NZ752693B2 - 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 (SA-4), and pharmaceutically acceptable salts thereof. The use of the compound in the manufacture of medicaments for the treatment of mood disorders including depression, postnatal depression, generalized anxiety disorder, bipolar disorder, major depressive disorder, and tremor is claimed. r, bipolar disorder, major depressive disorder, and tremor is claimed.

Description

-NOR C3,3-DISUBSTITUTED C21-N-PYRAZOLYL STEROIDS AND METHODS OF USE F This application is a divisional application of New Zealand Patent Application No. 713303, filed on 17 April 2014, and is related to International Patent Application No. , filed on 17 April 2014 and claims priority from International Patent Application No. 2013/074323, filed on 17 April 2013; each of which is incorporated herein by reference in its entirety.

Background of the Invention Brain bility is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately -70 mV, the cell or 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 rmeable membrane.

Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an tory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from - 70 mV to -50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na+ ions. The reduced membrane ial stimulates al excitability in the form of a naptic 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 utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal ne. GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an ochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, ing the neuron less susceptible to excitatory 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 eutically 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 addition 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 (1991)).

Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 30t—hydroxyreduced pregnan-ZO-one and 301—21-dihydroxy—5-reduced pregnan-ZO-one, metabolites of hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was ized 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 metabolites have been demonstrated to have profound effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130: 19-24 (1985); Pfaff, D.W and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al., JMed Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 227 (1987)). The levels of progesterone and its lites vary with the phases of the menstrual cycle. It has been well nted that the levels of terone 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, anxiety, and migraine headaches n, K, Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Subjects with PMS have a monthly recurrence of symptoms that are present in premenses and absent in nses.

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

Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating ts 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 sion (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 anxiety and irritability. PND-associated depression is not amenable to treatment by classic antidepressants, and women experiencing PND show an increased incidence 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 metabolites in the homeostatic regulation of brain excitability, which is manifested as an increase in seizure activity or symptoms ated with catamenial epilepsy, PMS, and PND. The correlation between d levels of progesterone and the symptoms associated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., JPsychosomObstet.

Gynaecol. 2:8-20 (1983)); Dalton, K, strual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone y of catamenial epilepsy," in Advances in Epileptology.‘ XVth Epilepsy International Symposium, Raven Press, New York , 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 treatment 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 ctive 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, compositions, and methods described herein are directed toward this end.

Summary of the Invention The t invention is based, in part, on the desire to provide novel 19-nor (i.e., C19 hyl) compounds, e.g, related to progesterone, deoxycorticosterone, and their lites, with good potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, ity, safety, nce and/or metabolism. One key feature of the compounds as described herein is disubstitution at the C3 position (eg, with one tuent being a 30: hydroxy moiety. The ors envision disubstitution at C-3 will eliminate the potential for oxidation of the hydroxy moiety to the ketone, prevent further metabolism, 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 effects, which may allow, in certain embodiments, administration orally and/or chronically. Another key feature of the compounds as described herein is the presence of a hydrogen at the C19 on ("19-nor") rather than a methyl group. The ors envision 19- nor compounds, as compared to their C19-methyl rparts, 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 aspect, provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein: — ents a single or double bond; R1 is substituted or unsubstituted C1_6 alkyl, substituted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2-6 l, or substituted or unsubstituted C3_5 carbocyclyl; R2 is en, 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, 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 en or substituted or unsubstituted C1_6 alkyl, tuted 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 en, substituted or unsubstituted C1_6 alkyl, or halogen, provided if the 2 n 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; 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, -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, e.g., -S(=O)RGA, 2RGA, -S(=O)2ORGA, -OS(=O)2RGA, -S(=O)2N(RGA)2, — N(RGA)S(=O)2RGA, substituted or unsubstituted C1_6 alkyl, tuted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 l, 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, tuted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C3_6 carbocylyl, substituted or tituted 3- to 6- membered heterocylyl, substituted or tituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting 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 aryl ring.

Steroids of a (I), sub—genera thereof, and pharmaceutically acceptable 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 present invention and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present ion is ed in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount.

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

Thus, in another aspect, provided are s of treating a CNS—related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention. In n embodiments, the CNS—related disorder is ed from the group consisting of a sleep disorder, a mood disorder, a phrenia 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 , subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically.

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

Definitions Chemical Definitions Definitions of ic 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 generally defined as described therein. Additionally, l principles of organic chemistry, as well as ic functional es and reactivity, are bed in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc, New York, 1989; and Carruthers, Some Modern Methods nic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1 987.

Compounds bed herein can comprise one or more asymmetric centers, and thus can exist in various ic 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 tography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry 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 asses compounds bed herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

When a range of values is listed, it is ed 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 tanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions ning 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 tood that when described herein any of the es defined forth below may be tuted with a variety of substituents, and that the respective definitions are intended to e such substituted moieties within their scope as set out below. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms s" 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 grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue. " refers to a radical of a straight—chain or branched saturated hydrocarbon 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 alkyl"). 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 ments, an alkyl group has 1 to 3 carbon atoms ("C1_3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1_2 ). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2_6 ). Examples of C1_6 alkyl groups include methyl (C1), ethyl (C2), n—propyl (C3), isopropyl (C3), l (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 ied, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an stituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e. g., for instance from 1 to 5 tuents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted 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 (- CH2CH3), 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 provided 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 substituents as described herein.

"Alkylene" refers to an alkyl group wherein two hydrogens are removed to provide a divalent 3O radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2—), ne (-CH2CH2-), ene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ne (-CH(CH3)CH2-,—CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, - H3)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 bonds), and optionally one or more carbon—carbon triple bonds (e.g., 1, 2, 3, or 4 — 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 l"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2_9 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2_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 l"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2_5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2_4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("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). Examples of C2_4 alkenyl groups e l (C2), 1—propenyl (C3), 2—propenyl (C3), 2O 1—butenyl (C4), nyl (C4), butadienyl (C4), and the like. Examples of C2_6 alkenyl groups include the aforementioned 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 substituted, 116., unsubstituted (an stituted alkenyl") or tuted (a "substituted alkenyl") with one or more substituents e.g., for ce from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C240 alkenyl. In n embodiments, the alkenyl group is substituted €2-10 alkenyl.

"Alkenylene" refers to an l group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups e, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., - CH=CHCH2-, -CH2-CH=CH-). ary 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)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, - CHZCHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-,-C(CH3)2-CHZCH-, -CH2- C(CH3)=CH-, H=C(CH3)-), and the like. yl" 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 double bonds) ("C240 alkynyl"). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an l group has 2 to 10 carbon atoms ("C2_10 alkynyl"). In some ments, 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 ments, an alkynyl group has 2 to 7 carbon atoms ("C2_7 alkynyl"). In some embodiments, 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 embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2_3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). 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, ethynyl (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 alkynyl include heptynyl (C7), l (Cs), and the like. Unless otherwise specified, each instance of an alkynyl group is ndently optionally substituted, 1'.e., unsubstituted (an "unsubstituted l") or substituted (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 l. In certain embodiments, the alkynyl group is substituted C240 alkynyl.

"Alkynylene" refers to a linear alkynyl group wherein two ens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, tuted 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., , sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i. 6., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("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 ("heteroC1_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 alkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC1_6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC1_5 alkyl"). In some ments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 atoms ("heteroC1_4 alkyl").

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

In some embodiments, a heteroalkyl group is a ted group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC2_6 alkyl"). Unless otherwise specified, each ce of a heteroalkyl 2O group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more tuents. In certain embodiments, the heteroalkyl group is an tituted CHo alkyl. In certain embodiments, the alkyl group is a substituted heteroC1_1o alkyl.

The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., l, 2, 3, or 4) heteroatoms (e. g., oxygen, sulfur, en, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted n nt 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 atoms ("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 l"). 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 ("heteroC2_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 heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("heteroC2_3 alkenyl"). In some embodiments, a alkenyl group has 2 to 6 carbon atoms, at least one double bond, and l or 2 heteroatoms ("heteroC2_6 alkenyl"), Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or tuted (a "substituted heteroalkenyl") with one or more tuents. In n embodiments, the heteroalkenyl group is an unsubstituted heteroC2_1o alkenyl. In certain embodiments, the heteroalkenyl group is a substituted 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, , nitrogen, boron, silicon, phosphorus) n the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more atoms is inserted n a carbon atom and the parent molecule, i.e., between the point of ment. In certain embodiments, a 2O heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms roCHo alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2_9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("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 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2_5 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms ("heteroC2_4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroC2_3 alkynyl"). In some ments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and l or 2 heteroatoms ("heteroC2_6 alkynyl"). Unless ise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or tuted (a "substituted heteroalkynyl") with one or more substituents. 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, l group, heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular "alkylene,w 66alkenylene,79 ‘6alkynylene," "heteroalkylene," "heteroalkenylene," or "heteroalkynylene," group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain, "Alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups may be tuted or unsubstituted with one or more substituents as described herein.

"Aryl" refers to a l of a monocyclic or polycyclic (e. g., ic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7: ons shared in a cyclic array) having 6—14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6_14 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., ). 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., cyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or cyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such ces, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, ene, hexalene, as-indacene, s-indacene, , indene, naphthalene, octacene, octaphene, ne, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted C644 aryl. In certain embodiments, the aryl group is tuted C6_14 aryl.

In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, y, C1-C8 , 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, SOaryl, SOgaryl; or R56 and R57 may be joined to form a cyclic ring ated or unsaturated) from 5 to 8 atoms, optionally 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 carbonyl, 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 aryl.

"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 optionally substituted alkyl group substituted by an optionally substituted aryl group.

"Heteroaryl" 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 aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5—10 membered aryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as y permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also es ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.

Bicyclic heteroaryl groups n one ring does not contain a heteroatom (e.g., indolyl, inyl, carbazolyl, and the like) the point of attachment can be on either ring, 1'.e., either the ring bearing a heteroatom (e.g., 2—indolyl) or the ring that does not contain a heteroatom (e.g., 5— indolyl).

In some embodiments, a aryl group is a 5—1 0 membered aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms ed in the ic ring system, wherein each heteroatom is independently selected from nitrogen, , 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 provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5—8 membered aryl"). 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 en, oxygen, and sulfur ("5—6 membered heteroaryl"). In some ments, the 5—6 membered heteroaryl has 1—3 ring heteroatoms ed from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 membered aryl 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 independently optionally substituted, 126., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5—14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5—14 membered heteroaryl. ary 5—membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, l and thiophenyl. Exemplary 5—membered heteroaryl groups containing two heteroatoms include, t limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5—membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, zolyl, and thiadiazolyl. ary 5—membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6— membered aryl groups containing one heteroatom include, without limitation, pyridinyl.

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

Exemplary 7—membered heteroaryl groups containing one atom include, without tion, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6—bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6— bicyclic heteroaryl groups include, without tion, naphthyridinyl, pteridinyl, quinolinyl, nolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. es of representative heteroaryls include the following: wherein 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.

"Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined , and refers to an optionally substituted alkyl group substituted by an ally 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"). ary C34, carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), entyl (C5), cyclopentenyl (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), eptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cg), cyclooctenyl (C3), o[2.2.l]heptanyl (C7), o[2.2.2]octanyl (C3), and the like. Exemplary C340 carbocyclyl groups e, 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 clic ("monocyclic carbocyclyl") or contain a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of ment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted yclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3_1o yclyl. In certain 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 ments, 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 ments, 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). es 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 lkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C340 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C340 cycloalkyl. ocyclyl" 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, sulfur, boron, phosphorus, and silicon ("3—10 membered cyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of ment can be a carbon or nitrogen atom, as valency s. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially unsaturated. cyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the cyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally tuted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or tuted (a "substituted heterocyclyl") with one or more tuents. In certain embodiments, the heterocyclyl group is unsubstituted 3—10 ed heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3—10 membered heterocyclyl.

In some embodiments, 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, oxygen, 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 membered non—aromatic ring system having ring carbon atoms and 1— 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5—6 membered heterocyclyl"). In some embodiments, the 5—6 membered heterocyclyl has 1—3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 membered cyclyl has 1—2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3—membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4—membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and nyl. Exemplary 5— ed heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, ofuranyl, tetrahydrothiophenyl, othiophenyl, idinyl, dihydropyrrolyl and pyrrolyl—2,5—dione. Exemplary S—membered cyclyl groups containing two atoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and idinone. Exemplary 5—membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6—membered heterocyclyl groups ning one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary ered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6—membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7—membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8— membered cyclyl groups containing one atom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary ered heterocyclyl groups fused to a C6 aryl ring (also ed to herein as a 5,6-bicyclic cyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.

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

Particular examples 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 ed from CR67, C(R67)2, NR67, O, and S; and each Y is selected 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), arbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, yl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, —S-aryl, alkyl,— S(O)-aryl, —S(O)2-alkyl, and -aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.

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

"Acyl" refers to a radical —C(O)R20, where R20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or tituted aryl, or substituted 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), cyclohexylcarbonyl, 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 membered heteroaryl), —C(O)-(CH2)[(C3-C10 cycloalkyl), and (CH2)t(4- membered heterocyclyl), wherein t is an integer from 0 to 4. In certain ments, R21 is C1- C8 alkyl, substituted with halo or hydroxy; or C3—C10 lkyl, 4—10 membered heterocyclyl, C6- C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with tituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 yalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

"Acylamino" refers to a radical —NR22C(O)R23, where each instance of R22 and R23 is independently en, substituted or unsubstitued alkyl, substituted or titued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R22 is an amino protecting group. Exemplary mino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary "acylamino" groups are — 24C(O)-C1-Cg alkyl, — 24C(O)-(CH2)t(C6-C10 aryl), — 24C(O)- (CH2)t(5-10 membered aryl), — 24C(O)—(CH2)t(C3-C10 cycloalkyl), and — 24C(O)- (CH2)t(4-10 membered heterocyclyl), wherein t is an integer from O to 4, and each R24 independently represents H or C1-C8 alkyl.In n 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 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or tituted C1-C4 haloalkoxy or hydroxy; and R26 is H, C1- C8 alkyl, substituted with halo or y; C3—C10 cycloalkyl, 4—1 0 membered cyclyl, C6-C10 aryl, arylalkyl, 5-10 ed 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 l —OC(O)R27, where R27 is hydrogen, substituted or unsubstitued alkyl, 3O substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined . Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certain embodiments, R28 is C1-C8 alkyl, substituted with halo or hydroxy; C3- C10 cycloalkyl, 4-10 membered heterocyclyl, C6—C10 aryl, arylalkyl, 5-10 ed heteroaryl or heteroarylalkyl, each of which is tuted with unsubstituted C1-C4 alkyl, halo, tituted C1-C4 alkoxy, unsubstituted C1-C4 kyl, 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, tuted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued aryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, utoxy, 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, koxy, thioaryloxy, thiol, alkyl-S(O)—, aryl—S(O)-, alkyl—S(O)2- and aryl-S(O)2-. Exemplary ‘substituted alkoxy’ groups e, 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), n t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by tituted C1-C4 alkyl, halo, unsubstituted C1-C4 , unsubstituted C1-C4 haloalkyl, tituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. ular exemplary ‘substituted alkoxy’ groups are - OCF3, -OCH2CF3, -OCH2Ph, -OCH2—cyclopropyl, -OCH2CH20H, and —OCH2CH2NMe2.

"Amino" refers to the radical -NH2. ituted amino" refers to an amino group of the formula -N(R38)2 wherein R38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued yclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted 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 ndently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, 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 y; C3-C8 alkenyl, 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 -(CH2)[(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1—C4 alkyl, halo, unsubstituted C1- C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1- C4 haloalkoxy or hydroxy; or both R38 groups are joined to form an alkylene group.

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

"Azido" 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 en, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or titued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstitued aryl, or an amino protecting group, wherein at least one of R62 is not a hydrogen. In certain embodiments, R62 is selected from H, C1-C3 alkyl, C3-C10 lkyl, 4-10 ed heterocyclyl, C6-C10 aryl, aralkyl, 5-10 membered 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 substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 , tituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R62 is other than H.

Exemplary "substituted 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 integer from 0 to 4, each R64 independently represents H or C1-C8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may lves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 kyl, unsubstituted C1-C4 hydroxyalkyl, or tituted C1—C4 haloalkoxy or hydroxy.

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

"Cyano" refers to the radical -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 .

"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. l cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

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

"Cycloalkenyl" refers to tuted or tituted 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 cycloalkenyl groups e, 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 located to impart aromaticity to the cycloalkenyl ring.

"Ethylene" refers to substituted or unsubstituted —(C-C)-.

"Ethenyl" refers to substituted or unsubstituted —(C=C)-.

"Ethynyl" refers to —(CEC)—.

"Nitrogen-containing heterocyclyl" group means a 4- to 7- membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but t tion, morpholine, piperidine (e. g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e. g. 2-pyrrolidinyl and 3- pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N—alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

"Thioketo" refers to the group =S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and aryl groups, as defined herein, are optionally substituted (e. g., "substituted" or stituted" alkyl, ituted" or stituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" 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 en atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a nd 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 different at each position. The term "substituted" is plated to include substitution with all permissible tuents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. For purposes of this ion, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the atoms 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, 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, a, —s020Raa, — OSOgRaa, -S(O)Raa, e.g., S(—O)Raa, OS(—O)Raa, Si(Raa)3, —OSi(Raa)3 —C(=S)N(Rbb)2, — Raa, —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, — P(RCC)2, —P(RCC)3, —OP(R°°)2, —OP(R°°)3, —B(R"a)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 aryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with O, l, 2, 3, 4, or 5 Rdd , or two l 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 ; 2O each ce of Ralal is, ndently, 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 cyclyl 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 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, CC)ORaa, C°)N(RCC)2, — SO;N(R°°)2, —SOZR°°, —SOzORCC, —SORaa, —C(=S)N(RCC)2, SRCC, —C(=S)SRc°, — P(=O)2Raa, —P(=O)(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 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, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with O, 1, 2, 3, 4, or 5 Rdd groups; each instance of RCC is, independently, selected from hydrogen, C1_1o alkyl, C1_1o oalkyl, C2_10 alkenyl, €2-10 alkynyl, €3-10 carbocyclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 membered heteroaryl, or two Rcc groups are joined to form a 3—14 ed 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 ; 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, — C(=O)R"e, —Co2H, —CO2R"", —0C(=0)Ree, —OCO2Ree, —C(=0)N(Rff 2, —0C(=0)N(Rff 2, — NRffC(=O)Ree, —NRffCO2Ree, — )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, —C(=S)SRee, —SC(=S)SRee, 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, heterocyclyl, aryl, and 2O heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two l Rdd substituents can be joined to form =0 or :8; each instance of R66 is, independently, selected from C1_6 alkyl, C1_6 perhaloalkyl, C2_6 l, C2_6 alkynyl, C3_10 carbocyclyl, CHO aryl, 3—1 0 membered cyclyl, and 3—10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg ; 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 ed cyclyl, C540 aryl and —10 membered heteroaryl, or two Rff groups are joined to form a 3—14 membered heterocyclyl or 5—14 membered aryl ring, wherein each alkyl, alkenyl, alkynyl, 3O yclyl, 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, 6 alkyl)2, —N(C1_6 alkyl)3l)C, —NH(C1_6 alkyl)2l}C, 1_6 alkyl) 5C, —NH3*>C, —N(OC1_6 alkyl)(C1_6 , —N(OH)(C1_6 alkyl), — NH(OH), —SH, —SC1_6 alkyl, —SS(C1_6 , —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 alkyl), —NHC(=O)NH2, —C(=NH)O(C1_6 alkyl),—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, — 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, 1_6 alkyl, —SOC1_6 alkyl, —Si(C1_6 alkyl)3, 1_6 alkyl)3 — C(=S)N(C1_6 alkyl)2, C(=S)NH(C1_6 alkyl), C(=S)NH2, —C(=O)S(C1_6 alkyl), —C(=S)SC1_6 alkyl, —SC(=S)SC1_6 alkyl, —P(=O)2(C1_6 alkyl), (C1_6 alkyl)2, —OP(=O)(C1_6 alkyl)2, —OP(=O)(OC1_6 2, C1_6 alkyl, C1_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C340 carbocyclyl, C6_1o aryl, 3—10 membered heterocyclyl, 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 nary 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., methansulfonate, 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., e, ethanoate, oate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency s, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary en 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, bb)Raa, CC)ORaa, —C(=NRCC)N(RCC)2, —SOgN(RCC)2, —SOzR°°, — , , —C(=S)N(R°°)2, —C(=O)SRC°, —C(=S)SRCC, —P(=O)2Raa, —P(=O)(Raa)2, — 3O P(=O)2N(R°°)2, —P(=O)(NRCC)2, C1_1o alkyl, C1_10 perhaloalkyl, C240 alkenyl, C240 alkynyl, C340 carbocyclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 membered aryl, or two RCC groups attached to a nitrogen atom are joined to form a 3—14 membered heterocyclyl or 5—14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Raw1 groups, and wherein R", Rbb, RCC and Rdd are as defined above.

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

Other definitions The term "pharmaceutically 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 t 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 able salts in detail in J. Pharmaceutical Sciences (1977) 66: 1—19. Pharmaceutically acceptable salts of the compounds of the t invention include those derived from le inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hloric acid, hydrobromic acid, phosphoric acid, sulfuric 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 pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, rate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, ate, lfate, heptanoate, hexanoate, odide, 2— hydroxy—ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, e, pectinate, persulfate, 3—phenylpropionate, phosphate, picrate, pivalate, nate, 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 alkaline earth 3O metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically able salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, ylate, sulfate, ate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (6.g, infant, child, adolescent) or adult subject (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 monkeys), cattle, pigs, , sheep, goats, rodents, cats, and/or dogs. In n embodiments, the t is a human. In certain embodiments, the subject is a non-human animal. The terms "human," (Cpatient," and "subject" are used interchangeably herein.

Disease, disorder, and ion are used hangeably herein.

As used herein, and unless ise 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 progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates an action that occurs before a subject begins to suffer from the specified e, disorder or condition ("prophylactic treatment").

In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired ical 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 factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of stration, and the age, health, and condition of the subject An effective amount encompasses 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 ation with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term peutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids ms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a ylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically ive amount of a compound means an amount of a eutic agent, alone or in ation with other , which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term "prophylactically ive amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic cy 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 Invention As described herein, the present invention provides 19-nor C3,3-disubstituted C21-pyrazolyl neuroactive steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein: -_—-- represents a single or double bond; R1 is substituted or unsubstituted C1-6 alkyl, tuted or unsubstituted C2_6 l, tuted or unsubstituted C2_6 alkynyl, or substituted or unsubstituted C3_6 carbocyclyl; R2 is hydrogen, halogen, substituted or unsubstituted C1_6 alkyl, tuted or unsubstituted C2_6 alkenyl, substituted or unsubstituted C2_6 l, 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 substituted 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 l, substituted or unsubstituted C2_5 alkynyl, or tuted 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 hydrogen 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, n, -N02, -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, 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 l, substituted or unsubstituted C2_6 alkynyl, substituted or unsubstituted C3_6 carbocylyl, or tuted or unsubstituted 3- to 6- membered heterocylyl; and each instance of RGA is independently hydrogen, substituted or unsubstituted C1_6 alkyl, substituted or tituted C2.6 alkenyl, tuted 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 protecting 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, 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 tituted c1.6 alkyl (e.g., -CH3, -CH2CH3, haloalkyl, e.g., -CF3) wherein RGA is substituted or unsubstituted C1_2 alkyl.

In certain ments, R1 is CH; 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), -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, tuted or unsubstituted C1.6 alkyl (e.g, -CH3, -CH2CH3, haloalkyl, e. g., -CF3) wherein RGA is tuted or unsubstituted C1-2 alkyl, It is understood, based on the aforementioned description, that steroids of Formula (I) encompass 3,3-disubstituted l9-nor neuroactive steroids 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 provided in Formula (LB), and wherein the B ring of the compound comprises a C5-C6 double bond (as ed in a (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 tituted C2_6 alkenyl, substituted or unsubstituted C2_6 alkynyl, or tuted 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 tituted C2_3alkyl, substituted or unsubstituted C3_ 4alkyl, substituted or unsubstituted C4_5alky1, or substituted or unsubstituted C5_6alkyl. Exemplary R1 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), 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, methyl, romethyl, trifluoromethyl, oroethyl, difluoroethyl, 2,2,2-trifluoro-l,l -dimethyl-ethyl, ymethyl, methoxyethyl, or ethoxymethyl.

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

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

In certain ments, R1 is C14; alkyl substituted with one or more —ORAl groups, wherein 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, —CH20CH3, —CH20CH2CH3, or —CH20CH2CH2CH3.

In certain embodiments, R1 is substituted or unsubstituted C36 alkenyl, e.g., substituted or unsubstituted C2_3alkeny1, substituted or unsubstituted kenyl, 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 ting of alkyl, halo, haloalkyl, alkoxyalkyl, or yl. In certain embodiments, R1 is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R1 is ethenyl.

In n embodiments, R1 is substituted or unsubstituted C36 alkynyl, e. g., substituted or unsubstituted C2_3a1kynyl, substituted or tituted C3_4alkynyl, substituted or unsubstituted kyny1, or substituted or unsubstituted C5_6alkynyl. In certain embodiments, R1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (e. g., CF3), alkoxyalkyl, cycloalkyl (e.g, cyclopropyl or utyl), or hydroxyl. In certain embodiments, R1 is selected from the group consisting of trifluoroethynyl, 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 tituted aryl, substituted or tituted carbocyclyl, and substituted or unsubstituted heterocyclyl.

In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4) tuted 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 certain 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, zolyl, thiadiazolyl, or olyl.

In certain embodiments, R1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, kyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R1 is ethynyl or propynyl, tuted with substituted or unsubstituted aryl. In certain embodiments, R1 is l 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 embodiments, R3&1 is ethynyl or propynyl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or exyl.

In certain embodiments, R1 is l or propynyl, tuted 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, substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, lyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In certain ments, R1 is ethynyl or propynyl, substituted with substituted 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, substituted with methoxy or ethoxy. In certain embodiments, R1 is ethynyl or propynyl, substituted with chloro. In certain embodiments, R1 is ethynyl or yl, 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 tituted C5_6 carbocyclyl. In certain embodiments, R1 is substituted or unsubstituted cyclopropyl 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 tituted C2_6 alkenyl, tuted or tituted C2_6 l, 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 unsubstituted C2_6 alkynyl, or substituted or unsubstituted C3_6 carbocyclyl.

In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is halogen, 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., substituted or unsubstituted C1_2alkyl, substituted or unsubstituted kyl, substituted or tituted C3_4a1ky1, substituted or tituted C4_ salkyl, or substituted 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 e a group R2 of formula -CH2F, -CHF2, -CF3)) or —ORA2. In certain embodiments, RAz is —CH3, -CH2CH3, or — CH2CH2CH3, z'.e., to provide a group R2 of a —OH, —OCH3, -OCH2CH3, or —OCH2CH2CH3.

In certain embodiments, R2 is substituted or unsubstituted C26 alkenyl, In certain embodiments, R2 is tuted 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 tituted C5_6alkynyl. In certain 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 embodiments, R2 is —CH3, -CH2CH3, —CH2CH2CH3, or substituted or tituted cyclopropyl.

In n embodiments, R2 is —ORA2. In certain embodiments, RA2 is hydrogen. In certain embodiments, RA2 is substituted or unsubstituted alkyl, e.g., tuted or unsubstituted C1_6alkyl, substituted or unsubstituted C1_2alkyl, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted kyl, tuted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_ 6alkyl. In certain embodiments, RA2 is hydrogen, —CH3, -CH2CH3, or —CH2CH2CH3, i.e., to e a group R2 of formula —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 unsubstituted C2_5 alkynyl, 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 certain embodiments, R3a is —ORA3 and R31) is hydrogen. In certain embodiments, wherein R3a is —ORA3, R3a is in the alpha or beta uration. In certain embodiments, wherein R3a is —ORA3, R321 is in the alpha configuration. In certain embodiments, wherein R3a is —ORA3, R3a is in the beta configuration. In certain embodiments, RA3 is en. In certain embodiments, RA3 is substituted or unsubstituted CH; alkyl, e.g., substituted or unsubstituted C1_2alkyl, tuted or unsubstituted C2_3alkyl, tuted or unsubstituted C3_4a1kyl, substituted or unsubstituted C4- salkyl, or substituted or unsubstituted C5_6alkyl. In certain embodiments, RA3 is hydrogen, —CH3, - CH2CH3, or 2CH3, z'.e., to provide a group R38 of formula —OH, —OCH3, -OCH2CH3, or — OCH2CH2CH3.

As generally defined herein, each instance of R43 and R41) is independently hydrogen, substituted or unsubstituted C1_6 alkyl, or halogen, ed 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 certain embodiments, 2 is a single bond, at least one of R4a and R4b is hydrogen. In certain 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, substituted or unsubstituted C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or tituted 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 certain embodiments, 2 is a single bond, at least one of R4a and R4b is halogen, e. g., .

In certain embodiments, 2 is a single bond, and both of R4a and R4b are en. 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, substituted 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 ents a single bond, R4a is a non-hydrogen 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 tuted or unsubstituted C5_6alkyl. In n 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 defined herein, 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, -OC(=O)ORGA, — C(=O)N(RGA)2, )C(=O)RGA, )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, tuted or unsubstituted C2_6 alkynyl, substituted or tituted C3_6 carbocylyl, or substituted or tituted 3- to 6- membered heterocylyl.

Furthermore, as generally defined herein, each instance 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 unsubstituted C3_6 carbocylyl, substituted or unsubstituted 3- to 6- ed heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, an oxygen protecting 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 tuted or tituted heterocylyl or heteroaryl ring. In certain 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 C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_6alkyl), tuted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 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 e an unsubstituted pyrazolyl, In certain embodiments, at least one of R5, R6, and R7 is a non-hydrogen substituent. As used herein, a R5, R6, and R7 "non-hydrogen substituent" means that R5, R6, and R7 are not hydrogen, but are any one of halogen, -N02, -CN, —CF3, -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, -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, 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— ed heterocylyl.

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

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

In certain embodiments, R5 is -OC(=O)RGA, e.g., -OC(=O)CH3_ In certain 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 —OC(=O)ORGA, e.g., )OCH3_ In certain embodiments, R5 is -OC(=O)ORGA, e.g., —OC(=O)OCH3, In certain embodiments, R6 is - OC(=O)ORGA, e.g., )OCH3, In certain embodiments, R7 is -OC(=O)ORGA, e.g., - OC(=O)OCH3, In certain 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 certain 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 ments, 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 ments, R7 is - N(RGA)C(=O)RGA, e.g., -NHC(=O)CH3, In certain ments, one of R5, R6, and R7 is - N(RGA)C(=O)ORGA, e.g., -NHC(=O)OCH3, In certain embodiments, R5 is -N(RGA)C(=O)ORGA, e.g., -NHC(=O)OCH3, In certain 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 n ments, R5 is —N(RGA)C(=O)N(RGA)2, e.g., - ’HC(=O)I\;H2 or -NHC(=O)N(CH3)2. In certain embodiments, R6 is -N(RGA)C(=O)N(RGA)2, e.g., - ’HC(=O)I\;H2 or -NHC(=O)N(CH3)2. In n 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, substituted or unsubstituted C1_6 alkyl (e. g., -CH3 or —CF3), substituted or unsubstituted 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 n ments, 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 tituted aryl or heteroaryl. In certain embodiments, one of R5, R6, and R7 is -S(=O)2RGA, e.g., 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 unsubstituted aryl or heteroaryl. In n embodiments, R6 is —SRGA, e.g., -SCH3, - scra, GA, e.g.,-S(=O)RGA, e.g., -S(=O)CH3, -S(=O)CF3; 2RGA, e.g., -S(=O)2CH3, — S(=O)2CF3, or -S(=O)2-Aryl, n 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 aryl. In certain embodiments, one of R5, R6, and R7 is - S(=O)20RGA. In certain embodiments, R5 is -S(=O)20RGA, e. g., -S(=O)20CH3, -S(=O)20CF3, or - S(=O)20Ary1, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain ments, R6 is -S(=O)20RGA, e.g., 20CH3, -S(=O)20CF3, or -S(=O)20Aryl, wherein Aryl is substituted or unsubstituted aryl or aryl. In certain embodiments, R7 is -S(=O)20RGA, e. g., 20CH3, -S(=O)20CF3, or -S(=O)20Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In n embodiments, one of R5, R6, and R7 is -OS(=O)2RGA. In certain embodiments, R5 is -OS(=O)2RGA, e.g., -OS(=O)2CH3, —OS(=O)2CF3, or -OS(=O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain ments, R6 is -OS(=O)2RGA, e. g., -OS(=O)2CH5, -OS(=O)2CF5, or -OS(=O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R7 is -OS(=O)2RGA, e. g., -OS(=O)2CH3, -OS(=O)2CF3, or )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 -S(=O)2-NH-Aryl, wherein Aryl is substituted or unsubstituted aryl or heteroaryl. In n 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 ments, R7 is 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 unsubstituted aryl or heteroaryl. In certain embodiments, R6 is - S(=O)2RGA, e.g., -NHS(=O)2CH3, O)2CF3, or O)2-Aryl, wherein Aryl is substituted or unsubstituted aryl or aryl. In certain embodiments, R7 is -N(RGA)S(=O)2RGA, e.g., -NHS(=O)2CH5, -NHS(=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 C2_3alkyl, substituted or unsubstituted C3_4alkyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted C5_ 6alkyl. 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), n—hexyl (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; difluoroethyl, 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 n 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 substituted or tituted C2-6 alkenyl, e.g., substituted or unsubstituted C2_3alkenyl, substituted or tituted C3_4alkenyl, substituted or tituted 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), tituted 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, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy.

In certain 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, tuted or unsubstituted C4_5alkynyl, or substituted or tituted 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 ments, 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 tuted or unsubstituted C54 carbocyclyl. In certain ments, 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 substituted or unsubstituted 3- to 6- membered heterocylyl, e. g., substituted or unsubstituted 3-4 membered heterocylyl, substituted or unsubstituted 4-5 membered heterocylyl, or substituted or unsubstituted 5-6 membered cylyl.

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 n, n RGA is substituted or unsubstituted C1_2 alkyl (e.g., —CH3, -CF3).

Exemplary combinations of R5, R6, and R7 as non-hydrogen substituents are contemplated herein.

N | P' R7 For example, in certain embodiments, the C21-pyrazolyl of formula W is a mono- substituted 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 .

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 (ii-c), wherein R5, R6, and R7 are each non-hydrogen substituents as defined herein.

N | F‘ R7 In certain embodiments, the C21-pyrazolyl of a W is a tri-substituted pyrazolyl ring wherein each of R5, R6, and R7 are non-hydrogen tuents as defined herein, Various ations ofCertain Embodiments Various combinations of certain embodiments 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, H3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, —CH2CH3, 2CH3, substituted or tituted cyclopropyl, fluoro, or chloro. In certain embodiments, R361 and R31) are both hydrogen. In certain embodiments, R321 and R3b are joined to form =O (oxo). In certain ments, wherein Ring B comprises a C5-C6 double bond, R461 is hydrogen, fluoro, -CH3, or - CF3. In certain embodiments, wherein 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 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, R4a is a non-hydrogen substituent and R4b is hydrogen. In certain embodiments, the C21—pyrazolyl ring is a mono-substituted lyl.

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, n RGA is substituted or unsubstituted C14 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 n embodiments, n R2 is hydrogen or a drogen beta substituent, provided is a steroid of Formula (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 embodiments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, —CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R3a and R3b are both hydrogen. In certain embodiments, R32' and R3b are joined to form =0 (oxo). In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is hydrogen, fluoro, -CH3, or - CF3. In certain 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 R41) are -CH3 or -CF3. In certain embodiments, n 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 ses a C5-C6 double bond, R43 is a non—hydrogen substituent and R41) is hydrogen. In certain embodiments, the C21-pyrazolyl ring is a mono-substituted pyrazolyl.

In certain embodiments, the C21-pyrazolyl ring is a di-substituted pyrazolyl. In certain ments, 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 CZl-pyrazolyl 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 en, provided is a steroid of Formula (I—A3), , or (I-C3): (I-Bs), (1-C3), or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CHzF, -CHF2, —CF3, —CH20CH3, or tuted or unsubstituted cyclopropyl. In certain embodiments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, —CH2CH2CH3, tuted 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 drogen substituent in the beta uration. In certain embodiments, wherein Ring B comprises a C5-C6 double bond, R431 is hydrogen, fluoro, -CH3, or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of RA":1 and R4b are en. 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 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 ments, the C21-pyrazolyl ring is a ubstituted 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, RGA, -CN, -N02, or n, 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-A4), (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, —OCH2CH2CH3, —CH3, 3, —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 n embodiments, wherein Ring B comprises a C5-C6 double bond, R4a is en, fluoro, -CH3, or -CF3. In certain embodiments, wherein Ring B does not comprises a C5-C6 double bond, both of R4a and R4b are hydrogen. In n 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 R4a 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 R41) is hydrogen. In certain 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), A, -C(=O)RGA, -CN, -N02, or n, wherein RGA is substituted or unsubstituted Cm 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 en.

In certain embodiments, wherein R321 and R3b are joined to form an oxo group, provided is a steroid of a (I-A5), (I-BS), or (I-C5): R 1 1 R43 R (I-AS), R" (1-35), (I—CS), or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CH2F, -CHF2, —CF3, H3, or substituted or unsubstituted cyclopropyl. In certain embodiments, R2 is —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, —CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or . 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 uration. In certain embodiments, wherein Ring B ses a C5-C6 double bond, R4a is hydrogen, fluoro, -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, n 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 drogen substituent and R4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is a mono-substituted pyrazolyl. In certain ments, 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 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 en.

In certain embodiments, wherein R4a is a non-hydrogen tuent, provided is a d of Formula (I-A6) or (I-B6): (I—A6) or (L136), or a pharmaceutically acceptable salt thereof. In certain embodiments, R1 is —CH3, —CH2CH3, — CHzF, -CHF2, —CF3, —CH20CH3, or tuted or unsubstituted 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, 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 embodiments, 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 certain embodiments, the C21-pyrazoly1 ring is a mono-substituted pyrazolyl. In n embodiments, the C21—pyrazoly1 ring is a di-substituted pyrazolyl. In certain ments, 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 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 n embodiments, R1 is —CH3, —CH2CH3, — CHzF, -CHF2, —CF3, —CH20CH3, or substituted or unsubstituted cyclopropyl, In certain embodiments, the C21-pyrazolyl ring is a mono—substituted pyrazolyl, In certain embodiments, the C21-pyrazolyl ring is a di-substituted pyrazolyl. In certain ments, 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 lyl, wherein each ce 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 n embodiments, a steroid of Formula (I) is selected from the group consisting of: and H6 and pharmaceutically acceptable salts thereof.

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

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

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

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

The pharmaceutical compositions provided 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, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

Generally, the compounds provided herein are administered in an ive amount. The amount of the compound ly administered will lly be ined 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, weight, and se 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. ts at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or ing 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 ition thereof over an ed 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 n embodiments, the chronic administration is ed to provide a constant level of the compound in the blood, e.g., within the eutic window over the extended period of time.

The pharmaceutical compostions of the t 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 compound in the blood to an effective level. The placement of the bolus dose s 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 continuous on, 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, followed 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 discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic , in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, 3O premeasured ampules or es of the liquid compositions or pills, tablets, capsules or the like in the case of solid itions. 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 representative ns. Using these dosing patterns, each dose provides from about 0.01 to about mg/kg of the compound provided herein, with red doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally 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 weight.

Injection dose levels range from about 0.1 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 adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.

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 e, for example, any of the following ingredients, or nds of a similar : a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a ning agent such as e or rin; 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 lly 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 containing 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. atively, the active ingredients may be formulated in a cream with, for example an -water cream base. Such ermal formulations are well-known in the art and generally include 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 provided herein.

The compounds provided herein can also be administered by a ermal . Accordingly, transdermal stration can be accomplished 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 representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

The present invention also s to the pharmaceutically acceptable formulations of a compound of the present invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are 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 es, which include, but are not d to, methylated, hydroxyalkylated, ed, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether odextrin, e.g., for example, sulfobutyl ether B—cyclodextrin, also known as Captisol®. See, e. g, US. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-B-cyclodextrin (e.g., 10-50% in water).

The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present ion. 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, te, succinate, 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 following ceutical compositions.

Exemplary ation 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 compound per tablet) in a tablet press.

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

Exemplary Formulation 3 , Liquid: A compound of the present ion (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 cellulose (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 compound of the present ion may be admixed as a dry powder with a dry gelatin binder in an imate 1:2 weight ratio. A minor amount of magnesium te is added as a lubricant. The mixture 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 ion may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of imately 5 mg/mL.

Exemplary Formulation 6 , Tablets: A compound of the present invention may be admixed as a dry powder with a dry gelatin binder in an imate 1:2 weight ratio. A minor amount of magnesium stearate is added as a ant. 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 ium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 8 — 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 e 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 present invention may be d as a dry powder with a dry n 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 , s: 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 mixture 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 ion is directed to C21 -substituted neuroactive 2O steroids designed, for example, to act as GABA modulators. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for the ment of anesthesia and/or sedation in a subject. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a nt disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal me, or tinnitus) in a subject in need (e. g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome).

Thus, in one , 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 t invention or a composition thereof. In n embodiments, the compound is administered by intravenous administration.

Earlier studies (see, e. g., Gee et al., European Journal ofPharmacology, 136:419-423 (1987)) trated that n 30c—hydroxylated steroids are orders of magnitude more potent as modulators of the GABA receptor complex (GRC) than others had reported (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 steroids are only e of much lower levels of effectiveness. In vitro and in vivo mental data have now demonstrated that the high y of these steroids allows them to be therapeutically useful in the modulation of brain excitability via the GRC (see, e.g., Gee et al., European l of cology, 136:419-423 (1987); 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 nds useful in treating stress, anxiety, insomnia, seizure disorders, and mood disorders, that are amenable to GRC-active agents, such as depression, in a therapeutically beneficial manner. rmore, 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, iazepines, and GABA) where therapeutically beneficial effects on stress, anxiety, sleep, mood disorders and seizure disorders have been previously elicited (see, e. g., Gee, KW. and Yamamura, H.I., "Benzodiazepines and Barbiturates: 2O Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders," in Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG. and Morselli, P.L., "Psychopharmacology of GABAergic Drugs," in pharmacology: 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 . These compounds 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 ds for the treatment and prevention of CNS—related conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and man mammals. Thus, and as stated earlier, the present invention es within its scope, and extends to, the recited methods of ent, as well as to the compounds for such methods, and to the use of such compounds for the preparation of ments useful for such methods. ary CNS ions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic 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 disorder (PTSD), compulsive disorders (e. g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e. g., status ticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention t ctivity disorder (ADHD)), dementia (e.g., Alzheimer’s type dementia, Lewis body type dementia, ar type dementia], movement ers [e.g., Huntington’s disease, Parkinson’s e], personality disorders [e.g., anti-social personality disorder, ive compulsive personality disorder], autism spectrum ers (ASD) [e.g., autism, monogenetic causes of autism such as ophathy’s, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., , 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 nds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. stration 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 afflicted with a condition associated with brain excitability, comprising 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 treating or preventing stress or anxiety in a subject, comprising administering to the subject 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 alleviating or preventing seizure activity in a t, comprising administering to the subject in need of such treatment an effective amount of a compound of the present ion.

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

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

In yet another aspect, provided is a method of alleviating 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 ion.

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

In yet another aspect, provided is a method of ng 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 administering to the subject a therapeutically ive amount of a nd of the present invention. In certain embodiments, the disorder is Alzheimer’s disease. In certain embodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present ion. In certain embodiments, the attention disorder is ADI-ID.

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

Anesthesia /Sedation esia is a pharmacologically d 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 provides the correct combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve very specific ations of results. Anesthesia allows patients to undergo y and other procedures without the distress and pain they would otherwise experience.

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

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

Minimal sedation is also known as anxiolysis. Minimal sedation is a nduced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be ed. Ventilatory and cardiovascular functions are lly unaffected.

Moderate sedation/analgesia (conscious on) is a drug-induced depression of consciousness during which the patient responds purposefully to verbal command, either alone or accompanied by light tactile stimulation. No entions are y necessary to in 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 aroused, but responds purposefully (not a reflex withdrawal from a painful stimulus) following repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may e 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 depression of neuromuscular function. Cardiovascular on may be impaired.

Sedation in the intensive care unit (ICU) allows the depression of patients' ess 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 control 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 neuromuscular blocking agents.

In some embodiments, sedation (e.g., long—term sedation, continuous sedation) is induced and maintained 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 ation half-life. ural sedation and analgesia, also referred to as conscious sedation, is a technique of administering sedatives or dissociative agents with or t sics to induce a state that allows a subject to tolerate sant procedures while ining cardiorespiratory function.

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

Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety ence 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 ension, often marked by trembling, g, confusion, dizziness, nausea, difficulty ing. 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 se; although the specific cause is not always apparent. In addition to recurrent cted 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 s. Accordingly, those suffering from panic er experience symptoms even outside of specific panic episodes. Often, normal changes in heartbeat are noticed by a panic er, leading them to think something is wrong with their heart or they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of body functioning occurs during panic attacks, wherein any perceived physiological change is interpreted as a le life threatening illness (i.e. extreme hypochondriasis).

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

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

Post-traumatic stress er or PTSD is an anxiety disorder which results from a traumatic experience, Post-traumatic stress can result from an extreme situation, such as , rape, hostage situations, or even s accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression. egeneralz've Diseases and Disorders The term "neurodegenerative disease" es diseases and ers that are ated with the progressive loss of structure or function of neurons, or death of neurons. Neurodegenerative diseases and disorders e, but are not limited to, Alzheimer’s disease (including the associated symptoms of mild, moderate, or severe cognitive ment); ophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by affective 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 ia, Parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette’s syndrome; head trauma; hearing ment and loss; Huntington’s disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including ias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia x, son’s disease, cephalitic parkinsonism, and progressively supranuclear palsy); muscular spasms and disorders associated with muscular spasticity or weakness including chorea (such as benign hereditary chorea, drug-induced , hemiballism, Huntington’s disease, neuroacanthocytosis, Sydenham’s chorea, and symptomatic chorea), dyskinesia (including tics such as complex 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, dystonic writer's cramp, hemiplegic dystonia, smal 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 follows cerebral stroke, oembolic , hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson’s disease; seizure; status epilecticus; ; tinnitus; tubular sclerosis, and Viral infection induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and alopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows al stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and c arrest. Methods of treating or preventing a neurodegenerative disease also include ng or preventing loss of neuronal function characteristic of neurodegenerative Epilepsy Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can e, but are not d to lized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-ma] seizures on awakening, West syndrome, - Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

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

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

Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e. g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non—convulsive status epilepticus, e. g., late onset e non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

Compositions described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super- refractory status epilepticus; non-convulsive status epilepticus, e. g., generalized status epilepticus, complex l status epilepticus; generalized periodic epileptiform discharges; and ic lateralized epileptiform discharges; prior to the onset of a seizure.

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

Based on the type of or 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 es are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain generating the seizures is sometimes called the focus.

There are six types of lized seizures. The most common and dramatic, and therefore the most well known, is the lized convulsion, also called the mal e. In this type of seizure, the patient loses consciousness and usually ses. The loss of consciousness is followed by generalized body stiffening (called the "tonic" phase of the seizure) for 30 to 60 seconds, then by Violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "postictal" or after-seizure phase). During grand-mal seizures, injuries and nts 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 patient, most often a child, typically interrupts an ty and stares y.

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

Clonic seizures are repetitive, ic 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 bed herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous es; 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 l seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; al onset seizures; nocturnal seizures; tal lobe seizures; post traumatic es; subtle es; Sylvan seizures; Visual reflex seizures; or withdrawal seizures.

Examples In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples bed in this application are offered to illustrate the compounds, ceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. als and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or red process ions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.

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

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

The compounds ed herein may be isolated and purified by known standard procedures.

Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative pyrazoles that have been listed herein. The nds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CEL® OK. 1H-NMR reported herein (e. g, for intermediates) may be a partial entation of the full NMR spectrum of a compound, e.g., a nd described herein. For example, the reported 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 es are provided in the Figures.

Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 um C18, 19*250 mm. Mobile phase: aectonitrile, water (NH4HC03) (30 L water, 24 g NH4HC03, 30 mL NH3.H20). Flow rate: 25 mL/min Exemplary l 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 ed in accordance with methods 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 purification methods known to those skilled in the art. In some embodiments, compounds bed 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 ne 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 ting group Example 1. Synthesis 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 hydrobromic 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.

Recrystallization 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), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H), .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 se 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 e 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 e 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 completed. 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 trated, purified by flash Chromatography on silica gel (Petroleum 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 (204.52 g, 550.89 mmol) in THF (500 mL) was added a solution of t—BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0°C, After the addition was completed, 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 e was cooled to room temperature and quenched with Sat.

NH4Cl, extracted with EtOAc (3*500 mL). The combined organic layers were washed with brine, dried and trated to give the crude product, which was purified by a flash column chromatography leum ether/ ethyl acetate50:1 to 10:1) to afford compound SA-D (38.4 g, 92%) as a white powder. 1H NMR: (400 MHz, CDCl3) 6 5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), .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 ice-bath. 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 ted. The mixture was cooled to 0 °C and 3.0 M aqueous NaOH solution (400 mL) followed 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 NagSgOg, brine, dried over Na2SO4 and concentrated in vacuum to give the crude product (43 g as ess oil. The crude product was used in the next step without , crude) further cation.

Synthesis of nd 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 n 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 mixture 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 t was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 8:1) to afford nd SA-F (25.0 g, yield:62.5%, over two steps) as a white powder. 1H NlVIR (SA-F): (400 MHz, CDC13) 6 2.57—2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m, 10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).

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 se bromine (5.52 g, 34.54 mmol). The reaction mixture was stirred at 17 0C for 1.5 h. The resulting solution was quenched with saturated aqueous NaHC03 at 0°C and extracted with EtOAc (150 mLXZ). The combined organic layers were dried and concentrated. The e 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 sed 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 ous tetrahydrofuraii was added dropwise and stirred 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 wasi'ied with saturated Nat-lCOg sohitiori, dried over NagSoi ed and trated to give a mixture of ESE-B and Sfi—C (:21 g, 70%) which was directly used in the next step without further purification A solution 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 ng 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 on was extracted 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) .

Synthesis of compound SB-D. To a solution of compound SB-C (16.8 g. 61.3 mmol) in methanol (250 mL) was added iodine (1.54 g, 6.1 mmol). After stirring at 60°C for 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 e = 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 suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL) at 0 °C was added ethyltriphenylphosphonium e (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 on 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 reaction mixture was extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and trated. The residue was purified by column tography (pertroleum ether/ethyl e = 30:1 to 20: 1) to afford compound SB-F (4.8 g, 16.7 mmol, 76% for two steps). 1H NMR (400 MHz, CDCl3), 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 nd 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 e was allowed to warm up and stirred at room temperature overnight. The reaction mixture was quenched with iced-cold water and ted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The white e was purified by flash column chromatography (pertroleum ether/ ethyl acetate = 20:1 to 10: 1) to give compound SB-G (2.5 g, 8.28 mmol, 49%; Rf: 0.35, petroleum ether/ethyl e = 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 complex (20 mL; 1.0 M solution in THF). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath 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 combined 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 oromethane had been shaken with l milliliters of H20 then separated from the water layer) was added Dess-Martin periodinate (5,5 g, 13 mmol). After stirring at room temperature for 24 h, the on mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with 10 % s Na2S2O3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (pertroleum ether/ ethyl e = 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 e (302 mg, 1.89 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 (600 mg).

Synthesis of compound SB—J. A solution of compound SB (600 mg, 1.5 mmol) in acetone 10 mL was d 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 reaction e was allowed to cool to room ature and the solvent 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 (pertroleum 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 e 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 on e was extracted 500 mL EtOAc, washed with 100 mL saturated Na2S03, 100 mL saturated NaHC03 and 100 mL brine and evaporated in vacuo then purified 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) d 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 e was evaporated in vacuo then purified by chromatography leum 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 compound SA-N. To a on 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 solution 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 evaporated 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 acetate = 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 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 e = 10: 1) to afford SA-Q as a white solid (210 mg, 60% . 1H NMR (400 MHz, , 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 00 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 reaction mixture was poured into ice-cold water (100 mL) and ted with 300 mL EtOAc, washed with 100 mL brine solution, and ated 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% .

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 mixture was quenched with 5 mL H20 and extracted with 100 mL EtOAc, washed with brine and evaporated in vacuo then purified by chromatography leum 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 (apparent 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 ng 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 temperature for one hour, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with 10% aqueous Na2S203 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to afford SA—T as a white solid (100 mg, 91%). The crude product was used in the next step without 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 on mixture was ed 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 bromine (150 mg, 0.33 mmol). After ng at room temperature for lh, the reaction mixture was poured into ice-water then extracted with EtOAc (10 mL x 3). The combined organic 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 r cation.

Example 4. Synthesis of SB-W compound NaH, DMSO BH3ITHF NaOH/H202 SB-U To a stirred solution 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 suspension of compound SB-F (2.2 g 7.2 mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred for r 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 residue was dissolved in dichloromethane and washed with H20 (3 x 50 mL) and brine (100 mL), dried over MgSO4, filtered, and trated. The crude target compound was purified by via silica gel chromatography (pertroleum ether/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 complex ( 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% s NaOH (10 mL) ed 30% aqueous solution of H202 (12mL). The mixture was allowed to stir at room temperature for 1 hour then extracted with EtOAc (3 x 100 mL). The ed organic layers were washed with 10% aqueous Na2S2O3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to afford crude nd SB- U ( 1.8g, 100%). The crude product was used in the next step without further purification.

Synthesis of compound 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 several 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 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 purified by tography 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 on of compound SB-V (600 mg, 1.65 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) ed 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 ed organic layers were washed with brine (200 mL), dried over MgSO4, filtered and trated to give crude compound SB-W (600 mg, 100%). The crude product was used in the next step t r 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 e 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 reaction mixture was quenched with iced-cold water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The white residue was purified by flash column chromatography (petroleum ether/ethyl e= 20:1 to 10: 1) to give compound SA—X Synthesis of compound SA-Y. To a solution of compound SA—X (200 mg, 0.66 mmol) in dry THF (5 mL) was added borane—tetrahydrofuran complex (2 ml, of 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 solution 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 product was used in the next step t further purification. sis 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 ature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with 10 % aqueous NaCl (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated The residue was purified by chromatography on. silica gei leum 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 compound SA-AA. To a solution of nd 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 stirring at room temperature 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 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 compound SA—DD and SA-EE. Compound mixture SA-BB and SA-CC (5.0 g, 16.7 mmol) was ved in dry ol (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 anhydrous 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 ed by addition of water (5 mL). 2 M NaOH solution (30 mL) was added followed by 30 % H202 (30 mL). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and ing solution was washed with brine (2X100 mL), dried over ium 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 e 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 ed and concentrated in vacuo. The residue was ed by flash chromatography ( petroleum ether/ ethyl acetate=15: 1) to afford product SA- HH (2.1g, 6.03 mmol, 43% (2 steps)) as white solid and product SA-II (2.2g, 6.32 mmol, Yield=45% (2 steps)) as white solid. nd 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 nt SA—II (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine (241 mg, 0.077 mL, 1.51 mmol). The solution was heated at 25 °C for 1.5 hours then the mixture was poured into cold water (50 mL) and the resulting solid was extracted with ethyl acetate (2>< 50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SA-JJ was used directly without further purification in the next step.

Example 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 on in THE) and the reaction mixture was stirred 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 e was stirred at ambient temperature for 1 hour and then extracted with EtOAc (3 X 100 mL). The combined EtOAc extracts were washed with 10 ‘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 reaction 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 nd 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 on of trimethylsufonium iodide (6.43 g 31.5 mmol) in 100 mL ofDMSO was added 60wt% NaH (1.26 g, 31.5 mmol). After ng 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 on mixture 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 reaction.

Synthesis of compound SB-N. Compound SB-M (1.6 g, 5 mmol) was dissolved in 60 mL of H20 saturated CHQClz. (Using a tory 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 % s Na2S203 (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated. The e was purified by chromatography on silica gel ( petroleum ether/ethyl e = 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. Methanol was evaporated off and the residue was dissolved in romethane 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 acetate = 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 nt 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 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 9. Synthesis of SB-FF compound selecflour 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 selectflour (90.22 g, 324.4 mmol) in portions at —4 °C. The resulting reaction e wasstirred at -4 0C for 3 h. After the TLC showed the reaction was completed, then the e was filtered and concentrated. The t 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, ill-i)? 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 on 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), .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 solution 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 mixture. The solution was stirred at 60 °C for 1.5 h .After the TLC showed the reaction was ted, and then the mixture was filtered and concentrated 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) .35 (m. 1H) .09 (m, 1H) 2.06- , , , 1.82 (m, 6H), .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 onal 15 h. The reaction mixture was cooled and extracted 1500 mL EtOAc, washed with brine and concentrated to afford SB-Z as the white solid (120 g, . 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) 1.01—0.94 (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 reaction was completed, then the reaction was quenched with aq.NaHC03. The reaction was extracted with 500 mL EtOAc, washed with brine and evaporated in vacuo. The resulting residue was purified by chromatography (Petroleum ether/ethyl acetate =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 stirred 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), .68 (m, 2H) .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 e was stirred at 23 °C for 1.5 h .

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

The on was extracted with 1000 mL EtOAc, washed with brine and evaporated in vacuo. The resulting residue was purified by chromatography (Petroleum ether/ethyl acetate =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 solution of SB-CC (19 g, 59.29 mmol) in dry THF (500 mL) was added C2H9BS (59.29 mL; 10 M solution in THF) at 0 0C. After ng at room temperature for 2 hour, the reaction mixture was cooled in an ice bath then quenched slowly with 3M aqueous NaOH (160 mL) ed by 30 % aqueous solution of H202 (100 mL). After stirring at 20 °C for 1.5 h, the mixture filtered and extracted with EtOAc (3 00 mL). The combined organic layers was treated with aq.Na28203, extracted, dried and trated 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 tography leum ether/ethyl acetate = 1511611) to afford SB-EE as the white solid (12 g, 60.15% , 1H NMR (SB-EE) (400 MHz, , 6 (ppm)=4.65-4.46 (m, 1H), 2.55—2.51 (m, 1H), 2.22—2.09 (m, 4H) 2.06-1.97 (m, 32H) 1.88-1.77 (m, 2H), 1.69-1.54 (m, 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 compound 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 d at 16 0C for 2 h.The reaction mixture was quenched with aq.NaHC03 and tratedThen 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 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) , Example 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 , 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 ide (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 pyridine. The organic layer was r washed with brine (200 mL), dried over magnesium sulfate and trated 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 r stirred at -78 °C for 2 hours and warmed to room temperature and stirred for 1 hour. The reaction was quenched by addition of water (10 mL). Most THF t was removed 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).

Synthesis 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 ol solvent was removed in vacuo. The residual solution was ied 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 magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography ( petroleum ether/ ethyl acetate=5: 1) to afford pure t SC- D (2.354 g, 8.162 mmol, Yield=23%) and pure product SC-E (5.306 g, 18.40 mmol, 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 a (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 e 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 d to warm to room temperature 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 aqueous layer was further extracted with ethyl acetate (2X100 mL).

The combined organic extracts were washed with brine (300 mL), dried over ium sulfate and concentrated in vacuo. The crude product SC-F was used directly without further purification in the next step. sis of compound SC-G. To a solution of crude reactant SC-F (1.749 g, 6.022 mmol) in dichloromethane (60 mL) was added pyridinium dichromate (PDC) (3.398 g, 9.033 mmol). The mixture was stirred at room temperature overnight. The solution was filtered through a short pad of celite. The celite was washed with CH2C12 (3X50 mL). The combined CH2C12 on was concentrated in vacuo. The residue was purified by flash chromatography ( petroleum ether/ ethyl acetate=5: 1) to afford product SC-G (1.298 g, 4.50 mmol, Yield=75%) as white solid. Compound SC-G: IIDIMR (400 MHz, CDC13) 6(ppm): 1.02 (3H, d), 0.91 (3H, s). sis of compound SC-H. To a solution of reactant SC-G (1.948 g, 6.754 mmol) in anhydrous ol (50 mL) was added p—toluenesulfonic acid monohydrate (128 mg, 0.6754 mmol). The solution was heated at 70 °C for 3 hours. The reaction was quenched by 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 combined organic ts 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= 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).

Synthesis of compound SC-I. To a solution of ethyltriphenylphosphonium bromide (8.795 g, 23.69 mmol) in anhydrous THF (20 mL) was added t—BuOK (2.658 g, 23.69 mmol). The solution then became reddish in color and was heated at 70 0C for 2 hours. Then the reactant SC-H (1.642 g, 4.909 mmol) was added in one portion. The solution was heated at 70 °C overnight. The reaction was quenched by the addition of water (10 mL). The mixture was diluted with ethyl acetate (200 mL) and the ing 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 temperature 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 aqueous layers were extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography ( petroleum ether/ ethyl acetate =10023) to afford crude t 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 d product to PPh3 is 3: 1, so the amount of desired t SC-J is 1.354 g (4.506 mmol), the yield is 92%. 1H NMR (500 MHZ, CDCl3) 6(ppm): 5.13 (1H, qt), 1.66 (3H, dt), 1.02 (3H, d), 0.91 (3H, 5). sis of compound SC-K. To a solution of trimethylsulfoxonium iodide (5.213 g, 23.69 mmol) in anhydrous DMSO (30 mL) was added sodium hydride (60% wt, 948 mg, 23.69 mmol).

The mixture was stirred at 25 °C for 1 hour. Then a solution of crude reactant (1.746 g, contaminated with some residual PPh3, theoretical amount, 1.354 g, 4.506 mmol) in anhydrous THF (10 mL) was added. The mixture was stirred at 25 OC overnight. The reaction was quenched by addition of water (5 mL). The mixture was diluted with ethyl acetate (3 00 mL) and the ing solution was washed with water (2X100 mL), followed by brine (100 mL) dried over magnesium sulfate and trated in vacuo. The crude product SC-K was used directly in the next step t further purification. sis 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 sion was stirred at 25 °C for 1 hour. Then the reaction was ed 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 tography ( 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 reactant SC-L (458 mg, 1.447 mmol) in anhydrous THF (15 mL) was added BH3.THF (1.0 M, 7.23 mL, 7.23 mmol), The on was stirred at 25 °C overnight. Then the reaction was ed 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 magnesium sulfate and concentrated in vacuo. The crude product was used directly 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, theoretical 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. sis of compound SC-O. To a solution of reactant SC-N (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, 1.505 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 (2><50 mL). The combined organic extracts were washed with brine (50 mL), dried over ium sulfate and concentrated in vacuo. The crude product SC-O was used directly t further purification in the next step.

Example 13. Synthesis of SC-Y compound Li, NH3(|) t-BuOH, THF p-TsOH.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 e was allowed to warm to room temperature and ammonia was evaporated overnight. The residue was dissolved in 0.5 N s 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 product was purified by flash chromatography (Petroleum ether/ethyl acetate = 4: 1) to get t SC-P (18.98 g, 68.7%) as white solid. 1H NMR (500 MHz, CDCl3) 6(ppm): 3.66 (1H, t), 2.29—2.27 (2H, m), 2.12—2.07 (2H, m), 1.83-1.81 (2H, m), 1.50 (1H, s), 0.77 (3H, s).

Synthesis of compound 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 \/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 extracted with EtOAc (200 mL><3).The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The white residue was purified by flash column chromatography (Petroleum ether/ethyl acetate = 5:1) to give product SC-Q (19.0 g, 94%) as 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 compound SC-Q (19.0 g, 65.07 mmol) in dichloromethane (100 mL) was added pyridinium dichromate (PDC) (48.9 g, 130.14 mmol). The mixture was stirred at room temperature ght. The solution was filtered h a short pad of celite. The celite was washed with CHzClz (3X100 mL). The combined CH2C12 solution was concentrated in vacuo. The residue was purified by flash tography ( 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 enesulfonic acid on sillica gel (80g), the mixture was stirred under 45 °C for 1 hour. The insouble 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 on mixture then was extracted with , 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 cation.

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 temperature. The reaction on was then ted with CHzClz (200 mL X3), the combined organic layer was washed with NaHC03 (100 mL) and brine, dried over Na2SO4 and concentrated. The residue was purified by tography (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 nd SC-V. To a solution of ethyltriphenylphosphonium e (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 on solution 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 magnesium 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 ng at room temperature for 1h, the reaction mixture was cooled in an ice bath then quenched slowly with 10% aqueous NaOH (12 mL) followed by 30% H202 (20 mL). The mixture was allowed to stir at room ture for 1h then extracted with EA (100 mLX3). The combined c layer was washed with 10% aqueous Na2S203 (50 mL), brine, dried over Na2SO4, filtered and concentrated to afford crude compound SC-W (1.86 g, 5.31 mmol). The crude t was used in the next step without r purification.

Synthesis of compound SC-X. To a solution 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 ed 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 residue 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 methanol (10 mL) was added 48% HBr (152 mg, 0.903 mmol) followed by bromine (0.08 mL, 1.505 mmol). The solution was heated at 25 °C for 1.5 hours. 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 directly without further purification in the next step.

Example 14. Synthesis of SC-EE compound PhSOzCH F2 LHMDS/THF HMPA SC-DD SC-EE aia 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 on (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 ed 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, , 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 compound SC-BB. To a solution of compound SflwAA (1131) mg, 0.299 mmol) and anhydrous 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 ol solution was decanted. out and the solid e 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).

Synthesis of compound SCvCC To a solution of compound 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 "IT-1F).

After stirring at room temperature 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 t was used in the next step without r purification.

Synthesis of compound SC-DD. To a on of crude compound SC-CC (210 mg) was dissolved in 10 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 (380 mg, 0.896 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with romethane (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 tography 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 e (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. Synthesis of SC-II compound NaOH/H202 SC-HH 80-" Synthesis of compound SC-FF. To a solution of nt 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 t ature for 15h. Sat. NH4C1 on (20mL) was added to quench the reaction and the resulting solution was extracted with ethyl e (3 ><100mL). 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 BH3.THF (1.0 M, 7.23 mL, 7.23 mmol) at room temperature, and the solution was stirred at 25 °C overnight. Then the reaction was quenched by addition of water (5 mL), 2 M NaOH solution (10 mL) was added ed by 30 % H202 (10 mL). The ing 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 further purification.

Synthesis of nd 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 pyridinium 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 combined 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, 9%) 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) 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 extracted with ethyl acetate (2><50 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SC-II was used directly without further purification in the next step.

Example 16. Synthesis of SC-SS compound 1.B2H6, THF 2. 10% NaOH, H202 1. separate 2. BrleBr Synthesis of nd SC-MM and SC-NN. A mixture of reactant e 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, ed and concentrated. The e 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 on of water (5 mL). 2 M NaOH on (20 mL) was added followed by 30 % H202 (20 mL). The mixture was d at room temperature for 1 hour. The mixture was diluted with ethyl e (200 mL) and resulting solution was washed with brine (2X100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude t mixture was used directly in the next step without further purification.

Synthesis of compound SC-QQ and SC-RR. To a solution of crude reactant 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 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=15: 1) to afford t SC-QQ (910 mg, 2.7 mmol, Yield=41% (2 ) as white solid and product SC-RR (850 mg, 2.5 mmol, Yield=39% (2 ) 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 extracted with ethyl acetate (2X50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product SC-SS was used directly 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 HgF {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 reactien mixture was quenched with saturated aqueous NH4C1 on (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 sulfate, filtered and concentrate, The residue was purified by silica. gel column Chromategraphy {perti‘oleum ether/ elliyl acetate iil O/ l) to give the e of cempeund SC-TT and SC-UU (l .53 g). The mixture was fui‘llier ed 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); SCnTT—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 , 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), .08 (m,1H), 0.88 (s, 3H).

Synthesis of compound SC—W‘W. To a on of compound 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 m (400 mg). After stirring 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 d under vacuum, and 20 mi brine was added followed by extracting with £120. The combined. ether phase was dried with MgSOZl, and the ether was removed to give the crude product, which was further purified by silica gel chromatography (petroleum ether/ethyl E=lO/l) to give product 99 mg, 69%. 1H NMR (500 MHz, , 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 ed slowly with 10% aqueous NaOI-i (1 mL) followed by 30% aqueous solution oszOg (12 mL). The mixture was allowed to stir at room temperature 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 nd 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 several milliliters of H20 then separated 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 c layers were washed with 10 % aqueous N32S203 (10 mL), hrine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by tography on silica gel (pertroleum ether/ ethyl acetate 1: 5) to afford compound SC-YY (70 mg, 70% for two steps) as a white solid. 1H NMR (500 MHz, , 6 (ppm), 4.21-4.11 (d, 2H), 2.19 (s, 3H), 0.62 (s, 3H).

Synthesis of compound 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 ium 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 THF Hzc H6 H SA SA-1 SA-2 To a sion 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 ted 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 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 (d,1H), 6.66 (d,1H) 5.03 (1H, AB), 4.93(1H, AB), 2.77 (1H, t), Loo-2.2 (m, 24H), 0.9 (s, 3H).

Example 19. Synthesis 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 e 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 mixture was purified with by e-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 purified with by reverse-phase prep-HPLC to afford the title compound 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 suspension 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 d 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, ed and concentrated. The residue 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 solution 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 stirred 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 . 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), .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 nd 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 mixture was stirred at RT for 15h. The residue 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 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), 2.05-2.01 (m, 1H), 1.00-1.90 (m, 22H), 0.67 (s, 3H). LCMS: rt=2.52 min, m/z=419.1 [M+H]+ e 24. Synthesis of compound SA—S To a suspension of K2C03 (25 mg, 0.18mmol) in THF (5 mL) was added o-4H-pyrazole (20mg, 0.18mmol) and SA (36 mg, 0.09mmol). The e was stirred at RT for 15h. The residue e 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. Synthesis of compound SA—9 HNN7 K2603, THF To a suspension of K2C03 (25 mg, ol) in THF (5 mL) was added 4-bromo-4H-pyrazole (26mg, 0.18mmol) and SA (36 mg, 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 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). e 26. Synthesis of compounds SA—10 and SA-ll SA-10 SA-11 To a suspension of K2C03 (55mg, l) 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 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 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), 2.07—2.04 (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), 1.00—1.90 (m, 22H). e 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- le (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 sulfate, filtered and trated. The residue e 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), 2.05-2.02 (m, 1H), .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 compound 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 solution of crude reactant (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 sulfate 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. sis of compound SA-lS To a solution of crude reactant (249.5 mg, 0.629 mmol, tical amount) in anhydrous THF (5 mL) was added 3.4-dimethyl-1H-pyrazole (120.7 mg, 1.256 mmol) followed by potassium ate (173.6 mg, 1.256 mmol). The solution was stirred at 25 °C ght then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2><100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel tography (petroleum ether/ ethyl acetate =1 :3) to afford product (56 mg, 0.136 mmol, Yield=22% (2 steps)) 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, m).0.67 (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 Pd(dppf)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 d at room temperature overnight. 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 (: eum 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) : 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 ature overnight then most THF solvent was removed in vacuo. The solution was neutralized by addition of acetic acid and the resulting mixture was d with dichloromethane (200 mL) and brine (50 mL). The organic layer was separated, dried over magnesium sulfate and trated in vacuo. The residue was purified by silica gel tography (: petroleum ether / ethyl acetate =4: 1) to afford t (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 hydrogen balloon ght. A small sample solution was filtered, concentrated in vacuo and characterized by 1HNMR to determine that the reaction was complete.

All on mixture was filtered by celite and the celite was washed with ethanol (20 mL). The combined filtrate was concentrated in vacuo. The residue was purified by a short pad of silica gel (: eum 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 nd 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) ed by potassium carbonate (173.6 mg, 1.256 mmol). The solution was stirred at 25 °C overnight and then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2><100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (: petroleum ether / ethyl acetate =2:3) to afford product (29.5 mg, 0.0714 mmol, Yield=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 ylthi0- 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 ature for 1 hour. The MeSSMe (128 mg, 0.12 mL, 1.361 mmol) was added at 0°C and reaction solution was stirred 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 ylsulf0nyl-1H—pyrazole. To a solution of the crude reactant (155.4 mg, 1.361 mmol, theoretical amount) in dichloromethane (2.7 mL) was added trifluoroacetic acid (0.1 mL) at 0°C. Then 3-chloroperbenzoic acid (m-CPBA, 85% wt, 863 mg, 4.25 mmol) was added in portions and the on was stirred at room temperature overnight. 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 concentrated in vacuo. The crude product was purified by silica gel chromatography ( ethyl acetate to ethyl acetate: methanol =10: 1) to afford product (51 mg, 0.349 mmol, 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, tical amount) in anhydrous THF (2.5 mL) was added 4-(methylsulfonyl)-lH-pyrazole (51 mg, 0.349 mmol) ed by potassium carbonate (48 mg, 0.349 mmol). The solution was heated at 40 °C for 2 hours then the solution was d 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 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), 2.17-2.26 (1H, s), 2.04 (1H, d> Example 33. sis 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 mixture 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 e was purified by silica gel column (Petroleum ether/ ethyl acetateifl/l to El} to give Cernpennd 813—18 (165 nrg, yield: 76%) as white . 1H NMR: (400 MHz, CDC13) 6 7.53 (s, 1H), 7.42 (s, 1H), 4.94-4.80 (m, 2H), 2.60-2.56 (m, 1H), 2.34 (s, 3H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.87-1.58 (m, 12H, contained 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 on e was stirred at -78 °C for 3h. LCMS indicated the reaction was complete. Then saturated aqueous Na2$203 was added to the e 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), .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), 1.15—1.07 (m, 3H), 0.68 (s, 3H). LCMS: rt = 1.14 min, m/z = 429.2 [M-HgO], 469.2 [M+Na]. e 36. Synthesis of compound SA-Zl / K2C03, THF N, I —> N 35°C, 15 h SA SA-21 To a suspension of Compound SA (100 mg, 0.25 mmol) in THF (25 mL) was added 4-fluoro-1H- pyrazole (64.5 mg, 0.75 mmol) and K2C03 (103 mg, 0.75mmol). The mixture was stirred at 35°C for 15h. Then the reaction mixture was extracted 50 mL EtOAc, washed with 100 mL H20 and 100 mL brine and evaporated in vacuo. The residue was ed by e-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), 4.77(1H,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- 3-carbonitrile (70 mg, 0.75 mmol) and K2C03 ( 103 mg, 0.75mmol). The mixture was stirred at 35°C for 15h. Then the reaction mixture was extracted. 50 mL EtOAc, washed with 100 mL H30 and. 100 mL brine and evaporated. in mezzo. The resulting residue was purified by e- phase prep-HPLC to afford SA-22 as a white solid ( 23 mg, nol, 24 % . 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 1H-pyrazole (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), .37 (m, 5H), 2.58 (t, 1H), .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 compound 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 stirred at room temperature overnight, then the reaction was diluted with EtOAc (20 mL). The resulting on was washed with brine (10 mL), dried over Na2SO4 and trated in vacuo.

The residue was purified by prep—HPLC to give SA—24 (30 mg, 24%) as a white solid. 1H NMR: (500 MHz, CDC13), 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)+ e 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 d 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 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 purified with by reverse-phase PLC to afford the title nd 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 ted with EtOAc (2 X 10 mL). The combined organic layers were washed with brine, dried over sodium e, filtered and concentrated. The residue was purified with by e-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), 7.81(s, 1H), 5.87 (t, 1H), 5.02 (AB, 1H), 4.90 (AB, 1H), 2.61 (t, 1H), 1.00—2.25 (m, 24H), 0.68 (s, 3H). LC-MS: rt=2.30min,m/z = 446.2 (M + 1).

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 4-(methy1su1fony1)- 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 c layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The al e 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, ol) 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 c layers were washed with brine, dried over sodium sulfate, filtered 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: rt=2.45min,m/z = 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 e 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 e mixture 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), .16 (m, 1H), 2.09—2.05 (m, 1H), .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 mixture 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), .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]+ Example 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 sion 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 e 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 concentrated in vacuo. The residual mixture 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 nd SA-35 SA-AA To a suspension 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 stirred at rt for 15h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 X 10 mL). The ed organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with by e-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), 4.88(AB,1H), 2.58(1H, t), 1.00—2.25 (24H, m), 0.88(3H, t), 0.68(s, 3H). LC-MS: rt=2.39min, m/z = 399.4 (1W +1).

Example 50. Synthesis of compound SB-l SB-1 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 (36 mg, 0.09 mmol). After stirring at room temperature for 15h, the reaction 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 concentrate. The reaction mixture was purified with by e-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 d 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 reverse phase prep-HPLC to afford desired 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 4-methylsulfonyl-1H-pyrazole (110 mg, 0.754 mmol) followed by potassium carbonate (130 mg, 0.942 mmol). The solution was heated at 25 °C ght and then the on 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 t which was contaminated with 4-methylsulfonyl-lH-pyrazole. The crude t 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 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 PLC 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 nds SB—S To a solution of crude nt (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 ate (198 mg, 1.435 mmol). The solution was heated at 60 °C overnight. Then the solution was diluted with ethyl e (200 mL). The resulting solution was washed with brine (2X100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by e phase prep-HPLC to afford desired product SB—S (12.4 mg, 0.0282 mmol, two steps l 9.8%) and by-product (4.2 mg, 0.00955 mmol, two steps overall 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 solution 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 on 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 product was purified by silica gel chromatography ( 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) : 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 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 concentrated. The on 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%). R (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), 0.69-2.25 (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 prep-HPLC 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 on was washed with brine (100 mL), dried over sodium e and concentrated in vacuo. The reaction mixture was purified with by e-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).

Example 59. Synthesis of compound SB-ll To a solution of crude reactant SB-FF (50.7 mg, 0.122 mmol, theoretical amount) in anhydrous THF (1.5 mL) was added 4-cyanopyrazole (22.7 mg, 0.244 mmol) followed by potassium carbonate (33.7 mg, 0.244 mmol). The solution was stirred at 25 °C overnight. Then the solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2>< 50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude t was purified by e phase PLC 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), 2.05-1.95 (m, 2H), 1.90- 1.60 (m, 6H), 1.50—1.20 (m, 15H), 0.70 (s, 3H). 19FNMR (376 MHz, CDC13) 6(ppm): 3.

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 ed 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 (SB-12): (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), .56 (m, 1H), 2.25-1.99 (m, 6H), 1.91-1.61 (m, 6H), 1.54-1.03 (m, 15H), 0.84-0.74 (m, 1H) 0.70 (s, 3H).

LCMS: rt = 1.23 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), 1H-pyrazolecarbonitri1e (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 finished. The reaction mixture was poured into brine (10 mL) and extracted with EtOAc (10 mLx2). Combined the c layers and dried over , concentrated 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 e 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 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), 1.07-1.18 (m, 5H), 0.75—0.91 (m, 1H), 0.71 (s, 3H). LCMS: rt = 1.25 min, m/z = 449.2 [M+H]+.

Example 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 ing mixture was stirred at 20°C for 30min, and extracted with EtOAc (5 mL x 3). The ed c layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuum. The residue was ed 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), .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), 1.65-1.90 (m, 6H), 1.45—1.55 (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 anhydrous 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 solution 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 product 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 1H-pyrazole (60 mg, 0.09mmol). The reaction e 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).

Example 68. Synthesis of nd SB-20 To a solution of crude nt SC-II(100 mg, 0.241 mmol) in anhydrous THF (5 mL) was added 3H-pyrazole (82 mg, 1.2 mmol) ed by potassium carbonate (170 mg, 1.2 mmol) and the solution was heated at 60 °C 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 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), 0.69-2.25 (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 on 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 on was heated at 60 0C for 2h. Then the reaction mixture was diluted 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 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. Synthesis of compound SB-22 83-22 To a solution 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 potassium 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 on was washed with brine (2X50 mL), dried over ium 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 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 e-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), 0.60-2.20 (m, 24H). LCMS: Rt = 2.27 min. m/z = 403.2 [M+H]+.

Assay Methods nds provided herein can be evaluated using various assays; examples of which are described below. d Inhibition ofTBPS Binding {3'5S:§-t-§":‘>;1.iryibicyclopliosphmoth101121113. (TBPS) g assays using rat brain cortical nes in the presence of 5 HM GABA has been described (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 following 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 fuged at 1500 x g for 10 min at 4 °C. The resultant supernatants are centrifuged at 10,000 x g for 20 min at 4 °C to obtain the P2 pellets. The P2 pellets 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 tion is t 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 %. ing 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 ice-cold 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 instead 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 ic binding and the l 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 studies as it has been demonstrated to robustly inhibit TBPS binding. s compounds are or can be screened to determine their potential as tors of ["8]- TBPS binding in vitro. These assays are or can be performed in accordance with the above discussed procedures.

Patch clamp electrophysiology ofrecombinant (11/92)); and 0:48.35 GABAA receptors Cellular electrophysiology is used to measure the pharmacological properties of our GABAA receptor tors 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 at1,82))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 te medium without antibiotics or antimycotics. Confluent clusters of cells are ically coupled (Pritchett et al, e 1306-1308. , 1988, 242, ). Because 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 cultivated at a density that s the recording of single cells (without e connections to other cells).

Whole cell currents were measured with HEKA EPC-10 amplifiers using PatchMaster software or by using the high throughput QPatch platform (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- e 10 mM, pH (NaOH) 7.4. In some cases 0.005% hor was also added. Intracellular (pipette) solution ned: 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 ruptured to assure electrical access to the cell interior (whole-cell patch-configuration). For experiments using the QPatch system, cells were transferred as suspension 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 receptors were stimulated by 2 uM GABA after sequential pre-incubation of increasing concentrations of the test article. cubation duration was 30 s and the on of the GABA stimulus was 2s. Test articles were dissolved in DMSO to form stock solutions (1 OmM). Test es were diluted to 0.01, 0.1, l, and 10 uM in bath solution. All trations of test articles were tested on each cell. The relative percentage 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 pharmacokinetics and a qualitative assessment of sedation were obtained in male Sprague Dawley rats ing to the following procedure. Rats were dosed by intravenous bolus dose (60 seconds) via the foot dorsal vein at doses ranging from 5 to 15 mg/kg in an appropriate vehicle. In order to assess on, rats were gently ined 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 s 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 s in the same manner. Recovery of ng reflex is defined as the ability of a rat to right itself completely within 20 seconds of being placed in dorsal recumbency. The duration of LRR is defined as the time interval n LR and the return of righting reflex.

Acute PTZMethod The anticonVulsant effect of test compounds were ed 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 available ad libitum. The mice were housed for 1 week prior to behavioral testing, at which time they d 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 ermined 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 weight.

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 ative ment 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). ately following the PTZ injection, mice were individually placed into observation chambers (25x15x15cm) and a three-channel timer was started. Each mouse was uously observed for min and the ing behaviors were recorded by observers d to the treatments: 1) 2O latency to clonic convulsions that persist for 3 sec and followed by an absence of righting reflex 2) latency to tonic convulsions, 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 analysis of variance with Dunnett's or Bonferroni's post-hoc test was used to detect significant differences in y and number between the vehicle 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" tes 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 compounds at GABAA-R.

SA-23 C D SA-16 C D For Table 3. GABAA receptors (X16272 and 0L4B38 %efficacy: "A" 10-100, "B" >100-500, "C" >500; D indicates the data is not ble 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. Minimal effective anticonvulsant doses are defined as the lowest dose which significantly s 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, employed in, or otherwise relevant to a given product or process unless indicated to the ry 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 es embodiments in which more than one, or all of the group members are present in, ed in, or otherwise relevant to a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For e, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is ent on the same base claim. Where elements are ted as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are ed to as comprising particular elements and/or es, certain embodiments of the invention or aspects of the ion consist, or consist essentially of, such elements and/or features. For es of simplicity, those embodiments have not been ically set forth in haec verba herein. 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 ed. Furthermore, 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 embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context 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 specification, the specification shall control. 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 reason, whether or not d 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 ic embodiments described herein. The scope of the t embodiments described herein is not ed to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the ing claims.

Other embodiments of the invention as described herein are defined in the following paragraphs: 1. A compound of Formula (I): or a pharmaceutically able salt thereof; 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 substituted or unsubstituted C3-6 carbocyclyl; 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 l, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl; R3a is en 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 unsubstituted C3-6 carbocyclyl, and R3b is hydrogen; 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 n 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; each instance of R5, R6, and R7 is, ndently, hydrogen, n, -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, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, or substituted or unsubstituted 3- to 6- membered heterocylyl; each instance of RGA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or tituted C3-6 ylyl, substituted or unsubstituted 3- to 6- ed 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 ening atoms to form a substituted or unsubstituted cylyl 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, 3, haloalkyl, e.g., -CF3) , wherein RGA is substituted or tituted 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, -N(RGA)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 tituted 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, wherein 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, 3, –CH2CH2CH3, substituted or unsubstituted cyclopropyl, fluoro, or chloro. 11. The compound of aph 10, wherein R2 is –CH3 or –OCH3. 12. The compound of paragraph 11, wherein R2 is –OCH3. 13. The compound of paragraph 1, n R2 is hydrogen. 14. The compound of paragraph 1, wherein R3a and R3b are both hydrogen.

. The compound of paragraph 1, wherein represents a single bond, and both of R4a and R4b are hydrogen. 16. The compound of paragraph 1, wherein represents a single bond, and both of R4a and R4b are fluoro. 17. The compound of paragraph 1, wherein represents a single bond, and R4a is hydrogen, fluoro, -CH3, or -CF3. 18. The compound of paragraph 1, wherein represents a single bond, and R4a is tuted or unsubstituted C1-6 alkyl, or halogen, and R4b is en. 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 paragraph 1, wherein at least two of R5, R6, and R7 are hydrogen. 22. The compound of paragraph 1, n 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, n RGA is substituted or tituted 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 -S(=O)2RGA. 27. The compound of paragraph 25, wherein RGA is –CH3. 28. The compound of aph 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, -S(=O)2ORGA, -OS(=O)2RGA, 2N(RGA)2, substituted or unsubstituted C1-6 alkyl (e.g., -CH3, -CH2CH3, haloalkyl, e.g., -CF3) , wherein RGA is tuted or unsubstituted C1-2 alkyl.

. The nd 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 substituted or unsubstituted C1-2 alkyl. 31. The compound of paragraph 29, wherein R6 is halogen (e.g., -F, -Cl, -Br), -NO2, –CN, or substituted or unsubstituted C1-6 alkyl (e.g., -CH3, -CH2CH3, haloalkyl, e.g., -CF3) , wherein RGA is substituted or tituted C1-2 alkyl. 32. The compound of paragraph 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, n at least five of R2, R3a, R3b, R4a, R4b, R5, R6, and R7 are hydrogen. 36. The compound of paragraph 35, wherein , R6 is halogen (e.g., -F, -Cl, -Br), -NO2, -CN, -C(=O)RGA, -C(=O)ORGA, -SRGA, -S(=O) RGA, -S(=O)2RGA, tuted or unsubstituted C1-6 alkyl (e.g., -CH3, -CH2CH3, haloalkyl, e.g., -CF3) , wherein RGA is substituted or unsubstituted C1-2 alkyl. 37. The compound of aph 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 tuted 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 paragraph 2, n the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and 42. The compound of aph 3, wherein the compound 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, comprising administering to the subject an effective amount of a compound of any one of aphs 1 to 19, or a pharmaceutically 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 convulsive disorder, a disorder of memory and/or cognition, a movement er, a personality disorder, autism um 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 nd is administered orally, subcutaneously, intravenously, or intramuscularly. 47. The method of paragraph 44 wherein the nd is administered chronically.

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

Claims (26)

What we claim is:

1. Use of a ceutically acceptable salt of a compound of the formula: H H H H HO H in the manufacture of a medicament for treating a mood disorder in a human subject.

2. Use of a compound of the formula: H H H H HO H in the manufacture of a ment for treating a mood disorder in a human subject.

3. The use of claim 1 or claim 2, wherein the mood disorder is depression.

4. The use of any one of claims 1 to 3, wherein the medicament is formulated for oral, subcutaneous, intravenous, or intramuscular administration.

5. The use of claim 4, wherein the medicament is ated for oral administration.

6. The use according to any one of claims 1-5, wherein the mood disorder is postnatal depression.

7. Use of a pharmaceutically acceptable salt of a compound of the formula: H H H H HO H in the manufacture of a medicament for modulating a GABAA receptor in a human subject.

8. Use of a compound of the formula: H H H H HO H in the manufacture of a medicament for ting a GABAA receptor in a human subject.

9. The use of claim 7 or claim 8, wherein the nd affects the GABAA receptor in a positive manner.

10. The use of any one of claims 7 to 9, wherein the subject has a mood disorder.

11. The use of claim 10, wherein the mood disorder is depression.

12. The use of any of claims 7 to 11, wherein the medicament is formulated for oral, subcutaneous, intravenous, or uscular administration.

13. The use of claim 12, n the medicament is formulated for oral administration.

14. Use of a pharmaceutically acceptable salt of a compound of the formula: H H H H HO H in the manufacture of a medicament for treating tremor in a human subject.

15. Use of a compound of the formula: H H H H HO H in the manufacture of a ment for treating tremor in a human subject.

16. The use of claim 14 or claim 15, wherein the ment is formulated for oral, subcutaneous, intravenous, or intramuscular administration.

17. The use of claim 16, wherein the medicament is formulated for oral administration.

18. The use according to claim 1 or claim 2, wherein the mood er is generalized anxiety

19. The use of claim 18, wherein the medicament is formulated for oral, subcutaneous, intravenous, or intramuscular administration.

20. The use of claim 19, wherein the medicament is formulated for oral administration.

21. The use according to claim 1 or claim 2, wherein the mood disorder is bipolar disorder.

22. The use of claim 21, wherein the bipolar disorder is bipolar I.

23. The use of claim 21, wherein the bipolar disorder is bipolar II.

24. The use of any one of claims 21-23, wherein the ment is formulated for oral, subcutaneous, intravenous, or intramuscular administration.

25. The use of claim 24, wherein the medicament is formulated for oral administration.

26. The use according to any one of claims 1-5, wherein the mood disorder is major depressive disorder. SAGE THERAPEUTICS INC. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: