is a drogen substituent and R4b is hydrogen. In n embodiments, the C21—pyrazolyl ring is a mono-substituted pyrazolyl.

In certain embodiments, the razolyl ring is a di-substituted pyrazolyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, - CF3), -C02RGA, -C(=O)RGA, -CN, -N02, or halogen, wherein RGA is tuted or unsubstituted C14 alkyl (e. g., —CH3, -CF3). In certain embodiments, the C21—pyrazolyl ring is an unsubstituted pyrazolyl, wherein each instance of R5, R6, and R7 is hydrogen.

In certain embodiments, wherein R2 is hydrogen or a non-hydrogen beta substituent, provided is a steroid of a (I-A2), (I-B2), or (I-CZ): (I—Bz), (1-C2), or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CHzF, -CHF2, —CF3, —CH20CH3, or substituted or unsubstituted cyclopropyl. In certain ments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, —CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain ments, R3a and R3b are both hydrogen. In certain embodiments, R32' and R3b are joined to form =0 (oxo). In certain ments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or - CF3. In certain embodiments, n Ring B does not comprises a C5-C6 double bond, both of R4a and R4b are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R41) are -CH3 or -CF3. In certain ments, wherein Ring B does not comprises a C5-C6 double bond, both of R43 and R41) are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, R43 is a non—hydrogen substituent and R41) is hydrogen. In n embodiments, the C21-pyrazolyl ring is a mono-substituted pyrazolyl.

In certain embodiments, the C21-pyrazolyl ring is a di-substituted pyrazolyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C1-2 alkyl (e. g., —CH3, CF3), -C02RGA, -C(=O)RGA, -CN, -N02, or halogen, wherein RGA is substituted or unsubstituted C14 alkyl (e. g., —CH3, -CF3). In certain embodiments, the razolyl ring is an unsubstituted pyrazolyl, wherein each instance of R5, R6, and R7 is hydrogen.

In certain embodiments, wherein R3a is hydrogen or a non-hydrogen alpha substituent, and R3b is hydrogen, provided is a steroid of Formula (I—A3), , or (I-C3): (1-C3), or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, 3, — CHzF, -CHF2, —CF3, —CH20CH3, or substituted or tituted cyclopropyl. In certain embodiments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, —CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R2 is a non- hydrogen substituent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration. In certain embodiments, wherein Ring B ses a C5-C6 double bond, R431 is hydrogen, fluoro, -CH3, or -CF3. In certain embodiments, n Ring B does not comprises a C5-C6 double bond, both of RA":1 and R4b are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R461 and R4b are -CH3 or -CF3. In certain embodiments, n Ring B does not comprises a C5-C6 double bond, both of R461 and R4b are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, R4a is a non-hydrogen substituent and R4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is a ubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a di- substituted lyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3), -C02RGA, —C(=O)RGA, -CN, -N02, or halogen, wherein RGA is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3). In certain embodiments, the C21- pyrazolyl ring is an unsubstituted pyrazolyl, wherein each instance of R5, R6, and R7 is hydrogen.

In certain embodiments, wherein R361 is hydrogen or a non-hydrogen beta substituent, and R3b is hydrogen, provided is a steroid of a , (I-B4), or (I-C4): (I—A4), R4a (1-34), (1-00, or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CHzF, -CHF2, —CF3, —CH20CH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is —OH, —OCH3, -OCH2CH3, H2CH3, —CH3, -CH2CH3, —CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain ments, R2 is a non- hydrogen substituent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta uration. In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or -CF3. In n embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4b are hydrogen. In certain embodiments, n Ring B does not comprises a C5-C6 double bond, both of R4a and R4b are -CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4b are fluoro. In certain embodiments, n Ring B does not comprises a C5-C6 double bond, R4a is a non-hydrogen substituent and R41) is hydrogen. In certain embodiments, the razolyl ring is a mono-substituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is a di- tuted pyrazolyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3), -C02RGA, -C(=O)RGA, -CN, -N02, or halogen, wherein RGA is substituted or unsubstituted Cm alkyl (e.g., —CH3, -CF3). In certain embodiments, the C21- lyl ring is an unsubstituted pyrazolyl, wherein each instance of R5, R6, and R7 is hydrogen.

In certain embodiments, wherein R321 and R3b are joined to form an oxo group, provided is a steroid of Formula (I-A5), (I-BS), or (I-C5): R 1 1 R43 R (I-AS), R" (1-35), (I—CS), or a ceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CH2F, -CHF2, —CF3, —CH20CH3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is —OH, —OCH3, H3, —OCH2CH2CH3, —CH3, -CH2CH3, 2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R2 is a non- hydrogen substituent in the alpha configuration. In n embodiments, R2 is a non-hydrogen substituent in the beta configuration. In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, , -CH3, or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R43 and R4b are hydrogen. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R461 and R4b are -CH3 or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4&1 and R41) are fluoro. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, R431 is a non-hydrogen tuent and R4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is a mono-substituted pyrazolyl. In certain embodiments, the razolyl ring is a di- substituted pyrazolyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3), —C02RGA, -C(=O)RGA, -CN, -N02, or halogen, wherein RGA is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3). In certain embodiments, the C21- pyrazolyl ring is an unsubstituted lyl, n each instance of R5, R6, and R7 is hydrogen.

In certain embodiments, wherein R4a is a drogen substituent, provided is a steroid of Formula (I-A6) or (I-B6): (I—A6) or (L136), or a pharmaceutically acceptable salt thereof. In certain ments, R1 is —CH3, —CH2CH3, — CHzF, -CHF2, —CF3, —CH20CH3, or substituted or unsubstituted cyclopropyl. In certain ments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, —CH2CH2CH3, substituted or unsubstituted ropyl, fluoro, or chloro. In certain embodiments, R2 is a non- hydrogen substituent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration. In certain embodiments, R3a and R3b are both hydrogen. In certain embodiments, R3a and R31) are joined to form =0 (oxo). In certain embodiments, R4a is fluoro, -CH3, or -CF3 and R41) is hydrogen. In certain ments, R4b is fluoro, -CH3, or -CF3 and R4a is hydrogen. In certain embodiments, both of R43 and R41) are -CH3 or -CF3. In certain embodiments, both of R4a and R4b are fluoro. In n embodiments, the C21-pyrazoly1 ring is a mono-substituted pyrazolyl. In certain embodiments, the C21—pyrazoly1 ring is a di-substituted pyrazolyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C1- 2 alkyl (e. g., —CH3, -CF3), -C02RGA, -C(=O)RGA, -CN, -N02, or halogen, wherein RGA is substituted or unsubstituted C1-2 alkyl (e.g., —CH3, -CF3). In certain ments, the C21- pyrazolyl ring is an unsubstituted pyrazolyl, wherein each instance of R5, R6, and R7 is hydrogen.

In certain embodiments, wherein R4a is a non-hydrogen substituent, provided is a steroid of Formula (I-A6) or (I-B6): (I-A7) or (1-37), or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CHzF, -CHF2, —CF3, —CH20CH3, or substituted or unsubstituted ropyl, In certain embodiments, the C21-pyrazolyl ring is a ubstituted lyl, In certain embodiments, the razolyl ring is a di-substituted pyrazolyl. In certain embodiments, at least one of R5, R6, and R7 is substituted or unsubstituted C14 alkyl (e.g., —CH3, -CF3), -C02RGA, -C(=O)RGA, -CN, - N02, or halogen, wherein RGA is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3). In certain embodiments, the C21 -pyrazolyl ring is an unsubstituted pyrazolyl, wherein each instance of R5, R6, and R7 is hydrogen. lO In certain embodiments, a steroid of Formula (I) is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

In certain embodiments, a steroid of Formula (I) is ed from the group consisting of: and H6 and pharmaceutically able salts thereof.

In certain embodiments, a steroid of Formula (I) is selected from the group consisting of: SD-7 SD-8 SD-9 and pharmaceutically acceptable salts thereof.

In certain embodiments, a steroid of a (I) is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

In certain ments, a steroid of Formula (I) is selected from the group consisting of: SA-17 SA-18 sA-33 SA-34 and pharmaceutically acceptable salts thereof.

In certain ments, a steroid of Formula (I) is selected from the group consisting of: N O \\ \z'3'=0 SB-21 pharmaceutically acceptable salts thereof.

Pharmaceutical Compositions In another aspect, the ion provides a pharmaceutical composition comprising a nd of the present ion (also referred to as the "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an ive 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.

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

Generally, the compounds provided herein are administered in an effective amount. The amount of the nd actually administered will typically be determined by a physician, in the light of the nt circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, , and response of the individual patient, the severity of the patient’s symptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for ping a particular ion generally include those that have a family history of the condition, or those who have been fied by genetic testing or screening to be particularly susceptible to developing the condition.

The pharmaceutical compositions provided herein can also be stered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subj ect’s life. In certain embodiments, the chronic administration is ed to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

The pharmaceutical compostions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the nd in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a uous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body.

Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, ed by continuous infusion.

The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically te units suitable as y dosages for human subjects and other mammals, each unit containing a predetermined quantity of active al calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. l unit dosage forms include prefilled, 3O premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.

With oral dosing, one to five and especially two to four and typically three oral doses per day are entative regimens. Using these dosing patterns, each dose provides from about 0.01 to about mg/kg of the compound ed , with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are lly selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by .

Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve te steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human t.

Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or n; an excipient such as starch or e, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon e; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Inj ectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such itions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointment or cream ning the active ingredient(s). When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water—miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and lly e additional ingredients to enhance the dermal penetration of stability of the active ingredients or Formulation. All such known transdermal formulations and ingredients are included within the scope ed herein.

The compounds ed herein can also be administered by a transdermal device. ingly, transdermal administration can be lished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 ofRemington ’3 Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of entative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically able formulations of a compound of the present ion. In one embodiment, the formulation comprises water. In r embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are Ot—, B— and y— cyclodextrins consisting of 6, 7 and 8 OH ,4—linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, ated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether B—cyclodextrin, e.g., for example, sulfobutyl ether B—cyclodextrin, also known as Captisol®. See, e. g, US. 5,376,645. In certain embodiments, the ation comprises opyl-B-cyclodextrin (e.g., 10-50% in water).

The present invention also relates to the ceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, ate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the ing ceutical compositions.

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

Exemplary Formulation 2 — Capsules: A compound of the t invention may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

Exemplary Formulation 3 , : A compound of the present invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U. S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl ose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.

Exemplary ation 4 , Tablets: A nd of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The e is formed into 450-900 mg tablets (150- 300 mg of active compound) in a tablet press.

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

Exemplary ation 6 , Tablets: A compound of the present ion may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor 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.

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

Exemplary Formulation 8 — Tablets: A compound of the present ion may be d as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 03-30 mg tablets (01-10 mg of active compound per tablet) in a tablet press.

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

Exemplary Formulation 10 , Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a ant. The e is formed into 270-450 mg tablets (90- 150 mg of active compound per tablet) in a tablet press.

Methods of Use and Treatment As generally described herein, the present invention is directed to C21 -substituted neuroactive 2O ds designed, for e, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the inducement of anesthesia and/or sedation in a subject. In some embodiments, such compounds are oned to be useful as therapeutic agents for treating a CNS-related er (e.g., sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus) in a subject in need (e. g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).

Thus, in one aspect, the present invention provides a method of inducing sedation and/or anesthesia 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 by intravenous administration.

Earlier studies (see, e. g., Gee et al., European Journal ofPharmacology, 9-423 (1987)) demonstrated that certain 30c—hydroxylated steroids are orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than others had ed (see, e. g., Maj ewska et al., Science 232: 1004-1007 (1986); Harrison et al., JPharmacol. Exp. Ther. 241 :346—3 53 (1987)).

Majewska et al. and Harrison et al. taught that 30t-hydroxy1atedreduced ds are only capable of much lower levels of effectiveness. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids allows them to be therapeutically useful in the modulation of brain excitability via the GRC (see, e.g., Gee et al., an Journal of Pharmacology, 136:419-423 ; Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

Various synthetic steroids have also been prepared as neuroactive steroids. See, for example, US.

Patent 5,232,917, which discloses neuroactive steroid compounds useful in ng stress, y, insomnia, seizure disorders, and mood disorders, that are amenable to GRC-active agents, such as depression, in a therapeutically beneficial manner. Furthermore, it has been previously demonstrated that these steroids interact at a unique site on the GRC which is distinct from other known sites of interaction (e. g., barbiturates, benzodiazepines, and GABA) where therapeutically beneficial s on stress, anxiety, sleep, mood disorders and seizure disorders have been previously elicited (see, e. g., Gee, KW. and ra, H.I., "Benzodiazepines and Barbiturates: 2O Drugs for the Treatment of y, Insomnia and Seizure Disorders," in Central Nervous System Disorders, l, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG. and Morselli, P.L., "Psychopharmacology of GABAergic Drugs," in Psychopharmacology: The Third Generation ofProgress, H.Y. Meltzer, ed., Raven Press, NY. (1987), pp. 183-195; and Gee et al., European Journal ofPharmacology, 136:419—423 (1987). These nds are desirable for their duration, potency, and oral activity (along with other forms of administration).

Compounds of the present invention, as described herein, are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS—related conditions in a subject. tion, as used herein, refers to the inhibition or potentiation of GABA or function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in s including humans and non-human mammals. Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.

Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep ers [e.g., insomnia], mood disorders [e.g., depression, mic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or 11), anxiety disorders (e. g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress er , compulsive disorders (e. g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e. g., status epilepticus (SE)), seizures], ers of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), ia (e.g., Alzheimer’s type dementia, Lewis body type ia, vascular type dementia], movement disorders [e.g., Huntington’s disease, Parkinson’s disease], personality disorders [e.g., anti-social personality disorder, obsessive compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenetic causes of autism such as synaptophathy’s, e.g., Rett syndrome, Fragile X me, Angelman me], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, c pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and/or withdrawal syndromes [e.g., addition to opiates, cocaine, and/or alcohol], and tinnitus.

In yet another aspect, provided is a combination of a compound of the present invention and another pharmacologically active agent. The compounds ed herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or ted with a condition associated with brain excitability, sing administering to the subject an effective amount of a compound of the present invention to the subj ect.

In yet another aspect, provided is a method of ng or preventing stress or anxiety in a subject, sing administering to the subject in need of such ent an effective amount of a compound of the present ion, or a composition thereof.

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

In yet another aspect, ed is a method of alleviating or preventing insomnia in a t, comprising administering to the t in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep and ining substantially the level of REM sleep that is found in normal sleep, wherein ntial rebound insomnia is not induced, comprising administering an effective amount of a compound of the present invention.

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

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

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

In yet another aspect, provided is a method of cognition enhancement or treating memory disorder by stering to the subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer’s disease. In certain embodiments, the disorder is Rett syndrome.

In yet another , provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the t invention. In certain embodiments, the attention er is ADI-ID.

In n embodiments, the compound is administered to the subject cally. In certain embodiments, the compound is administered to the subject , subcutaneously, intramuscularly, or intravenously.

Anesthesia /Sedation Anesthesia is a pharmacologically induced and 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 which alone es the correct ation of effects, or occasionally with a combination of drugs (e.g., hypnotics, ves, paralytics, analgesics) to achieve very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the ss and pain they would otherwise experience.

Sedation is the reduction of irritability or agitation by stration of a pharmacological agent, generally to facilitate a medical procedure or diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to l anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient ds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically unaffected.

Moderate on/analgesia (conscious sedation) is a drug-induced sion of consciousness during which the patient ds purposefully to verbal command, either alone or anied by light tactile stimulation. No entions are usually necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily d, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent atory on may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually maintained.

General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced sion of neuromuscular function. vascular function may be impaired. on in the intensive care unit (ICU) allows the depression of patients' awareness of the environment and reduction of their response to external stimulation. It can play a role in the care of the critically ill patient, and encompasses a wide spectrum of symptom l that will vary between patients, and among individuals throughout the course of their illnesses. Heavy sedation in critical care has been used to facilitate endotracheal tube tolerance and ventilator synchronization, often with uscular blocking agents.

In some embodiments, sedation (e.g., long—term sedation, continuous sedation) is induced and ined in the ICU for a prolonged period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1 month, 2 months). Long-term sedation agents may have long duration of action.

Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as ous on, is a technique of stering sedatives or dissociative agents with or without analgesics to induce a state that allows a subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.

Anxiety ers Anxiety disorder is a blanket term covering several ent forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety 2O disorders.

Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or ion. Those ing from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, ulty breathing. These panic attacks, defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always nt. In addition to recurrent unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic er experience symptoms even outside of ic panic episodes. Often, normal changes in heartbeat are noticed by a panic sufferer, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived logical change is interpreted as a possible life threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and sions (urges to perform specific acts or rituals). The OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist. Often the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm. And in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual red by nervousness. In a ty of cases, sufferers of OCD may only ence obsessions, with no overt compulsions; a much smaller number of sufferers experience only sions.

The single largest category of y disorders is that of Phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or ion. Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience, Post-traumatic stress can result from an extreme situation, such as combat, rape, e situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure dual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant ors, and depression.

Neurodegeneralz've Diseases and Disorders The term degenerative disease" includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer’s disease (including the ated symptoms of mild, moderate, or severe cognitive ment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic—induced acute akathisia, acute dystonia, Parkinsonism, or e esia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; e X syndrome; Gilles de la Tourette’s me; head trauma; hearing impairment and loss; Huntington’s disease; Lennox syndrome; pa-induced dyskinesia; mental retardation; movement disorders including akinesias and akinetic (rigid) syndromes (including basal ganglia ication, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson’s e, postencephalitic parkinsonism, and ssively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism, Huntington’s disease, neuroacanthocytosis, Sydenham’s chorea, and symptomatic chorea), dyskinesia (including tics such as x tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as rest tremor, postural tremor, and intention tremor) and ia (including axial dystonia, ic 's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic injury which s cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, , perinatal asphyxia and c arrest; Parkinson’s disease; seizure; status ticus; stroke; tinnitus; tubular sclerosis, and Viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows al stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, a, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include ng or preventing loss of neuronal function characteristic of neurodegenerative disorder.

Epilepsy sy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-ma] seizures on awakening, West me, Lennox- Gastaut syndrome, partial sy, e.g., temporal lobe epilepsy, l lobe epilepsy, benign focal sy of childhood.

Status epilepticus (SE) Status epilepticus (SE) can include, e.g., convulsive status epilepticus, e.g., early status ticus, established status epilepticus, refractory status ticus, super-refractory status epilepticus; non- convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges.

Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered. Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a l anesthetic is generally administered. Super refractory status epilepticus is characterized by status tic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.

Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e. g., x partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status ticus; 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.

Compositions bed herein can also be administered as a lactic to a subject having a CNS disorder e.g., a tic brain injury, status ticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, ished status epilepticus, refractory status epilepticus, super- refractory status epilepticus; non-convulsive status epilepticus, e. g., generalized status epilepticus, x partial status epilepticus; lized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.

Seizure A seizure is the physical gs or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." Convulsions are when a person’s body shakes rapidly and rollably. During convulsions, the person’s muscles contract and relax repeatedly.

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

Generalized seizures are produced by electrical impulses from hout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

There are six types of lized seizures. The most common and dramatic, and therefore the most well known, is the generalized convulsion, also called the grand-mal e. In this type of seizure, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 s, then by Violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand-mal seizures, injuries and accidents may occur, such as tongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms. The t, most often a child, lly interrupts an activity and stares blankly.

These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of g time." Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. ts sometimes describe the jerks as brief electrical shocks. When Violent, these seizures may result in dropping or involuntarily throwing s.

Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acute repetitive es; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; e seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic es; generalized onset seizures; infantile spasms; nian es; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic es; subtle seizures; Sylvan seizures; Visual reflex seizures; or withdrawal seizures.

Examples In order that the invention described herein may be more fully tood, the following examples are set forth. The synthetic and biological examples bed in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope.

Materials and Methods The compounds provided herein can be prepared from readily available starting als using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, res, etc.) are given, other process conditions can also be used unless otherwise stated.

Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

Additionally, as will be nt to those skilled in the art, conventional ting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a le ting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

The compounds provided herein may be isolated and purified by known rd procedures.

Such procedures e (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the ation of representative pyrazoles that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting als and reagents by one d in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK. 1H-NMR reported herein (e. g, for ediates) may be a partial representation of the full NMR spectrum of a compound, e.g., a compound described herein. For example, the ed 1H NMR may exclude the region between 8 (ppm) of about 1 to about 2.5 ppm. Copies of full 1H—NlVlR spectrum for representative examples are provided in the Figures.

Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 um C18, 19*250 mm. Mobile phase: itrile, water 03) (30 L water, 24 g 3, 30 mL NH3.H20). Flow rate: 25 mL/min Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HC03), B: acetonitrileGradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50mm, 35 mm at 45 C.

Synthetic Procedures The compounds of the invention can be prepared in accordance with s described in the art (Upasani et al., J. Med. Chem. 1997, 40:73-84; and Hogenkamp er al., J. Med. Chem. 1997, 40:61- 72) and using the appropriate reagents, starting materials, and cation methods known to those skilled in the art. In some embodiments, compounds described herein can be prepared using methods shown in general Schemes 1-4, comprising a nucleophilic substitution of 19-nor pregnane bromide with a neucleophile. In certain embodiments, the nucleophile reacts with the l9-nor pregnane bromide in the presence of K2C03 in THF.

Scheme 1 Nucleophile RNu R0 = H, oxygen protecting group 2O Scheme 2 Nucleophile RNu R0 = H, oxygen protecting group Scheme 3 Nucleophile RNu R0 = H, oxygen protecting group Example 1. sis of SA and SA intermediates EtPPthr 1)9-BBN,THF t-BuOK,THF 2). 10% NaOH, H202 Brz, aq. HBr MeOH Synthesis of compound SA-B. Compound SA (50 g, 184 mmol) and palladium black (2.5 g) in tetrahydrofuran (300 mL) and concentrated romic acid (1.0 mL) was hydrogenated with 10 atm hydrogen. After stirring at room temperature for 24h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the crude compound. tallization from acetone gave compound SA-B (42.0 g, yield: 83.4%) as white powder. 1H NMR: (400 MHz, CDCl3) 5 2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24 (s, 3H), 2.18-2.15 (m, 1H), .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).

Synthesis of compound SA-C. A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL anhydrous toluene was added dropwise to the methyl aluminum bis(2,6-di-tert-butylmethylphenoxide (MAD) (459.19 mmol, 3.0 eq, freshly prepared) solution under N2 at -78°C. After the addition was completed, the reaction mixture was stirred for 1 hr at -78°C. Then 3.0 M MeMgBr (153.06 mL, 459.19 mmol) was slowly added dropwise to the above mixture under N2 at -78°C. Then the reaction mixture was stirred for 3 hr at this temperature. TLC (Petroleum ether/ethyl acetate = 3:1) showed the on was ted. Then ted aqueous NH4Cl was slowly added dropwise to the above mixture at -78°C. After the addition was completed, the mixture was filtered, the filter cake was washed with EtOAc, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated, purified by flash Chromatography on silica gel leum ether/ ethyl acetate20:1 to 3:1) to afford compound SA-C (40.2 g, yield: 90.4%) as white powder. 1H NMR: (400 MHz, CDCl3) 6 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).

Synthesis of compound SA-D. To a solution of PPthtBr 2 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 ted, the reaction mixture was stirred for 1 h 60°C, 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 to 60 0C for 18 h. The reaction mixture was cooled to room temperature and ed with Sat.

NH4Cl, 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 a flash column tography (Petroleum ether/ ethyl acetate50:1 to 10:1) to afford compound SA-D (38.4 g, yield:92%) as a white powder. 1H NMR: (400 MHz, CDCl3) 6 .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).

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.Me2$ (126 mL, 1.26 mol) under th. After the addition was completed, the reaction mixture was stirred for 3 h at room temperature (14-20 °C).

TLC (Petroleum ether/ ethyl acetate3:1) showed the reaction was completed. The mixture was cooled to 0 °C and 3.0 M aqueous NaOH solution (400 mL) ed by 30% aqueous H202 (30%, 300 mL) was added. The mixture was stirred for 2 h at room temperature (14-20 °C), and then filtered, extracted with EtOAc (3*500 mL). The combined organic layers were washed with saturated aqueous g, brine, dried over Na2SO4 and concentrated in vacuum to give the crude t (43 g as colorless oil. The crude product was used in the next step without , crude) further purification.

Synthesis of compound SA—F. To a solution of SA—E (43.0 g, 134.16 mmol) in dichloromethane (800 mL) at 0 °C and FCC (538 g, 268.32 mmol) was added portion wise. Then the reaction mixture was stirred at room temperature (16-22 0C) for 3 h, TLC (Petroleum ether/ ethyl acetate3:1) showed the on was completed, then the reaction e was filtered, washed with DCM. The organic phase was washed with saturated aqueous N323203, brine, dried over Na2SO4 and concentrated in vacuum to give the crude product. The crude product was ed by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 8:1) to afford compound SA-F (25.0 g, yield:62.5%, over two steps) as a white powder. 1H NlVIR (SA-F): (400 MHz, CDC13) 6 .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).

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 was added dropwise bromine (5.52 g, 34.54 mmol). The reaction mixture was stirred at 17 0C for 1.5 h. The ing on was quenched with saturated aqueous NaHC03 at 0°C and extracted with EtOAc (150 mLXZ). 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 afford compound SA (9.5 g, yield: 76.14%) as a white solid. LC/MS: rt .4 min , m/Z 379.0, 381.1, 396.1.

Example 2. sis of SB and SB intermediates aq. HCI, THF BH3ITHF NaOH/Hzo2 CF3COZNa Synthesis of compounds SB-B and SB—C. Small pieces of lithium (7.63 g 1.1 rnoi) were added to 2.7 L of condensed ammonia, in a, three neck flask at —70 °C. As soon as ail iithium was dissolved, the hive solution was warmed to —50C A seiution of 19~norandrost~4~ene—3,i7vdione sets (1, 30 g, MO mmol) and tart—1311011 (814- g, l 10 mmol) in 800 mi of anhydrous tetrahydrofuraii was added dropwise and d for 90 min until the reaction mixture turn ed light yellow. Ammonium chloride (70 g) was added and excess ammonia was ieft to evaporate. The residue was extracted with 0. SN HC] (500 mil) and dichloroniethane (530 mL x 2). The combined organic iayers were ed with ted Nat-lCOg ori, dried over NagSoi fiitered and concentrated to give a mixture of ESE-B and Sfi—C (:21 g, 70%) which was directly used in the next step without further cation A on of SB~B and 834? (21 g, 76 mmol) in 50 mL of anhydrous dichloromethane was added to a suspension of pyridinium chlorochromate (PCC) (32.8 g, 152 mmol) in 450 mL of dichloromethane. After stirring at room temperature for 2h, 2N NaOH solution (500 mL) was added to the dark brown reaction mixture and stirred for another 10 min.

The resulting solution was ted with dichloromethane, the combined organic layers were washed with 2N HCl, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ethyl acetate = 20:1 to 10: 1) to afford title compound SB-C(16.8 g, 80%) as a white solid. 1H NMR of SB-B (400 MHz, CDC13), 6 (ppm), 3.65 (t, ii—i. 1H), 0.77 (s, 3331). 1H NMR of SB—C (400 MHz, CDC13), 6 (ppm), 0.88 (s, 3H) . sis 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 12h, the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (200 mL) and washed with saturated NaHC03 (150 mL), brine, dried over Na2SO4, filtered and concentrated.

The residue was purified by chromatography on basic alumina (pertroleum ether/ ethyl acetate = 100:1) to give compound SB-D (14 g, 43.8 mmol, 71%). 1H NMR (400 MHZ, CDC13), 5 (ppm), 3.18 (s, 3H), 3.12 (s, 3H), 0.85 (s, 3H).

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

Synthesis of compound SB-F. A solution of crude compound SB-E (7.36g, 21.9 mmol ) in THF ( 50 mL) was acidified to pH = 3 by 1N aqueous HCl. After stirring at room temperature for 12 h, the on mixture was extracted with ethyl acetate (250 mL x 3). The combined c layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (pertroleum ether/ethyl acetate = 30:1 to 20: 1) to afford compound SB-F (4.8 g, 16.7 mmol, 76% for two steps). 1H NMR (400 MHz, , 6 (ppm), .12—5.10 (m, 1H), 0.77 (s, 3H).

Synthesis of compound SB-G. To a solution of MeMgBr (28 mmol, 1M in THF) in THF (50 mL) at 0 °C was added a solution of compound SB—F (4.8 g, 16.8 mmol) in dry THF (10 mL) via syringe pump over 30 min. After stirring at 0 °C for 5 h, the reaction mixture was allowed to warm up and stirred at room temperature ght. The reaction mixture was quenched with iced-cold water and extracted with ethyl acetate (150 mL x 3). The combined c layers were washed with brine, dried over sodium sulfate, ed and trated. The white e was purified by flash column chromatography (pertroleum ether/ ethyl acetate = 20:1 to 10: 1) to give nd SB-G (2.5 g, 8.28 mmol, 49%; Rf: 0.35, petroleum ether/ethyl acetate = 10: 1). 1H NMR (400 MHz, CDC13), 6 (ppm), 5.05—5.03 (m, 1H), 1.21 (s, 3H), 0.90 (s, 3H).

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 x (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 then quenched slowly with 10% aqueous NaOH (10 mL) followed by 30% s solution of H202 (12 mL). After stirring at room temperature for one hour, the mixture was extracted with EtOAc (3 x 100 mL). The ed organic layers were washed with 10% aqueous Na2S203 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to afford crude compound SB-H (2g, 100%). The crude product was used in the next step without further purification.

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 had been shaken with several milliliters of H20 then separated from the water layer) was added artin periodinate (5,5 g, 13 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (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. The residue was ed by chromatography on silica gel (pertroleum ether/ ethyl acetate = 10:1 to 5: 1) to afford compound SB-I (1g, 3.14 mmol, 47% for two steps) as a white solid. 1H NMR (400 MHZ, CDCl3), 5 (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).

Synthesis of compound SB. To a solution of compound SB-I (600 mg, 1.89 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) followed by bromine (302 mg, 1.89 mmol). After stirring at room temperature for 1h, the on mixture was poured into ice-water then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered and concentrated to give crude compound SB (600 mg).

Synthesis of compound SB—J. A on of compound SB (600 mg, 1.5 mmol) in acetone 10 mL was treated with CF3COOH (6.8 mL) and Eth (9.5 mL). After refluxed for 30 min, CF3COONa salt (4.49 g, 33 mmol) was added in parts over a period of 10 hr. The on mixture was allowed to cool to room temperature and the t was removed in vaccuo. The residue was extracted with ethyl acetate, dried over MgSO4, filtered and concentrated. The mixture was purified by chromatography on silica gel oleum ether/ethyl acetate = 10:1 to 3:1) to afford SB-J (300 mg, yield: 50% for two steps). 1H NlV[R (400 MHz, CDC13), 5 (ppm), 423-4. 13 (m, 2H), 2.48-2.44 (m), 0.64 (s, 3H).

Example 3. Synthesis of SA-V compound AcCI. A020 reflux EtPPthr ,THF 1) BH3yTHF MeS+I' —> —, 2)anaOH,H202 NaH,DMSO Synthesis of compound SA-K. Compound SA-J (10 g, 36.7 mmol) was added to 50 mL acetyl chloride and 50 mL acetic anhydride. The reaction mixture was heated to 120°C for 5 h, evaporated in vacuo to afford SA-K as a white solid (10 g, 87% yield).1H NMR (400 MHz, CDC13), 5 (ppm), 5.78 (s, 1H), 5.55 (s, 1H),2.4(2H,dd) , 2.13 (s, 3H), 0.90 (s, 3H).

Synthesis of compound SA—L. To a solution of reactant SA-K (10 g, 31.8 mmol) in 200 mL THF and 20 mL H20, was added mCPBA (11 g, 63.6 mmol) at 0°C, stirred at rt for 15 h, the reaction mixture was extracted 500 mL EtOAc, washed with 100 mL ted , 100 mL saturated NaHC03 and 100 mL brine and evaporated in vacuo then ed by silica gel flash chromatography on silica gel (Petroleum ether/ethyl acetate = 5: 1) to afford SA—L-l as a white solid (2.2 g, 24% yield) (eluted first) and SA—L as the white solid ( 1,1 g, 12% yield) (eluted ). SA—L-l: 1H NMR (400 MHz, CDC13), 6 (ppm), 5.92 (s, 1H), 4.44 (s, 1H), 0.95 (s, 3H).

SA-L: 1H NMR (400 MHz, CDC13), 6 (ppm), 6.25 (s, 1H), 4.28-4.25 (m, 1H), 0.93 (s, 3H).

Synthesis of compound SA—M. To a solution of SA—L (2 g, 6.94 mmol) in 50 mL EtOAc, was added Pd\C 200 mg. The reaction mixture was hydrogenated in 1 atm H2 for 15 h. The reaction mixture was evaporated in vacuo then purified by chromatography (Petroleum ether/ethyl acetate = 1:2) to afford SA-M as a white solid (1.5 g, 75% yield). "H NMR. (400 MHZ, CDClg), (3 (ppm), 3.97 (td, 1H), 0.88 (s, 311).

Synthesis of nd SA-N. To a solution of SA—M( 1 g, 3.4 mmol) in 100 mL MeOH, was added TSOH 50 mg, heated to 60 0C for 2 h. The reaction mixture was extracted 500 mL EtOAc, washed with 100 mL sat. NaHC03, 100 mL brine solution and evaporated m memo to afford SA- N as a white solid (1 g, 91% yield).

Synthesis of compound SA—O. To a on of ethyltriphenylphosphonium bromide (10.67 g, 28.84 mmol) in 30 mL THF, was added KOt-Bu (3.23 g, 28.80 mmol). The reaction was heated to 60 °C for 1 h. SA-N (3.23 g, 9.6 mmol) was added to the mixture, stirred at 60 °C for 15 h. The reaction mixture was extracted 500 mL EtOAc, washed with brine solutions, and evaporated in vacuo ated then purified by chromatography (Petroleum ether/ethyl acetate = 3: 1) to afford SA—O as a white solid (2 g, 62% yield). 1H NMR (400 MHz, MeOD), 6 (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) Synthesis of compound SA-P. To a solution of SA-O (0.5 g, 1.43 mmol) in 10 mL DCM, was added DAST 0.5 mL at -78°C. The reaction mixture was stirred at -78°C for 30 min, then was quenched with 5 mL sat. NaHC03 extracted with 50 mL DCM, washed with brine, dried and concentrated in vacuo, purified by chromatography (Petroleum ether/ethyl e = 30: 1) to afford SA-P as a white solid 175 mg, 35% yield.

Synthesis of compound SA—Q. To a solution of SA—P (350 mg, 1 mmol) in 20 mL THF, was added 2 M HCl 2 mL, stirred at rt for 1 h. The reaction mixture was quenched with 5 mL H20 and extracted with 100 mL EtOAc, washed with brine and ated in vacuo then purified by chromatography (Petroleum ether/ethyl acetate = 10: 1) to afford SA-Q as a white solid (210 mg, 60% yield). 1H NMR (400 MHz, CDCl3), 6 (ppm) 517—5. 14 (m, 1H), 4.80-4.66 (m, 1H), 2.61- 2.57 (m, 1H), 1.79 (d, 3H), 0.93 (s, 3H).

Synthesis of compound SA—R. To a stirred solution of trimethylsulfonium iodide (3.2 g 16 mmol) in 10 mL ofDMSO was added NaH (60%;400 mg 16 mmol). After stirring at room temperature for 1h, a suspension of SA—Q (486 mg, 1.6 mmol) in 5 mL ofDMSO was added dropwise. After 15 h, the on mixture was poured into ice-cold water (100 mL) and extracted with 300 mL EtOAc, washed with 100 mL brine solution, and evaporated in vacuo then purified by chromatography (Petroleum ether/ethyl acetate = 10: 1) to afford SA-R and its isomer as a white solid (290 mg, 58% yield).

Synthesis of compound SA-S. To a solution of SA—R and its isomer (300 mg, 0.94 mmol) in 10 2O mL THF, was added LiAH4 (100 mg, 2.7 mmol) stirred at rt for 1 h. The reaction e was quenched with 5 mL H20 and extracted with 100 mL EtOAc, washed with brine and evaporated in vacuo then purified by chromatography (Petroleum ether/ethyl acetate = 3: 1) to afford SA-S as a white solid (140 mg, 48% yield). 1H NMR (400 MHZ, CDC13), 6 (ppm) 5.15-5.12 (m, 1H), 4.72- 4.60 (m, 1H), 1.70 ent d within m), 1.27 (apparent s within m), 0.92 (s, 3H).

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 then quenched slowly with % aqueous NaOH (1 mL) followed by 30% aqueous solution of H202 (1 mL). After stirring at room ature for one hour, the mixture was extracted with EtOAc (3 x 100 mL). The ed organic layers were washed with 10% aqueous 3 (100 mL), brine (100 mL), dried over MgSO4, ed and concentrated to afford SA—T as a white solid (100 mg, 91%). The crude product was used in the next step t further purification.

Synthesis of compound SA-U. To a solution of SA-T (100 mg, 0.29 mmol in 20 mL DCM, was added FCC (190 mg, 0.87 mmol), stirred at rt for 2 h. The reaction mixture was quenched with 5 mL H20 and extracted with 100 mL EtOAc, washed with brine and evaporated in vacuo then purified by chromatography (Petroleum ether/ethyl acetate = 3:1) to afford SA-U as a white solid (53 mg, 53% yield). 1H NMR (400 MHz, CDC13), 6 (ppm) 4.71-4.57 (m, 1H), 2.54(1H, t), 1.28 (apparent s within m), 0.58 (s, 3H).

Synthesis of compound SA-V. To a solution of SA-U (40 mg, 0.11 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%) followed by e (150 mg, 0.33 mmol). After stirring at room ature for lh, the reaction mixture was poured into ice-water then extracted with EtOAc (10 mL x 3). The combined c layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give crude compound SA—V as a white solid (40 mg, 80% yield). The crude product was used in the next step without further purification.

Example 4. Synthesis of SB-W nd NaH, DMSO BH3ITHF NaOH/H202 SB-U To a stirred on of trimethylsulfonium iodide (81 g, 36.9 mmol) in 100mL ofDMSO was added NaH (60%; 1.26 g 31.5 mmol). After stirring at room temperature for 1h, a sion of compound SB-F (2.2 g 7.2 mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred for another 2.5 h, then poured into ice-cold water and extracted with ether (100 mL x 3).

The combined ether layers were then washed with brine (100 mLx 3), dried over MgSO4, filtered, and concentrated to give the crude product SB~S (2.2 g). The crude product was used in the next step without further purification.

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 reflux for 6 h.

Ethanol was evaporated off and the e was dissolved in dichloromethane and washed with H20 (3 x 50 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. The crude target compound was purified by via silica gel chromatography (pertroleum ethyl acetate = :1 to 5: 1),and concentrated to give SB-T (1.8 g, 82%) as a white solid. 1H NMR (500 MHz, CDC13), 6 (ppm), 5.03-5.01 (m, 1H), 3.43 (q, 2H), 3.13 (s, 2H), 0.80 (s, 3H) .

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 x ( 20 mL of 1,0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (10 mL) followed 30% aqueous solution of H202 (12mL). The mixture was allowed to stir at room temperature for 1 hour then ted 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 afford crude compound SB- U ( 1.8g, 100%). The crude product was used in the next step without further cation. sis of nd SB-V. To a solution of crude compound SB-U ( 1.8g, 5.2mmol ) was dissolved in 60 mL of H20 saturated dichloromethane (dichloromethane had been shaken with l milliliters of H20 then separated from the water layer) was added Dess-Martin periodinate ( 4.4g, 10.4 mmol ). After stirring at room temperature for 24 h, the reaction mixture was ted with dichloromethane (3 x 100 mL). The combined organic layers were washed with 10 % aqueous 3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ ethyl acetate = 10:1 to 5: 1) to afford SB-V ( 1 g, 2.8 mmol, 56% for two steps) as a white solid. 1H NMR (400 MHZ, CDC13), (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 = 7.25 min. m/z = 345.1 [M-17]+.

Synthesis of compound SB-W. To a solution of compound SB-V (600 mg, 1.65 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) followed by bromine (264 mg, 1.65 mmol).

After stirring at room temperature for 1h, the reaction mixture was poured into ice-water then extracted with ethyl acetate (100 mL x 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]+.

Example 5. Synthesis of SA-AA compound _ Br2/HBr RT —’rt Synthesis of compound SA-X. To a solution of EtMgBr (5 mmol, 1M in THF) in THF (20 mL) at 0°C was added a solution of compound SA—W (858mg, 3 mmol) in dry THF (5 mL) Via syringe pump over 30 min. After stirring at 0°C for 5h, the reaction mixture was allowed to warm up and stirred at room temperature overnight. The on mixture was quenched with iced-cold water and extracted with EtOAc (15 mL x 3). The combined c layers were washed with brine, dried over sodium e, filtered and trated. The white residue was purified by flash column chromatography (petroleum ether/ethyl acetate= 20:1 to 10: 1) to give compound SA—X (900mg).

Synthesis of compound SA-Y. To a solution of compound SA—X (200 mg, 0.66 mmol) in dry THF (5 mL) was added —tetrahydrofuran complex (2 ml, of 1,0 M solution in THF), After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath their quenched slowly with 10% aqueous NaOl-E (1 mL) followed by 30% aqueous on ol‘HgOg (1.2 mL). The mixture was allowed to stir at room temperature for 1 hour then extracted with EtOAc (3 x if: mL). The combined. organic layers were washed with 19% aqueous Na2S203 (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to afford compound SA-Y (260 mg, crude). The crude t was used in the next step without further purification.

Synthesis of compound SA—Z. To a solution of compound SA-Y (260mg, crude) was dissolved in mL dichloromethane was added FCC (449 mg,). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The ed organic layers were washed with 10 % aqueous NaCl (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated The residue was purified by chromatography on. silica gei (petroleum ether/ethyl acetate = 4:1 to 2: 1) to afford title SA-Z ( l 5 mg,) as a white soiid. 1H NlVIR (500 MHz, CDC13), 6 (ppm), 2.49 (1H, t), 0.84(,t 3H), 0.59 (s, 3H).

Synthesis of nd SA-AA. To a solution of compound SA-Z (30 mg, 0.09mmol) in MeOH (5 mL) was added 2 drops of HBr (48%) followed by bromine (100 mg, 0.62 mmol). After ng at room ature for 1h, the reaction e was poured into ice-water then extracted with ethyl acetate (15 mL x 3), The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give compound SA-AA (36mg crude ). The crude product was used in the next step without further purification.

Example 6. Synthesis of SA-JJ compound 1iB2H6, THF 2. 10% NaOH, H202 Pcc/DCM Synthesis of nd SA—DD and SA-EE. Compound e SA-BB and SA-CC (5.0 g, 16.7 mmol) was dissolved in dry methanol (250 mL), and Na metal (1.2g, 50.0 mmol) was added and the solution was refluxed for 16 h. Methanol was then evaporated off and the residue was dissolved in dichloromethane and washed with H20 (3 x 50 mL) and brine (100 mL), dried over MgS04, filtered, and concentrated. The crude target compound was purified by via silica gel chromatography (petroleum ether/ethyl acetate = 10:1 to 5:1), and concentrated to give the product mixture SA-DD and SA-EE (4.6g, 83%) as a white solid.

Synthesis of compound SA-FF and SA-GG. To a solution of reactant mixture SA-DD and SA- EE (4.6g, 13.9 mmol) in ous THF (30 mL) was added BH3.THF (1.0 M, 27.7 mL, 27.7 mmol), the solution was stirred at 25 OC overnight, then the reaction was quenched by addition of water (5 mL). 2 M NaOH on (30 mL) was added followed by 30 % H202 (30 mL). The mixture was stirred at room temperature for 1 hour. The mixture was d with ethyl acetate (200 mL) and resulting on was washed with brine (2X100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product mixture was used directly in the next step without further purification.

Synthesis of compound SA—HH and SA—II. To a solution of crude reactant mixture SA-FF and SA-GG (4.9g, 13.9 mmol, theoretical amount) in dichloromethane (40 mL) was added Pyridinium chlorochromate (PCC) in portions (6.0g, 27.8 mmol). The solution was stirred at 25 CC overnight 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 in vacuo. The residue was purified by flash chromatography ( petroleum ether/ ethyl e=15: 1) to afford product SA- HH (2.1g, 6.03 mmol, Yield=43% (2 steps)) as white solid and product SA-II (2.2g, 6.32 mmol, Yield=45% (2 steps)) as white solid. Compound SA-HH: 1HNMR (500 MHZ, CDC13) 5 (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: 1HNMR (500 MHz, CDC13) 6 (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).

Synthesis of compound SA—JJ. To a solution of reactant SA—II (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% romic 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 then the mixture was poured into cold water (50 mL) and the resulting solid was ted 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 without further cation in the next step. e 8. Synthesis of SB-R compound 1). BH3_THF 2). H202, NaOH Me38+|‘ NaH, DMSO Separate Synthesis of compound SB-K. To a solution ot‘eompound SBIE (5 g, 15 mmol) in dry THF (20 mL) was added horarieetetrahydrofurari complex (30 mL of 1.0 M solution in THE) and the reaction mixture was d at ambient temperature for 1 hour then 10 % aqueous NaOH (56 mL) was slowly added. The mixture was cooled in ice and 3 % aqueous solution of 155203 (67mL) was slowly added. The mixture was stirred at ambient temperature for 1 hour and then ted with EtOAc (3 X 100 mL). The ed EtOAc ts were washed with 10 ‘34: aqueous 1x12128203 (100 mL), hrihe (100 mL), dried over MgSfiq. Filtration and removal of the solvent gave the crude product 3.2. g for next step on Synthesis of compound SB-L. To a solution of compound SB-K (3.2 g, 9 mmol) in THF (40 mL) was added 2M HCl (3 mL). The reaction on was stirred at RT for 12h 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 give 2.2 g of the product as a white solid, yield:81.40%.

Synthesis of compound SB-M. To a stirred solution of trimethylsufonium iodide (6.43 g 31.5 mmol) in 100 mL ofDMSO was added 60wt% NaH (1.26 g, 31.5 mmol). After stirring at room temperature (15°C) for 1h, a solution of compound SB—L (2.2 g 7.2 mmol) in 20 mL ofDMSO was added dropwise. After 2.5 h, the reaction e was poured into ice-cold water and extracted with ether (100 mLx3). The combined ether layers were then washed with brine (100 mLx3), dried (MgSO4), filtered, and concentrated to give the crude product 1.6. g for next step Synthesis of compound SB-N. Compound SB-M (1.6 g, 5 mmol) was dissolved in 60 mL of H20 saturated CHQClz. (Using a separatory funnel, the CH2C12 had been shaken with several milliliters of H20 and then separated from the water layer). DMP was added (4.2 g, 10 mmol), and the resultant reaction mixture was vigorously stirred for 24 h. The reaction solution was diluted with DCM (100 mL), washed with 10 % aqueous Na2S203 (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel ( petroleum ether/ethyl acetate = 20:1 to 10: 1) to afford title compound (1.2 g, 3.79 mmol, 75%) as a white solid. 1H NMR (400 MHz, CDC13) 8 (ppm): 2.63 (s, 1H), 2.59 (s, 1H), 2.12 (s, 3H), 0.63 (s, 3H) . sis 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. ol was evaporated off and the residue was dissolved in dichloromethane and washed with H20 (3 x 50 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. The crude target compound was purified by silica gel chromatography ( petroleum ether/ethyl e = 10:1 to 5: 1) to give SB-P (300 mg, 25%, SB-Q (300mg, 25%) as a white solid. SB-P: 1H NMR (400 2O MHz, CDC13) 5 (ppm): 3.39 (s, 3H), 3.19 (s, 2H), 2.54 (t, 1H), 0.61 (s, 3H). SB-Q: 1H NMR (400 MHz, CDC13) 6 (ppm): 3.39 (s, 5H), 3.37 (s, 2H), 2.52 (t, 1H), 0.62 (s, 3H).

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, 0139 mL, 2.725 mmol). The solution was heated at 25 °C for 1.5 hours. Then the mixture was poured into cooled water (50 mL). The resulting solution was extracted with ethyl e (2X 100 mL). The combined organic ts were washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was used directly without further purification in the next step. e 9. Synthesis of SB-FF compound lour H2 —> —> CH3CN, rt, 15 h .0 EtOAc 41.8 % 57.38% SA-K SA-KK cat. TsOH EtPPh3Br HC|,THF —> /O —>O —> CH30H t-BuOK,THF / 76.23 % /O /O O 64.33% 100 % SB-Y SB-Z MeSOI 1) BH3MeZS THF,t—BuOK 2) aq. NaOH, H202 100 0A: 100 % SB-BB PCC Brz HBr CHZCIZ MeOH 60.15 % 83.03 % Synthesis of compound SB-IGC To a solution of SA—K (68 g, 216.27 mmol) in 600 mL CH3CN, was added flour (90.22 g, 324.4 mmol) in portions at —4 °C. The resulting reaction mixture wasstirred at -4 0C for 3 h. After the TLC showed the reaction was completed, then the mixture was filtered and concentrated. The product was purified by column chromatograph on silica gel eluted with (Petroleum ether/ ethyl acetate20:1-15:1-10:l-8:1-6:l-5:l) to afford SB-KK (26.3 g, 41.8 % yield) as white solid. 1H NMR (SB-KK) (400 MHz, CDC13), 6 (ppm), 6.02-5.94 (m, 1H,), .20-5.01 (m, 1H), 2.55-2.26 (m, 6H), 2.16—2.05 (m, ? 2.01—1.83 (m, 43), 1.48422 (in, 5H}, 0.984178 (m, (SH).

Synthesis of compound SB-X. To a solution of SB-KK (27 g, 92.98 mmol) in EtOAc (350 mL) at 20 °C, then Pd/C(2.7 g, 5 % ) was added in the mixture. The solution was stirred at 20 °C, 1 atm for 10 h under hydrogen. .After the LCMS showed the reaction was completed, and then the mixture was filtered and concentrated. The product was purified by column chromatograph on silica gel eluted with (Petroleum ether/ ethyl acetate40:1-35:1-30:1-25:1-20:1-15:1-10:1-6:1) to give SB-X (15.6 g, 56.38 %) as white solid. 1H NMR (SB-X) (400 MHZ, CDClg), 6 (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, , 111).

Synthesis of compound SB-Y. To a on of SB-X (47 g, 160.75 mmol) in MeOH (600 mL) at 23 °C, then 2.35 g of TsOH was added in the e. The solution was stirred at 60 °C for 1.5 h .After the TLC showed the reaction was completed, and then the mixture was filtered and trated to give SB-Y (35 g, 64.33 %) as white solid. 1H NMR (SB-Y) (400 MHz, CDCl3), 6 (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), 105-096(11). 1H} 0.89 (s, 3H) 0.83-0.77 (m, , , 111).

Synthesis of compound SB-Z. To a solution of ethyltriphenylphosphonium bromide (115.17 g, 310.23 mmol) in 150 mL THF, was added KOt-Bu (34.81 g, 310.23 mmol). The reaction mixture was heated to 60 CC for 1 h and SB-Y (35 g, 103.41 mmol) was added to the mixture which was stirred at 60 CC for an additional 15 h. The on mixture was cooled and extracted 1500 mL EtOAc, washed with brine and concentrated to afford SB-Z as the white solid (120 g, crude). 1H NMR (SB-Z) (400 MHz, CDC13), 6 (ppm)=5.13-5.07 (m, 1H), 4.67-4.54 (m, 1H), 3.14 (s, 311) 3.09 , (s, 3H),2.42-2.15 (111, 31-1), 1.92-1.79 (m, 3H), 1.67-1.61 (m, 411) 1.57—1.50 (m, 2H) 1.45—1.15 (m, 10H) .94 (an, 11-1) 0.92 (s, 31-1; 0.90-0.84 (m, , , , , 111).

Synthesis of compound SB-AA. To a solution of SB—Z (120 g, crude) in 600 mL THF, was added 2M aqueous HCl 90 mL. the reaction mixture was stirred at 22 0C for 1h . After the TLC showed the on was completed, then the reaction was quenched with C03. The reaction was extracted with 500 mL EtOAc, washed with brine and evaporated in vacuo. The ing residue was purified by chromatography (Petroleum ether/ethyl e =150:1-125:1-100:1-80:1-60:1- 50:1) to afford SB-AA as the white solid (24 g, 76.23 % yield). 1H NMR (SB-AA) (400 MHz, CDCl3), 6 (ppm)=5.13 (m, 1H), 4.65-4.48 (m, 1H), 2.62-2.42 (m, 1H} 1.92— , 244—2071;", 311), 1.80 (m, 11-1}, 1.72—1.55 (m, 8H) 1.36-1.08 , (111, 61-1} 0.92 (s 31-1) 0.83-0.73 (m, 111) , , .

Synthesis of compound SB-BB. To a solution of Me3SOI (78.07 g, 354.75 mmol) in 50 mL THF, was added a solution of t-BuOK( 39.81 g, 354.75 mmol) in 50 mL THF. The reaction mixture was stirred at 60 °C for 1.5 h . Then a solution of SB-AA (24 g, 78.83 mmol) in THF (300 mL) was added in the reaction. The reaction was d for 2.5 h at 23 °C. After the TLC showed the reaction was completed, then the reaction was quenched with ice water. The reaction was extracted with 500 mL EtOAc, washed with brine and evaporated in vacuo to afford SB-BB as crude product (50 g). 1H NMR (SB-BB) (400 MHz, CDC13), 6 (ppm)=5.20—5.11 (m, 1H), 4.65-4.52 (m, 1H), 2.74-2.68 (m, 2H) 2.48-1.81 (m, 913) 1.72-1.64 (m, 4H) 1.55-1.06 (m, 10H) 0.97-0.89 , , , , (m, 3H) 0.85-0.77 (m, 1H).

Synthesis of compound SB-CC. To a solution of SB-BB (50 g, crude) in 300 mL THF, was added LiAlH4 (8.99 g, 236.49 mmol) at 0 0C. the reaction mixture was stirred at 23 °C for 1.5 h .

After the TLC showed the reaction was completed, then the on was quenched with water.

The reaction was extracted with 1000 mL EtOAc, washed with brine and evaporated in vacuo. The resulting residue was purified by chromatography (Petroleum ethyl e =100:l-80:1- 60: 1-50:1-40:1-30: 1) to afford SB-CC as the white solid (19 g, 75.19 % yield). 1H NMR (SB-CC) (400 MHz, CDC13), 5 (ppm)=5.17-5.07 (m, 1H), 4.66-4.48 (m, 1H), 2.41—2.32 (m, 1H) 2.28-2.15 (m, 23) 2.09—2.05 (m, 1H), 1.88-1.75 1.40—1.31 (m, 1H), 1.25— , (111,21-11), 1.68-1.64 (m, 3H) , 1.13 (m, 93) 0.89 (s, 3H} 0.81-0.72 (m, , , 111).

Synthesis of compound SB-DD. To a on 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 0C. After stirring at room temperature for 2 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 3M aqueous NaOH (160 mL) followed by 30 % s solution of H202 (100 mL). After ng at 20 °C for 1.5 h, the mixture ed and extracted with EtOAc (3 00 mL). The combined organic layers was treated with aq.Na28203, extracted, dried and concentrated to afford SB-DD as the crude (21 g, crude). The crude product was used in the next step without further purification.

Synthesis of compound SB-EE. To a solution of SB-DD (21 g, 59.29 mmol) in 200 mL CH2C12, was added PCC (25.56 g, 118.58 mmol) at 0 °C, stirred at 22 °C for 2 h. The reaction mixture was filtered and ted with 20 mL CHzClz, washed with aq.NaHC03, aq.Na2S203, brine and evaporated in vacuo. The residue was purified by chromatography leum ether/ethyl acetate = 1511611) to afford SB-EE as the white solid (12 g, 60.15% yield), 1H NMR (SB-EE) (400 MHz, CDC13), 6 (ppm)=4.65-4.46 (m, 1H), .51 (m, 1H), 2.22—2.09 (m, 4H) 2.06-1.97 (m, 32H) 1.88-1.77 (m, 2H), .54 (m, 51-1), 1.48-1.30 (m, 3H) 1.28-1.05 (m, , , 111-1) 0.83-0.72 (111., IE) 0.63 , (s, 3H).

Synthesis of nd SB-FF. To a solution of SB—EE (12 g, 35.66 mmol) in 1500 mL MeOH, was added HBr (5 drops) and Bl‘z (2.01 mL, 3923 mmol) at 0 0C. The reaction was stirred at 16 0C for 2 h.The reaction mixture was quenched with C03 and concentratedThen the mixture was extracted with 1000 ml EtOAc, washed with brine and evaporated in vacuo. The product was purified by column chromatograph on silica gel eluted with (Petroleum ether/ethyl acetate = 12: 1- :1-8:1-6:1-3:1) to afford SB-FF as the white solid (12.3 g, 83.03% yield). 1H NMR (SB-FF) (400 MHz, CDClg), 6 (ppm)=4.64-4.47 (m, 1H), 3.95-3.86 (m, 2H), 2.89-2.80 (m, 1H) 2123-216 (m, 1H) 2.07-1.64 (m, SH) 1.46—1.06 (m, 14H} 0.67 (s, 3H) , , 083-074(211, 1H) , e 12. Synthesis of SC-O compound 1). LiHMDS, HMPA, THF 2). Mel Li, NH3(I) —>Me, t-BuOH, THF ' X=O; OH&H sc-F Ph3PEtBr t-BUOK, THF Me380I, NaH DMSO-THF 1). BH3, THF Synthesis of compound SC-B. To a solution of reactant SC-A (10.0 g, 36.44 mmol) in pyridine (30 mL) was added acetic anhydride (5.0 mL, 52.89 mmol). The mixture was stirred at 60 CC overnight. Then the solution was poured into ice-water (200 mL). The white precipitate was filtered and dissolved in ethyl acetate (300 mL). The resulting solution was washed with sat.

CuSO4.5H20 solution (2 X200 mL) in order to remove residual ne. 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 afford product SC-B (11.125 g, 35.16 mmol, Yield=96%) as white solid. lI-INMR (500 MHz, CDCl3) 6(ppm): 5.83 (1H, s), 4.62 (1H, dd), 2.05 (3H, s), 0.86 (3H, 5).

Synthesis of nd 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 in THF solution, 1774 mL, 17.74 mmol) at -78°C. The solution was stirred at -78°C for 30 minutes. Then HMPA (3.09 mL, 17.74 mmol) was added. The solution was stirred at -78 °C for another 30 minutes. Then iodomethane (2.76 mL, 44.37 mmol) was added.

The solution was further stirred at -78 °C for 2 hours and warmed to room temperature and d for 1 hour. The reaction was quenched by addition of water (10 mL). Most THF solvent was d in vacuo. Then the residue was diluted with ethyl acetate (300 mL) and the resulting solution was washed with brine (2><200 mL), dried over magnesium sulfate. Removal of solvent in vacuo afforded crude product SC-C (4.50 g, 13.62 mmol, Yield=92%) as thick oil. The crude product was used in the next step without further purification. 1IH‘IMR (500 MHz, CDC13) 5(ppm): 5.75 (1H, s), 4.62 (1H, t), 2.05 (3H, s), 1.10 (3H, d), 0.86 (3H, s). sis of compound SC-D & 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 0C for 1 hour. Then most methanol t was removed in vacuo. The residual solution was acidified by 2 M HCl to pH 5-6. The aqueous layer was extracted with ethyl acetate (3X100 mL). The combined organic extracts were washed with brine (200 mL), dried over ium e and trated in vacuo. The e was purified by flash chromatography ( petroleum ether/ ethyl acetate=5: 1) to afford 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 solid. Compound SC-D: 1I-INMR (500 MHz, CDC13) 6(ppm): 5.81 (1H, s), 3.67 (1H, t), 1.11 (3H, d), 0.81 (3H ,s).

Compound SC-E: IHNMR (500 MHz, CDC13) 6(ppm): 5.74 (1H, s), 3.67 (1H, t, J=8.5 Hz), 1.11 (3H, d), 0.81 (3H, s).

Synthesis of compound SC-F. To liquid ammonia (200 mL) was added lithium (1.80 g, 260 mmol) at -78 CC. The liquid then turned to deep blue. Then a solution of reactant SC-D (3.0 g, .40 mmol) in t-BuOH (1.0 mL, 10.40 mmol ) and THF (100 mL) was added to Li-ammonia solution. The mixture was stirred at -78 0C for 4 hours. Then NH4Cl solid (20 g) was added to quench the reaction. The mixture was turned from deep blue to white. The mixture was allowed to warm to room ature and ammonia was evaporated in a hood overnight. To the residue was added water (300 mL). The mixture was acidified by conc. HCl to pH 6-7. Then ethyl acetate (300 mL) was added. The separated s layer was further extracted with ethyl acetate (2X100 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 without further purification in the next step.

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 ature overnight. The solution was filtered through a short pad of . The celite was washed with CH2C12 (3X50 mL). The combined CH2C12 solution was concentrated in vacuo. The residue was purified by flash chromatography ( eum ether/ ethyl acetate=5: 1) to afford product SC-G (1.298 g, 4.50 mmol, Yield=75%) as white solid. nd SC-G: IIDIMR (400 MHz, CDC13) 6(ppm): 1.02 (3H, d), 0.91 (3H, s).

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 on was heated at 70 °C for 3 hours. The on was quenched by addition of sat. Na2C03 solution (10 mL). Most methanol solvent was removed in vacuo. Then the residue was diluted with ethyl acetate (200 mL). The ing solution was washed with sat. Na2C03 solution (2><100 mL). The combined aqueous layers were extracted with ethyl acetate (50 mL).

The ed organic extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was ed by flash chromatography (petroleum ether/ ethyl acetate= 10: 1, added 0.1% NE’E3) to afford product SC-H (652 mg, 1.949 mmol, Yield=29%) as white solid. Furthermore, starting material (1.338 g) was also recovered. So the yield based on recovered starting material is 92%. 1H NMR (500 MHz, d6—acetone) 6(ppm): 3,079 (3H, 5), 3.075 (3H, s), 2.38 (1H, dd), 1.98 (1H, dd), 0.91 (3H, d), 0.85 (3H, 5). sis 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 then became reddish in color and was heated at 70 0C for 2 hours. Then the nt 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 d 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.

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 ature for 1 hour. The mixture was diluted with ethyl acetate (300 mL) and the resulting solution was washed with sat. NagCO3 solution (2X 100 mL). The combined s 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 =10023) to afford crude product SC-J (1.746 g) as white solid which was contaminated with some inseparated PPh3. Judged by the integration of 1HNMR spectrum, the ratio of desired product to PPh3 is 3: 1, so the amount of desired product SC-J is 1.354 g (4.506 mmol), the yield is 92%. 1H NMR (500 MHZ, CDCl3) : 5.13 (1H, qt), 1.66 (3H, dt), 1.02 (3H, d), 0.91 (3H, 5). sis of nd 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 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 e was d at 25 OC overnight. The reaction was quenched by addition of water (5 mL). The mixture was diluted with ethyl acetate (3 00 mL) and the resulting solution was washed with water (2X100 mL), followed by 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.

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. Then the on was quenched by addition of ethyl acetate (5 mL) followed by water (5 mL), A white solid was filtered and thoroughly washed with ethyl acetate (5x 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 afford product SC-L (458 mg, 1.447 mmol, 2 steps total yield=32%) as white solid.

Synthesis of compound SC-M. To a solution of nt 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), The solution was d at 25 °C overnight. Then the reaction was quenched by addition of water (5 mL). 2 M NaOH solution (10 mL) was added followed by 30 % H202 (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and resulting solution was washed with brine (2X100 mL), dried over ium sulfate and concentrated in vacuo. The crude product was used ly in the next step t further purification, Synthesis of compound SC-N. To a solution of crude reactant SC-M (484 mg, 1.447 mmol, tical amount) in dichloromethane (40 mL) was added pyridinium dichromate (PDC) in portions (1633 mg, 4.341 mmol). The solution was stirred at 25 °C overnight. Then the mixture was filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3 ><50 mL). All filtrate was combined and concentrated in vacuo. The residue was purified by flash chromatography ( petroleum ether/ ethyl acetate=8: l) to afford product SC-N (305 mg, 0.917 mmol, Yield=63% (2 steps)) as white solid. 1H NMR (500 MHZ, CDCl3) 6(ppm): 2.54 (1H, t,), 2.12—2.19 (1H, m), 2.12 (3H, s 0.92 (3H, d), 0.61 (3H, s). 13CNMR (100 MHz, CDC13) 5(ppm): 209.75, 71.09, 63.96, 55.89, 47.96, 47.80, 47.00, 44.35, 41.19, 40.22, 39.05, 37.95, 34.49, 33.14, 31.54, 30.92, 28.46, 25.82, 24.22, 22.76, 15.14, 13.45.

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. Then the mixture was poured into cooled water (50 mL). The ing solid was extracted with ethyl acetate (2><50 mL). The combined organic ts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SC-O was used ly without further purification in the next step.

Example 13. Synthesis of SC-Y compound Li, NH3(|) t-BuOH, THF .H20 . m-CPBA CHzclz PhMe CHzclz EtPPhBBr MeO 1). BH3, THF MeO —>Me —> , THF 2). aq. NaOH, H202 Synthesis of compound SC-P. To NH3 (liquid, 20 L) was added lithium (7.0 g, 1 mol) at -78 CC.

After the liquid was turned to 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. Then NH4C1 solid (50 g) was added to quench the reaction. The mixture was turned from deep blue to white. The mixture was allowed to warm to room temperature and ammonia was evaporated overnight. The residue was dissolved in 0.5 N aqueous HCl (50 mL) and extracted with dichloromethane (200 mLX3). The combined organic layers were washed with saturated NaHC03 (200 mL) and brine (200 mL), dried over magnesium sulfate and concentrated in vacuo. The crude t was purified by flash chromatography (Petroleum ether/ethyl acetate = 4: 1) to get product SC-P (18.98 g, 68.7%) as white solid. 1H NMR (500 MHz, CDCl3) : 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).

Synthesis of nd SC-Q. A sample of 19.0 g compound SC-P (68.84 mmol) was dissloveed in 50 mL THF at 0 0C. Then 70 mL MeMgBr in THF(31\/I) was added dropwise in 30 minThe reaction was kept at 0 °C for 8 h. The reaction mixture was quenched with ice-cold water and ted with EtOAc (200 mL><3).The combined organic layers were washed with brine, dried over sodium e, 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 white solid. 1H NMR (500 MHz, CDCl3) 6 (ppm): 5.78 (1H, br), 5.36 (1H, t), 3.67 (1H, t), 1.73 (3H, s), 0.77 (3H, 3).

Synthesis of compound SC-R. To a solution of nd 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 ed through a short pad of . The celite was washed with CHzClz (3X100 mL). The combined CH2C12 solution was concentrated in vacuo. The residue was purified by flash chromatography ( Petroleum ether/ethyl acetate =5: 1) to afford product SC-R (10.0 g, 53%) as white solid. 1H NMR (500 MHz, CDCl3) 6 (ppm): 2.44 (1H, dd), 2.07 (1H, m), 1.21 (3H, s), 0.87 (3H, 5).

Synthesis of compound SC-S. To a solution of compound SC-R (5.0 g, 17.2 mmol) in anhydrous toluene (100 mL) was added to the p-toluenesulfonic acid on sillica gel (80g), the mixture was stirred under 45 °C for 1 hour. The le bi-products were removed from sillica 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.

Synthesis of compound SC-T. To a solution of compound SC-S (3.20 g, 11.75 mmol) in 10 mL anhydrous dichloromethane was added mCPBA (4.04 g, 23.50mmol), and the reaction mixture was stirred over night at room teperature. The reaction e then was extracted with CH2C12, the combined organic layer was washed twice with NaHC03 (100 mL) and brine, dried over Na2S04 and concentrated. The crude product SC-T was used in the next step without further purification.

Synthesis of compound SC-U. To a solution of compound SC-T (11.75 mmol) in methanol was added H2SO4 (0.5mL), and the reaction mixture was stirred for 2h at room ature. The reaction solution was then extracted with CHzClz (200 mL X3), the combined organic layer was washed with NaHC03 (100 mL) and brine, dried over Na2SO4 and trated. The residue was purified by chromatography (Petroleum ether/ethyl acetate = 10: 1) to afford compound SC-U (3.30 g, 10.30 mmol, Yield = 87% for two steps) as white solid.

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 was turned to reddish and heated at 70 0C for 3 hours. Then compound SC-U (3.30 g, 10.30 mmol) was added in one portion. The reaction on was heated at 70 °C overnight, then was quenched by the addition of water (10 mL). The mixture was diluted with EtOAc (200 mL) and the resulting solution was washed with brine (2X100 mL), dried over ium sulfate and concentrated in vacuo. The crude product SC-V (1.90 g) was used directly in the next step without further purification.

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-TI‘IF (l 8 mL of 1.0M solution in THF). After stirring at room temperature for 1h, the reaction mixture was cooled in an ice bath then quenched slowly with 10% s NaOH (12 mL) followed by 30% H202 (20 mL). The mixture was allowed to stir at room teperature for 1h then extracted with EA (100 mLX3). The combined organic layer was washed with 10% aqueous Na2S203 (50 mL), brine, dried over Na2SO4, ed and concentrated to afford crude compound SC-W (1.86 g, 5.31 mmol). The crude t was used in the next step without further purification.

Synthesis of compound SC-X. To a on of crude compound SC-W (1.86 g, 5.31 mmol) in dichloromethane (50 mL) was added pyridinium dichromate (PDC) in portions (3.98 g, 10.62 mmol). The solution was stirred at 25 oC overnight. Then the mixture was filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3X50 mL). All filtrate was combined and concentrated in vacuo. The e was purified by flash chromatography (Petroleum ether/ethyl acetate =10: 1) to afford product SC-X (1.20 g, 3.45 mmol, 65%) as white solid. 1imMR (500 MHz, CDC13) 5(ppm): 3.33 (3H, s), 3.04 (1H, s), 2.53 (1H, t), 2.12 (3H, s within m), 1.26 (3H, s within 111), 0.62 (3H, s) Synthesis of compound SC-Y. To a solution of reactant SC-X (100 mg, 0.287 mmol) in ol (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. Then the mixture was poured into cooled water (50 mL). The resulting solid was extracted with ethyl acetate (2X 50 mL), The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product s used ly without further purification in the next step.

Example 14. sis of SC-EE compound PhSOzCH F2 HMPA SC-DD SC-EE Syntheaia of compound SC~Z and SCwAA. To a. solution of compound SA~E (800 mg, 2.79 mmol) and PhSQgCFZH (540 mg, 2.79 mmoi) in THF (25 mi...) and HMIPA (0.5 mL) at ~7 "C under N; was at t ed LHMDS (4 mL, 1M in THF) dropwise. After stirring at 478 "C for 2 h, the reaction mixture was quenched with saturated aqueous NH.;Cl solution (10 mL) and allowed to warm to room temperature then extracted with 3:20 {20 mil X 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrate. The residue was purified by silica gel column chromatography {pertroleum ether/ ethyl acetate 10/ l) to give the mixture of compound SC—Z and SC—AA (700 mg), The mixture was further purified by chiral— HPLC to afford compound SC-Z (290 mg, t=== 4.3l min). 1H NMR (400 MHz, CDC13), 6 (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 (260 mg, t==== 5.66 min). 1H NMR (400 MHz, CDC13), 6 (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).

Synthesis of nd SC-BB. To a solution of compound SflwAA (1131) mg, 0.299 mmol) and ous NangPO4 (100 mg) in anhydrous methanoi {5 mL} at —‘20 °C under N; was added Na/Hg amalgam (500 mg). After stirring at —20 0C to 0 CC for 1 h, the methanol solution was decanted. out and the solid residue was washed with Et20 (5 x 3 mL). The comhined organic layers were washed with brine (:20 mL), dried over MgSO/i, filtered and concentrated. The residue was purified by silica gel chromatography (pertroieum ether/ ethyl acetate = '10" l) to give compound SC—BB (36 mg, 0.106 mmol, 51%). 1H NNIR (400 MHZ, CDC13), 5 (ppm), 6.02-5.88 (t, 1H), .17-5.15 (m, 1H), 0.88 (s, 3H). sis of compound SCvCC To a solution of nd SC»BB (150 mg, 0.443 mmol) in dry THE (5 mL) was added borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution in ).

After stirring at room ature for 1 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (1 mL) followed 30% aqueous solution of H202 (1.2 mL). The mixture was allowed to stir at room temperature for l hour then extracted with EtOAc (3 x l0 mL). The combined organic layers were washed with 10% aqueous Na2S203 (10 mL), brine (if) mL), dried over Mg804, filtered and concentrated to afford crude compound SC—CC (210 mg). The crude product was used in the next step without further purification. sis of compound SC-DD. To a solution of crude compound SC-CC (210 mg) was dissolved in 10 mL of H20 saturated dichloromethane (dichloromethane had been shaken with several iters of H20 then separated from the water layer) was added Dess-Martin periodinate (380 mg, 0.896 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with l0 % aqueous Na2S203 (10 mL), brine (10 mL), dried over h’lgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel oleurn ether/ ethyl acetate 5: l) to afford compound SC-DD (90 mg, 0.254 mmol, (J!7%) as a white solid. 1H NMR (400 MHZ, CDC13), 5 (ppm), 6.01-5.73 (t, 1H), 2.55-2.54 (m, 1H), 2.12 (s, 3H), 0.62 (s, 3H).

Synthesis of compound SC-EE. To a solution of compound SC-DD (80 mg, 0.226 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%) followed by bromine (100 mg, 0.63 mmol). After stirring at room ature for 1h, the reaction mixture was poured into ice-water then extracted with ethyl acetate (15 mL x 3), The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give crude compound SC-EE (95 mg). The crude product was used in the next step without further purification.

Example 15. sis of SC-II compound BH3/THF NaOH/H202 SC-HH 80-" Synthesis of compound SC-FF. To a solution of reactant SB-F (4,4 g, 15.38 mmol) in dry THF (50 mL) was added ethylmagnesium bromide (3M in THF, 5128 mL) dropwise at 0°C. The solution was then slowly warmed and stirred at ambient temperature for 15h. Sat. NH4C1 solution (20mL) was added to quench the reaction and the resulting solution was extracted with ethyl e (3 L). The extracts were washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography ( petroleum ether: ethyl acetate=10: 1) to afford product SC-FF (3.15g, 10.00mmol, 64.8%) as a white solid.

Synthesis of compound SC-GG. To a solution of reactant SC-FF (500 mg, 1.58 mmol) in anhydrous THF (10 mL) was added F (1.0 M, 7.23 mL, 7.23 mmol) at room temperature, and the solution was stirred at 25 °C overnight. Then the on was quenched by on of water (5 mL), 2 M NaOH solution (10 mL) was added followed by 30 % H202 (10 mL). The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was diluted with ethyl acetate (200 mL) and 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 r cation.

Synthesis of compound SC-HH. To a solution of reactant SC-GG (6.53 g, 19.67 mmol) in anhydrous DCM (100mL) cooled in an ice-water cooling bath was added nium chlorochromate (8.48g, 39.34mol) in portions. The mixture was stirred at ambient temperature 2O overnight. The solution was then diluted with DCM (50mL) and filtered, The ed organic solutions were washed with brine (100mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography ( petroleum ether: elthyl acetate=10: 1) to afford product SC-HH (2.5g, 7.53mmol, yield39%) as a white solid. 1IH‘IMR (500 MHz, CDC13) (ppm): 2.54 (1H, t), 2.11 (3H,s), 1.42—1.45 (2H, q), 0.91 (3H, t), 0.62 (3H, 5).

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, 0.884mmol) ed by bromine (241 mg, 0.077 mL, 1.505 mmol). The solution was heated at 25 °C for 1.5 hours, then the mixture was poured into cooled water (50 mL). The ing solid was extracted with ethyl acetate (2><50 mL). The combined organic extracts were washed with brine (20 mL), dried over ium sulfate and concentrated in vacuo. The crude product SC-II was used directly without further cation in the next step.

Example 16. Synthesis of SC-SS compound 1.B2H6, THF 2. 10% NaOH, H202 1. separate 2. BrleBr Synthesis of compound SC-MM and SC-NN. A mixture of nt mixture SA—KK and SA-LL (3.0g, 10.0mmol, 1:1) was added dry (Bu)4NF, then the mixture was heated 100 °C overnight. The residual mixture was poured in to 50 mL H20 and extracted with EtOAc (2 X 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 afford product mixture SC-MM and SC-NN (2.1g, 6.5 mmol, 65%) as white solid.

Synthesis of compound SC-OO and SC-PP. To a solution of reactant mixture SC-MM and SC- NN (2.1g, 6.5 mmol) in anhydrous THF (30 mL) was added BH3.THF (1.0 M, 13.0 mL, 13.0 mmol), the solution was stirred at 25 OC overnight. Then the reaction was quenched by addition of water (5 mL). 2 M NaOH on (20 mL) was added followed by 30 % H202 (20 mL). The e was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and resulting solution was washed with brine (2X100 mL), dried over magnesium e and concentrated in vacuo. The crude product mixture was used directly in the next step without further purification.

Synthesis of compound SC-QQ and SC-RR. To a solution of crude nt mixture SC-OO and SC-PP (2.2g, 6.5 mmol, theoretical amount) in dichloromethane (40 mL) was added Pyridinium chlorochromate (Pcc) in portions (2.8g, 13.0 mmol). The solution was stirred at 25 CC overnight. Then the e was filtered through a short pad of silica gel and the silica gel was washed with romethane (3 ><50 mL). All filtrate was combined and concentrated in vacuo.

The residue was purified by flash chromatography ( petroleum ether/ ethyl acetate=15: 1) to afford product SC-QQ (910 mg, 2.7 mmol, Yield=41% (2 steps)) as white solid and product SC-RR (850 mg, 2.5 mmol, Yield=39% (2 steps)) as white solid. Compound SC-QQ: IIHVMR (500 MHz, CDC13) 5(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: 1I-lNlVIR (500 lVIHz, CDC13) 6(ppm): 4.45 (AB> 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. Then the mixture was poured into cooled water (50 mL). The resulting solid was ted with ethyl acetate (2X50 mL). The combined c extracts were washed with brine (50 mL), dried over magnesium sulfate and trated in vacuo. The crude product SC-SS was used directly without further purification in the next step.

Example 17. Synthesis of SA-ZZ compound PhSOZCHZF LHMDS/THF HMPA PhOZSFHC ; _ Ho‘ 9 SC-TT Synthesis 0f cumpound SCiTT and SC—UU. To a selu‘rien of eempeund SEN?" (1 3g, 4.5, mmol) and HiSOgCHgF {790 mg, 4.5 mmol) in THF (25 ml...) and Elli/{PA (0.5 mL) at —78 0C under N; was added LHMDS (5.5 mL, 1M in THF) dropwise. After stirring at —78 °C for 2 h, the en mixture was ed with saturated aqueous NH4C1 solution (l 0 ml.) and allewed to warm m mom temperamre then extracted with 1:31:20 {20 ml, X 3}. The combined organic layers were washed with brine, dried over sodium e, filtered and concentrate, The residue was purified by silica. gel column Chromategraphy {perti‘oleum ether/ elliyl e iil O/ l) to give the mixture of cempeund SC-TT and SC-UU (l .53 g). The mixture was fui‘llier purified by ehiral-l-{PLC to afferd compound SGTT-l (220 mg, iii 3.4lmin). 1H NMR (500 MHz, CDC13), 6 (ppm), 7.99- 7.97 (m, 2H), 7.75-7.74 (m, 1H), .55 (m, 2H), 5.13-5.09 (m, 1H), 4.86-4.78 (d, 1H,), 0.88 (s, 3H); Z (200 mg, tii- 3.66 min); 1H NMR (500 MHz, CDC13), 6 (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); scum}: i (235 mg, i=2 4.9mm). 1H NMR (500 MHz, CDC13), 6 (ppm), 799—797 (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—Z (220 mg, i=2 .2 min). 1H NMR (500 MHz, CDC13), 5 (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).

Synthesis of compound SC—W‘W. To a solution of nd SC—TT—l (200 mg, 0.434 mmol) and anhydrous NagHPOa (100 mg) in anhydrous methanol (l 5 mL) at —20 "C under N2 was added Na/Hg amalgam (400 mg). After ng at —20 0C to 0 CC for l h, the methanol solution was decanted out and the solid residue was washed with Eth (5 x 3 mL). The solveiit of combined organic phase was removed under vacuum, and 20 mi brine was added followed by extracting with £120. The combined. ether phase was dried with , and the ether was removed to give the crude product, which was r purified by silica gel chromatography (petroleum ether/ethyl acetatE=lO/l) to give t 99 mg, 69%. 1H NMR (500 MHz, CDC13), 6 (ppm), 5.12-5.10 (m, 1H,), 421—2411 (d, 2H), 0.88 (s, 3H).

Synthesis of compound SC-XX. To a solution of compound SC-W’W (95 mg, 0.296 mmol) in dry THE (5 mL) was added borane-tetrahydrofuran complex (1 mL of "l .0 M solution in THE) After stirring at room temperature for 1, hour, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOI-i (1 mL) followed by 30% aqueous solution oszOg (12 mL). The e was allowed to stir at room ature for 1 hour then extracted with EtQAc (3 x it) mL). The combined organic layers were washed with 10% aqueous Nags-203 (10 mL), hrine (l 0 mL), dried over MgSO4, filtered and concentrated to afford compound SC—XX (l 20mg crude). The crude product was used in the next step without further purification. 2O Synthesis of compound SC-YY. To a solution of compound SC-XX (120 mg crude) was dissolved in 10 mL of wet dichloromethane (dichloromethane had been shaken with l milliliters of H20 then ted from the water layer) was added Doss-Martin periodinate (300 mg, 707 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with 10 % aqueous N32S203 (10 mL), hrine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel oleum ether/ ethyl acetate 1: 5) to afford compound SC-YY (70 mg, 70% for two steps) as a white solid. 1H NMR (500 MHz, CDC13), 6 (ppm), 4.21-4.11 (d, 2H), 2.19 (s, 3H), 0.62 (s, 3H).

Synthesis of nd SC-ZZ. To a solution of 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. Then the mixture was poured into cooled 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 without further purification in the next step.

Example 18. Synthesis of compounds SA—l and SA-2 H 0 ,N CF3 K2003,THF Hzc H6 H SA SA-1 SA-2 To a suspension of K2C03 (50mg, 0.36mmol) in THF (5 mL) was added 5-(trifluoromethyl)-1H- pyrazole ( 80mg, 0.59mmol) and SA ( 100 mg, 0.25 mmol). The mixture was stirred at rt for 15h.

The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 X 10 mL). The combined c layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid SA-l (15 mg, 13.2% ). SA-2 (5 mg, 4.4% ). SA-l: 1H NMR(500MHZ,CDC13), 6 (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: lH NMR(500MHZ,CDC13), 5 (ppm), 7.57 , 6.66 (d,1H) 5.03 (1H, AB), 4.93(1H, AB), 2.77 (1H, t), 2 (m, 24H), 0.9 (s, 3H).

Example 19. sis of compound SA—3 To a suspension of K2C03 (50 mg, 0.36mmol) in THF (5 mL) was added ethyl 1H-pyrazole carboxylate ( 100 mg, 0.71 mmol) and SA ( 72 mg, 0.18 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 X 10 mL).

The combined organic layers were washed with brine, dried over sodium sulfate, ed and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (18mg, 21.6% ). 1H NMR (500 MHz, CDCl3), 6 (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).

Example 20. Synthesis of compound SA-4 SA-4 To a suspension of K2C03 (50 mg, ol) 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 rt for 15h. The reaction mixture was poured in to 5 mL H20 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 mixture was ed with by reverse-phase prep-HPLC to afford the title nd as a white solid (9mg, 17.4%). 1H NMR (500 MHz, CDC13), 6 (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> Example 21. Synthesis of compound SA—S SA SA-5 To a sion of K2C03 (50 mg, 0.36mmol) in THF (5 mL) was added ethyl 1-(1H-pyrazol yl)ethanone (100 mg, 0.91 mmol ) and SA (50 mg,0. 12 mmol). The mixture was stirred at rt for 15h. The on mixture was poured in to 5 mL H20 and extracted with EtOAc (2 X 10 mL).

The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The e mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (37mg, 65%): 1H NNIR (500 MHz, CDC13), 6 (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).

Example 22. Synthesis of compound SA—6 A on of SA (350 mg, 0.88 mmol) and K2C03 (243.5 mg, 1.76 mmol) in 10 mL dry DMF was added 4-methyl-1H-pyrazole (144.6 mg, 1.76 mmol) under N2 at room temperature. The reaction mixture was d for 18h at this temperature. The reaction mixture was poured to water, extracted with EtOAc (2*50 mL), the organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated, purified by flash chromatography silica column (petroleum ether/ ethyl acetate 10:1 to 2:1) to afford SA—6 (230 mg, yield: 65.5%) as a white powder. 1H NMR (400 MHz, CDC13), 6 (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 = 1.29 min, m/z = 399.2 [M+H]+.

Example 23. Synthesis of compound SA—7 To a suspension of K2CO3 (25 mg, 0.18mmol) in THF (5 mL) was added 4-chloro-4H-pyrazole (21mg, 0.21 mmol) and SA (36 mg, 0.09 mmol). The e was stirred at RT for 15h. The residue mixture was poured in to 5 mL H20 and ted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue e was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (8mg, 21% ): 1H NMR (500 MHz, CDC13), 6 (ppm), 7.45 (s, 1H), 7.41 (s, 1H), 490 (AB, 1H), 481 (AB, 1H), 2.57 (t, 1H), 2.22-2.16 (m, 1H), .01 (m, 1H), 1.00-1.90 (m, 22H), 0.67 (s, 3H). LCMS: rt=2.52 min, m/z=419.1 [M+H]+ Example 24. Synthesis of compound SA—S To a suspension of K2C03 (25 mg, 0.18mmol) in THF (5 mL) was added 4-nitro-4H-pyrazole (20mg, 0.18mmol) and SA (36 mg, 0.09mmol). The e was stirred at RT for 15h. The residue mixture was poured in to 5mL H20 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 mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (12mg, 31% )1 1H NMR (500 MHz, CDC13), 6 (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).

Example 25. sis of compound SA—9 HNN7 K2603, THF To a suspension of K2C03 (25 mg, 0.18mmol) in THF (5 mL) was added 4-bromo-4H-pyrazole (26mg, ol) and SA (36 mg, 0.09mmol). The mixture was d at RT for 15h. The residue mixture was poured in to 5mL H20 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 mixture was purified with by reverse-phase prep-HPLC to afford the SA-9 as a white solid (9mg, 22% ): 1H NMR (500 MHz, CDClg), 6 (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).

Example 26. Synthesis of compounds SA—10 and SA-ll SA-10 SA-11 To a suspension of K2C03 (55mg, 0.4mmol) in THF (SmL) was added 3-methy1—4H-pyrazole (33mg, 0.4mmol) and SA (79 mg, 0.2mmol). The mixture was stirred at RT for 15h. The residue mixture was poured in to SmL H20 and ted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue e was purified with by reverse-phase prep-HPLC to afford SA-10 as a white solid (9mg,11% ) and SA-ll as a white solid (11mg, 14%). Compound SA-10: 1H NMR (400 MHZ, CDC13), 5 (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), .04 (m, 1H), 1.00—1.90 (m, 22H), 0.69 (s, 3H). Compound SA-11: 1H NMR (400 MHz, CDC13), 5 (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), .90 (m, 22H).

Example 27. Synthesis of compound SA-12 To a suspension of K2C03 (25 mg, 0.18mmol) in THF (5 mL) was added 3,5-dimethyl-4H- pyrazole (17mg, 0.18mmol) and SA (36mg, 0.09mmol). The mixture was stirred at RT for 15h.

The residue mixture was poured in to 5mL H20 and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium e, filtered and concentrated. The e mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (11mg, 30%): 1H NMR (500 MHz, CDC13), 6 (ppm), 5.86 (s, 1H), 4.79 (AB, 1H), 474 (AB, 1H), 2.57 (t, 1H), 2.21(s, 3H), 2.18-2.16 (m, 1H), 2.11(s, 3H), .02 (m, 1H), 0.90-1.80 (m, 22H), 0.68 (s, 3H).

Example 28. Synthesis of compound SA-13 SA SA-1 3 To a suspension of K2CO3 (50 mg, 0.36mmol) 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 RT for 15h. The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and trated. The residue was purified with by reverse—phase prep-HPLC to afford the title nd as a white solid (11mg,31.3% ). 1HNMR (400 MHz, CDC13), 6 (ppm), 7.56 (d,1H), 7.44 (d, 1H), 6.35 (s,lH), 495 (AB, 1H), 4.92 (AB,1H), 2.60 (1H, t), 1.00-2.25 (m, 24 H), 0.68 (s, 3H).

Example 29. Synthesis of compound SA-14 To a on of crude nt (124.8 mg, 0.315 mmol, theoretical amount) in anhydrous THF (2.5 mL) was added 4-(trifluoromethyl)—lH-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 then the solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2><50 mL), dried over magnesium e and concentrated in vacuo. The crude product was purified by silica gel chromatography ( petroleum ether/ ethyl acetate =1 :1) to afford product (69 mg, 0.152 mmol, Yield=48% (2 steps)) as white solid. 1ILHVMR (500 MHZ, CDCl3) 6(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). 1002 10 (24H, m).19FNMR (376 MHz, CDC13) 6(ppm): —56.46. LCMS: rt = 2.52 min, m/z = 453.2 [M+H]+ Example 30. Synthesis of compound SA-lS To a solution of 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 d at 25 °C overnight then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2><100 mL), dried over magnesium e and concentrated in vacuo. The crude product was ed by silica gel chromatography (petroleum ether/ ethyl acetate =1 :3) to afford product (56 mg, 0.136 mmol, 22% (2 ) as white solid. 1I-lNlVIR (400 MHZ, CDC13) 5(ppm): 7.08 (1H, s), 4.77 (1H, AB), 4.76 (1H, AB), 2.55 (1H, t), 2.18 (3H, s), 100-220 (24H, 7 (3H, s).

LCMS: rt = 2.41 min, m/z = 413.2 [M+H]+ Synthesis of 4-ethyl-1H-pyrazole Me3Si I \\ i—fl\ Z—SiMes / \ H20LiOH H2,Pd/C / \ N,N f)C|2,CH2C|2 N,N THF--H20 EtOH N,N H Cul, EtzNH, THF H H Synthesis of 4-ethynyltrimethylsilane—lH-pyrazole. To a solution of reactant (3.88 g, 20 mmol), Pd(dppf)C12.CH2Clg (2.45 g, 3 mmol), CuI (0.571 g, 3 mmol) in EthH (30 mL) and THF (30 mL) was added ethynyltrimethylsilane (9.823 g, 14.1 mL, 100 mmol) under N2 atmosphere and the mixture was stirred at room temperature ght. Then the black solution was 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 afford product (1.90 g, 11.57 mmol, Yield=58%) as brownish solid. 1Ifl‘IMR (500 MHZ, DMSO-d6) 5(ppm): 13.12 (1H, br), 8.07 (1H, s), 7.65 (1H, s), 0.19 (9H, s).

Synthesis of 4-ethynyl-1H-pyrazole. To a solution of 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 then most THF solvent was d in vacuo. The solution was neutralized by 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 in vacuo. The residue was purified by silica gel chromatography (: petroleum ether / ethyl acetate =4: 1) to afford product (828 mg, 8.99 mol, Yield=78%) as pale brownish solid. 1I-INMR (500 MHz, DMSO-d6) 6(ppm): 13,11 (1H, br), 8.05 (1H, s), 7.65 (1H, s), 3.95 (1H, 5).

Synthesis of 4-ethyl-1H-pyraz01e. To a solution of 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 with a en balloon overnight. A small sample solution was filtered, concentrated in vacuo and characterized by 1HNMR to determine that the reaction was complete.

All reaction mixture was ed by celite and the celite was washed with ethanol (20 mL). The combined te was concentrated in vacuo. The residue was purified by a short pad of silica gel (: petroleum ether/ ethyl acetate =3:1) to afford product (643 mg, 6.69 mmol, Yield=74%) as pale yellow liquid 1HNMR (500 MHz, DMSO-d6) 6(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).

Example 31. Synthesis of compound SA-l6 SA-16 To a solution of 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 ing 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 e =2:3) to afford product (29.5 mg, 0.0714 mmol, 1 1% (2 steps)) as white solid. 1I-INMR (400 MHz, CDC13) 8(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 = 2.34 min, m/z = 413.1 [M+H]+ Synthesis of 4-methylsulf0nyl- lH-pyrazole / \\ / Br S (\ 1). Iii-BUD, THF' (\ m-CPBA (y 2). MeSSMe CF CO H CH CI3 2 , 2 2 N—NH N—NH N-NH Synthesis of 4-methylthi0- lH-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. The MeSSMe (128 mg, 0.12 mL, 1.361 mmol) was added at 0°C and reaction solution was d at room temperature for 2 hours. The reaction was poured into ethyl acetate (50 mL) and water (50 mL). The separated organic layer was washed brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. Due to its smell, the crude product was used in next oxidation reaction without further purification.

Synthesis of 4-methylsulf0nyl-1H—pyrazole. To a solution of the crude reactant (155.4 mg, 1.361 mmol, theoretical ) in dichloromethane (2.7 mL) was added trifluoroacetic acid (0.1 mL) at 0°C. Then 3-chloroperbenzoic acid (m-CPBA, 85% wt, 863 mg, 4.25 mmol) was added in portions and the solution was stirred at room temperature ght. The solution was diluted with ethyl acetate (100 mL) and the resulting solution was washed with sat. Na2C03 solution (3><50 mL) followed by brine (50 mL), dried over magnesium sulfate and trated in vacuo. The crude product was purified by silica gel chromatography ( ethyl e to ethyl acetate: methanol =10: 1) to afford product (51 mg, 0.349 mmol, Yield=26% (2 steps)) as pale yellow thick oil. 1ILHVMR (500 MHz, CDCl3) 6(ppm): 8.04 (2H, s), 3.14 (3H, s).

Example 32. Synthesis of compound SA-l7 (a) To a solution of crude reactant (124.8 mg, 0.315 mmol, theoretical amount) in anhydrous THF (2.5 mL) was added 4-(methylsulfonyl)-lH-pyrazole (51 mg, 0.349 mmol) followed by potassium carbonate (48 mg, 0.349 mmol). The solution was heated at 40 °C for 2 hours then the solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2X50 mL), dried over magnesium e and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford t SA—l7 (4 mg, 5 mmol, Yield=2.8% (2 steps) as a white solid. 1I-INMR (400 MHz, CDC13) 6(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), .26 (1H, s), 2.04 (1H, d> Example 33. Synthesis of compound SA-18 SA SA-1 8 T0 a mixture of SA (200 mg, 0.50 mmol) and K2C()3 {138.2 mg, 1.00 mmol) in 5 mL dry EMF was added 4-(methyithio)-lH—pyrazcle(114.2 mg, 1.00 mmol) under N; at room temperature (25°C). The reactien e was stirred at the same temperature for 18 h. The reaction mixture was poured into water and extracted with EtOAc (50 mLXZ). The organic layers were washed with brine, dried ever 1‘s 21;; S04, filtered and concentrated in vacuum. The residue was purified by silica gel column (Petroleum ether/ ethyl acetateifl/l to El} to give Cernpennd 813—18 (165 nrg, yield: 76%) as white powder. 1H NMR: (400 MHz, CDC13) 6 7.53 (s, 1H), 7.42 (s, 1H), .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 H20), 1.49-1.27 (m, 14H), 1.15-1.07 (m, 2H), 0.67 (s, 3H). LCMS: rt = 1.32 min, m/z = 431.2 [M+H]+ Example 35. Synthesis of compound SA-20 \ m-CPBA S\ DCM, -78°C SA SA-20 To a solution of SA (1000 mg, 0.23 mmol) in 10 mL ofDCM was added m-CPBA (51.86 mg, 0.26 mmol) at -78 °C. Then the reaction e was stirred at -78 °C for 3h. LCMS ted the reaction was complete. Then saturated aqueous 3 was added to the mixture at -78 °C. Then the reaction was allowed warm to room temperature(16-22 0C). The resulting mixture was extracted with EtOAc (50 mLx2), washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuum. 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. 1H NMR: (400 MHz, CDC13) 5 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 H20), 1.48-1.40 (m, 7H), 1.33-1.28 (m, 8H), .07 (m, 3H), 0.68 (s, 3H). LCMS: rt = 1.14 min, m/z = 429.2 [M-HgO], 469.2 [M+Na].

Example 36. Synthesis of compound SA-Zl / K2C03, THF N, I —> N 35°C, 15 h SA SA-21 To a suspension of nd SA (100 mg, 0.25 mmol) in THF (25 mL) was added 4-fluoro-1H- pyrazole (64.5 mg, 0.75 mmol) and K2C03 (103 mg, 0.75mmol). The mixture was stirred at 35°C for 15h. Then the reaction mixture was ted 50 mL EtOAc, washed with 100 mL H20 and 100 mL brine and evaporated in vacuo. The residue was purified by reverse-phase prep-HPLC to afford SA-21 as a white solid (19 mg, 0.05 mmol, 20 % yield). 1H NMR (500 MHZ, CDCl3), 6 (ppm), 7.37 (1H,d), 7.30 (1H,d), 4.85(1H,AB), H,AB), 2.57 (t,1H), 2.2 (bq, 1H), 2.1 (bd, 1H), 1.00—19 (22H, m), 0.67 (s, 3H). LCMS: Rt. = 2.31 min, MS (ESI) m/z: 403.4 [M+H] f Example 37. Synthesis of compound SA-22 / K2003, THF N\ I —> u 35°C, 15 h SA-22 To a suspension of Compound SA (100 mg, 0.25 mmol) in THF (25 mL) was added lH-pyrazole- onitrile (70 mg, 0.75 mmol) and K2C03 ( 103 mg, 0.75mmol). The mixture was stirred at 35°C for 15h. Then the reaction e was extracted. 50 mL EtOAc, washed with 100 mL H30 and. 100 mL brine and evaporated. in mezzo. The resulting e was purified by reverse- phase prep-HPLC to afford SA-22 as a white solid ( 23 mg, 0.056mnol, 24 % yield). 1H NlVIR (500 MHz, CDC13), 6 (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 = 2138 min, MS (ESI) m/z: 410.2 [M+H] +.

Example 38. Synthesis of compound SA-23 HN’N K2C03, THF To a suspension of K2C03 (55 mg, 0.4 mmol) in THF (5 mL) was added azole (28mg, 0.4mmol) and Compound SA-JJ (85 mg, 0.2mmol). The mixture was stirred at RT for 15h then the residue mixture was poured into 5 mL H20 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 mixture was purified by reverse-phase prep-HPLC to afford SA-23 as a white solid (29 mg,35% ). IHNMR (500 MHz, CDC13) 6 (ppm): 7.55 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 488 (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 = 2.27 min, m/z = 415.3 [M+H]+ Example 39. Synthesis of compound SA-24 SA-JJ SA-24 To a solution of nd SA-JJ (120 mg, 0.28 mmol) in THF (3 mL) was added K2C03 (190 mg, 1.4 mmol) and 1H-pyrazolecarbonitri1e (130 mg, 1.4 mmol). The resulting solution was d at room temperature overnight, then the reaction was diluted with EtOAc (20 mL). The ing solution was washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo.

The residue was purified by prep—HPLC to give SA—24 (30 mg, 24%) as a white solid. 1H NMR: (500 MHz, , 6 (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, 5), 060-21 (23H, m). LC-MS: rt=2.25 min; m/z=440.4 (M+H)+ Example 40. Synthesis of compound SA-25 K2003, THF, °C, 15 h SA'25 SA'V To a. suspension. of SA-V (20 mg, 0.04 mmol) in THF (5 mi...) was added pyrazole (30 mg, 0.45 mmol) and K2033 (60 mg, 0.45mrriol‘). The mixture was stirred at 25°C for 15h Then the reaction mixture was purified with by reverse~pirase prep-E-{PLC "to afford SA-25 as a white soiid (l 1 mg, 57% yield). 1H NMR (500 MHz, CDC13), 6 (ppm), 7.56 (s, 1H), 7.42 (s, 1H), 6.33 (5, 11-1), 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).

Example 42. Synthesis of compound SA-27 SC-EE To a suspension of K2C03 (25 mg, 0.18mmol) 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 rt for 15h. The reaction e was poured in to 5 mL H20 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 mixture was purified with by reverse-phase PLC to afford the title compound as a white solid (12mg, 34.3%). 1HNMR(5001\/IHz,CDC13)6(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).

Example 43. Synthesis of compound SA-28 SC-EE SA-28 To a suspension of K2C03 (25 mg, 0.18 mmol) in THF (5 mL) was addele-pyrazole carbonitrile (20 mg, 0.23 mmol) and SC-EE (36 mg, 0.09 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 X 10 mL). The ed organic layers were washed with brine, dried over sodium sulfate, ed and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (22 mg, 61.6%). 1I-INlVIR (400 MHz, CDC13), 6 (ppm): 7.86 (s, 1H), , 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: 0min,m/z = 446.2 (M + 1).

Example 44. Synthesis of compound SA-29 SC-EE SA-29 To a suspension of K2C03 (127 mg, 0.92 mmol) in THF (5 mL) was added hy1su1fony1)- 1H-pyrazole (67 mg, 0.46 mmol) and the reactant (200 mg, 0.46 mmol) and the resulting mixture was stirred at room temperature for 15h. Then the mixture was poured in to 20 mL H20 and extracted with EtOAc (2 X 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 with by reverse-phase prep-HPLC to afford the title compound SA-29 as a white solid (46 mg, 0.0923 mmol, yield=20%). 1I-INNIR (500 MHZ, CDC13) 5 (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 = 2.10 min, m/z = 499.3 [M+H]+ Example 61. Synthesis of compound SA—30 o h\ N/NH K2C03, THF SA-AA To a suspension of K2C03 (25 mg, 0.18mmol) in THF (5 mL) was added 1H-pyrazole carbonitrile (20 mg, 0.21 mmol) and SA-AA (36 mg, 0.087 mmol). The mixture was stirred at rt for 15h. Then the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium e, ed and concentrated. The residue was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (10 mg, 27.0%). 1I-INlVIR (400 MHz, CDC13), 6 (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: 5min,m/z = 424.3(M+ + 1).

Example 45. Synthesis of compound SA-31 SA-31 SC-SS To a suspension of K2C03 (55 mg, 0.4 mmol) in THF (5 mL) was added lH-pyrazole (28mg, 0.4mmol) and Compound SC-SS (83 mg, 0.2 mmol). The mixture was stirred at RT for 15h then the residue mixture was poured into 5 mL H20 and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and trated. The residue e was purified by reverse-phase prep-HPLC to afford SA-31 as a white solid (7 mg, 9% ). Compound SA—3l: 1I-INMR (500 MHz, CDCl3) 6 (ppm): 7.55 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.88 (AB, 1H), 4.48 (AB x d, 1H), 4.38 (AB x 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 = 2.15 min, m/z = 403.3 [M+H]+ Example 46. Synthesis of compound SA—32 H6 H SC-SS SA-32 To a suspension of K2CO3 (55 mg, 0.4 mmol) in THF (5 mL) was added 1H-pyrazole carbonitrile (37mg, 0.4mmol) and Compound SC-SS (83 mg, 0.2 mmol). The mixture was stirred at RT for 15h then the residue e was poured into 5 mL H20 and extracted with EtOAc (2 X mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase prep-HPLC to afford SA-32 as a white solid (20 mg, 23%). Compound SA-32: IIDIMR (500 MHz, CDCl3) 6 (ppm): 7.86 (s, 1H), 7.81 (s, 1H), 5.02 (AB, 1H), 491 (AB, 1H), 4.48 (AB >< d, 1H), 4.38 (AB x 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 = 2.22 min, m/z = 428.3 [M+H]+ e 47. Synthesis of compound SA-33 \350 o 5 Br ofi‘g/ N’N O & O N-NH F K2CO3, THF F H6 H H5 H SC-SS SA-33 To a suspension of K2C03 (119 mg, 0.86 mmol) in THF (5 mL) was added 4-(methylsulfonyl)- lH-pyrazole (63 mg, 0.43 mmol) and reactant SC-SS (180 mg, 0.43 mmol) and the mixture was stirred at RT for 15h. The residual mixture was poured in to 20 mL H20 and extracted with EtOAc (2 X 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and trated in vacuo. The residual e was purified with by reverse-phase prep-HPLC to afford the title compound SA-33 as a white solid (53 mg, 0.110 mmol, Yield=25.6 %). 1HNMR (500 MHz, CDCl3) 5 (ppm): 7.93 (s, 1H), 7.87 (s, 1H), 5.02 (AB, 1H), 4.92 (AB, 1H,), 4.48 (ABXd), 4.39 (ABXd, 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 = 2.06 min, m/z = 481.2 [M+H]+ Example 49. Synthesis of compound SA-35 SA-AA To a sion of K2C03 (25 mg, 0.18mmol) in THF (5 mL) was addele-pyrazole (20mg, 0.23 mmol) and SA-AA (36 mg, 0.09 mmol). The mixture was d at rt for 15h. The reaction mixture was poured in to 5 mL H20 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 with by reverse-phase prep-HPLC to afford SA-35 as a white solid (8mg, 21.6%). 1H NMR (400 MHz, CDC13), 5 (ppm), 7.53(1H,s), 7.41(1H,s) 6.33 (s,1H), 4.97(AB,1H), B,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 (1W +1).

Example 50. sis of compound SB-l SB-1 To a suspension of K2C03 (25 mg, 0.18 mmol) in THF (5 mL) was added le (13 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol). After stirring at room temperature for 15h, the reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and trate. The reaction mixture was purified with by reverse-phase prep-HPLC to 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).

Example 51. Synthesis of compound SB-Z 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 0C for 2 hours. Then the solution was diluted with ethyl acetate (200 mL). The resulting on 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 afford d product (34.6 mg, 0.0845 mmol, two steps overall yield=27%) as a white solid. 1I-INMR (400 MHz, CDC13) 6(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 = 2.26 min, m/z = 410.2 [M+H]+ Example 52. Synthesis of compound SB-3 SB SB-3 To a solution of crude reactant (374.3 mg, 0.942 mmol, theoretical amount) in anhydrous THF (7.5 mL) was added ylsulfonyl-1H-pyrazole (110 mg, 0.754 mmol) followed by potassium ate (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 (2X 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 afford crude product which was contaminated with 4-methylsulfonyl-lH-pyrazole. The crude product was then re-crystallized from ethyl acetate to afford pure product (38.4 mg, 0.083 mmol, two steps overall yield=8.8%) as white solid. 1HNMR (500 MHz, CDC13) 6(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), 09225 (21H, m), 0.68 (3H, s). LCMS: rt = 2.15 min, m/z = 463.3 [M+H]+ Example 53. Synthesis of compound SB-4 SB-R SB-4 To a solution of 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 OC overnight. Then the solution was d with ethyl acetate (100 mL). The resulting solution was washed with brine (2X50 mL), dried over magnesium sulfate and trated in vacuo. The crude product was ed by reverse phase prep-HPLC to afford product SB-4 (7 mg, 0.0169 mmol, two steps overall yield=12%) as white solid. 1ILHVMR (400 MHz, CDC13) 5 (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 = 2.31 min, m/z =415.3 [M+H]+ Example 54. Synthesis of compounds SB—S To a solution of 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. Then the on was diluted with ethyl acetate (200 mL). The ing solution was washed with brine (2X100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was ed by reverse phase prep-HPLC to afford desired product SB—S (12.4 mg, 0.0282 mmol, two steps overall 9.8%) and by-product (4.2 mg, 5 mmol, two steps overall yield=3.3%) as white solid. Compound SB-S 1HNMR (400 MHz, CDC13) 5(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 = 2.32 min, m/z =440.2 [M+H]+ Example 55. Synthesis of compound SB-7 To a on of 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 the solution was 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 t was purified by silica gel tography ( petroleum ether/ ethyl acetate =1 :3) to afford crude product which was contaminated with 4—methylsulfonyl-1H-pyrazole. The crude product was then re—crystallized from ethyl acetate to afford pure product (50 mg, 0.101 mmol, two steps overall yield=12%) as white solid. 1I-INMR (500 MHz, CDC13) 6(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 = 2.13 min, m/z = 493.0 [M+H]+ Example 56. Synthesis of compound SB-S SB-W SB-8 To a suspension of K2C03 (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 ng at room temperature for 15h, the reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, ed and concentrated. The reaction mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (15.6 mg, 0.073 mmol, 40.4%). 1ILHVMR (500 MHz, CDC13) 6 (ppm): 7.54 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 497 (AB, 1H), 4.87 (AB, 1H), 3.52 (q, 2H), 3.21 (s, 2H), 2.59 (t, 1H), 0.69 (s, 3H), .25 (m, 24H). LCMS: Rt = 2.35 min. m/z = 429.4 [M+H]+.

Example 57. Synthesis of compound SB-9 To a suspension of K2C03 (63 mg, 0.46 mmol) in THF (10 mL) was added 4-cyanopyrazole (43 mg, 0.46 mmol) and compound SB-W (100 mg, 0.23 mmol). After stirring at room temperature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 X 10 mL).

The combined organic layers were washed with brine (2 X 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse-phase PLC to afford SB-9 as a white solid (43.5 mg, 0.095 mmol, 41.7%). 1IH‘IMR (500 MHz, CDCl3) 6 (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 = 2.37 min. m/z = 454.4 .

Example 58. Synthesis of compound SB-lO . "\ 3 E" _ —> H K2003, THF, °C, 15 h To a suspension of SB-FF (40 mg, 0.09 mmol) in THF (5 mL) was added lH-pyrazole ( 30 mg, 0.45 mmol) and K2C03 ( 60 mg, 0.45mmol). The mixture was stirred at 25°C for 15h. 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 ed with by reverse-phase prep-HPLC to afford SB-10 as a white solid (15 mg, 38% yield). 1H NMR (400 MHz, CDC13), 6 (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). e 59. Synthesis of compound SB-ll To a solution of crude reactant SB-FF (50.7 mg, 0.122 mmol, theoretical ) 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 on was stirred at 25 °C overnight. Then the solution was d with ethyl acetate (100 mL). The resulting solution was washed with brine (2>< 50 mL), dried over magnesium sulfate and trated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford desired product (142 mg, 0.0332 mmol, two steps overall yield=27%) as white solid. 1I-INMR (400 MHz, CDC13) 6(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), .95 (m, 2H), 1.90- 1.60 (m, 6H), 1.50—1.20 (m, 15H), 0.70 (s, 3H). 19FNMR (376 MHz, CDC13) 6(ppm): —193.13.

LCMS: rt = 2.13 min, m/z = 428.0 [M+H]+ Example 60. Synthesis of compound SB-12 SB-FF $3.12 To a solution of SB-FF (85 mg, 0.20 mmol) in 2 mL of D1V1F was added 4-methyl-1H-pyrazole (33.6 mg, 0.41 mmol) and K2C03 (84. 84 mg, 0.61 mmol). 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 mLx2). The combined organic layers were dried and concentrated in vacuum. 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: 316 %) as a white solid. 1H NMR ): (400 MHz, CDC13) 6 7.34 (s, 1 H), 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), .61 (m, 6H), 1.54-1.03 (m, 15H), 0.84-0.74 (m, 1H) 0.70 (s, 3H).

LCMS: rt = 1.23 min, m/z = 417.2 [M+H]+.

Example 61. Synthesis of compound SB-l3 HQCN K2003, DMF SB-FF SB-13 A mixture of SB-FF (100 mg, 0.241 mmol), azolecarbonitri1e (45 mg, 0.48 mmol), K2C03 (66 mg, 0.48 mmol) and DMF (3 mL) were stirred at room temperature for 2 h. TLC showed the reaction was ed. The reaction mixture was poured into brine (10 mL) and extracted with EtOAc (10 mLx2). Combined the organic layers and dried over Na2804, trated to give crude product, which was purified by silica gel column to give SB-13 (30 mg, yield: 28%) as a white solid. 1H NMR: (400 MHz, CDC13) 8 7.48 (s, 1H), 6.73 (s, 1H), 4.79—4.97 (m, 2H), 4.47-4.65 (m, 1H), 2.56-2.63 (m, 1H), 2.30—2.20 (m, 1H), 2.10—2.00 (m, 1H), 1.90-1.60 (m, 6H), 1.50—1.20 (m, 15H), .75 (m, 1H), 0.70 (s, 3H). LCMS: rt = 1.23 min, m/z = 428.2 [M+H]+.

Example 62. Synthesis of SB-14 To a solution of SB-FF (100 mg, 0.24 mmol) in DlVIF (2 mL) was added A1 (55 mg, 0.48 mmol) and K2CO3 (100 mg, 0.72 mmol) at 19°C. The reaction was stirred at 19°C for 16 h. The resulting mixture was poured into water (3 ml). The mixture was extracted with EtOAc (2 mL x 3). The combined organic layers was washed with brine (5 mL), dried over Na2$O4 and concentrated in vacuum. The residue was purified by silica gel column (Petroleum ether/ethyl acetate = 10/1 to 3/1) to give SB-14 (80 mg, yield: 74%) as a pink solid. lH NlVIR: (400 MHz, CDCl3) 6 7.53 (s, 1H), 7.43 (s, 1H), 4.79—4.97 (m, 2H), 4.47-4.65 (m, 1H), 2.56-2.63 (m, 1H), 2.35 (s, 3H), 2.19-2.26 (m, 1H), 2.00-2.08 (m, 2H), 1.63-1.92 (m, 5H), 1.35—1.57 (m, 5H), 1.20—1.132 (m, 5H), .18 (m, 5H), 0.75—0.91 (m, 1H), 0.71 (s, 3H). LCMS: rt = 1.25 min, m/z = 449.2 [M+H]+. e 63. Synthesis of SB-15 SB-14 SB-15 To a solution of SB-14 (80 mg, 0.19 mmol) in DCM (5 mL) was added m-CPBA (90 mg, 0.45 mmol) at 0°C. The reaction mixture was stirred at 20 0C for 2 h. Saturated aqueous NaS203 solution (5 mL) was added. The resulting mixture was stirred at 20°C for 30min, and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by silica gel column (Petroleum ether/ethyl acetate = 1/2) to give SB-lS (30 mg, 47%) as a white solid. 1H NMR: (400 MHz, CDC13) 57.93 (s, 1H), 7.87 (s, 1H), 4.87-5.07 (m, 2H), 4.48-4.66 (m, 1H), 3.14 (s, 3H), 2.58-2.68 (m, 1H), 2.17—2.30 (m, 1H), 1.97-2.12(m, 2H), .90 (m, 6H), .55 (m, 3H), 1.05—1.40 (m, 12H), 0.80-0.91 (m, 1H), 0.71 (s, 3H). LCMS: rt = 0.85 min, m/z = 481.2 [M+H]+.

Example 66. Synthesis of compound SB-18 SC-O 83-18 To a solution of crude reactant SC-O (62 mg, 0.150 mmol) in ous THF (5 mL) was added 1H-pyrazole (20.4 mg, 0.30 mmol) followed by potassium carbonate (41.5 mg, 0.30 mmol). The solution was heated at 50 °C overnight. Then the on was diluted with ethyl acetate (100 mL).

The resulting solution was washed with brine (2X50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford t SB-18 (10 mg, 0.0251 mmol, Yield=17%) as white solid. 1I-H\IMR (500 MHz, CDC13) 6(ppm): 7.55 (1H, s), 7.41 (1H, s), 6.33 (1H, s), 4.97 (1H, AB), 4.89 (1H, AB), 2.59 (1H, t), 2.20 (1H, dd), 0.60-2.05 (22H, m), 0.69 (3H, 8).

Example 67. Synthesis of SB-19 K2003 1 THF 83-19 To a solution of compound SC-Y (60mg, crude) in dry THF (2 mL) was added potassium carbonate (100 mg) and azole (60 mg, 0.09mmol). The reaction mixture was stirred at ambient temperature for 16 hour, and then extracted with EtOAc (3 X 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC to afford title compound SB-19 (7mg, 12%) as white solid. 1H NMR (500 MHz, CDC13) 6 (ppm): 7.54 (1H, d), 7.41 (1H, d), 6.33 (1H, t), 4.96 (1H, AB), 4.88 (1H, AB), 3.33 (3H, s), 3.04 (1H,s), 2.58 (1H, t), 0.60-2.20 (22H, m), 0.68 (3H, s). e 68. Synthesis of compound SB-20 To a solution of crude reactant SC-II(100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 3H-pyrazole (82 mg, 1.2 mmol) followed by potassium carbonate (170 mg, 1.2 mmol) and the solution was heated at 60 °C for 2h. Then the reaction mixture was d with ethyl acetate (100 mL). The resulting on was washed with brine (2X50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-20 (24 mg, 0.06 mmol, Yield=25%) as white solid. 1I-H‘IlVIR (500 MHZ, CDCl3) (ppm); 7.55 (1H, d), 7.41 (1H, d), 6.33 (1H, t), 4.95 (1H, AB), 4.89 (1H, AB), 2.59 (1H, t), 0.69 (3H, s), .25 (24H, m). LCMS: rt=2.46 min, m/z=399.2 [M+H]+ Example 69. Synthesis of compound SB-21 SC-II SB-21 To a solution of crude reactant SC-II (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 1H-pyrazolecarbonitrile (112 mg, 1.2 mmol) followed by potassium carbonate (170 mg, 1.2 mmol) and the solution was heated at 60 0C for 2h. Then the reaction mixture was diluted with ethyl acetate (100 mL). The resulting on was washed with brine (2X50 mL), dried over magnesium sulfate and trated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB-21 (46 mg, 0.109 mmol, Yield=45%) as a white solid. 1I-H‘IMR (500 MHz, CDC13) 6(ppm): 7.86 (1H, s), 7.81 (1H, s), 5.00 (1H, AB), 4.92 (1H, AB), 2.61 (1H, t), 0.67 (3H, s), 0.67-2.25 (24H, m). LCMS: rt=2.47 min, m/z=424.2 [M+H]+ Example 70. sis of compound SB-22 83-22 To a on of crude reactant SC—ZZ (100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 1H-pyrazolecarbonitrile(112 mg, 1.2 mmol) followed by ium ate (170g, 1.2 mmol). The solution was heated at 60 0C for 2h then the solution was cooled to room temperature and diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2X50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to afford product SB—22 (38 mg, 0.09mmol, Yield=3 8%) as white solid. 11mm (500 MHz, CDC13) 6(ppm): 7.86 (1H, s), 7.81 (1H, s), 5.87 (2H, d),5.02 (1H, AB), 4.90 (1H, AB), 4.17 (2H, d), 2.61 (1H, t), 0.70—2.25 (22H, m), 0.68 (3H, s). LCMS: rt=2.24min, m/z=428 [M+H]+ Example 71. Synthesis of SB-23 N—NH KZCO3/THF FHzc ,‘z HO F1 SB 33-23 To a suspension of K2C03 (19 mg, 0.14 mmol) in THF (5 mL) was added Pyrazole (10 mg, 0.14 mmol) and compound SB (30 mg, 0.07 mmol). After stirring at room ature for 15h, the reaction mixture was poured into 5 mL H20 and extracted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine (2 X 10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was d by reverse-phase prep-HPLC to afford SB-23 as a white solid ( 19.3 mg, 66%). 1H NMR (500 MHz, CDC13), 5 (ppm), 7.55 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 488 (AB, 1H), 4.17 (d, 2H), 2.59 (t, J = 9.0 Hz, 1H), 0.69 (s, 3H), .20 (m, 24H). LCMS: Rt = 2.27 min. m/z = 403.2 [M+H]+.

Assay Methods Compounds provided herein can be evaluated using various assays; examples of which are described below. d Inhibition ofTBPS Binding {3'5S:§-t-§":‘>;1.iryibicyclopliosphmoth101121113. (TBPS) binding assays using rat brain cortical membranes in the presence of 5 HM GABA has been bed (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, M01. Pharmacol. 1994, 46, 977-985; Lewin, AH et al., M01.

Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed ing decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/teflon homogenizer and centrifuged at 1500 x g for 10 min at 4 °C. The resultant atants are centrifuged at 10,000 x g for 20 min at 4 °C to obtain the P2 pellets. The P2 s are resuspended in 200 mM NaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000 x g for 10 min at 4 0C. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 11L) of the membrane suspensions are incubated with 3 nM [3SS]-TBPS and 5 HL aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final 05%) in the presence of 5 uM GABA. The incubation is brought to a final volume of 1.0 mL with buffer. Nonspecific binding is determined in the presence of 2 11M unlabeled TBPS and ranged from 15 to 25 %. Following a 90 min incubation at room temp, the assays are terminated by filtration through glass fiber filters (Schleicher and Schuell No, 32) using a cell harvester (Brandel) and rinsed three times with ld buffer. Filter bound radioactivity is measured by liquid scintillation spectrometry. Non-linear curve fitting of the overall data for each drug averaged for each concentration is done using Prism Pad). The data are fit to a partial d of a full inhibition model if the sum of squares is significantly lower by F-test. Similarly, the data are fit to a two component instead of a one component inhibition model if the sum of squares is significantly lower by F-test. The concentration of test compound producing 50% inhibition (IC50) of specific binding and the maximal extent of inhibition (Imax) are determined for the individual experiments with the same model used for the overall data and then the means i SEMs of the individual experiments are calculated. Picrotoxin serves as the positive control for these s as it has been demonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential as modulators of ["8]- TBPS binding in vitro. These assays are or can be med in accordance with the above sed procedures.

Patch clamp electrophysiology ofrecombinant )); and 0:48.35 GABAA receptors Cellular electrophysiology is used to measure the pharmacological properties of our GABAA receptor modulators in heterologous cell systems. Each compound is tested for its ability to affect GABA mediated currents at a submaximal agonist dose (GABA EC20 = 2uM). LTK cells are stably transfected with the ))2 subunits of the GABA receptor and CHO cells are transiently transfected with the @635 subunits via the Lipofecatamine method. Cells were passaged at a confluence of about 50-80% and then seeded onto 35mm sterile culture dishes containing 2 ml culture complete medium without antibiotics or antimycotics. Confluent clusters of cells are ically d (Pritchett et al, Science 1306-1308. , 1988, 242, ). e responses in distant cells are not adequately voltage clamped and because of uncertainties about the extent of coupling (Verdoorn et al., Neuron 1990, 4, 919-928. ), cells were ated at a density that s the recording of single cells (without visible connections to other cells).

Whole cell currents were measured with HEKA EPC-10 amplifiers using PatchMaster software or by using the high throughput QPatch rm (Sophion). Bath solution for all experiments contained (in leI): NaCl 137 mM, KCl 4 mM, CaClz 1.8 mM, MgC12 1 mM, HEPES 10 mM, D- Glucose 10 mM, pH (NaOH) 7.4. In some cases 0.005% cremophor was also added. Intracellular te) solution contained: KCl 130 mM, MgC12 1 mM, Mg-ATP 5mM, HEPES 10 mM, EGTA 5mM, pH 7.2. During experiments, cells and solutions were maintained at room temperature (19°C - 30°C). For manual patch clamp recordings, cell culture dishes were placed on the dish holder of the microscope and continuously perfused (1 ml/min) with bath solution. After formation of a Gigaohm seal between the patch electrodes and the cell (pipette resistance range: 2.5 M52 - 6.0 M52; seal resistance range:>1 G9) the cell membrane across the pipette tip was ed to assure electrical access to the cell interior (whole-cell patch-configuration). For experiments using the QPatch , cells were transferred as sion to the QPatch system in the bath solution and automated whole cell recordings were performed.

Cells were voltage clamped at a holding potential of -80 mV. For the analysis of test articles, GABA ors were stimulated by 2 uM GABA after sequential pre-incubation of increasing concentrations of the test e. Pre—incubation duration was 30 s and the duration of the GABA stimulus was 2s. Test articles were dissolved in DMSO to form stock solutions (1 OmM). Test articles were diluted to 0.01, 0.1, l, and 10 uM in bath solution. All concentrations of test articles were tested on each cell. The relative tage potentiation was defined as the peak amplitude in response to GABA EC20 in the presence of the test article divided by the peak amplitude in response to GABA EC20 alone, multiplied by 100.

Loss ofRighting Reflex in Rats The plasma cokinetics and a qualitative assessment of sedation were obtained in male Sprague Dawley rats according to the following procedure. Rats were dosed by intravenous bolus dose (60 s) via the foot dorsal vein at doses ranging from 5 to 15 mg/kg in an appropriate e. In order to assess sedation, rats were gently restrained by hand to a lateral position for dose administration. If decreased muscle tone was observed during dose administration, restraint was gradually reduced. If the animal was unable to return to an upright position, the time was recorded as the onset of loss of righting reflex (LRR). In the event that LRR did not occur during dosing, the animals were evaluated at 5 minute intervals thereafter by being placed in dorsal recumbency. Sluggish or incomplete righting twice consecutively within a 30 second interval qualifies as a loss of righting reflex. After onset of LRR, animals were assessed every 5 minutes in the same manner. Recovery of righting reflex is defined as the ability of a rat to right itself completely within 20 s of being placed in dorsal recumbency. The duration of LRR is defined as the time al between LR and the return of righting reflex.

Acute PTZMethod The anticonVulsant effect of test compounds were assessed in the pentylenetetazol-induced seizure assay in mice similar to methods described in Giardina & Gasior (2009) Curr Protoc Pharmacol, Chapter 5. Male CD-1 mice were housed in groups of five under controlled conditions (temperature of 22i2°C and 12: 12 light—dark cycle, lights on at 8:00 am) and water and food were ble ad libitum. The mice were housed for 1 week prior to behavioral testing, at which time they weighed 25-35g. Pentylenetetrazol (PTZ, Sigma) was dissolved in sterile 0.9% saline at a concentration of 12 mg/mL concentration for subcutaneous administration. Test compounds were formulated and administered via oral gavage or intraperitoneal injection at a predetermined time- point (typically 30 or 60 minutes) prior to PTZ injection. All solutions were made fresh and were given in a volume of 10ml/kg body .

Mice were acclimated to the test room for at least 30 min before compound administration. Mice were randomized into at least four test groups (vehicle and at least three doses of the test compound) with 10 mice per group. After compound administration, mice were observed for qualitative assessment of sedation for a pre—determined time point (30 or 60 minutes). Following the drug pretreatment time the mice were injected so. with PTZ (120 mg/kg). Immediately following the PTZ injection, mice were dually placed into observation chambers (25x15x15cm) and a channel timer was started. Each mouse was continuously observed for min and the following behaviors were recorded by observers blinded to the treatments: 1) 2O latency to clonic convulsions that persist for 3 sec and followed by an e of righting reflex 2) latency to tonic sions, characterized by the rigid extension of all four limbs that exceeded a 90 degree angle with the body 3) latency to death 4) number of clonic and tonic convulsions. Data are presented as mean i S.E.M and one-way is of variance with Dunnett's or Bonferroni's post-hoc test was used to detect significant differences in latency and number between the e and dose group. p values <0.05 were regarded as statistically significant.

Table 1. TBPS binding of the exemplary compounds.

For Table 1: TBPS: A" indicates an IC50 <10 nM, "B" indicates an IC50 10 to <50 nM, "C" tes an IC50 50 nM to <100 nM, "D" indicates an IC50 100 nM to <500 nM, and "E" indicates IC50 greater than or equal to 500 nM.

Table 2. Electrophysiological evaluation of the exemplary compounds at GABAA-R.

For Table 2, EC50: "A" indicates an EC50 <100 nM, "B" indicates an ECso 100 to less than or equal to 500 nM, "C" indicates an EC50 >500 nM to 1000 nM, "D" indicates ICso >1000 nM to 2000 nM, and "E" indicates EC50 >2000 nM. Emax: "A" indicates an Emax of 0 to 500, "B" indicates an Emax of >500 to 1000, "C" indicates an Emax of >1000.

Table 3. Electrophysiological evaluation of the exemplary nds at GABAA-R.

SA-23 C D SA-16 C D For Table 3. GABAA receptors (X16272 and 0L4B38 acy: "A" 10-100, "B" >100-500, "C" >500; D indicates the data is not available or has not been determined.

Table 4. Loss of Righting Reflex (Rat IV, 5 mpk) A<15 min; B 15-60 min; C > 60 min LRR: Loss of Righting Reflex Table 5. l effective anticonvulsant doses are defined as the lowest dose which significantly reduces the latency to tonic es in PTZ-treated mice Anticonvulsive Effect Dose A < 3 mpk; B23 mpk Other ments In the claims articles such as ‘4 " 66 a an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, ed in, or otherwise relevant to a given product or s unless indicated to the contrary or otherwise evident from the context, The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given t or process.

Furthermore, the invention encompasses all ions, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is uced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the ts is also disclosed, and any t(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba . It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps.

Where ranges are given, endpoints are included. rmore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub—range within the stated ranges in different ments of the invention, to the tenth of the unit of the lower limit of the range, unless the t clearly dictates otherwise.

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant ication, the specification shall l. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any , whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended . Those of ordinary skill in the art will appreciate that various s and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Other embodiments of the invention as described herein are defined in the following paragraphs: 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: represents a single or double bond; R1 is substituted or unsubstituted C1-6 alkyl (e.g., haloalkyl, e.g., -CHF2, -CH2F, -CH2OCH3, -CH2OCH2CH3), substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or tuted or unsubstituted C3-6 yclyl; R2 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or –ORA2, wherein RA2 is hydrogen or substituted or tituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl; R3a is hydrogen or –ORA3, n RA3 is hydrogen or substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, and R3b is en; or R3a and R3b are joined to form an oxo (=O) group; each instance of R4a and R4b is independently hydrogen, tuted or unsubstituted C1-6 alkyl, or halogen, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 and R4a are each ndently provided in the alpha or beta configuration, and R4b is absent; each ce of R5, R6, and R7 is, independently, hydrogen, halogen, -NO2, -CN, -ORGA, -N(RGA)2, -C(=O)RGA, -C(=O)ORGA, -OC(=O)RGA, -OC(=O)ORGA, -C(=O)N(RGA)2, -N(RGA)C(=O)RGA, -OC(=O)N(RGA)2, -N(RGA)C(=O)ORGA, -N(RGA)C(=O)N(RGA)2, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, -N(RGA)S(=O)2RGA, substituted or unsubstituted C1-6 alkyl (e.g., haloalkyl), substituted or unsubstituted C2-6 alkenyl, tuted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 ylyl, or substituted or unsubstituted 3- to 6- membered cylyl; each instance of RGA is independently hydrogen, tuted or unsubstituted C1-6 alkyl, tuted or unsubstituted C2-6 alkenyl, substituted or tituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to , nitrogen protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring; and wherein R1 is C1-6 alkyl optionally substituted with alkoxy or one to two halo groups (e.g., fluoro), or wherein at least one of R5, R6, and R7 is halogen (e.g., -F, -Cl, -Br), -NO2, -CN, -ORGA, -N(RGA)2, -C(=O)RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, substituted or unsubstituted C1-6 alkyl (e.g., -CH3, -CH2CH3, kyl, e.g., -CF3) , wherein RGA is substituted or unsubstituted C1-2 alkyl. 2. The compound of Formula (I) of paragraph 1, wherein R1 is C1-6 alkyl optionally substituted with alkoxy or one to two halo groups (e.g., fluoro), and at least one of R5, R6, and R7 is halogen (e.g., -F, -Cl, -Br), -NO2, -CN, -ORGA, )2, -C(=O)RGA, -C(=O)ORGA, -SRGA, -S(O)RGA, e.g.,-S(=O)RGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, substituted or unsubstituted C1-6 alkyl (e.g., -CH3, -CH2CH3, haloalkyl, e.g., -CF3), wherein RGA is substituted or unsubstituted C1-2 alkyl. 3. The compound of Formula (I) of paragraph 1, wherein the compound is selected from a compound of Formula (I-A): (I-A). 4. The compound of Formula (I) of paragraph 1, wherein the compound is selected from a compound of Formula (I-B): (I-B).

. The compound of paragraph 1, wherein R1 is unsubstituted C1-6 alkyl. 6. The compound of paragraph 1, wherein R1 is a C1-6 alkyl optionally tuted with alkoxy. 7. The compound of paragraph 1, n R1 is a C1-6 alkyl optionally substituted with one or two halo (e.g., fluoro). 8. The compound of paragraph 1, wherein R1 is –CH3, –CH2CH3, –CH2F, -CHF2, –CH2OCH2CH3, or H3. 9. The compound of paragraph 8, wherein R1 is –CH3.

. The compound of paragraph 1, wherein R2 is –OH, –OCH3, -OCH2CH3, –OCH2CH2CH3, –CH3, -CH2CH3, –CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 11. The compound of paragraph 10, wherein R2 is –CH3 or –OCH3. 12. The compound of paragraph 11, wherein R2 is –OCH3. 13. The compound of paragraph 1, wherein R2 is hydrogen. 14. The compound of paragraph 1, wherein R3a and R3b are both hydrogen.

. The compound of paragraph 1, wherein ents a single bond, and both of R4a and R4b are en. 16. The compound of paragraph 1, wherein represents a single bond, and both of R4a and R4b are . 17. The compound of paragraph 1, wherein represents a single bond, and R4a is en, , -CH3, or -CF3. 18. The compound of paragraph 1, wherein ents a single bond, and R4a is substituted or unsubstituted C1-6 alkyl, or halogen, and R4b is hydrogen. 19. The compound of paragraph 18, wherein R4a is fluoro.

. The compound of paragraph 1, wherein at least one of R5, R6, and R7 is hydrogen. 21. The compound of aph 1, wherein at least two of R5, R6, and R7 are hydrogen. 22. The compound of paragraph 1, wherein all of R5, R6, and R7 are hydrogen. 23. The compound of paragraph 1, wherein at least one of R5, R6, and R7 is substituted or unsubstituted C1-2 alkyl (e.g., -CF3), -CO2RGA, -C(=O)RGA, -CN, -NO2, halogen, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is substituted or unsubstituted C1-2 alkyl. 24. The compound of paragraph 23, wherein at least one of R5, R6, and R7 is -CN.

. The compound of paragraph 23, wherein at least one of R5, R6, and R7 is -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is substituted or unsubstituted C1-2 alkyl. 26. The compound of paragraph 25, wherein at least one of R5, R6, and R7 is 2RGA. 27. The compound of paragraph 25, wherein RGA is –CH3. 28. The compound of paragraph 1, wherein R5 and R7 are hydrogen. 29. The compound of paragraph 1, wherein R6 is halogen (e.g., -F, -Cl, -Br), -NO2, -CN, -ORGA, -N(RGA)2, -C(=O)RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, -S(=O)2RGA, 2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, substituted or unsubstituted C1-6 alkyl (e.g., -CH3, -CH2CH3, haloalkyl, e.g., -CF3) , wherein RGA is substituted or unsubstituted C1-2 alkyl.

. The compound of paragraph 29, wherein R6 is -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is tuted or unsubstituted C1-2 alkyl. 31. The compound of paragraph 29, wherein R6 is halogen (e.g., -F, -Cl, -Br), -NO2, –CN, or tuted or unsubstituted C1-6 alkyl (e.g., -CH3, 3, haloalkyl, e.g., -CF3) , wherein RGA is substituted or unsubstituted C1-2 alkyl. 32. The compound of aph 1, wherein R2, R3a, R3b, R4a, and R4b are hydrogen. 33. The compound of paragraph 1, wherein at least three of R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are hydrogen. 34. The compound of paragraph 1, wherein at least four of R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are hydrogen.

. The compound of paragraph 1, wherein at least five of R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are en. 36. The compound of paragraph 35, wherein , R6 is halogen (e.g., -F, -Cl, -Br), -NO2, -CN, RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, 2RGA, substituted or unsubstituted C1-6 alkyl (e.g., -CH3, 3, haloalkyl, e.g., -CF3) , wherein RGA is substituted or unsubstituted C1-2 alkyl. 37. The compound of paragraph 36, wherein R6 is -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is substituted or unsubstituted C1-2 alkyl. 38. The compound of paragraph 36, wherein R6 is -CN. 39. The compound of paragraph 36, wherein R1 is substituted or unsubstituted C1-6 alkyl (e.g., haloalkyl, e.g., -CF3, -CHF2, -CH2F) or alkoxy. 40. The compound of paragraph 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . 41. The compound of aph 2, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and 42. The compound of paragraph 3, wherein the nd is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , and . 43. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of the preceding paragraphs, and a pharmaceutically able excipient. 44. A method for treating a CNS–related disorder in a subject in need thereof, sing administering to the subject an effective amount of a compound of any one of paragraphs 1 to 19, or a ceutically acceptable salt thereof. 45. The method of paragraph 44, wherein the CNS–related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a sive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus. 46. The method of paragraph 44 wherein the compound is administered orally, subcutaneously, intravenously, or uscularly. 47. The method of aph 44 wherein the compound is administered chronically.

Still further embodiments are within the scope of the following claims.

Claims (64)

What we claim is:

1. A compound of Formula (I): O R7 H H H H 5 R4b R4a (I) or a pharmaceutically acceptable salt thereof; wherein: represents a single or double bond; R1 is C1-6 alkyl ally substituted with alkoxy or one to two halo groups; R2 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or –ORA2, wherein RA2 is hydrogen or substituted or unsubstituted C1-6 alkyl, tuted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl; R3a is hydrogen or –ORA3, wherein RA3 is hydrogen or substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or tituted C3-6 carbocyclyl, and R3b is en; or R3a and R3b are joined to form an oxo (=O) group; each instance of R4a and R4b is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 and R4a are each independently provided in the alpha or beta uration; each instance of R5, R6, and R7 is, independently, hydrogen, halogen, -NO2, -CN, -ORGA, - N(RGA)2, -C(=O)RGA, ORGA, )RGA, -OC(=O)ORGA, -C(=O)N(RGA)2, - N(RGA)C(=O)RGA, -OC(=O)N(RGA)2, -N(RGA)C(=O)ORGA, -N(RGA)C(=O)N(RGA)2, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, -N(RGA)S(=O)2RGA, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 l, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, or substituted or unsubstituted 3- to 6- membered cylyl; and at least one of R5, R6, and R7 is halogen, -NO2, -CN, -ORGA, -N(RGA)2, -C(=O)RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, or substituted or unsubstituted C1-6 alkyl, wherein RGA is substituted or unsubstituted C1-2 alkyl; and each ce of RGA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, tuted or tituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when ed to oxygen, en protecting group when attached to nitrogen, or two RGA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring; wherein each substituted cyclyl is independently tuted with one or more substituents ed from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminosulfonyl, ylamino, 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; each substituted alkyl, alkenyl, alkynyl, carbocyclyl, and heteroaryl is independently substituted with one or more substituents selected from the group consisting of halogen, oxo, -CN, - NO2, -N3, -OH, -ORaa, -N(Rbb)2, -SH, -SRaa, -C(=O)Raa, -CO2H, -CHO, -CO2Raa, -OC(=O)Raa, - C(=O)N(Rbb)2, (=O)Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 yclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each substituent is attached to a carbon atom, and each alkyl, l, alkynyl, yclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each Raa is independently selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered aryl, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each Rbb is independently selected from the group consisting of hydrogen, -OH, -ORaa, - N(Rcc)2, -CN, -C(=O)Raa, N(Rcc)2, -CO2Raa, -SO2Raa, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 ed heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, yclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each Rcc is independently selected from the group consisting of hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered aryl ring, wherein each alkyl, alkenyl, l, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each Rdd is independently selected from the group consisting of halogen, -CN, -NO2, -N3, - SO3H, -ORff, -N(Rff)2, -SRff, C(=O)Rff, f, -C(=O)N(Rff)2, -NRffC(=O)Ree, -SO2Rff, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 ed heterocyclyl, C6-10 aryl, 5- 10 membered heteroaryl, or two geminal Rdd substituents can be joined to form =O or =S; and each Rff is independently selected from the group consisting of hydrogen and C1-6 alkyl wherein the compound of Formula (I) is not H H H3C H H HO H .

2. The compound of a (I) of claim 1, wherein R1 is C1-6 alkyl optionally substituted with alkoxy or one to two fluoro groups.

3. The compound of a (I) of claim 1, wherein the compound is selected from a compound of Formula (I-A): O R7 H H H H R1 H R4a (I-A)

4. The compound of Formula (I) of claim 1, wherein the compound is ed from a compound of Formula (I-B): O R7 H H H H R1 H R4a (I-B)

5. The compound of claim 1, wherein R1 is tituted C1-6 alkyl.

6. The compound of claim 1, wherein R1 is a C1-6 alkyl optionally substituted with alkoxy.

7. The compound of claim 1, wherein R1 is a C1-6 alkyl optionally substituted with one or two halo.

8. The compound of claim 1, wherein R1 is –CH3, –CH2CH3, –CH2F, -CHF2, –CH2O CH2CH3, or –CH2OCH3.

9. The compound of claim 8, wherein R1 is –CH3.

10. The compound of any one of claims 1 to 9, wherein R2 is –OH, –OCH3, -OCH2CH3, – OCH2CH2CH3, –CH3, -CH2CH3, –CH2CH2CH3, substituted or unsubstituted ropyl, fluoro, or chloro.

11. The compound of claim 10, wherein R2 is –CH3 or –OCH3.

12. The compound of claim 11, wherein R2 is –OCH3.

13. The nd of any one of claims 1 to 9, wherein R2 is hydrogen.

14. The compound of any one of claims 1 to 13, wherein R3a and R3b are both hydrogen.

15. The compound of claim 1, wherein represents a single bond, and both of R4a and R4b are hydrogen.

16. The compound of claim 1, wherein represents a single bond, and both of R4a and R4b are fluoro.

17. The compound of claim 1, wherein represents a single bond, and R4a is hydrogen, fluoro, -CH3, or -CF3.

18. The compound of claim 1, wherein represents a single bond, and R4a is tuted or unsubstituted C1-6 alkyl, or halogen, and R4b is hydrogen.

19. The compound of claim 18, wherein R4a is fluoro.

20. The compound of any one of claims 1 to 19, wherein at least one of R5, R6, and R7 is

21. The compound of any one of claims 1 to 19, wherein at least two of R5, R6, and R7 are hydrogen.

22. The compound of any one of claims 1 to 19, wherein at least one of R5, R6, and R7 is substituted or unsubstituted C1-2 alkyl, -CO2RGA, -C(=O)RGA, -CN, -NO2, halogen, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is substituted or unsubstituted C1-2 alkyl.

23. The nd of claim 22, wherein at least one of R5, R6, and R7 is -CN.

24. The nd of claim 22, wherein at least one of R5, R6, and R7 is -SRGA, -S(=O) RGA, - RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is substituted or unsubstituted C1-2 alkyl.

25. The compound of claim 24, wherein at least one of R5, R6, and R7 is -S(=O)2RGA.

26. The compound of claim 24, wherein RGA is –CH3.

27. The compound of any one of claims 1 to 19, wherein R5 and R7 are hydrogen.

28. The compound of claim 1, wherein R6 is halogen, -NO2, -CN, -ORGA, )2, -C(=O)RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, substituted or unsubstituted C1-6 alkyl , wherein RGA is tuted or unsubstituted C1-2 alkyl.

29. The compound of claim 28, wherein R6 is -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is substituted or unsubstituted C1-2 alkyl.

30. The compound of claim 28, wherein R6 is n, -NO2, –CN, or substituted or unsubstituted C1-6 alkyl, wherein RGA is substituted or unsubstituted C1-2 alkyl.

31. The compound of claim 1, wherein R2, R3a, R3b, R4a, and R4b are hydrogen.

32. The compound of claim 1, n at least three of R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are hydrogen.

33. The compound of claim 1, wherein at least four of R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are hydrogen.

34. The compound of claim 1, wherein at least five of R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are

35. The compound of claim 34, wherein , R6 is halogen, -NO2, -CN, -C(=O)RGA, -C(=O)ORGA, - SRGA, -S(=O) RGA, -S(=O)2RGA, substituted or unsubstituted C1-6 alkyl , wherein RGA is substituted or unsubstituted C1-2 alkyl.

36. The compound of claim 34, wherein R6 is -SRGA, -S(=O) RGA, -S(=O)2RGA, -S(=O)2ORGA, or -S(=O)2N(RGA)2, wherein RGA is substituted or unsubstituted C1-2 alkyl.

37. The compound of claim 35, n R6 is -CN.

38. The compound of claim 35, wherein R1 is unsubstituted C1-6 alkyl.

39. A compound ed from the group consisting of: N N N N O O O H H H H H H H H H H H H HO H , HO H , HO H , O O O N N N H H H N S H H H H H H H S H H HO H , HO H , HO H , F CN N N N O N O N H H H H H H H H H H H H HO H , HO H , HO H , H H N CN H H O H H H H HO H , HO H , S O NC N N N N N O O O H H H H H H H H H H H H O O O HO H , HO H , HO H , N N O O H H H H H H H H H H H H HO H HO H HO H F , F , F , O O N N N S H H H H N H H CN H H H H F , F , N N N N N O HH N O H H O H H H H H HO F2HC H H H HO H F , F , HO H , N N N N N O O O H H H H H H Me MeO Me H H Me H H H F CH H HO H HO , H , HO H , S O CN N N N N N O O O H H H H H H F2HC H H H H H H HO H , HO H , HO H , N N N N N O O O H H H H H H H H H H H H HO H , HO H , HO H , O N NC S O N N N N N N O O O H H H H H H F F F H H H H H H HO H , HO H , HO H , N O N N N N O O H H H H H H H H HO H , and HO H .

40. A compound ed from the group consisting of: N O N N N N N CF3 O O H H H H H H H3C H H H3C H H H3C H H HO H HO H HO H SA-1 , SA-2 , SA-3 , N N N N N N O O H H H H H H H3C H H H H H H HO H3C H3C HO H HO H SA-5 , SA-6 , SA-7 , NO2 Br N N N N N N O O O H H H H H H H H H H H3C H3C H H HO H HO H HO H SA-8 , SA-9 , SA-10 N N N N N N O O H H H H H H H H H H H3C H H H3C HO H HO H HO H SA-11 , SA-12 , SA-14 , N N N N O O O H H H H H H H H H H H H HO H HO H HO H SA-15 , SA-16 , SA-17 , O O N N N H H H H N S H H S H H HO H HO H SA-18 , SA-20 , N O N O N N H H H H H H H H OMe H H H H HO H HO H SA-21 , SA-22 , SA-23 , N N N N O O H H N CN H H H H O H H F H H H H HO H H F HO H SA-24 , SA-25 , SA-27 , S O CN N N N N O O O H H H H H H F2HC H H H H H H HO H F HO H HO H SA-28 , SA-29 , SA-30 , NC S O N N N N N O O O H H F H H H H H H F H H H H HO H HO H HO H SA-31 , SA-32 , SA-33 , and H H H H HO H SA-35

41. A nd selected from the group consisting of: N O N N N N N N O O O H H H H H H H H H H H H HO H O H HO HO H SB-2 , SB-3 , SB-4 , N N N H H H H H H H H H H H H O O HO O HO H HO H SB-5 , SB-7 , SB-8 , N N N N O O H H H H H H H H H H H H O HO H HO H HO H F F SB-9 , SB-10 , SB-11 , N N O H H N H H H H N H H H3C H H H H HO H HO H HO F F H SB-12 , SB-13 , SB-14 , O N N N N O O H N S H O H H H H H H Me MeO Me H H Me H H HO H HO H SB-15 , SB-18 , SB-19 , N N N N O O H H H H H H H H H H H H HO H HO HO H H SB-20 , SB-21 , SB-22 , and H H FH2C H H HO H SB-23 .

42. A pharmaceutical composition comprising a compound or pharmaceutically able salt thereof of any one of the preceding claims, and a ceutically acceptable excipient.

43. Use of a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a CNS–related disorder in a subject in need thereof.

44. The use of claim 43, n the CNS–related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a sive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or us.

45. The use of claim 43 wherein the medicament is formulated for administration orally, subcutaneously, intravenously, or intramuscularly.

46. The use of claim 43 wherein the ment is formulated for administration chronically.

47. A process for preparing a compound of Formula SA-4: H H H H HO H SA-4, the s comprising: reacting a compound of Formula SA H H H H HO H SA, with a compound represented by: HN , in the presence of a base and an c solvent to provide the nd of a SA-4.

48. The process of claim 47, wherein the base is potassium carbonate, and the organic solvent is tetrahydrofuran.

49. The process of claim 47 or 48, further comprising preparing the compound of Formula SA H H H H HO H SA, by reacting a compound of Formula SA-F: H H H H HO H SA-F, with Br2 in the presence of an acid to provide the compound of Formula SA.

50. The process of claim 49, wherein the acid comprises hydrogen bromide.

51. The process of any one of claims 47-50, further comprising preparing the compound of Formula SA-F: H H H H HO H SA-F, by reacting a compound of Formula SA-E: H H H H HO H SA-E, with an l oxidizing agent in the presence of a solvent to provide the compound of a SA-

52. The process of claim 51, wherein the alcohol oxidizing agent is pyridinium chlorochromate, and the solvent is dichloromethane.

53. The process of any one of claims 47-52, further comprising preparing the compound of Formula SA-E: H H H H HO H SA-E, by reacting a compound of Formula SA-D: H H H H HO H SA-D, with: a) a borane reagent; then b) a hydroxide base and an oxidizing agent; in the presence of a t to provide the compound of Formula SA-E.

54. The process of claim 53, wherein the borane reagent is 9-borabicyclo[3.3.a]nonane or borane dimethylsulfide, the hydroxide base is sodium ide, the oxidizing agent is hydrogen peroxide, and the solvent is tetrahydrofuran or water.

55. The process of any one of claims 47-54, further comprising preparing the compound of Formula SA-D: H H H H HO H SA-D, by reacting a compound of Formula SA-C: H H H H HO H SA-C, with EtPPh3Br in the presence of a base and a solvent to provide the compound of Formula SA-D.

56. The process of claim 55 wherein the base is potassium utoxide, and the solvent is ydrofuran.

57. The process of any one of claims 47-56, further comprising preparing the compound of Formula SA-C: H H H H HO H SA-C, by ng a compound of Formula SA-B: H H H H H SA-B, with methylmagnesium bromide in the presence of a Lewis acid, and an organic solvent to provide the compound of Formula SA-C.

58. The process of claim 57, wherein the Lewis acid is methyl aluminum bis(2,6-di-tert-butyl methylphenoxide) and the solvent is ydrofuran.

59. The process of any one of claims 47-58, further comprising preparing the compound of Formula SA-B: H H H H H SA-B, by enating a compound represented by: H H H H O (A), to provide the nd of Formula SA-B.

60. The s of claim 59, wherein hydrogenating comprises contacting the nd of formula A with H2, a palladium catalyst, and an acid in the presence of an organic solvent.

61. The process of claim 60, wherein the hydrogen is about 10 atm hydrogen, the palladium catalyst is palladium black, the acid is hydrobromic acid, and the solvent is tetrahydrofuran.

62. A process for preparing a compound of Formula SA-C: H H H H HO H SA-C, the process comprising: ng a compound of Formula SA-B: H H H H H SA-B, with methylmagnesium bromide in the presence of a Lewis acid, and an organic solvent to provide the compound of Formula SA-C.

63. The process of claim 62, n the Lewis acid is methyl aluminum bis(2,6-di-tert-butyl methylphenoxide) and the solvent is tetrahydrofuran.

64. A compound represented by: H H H H HO H . SAGE THERAPEUTICS INC. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: