NZ712156B2 - Neuroactive steroids, compositions, and uses thereof - Google Patents

Abstract

Provided are methods of evaluating or treating a patient, e.g., a patient having a disorder described herein, comprising: a) optionally, acquiring a patient sample; b) acquiring an evaluation of and/or evaluating the sample for an alteration in the level 24(S)- hydroxycholesterol compared to a reference standard; and c) administering a compound of formula (I-w). ence standard; and c) administering a compound of formula (I-w).

Description

NEUROACTIVE STEROIDS, ITIONS, AND USES THEREOF RELATED APPLICATIONS {0001] The present application claim priority under 35 U.S.C. § ll9(e) to US. ional patent application U.S.S.N 61/780,671, filed March 13, 2013, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION {0002] Brain excitability is defined as the level of arousal of an animal, a uum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are sible 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 interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (Kt Na+, Cl-, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released as a result of neuronal action ials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from -70 inV to -50 mV). This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase the membrane permeability ofNa+ ions. The reduced membrane potential increases the probability of generating a postsynaptic action potential, which s to an increase in neuronal excitability. {0003] NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission. Activating these receptors butes to synaptic plasticity in some circumstances and excitotoxicity in others. These receptors are —gated ion ls that admit Ca2+ after g of the neurotransmitters glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function. NMDA receptors are meric complexes comprised of NRl and/or NR3 subunits and possess , NR2, ct recognition sites for ous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. Positive modulators may be useful as therapeutic agents with potential clinical uses as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or defective (see, eg, Horak et al., J. oscience, 2004, 24(46), 10318-10325). In WO 60441 contrast, negative modulators may be useful as therapeutic agenst with ial clinical uses in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (6g, treatment resistant depression). {0004] Neuroactive steroids such as nolone sulfate (PS) have been shown to exert direct modulatory effects on several types of neurotransmitter receptors, such as GABAA, glycine, AMPA, kainate, and NMDA receptors. NMDA receptors are positively modulated by PS; however, the degree of modulation varies considerably, cg, depending upon the subunit composition of the receptor. {0005] In addition to PS, several other r0xy steroids have been shown to potentiate NMDA receptors (see, cg, Paul et al, J. Pharm. and Exp. Ther. I994, 27l, 677- 682; Madau et al., Program No. B87. 2009 Neuroscience Meeting Planner. o, IL: Society for Neuroscience, 2009; Connick et al., Program No. 613.1/B86. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009; Paul el al., J.

Neurosci. 2013, 33, l7290-l7300).

SUlVIlWARY OF THE INVENTION {0006] Described herein are, inter alia, methods of evaluating or treating a t, eg, a patient having a er described herein, comprising: a) optionally, acquiring a patient ; b) acquiring an evaluation of and/or evaluating the sample for an tion in the level 24(8)-hydroxycholesterol compared to a reference rd. In certain embodiments, the methods further comprise stering to the t an effective amount of 24(8)- hydroxycholesterol or a structurally-related sterol or steroid, an oxysterol, an agonist of an NMDAR or a positive allosteric modulator (PAM) of an NMDAR. or a compound described herein such as a compound of formula (I). In certain embodiments, the methods further comprise administering to the patient an effective amount of an antagonist of an NMDAR or a negative allosteric modulator (NAM) of an NMDAR. or a compound described herein such as a compound of formula (I). In some ments, the method further comprises administering to a subject a compound that augments (6g, increases) the endogenous activity or amount of 24(s)- hydroxycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for example, a compound that inhibits 24- hydroxycholesterol 7alpha-hydroxylase (CYP39). In some embodiments, the method further comprises administering to a subject a compound that reduces the endogenous activity or amount of 24(s)-hydroxycholesterol, such as a compound that activates an enzyme that produces 24(s)- liydroxycholesterol, for example, a compound that activates cholesterol 24(S)-hydroxylase ). {0007] In certain embodiments, the hydroxycholesterol structurally-related sterol or steroid, or oxysterol is naturally occurring compound (eg, a compound that is naturally occurring in the brain of a subject) such as a naturally occurring sterol or steroid. In some ments, the method comprises stering to the t 24(S)—hydroxycholesterol.

In some embodiments, the method comprises administering to the subject a compound described herein such as a nd ofFormula (l). In certain embodiments, the method comprises administering to the patient an effective amount of an antagonist of an NMDAR or a negative allosteric modulator (NAM) of an NMDAR, or a compound described herein such as a compound of formula (I). In some ments, the method ses administering to a subject a compound that augments (6g, increases) the endogenous activity or amount of 24(s)- hydroxycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for e, a compound that inhibits 24—hydroxycholesterol 7alplia-hydroxylase (CYP3 9). In some embodiments, the method comprises stering to a subject a compound that reduces the endogenous activity or amount of 24(5)- hydroxycholesterol, such as a compound that activates an enzyme that produces 24(5)- ycholesterol, for example, a compound that activates cholesterol 24(S)-liydroxylase (CYP46). {0008] In some embodiments, the 24(S)—hydr0xycholesterol is compared to a reference rd wherein the reference standard is a standard previously acquired from the patient. In some embodiments, the reference standard is an external nce standard not associated with a patient sample (6g, a universal standard or a standard from a treatment and/or diagnosis guideline).

In some ments, when the level of 24(S)-hydroxycholesterol is reduced relative to a standard, the method is indicative that the patient is a suitable candidate for treatment with 24(S)-hydroxycholesterol or a structurally-related sterol or steroid, an oxysterol, an agonist of an NMDAR or a positive allosteric modulator (PAM) of an NMDAR, a compound that augments (6g. increases) the endogenous activity or amount of 24(s)- hydroxycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for example, a compound that inhibits 24-hydroxycholesterol 7alpha-hydroxylase (CYP3 9) or a compound described herein such as a compound of formula (I). In certain embodiments, when level of 24(S)-hydroxycholesterol is elevated relative to a reference standard, the method is tive the patient is a suitable candidate for treatment with an antagonist of an NMDAR, a negative eric modulator (NAM) of an NMDAR, or a compound that reduces the endogenous ty or amount of 24(s)—hydroxycholesterol, such as a compound that activates an enzyme that produces 24(s)— hydroxycholesterol, for example, a compound that activates cholesterol 24(S)-hydroxylase (CYP46). In certain embodiments the method further comprises administering to the patient an effective amount of 24(8)- hydroxycholesterol or a structurally-related sterol or steroid, an oxysterol, an agonist of an NMDAR or a positive eric modulator (PAM) of an NMDAR, a compound that augments (6g. increases) the endogenous activity or amount of 24(s)- hydroxycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for example, a compound that inhibits 24-hydroxycholesterol 7alpha-hydroxylase (CYP3 9), or a compound described herein such as a compound of formula (I). In certain embodiments the method r comprises withholding treatment of the patient with of 24(8)- hydroxycholesterol or a urally-related sterol or steroid, an oxysterol, an agonist of an NMDAR or a positive allosteric modulator (PAM) of an NMDAR, a compound that augments (rag, increases) the endogenous activity or amount of 24(s)- hydroxycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for example, a compound that inhibits 24-hydroxycholesterol 7alpha-hydroxylase (CYP3 9), or a nd described herein such as a compound of formula (I). In certain embodiments, the method further comprises administering to the patient an effective amount an antagonist of an NMDAR or a negative allosteric modulator (NAM) of an NMDAR, a compound that reduces the endogenous activity or amount of 24(s)-hydroxycholesterol, such as a compound that activates an enzyme that produces 24(s)— hydroxycholesterol, for example, a nd that activates cholesterol 24(S)-hydroxylase (CYP46), or a nd described herein such as a compound of formula (I). {0009] In some embodiment, when level of hydroxycholesterol is elevated relative to a reference standard or reduced relative to a reference standard, the patient is further evaluated for a mutation or polymorphism in a biosynthetic enzyme invoved in the synthesis or metabolism of ydr0xycholesterol. In some embodiments, when level of 24(8)- hydroxycholesterol is elevated relative to a reference standard or reduced relative to a nce standard, the patient is determined to have a on or polymorphism in a biosynthetic enzyme d in the synthesis or lism of 24(s)hydr0xycholesterol. {0010] In certain embodiments, the level of 24(S)-hydroxycholesterol is measured by evaluation of the level 24(S)-hydroxychoiesterol or a fragment or metabolite thereof in a subject. In certain embodiments, the level of 24(S)-hydroxycholesterol is measured by chromatographic (3g, HPLC), spectroscopic (cg, MS) or nuclear magnetic resonance (NMR) methods. {0011] In certain embodiments, the patient sample is a fluid , eg. a blood sample. In n embodiments, the patient sample is a biopsy, 8g, a brain biopsy, isolate, or surgical specimen. In certain embodiments, the patient sample is acquired prior to administration of a therapy.

In certain embodiments, a first y is administered before evaluation of the patient and/or administration of 24(Sf)-hydroxycliolesterol or a structurally-related sterol or steroid, an oxysterol, an agonist of an NMDAR or a ve allosteric modulator (PAM) of an NMDAR, a compound that augments (cg, ses) the endogenous activity or amount of 24(5)— hydroxycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)— hydroxycholesterol, for example, a compound that inhibits 24-hydroxycholesterol 7alphahydroxylase (CYP39), or a compound described herein such as a nd of formula (I).

In certain embodiments, the patient sample is acquired after administration of the therapy other than administration of 24(8)-liydroxycholesterol or a structurally-related sterol or steroid, an oxysterol, an agonist of an NMDAR or a positive eric modulator (PAM) of an NMDAR, a compound that augments (6g, increases) the endogenous ty or amount of 24(s)- hydroxycholesterol, such as a nd that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for example, a compound that inhibits 24-hydroxycholesterol 7alpha-hydroxylase (CYP3 9), or a compound described herein such as a compound of a (I). In certain embodiments, a first therapy is administered before evaluation of the patient and/or administration of an antagonist of an NMDAR or a negative allosteric modulator (NAM) of an NMDAR, a compound that reduces the endogenous activity or amount of 24(s)—hydroxycholesterol, such as a compound that activates an enzyme that produces 24(s)— hydroxycholesterol, for example, a compound that tes cholesterol 24(S)-hydroxylase (CYP46), or a compound bed herein such as a compound of formula (I). In certain embodiments, the patient sample is acquired after administration of the therapy other than administration of an nist of an NMDAR or a ve allosteric modulator (NAM) of an NMDAR, a compound that s the endogenous activity or amount of 24(s)- hydroxycholesterol, such as a compound that activates an enzyme that produces 24(s)— hydroxycholesterol, for example, a compound that activates cholesterol 24(S)-hydroxylase (CYP46), or a nd described herein such as a compound of formula (I). {0012] In one aspect, also described herein are kits or ts comprising a plurality of agents capable of interacting with 24(S)—hydroxycholesterol. In certain embodiments, the agent is an NMDAR or NMDA. In some embodiments, an agent is comprises a label such as a radioactive or fluorescent label. In some embodiments, the agent is a probe that interacts with hydroxycholesterol. {0013] In certain embodiments, the 24(8)-hydroxycholesterol is derived from a patient sample, cg, blood, plasma, serum, cerebrospinal fluid, circulating, and interstitial fluid levels or surgical en. {0014] In certain ments, a value for the level of 24(S)—hydroxycholesterol is determined. In certain embodiments, the value is compared to a reference standard, eg, the level of 24(LS)—hydroxycholesterol a patient sample. {0015] In one aspect, also described herein are methods of assaying in a subject sample the level of 24(S)—hydroxycholesterol; comprising an agent capable of interacting with 24(8)- hydroxycholesterol (6.3., a probe, NMDA, or an NMDAR); and wherein the method comprises assaying the level of 24(S)-hydroxycholesterol. {0016] In certain embodiments, the 24(S)-hydroxycholesterol is derived from a patient sample, cg, blood, , serum, ospinal fluid, circulating, and titial fluid levels or surgical en. {0017] In certain embodiments, a value for the level of 24(S)-hydroxycholesterol is determined. In n embodiments, the value is compared to a reference standard, e.g., the level of 24(S)-hydroxycholesterol a patient sample. {0018] In one aspect, also described herein are reaction mixtures comprising: comprising 24(S)-hydrox_vcholesterol and an agent e of interacting with 24(S)-hydroxycholesterol (e.g., a probe, NMDA, or an NlVIDAR). {0019] In one aspect also described herein are s of making a reaction mixture comprising: ing 24(S)—hydroxycholesterol with an agent capable of interacting with 24(8)- hydroxycholesterol (e.g., a probe, NMDA, or an NMDAR). {0020] New compounds described herein are potential NMDA receptor modulators (e.g., a positive allosteric modulator (116., a PAM) or a negative allosteric modulator (116., a NAM» and compounds that increase or decrease the endogenous activity of 24(8)— hydroxycholesterol and thus are useful for preventing and/or treating a broad range of CNS- related conditions, including but not d to schizophrenia, depression, bipolar disorder (cg, I and/or II), schizoaffective disorder, mood disorders, y ers, personaiity disorders, psychosis, compuisive disorders, post-traumatic stress disorder (PTSD), Autism spectrum disorder (ASD), dysthymia (mild depression), social anxiety disorder, obsessive compulsive disorder (OCD), pain (cg, a painful syndrome or disorder), sleep disorders, memory disorders (cg, memory impairment), dementia, Alzheimer‘s Disease, a seizure disorder (cg, epilepsy), traumatic brain injury, stroke, addictive disorders (eg, addiction to opiates, e, and/or alcohol), autism, Huntington's Disease, insomnia, Parkinson's disease, withdrawal syndromes, or us. These compounds are expected to show improved in viva potency, cohinetic (PK) properties, oral bioavailability, formuiatabiiity, stability, and/or safety. In some embodiments, a compound described herein can be used to improve learning. In some embodiments, a compound bed herein can be used to treat an overdose, 8g, a drug overdose such as a ketainine or PCP overdose. {0021] The s described herein cg, methods of evaiuation and treatment can be used with a compound described herein. Exemplary compounds described herein include an t of an NMDAR or a positive ailosteric modulator (PAM) of an NMDAR. In some ments, a compound described herein is a ve allosteric moduiator (NAM) of an NMDAR. Compounds described herein also include naturaliy and non-naturally occurring steroids and sterols such as 24(S)—hydrxchoiesterol. In some embodiments, the compound is an oxysterol. In some embodiments, the compound is a 3-[3 hydroxyl steroid with a C-l 7 B side alkyl side chain and optionai substitutions at various positions of the steroid ld, as shown in the compound of Formula (I). In some embodiments, the methods are used with a nd that augments (cg, ses) the endogenous activity or amount of 24(3)- hydroxycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for exampie, a compound that inhibits 24-hydroxycholesteroi 7alphahydroxylase (CYP39) or a compound that reduces the endogenous activity or amount of 24(s)-hydroxycholesterol, such as a compound that activates an enzyme that produces 24(5)- hydroxycholesterol, for e, a compound that activates cholesterol 24(S)-hydroxylase (CYP46). {0022] In some embodiments, the nd used in a method described herein, e.g., a method of evaluation or treatment described herein is a nd according to Formula (I): or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, ic variant, or N—oxide thereof, or a combination thereof; wherein: Z is a group of the formula (i), (ii), (iii), (iv), or (V): R1 R1 R20 " L2"OR24 "bub. L1_<_x2_R24 Rm (1), m (ii), L3 0 L3 R26 L3 R26 v.11. Y/ ~51,/ XYRZS at" Y/ RZ4 (iii), R26 (iv), or YR25 (v); R", R", R19, R20, R23", Rm, and R24 are as defined herein; and the group —XR3b at the C3 position is alpha or beta. {0023] For example, in certain embodiments, the compound of Formula (I) is of Formula (I-w): R11a Z Rea (LI-w) or a pharmaceutically acceptable salt thereof; wherein: Z is a group of the formula (i), (ii), (iii), (iv), or (v): R1 R1 R20 " L2~OR24 m L1.‘<‘X2"R24 R" (i), "in (ii), 1'11/L3\f0 /L3 R26 ""9 "mg/L3 R24 (iii), R215; @3ng "(In {0029] In certain embodiments, L3 is a group of formula: F F 3 g F F MAO/\f’ my/LOAJAI‘; MAO/\g‘: 1%onA; , R/xoxfj , aiOX3’R/OW;’ a/Voya 1.75/0foF F F F F F WYY/OVFYWF Y/O ‘5?) O 1.77 Y O 157 F F Y f\/O\fr ‘L'u/OW/E’ B570}; R/LYO {0030] In certain ments, Z is of formula R24 L O 157/ Y {0031] In certain ments, the group R24 is of the formula: F F RAG/\n/CFS MAO/\n/CFa /CFs M/\O> "H1?/\O /'\ Pr 0 O /\[01/ IPI" O/T 9 ’ 7 7 u! F F F F . /LF F OWIPr "kg/\OWP‘F. .

"RAG/firipr "Hy/\Oxl/Pr "'19 O O O O a : 9 a 2014/026633 F F F fi/OWCFS R/OWCFGI bra/0W5?" "Hy/OWE 0 O 0 , , , 7 HI Tl .n En? En) fr‘0; F0} 3 O O 9 a a o o 0 2 15'68kCF3 ‘11, CF RMCF "a, CF3 o 5 o z o 0 "H17 CF8 "a, CF3 RAM RMIPT o o o 2 O : a/E\/U\ipr fl/VkiPr 1% iPr "Hg iPr F F F F 3 3 , , 0r 0 /L3 R26 "1'7 YRZS {0032] In certain embodiments, Z is of formula R26 {0033] In certain embodiments, wherein Y is —O— and L3 is an aikyiene 0r heteroalkylene group. m/LXYRZS {0034] In certain embodiments, the group R26 is of the formula: "aw/Om] H ’a/‘o/WQH) 31/wa .nqu /L3 R25 {0035] In certain embodiments, Z is of formula YRZS {0036] In certain embodiments, Y is —O— and L3 is an alkyiene or heteroalkylene.

L3 R26 a/ Y {0037] In certain embodiments, the group YRZS is of the formula: OH 5H OH OH ornth/OW. {0038] In certain embodiments, the group —X1R3b is in the beta position, and R321 is in the alpha position. In n embodiments, —X1R3b is —OH. In n embodiments, R3a is en. In certain embodiments, R33 is substituted or unsubstituted aikyl. In certain embodiments, R6b is halogen or substituted or unsubstituted alkyl. In certain embodiments, R2 is hydrogen or —ORBI. In certain embodiments, R"b is en or —ORBl, and Rm is hydrogen. In certain embodiments, R"3 and R111) together form an 0x0 group. In certain embodiments, """ represents a single bond, and the hydrogen at C5 is in the alpha position. In certain embodiments, represents a double bond. In certain embodiments, R19 is —CH3. {0039] In r aspect, provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceuticaliy acceptable carrier. In certain embodiments, the compound of the present invention is ed in an effective amount. In certain embodiments, the compound of the present invention is provided in a therapeuticaliy effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount. {0040] In certain s, compounds of the present invention are provided as negative allosteric modulators (NAM) ofNMDA receptor and thus are useful for ting and/or treating a broad range ofCNS conditions inciuding but not iimited to schizophrenia, depression, bipolar disorder (I and II), schizoaffective disorder, mood disorders, y disorders, personality disorders, psychosis, compulsive disorders, post—traumatic stress disorder (PTSD), Autism um disorder (ASD), dysthymia (mild depression), sociai anxiety disorder, obsessive compulsive disorder (OCD), all pain syndromes and disorders, sleep disorders, memory disorders and dementia including Alzheimer’s Disease, epilepsy and any seizure ers, traumatic brain injury (TBI), stroke, addictive disorders including opiates and cocaine and alcohol, autism, Huntington's Disease, ia, Parkinson‘s disease, awal syndromes, or tinnitus. For example, in one aspect, provided is a method of NMDA or modulation comprising stering an effective amount of a compound of the present invention to a subject in need thereof. In another aspect, provided is a method of ting CNS-activity comprising administering an effective amount of acompound of the present invention to a subject in need thereof. In yet another aspect, provided is a method of modulating brain excitability comprising administering an effective amount of a compound of the present ion to a subject in need thereof.

Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description, examples, and . [0041a] A definition of the specific embodiment of the invention as claimed herein follows. [0041b] In a broad format, the ion provides use of a compound of Formula (I-w): or a pharmaceutically acceptable salt thereof; wherein: Z is a group of the formula (i), (ii), (iii), (iv), or (v): (i), (ii), (iii), (iv), or (v) L1 and L2 are selected from a group consisting of a bond, a substituted or unsubstituted C1–C6 alkylene, a substituted or unsubstituted C2–C6 alkenylene, substituted or unsubstituted C2–C6 alkynylene, a substituted or unsubstituted hetero C1– C6 ne, a substituted or unsubstituted hetero C2–C6 alkenylene, and a tuted or unsubstituted hetero C2–C6 alkynylene; L3 is a substituted or unsubstituted C1–C6 alkylene, a substituted or unsubstituted C2–C6 alkenylene, substituted or tituted C2–C6 alkynylene, a substituted or unsubstituted hetero C1–C6 alkylene, a substituted or unsubstituted hetero C2–C6 alkenylene, or a substituted or unsubstituted hetero C2–C6 alkynylene; each instance of X1 and X2 is ndently –O–, –S–, or –NH–; R1 is hydrogen or substituted or unsubstituted alkyl; R3b is hydrogen; R3a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or tuted or unsubstituted alkynyl; each instance of R2, R11a, and R11b is independently hydrogen or –ORB1, wherein wherein RB1 is hydrogen or substituted or unsubstituted alkyl, or R11a and R11b are joined to form an oxo (=O) group; each of R6a and R6b is independently hydrogen, halo, or substituted or unsubstituted alkyl, and represents a single or double bond, ed if a double bond is present, then one of R6a or R6b is absent, and provided if a single bond is present, then the hydrogen at C5 is in the alpha or beta position; each instance of R19 and R20 is independently hydrogen or –CH3; and each instance of R23a and R23b is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R23a and R23b are joined together to form substituted or unsubstituted C3–C6 cycloalkyl; R24 is hydrogen or substituted or unsubstituted alkyl; Y is –O–, –S–, or –NRZ5–; RZ4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted l, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORZ5, –SRZ5, or –N(RZ5)2; each instance of RZ5 is independently en or substituted or unsubstituted alkyl; each ce of RZ6 is independently hydrogen or substituted or unsubstituted alkyl, or two RZ6 groups are joined to form a C3–6 carbocyclic ring; and the subscript n is 0 or 1; in the manufacture of a ment for treating a disorder in a patient where a sample from the t has been acquired, and the level of 24(S)-hydroxycholesterol in the sample has been ted and determined to be lower than the level of hydroxycholesterol in a previous sample from the patient. [0041c] In a broad , the invention also provides a use of a compound of a (I-w) or pharmaceutically acceptable salt thereof in the manufacture of a medicament for ng a central nervous system (CNS) disease or disorder related to NMDA receptor modulation in a t having an alteration in the level of 24(S)-hydroxycholesterol in a sample from the patient ed to a reference standard from a treatment and/or sis guideline; wherein the compound of Formula (I-w) has the structure: R11a Z R11b R3b X1 R6a R6b or a pharmaceutically acceptable salt thereof; wherein: Z is a group of the formula (iii), (iv), or (v): L3 O L3 RZ6 L3 RZ6 YRZ5 RZ4 RZ6 or YRZ5 (iii), (iv), (v) L3 is a substituted or unsubstituted C1–C6 alkylene, a substituted or unsubstituted C2– C6 alkenylene, substituted or unsubstituted C2–C6 alkynylene, a substituted or unsubstituted hetero C1–C6 alkylene, a substituted or unsubstituted hetero C2–C6 alkenylene, or a substituted or unsubstituted hetero C2–C6 alkynylene; X1 is –O–, –S–, or –NH–; R3b is hydrogen; R3a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; each instance of R2, R11a, and R11b is independently hydrogen or –ORB1, n wherein RB1 is hydrogen or substituted or unsubstituted alkyl, or R11a and R11b are joined to form an oxo (=O) group; each of R6a and R6b is independently en, halo, or tuted or unsubstituted alkyl, and represents a single or double bond, provided if a double bond is present, then one of R6a or R6b is , and provided if a single bond is t, then the hydrogen at C5 is in the alpha or beta position; R19 is hydrogen or –CH3; Y is –O–, –S–, or –NRZ5–; RZ4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, tuted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –ORZ5, –SRZ5, or –N(RZ5)2; each instance of RZ5 is independently hydrogen or substituted or tituted alkyl; and each instance of RZ6 is independently hydrogen, or two RZ6 groups are joined to form a C3–6 carbocyclic ring; wherein each of said substituted C1–C6 alkylene, substituted C2–C6 alkenylene, substituted C2–C6 alkynylene, substituted hetero C1–C6 alkylene, substituted hetero C2–C6 lene, substituted hetero C2–C6 alkynylene, substituted alkyl, substituted alkenyl andsubstituted l is independently substituted with one or more halogen, C1-10 alkyl, - OH, ORaa, -N(Rbb)2; wherein Raa is C1-10 alkyl; and each Rbb is independently hydrogen or C1-10 alkyl.

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 n, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein.

Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University e Books, Sausalito, 1999; Smith and March, s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge sity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a e of stereoisomers, ing racemic mixtures and mixtures enriched in one or more isomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and tions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and l Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described 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 intended to encompass each value and sub–range within the range. For example "C1–6 alkyl" is intended to encompass, C1, C2, C3, [Followed by page 17] PCT /0S2014/026633 C4, Cs, C6, C1-6, C1-s, C1--4, C1-3, C1-2, C2---6, C2-s, C2--4 , C2-3, C3---6, C3_5, C3--4 , C+-6, C4-- s, and Cs-6 alkyl.

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, ceutical compositions containing such compounds and methods of using such nds and compositions, the ing tenns, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless ise , the term "substituted" is to be defined as set out below. It should be fmther understood that the terms "groups" and "radicals" can be considered interchangeable when used herein. The es "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 ue or more than one analogue.

"Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from l to 20 carbon atoms ("C1_20 alkyl"). In some ments, an alkyl group has l to 12 carbon atoms ("C1_12 alkyl"). In some ments, 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_8 alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1_7 alkyl"). In some embodiments, an alkyl group has l to 6 carbon atoms ("C1_6 alkyl", also ed to herein as "lower alkyl"). In some embodiments, an alkyl group has l to 5 carbon atoms ("C1-s alkyl"). In some embodiments, an alkyl group has l to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1_3 alkyl"). In some embodiments, an alkyl group has l to 2 carbon atoms ("C1_2 alkyl"). In some embodiments, an alkyl group has l carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2---6 alkyl"). es of C1_6 alkyl groups include methyl (C1), ethyl (C2), n propyl- (C3), isopropyl (C3), n butyl- (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n pentyl- (Cs), 3 pentanyl- (Cs), amyl (Cs), neopentyl (Cs), 3 methyl- butanyl (C5), ry amyl (C5), and n hexyl- (C6). Additional examples of alkyl groups include n heptyl- (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents; e.g., for instance from I to 5 substituents, I to 3 substituents, or I substituent. In certain embodiments, the alkyl group is unsubstituted C140 alkyl (cg, —CH3). In certain embodiments, the alkyl group is substituted CHQ alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CHQCHg), iPr (-CH(CH3)2), nPr (-CHzCH3CH3), n—Bu (-CHZCH2CH3CH3), or i-Bu (-CH;CH(CH3)2). {0047] As used herein, "alkylene," "alkenylene," and ylene," refer to a divalent radical of an alkyl, alkenyl, and l group, respectively. When a range or number of carbons is provided for a particular "alkylene, )3 csalkenylene," and "alkynylene" group, it is tood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. "Alkylene," "alkenylene," and "alkynylene" groups may be substituted or unsubstituted with one or more substituents as described . {0048] "Alkylene" refers to an alkyl group wherein two hydrogens are d to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not d to, methylene (-CH2-), ethylene ('CHQCHQ'), propylene (-CHzCHgCH3-), butylene HgCHzCH3-), pentylene (-CHZCH2CH2CH3CH3- ), ne (-CHZCH2CH2CH3CH3CHg-L and the like. ary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, e but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), tuted ethylene (-CH(CH3)CH3-,- CH2CH(CH3)-, —C(CH3)2CH2-,-CH3C(CH3)3-), substituted propylene (-CH(CH3)CH3CH2-, - CHZCH(CH3)CH2—, —CH2CH3CH(CH3)-, -C(CH3);CH;,CH2-, -CH2C(CH3)3CH2-, - CH2CH2C(CH3)3—), and the like. {0049] "Alkenyl" refers to a radical of a ht—chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon—carbon double bonds (eg, I, 2, 3, or 4 double bonds), and no triple bonds ("Cargo l"). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C240 alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("CH alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("CH alkeny "). In some embodiments, an l group has 2 to 7 carbon atoms ("C34 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("CH alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("CH alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("CH alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C34 alkenyl").

In some embodiments, an alkenyl group has 2 carbon atoms ("C3 alkenyl"). The one or more carbon—carbon double bonds can be internal (such as in 2—butenyl) or terminal (such as WO 60441 in l—butenyi). Examples ofCH ailrenyi groups include ethenyi (C2), l—propenyi (C3), 2— propenyl (C3), l—butenyi (C4), 2—butenyl (C4), butadienyl (C4), and the like. Examples of C2, 6 alkenyl groups inciude the aforementioned CH aikenyi groups as weli as yi (C 5), pentadienyl (C5), hexenyl (C6), and the like. onal examples of alkenyl include heptenyl (C7), octenyi (Cs), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, 116., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted aikenyi") with one or more substituents cg, for instance from 1 to 5 substituents, l to 3 substituents, or 1 substituent. In certain embodiments, the aikenyl group is unsubstituted C240 alkenyi. In certain embodiments, the alkenyl group is substituted (32,10 alkenyl. {0050] "Alkenylene" refers to an all In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkyiiyl"), The one or more —carbon triple bonds can be internal (such as in 2—butynyl) or terminal (such as in l— butynyl). es ofCH alkynyl groups include, without limitation, ethynyl (C2), 1— propynyl (C3), 2—propynyl (C3), l—butynyl (C4), nyl (C4), and the like. Examples of CH alkenyl groups include the aforementioned CH alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of l include heptynyl (C7), octynyl (C3), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.€., unsubstituted (an "unsubstituted alkynyl") or tuted (a "substituted alkynyl") with one or more tuents; e.g., for instance from I to 5 substituents, l to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted CHO alkynyl. In certain embodiments, the alkynyl group is substituted C3,") alkynyl. {0052] "Alkynylene" refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted.

Exemplary divalent alkynylene groups include, but are not limited to, tuted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. {0053] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined , which further comprises 1 or more (6g, 1, 2, 3, or 4) heteroatoms (6g, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is ed between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, 116., between the point of ment. In certain embodiments, a heteroalkyl group refers to a saturated group having from l to l0 carbon atoms and l, 2, 3, or 411eteroatoms roCHo alkyl"). In some embodiments, a heteroalkyl group is a ted group having 1 to 9 carbon atoms and l, 2, 3, or 4 heteroatoms ("heteroCng alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and l, 2, 3, or 4 heteroatoms ("heteroCH allryl"). In some embodiments, a heteroalkyl group is a saturated group having I to 7 carbon atoms and l, 2, 3, or 4 heteroatoms ("heteroCH allry ") In some embodiments, a heteroalkyl group is a group having I to 6 carbon atoms and l, 2, or 3 heteroatoms ("heteroC H, all Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroaikenyl") with one or more substituents. In certain embodiments, the heteroaikenyi group is an unsubstituted heteroCHo aikenyi. In certain embodiments, the heteroalkenyl group is a substituted heteroCHo alkenyl. {0055] The term "heteroalkynyl," as used herein, refers to an all In some embodiments, a alkynyl group has 2 to 6 carbon atoms, at least one triple bond, and l, 2, or 3 heteroatoms ("heteroCH alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and l or 2 heteroatorns roCH alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms ("heteroCzu alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and l heteroatom ("heteroCH alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and l or 2 heteroatoms ("heteroCH l"). Unless otherwise specified, each instance of a alkynyl group is independently unsubstituted (an stituted lieteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroCHo alkynyl. In certain embodiments, the alkynyl group is a tuted heteroCHO alkynyl. {0056] As used herein, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene," refer to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," or "heteroalkynylene," group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. "Alkylene," "alkenylene,9) (Lalkyiiylene, 9) (Lheteroalkylene," "lieteroalkenylene," and "heteroalkynylene" groups may be substituted or tituted with one or more substituents as described herein. {0057] "‘Aryl" refers to a radical of a monocyclic or polycyclic (cg, bicyclic or tricyclic) 4n+2 aromatic ring system (eg, having 6, 10, or 14 TC electrons shared in a cyclic array) having 6—14 ring carbon atoms and zero atoms provided in the aromatic ring system ("C644 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; cg, plienyl). In some embodiments, an aryl group has ten ring carbon atoms ("C m aryl"; cg, naphthyl such as l—naphthyl and 2—naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C14 aryl"; cg, anthracyl). "Aryl" also includes ring s wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the l or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. l aryl groups include, but are not limited to, groups d from aceanthrylene, acenaphthylene, nanthrylene, anthracene, azulene, benzene, chrysene, coronene, lluoranthene, fluorene, hexacene, hexaphene, ne, as-indacene, cene, indane, indene, alene, octacene, octaphene, octalene, ovalene, penta—2,4-diene, pentacene, pentalene, pentaphene, perylene, plienalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include , naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, 126., 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 substituted CH4 aryl. {0058] In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C3 alkoxy, and amino. {0059] 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-C3 alkyl, C1-C8 haloalkyl, 4-l0 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylarnino, arylamino, heteroarylamino, NRSSCORSQ, NRSSSORS'QNRSSSOQR"‘9, wherein each W is selected from C(R66)2, RR", 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-Cm aryl, and 5-10 membered heteroaryl. {0061] "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. {0062] "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. {0063] "Heteroaryl" refers to a radical of a 5—10 ed monocyclic or bicyclic 4n+2 aromatic ring system (cg, having 6 or 10 n electrons shared in a cyclic array) having ring carbon atoms and l—4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from en, oxygen and sulfur ("5—10 meinbered heteroaiyl"). In aryl groups that contain one or more en atoms, the point of attachment can be a carbon or nitrogen atom, as valency s. Heteroaryl bicyclic ring systems can e one or more heteroatoms in one or both rings. "Heteroaryl" includes ring s 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 heteroaiyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the aryl ring system. "Heteroaryl" also includes ring systems n 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 wherein one ring does not contain a heteroatom (e. 0., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, 116., either the ring bearing a heteroatom (6g, 2—indolyl) or the ring that does not contain a heteroatom (ag, lyl). {0064] In some embodiments, a heteroaryl group is a 5—10 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—10 membered ary "). In some embodiments, a aryl 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 en, , and sulfur ("5—8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5—6 membered aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms ed in the aromatic ring system, wherein each heteroatom is ndently selected from nitrogen, oxygen, and sulfur ("5—6 membered heteroaryl"). In some embodiments, the —6 membered aryl has I—3 ring atoms selected from nitrogen, oxygen, and sulfur. In some ments, the 5—6 membered heteroaryl has 1—2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each ce of a heteroaryl group is ndently optionally substituted, i.€._. unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is tituted 5—l4 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5—14 membered heteroaryl. {0065] Exemplary ered heteroaryl groups containing one heteroatom include, without limitation, pyn‘olyl, furanyl and thiophenyl. Exemplary 5—1nembered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, lyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. ary S—niembered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5—membered aryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6—membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6—membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6—membered heteroaryl groups containing three or four heteroatoms 2014/026633 include, Without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7—membered heteroaryl groups containing one heteroatom e, Without limitation, azepinyl, oxepinyl, and thiepinyl. Exempiary 516—bicyclicheteroaryl groups include, Without iimitation, indolyl, isoindoiyl, indazolyl, riazolyl, benzothiophenyl, isobenzotbiophenyl, benzofuranyl, benzoisofuranyl, idazoiyi, benzoxazolyl, benzisoxazoiyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyi, iadiazolyl, indolizinyl, and purinyl. Exemplary 6,6— bicyclic heteroaryl groups include, Without tion, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazoiinyl. {0066] Examples of representative heteroaryis include the following: Tr} \[SN, at"), {—1he {£le[ND\\ ~93 \ [NJ co\N\ \\ 31:]me M O? wherein each Y is selected from carbonyl, N, NR", 0, and S; and R65 is independently en, C1-C8 alkyl, C3-C10 cycioalkyl, 4-10 membered heterocyclyl, C5-C10 aryl, and 5—H) membered heteroaiyl. {0067] oaralkyl" is a subset of alkyi and heteroaryl, as defined , and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group. {0068] "Carbocyciyi" or "carbocyclic" refers to a radical of a non—aromatic cyclic hydrocarbon group having from 3 to l0 ring carbon atoms ("€340 carbocyclyl") and zero heteroatoms in the non—aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("CH carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3,6 carbocyclyi"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3,6 carbocyclyi"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C540 yclyl"). Exemplary CM carbocyclyl groups include, Without limitation, cyclopropyl (C3), cyclopropenyl (C3), WO 60441 cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C5), cyclohexadienyl (C6), and the like. Exemplary CH carbocyclyl groups include, without limitation, the aforementioned CH carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C 7), eptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.l}heptanyl (C7), bicyclo[2.2.2}0ctanyl (C3), and the like. Exemplary C340 carbocyclyl groups include, without limitation, the aforementioned C342, carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C m), octahydro—lH—indenyl (C9), decahydronaphthalenyl (C10), spiro{4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contain a fused. bridged or spiro ring system such as a ic system clic 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 attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring . Unless otherwise ed, each instance of a carbocyclyl group is ndently optionally substituted, 126., tituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain ments, the carbocyclyl group is unsubstituted C340 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C340 carbocyclyl. {0069] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to l0 ring carbon atoms ("C340 cycloalkyl"). In some ments, a cycloall In n embodiments, the cycloalkyl group is substituted C3,10 lkyl. {0070] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3— to lO—membered non—aromatic ring system having ring carbon atoms and l to 4 ring heteroatoms, n each atom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3—10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency s. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, d or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or can be partially rated. Heterocyclyl bicyclic ring systems can e one or more atoms 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 heterocyclyI 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 heterocyclyi ring, and in such instances, the number of ring members continue to designate the number of ring s in the heterocyciyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, 126., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3—l0 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3—l0 membered heterocyclyl. {0071] In some embodiments, a heterocyclyl group is a 5—H) membered non— aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, , sulfur, boron, phosphorus, and siIicon ("5—10 membered heterocyclyl"). In some embodiments, a heterocyclyl 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, , and sulfur ("5—8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5—6 membered omatic 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 en, oxygen, and sulfur. In some embodiments, the 5—6 membered heterocyclyl has l—2 ring heteroatoms selected from nitrogen, oxygen, and sulfin‘.

In some ments, the 5—6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. {0072] 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 thietanyl. Exemplary 5—membered heterocyclyl groups containing one heteroatom include, without tion, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrohdinyl, opyrrolyl and pyrrolyl—2,5— dione. Exemplary 5—membered heterocyclyl groups ning two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-Z-one, Exemplary —membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and azolinyl. ary 6—membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and l. Exemplary 6—membered cyclyl groups containing two heteroatoms include, t limitation, piperazinyl, morpholinyl, dithianyl, yl.

Exemplaiy 6—membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7—membered heterocyclyl groups ning one heteroatom include, without tion, yl, oxepanyl and thiepanyl. Exemplary 8— membered heterocyclyl groups containing one heteroatom include, without limitation, yl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C 6 aiyl ring (also refen‘ed to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6—1nembered heterocyclyl groups fused to an aryl ring (also ed to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. {0073] Particular examples of cyclyl groups are shown in the following illustrative examples: if) 0 i O Cw —:|Y Y/é/ W ©:W>/Y wherein each W is selected from CR67, C(R67); NR", 0, and S; and each Y is selected from NR", 0, and S; and R67 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered cyclyl, C6—C7") aryl, 5-10 membered heteroaiyl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, ino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alky1, —S-aryl, -S(O)—all Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives. {0074] o" when used to be a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a en" oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, ag, lieteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, cg. heteroaryl, lkenyl, eg,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. {0075] "Acyl" refers to a radical -C(O)RZO, where R20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or titued carbocyclyl, substituted or unsubstituted cyclyl, substituted or unsubstituted 211371, or substituted or titued heteroaryl, as defined herein "Alkaiioyl" is an acyl group wherein R20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl , acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH,3Ph), —C(O)— C1-C3 alkyl, —C(O)-(CH2)I(C6-Cm aryl), —C(O)—(CH3)t(5—10 membered heteroaryl), —C(O)- (CHZMCg-Cm cycloalkyl), and (CH2){4-10 membered heterocyclyl), wherein t is an 2014/026633 integer from 0 to 4. In certain embodiments, R21 is C1-C8 alkyl, substituted with halo or hydroxy; or C3-Cm 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, tituted C 1—C4 alkoxy, unsubstituted C 1-C4 haloalkyl, unsubstituted C1— C4 hydroxyalkyl, or tmsubstituted C1-C4 haloalkoxy or hydroxy. {0076] "Acylamino" refers to a radical —NR22C(O)RZ3, where each instance of R22 and R23 is independently hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued l, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or tmsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R22 is an amino protecting group. Exemplary inino" groups include, but are not limited to, fonnylainino, amino, cyclohexylcarbonylamino, exylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary mino" groups are —NR24C(O)-C1-Cg alkyl, —NR34C(O)-(CH2)t(C5-C10 aryl), —NR24C(O)-(CH3)t(5-10 membered heteroaryl), —NR34C(0)- (CHZMCg-Cm lkyl), and —NR24C(O)—(CH2)(4-10 membered heterocyclyl), wherein t is an integer from O to 4, and each R24 independently represents H or C 1-Cg alkylln certain embodiments, R35 is H, C1-C8 alkyl, substituted with halo or hydroxy; C3-C l0 Cycloalkyl, 4- membered heterocyclyl, C6-C10 aryl, arylalkyl, 5-10 inembered heteroaryl or heteroarylalliyl, 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 koxy or y; and R26 is H, C1-C8 all In certain embodiments, the halo group is either fluoro or chloro. {0090] "Hydroxy" refers to the radical -OH. {0091] "Nitro" refers to the radical —N02. {0092] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups e. but are not d to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl. exylethyl, cycloheptylethyl, and cyclooctylethyl, and the like. {0093] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups e, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylniethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl. morpholinylethyl, and the like. {0094] "Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, ing fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of e, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like. {0095] "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. 2014/026633 {0096] "Ethenyl" refers to tuted or unsubstituted —(C=C)-. {0097] "Ethylene" refers to substituted or unsubstituted —(C-C)-. {0098] "Ethynyl" refers to —(CEC)-. {0099] "Nitrogen-containing heterocyclyl" group means a 4- to 7 - membered non— aromatic cyclic group ning at least one en atom, for e, but without limitation, morpholine, piperidine (cg. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (6g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, idone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N- methyl piperazine. Particular examples include azetidine, done and piperazone. {00100} "Thioketo" refers to the group =8. {00101} Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (6g, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" l, "substituted" or "unsubstituted" l, "substituted" or "unsubstituted" carbocyclyl, ituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (eg, a carbon or nitrogen atom) is replaced with a sible substituent, eg, a substituent which upon substitution results in a stable compound, eg., a compound which does not spontaneously undergo ormation such as by rearrangement, 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 contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, 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. {00102] ary carbon atom tuents include, but are not limited to, halogen, — CN, N03, N3, SOZH, sogH, OH, 0R", ON(Rbb)2, —N(Rbb)3, —N(Rbb);x, — )Rbb, SH, SR", ssn"; C(—O)R", COZH, CHO, C(OR");, —CO;Ra", — oceomfla, —OCO;Ra", —C(=O)N(Rbb)g, —OC(=O)N(Rbb)2, —NRbbC(=O)R", —NRbbC02Ra", — =O)N(Rbb)g, —C(=NRbb)Raa, —C(=NRbb)OR""‘, —OC(=NRbb)Raa, —OC(=NRbb)OR", — C(=NRbb)N(Rbb)3, —OC(=NRbb)N(Rbb)2, —NRbbC(=NRbb)N(Rbb)2, —C(=O)NRbbSOgR", — NRbbsoznaa, —SOgN(Rbb)2, —S02Raa, 3, ", stone", est—om", smnflng, —OSi(Ra")3 —C(=S)N(Rbb)2, —C(=O)SR""‘, —C(=S)SR"", —SC(=S)SR", —SC(=O)SR"", —OC(=O)SR‘""", )OR", )R"3, —P(=O)2R", —OP(=O)2Ra’", —P(=O)(Ra"’)3, — 0P<=O>2, —0P<=0><;0R°°>z, —P<=0>2N2, —0P(=0>2N2, (NR"">;, — OP(:O)(NRbb)2.. —NR""P<=O><0R°C>2, —NRbbP(=0)2.. —P(R°°>2, —Pz, — OP(R°°)3, —B(R")2, —B(ORc°)3, —BRaa(OR°c), C 140 alkyl, C140 perhaloalkyl, C240 alkenyl, C3,") aikynyl, C340 carbocyclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 inembered heteroaryl, wherein each alkyl, l, alkynyl, carbocyclyl, heterocyclyi, aryl, and heteroaryl is independently substituted with O, l, 2, 3, 4, or 5 Rdd groups; or two geminal hydrogens on a carbon atom are replaced with the group =0, :8, =NN(Rbb)3, =NNR‘3‘"C(=0)R"Q, C(=O)OR"a, = inbsFobRaa, =NRbb, or =NOR°C; each instance of Raa is, independently, seiected from CHo alkyl, CHO perhaloalkyl, C340 aikenyi, C340 aikynyl, C3,10 carbocyclyl, 3—14 membered heterocyclyl, C(Hi aryl, and —14 membered heteroaryl, or two Rail groups are joined to form a 3—14 inembered heterocyclyi or 5—l4 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aiyl, and heteroaryl is ndently substituted with 0, l, 2, 3, 4, or 5 Rdd groups: each instance of Rbb is, independently, selected from hydrogen, —OH, —OR8"’, — N(R°°)3, —CN, —C(=O)Ra3, N(R°°)2, a, —SOgRaa, —C(=NR°°)OR", — C(=NR"°)N(R°°)3, RC°)3, —SOgR°°, —SOgOR"°, —SOR", —C(=S)N(R°°)2, —C(=O)SRC°, — C<=S>SR"°, —P<=0>2R", —P(=O)(Raa)z, —P<=0)2Nz, —P(=O>(NR°'°>2, CHO aikyl, CHO perhaloalkyl, C240 l, C240 alkynyl, C340 carbocyclyl, 3—14 membered heterocyclyl, C(c14 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, alkenyi, l, carbocyclyl, heterocyclyl, aryi, and heteroaryl is independently substituted with 0, l, 2, 3, 4, or 5 Rdd groups; each instance of RC0 is, independently, seiected from hydrogen, C140 aikyi, CHO perhaloalkyl, C340 alkenyl, C2,10 alkynyl, C340 carbocyclyl, 3—14 inernbered heterocyclyl, CH4 aryl, and 5—14 membered heteroaryl, or two Rcc groups are joined to form a 3—14 inenibered heterocyclyl or 5—14 membered heteroaryl ring, wherein each alkyl, alkenyi, WO 60441 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is ndently substituted with O, l, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, ed from halogen, —CN, —N02, —N3, — SOQH, —SO¢,H, —OH, —0R€e, —ON(Rff)3, —N(Rff)3, —N(Rff)3+X’, —N(ORee)Rfi, —SH, —SR", — SSR", —C(=O)Ree, —CO;H, —CO;Ree, —OC(=O)RCC, —OCO;R€€, —C(=O)N(Rfi)3, — ocC, —N(OCH,~ alkyl)(C1,6 alkyl), (C,,6 alkyl), —NH(OH), —SH, —SC H, alkyl, —SS(CH; alkyl), —C(=O)(CH, alkyl), —C02H, —CO_7(CH, alkyl), )(CM , —OCO;(CH, alkyi), —C(=O)NH3, )N(C1,6 alky1)2, — OC(=O)NH(C1,6 alkyl), —NHC(=O)( CM alkyl), —N(C1s6 alkyl)C(=O)( (31,6 alkyl), — NHCOZ(CH; alkyl), —NHC(=O)N(C145 alkyl)2,—NHC(=O)NH(C1,6 alkyl), —NHC(=O)NH2, —C(=NH)O(CH, alkyl),—OC(=NH)(C1,6 alkyl), —OC(=NH)OCH, alkyl, —C(=NH)N(C H, alkyl); —C(=NH)NH(C1,6 , —C(=NH)NH;, —OC(L=NH)N(LC145 alkylb, — OC(NH)NH(CHS , —OC(NH)NH2, —NHC(NH)N(CH, allryl)2, NH)NH2, — NHSOZ(C1,6 allryl), C H, alkyl); —SOgNH(CH, alkyl), —SOgNHg,—SOZCHS alkyl, — SOgOC14 alkyl, —OSOZCH, alkyl, 6 alkyl, —Si(C145 alkyl)3, —OSi(CM alkyl); — (Cw alkyl)2, C(=S)NH(CH, , C(=S)NH2, —C(=O)S(CH, alkyl), —C(=S)SCH, alkyl, —SC(=S)SCH3 alkyl, —P(=O)2(C 1,6 alkyl), —P(=O)(C1,6 alkyl)3, —OP(=O)(C1,6 alkyl); — OP(=O)(OCM alkyl)2, C145 alkyl, C145 perhaloalkyl, (33,6 alkenyl, C24 alkynyl, C340 carbocyclyl, C(Ho aryl, 3—10 membered heterocyclyl, 5—l0 membered heteroaryl; or two geininal gg’ tuents can be joined to form =0 or =8; wherein X is a counterion. {00103} A "counter-ion" or "anionic. counterion" is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality.

Exemplary counterions include halide ions (cg, F’, Cl’, Br", F), N037, C1047, OH, HgPOI, H8047, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p—toluenesulfonate, benzenesulfonate, lO—camphor sulfonate, naphthalene—Z—sulfonate, alene—l—sulfonic acid—S—sulfonate, l—sulfonic acid—Z—sulfonate, and the like), and carboxylate ions (cg, acetate, ethanoate, oate, te, glycerate, lactate, tartrate, glycolate, and the like). {00104} en atoms can be substituted or unsubstituted as valency permits, and e primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, —OH, —0Ra", —N(R°°)3, —CN, — C(=O)R", —C(=O)N(R°°)g, ", 5021i": —C(=NRbb)Raa, —C(=NR°°)OR", — C(=NRC°)N(R°°)3, —SOgN(Rc°)3, —SOgR°", —SO;OR"‘, —SOR""‘, —C(=S)N(R°C 2, —C(=O)SR°°, — C(ZS)SRCCQ —P(:O)2Rafla —P(:O)(Rafl)2a —P(:O)2N(RCC)2, —P(:O)(NRCC)27 C1710 alkyl, C1710 perhaloalkyl, C340 alkenyl, C2,10 alkynyl, C340 carbocyclyl, 3—14 membered heterocyclyl, C(F14 aryl, and 5—14 membered heteroaryl, 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 all } These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other definitions {00115} "Phannaceutically able" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the US. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. {00116} "Pharrnaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (l) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, c acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4—hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, l,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, robenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2}-octene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary cetic acid, lauryl sulfuric acid, ic acid, glutamic acid, ynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is ed by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolarnine, triethanolamine, N- methylglucamine and the like. Salts r include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic onality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable ic counter- ion of an acidic functional group. Such s are exemplified by sodium, potassium, calcium, magnesium, ammonium, lkylammonium cations, and the like (see, e.g., Berge, (3161]., J Pharm. Sci. 66(1): 1-79 (Jan."77) . {00117} "Pharmaceutically acceptable vehicle" refers to a diluent, adiuvant, excipient or carrier with which a compound of the invention is administered. {00118} "Pharmaceutically acceptable metabolically cleavable group" refers to a group which is cleaved in vivo to yield the parent molecule of the structural a ted herein. Examples of metabolically cleavable groups include -COR, -COOR,—CONRR and — CHQOR radicals, where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of all Representative solvates include hydrates, ethanolates and methanolates. {00121} A "subject" to which administration is contemplated includes, but is not limited to, humans , a male or female of any age group, e.g., a pediatric subject (6g, infant, child, adolescent) or adult subject (6g, young adult, middle—aged adult or senior adult» and/or a non-human , e.g., a mammal such as primates (8g, cynomolgus s, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non— human animal. The terms "human," "patient," and "subject" are used interchangeably . {00122} An "effective amount" means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention. The "effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc, of the subject to be treated. A "therapeutically effective amount" refers to the effective amount for therapeutic treatment. A "prophylatically ive amount" refers to the effective amount for prophylactic treatment.

} "Preventing" or "prevention" or ylactic treatment" refers to a reduction in risk of ing or ping a disease or disorder (1.26., causing at least one of the clinical symptoms of the disease not to develop in a t not yet exposed to a disease— g agent, or predisposed to the disease in advance of e onset. {00124} The term "prophylaxis" is related to "prevention," and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Nonlimiting examples of prophylactic es may include the stration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for osis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high. {00125} "Treating" or "treatment" or "therapeutic ent" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (Ila, arresting the disease or reducing the manifestation, extent or ty of at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (cg, stabilization of a discernible symptom), physiologically, (6g, stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease. {00126} As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a nd can contain one or more non- radioactive es, such as for example, deuterium (2H or D), carbon-l3 (13C), nitrogen-15 (ID-N), or the like. It will be understood that, in a nd where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may e the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.€., 3H, and -l4, i.e., 14C, are particularly useful for this e in View of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as UC, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate or ncy. All ic variants of the compounds provided herein, ctive or not, are ed to be encompassed within the scope of the invention. {00127} It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence ofbonding of their atoms or the arrangement of their atoms in space are termed rs." s that differ in the arrangement of their atoms in space are termed "stereoisomers." {00128} Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non—superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four ent groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the 2014/026633 R- and S-sequencing rules of Calm and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatoiy (118., as (+) or (—)-isomers respectively). A chiral nd can exist as either individual enantiomer or as a mixture f. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". {00129} "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and ons.

Thus, two structures may be in equilibrium through the movement of TC electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly onverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are se formed by ent with acid or base. Tautomeric forms may be relevant to the ment of the optimal chemical reactivity and biological activity of a compound of interest. {00130} As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (116., in enantiomeric excess). In other words, an "S" form of the compound is ntially free from the "R form of the compound and is, thus, in enantiomeric excess of the ""R form. The term "enantiomerically pure" or "pure enantionier" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the nd. {00131} As used herein and unless otherwise indicated, the term "enantiomerically pure R-compound" refers to at least about 80% by weight R-compound and at most about % by weight S-compound, at least about 90% by weight R-compound and at most about % by weight S-compound, at least about 95% by weight ound and at most about % by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R—conipound or at most about 0.1% 2014/026633 by weight ound. In certain embodiments, the weights are based upon total weight of {00132} As used herein and unless otherwise indicated, the term "enantiomerically pure ound" or "S-compound" refers to at least about 80% by weight S-compound and at most about 20% by weight R—compound, at least about 90% by weight S-compound and at most about 10% by weight R—compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R—compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound. {00133} In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, e, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R—compound can se, for example, about 90% excipient and about 10% enantiomerically pure R-compound. 1n certain embodiments, the enantiomerically pure R—compound in such itions can, for example, comprise, at least about 95% by weight R—compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S—compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example. comprise, at least about 95% by weight S-compound and at most about 5% by weight R—compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no ent or carrier.

} The nds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof. {00135} Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of chemistry and the separation of stereoisomers are well-known in the art. {00136} One having ordinary skill in the art of organic synthesis will recognize that the m number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether WO 60441 it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so Iong as the aromatic ring is ally feasible and stable.

DETAILED DESCRIPTION OF CERTAIN EIVIBODIIVIENTS OF THE INVENTION {00137} In certain aspects, provided herein are 3-0i and 3B-hydroxy steroid compounds as NMDA receptor moduiators and thus, usefiiI for ting and/or treating a broad range ofCNS ions, among them, schizophrenia, depression, bipolar er (cg. land/or II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, compulsive disorders, post-traumatic stress disorder (PTSD), Autism spectrum er (ASD), dysthymia (mild depression), social anxiety disorder, obsessive compulsive er (OCD), pain (eg, a painful syndrome or disorder), sleep ers, memory disorders, dementia, Alzheimer‘s Disease, a seizure disorder (cg, epiiepsy), traumatic brain injury, stroke, addictive disorders (cg, addiction to opiates, cocaine, and/or alcohoI), autism, Huntington's Disease, insomnia, son's disease, Withdrawal syndromes, or tinnitus.

These compounds are expected to show improved in wit-70 potency, pharmacokinetic properties (PK) properties, orai bioavailability, formulatability, stability, and/0r safety.

Compounds {00138} Exemplary compounds described herein inciude an agonist of an NMDAR or a positive aliosteric modulator (PAM) of an NMDAR. In some embodiments, the compounds bed herein incIude an antagonist of an NMDAR or a NAM. nds described herein include naturally and non-natrualiy occurring steroids and sterols such as 24(S)-hydrxcholesteroi. In some embodiments, the compound is an oxysterol. In some embodiments, the compound is a 3-B hydroxyi steroid with a C-l 7 B side aikyi side chain and optional substitutions at various positions of the steroid scaffold, as shown in the compound of Formula (I), Additional exempiary compounds include a compound that augments (cg, ses) the endogenous activity or amount of 24(s)- hydroxycholesteroi, such as a compound that inhibits an enzyme that metabolizes 24(s)— hydroxychoIesterol, for e, a compound that inhibits 24-hydroxycholesterol -hydroxylase (CYP39), or a compound that reduces the endogenous activity or amount of 24(s)-hydroxycholesterol, such as a compound that activates an enzyme that produces 24(s)- hydroxychoiesterol, for example, a compound that activates cholesterol 24(S)-hydroxylase (CYP46). {00139} In some embodiments, the compound used in a method described herein, eg, a method of evaluation or treatment described herein is a compound ing to Fonnuia (I): or a pharmaceutically acceptabie salt, solvate, prodmg, stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof; wherein: Z is a group of the formula (i), (ii), (iii), (iv), or (V): R1 R1 R20 n L2—0R24 m" L1+X2-R24 R23b (1),.. "W (n),..

L3 o L3 R26 L3 R26 "I?" Y/ 1""x XYRZS "a" Y/ R24 - (iii), R26 . YRZ5 (iv), or (v) L1 and L2 are selected from a group consisting of a bond, a substituted or tituted C1—C6 alkylene, a substituted or unsubstituted C2—C6 alkenylene, substituted or tituted C2—C6 alkynylene, a substituted or unsubstituted hetero C1—C6 alkylene, a substituted or unsubstituted hetero C3—C6 alkenylene, and a substituted or unsubstituted hetero C3—C6 alkynylene; L3 is a substituted or unsubstituted C1—C5 alkylene, a substituted or unsubstituted C3— C6 alkenylene, substituted or unsubstituted C2—C6 alkynylene, a substituted or unsubstituted hetero C1—C6 ne, a substituted or unsubstituted hetero Cz—CG alkenylene, or a substituted or unsubstituted hetero C3—C6 alkynylene; each ce of X1 and X2 is ndently —O—, —S—, — , wherein each instance of RX is independently hydrogen, substituted or unsubstituted alkyi, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or unsubstituted yclyl, substituted or unsubstituted heterocyciyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaikyi, or an amino protecting group; R1 is hydrogen? substituted or unsubstituted alkyL substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or unsubstituted carbocyclyi.‘ substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, tuted or tituted heteroaryl, halo, N3, N02, SCN, CN, OR‘M, SRAI, NORM); —N=NRA1, —N=C(RA1)2.. —N(0RA1)(RA‘),—C(=0)RA1, —C(=0)ORA1, SRA‘, —C(=0)N(RA1)2, — C(=0f)N(0RA1)(RAI),—OC(=0)RA‘, —OC(=O)ORA1, —0C(=0)SRA& —0C(=0)N(RA1)2, — NRA‘C(=0)RA1, —NRA1C(=0)0RA1, —NRA1C(=0)SRA1, —NRA1C(=O)N(RA’)2, —SC(=O)RA2, —SC(=O)ORAI, —SC(=O)SRA‘, —SC(=0)N(RA1)Z, —0S(=0)2RA'~", —0$(=0)20RA1, —S— RA3, —S—S(=O)20RA1, —S(=0f)RA3, —SOZRA2, —NR‘MSOZRA2, or —sogN(RA‘)2, wherein RAl is hydrogen, substituted or tituted alkyl, substituted or unsubstituted aikenyi, tuted or tituted alkynyl, substituted or tituted carbocyclyl, substituted or tituted heterocyclylv substituted or unsubstituted aryi.‘ or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RA1 groups are joined to form an substituted or unsubstituted heterocyclic ring; and R 2 is tuted or unsubstituted aikyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or unsubstituted carbocyclyl, substituted or tituted heterocyclyi, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryi, or an RA1 group and an RA2 group are joined to form an substituted or unsubstituted heterocyclic ring; each instance of R2, R4", R41: R", R", RH", and RMb is ndentiy hydrogen, —OH, halo, substituted or unsubstituted aikyl, substituted or unsubstituted alkenyL substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N3, — N03, SCNv CN, ORBl, SRBI, 2, —N=NRBE —N=C(RBI)3, —N(ORBl)(RBi), — B£ —C(=0)0RB‘, SRB1, —C(=0)N(R")2, —C(=O)N(ORB1)(RB‘),—OC(=O)RB11 —OC(=0)0RB‘, —OC(=O)SRBI, —OC(=O)N(RBI)3, —NRB1C(=0)RB‘, —NR31C(=0)0RB‘, — NRB‘C(=0)SRBI, —NRBIC(=0)N(RBI)2, —SC(=0)RB{ —SC(=0)0RB1, —SC(=0)SRB£ — SC(=O)N(RBX)2, —OS(=O)3RBE, —03(=0)20RB£ —S—S(=O)3RB2, —s—S(=0)20RB‘, — S(=O)RBZ, —SOZRBE, —NRBISOgRB2, or —SO-2N(RBI)3, wherein RBl is hydrogen, substituted or unsubstituted alkyi, substituted or unsubstituted l, substituted or unsubstituted alkynyl, WO 60441 substituted or unsubstituted carbocyclyi, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryi, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RBI groups are joined to form an substituted or unsubstituted heterocyciic ring; and RB: is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or an RBI group and an R132 group are joined to form an substituted or unsubstituted heterocyciic ring; or optionally wherein each of R4a and K", and/or R7" and R7b, and/or RIla and R11b are joined to form an oxo (=0) group; R33 is hydrogen, substituted or tituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyi, substituted or tituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3b is hydrogen, —C(=0)RC1,—C(=0)0RC1,—C(=0)SRC1, —C(=O)N(RC1)2, — sewn", —S(=0)20R", —P(=O>2R", —P(=0)2OR", —P(=O>(0R")2.. 2» 0r - RC2)(ORCI), wherein RC1 is hydrogen, substituted or unsubstituted alkyi, substituted or unsubstituted alkenyl, tuted or unsubstituted aikynyl, substituted or unsubstituted carbocyclyl, tuted or unsubstituted heterocyciyi, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfiir atom, a en protecting group when attached to a nitrogen atom, or two RC1 groups are joined to form an tuted or unsubstituted cyclic ring; and RC2 is substituted or tituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted l, substituted or unsubstituted carbocyclyl, substituted or tituted heterocyciyi, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each of Rf" and R6er is independently hydrogen, halo, substituted or unsubstituted alkyl, tuted or unsubstituted alkenyl, or substituted or unsubstituted aikynyl, and """ represents a single or double bond, provided if a double bond is present in Ring B, then one of R6a or R6er is absent, and provided if a single bond is present in Ring B7 then the hydrogen at C5 is in the alpha or beta position; R14 is hydrogen or substituted or unsubstituted alkyl; R17 is hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted yclyi, substituted or tituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or —ORD1, wherein RDI is hydrogen, substituted or unsubstituted alkyl, substituted or Luisubstituted alkenyl, tuted or unsubstituted aikynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aiyl, substituted or unsubstituted heteroaryl, or an oxygen protecting group; each instance of R18, R195 and R20 is ndently hydrogen or substituted or unsubstituted alkyi; and each instance of Rwand R23b is independentiy hydrogen, halogen, or substituted or unsubstituted aikyl, or R233 and R2313 are joined together to form substituted or unsubstituted C3—C6 cycloaikyl; R24 is hydrogen, substituted or unsubstituted alkyl, substituted or titued alkenyl, substituted or unsubstituted alkynyl, substituted or tituted carbocyclyi, tuted or unsubstituted heterocyclyl, substituted or tuisubstitued aryl, substituted or tituted heteroaryl, —C(=0)RE1, 0RE*, —C(=0)SRE1, —C(=0)N(RE‘)3, — S(=O)2RE2, —S(=O)20RE1, —P(=O)2REZ, —P(=0)20RE1, —P(=0)(0RE‘)2, —P(=O)(RE2)2, or — P(=O)(RE2)(ORE1), wherein RE} is hydrogen, substituted or unsubstituted aikyl, substituted or unsubstituted alkenyl, substituted or tituted aikynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyciyi, tuted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when ed to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RE! groups are joined to form an substituted or unsubstituted heterocyclic ring; and R132 is substituted or tituted aikyi, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or tituted carbocyclyl, substituted or unsubstituted heterocyciyi, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryi; Y is —O—, —S—, or —NRZS—; RZ4 is independently substituted or tituted aikyi, substituted or unsubstituted alkenyl, substituted or tituted alkynyi, substituted or unsubstituted carbocyciyi, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aiyh substituted or unsubstituted heteroaiyl, —ORZS, —SRZS or —N(RZS)2; each instance of RZ5 is independently hydrogen, tuted or unsubstituted allryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RZS groups are joined to form a substituted or tituted heterocyclic ring; and each instance of RZ6 is independently hydrogen or substituted or unsubstituted alkyl, or two RZG groups are joined to form a C34 carbocyclic ring; and the subscript n is 0, l, 2, or 3. {00140} In certain embodiments, when R33 is H, n is l, and R19 is Me; then R1 is other than H, ailryl, alkenyl, or alkynyl. In certain ments, when R3a is H, R3b is —COMe, R19 is Me, and n is 0; then R1 is OH. In certain embodiments, when R38 is H, n is 0, and R20 is alkyl; then R1 is other than OH. In n ments, when R19 is Me; then R1 is other than H, alkyi, l, or alkynyl. In certain embodiments, R1 is H; and R19 is other than Me.

In certain embodiments, each R1 and R3" is H; and R19 is other than Me.

} In certain embodiments, when R38 is H, then R1 is other than H, substituted or unsubstituted alkyl, substituted or tituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, when R33 is H, then R1 is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, N3, N03, SCN, CN, ORA}, SR", N(RA‘)2, —N=NRA1,—N=C(RA‘)Z,—N(0RA1)(RA‘),—C(=O)RAI, —C(=O)ORA‘, —C(=0)SRA‘, — C(=0)N(RA1)Z,—C(=0)N(0RAl)(jRAi),—0C(=0)RA1, —OC(=O)ORA1,—OC(=O)SRA1, — OC(=O)N(RA1)2, —NRA*C(=0)RA1, —NR~"‘C(=0)ORA1, —NRA1C(=O)SRA1,— NRAIC(=O)N(RA1)2, —SC(=O)RA2, —SC(=O)ORA1, )SRA1, —SC(=0)N(RA1)2, — OS(=O);RA2, —OS(=O)20RA1, —S—S(=O)2RA2, —S—S(=0)30RA‘, —S(=O)RM, —503RA1, — NRA‘SOZRM, or —s02N(RA‘)2. {00142} In certain further ments, the following compounds are specifically excluded: and H0 and pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautorner, isotopic variant, or e thereof, or a combination thereof. . t 3 Various embodzmenfs oj R ‘7 {00143} As generally defined above, R3a is en, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynylv substituted or unsubstituted yclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. It is lly understood that R33 may be in the alpha (down) or beta (up) position. In certain embodiments, R3a is alpha. . . 3. . In certain embodiments, R a 15 beta‘ 2014/026633 {00144} In certain embodiments, R38 is hydrogen. {00145} In certain embodiments, R361 is substituted or unsubstituted alkyl, cg, substituted or unsubstituted CHalkyl, substituted or unsubstituted C Halkyl, substituted or unsubstituted CHalkyl, substituted or unsubstituted CHalkyi, substituted or unsubstituted Cmsalkyi, or substituted or unsubstituted CMalkyl. Exemplary R3a CHaikyl groups include, but are not limited to, substituted or tituted methyl (Cg), ethyl (C2), n—propyl (C3), isopropyl (C3), n—butyl (C4), tert—butyl (C4), tyl (C4), iso—butyl (C4), n—pentyl (C5), 3— pentanyl (C5), amyl (C5), neopentyi (C5), 3—methyl—2—butanyi (C5), tertiary amyl (C5), n— hexyi (C6), CM alkyl substituted with I, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups (eg, —CF3, —CH3F, —CHF2, difluoroethyl, and 2,2,2—trifluoro—l ,l—dimethyl—ethyi), CH, alkyl substituted with i, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups (e.g., —CH3Cl, —CHC12), and CH, aikyl substituted with aikoxy groups (eg, —CH30CH3 and —CH30CH2CH3). In certain embodiments, R321 is substituted alkyl, eg, R33 is haloalkyi, alkoxyalkyl, or aminoalkyl. In certain embodiments, R33 is Me, Et, n-Pr, n-Bu, i-Bu, fiuoromethyl, chloromethyl, difluoromethyi, trifluoromethyl, trifluoroethyl, oethyl, 2,2,2-trifiuorol ,l-dimethyl-etliyl, methoxymethyl, methoxyethyi, or ethoxymethyl. In certain embodiments, R3a is Me, Et, n-Pr, n-Bu, or i-Bu. In n embodiments, R32) is metlioxymethyl, ethoxymethyl, propoxymethyi, xyethyl, or etlioxyetliyl. In certain embodiments, R3.3 is romethoxymethyl. In certain embodiments, R3" is etliyl, chloromethyl, difluoromethyi, trifluoromethyl, difiuoroethyi, trifluoroethyl, or 2,2,2-trifluoro- l,I-dimethyl-etliyl. In n ments, R3a is trifluoromethyl. {00146} In certain embodiments, R3ais substituted or unsubstituted alkenyl, e.g., substituted or unsubstituted CHalkenyl, substituted or unsubstituted C2,3a§kenyi, substituted or unsubstituted analkenyl, substituted or unsubstituted CHaIkenyl, or substituted or unsubstituted C5,6alkenyl. In certain embodiments, R3a is etheny'l (C3), yl (C 3), or butenyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyi, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R3a is ethenyl, propenyl, or l, unsubstituted or substituted with alkyl, halo, kyl, alkoxyalkyl, or hydroxy. In certain embodiments, R3a is etlienyl. {00147} In n embodiments, R3C1 is substituted or unsubstituted alkynyi, 8g, substituted or unsubstituted CHalkynyl, substituted or unsubstituted CHalkynyl, substituted or unsubstituted analkynyl, substituted or unsubstituted Ctsalkynyl, or substituted or unsubstituted C54alkynyl. Exempiary substituted or tituted R33 aikynyl groups include, but are not Iimited to, ethynyl, yl, or butynyi, tituted or substituted with alkyl, halo, haloalkyi (cg, CF3), alkoxyalkyl, cycioalkyl (6g, cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R33 is selected from the group ting of trifluoroethynyl, ropylethynyl, cycIobuterthynyl, and propynyl, fluoropropynyl, and ethynyi. In certain embodiments, R33 is ethynyl (C2), propynyl (C3), or butynyl (C4), unsubstituted or substituted with one or more substituents selected from the group ting of substituted or unsubstituted aryi, substituted or unsubstituted heteroaryi, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted lieterocyclyl. In certain embodiments, R33 is ethynyl (C3), propynyl (C3), or butynyl (C4) tuted with substituted phenyl. In certain embodiment, the phenyl substitutent 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, R33 is ethynyl (C3), propynyl (C3), or butynyl (C4) substituted with substituted or unsubstituted pyrrolyl, imidazonI, pyrazolyl, oxazoyl, thiazoiyi, isoxazoyi, 1,2,3-triazolyl, I,2,4-triazoiyi, oxadiazolyl, thiadiazonI, 01‘ tetrazoiyl. {00148} In certain embodiments, R3ais ethynyl, propynyi, or butynyl, tituted or substituted with alkyI, halo, haloaikyI, alkoxyalkyl, or hydroxyl. In certain ments, R3a is ethynyi or propynyi, substituted with substituted or unsubstituted aryl. In certain embodiments, R32) is ethynyl or propynyl, substituted with phenyi unsubstituted or substituted with halo, alkyl, alkoxy, haloaIkyl, trihaloaIkyI, or acyI. In n embodiments, R33 is ethynyl or propynyl, substituted with substituted or unsubstituted carbocyclyl. In certain embodiments, R33 is ethynyl or propynyl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyciopentyl, or exyl. In certain ments, R361 is ethynyl or propynyl, substituted with substituted or tituted heteroaryI. In n embodiments, R33 is ethynyI or propynyl, tuted with substituted or unsubstituted pyridinyl, or pyrimidinyl. In certain embodiments, R3;" is ethynyl or propynyl, tuted with tuted or unsubstituted pyrroiyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, I,2,3-triazolyl, l,2,4-triazolyl, oxadiazolyi, azolyl, tetrazolyi. In certain embodiments, R3a is ethynyi or propynyl, substituted with substituted or unsubstituted heterocyclyl. In certain embodiments, Rhis ethynyI or propynyl, substituted with substituted or unsubstituted pyrroIidinyl, piperidinyl, piperazinyl, or mopboiinyi. In certain embodiments, R33 is yl or butynyI, substituted with hydroxyi or alkoxy. In certain embodiments, R33 is propynyi or butynyl, substituted with methoxy or ethoxy. In certain embodiments, R3" is ethynyl or propynyl, substituted with Ci. In certain embodiments, R3a is ethynyl or propynyi, substituted with trifluoromethyl. {00149} In certain embodiments, R3a is substituted or unsubstituted carbocyclyl, e.g., substituted or unsubstituted C3,6carbocycly1, tuted or tituted CHcarbocyclyI, substituted or unsubstituted C44 carbocyclyl, or substituted or unsubstituted C54, carbocyclyi. {00150} In certain embodiments, R33 is substituted or unsubstituted heterocyclyl, eg, substituted or unsubstituted 3—6 membered heterocyclyl, substituted or tituted 3—4 membered heterocyclyl, substituted or unsubstituted 4—5 membered cyciyi, or tuted or unsubstituted 5—6 membered heterocyclyl. {00151} In certain embodiments, R3a is substituted or unsubstituted aryi. In certain embodiments, R32) is substituted or unsubstituted phenyl. {00152} In certain embodiments, R33 is substituted or unsubstituted heteroaryl, tag, optionally substituted 5— to 6—membered heteroaryi. {00153} Fuither embodiments of R3", as a substituted or unsubstituted aikyi, substituted or unsubstituted aikenyl, and substituted or unsubstituted alkynyl groups, are depicted below: wherein each instance of R3° is hydrogen, haio, or —ORH, wherein RF1 is substituted or unsubstituted alkyi; and each instance of R3d is hydrogen, haio, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted cyclyl. {00154} In n embodiments, at least one R30 is hydrogen. In certain embodiments, at least two R30 is hydrogen. In ceitain embodiments, each R30 is en. In certain embodiments, at ieast one R3c is halogen (e.g., fluoro, chioro, bromo, iodo). In n ments, at ieast two R30 are halogen (cg, fluoro, chloro, bromo, iodo). In certain ments, each R3C is haiogen (e. 0., , to provide the group —CF3). In certain embodiments, at ieast one RSC is —ORFl (e.g., OMe or 0130. In certain embodiments, at least two RSc is —ORF1 (cg, OMe or OEt). In certain embodiments, at ieast one R3C is hydrogen, F, —OMe, 0r —OEt. In n embodiments, one of R30 is F, —OMe, or OEt; and the rest are {00155} In certain embodiments, at least one R3‘11 is hydrogen. In certain embodiments, each R2c is hydrogen. In certain embodiments, at least one R3d is halogen (Cg, fluoro, chloro, bromo, lodo). In certain embodiments, each R3d is halogen (6g, fluoro, chIoro, bromo, lodo). In n embodiments, each of R3d is alkyl, eg, each of R2c is Me. In certain embodiments, one of R3d is alkyl, and the other is hydrogen, eg, one of R3d is Me; and the other is hydrogen. In certain embodiments, one of R3d is substituted or tituted carbocyclyl, cg, cyciopropyl or cyciobutyi, and the other is hydrogen. In certain embodiments, at least one R3d is en, —F, —Br, —Cl, —I, —CH3, —CF3, cyclopropyl, or utyl. In certain embodiments, each instance of R3d is H. In certain embodiments, each instance of R3d is halogen (6g, fluoro, , bromo, iodo). In certain embodiments, each instance of R3d is alkyi, e.g., —CH3, —CF3, —CH2CH3C1. In certain embodiments, each instance of R3d is substituted or unsubstituted carbocyclyl, 6g, cyciopropyl or cyciobutyl. In certain embodiments, R3d is substituted or unsubstituted cyclopropyl. In certain embodiments, each instance of R3dis hydrogen, F, Br, C1, I, CH3, CFg, CHgCH2Ci, cyclopropyi, or cyclobutyi. In certain ments, R3d is Me or C1. In certain embodiments, R3d is substituted or unsubstituted heterocyclyl.

Various embodiments OfiXI-R'qb {00156} As generaIly defined above, for group —X1R3b, X1 is independently —O—, —S—, or —N(RX)—, wherein each instance of RX is independently hydrogen, substituted or unsubstituted alkyi, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyi, substituted or unsubstituted yclyi, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, tuted or unsubstituted alkyl, or an amino ting group; and R3" is hydrogen, —C(=0)R", —C(=0)0R", SRCI, N(R")3, —S(=0)2R", —S(=0)20RCE —P<=0)2RC1,—P(=O)20R",—P(=O>(0R")2, —P<=Of>2R", —S<=0i>zoR‘", —P<=0)2RC2 —P<=O)20RC‘, —P(=0>(0R")2, — P<=0)2, or (R")(0RC‘). {00160} In certain embodiments, at least one instance of RC1 is hydrogen or a protecting group, i.€., an oxygen protecting group when attached to an oxygen atom, sulfur protecting group when attached to an sulfur atom, or a en protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of RC1 is hydrogen. {00161} In certain ments, at ieast one instance of RC1 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C ingalkyl, tuted or unsubstituted Cygalkyl, substituted or unsubstituted l, substituted or unsubstituted C3,4alkyl, tuted or unsubstituted yl, or tuted or unsubstituted Csngalkyl. Exempiary RC1 Cmalkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C3), n—propyl (C3), isopropyl (C3), l (C4), tert—butyl (C4), tyl (C4), iso— butyI (C4), n—pentyl (C5), 3—pentanyl (C5), amyl (C5), neopentyl (C5), 3—methyI—2—butanyl (C5), tertiary amyl (C5), n—hexyi (C6), CH, alkyl substituted with I, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups (cg, —CF3, —CH2F, —CHF3, difluoroethyl, and 2,2,2—trifluoro—I,I— dimethyl—ethyl), CM alkyl substituted with l, 2, 3, 4, 5, 6, 7, 8, 9, II), or more chloro groups (eg, —CH3CI, —CHC13), and C 1,6 alkyi substituted with alkoxy groups (eg, —CH30CH3 and —CH20CH3CH3), {00162} In certain embodiments, at least one instance of RC1 is substituted or unsubstituted alkenyl, 8g, substituted or unsubstituted nyl, substituted or unsubstituted C2,3alkenyl, substituted or unsubstituted CHalkenyl, substituted or unsubstituted Casalkenyl, or tuted or unsubstituted CMalkenyl. {00163} In certain embodiments, at least one instance of RCl is substituted or unsubstituted l, e.g., substituted or unsubstituted C243alkYDYl, substituted or unsubstituted CHalkynyl, substituted or unsubstituted analkynyl, substituted or tituted Casalkynyl, or substituted or unsubstituted C5,6alkynyl. {00164} In certain embodiments, at Ieast one instance of RC1 is tuted or unsubstituted carbocyclyl, cg, substituted or unsubstituted C34carbocyclyi, substituted or tituted ancarbocyclyl, substituted or unsubstituted Cms carbocyclyl, or substituted or unsubstituted C54, carbocyclyl.

} In certain embodiments, at least one ce of RC1 is substituted or unsubstituted heterocyclyl, e.g., substituted or unsubstituted 3—6 membered heterocyclyl, substituted or unsubstituted 3—4 membered heterocyclyl, substituted or unsubstituted 4—5 membered heterocyclyl, or substituted or unsubstituted 5—6 membered heterocyclyl. {00166} In certain embodiments, at Ieast one instance of RC1 is substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyi. {00167} In certain ments, at least one ce of RC1 is tuted or unsubstituted heteroaryl, tag, optionally substituted 5— to 6—membered heteroaryl. {00168} In certain embodiments, two RC1 groups are joined to form a substituted or unsubstituted heterocyclic ring, e.g., a substituted or unsubstituted piperidinyl, tuted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring. {00169} In certain ments, R31) is —C(=0)RC1, —C(j=O)ORCl, —C(=O)N(RC1)2 or — C(=O)N(ORC1)(R 1'1), wherein RC1 is as defined herein {00170} In certain embodiments, R3b is —C(=O)RC1, e.g., for example, wherein RC1 is, for example, substituted or unsubstituted methyl (Ci), ethyl (C3), n—propyl (C3), isopropyi (C3), n—butyl (C4), utyl (C4), tyi (C4), iso—butyl (C4), 11—pentyl (C5), 3—pentanyl (C5), amyl (C5), neopentyl (C5), 3—met11yl—2—butanyl (C 5), tertiary ainyl (C5), or n—hexyl (C6). In certain embodiments, R3b is —C(=O)CH3. In n embodiments, R3b is — C(=O)(CH3)mCOgH, wherein m is an integer between 2 and 5, inclusive. In certain embodiments, in is 2. In certain embodiments, m is 3. In certain embodiments, in is 4. In certain embodiments, m is 5. In certain embodiments, R3b is —C(=O)CH2CH3C(=O)OH. {00171} In certain embodiments, R3b is ORC1, tag, for exampie, wherein RC1 is, for example, substituted or unsubstituted methyl (Ci), ethyl (C3), n—propyl (C3), isopropyi (C3), n—butyl (C4), tert—butyl (C4), sec—butyi (C4), iso—butyl (Ci), n—pentyl (C 5:), 3—pentanyl (C5), amyi (C5), neopentyl (C5), 3—methyl—2—butanyl (C5), tertiary amyl (C5), or n—hexyl (C6)- {00172} In certain ments, R3b is —C(=O)SRC1, e.g., for e, wherein RC1 is, for example, substituted or tituted methyl (C1), ethyl (C3), n—propyl (C3), isopropyi (C3), n—butyl (C4), tert—butyl (C4), tyI (C4), iso—butyl (C4), n—pentyl (C5), 3—pentanyl (C5), amyl (C5), neopentyl (C5), 3—methyl—2—butanyl (C5), tertiary amyl (C5), or n—hexyl (C6). {00173} In certain embodiments, R3b is —C(=O)N(RC1)3, e.g., —C(=O)NH3 or — C(=O)NHRC1, wherein RC1 is, for example, substituted or unsubstituted methyl (C1), ethyl (C3), n—propyl (C3), isopropyl (C3), n—butyI (C4), tert—butyi (C4), tyl (C4), iso—butyI (C4), n—pentyi (C5), 3—pentanyl (C 5), amyl (C5), neopentyi (C5), 3—methyI—2—butanyl (C5), tertiary amyl (C5), or n—hexyl (C6), or R1 is —C(=O)N(RC1)2 wherein the two RC1 groups are joined to form a substituted or unsubstituted heterocyclic ring, e.g., substituted or unsubstituted piperidinyi, tuted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring. {00174} In certain embodiments, R3b is —S(=O)3RC1 or —S(=O)30RC1, wherein RCl is, for example, hydrogen, or substituted or unsubstituted methyl (C1), ethyl (C2), n—propyi (C3), isopropyl (C3), n—butyl (C4), tert—butyl (C4), sec—butyl (C4), iso—butyl (C4), n—pentyl (C5), 3— pentanyl (C5), amyl (C5), neopentyi (C5), yl—2—butanyi (C5), tertiary amyl (C5), or n— hexyI (C6), or substituted or unsubstituted phenyl. In n embodiments, R3b is — S(=O)2RCI. In n embodiments, R3b is —S(=O)20RC1, e.g., -SOgH. {00175} In certain embodiments, R3b is —P(=O)3RC1, —P(=O)ZORC1, —P(=O)(ORC1)3, — P(=O)(RC1);, or —P(=O)(RCI)(ORC1), wherein each RC1 is, for example, independently hydrogen, substituted or unsubstituted methyl (C 1), ethyl (C3), n—propyi (C3), pyl (C3), n—butyl (C4), tert—butyi (C4), sec—butyl (C4), iso—butyl (C4), n—pentyl (C5), 3—pentanyi (C5), amyl (C5), neopentyl (C5), yI—2—butanyi (C5), tertiary amyl (C5), or n—hexyl (C6), or substituted or unsubstituted phenyl. In certain embodiments, R3b is —P(=O)2RC1. In certain embodiments, R1 is —P(=O)20RC1. In n embodiments, R3b is —P(=O)(OR 1'1); In certain embodiments, R1 is —P(=O)(RC1)2. In n embodiments, R3b is —P(=O)(RC1)(ORC1).

Various embodiments n Z is a group qffbrmula (i) or (ii) {00176} In certain embodiments, Z is a group of formula (i): 2014/026633 R20 Rzaa "m L1__<_x2__R24 R23b (t). {00177} In other embodiments, Z is a group of formula (ii): {00178} As generaIly defined above, L1 and L2 is a bond (116., in other words, is absent) or is a substituted or tituted C1—C6 ne, a tuted or unsubstituted C2—C6 alkenylene, substituted or unsubstituted C3—C6 alkynylene, a substituted or unsubstituted hetero C1—C6 alkylene, a tuted or unsubstituted hetero C2—C6 alkenylene, or a substituted or unsubstituted hetero C3—C6 alkynylene. {00179} In certain embodiments, L1 or L2 is a bond. {00180} In certain embodiments, L1 or L2 is a substituted or unsubstituted C 1—C6 alkylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C1—C4 alkylene.

In certain embodiments, L1 or L2 is a substituted or unsubstituted C1—C3 aikylene. In certain embodiments, If or L12 is a substituted or unsubstituted C1—C3 alkylene. In certain embodiments, If or L2 is a substituted or tituted C1 ne. In certain embodiments, L1 or L2 is a tuted or unsubstituted C3 alkylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C3 alkylene. In certain embodiments, L1 or L2 is a substituted or tituted C4 alkylene. In certain embodiments, L1 or L2 is a tuted or unsubstituted C5 alkyiene. In certain embodiments, If or L2 is a substituted or tituted C5 alkylene.

In certain embodiments, L1 or L2 is an aikyiene group, as described above, substituted with one or more substituents selected from the group consisting of substituted or unsubstituted alkyl and halo. In certain embodiments, L2 or L2 is -CH2-, -CHMe-, -CMe3-, -CH3-CH3-, - CFg-CHg-, -CHg-CMe3—, -CH3—CHz-CH3-, or -CH2-CH2-Cl\’l€g-. {00181} In certain embodiments, L1 or L2 is a substituted or unsubstituted C3—C6 lene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C3—C5 alkenylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C2—C4 alkenylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C3—C3 alkenylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C2 alkenyiene.

In certain embodiments, L1 or L2 is a substituted or unsubstituted C 3 alkenylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C4 alkenylene. In certain ments, L1 or L2 is a substituted or unsubstituted C5 lene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C6 alkenylene. In certain embodiments, L1 or L2 is an alkenylene group, as described above, substituted with one or more substituents ed from the group consisting of substituted or unsubstituted aikyl and halo. {00182} In certain embodiments, If or L2 is a substituted or unsubstituted C2—C6 alkynylene. In certain embodiments, If or L2 is a substituted or unsubstituted C2—C5 alkynylene. In certain embodiments, If or L2 is a substituted or unsubstituted C2—C4 alkynylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C3—C3 lene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C3 alkynylene.

In certain ments, L1 or L2 is a substituted or unsubstituted C3 alkynyiene. In certain ments, L1 or L2 is a substituted or unsubstituted C4 alkynylene. In n embodiments, L1 is a substituted or unsubstituted C5 alkynylene. In certain embodiments, L1 or L2 is a substituted or unsubstituted C6 alkynyiene. In certain embodiments, If or L2 is an alkynylene group, as bed above, tuted with one or more substituents selected from the group consisting of substituted or unsubstituted alkyl and haio. {00183} Furthermore, in certain embodiments, L1 or L2 is substituted or unsubstituted heter0C1,6alky'lene, e.g.. substituted or unsubstituted heteroCHalkylene, substituted or unsubstituted hetei'oC3,3allsnA£ —0C(=0)N(RA1)2, —NRA‘C(=0)RA1, —NRA‘C(=0)0RA1,—NRAlc(=0)SRA‘, — NRAIC(=0)N(RA‘)2, —SC(=O)RA2, —SC(=0)0RA‘, —SC(L=O)SRA1, —SC(=0)N(RA1)2, — 2RA2, —OS(=O)ZORA1,—S—S(=O)2RM, —S—S(=0)20RA‘, —S(=0)RA3, court", — NR‘MSOZRAQ, or —SOgN(R‘M)2, wherein R" is hydrogen, substituted or unsubstituted alkyl, tuted or unsubstituted alkenyl, substituted or tituted alkynyl, substituted or tituted carbocyclyl, substituted or tituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two RAl groups are joined to form an substituted or unsubstituted heterocyciic ring; and RAB is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or tituted carbocyclyl, tuted or tituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or an RN group and an RA’Z' group are joined to form an substituted or unsubstituted heterocyclic ring. {00185} In certain embodiments, R1 is hydrogen. {00186} In certain embodiments, R1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl. In n embodiments, R1 is substituted or Lursubstituted alkyl, e.g., Me, Et, or i—Pr. In certain embodiments, R1 is substituted or unsubstituted alkenyl, e.g., substituted or unsubstituted ethenyl or substituted or unsubstituted propenyl. In certain embodiments, R1 is substituted or unsubstituted alkynyi. {00187} In certain embodiments, R1 is selected from substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl. {00188} In n embodiments, R1 is substituted or unsubstituted aryl, e.g., .

} In certain embodiments, R1 is substituted or unsubstituted heteroaryl, e.g., a substituted or tituted heteroaryl selected from pyrroiyl, imidazolyl, pyrazolyl, oxazoyi, thiazoiyi, isoxazoyi, 1,2,3-triazolyl, I,2,4-triazoiyi, oxadiazolyl, thiadiazoiyi, tetrazolyl, nyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazonyi, quinoxilinyi, naphthyr‘idiriyl, indolyl, irrdazolyl, benzirnidazloyl, pyr‘r‘olopyridinyl, opyrimidinyl, pyridopyrimidinyi, or l. In certain embodiments, the heteroaryl group is substituted with one or more groups selected from substituted or unsubstituted aikyi, haloalkyl, aikenyl, substituted or unsubstituted alkynyl, oxo, hydoxy, halo, alkoxy, yi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or tituted -SO- alkyl, substituted or tituted —SO;—aIkyi, tuted or unsubstituted -SO-aryl, substituted or unsubstituted —SOg-aryl, substituted or tituted -SO—heteroaryi, substituted or unsubstituted —SO;—heteroaryl, amino, cyano, and acyl. In certain embodiments, R1 is imidazoiyl, pyrazolyl, 1,2,3-triazolyl, I,2,4-triazolyl, oxadiazoiyi, thiadiazolyl, or tetrazolyl; each unsubstitued or substituted with one or two groups independently selected from oxo, Me, F, Cl, -CN, and -CF3. In certain embodiments, R1 is quinoiinyl, isoquinoiinyi or purinyl; each unsubstitued or substituted with one or two groups independently ed from oxo, Me, F, C1, -CN, and -CF;. {00190} In certain embodiments, R1 is —ORA1. In certain embodiments, R1 is -O— quinoiinyl, -O—isoquinolinyl,- O—purinyl, each unsubstitued or substituted with one or two groups independently selected from Me, F, CI, -CN, and -CF3. In certain embodiments, R1 is —OH or -O-CO-CH2-CH2-COZH. {00191} In certain embodiments, R1 is —SRA1, In certain embodiments, Rl is S- quinoiinyl, -S-isoquinolinyl, or -S-purinyl, each unsubstitued or substituted with one or two groups independently selected from Me, F, Ci, -CN, and -CF:,. In certain embodiments, R1 is —SH. {00192} In certain embodiments, R1 is —OS(=O)3RA3. In certain embodiments, R1 is — OS(=O)20RA1; e.g., -O-SOgH. In certain embodiments, R1 is —S—S(=O)3RAZ. In certain embodiments, R1 is —S—S(=O)ZORA1; cg, -S-803H. {00193} As ily defined above, R20 is independently hydrogen or substituted or tituted alkyi. In certain embodiments, R20 is hydrogen. In certain embodiments, R20 is substituted or unsubstituted alkyl (e.g., -CH3). {00194} As generaily defined above each instance of R233 and R23b is independently hydrogen, halogen, or substituted or unsubstituted aikyl, or R23:1 and R231) are joined er to form tuted or tituted C3—C6 cycioalkyl. In certain embodiments, each instance of R238 and RM is hydrogen. In certain embodiments, one of R23a and R23b is haiogen, 6.3., fluoro, and the other of R33;1 and R23b is hydrogen, halogen, or substituted or unsubstituted alkyl. In certain embodiments, each instance of R23a and R23b is haiogen, eg, fluoro. In certain embodiments, each instance of R23a and R23b is independentiy substituted or unsubstituted alkyi. In certain ments, each of R233 and R23b is Me. In certain WO 60441 embodiments, one of R23a and R23b is H. 7321 In certain embodiments, one of R" and R23b is H; and the other is substituted or tituted aikyl. In n embodiments, one of R23a and R23b is H; and the other is Me or Et. In certain embodiments, R23a and R23b are joined together to form substituted or unsubstituted C3—C6 cycloaikyi. In certain embodiments, R23a and R23b are joined together to form a substituted or unsubstituted cyclopropyi. {00195} In certain embodiments, the group WM" "4"" or is of the formuia: )III F F "I! F F am!) "ask/\f,KM; RAKE/943‘}, F F g 3., we" WK"?aw 2M A= = "a, "a r A F F 1 FF, FF, FF’LL'H Exam-"H E‘- } As generaily defined above, X2 is independently —O—, —S—, or —N(RX —, wherein each instance of RX is independently hydrogen, substituted or unsubstituted alkyi, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyi, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyi, or an amino protecting group.

} In certain embodiments, X2 is —O—. In certain embodiments, X2 is —S—. In certain embodiments, X2 is —N(RX)—. In certain embodiments, RX is alkyl. In certain embodiments, RX is Me, Et, or i-Pr. In certain embodiments, RX is hydrogen. {00198} In certain embodiments, X1 is —O— and X2 is —O—. In n ments, X1 is —O— and X2 is —S—. In certain embodiments, X1 is —O— and X'3 is —N(RX)—. In certain embodiments, X1 is —S— and X.2 is —O—. In certain embodiments, X1 is —S— and X2 is —S—. In certain embodiments, XI is —S— and X2 is —N(RX)—. In certain embodiments, X1 is —N(RX)— and X2 is —O—. In n embodiments, X1 is —N(RX)— and X2 is —S—. In certain embodiments, X1 is —N(RX)— and X2 is —N(RX)—. {00199} As generaily defined above, R24 is H, substituted or unsubstituted aikyi, substituted or unsubstitued alkenyl, substituted or unsubstituted i, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstitued aryl, substituted or unsubstituted heteroaryl, —C(=O)RE1, ORE1, — C(=O)SRE1, —C(=O)N(RE1)2, —S(=O)2RE3, —S(=O);ORE1, —P(=O)2RE2, —P(=O);ORE1, — 0RE‘)2, —P<=0>(RE3>2, or —P(=o><0RE1>. {00200} In n embodiments, R24 is hydrogen. {00201} In certain ments, R24 is substituted or unsubstituted alkyl. In certain embodiments, R24 is alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of haio or and hydroxyi. In certain embodiments, R24 is tuted or unsubstitued alkenyl. In certain embodiments, R2’4 is substituted or unsubstituted aikynyl.

In certain embodiments, R24 is substituted or unsubstituted carbocyclyl. In certain ments, R24 is substituted or unsubstituted heterocyclyi. In certain embodiments, R24 is substituted or unsubstitued aryi. In certain embodiments, R341 is substituted or unsubstituted aryl. {00202} In certain embodiments, R24 is —C(=O)RE1, 6.5;, R24 is —C(=O)(CH2)pC02H, n p is an integer between 2 and 5, inclusive. In certain embodiments, p is 2. In n embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain ments, R24 is —C(=O)ORE1. In certain embodiments, R24 is —C(=O)SRE1. In certain embodiments, R241 is —C(=O)N(RE1)3. In certain embodiments, R24 is —S(=O)3RE2. In certain embodiments, R24 is —S(=O)ZORE1; e.g., -SO;H. In certain embodiments, R24 is — RE2. In n embodiments, R24 is —P(=O)ZORE1. In certain embodiments, R24 is — P(=O)(ORE1);. In certain embodiments, R24 is —P(L=O)(RE2);. In certain embodiments, R24 is — P(=0)(RE2)(0RE‘). {00203} As lly defined above, the subscript n is 0, l, 2, or 3. In certain ments, n is O. In certain embodiments, n is I. In certain embodiments, n is 2. In certain embodiments, n is 3.

Various embodiments wherein Z is a group offbrmula (iii), (it), or (w {00204} In certain embodiments, Z is a group of formula (iii), (iv), or (V): "Lari—YO 3 R26 R/LXYRE RZS 33/L3\l/ R24 (iii), RZS (iv), or Yst (v). {00205} In certain ments, L3 is substituted or unsubstituted C Maikylene, e.g., substituted or unsubstituted CHalkylene, substituted or tituted C2,3alkyiene, substituted or unsubstituted C3,4all } In any of the above or below instances, in certain ments, at least one instance of RZS is substituted or unsubstituted l, e.g., substituted or unsubstituted C3, galkenyl, substituted or unsubstituted nyl, substituted or unsubstituted CHalkenyl, tuted or unsubstituted C4,5alkenyl, or substituted or unsubstituted CMalkenyl. {00210} In any of the above or below instances, in certain embodiments, at least one instance of RZ5 is tuted or unsubstituted alkynyl, cg, substituted or unsubstituted C3, galkynyl, substituted or unsubstituted C;,3alkynyl, substituted or unsubstituted CHalkynyl, substituted or unsubstituted Crusalkynyi, or substituted or unsubstituted CHalkynyI. {00211} In any of the above or below instances, in certain embodiments, at least one instance of R25 is substituted or unsubstituted yclyl, 6.3., substituted or unsubstituted C3,6carbocyclyl, substituted or unsubstituted C3,4carbocyclyi, substituted or unsubstituted CL carbocyclyl, or tuted or unsubstituted CH, carbocyclyi. {00212} In any of the above or below instances, in n embodiments, at least one instance of RZS is substituted or tituted heterocyclyl, eg. substituted or unsubstituted 3—6 membered heterocyciyl, substituted or unsubstituted 3—4 membered heterocyclyl, substituted or unsubstituted 4~5 membered heterocyclyl, or substituted or unsubstituted 5—6 membered heterocyclyl. {00213} In any of the above or below instances, in certain embodiments, at least one instance of RZ5 is tuted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl. {00214} In any of the above or below instances, in certain embodiments, at least one instance of RZS is substituted or unsubstituted heteroaryl, e.g., optionaliy substituted 5—6 membered heteroaiyl. {00215} In any of the above or below instances, in certain embodiments, RZS is at protecting group, e.g.. an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a en protecting group when attached to a nitrogen atom.

} In certain embodiments, wherein two RZS are attached to a nitrogen atom, the two RZ5 groups arejoined to form a substituted or unsubstituted heterocyclic ring, eg, a tuted or tituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring. {00217} Furthermore, in any of the above or below instances, in certain embodiments, each instance of RZ6 is ndently hydrogen, substituted or unsubstituted alkyl, or two RZ6 groups are joined to form a C34) carbocyclic ring. {00218} In certain embodiments, at least one instance of RZ6 is en. {00219} In certain embodiments, at least one instance of RZ6 is substituted or tituted alkyl, eg. substituted or unsubstituted C{,6alkyl, substituted or unsubstituted CHalkyl, substituted or unsubstituted C2,3alkyl, substituted or unsubstituted C3,4all } Exemplary L3 alkylene groups e, but are not limited to: F F : F F KQUQfi/va, ,E/lvafi 3/1/37 "ma/pf" 4Y3 Illl NH "(>6 ">55MW awF F View "(by {00240} Exemplary L3 alkenylene groups include, but are not limited to: ~3ng "flea via/Mg: "mi, ix, "91 Wk, "@505 and «WV». {00241} ary L3 beteroalkylene groups include, but are not limited to: 2014/026633 MAO/\g‘s RAOAfi MAO/\f‘ ~117onfa , , , , RACK}: E/LOXEJF F F F wig/OW}? REA/Cy "IE/0%}? . .

"Rig/O\JJJ: ~1.,.L)/O\/LL‘s J‘é\/0\Jfi: 3/(DYE? 39/0X35 "HE/0vVaF F H" Ark?V0}; "2/OYEOI 3" 0y R/LYO {00242} In certain embodiments, the group R24 wherein L3 is an alkylene 0r heteroalkylene group, is of the formula: F F Fs Rio/\n/Cfi 1'11/:\o/\n/CF3 WCFS o O 0 O , 7 ., , /L F F F CF3 /:\ F CFB /\ iPr a o /L "a o "a, 0% ‘91 o/\"/iPr o o o o , 1 > Ill F F AF F O>81/iPr RAO>SKiPr "'71., o o o , , , 7 F F F F E/OWCFS R/OWCFS "Hy/OW"? "Ev/OWiPr O 0 0 O Vodka K?"Kim: "(00&1 2/">5": Q (-21 is"0;" ‘44»:O}fi 3 3‘'3'?o o , 7 ; F F F F g F F may/WWI" Pr RHWIPV HEWIP" .8? o o o o , a , O O E O ‘111w/\)J\CF 3 1,1, CF3 "517/.\/U\CF3 O O E O O "H11 CF3 ‘12,flakes? F F F "L9 IPr 157M?!" , , O O 5 O _ O "LLB/:\/U\iPr "Ravi—"\Pr "HEM"? "1L, IPr ; o o '11'1/\O HEW/LO RWOH or O , .

L R26 {00243} In certain embodiments, the group R26 wherein Y is —O— and L3 is an alkylene or aikyiene group, is of the formula: E/OWH a/LofigH RAOAKOH epoxy. null a/X:WW"ull :JVZ:M:MoiUI TI 'TI my/i/VOH’ 3M0", "’12ng fi/‘figH urlll OH OH nLH/VY or WWW / XYRZS ‘ . Z6 {002441 In certam embodnnents, the group R wherein Y is —NH— and L3 is an alkylene or heteroalkyiene group, is of the a Ill" 1&5 m/ ‘11,? 0%/L0 "I177/\ HR25 HRZ5 5 1.17 0%/\ HR25 "1111/0OJ Various embodiments ofR‘m, R47), R6, R7", R717, R14, R17, R18, and R19 {00251} As generaily defined above, each instance of R", R4b, Rh, and R717 is ndently hydrogen, —OH, haio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyciyi, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, N3 N03, SCN, CN,ORB1, SRBI, N(RBI)3, — N=NRB‘, —N=C.(RB‘)2, —N(0RB‘)(RB‘), —C(=O)RBI, —C(=O)ORBI, —C(=O)SRBI, — C(=O)N(Rb‘)3, —C(=O)N(ORB1)(RBI),—OC(=O)RBI, —OC(=0)0RB£ —OC(=O)SRB’, — OC(=0)N(R31)3,—NR*31C(=0)RB‘, —NR31C(=0)0RB‘, —NRB‘C(=O)SRBI, — NRB’C(=O)N(RBI)2, —SC(=O)RBZ, —SC(=0)0RB‘, —SC(=O)SRB1, )N(RBI);, — 3RBZ, —OS(=0)20RB‘, —S—S(=O)3RBZ, O)30RBI, RBZ, $021132, — NRBISOZRBZ, or —SO2N(RBI)3, wherein RBl is hydrogen, substituted or unsubstituted alkyl, tuted or unsubstituted alkenyl, substituted or unsubstituted alkynyi, substituted or unsubstituted carbocyclyl, substituted or tituted heterocyclyl, substituted or unsubstituted ar‘yl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when ed to a nitrogen atom, or two RBI groups are joined to form an substituted or unsubstituted heter‘ocyciic ring; and RB: is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or an RBI group and an R132 group are joined to form an substituted or unsubstituted heterocychc ring; or optionally wherein each of R4a and K", and/or R7" and R7b are joined to form an 0x0 (=0) group. {00252} In certain embodiments, each instance of R4a and R4b is hydrogen. In certain ments, one of R43 and R4}) is hydrogen. In certain embodiments, one of R4;1 and R4b is hydrogen; and the other is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted aikynyl. In certain ments, one of R43 and R41) is hydrogen; and the other is Me, Et, ethenyI, ethynyl, yl, or propynyl. In certain embodiments, each of R4a and R41) is independently substituted or unsubstituted alkyi. In n embodiments, each of R4a and R4b is Me. {00253} In certain ments, each instance of R7a and R7b is hydrogen. {00254} As generally defined above, each of R6a and R6b is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, and represents a single or doubie bond, ed if a double bond is present in Ring B, then one of R6a or R613 is absent, and provided if a single bond is present in Ring B, then the en at C5 is in the alpha or beta position. {00255} In certain embodiments, wherein """ represents a single bond, each instance of R63 and R6b is hydrogen. In certain embodiments, each instance of R6a and R6b is halo, e.g., fluor‘o. {00256} In certain embodiments, wherein """" represents a single bond, R63 is hydrogen, and R6b is haio, substituted or unsubstituted alkyl, substituted or unsubstituted l, or substituted or unsubstituted aikynyl. In certain ments, R68 is hydrogen, and R6b is halo (cg, fluoro). In certain embodiments, R6‘1 is hydrogen, and R6b is substituted or unsubstituted aikyl, 8g, substituted or tituted I, substituted or unsubstituted CHalkyi, substituted or tituted C2,3alkyl, substituted or unsubstituted C3,4aii } As generaily defined above, R14 is H or substituted or unsubstituted alkyl. In certain embodiments, R14 is H. In certain embodiments, R14 is substituted or unsubstituted alkyl (cg, -CH3). {00261} As generaily defined above, R18 is independently hydrogen or substituted or unsubstituted alkyi. In certain embodiments, R18 is en. In certain ments, R18 is substituted or unsubstituted alkyl (e.g.. -CH3). {00262} As generally defined above, R19 is independently hydrogen or substituted or unsubstituted alkyi. In certain embodiments, R19 is hydrogen. In certain embodiments, R19 is tuted or tituted alkyl (e.g., -CH3). {00263} In certain embodiments, R14 is hydrogen, R18 is -CH3 and R19 is -CH3. {00264} In certain embodiments, R14 is hydrogen, R18 is -CH3 and R19 is hydrogen.

Additional embodiments ofFormula (I) {00265} Various ations of the above embodiments are futher contemplated herein. For exampie, in certain ments, the compound of Formula (I) is of Formula (I- w) : (I-w) or a pharmaceuticaliy able salt, solvate, prodrug, stereoisorner, tautomer, isotopic t, or N—oxide thereof, or a combination thereof. In certain embodiments, R3b is hydrogen. In certain embodiments, the group —X1R3b at the C3 position is beta. In certain embodiments, R33 is hydrogen or substituted or unsubstituted aikyi. In certain embodiments, R2 is hydrogen or —ORBI. In certain embodiments, R"a is hydrogen and R11b is hydrogen or — ORB}. In certain embodiments, ‘‘‘‘‘ represents a single bond, R5 is alpha (down) and R63 is hydrogen. In certain embodiments, """ ents a double bond. In certain embodiments, R62) and R6b are both hydrogen. In certain embodiments, R63 is halo, cg, fluoro, or alkyl. In certain embodiments, R6h is halo, Lag, fluoro, or alkyl, and R68 is hydrogen. In certain embodiments, R6.3 and R6b are both halo, cg, fluoro. In certain embodiments, R19 is methyl. {00266} In certain embodiments, the compound of Formula (I) is of Formula (I-X): (1-10 or a pharmaceuticaliy acceptabie salt, solyate, prodrug, stereoisomer, tautomer, ic variant, or N—oxide thereof, or a combination thereof. In certain embodiments, the group — OH at the C3 position is beta. In certain embodiments, R38 is en or substituted or tituted alkyi. In certain embodiments, R2 is hydrogen or —ORB1. In certain embodiments, R113 is hydrogen and R111) is hydrogen or —ORB 1. In certain embodiments, represents a single bond, R5 is alpha (down) and R63 is hydrogen. In certain embodiments, """ represents a double bond. In certain embodiments, R6a and R6b are both hydrogen. In certain embodiments, R68 is halo, (1g. or alkyi. In certain _. fluoro, embodiments, R6b is halo, e.g., fluoro, or alkyl, and R6a is hydrogen. In n embodiments, R68 and R6}) are both halo, cg, . In certain embodiments, R19 is methyl. {00267} In certain embodiments, the compound of Fomiula (I) is of Formula (I-y): or a pharmaceutically acceptable salt, e, prodrug, stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination f. In n embodiments, the group — OH at the C3 position is beta. In certain embodiments, R3a is en or substituted or unsubstituted alkyl. In certain embodiments, R2 is hydrogen or —ORB 1. In certain embodiments, R11" is hydrogen and R11b is hydrogen or —ORBI. In certain embodiments, represents a single bond, R5 is alpha (down) and R63 is hydrogen. In certain embodiments, """ ents a double bond. In certain embodiments, R63 and R6b are both hydrogen. In certain embodiments, R6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R6b is halo, 6.3., fluoro, or alkyi, and R6" is hydrogen. In certain embodiments, R621 and R6b are both halo, e.g., fiuoro. {00268} In certain embodiments, the nd of Formula (I) is of Formula (I—z): or a pharmaceuticaliy acceptabie salt, solyate, prodrug, stereoisomer, tautomer, isotopic variant, or N—oxide f, or a combination thereof. In certain embodiments, the group — OH at the C3 position is beta. In certain embodiments, R38 is en or substituted or tituted alkyI. In certain embodiments, R2 is hydrogen or —ORB1. In certain embodiments, R113 is hydrogen and R111) is en or —ORBI. In certain embodiments, represents a single bond, R5 is alpha (down) and R63 is hydrogen. In certain embodiments, """ represents a double bond. In certain embodiments, R6a and R6b are both hydrogen. In certain embodiments, R68 is halo, 6g, fluoro, or aIkyI. In n embodiments, R6b is halo, e.g., fluoro, or alkyI, and R6a is hydrogen. In certain embodiments, R6a and R613 are both halo, cg, fiuoro. {00269} In certain embodiments, the compound of a (I) is of Formula (1-31), (I- 32), or (I—a3): (I-aS) or a pharmaceuticaliy able salt, solyate, prodrug, stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof. In certain embodiments, R3b is hydrogen. In certain embodiments, the group —OR3b at the C3 position is beta. In certain embodiments, R3a is hydrogen or substituted or unsubstituted aIkyi. In certain embodiments, R2 is hydrogen or —ORBl. In certain embodiments, R"a is hydrogen and R11b is hydrogen or — ORBI. In certain embodiments, R63 and R6b are both hydrogen. In certain embodiments, R6:] is halo, eg, fiuoro, or alkyl. In certain embodiments, R6b is halo, cg, fluoro, or alkyl, and R6:1 is hydrogen. In n embodiments, R681 and R6b are both halo, cg, fluoro. {00270} In certain embodiments, the compound of Formula (I) is of Formula (I-b 1), (1- b2), or (1-113): R53 ), (I-bZ), (I—bS) or a pharmaceuticaliy acceptable salt, solvate, prodrug, stereoisonier, tautomer, isotopic variant, or N—oxide thereof, or a combination f. In certain embodiments, R3b is hydrogen. In certain ments, R38 is hydrogen or substituted or unsubstituted aikyl. In certain embodiments, R2 is hydrogen or —ORB 1. In certain embodiments, RHa is en and R"b is hydrogen or —ORBI. In certain embodiments, R6'91 and R6b are both hydrogen. In certain embodiments, R621 is halo, 6g, fluoro, or aikyi. In certain ments, R6b is halo, eg, fluoro, or alkyl, and R6a is hydrogen. In certain embodiments, R6a and R6b are both haio, eg, fiuoro. {00271} In certain embodiments, the compound of Formula (I) is of Formula (I-cl), (I- c2), or (I-c3): R53 (I—ci), (I-c2), (1-03) or a pharmaceutically acceptable salt, solvate, prodmg, stereoisomer, tautomer, ic variant, or e thereof, or a combination thereof. In certain embodiments, R3b is hydrogen. In certain embodiments, R321 is hydrogen or substituted or unsubstituted alhyl. In certain embodiments, R2 is hydrogen or —ORBI. In certain ments, R"a is hydrogen and R"b is hydrogen or —ORBI. In certain embodiments, R68 and R6b are both en. In certain embodiments, R63 is halo, 6g, fluoro, or alkyl. In certain embodiments, R6b is halo, e.g., fluoro, or alkyl, and R6a is hydrogen. In certain embodiments, R6" and R6b are both halo, e.g., fluoro. {00272} In certain embodiments, the compound is of Formula (I—d): (1-11) or a pharmaceutically acceptable salt, solvate, prodmg, stereoisomer, er, isotopic variant, or N—oxide thereof, or a combination thereof. In n embodiments, R3b is hydrogen. In certain embodiments, the group —X1R3b at the C3 position is beta. In certain embodiments, R33 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2 is hydrogen or —ORBI. In certain embodiments, R"a is hydrogen and R11b is hydrogen or — ORB}. In certain embodiments, ‘‘‘‘‘ represents a single bond, R5 is alpha (down) and R63 is hydrogen. In certain ments, """ represents a double bond. In certain embodiments, R62) and R6b are both hydrogen. In certain embodiments, R63 is halo, e.g., fluoro, or alkyl. In certain ments, R6h is halo, cg, fluoro, or alkyl, and R68 is hydrogen. In certain embodiments, R6.3 and R6b are both halo, e.g., fluoro. In certain embodiments, R19 is methyl. In n embodiments, each R26 is independently hydrogen or methyl. {00273} In certain embodiments, the compound is ofFormula (I—e): L3 RZG (1-6) or a ceuticaliy acceptable salt, solvate, prodrug, isomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof. In certain embodiments, R321 is hydrogen or substituted or tituted alkyl. In certain embodiments, R2 is hydrogen or — ORB}. In certain embodiments, R"3 is hydrogen and R11b is hydrogen or —ORB1. In certain embodiments, """ represents a single bond, R5 is alpha (down) and R68 is hydrogen. In certain embodiments, """ represents a double bond. In certain embodiments, R6a and R6b are both hydrogen. In certain embodiments, R6a is halo, ag, fluoro, or aIkyl. In certain ments, R6b is halo, e.g., fluoro, or alkyl, and R62‘ is hydrogen. In certain embodiments, R6a and R6b are both halo, e.g., fluoro. In certain ments, R19 is methyl. In certain embodiments, each RZ6 is independently hydrogen or methyl. {00274] In certain embodiments, the compound is of Formula (I—f): (1-1) or a pharmaceuticaliy acceptabie salt, solvate, prodrug, stereoisomer, er, isotopic variant, or N—oxide thereof, or a combination thereof. In certain embodiments, R3b is hydrogen. In certain embodiments, the group —X1R3b at the C3 position is beta. In n embodiments, R32) is hydrogen or substituted or unsubstituted aikyi. In certain embodiments, R2 is hydrogen or —ORBI. In certain embodiments, R"a is hydrogen and R11b is hydrogen or — ORBI. In certain embodiments, """ represents a single bond, R5 is alpha (down) and R621 is en. In n embodiments, """ represents a double bond. In certain embodiments, R63 and R613 are both hydrogen. In certain embodiments, R6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R613 is halo, 6g, fluoro, or alkyl, and R6" is hydrogen. In certain ments, R62) and R613 are both halo, 6g, fluoro. In certain embodiments, R19 is methyl. In certain embodiments, each RZ6 is independently hydrogen or meth3'1. In certain embodiments, RZ5 is hydrooen or methyl. a a: - {00275} In certain embodiments, the compound is of Formula (I-g): NHRZS R1 1a L3 R26 R55 R61) (I-g) or a pharmaceuticaliy acceptable salt, solvate, , stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof. In certain embodiments, R3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2 is hydrogen or — ORBI. In certain embodiments, R113 is hydrogen and R11b is hydrogen or —ORB1. In certain embodiments, """ represents a single bond, R5 is alpha (down) and RGa is hydrogen, In certain embodiments, """ represents a double bond. In n ments, R62’ and R6b are both hydrogen. In certain embodiments, R6a is halo, 6g, fluoro, or aikyl. In certain embodiments, R6b is halo, e.g., fluoro, or alkyl, and R6:1 is hydrogen. In certain ments, R6" and R6b are both halo, e.g., fiuoro. In certain embodiments, R19 is methyl. In n embodiments, each RZ6 is independently hydrogen or methyl. In certain embodiments, RZS is hydrogen or methyl. {00276} In certain embodiments, the compound is of a (I—h): R118 L3/k R25 (1-1!) or a ceuticaliy abie salt, solyate, prodrug, stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof. In certain embodiments, R"b is hydrogen. In certain embodiments, the group —X1R3b at the C3 position is beta. In certain embodiments, R38 is hydrogen or substituted or unsubstituted aikyi. In certain embodiments, R2 is hydrogen or —ORB1. In certain embodiments, R"a is hydrogen and R111) is hydrogen or — ORB}. In certain embodiments, """ represents a single bond, R5 is alpha (down) and R621 is hydrogen. In n embodiments, """ represents a double bond. In certain embodiments, R6.3 and R6h are both en. In certain embodiments, R6a is halo, e.g., fluoro, or alkyl. In n embodiments, R6b is halo, e.g., fluoro, or alkyl, and R63 is hydrogen. In certain embodiments, R63 and R6b are both halo, e.g., fluoro. In certain embodiments, R19 is . In certain embodiments, R26 is isopropyl. {00277] In certain embodiments, the compound is of Formula (I—i): L3/]\ RZ6 L St) R63 R (I'i) or a pharmaceuticaliy acceptable salt, solvate, prodmg, stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof. In certain embodiments, R3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R2 is hydrogen or — ORBI. In certain embodiments, R113 is hydrogen and R11b is hydrogen or —ORB1. In certain embodiments, """ ents a single bond, R5 is alpha (down) and RGa is hydrogen. In certain embodiments, """ represents a double bond. In certain embodiments, R62’ and R6b are both en. In certain embodiments, R6a is halo, e.g., fluoro, or aikyl. In certain embodiments, R6b is halo, e.g., fluoro, or alkyl, and R6:1 is hydrogen. In certain embodiments, R6" and R6b are both halo, e.g., fiuoro. In certain embodiments, R19 is methyl. In certain embodiments, R26 is pyl. {00278} Additionai embodiments of Formula (I) e compounds of the following formula: L2_OR24 9—01224 R19 19 R3130 R3130 (IV-a) ' (IV-b) L2WOR24 4 CF3/li. I," R3130 R3bo (IV-c) (IV-d) or L2—0R24 (IV-e) L2 OH LZ—‘OH 19 19 III, HO HO (V-a) ’ (V-b) 2014/026633 R1 R1 L2—————OH LQ—OH R19 R19 CF3/I1. \ll ’ HO HO (v-0) (V-d) or L2--OH \/1/ (V-e) R1 R‘ n n MeMe Me R19 R19 R24 R24 \//I .

Rsbo R3bo (VI-a) ’ (VI-b) Me " Me MeMe R19 R24 CF \\ /l I , R3b or (WC) (Vl-d) 19 R24 \III.

(VI-e) R1 R‘ MeM MeMe R19 OH R19 OH \II., HO HO (VII-b) ’ (VII-a) ' Me Me R19 OH ‘9 OH CF3/h.

\/I I HO ' H0 or (VH'C) 19 OH \IIn (VII-e) WO 60441 OR24 R3bO H OH (IX) LZ—OH LZ—OH Lz—OH Xlla or Xllb {00279} In certain embodiments the compound is any one of the following nds: CH3 CH3 OH OH CF3,. CH3,.

HO HO 3CH3 3 OH OH H3CO F \,,,, \,, 9 3 CH3CCH3 CH3CCH3 OH OH \\:., H\\"" OH H3C CH3 Cl\§lv HO HO WO 60441 H C3 r: F OH HO HO 3 1 F CH 30H3 HO HO 3CH3 OH OH HO HO , 3 CH3 CH3 CH3 CH3 OH H OH HO HO 3 7 OH OH HO HO > > 2014/026633 CH3 CH3 CH3 CH3 OH H OH CF3,, HO HO , 7 CH CH 3CH3 3CH3 H OH H OH H300 CH3,, \II:,_ HO HO , , CH CH 3CH3, 3CH3 H OH H OH \Ilh, \\'II,.

HO HO 7 , 3CH3 CH3CH3 H OH H OH \ CI HO HO 7 , H C3 OH OH H H30 CH3 H HO HO WO 60441 H FFOH H HO H0 3 .9 CH3 CH3 H OH H OH HO HO 3(2H3 H OH H OH H OH H OH CH3 CH3 CH3 CH3 H OH H OH HO HO > 1 WO 60441 WO 60441 0WOWCH3 H301," or a pharmaceutically acceptable salt, solvate, prodmg, isomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof.

} In certain embodiments the compound is any one of the following compounds: CH3 CH3 CH3 CH3 SH NH2 HO HO , , CH3 CH3 CH3 CH3 HN—CH3 OH HO HS 1 3 CH3 SCH CH3 3 H2N 3 CH3 CH3 CH3 CH3 H SH H NH2 HO HO WO 60441 CH3 CH3 CH3 CH3 H HN—CH3 H OH HO HS CH3 CH3CH CH3 3 H OH H H3C\ HZN N 2‘ a CH3 CH3 CH3 CH3 NIH ""H NH2 HN‘CHg HO H0 , , WO 60441 HON" H OH "ONE \/ N" Flown or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomen tautomer, isotopic variant, or N—oxide thereof, or a ation thereof. {00281} In certain ments the compound is any one of the following compounds: WO 60441 H30".

H3C,,,, ’ 0V0 H30," O O o O z \_.—< H3010. H3C’/,, HO HO OHHS 0 CH3 9 7 or a pharmaceuticaliy acceptable salt, solvate, g? stereoisomer, tautomer, isotopic variant, or N—oxide thereof? or a ation thereof. {00282} In certain embodiments the compound is any one of the following compounds: WO 60441 or a pharmaceutically acceptable salt, solvate, prodmg, stereoisomer, tautomer, isotopic variant, or e thereof, or a combination thereof.

} In certain embodiments the compound is any one of the following compounds: 3 3 or a pharmaceutically acceptable salt, solvate, prodmg, stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination f. {00284} In certain embodiments the nd is any one of the ing compounds: or a pharmaceutically acceptable salt, solvate, prodmg, stereoisomer, tautomer, isotopic variant, or N—oxide thereof, or a combination thereof. {00285} In certain embodiments the compound is any one of the following compounds: 2014/026633 Ho,,,_ H01," H30 H30 H H ,or 7 or a pharmaceutically able salt, solvate, prodrug, stereoisomer, er, isotopic variant, or N—oxide thereof? or a combination thereof. {00286} In certain embodiments, the compound is a compound of Formula (I) is a compound ofFormula (I-q), (I-q) and pharmaceutically acceptable salts thereof; wherein: R1 is substituted or unsubstituted alphatic; R3 is hydrogen, halogen, substituted or tituted C1_6alkyl, substituted or unsubstituted cyclopropyl, or —ORA2, n RA2 is hydrogen or substituted or unsubstituted alkyl; R33 is hydrogen or —ORA3 wherein R" is hydrogen or substituted or unsubstituted alkyl, and R3b is hydrogen; or R321 and R3b are joined to form an 0X0 (=0) group; R4 is hydrogen, substituted or unsubstituted alkyl, or halogen; X is —C(RX :— or —O-, wherein RX is hydrogen or fluorine, or one RX group and R5b are joined to form a double bond; each instance of R5" and ij is independently hydrogen or fluorine; 2014/026633 R681 is a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyi, substituted and unsubstituted aikenyi, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclyl, tuted and unsubstituted heterocyclyL substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl group.‘ wherein the non-hydrogen group is optionaliy substituted with fluorine; and R61) is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; — represents a single or double bond, provided if a single bond is present, then the hydrogen at C5 is in the alpha configuration; and further provided that: (l) at least one of RX, R5", and R5b is fluorine; or (2) at least one of R661 and R6b is a non-hydrogen group substituted with a fluorine; or (3) R6a is a non—hydrogen group comprising n two and ten carbon atoms. {00287} In n embodiments, the compound of the present invention is a pharmaceuticaliy acceptable salt. {00288} As lly described herein, compounds of formula (I-q) wherein the hydrogen at C5 is provided in the beta configuration demonstrate loss ofNMDA potentiation compared to compounds wherein the hydrogen at C5 is alpha, or wherein a double bond is present at C5-C6. Thus, the compound of Formula (I—q) asses only compounds of Formula (I-qA) and (I-qB): (I-qA) (I-qB) and ceutically acceptabie salts thereof.

Group Riafcampozma’s (jformula (I—q) {00289} As generaily defined herein" R1 is tuted or unsubstituted alphatic, 17.6., substituted or tituted alkyl, substituted or unsubstituted alkenyl, tuted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl. {00290} In certain embodiments, R1 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted Cmalkyl, substituted or unsubstituted CHalkyi, substituted or unsubstituted C2,3alkyl, substituted or unsubstituted CHalkyi, substituted or unsubstituted CMalkyI, or substituted or unsubstituted C5,(,all In certain ments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, triazolyl, zolyi, thiadiazolyl, tetrazolyi. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or tituted heterocyclyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolidinyl, dinyl, piperazinyl, or mopholinyl. In certain embodiments, R1 is propynyl or butynyl, substituted with liydroxyi 0r alkoxy. In certain embodiments, R1 is propynyl or butynyi, tuted with methoxy or ethoxy. In certain embodiments, R1 is ethynyl or propynyl, substituted with chloro. In certain embodiments, R1 is ethynyl or propynyl, substituted with trifluoromethyl. {00297} In certain embodiments, R1 is substituted or unsubstituted carbocyclyi, cg, substituted or unsubstituted C3,6carbocyclyl, substituted or unsubstituted CHcarbocyclyl, substituted or unsubstituted C44 carbocyclyl, or substituted or unsubstituted C54, yclyi.

In certain embodiments, R1 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted utyl.

Groups R3, R3", R35, and R4 ofcompounds offormzda (I-q) {00298} As generally defined herein, R2 is hydrogen, halogen, substituted or unsubstituted C1.6all } In certain embodiments, both R33 and R3b are both hydrogen.

} In certain embodiments, RS" and R313 are joined to form an oxo (=0) group. {00302} In certain embodiments, R33 is —ORA3 and R3b is hydrogen. In certain embodiments, wherein R33 is —ORA3, R3a is in the alpha or beta configuration. In certain embodiments, wherein R3a is —ORM, R3" is in the alpha configuration, In certain embodiments, wherein R3a is —OR‘AC‘, R33 is in the beta configuration. In certain embodiments, RA3 is hydrogen. In certain embodiments, RA3 is substituted or unsubstituted alkyl, 6g, substituted or unsubstituted CHalkyl, tuted or unsubstituted C Halkyi, substituted or unsubstituted C2,3a1kyl, substituted or unsubstituted CHalkyi, substituted or unsubstituted Casalkyl, or substituted or unsubstituted C54aikyl. In certain embodiments, RA3 is hydrogen, —CH3, 3, or —CH2CH3CH3, i.€., to provide a group R3a of formuia — OH, —OCH3, -OCH2CH3, or —OCH2CH2CH3. {00303} As generaily defined herein, R4 is hydrogen, substituted or unsubstituted alkyl, or haiogen. In certain ments, R4 is hydrogen. In certain embodiments, R4 is halogen, cg, fluoro. In certain ments, R4 is substituted or unsubstituted alkyl, cg, substituted or unsubstituted C Malkyl, substituted or tituted CHaikyi, substituted or unsubstituted C2,3alky'i, substituted or unsubstituted analkyi, substituted or unsubstituted Casaikyl, or substituted or unsubstituted CMalkyl. In certain embodiments, R4 is C 1 aikyl, 8g, -CH3 or - CF3. In certain embodiments, R4 is en, -CH3, or —F. In certain embodiments, wherein :4: ents a singie bond, R4 is a non-hydrogen tutent in the alpha configuration. In certain embodiments, wherein — represents a singie bond, R4 is a non-hydrogen substituent in the beta configuration.

Group X, R5", 12%, R6". and R" of’compozmds offbrrmtla (I—q) {00304} As generally defined herein, X is —C(RX)2— or —O-, wherein RX is en or e, or one RX group and R5b are joined to form a double bond; each of RSa and R5b is independently hydrogen or fluorine; R6" is a non-hydrogen group selected from the group consisting of substituted and unsubstituted aikyl, substituted and unsubstituted alkenyl, substituted and unsubstituted aikynyl, substituted and unsubstituted carbocyclyl, substituted and tituted heterocyclyl, tuted and unsubstituted aryl, and substituted and unsubstituted heteroaryl group, wherein the non-hydrogen group is optionally substituted with fluorine; and R6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; provided: (I) at least one of RX, R5", and R5b is fluorine; or (2) at least one of R6" and R6b is a non-hydrogen group substituted with fluorine; or (3) R621 is a non- hydrogen group sing n two and ten carbon atoms. {00305} In n embodiments, X is —O—. In certain embodiments, X is —CH2—. In certain embodiments, X is —CF2—. {00306} In certain embodiments, at Ieast one of R5a and R5b is hydrogen. In certain embodiments, at least one of R5'" and R . . . . is fluorine. In certain embodiments, R5:1 and R5b are both hydrogen. In certain embodiments, R58 and R5b are both fluorine. In certain embodiments, RX and R513 are joined to form a double bond, e.g., CITS or trams doubie bond. {00307} In certain embodiments, R63 is a non-hydrogen group, as described herein, which is not substituted with fluorine. In n ments, R6.3 is substituted or unsubstituted alkyi (6g, —CH3, —CH3CH3,—CH(CH3)2), substituted or unsubstituted i, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyciyl (6.9, isopropanol). In certain embodiments, R63 is a non-hydrogen group, as described herein, which is substituted with fluorine. {00308} In n embodiments, R6a is a drogen group, as described herein, and R6b is hydrogen. In certain embodiments, R63 is a non-hydrogen group, as described herein, and R6b is a substituted or unsubstituted alkyl group optionally substituted by fluorine. In certain embodiments, R6b is an aikyi group which is not substituted with fluorine. In certain embodiments, R68 is an alkyl group which is tuted with fluorine. {00309} In certain ments, R6b is hydrogen. In certain embodiments, R6’13 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted CMalkyl, substituted or unsubstituted C , substituted or unsubstituted l, substituted or unsubstituted yi, substituted or unsubstituted Casalkyl, or substituted or unsubstituted C5,6alkyl, optionally substituted by fluorine. In certain embodiments, R6b is C; aikyl optionally substituted by fluorine, e.g., —CH3 or —CF3. {00310} In certain ments, R661 is substituted or unsubstituted alkyi, cg, substituted or unsubstituted kyl, substituted or unsubstituted C Halkyi, substituted or unsubstituted CHalkyl, substituted or tituted analkyi, substituted or unsubstituted Casalkyi, or substituted or unsubstituted C5,(,all In certain embodiments, R6a is substituted with one or more —ORA6 groups, wherein RA6 is hydrogen or substituted or unsubstitued alkyl. In n ments, R6a is a substituted or unsubstituted C24 alkyl, substituted or unsubstituted C33 alkenyl, substituted or unsubstituted C33 alkynyl, or substituted or unsubstituted C3 carbocyclyl, and R6b is —CH_;. In certain embodiments, R62) is a unsubstituted C34 aikyl, tituted C33 alkenyl, or tituted C33, alkynyl, or unsubstituted C3 carbocyclyl, and R6b is —CH3. In certain embodiments, R6a is a drogen group substituted with fluorine, and R6b is —CH3.

Various Combinations ofCertain Embodiments {00320} Various combinations of n embodiments are futher contempiated herein. {00321} For example, in certain embodiments, wherein X is —CH2— and R5a and R5b are both hydrogen, provided is a compound of Formula (I-qa): (I-qaf) or a pharmaceuticaliy acceptabie salt thereof. In certain embodiments, R6a is a non-hydrogen group sing between two and ten carbon atoms. In certain embodiments, at least one of R6:1 and R6b is a non—hydrogen group substituted with e. In certain embodiments, the carbon to which R63 is attached is in the (S) configuration. In n embodiments, the carbon to which R68 is attached is in the (R) configuration. In n embodiments, R6a is methyl (C 1) optionaliy substituted with one or more fluorines, e.g., -CH3 or -CF3. In certain embodiments, R62) is substituted or tituted ethyI (C2), substituted or unsubstituted n— propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R(m is — CH20RA6, —CH;CH;ORA6, or —CH2CH2CHZORA6. In n embodiments, R621 is substituted or unsubstituted Vinyl (C3) or substituted or unsubstituted allyi (C3). In certain embodiments, R63 is substituted or unsubstituted l (C2) or substituted or unsubstituted propargyl (C3). In certain ments, R62’ is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF3. In certain embodiments, — represents a single bond, and the hydrogen at C5 is alpha. In certain embodiments, ~—_-; represents a double bond. In certain embodiments, R1 is —CH3 or — CH2CH3. In certain embodiments, R2 is hydrogen, —OH, —OCH3, —OCH3CH3, — OCHgCHgCHg, —CH3, -CH3CH3, —CH2CH2CH3, cyclopropyi, fluoro, or chloro. In n embodiments, R2 is a non-hydrogen substitutent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration. In certain embodiments, R32) and R3b are both hydrogen. In certain embodiments, R33 and R31) are joined to form =0 (0X0). In certain embodiments, R4 is hydrogen. {00322} In certain embodiments, wherein X is —CH2- and R53 and R5b are both fluorine, provided is a compound of Formula (I—qb): (I-qb) or a pharinaceuticaliy abie salt thereof. In certain embodiments, R6a is a non-hydrogen group comprising between two and ten carbon atoms. In certain embodiments, at least one of R621 and R61) is a non-hydrogen group substituted with fluorine. In certain embodiments, the carbon to which R63 is attached is in the (S) configuration. In certain embodiments, the carbon to which R68 is attached is in the (R) ration. In n embodiments, R6a is methyl (C1), optionaliy substituted with one or more es, eg. —CH3 or -CF;. In certain embodiments, R62) is substituted or unsubstituted ethyI (C2), substituted or unsubstituted n— propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R63 is — CHZORM, —CH2CH20RA6, or —CH3CHZCH30RA6. In certain embodiments, R6" is substituted or unsubstituted Vinyl (C2) or tuted or unsubstituted allyi (C3). In certain embodiments, R62) is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is hydrogen. In n embodiments, R6b is —CH:, or —CF3. In certain embodiments, — represents a single bond, and the hydrogen at C 5 is alpha. In certain embodiments, — represents a double bond. In certain embodiments, R1 is —CH3 or — CH3CH3 In n embodiments, R2 is hydrogen, —OH, —OCH3, —OCH3CH3, — OCHgCHZCH3, —CH3, -CH2CH3, 3CH3, cyclopropyi, fluoro, or chloro. In certain embodiments, R2 is a non-hydrogen substitutent in the alpha configuration. In certain embodiments, R2 is a non—hydrogen substituent in the beta configuration. In certain embodiments, R38 and R3b are both en. In certain embodiments, R3" and R3b are joined to form =0 (oxo). In certain embodiments, R4 is en. {00323} In certain embodiments, wherein X is —C(RX)2— and one RX group and R5b are joined to form a trans double bond, provided is a compound of a (I—qc): (jI-qc) or a pharmaceuticaliy acceptable salt thereof. In certain embodiments, R6a is a non-hydrogen group comprising between two and ten carbon atoms. In n embodiments, at least one of R6" and R6b is a non-hydrogen group substituted with fluorine. In n embodiments, the carbon to which R681 is attached is in the (S) configuration. In certain embodiments, the carbon to which R6a is ed is in the (R) configuration. In certain embodiments, R63 is methyl (C1) optionaliy substituted with one or more fluorines, cg, -CH3 or -CF:,. In certain embodiments, R63 is substituted or unsubstituted ethyi (C3), substituted or unsubstituted n— propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R63 is — , —CH2CH20RA6, or —CH3CHZCH30RA6. In n embodiments, R6" is substituted or unsubstituted Vinyl (C2) or substituted or unsubstituted allyi (C3). In certain embodiments, R62) is substituted or tituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain ments, R6a is substituted or tituted cyclopropyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF3. In certain embodiments, ~22: represents a single bond, and the en at C5 is alpha. In certain embodiments, -—- represents a double bond. In certain embodiments, R1 is —CH; or — CH2CH3. In certain embodiments, R2 is hydrogen, —OH, —OCH3, —OCH3CH3, — OCHZCHZCH3, —CH3, -CH;CH3, —CH3CH2CH3, cyclopropyi, fluoro, or chloro. In certain embodiments, R2 is a non-hydrogen substitutent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration. In n embodiments, R33 and R3b are both en. In ceitain embodiments, R3a and R3b are joined to form =0 (0X0). In certain embodiments, R4 is hydrogen. {00324} In certain ments, the compound of Formula (I-q) is selected from a compound of a (I-qd): S 05 R1 (I-qd) or a pharmaceuticaliy abie salt f. In certain embodiments, R6" is a non-hydrogen group comprising between two and ten carbon atoms. In certain embodiments, at least one of R6;1 and R6b is a non-hydrogen group substituted with ne. In certain embodiments. the carbon to which R6a is attached is in the (8) uration. In certain embodiments, the carbon to which Rfia is attached is in the (R) configuration. In certain embodiments, R621 is methyl (C1) optionally substituted with one or more fluorines, 6.0., —CH3 or -CF_;. In certain embodiments, R68 is substituted or unsubstituted ethyl (C3), substituted or unsubstituted n— propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R68 is — CHgORAG, —CH2CHZORA6, or —CH3CH2CHQORA6. In certain embodiments, R63 is substituted or unsubstituted Vinyl (C2) or substituted or unsubstituted allyi (C3). In certain embodiments, R6a is substituted or unsubstituted ethynyl (C3) or substituted or unsubstituted propargyl (C3). In certain embodiments, R62‘ is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is hydrogen. In certain ments, R6b is —CH3 or —CF3. In certain embodiments, -=—= represents a single bond, and the hydrogen at C 5 is alpha. In certain embodiments, — represents a double bond. In certain embodiments, R1 is —CH3 or — CH3CH3. {00325} In certain embodiments, the compound of Formula (I—q) is selected from a compound of Formula (I—qe): R; (I-qe) or a ceuticaliy acceptable salt thereof. In certain embodiments, R6a is a non-hydrogen group comprising between two and ten carbon atoms. In certain embodiments, at least one of R6" and R6b is a non-hydrogen group substituted with fluorine. In certain embodiments, the carbon to which R681 is attached is in the (S) configuration. In certain embodiments, the carbon to which R621 is attached is in the (R) configuration. In certain embodiments, R6" is methyl (C1) optionaliy substituted with one or more es, cg, -CH3 or -CF:,. In certain embodiments, R68 is tuted or unsubstituted ethyl (C2), tuted or unsubstituted n— propyl (C3), or substituted or unsubstituted pyl (C3). In certain embodiments, R63 is — CHZORN’, —CH2CH20RA6, or —CH3CHZCH30RA6. In certain embodiments, R6" is substituted or unsubstituted Vinyl (C2) or substituted or unsubstituted allyi (C 3). In certain embodiments, R62) is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted gyl (C3). In certain embodiments, R63 is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF;. In certain embodiments, R1 is —CH3 or —CH2CH3. {00326} In certain embodiments, the compound of a (I—q) is selected from a compound of Formula (I-qf): R1 9 (I-qf) or a pharmaceutically acceptabie salt thereof. In ceitain embodiments, R6" is a non-hydrogen group comprising between two and ten carbon atoms. In certain embodiments, at least one of R6" and R6b is a drogen group substituted with e. In certain embodiments, the carbon to which R6:1 is attached is in the (S) configuration. In certain embodiments, the carbon to which R63 is attached is in the (R) configuration. In n ments, R6a is methyl (C1) optionally substituted with one or more fluorines, 6.0., -CH3 or -CF3. In certain embodiments, R6a is tuted or unsubstituted ethyl (C2), substituted or unsubstituted n— propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R6") is — CH20RA6, —CH;CH;ORA6, or —CH2CH2CH20RA6. In certain embodiments, R6'61 is substituted or unsubstituted Vinyl (C3) or substituted or unsubstituted allyi (C3). In certain embodiments, R63 is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF3. In certain embodiments, R1 is —CH3 or —CH2CH3. {00327} In certain ments, a compound of Formula (I—q) is selected from the group consisting of: WO 60441 WO 60441 WO 60441 ’1 OH WO 60441 6-10 6-1 2 6-13 6-14 6-17 WO 60441 WO 60441 WO 60441 -12 10-12A -123 10-13 -14 WO 60441 11-17 11-18 11-19 and pharmaceutically acceptable salts f.

Pharmaceutical Compositions {00328} In r aspect, the invention provides a ceutical composition comprising a phannaceutically acceptable carrier and a ive amount of a compound of Formula (I). {00329} When employed as pharmaceuticals, the compounds provided herein are lly administered in the form of a pharmaceutical composition. Such itions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. {00330} In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier. {00331} The present invention also relates to a compound of the present invention or pharmaceutical composition thereof for use as a pharmaceutical or a medicament. {00332} Generally, the compounds provided herein are administered in a therapeutically ive amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant stances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the it’s symptoms, and the like. {00333} The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds provided herein are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration. {00334} The compositions for oral administration can take the form of bulk liquid ons or suspensions, or bulk powders. More commonly, r, the compositions are presented in unit dosage forms to facilitate accurate . The term "unit dosage forms" refers to physically te units suitable as unitary s for human subjects and other mammals, each unit ning a predetermined quantity of active material calculated to produce the desired therapeutic effect. in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

In such compositions, the compound is usually a minor component (from about 0.1 to about St % by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids l for forming the desired dosing form. {00335} Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and sing agents. colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose. a disintegrating agent such as alginic acid.

Primogel, or corn ; a lubricant such as magnesium stearate; a glidant such as dal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl late, or orange flavoring. {00336} lnjectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. {00337} Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, ably from about 0.1 to about 10% by weight. and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a inic or a water-miscible ointment base. Alternatively, the active ients may be formulated in a cream with. for example an oil-in-water cream base.

Such transdermal formulations are nown in the art and generally include additional ients to enhance the dermal ation of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein, 2014/026633 {00338} The compounds provided herein can also be administered by a transdermal . Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety. {00339} 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 of Remington ’3 Pharmaceutical Sciences, l7th edition, 1985, Mack Publishing Company, , Pennsylvania, which is incorporated herein by reference. {00340} The above-described components for orally administrable, injectable, 0r topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 ofRemington ’s The Science and Practice ofPharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference. {00341} The compounds of this invention can also be administered in ned release forms or from sustained release drug ry systems. A ption of representative sustained release materials can be found in ton ’5 Pharmaceutical Sciences. {00342} The present invention also s to the phannaceutically able formulations of a compound of the present invention. In one embodiment, the formulation ses water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are a—, {3— and y— extrins consisting of 6, 7 and 8 oc—l ,4—linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and srtlfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether B—cyclodextrin, e.g, for example, sulfobutyl ether [3— cyclodextrin, also known as CaptisolO. See, cg, US. 5,376,645. In certain embodiments, the formulation ses hexapropyl-B-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl-{3-cyclodextrin (10-50% in water). {00343} The present invention also relates to the phamiaceutically acceptable acid addition salt of a nd of the t invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i. c a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, ate, acetate, lactate, citrate, tartrate, succinate, maleate, furnarate, benzoate, para-toluenesulfonate, and the like.

} The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in ance with this invention. The present invention, however, is not limited to the ing ceutical compositions. {00345} Exemplary Formulation I — 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. {00346} Exemplary Formulation 2 — Capsules: A compound of the t invention may be admixed as a dry powder with a starch t in an approximate 1:1 weight ratio, The e is filled into 250 mg capsules (125 mg of active compound per capsule). {00347} ary Formulation 3 — Liquid: A compound of the present ion (125 mg) may be admixed with sucrose (1.75 g) and n gum (4 mg) and the resultant mixture may be blended, passed through a N0. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate ( 10 mg), flavor, and color are diluted with water and added with ng. Sufficient water may then be added to produce a total volume of 5 {00348} ary Formulation 4 — 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 lubricant. The mixture is formed into 450—900 mg tablets (150-300 mg of active compound) in a tablet press. {00349} Exemplary Formulation 5 — Injection: A nd of the present invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL. {00350} Exemplary Formulation 6 — 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 90—150 mg tablets (30—50 mg of active compound per tablet) in a tablet press. {00351} 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 amomit of magnesium stearate is added as a lubricant. The mixture is formed into -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 mixture is formed into 03—30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press. {00353} azjy Formulation 9 — Tablets: A nd of the present invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.

A minor amount of magnesium stearate is added as a lubricant. The e is formed into 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 ion 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 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

} Injection dose levels range from about 0.1 mg/kg/hour to at least /hour, all for from about i to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/lrg to about 10 ing/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. {00356} For the prevention and/or treatment of long-term conditions the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are entative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg. {00357} Transdermal doses are generally selected to e similar or lower blood levels than are ed using injection doses. {00358} When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at rislr for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.

Subjects at rislr 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 screening to be particularly susceptible to developing the condition.

Alefhoa’s QfEVaZUdinH, em and Use {00359} Described herein are, inter alia, methods of evaluating or treating a patient, eg, a patient having a disorder described herein. In some embodiments, a compound described herein is administered to a patient (eg, an effective amount of a compound described herein). In some embodiments, the method includes optionally, acquiring a patient sample and acquiring an tion of and/or evaluating the sample for an alteration in the level 24(S)—hydroxycholesterol compared to a reference standard. In certain ments, the responsive to the evaluation, a patient is treated for a disorder described herein with a compound bed herein, eg, a patient is stered an effective amount of 24(8)- hydroxycholesterol or a structurally-related sterol or steroid, an oxysterol, an agonist of an NMDAR or a positive allosteric tor (PAM) of an NMDAR, a compound that augments (e.g., increases) the endogenous activity or amount of 24(s)- ycholesterol, such as a compound that inhibits an enzyme that metabolizes 24(s)- hydroxycholesterol, for example, a nd that inhibits 24-hydroxycholesterol 7alpha-hydroxylase (CYP39), or a compound described herein such as a compound of formula (I). In some embodiments, the compound is an antagonist of an NMDAR or a NAM, or a compound that reduces the endogenous ty or amount of 24(s)-hydroxycholesterol, such as a compound that activates an enzyme that produces 24(s)- hydroxycholesterol, for example, a compound that activates cholesterol 24(S)—hydroxylase (CYP46). {00360} "Acquire" or ring" as the terms are used herein, refer to obtaining possession of a physical entity, or a value, eg, a numerical value, by "directly acquiring" or "indirectly acquiring" the physical entity or value. "Directly acquiring" means ming a process (6. 0., performing a synthetic or analytical method) to obtain the physical entity or value. "Indirectly acquiring" refers to receiving the al entity or value from another party or source (eg, a third party laboratory that directly acquired the physical entity or value). ly acquiring a physical entity includes performing a process that includes a al change in a physical substance, (1g, a starting material. Exemplary changes include making a physical entity from two or more starting als, shearing or fragmenting a substance, separating or purifying a substance, ing two or more separate entities into a 2014/026633 mixture, performing a chemical reaction that includes breaking or forming a covalent or non— covalent bond. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, cg, performing an analytical process which includes a physical change in a substance, ag, a , analyte, or reagent (sometimes referred to herein as "physical analysis"), performing an analytical method, ag. a method which includes one or more of the ing: separating 0r purifying a substance, eg, an analyte, or a fragment or other derivative thereof, from another substance; combining an analyte, or fragment or other derivative thereof, with another substance, cg, a buffer, solvent, or reactant; or changing the structure of an analyte, or a fragment or other derivative thereof, rag, by breaking or forming a covalent or non—covalent bond, between a first and a second atom of the analyte; or by changing the structure of a reagent, or a fragment or other derivative thereof, eg, by ng or forming a covalent or valent bond, between a first and a second atom of the reagent. {00361} "Acquiring a sample" as the term is used herein, refers to obtaining sion of a sample, eg, a tissue sample or nucleic acid sample, by "directly ing" or "indirectly acquiring" the sample. "Directly acquiring a sample" means performing a process (eg, performing a physical method such as a surgery or extraction) to obtain the sample.

"Indirectly acquiring a sample" refers to ing the sample from another party or source (eg, a third party laboratory that directly acquired the sample). Directly acquiring a sample includes performing a process that includes a al change in a physical substance, eg, a starting material, such as a tissue, cg, a tissue in a human patient or a tissue that has was previously isolated from a patient. ary changes include making a physical entity from a starting material. dissecting or scraping a tissue; separating 0r purifying a substance (e.g., a sample tissue or a nucleic acid ); ing two or more separate entities into a e; performing a chemical reaction that includes breaking or forming a covalent or non- covalent bond. Directly ing a sample includes performing a process that includes a physical change in a sample or another substance, eg, as bed above. {00362} As used , a patient who is a "candidate" is a one likely to respond to a particular therapeutic regimen, relative to a reference patient or group ofpatients. A "non- candidate" t is one not more likely to respond to a particular therapeutic n, relative to a reference patient or group of patients. 2014/026633 {00363} The compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non—human mammals. Thus, and as stated earher, the present invention es within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the ation of medicaments useful for such methods. In one aspect, compounds described herein are contemplated as therapeutic agents, e.g., for the treatment of CNS ions in mammals, such as for the treatment of schizophrenia, sion, r disorder (e.g., I and/or II), schizoaffective er, mood ers, anxiety disorders, personality disorders, psychosis, compulsive disorders, post- traumatic stress disorder (PTSD), Autism spectrum disorder (ASD), dysthymia (miid sion), social anxiety disorder, obsessive compulsive disorder (OCD), pain (cg, a l syndrome or disorder), sleep disorders, memory ers (e.g., memory impairment), dementia, Alzheimer‘s Disease, a seizure disorder (e.g., sy), traumatic brain injury (TBI), stroke, addictive disorders (8.57., addiction to opiates, cocaine, and/or alcohol), autism, Huntington's Disease, insomnia, son's e, Withdrawal syndromes, or tinnitus. In some embodiments, a compound described herein can be used to improve learning in a subject (cg, improve cognative function). In certain embodiments, the compounds of the present invention are useful in the treatment of depression, anxiety, mood disorders, sleep disorders, memory disorders (6g, memory impairment), traumatic brain injury, stroke, epilepsy, cognative disfunction, and schizophrenia. In some embodiments, a compound described herein can be used to treat an overdose, 6g, a drug se such as ketamine or PCP overdose. {00364} Exemplary CNS conditions related to NMDA—modulation include, but are not limited to, adjustment disorders, anxiety disorders (inciuding ive-compulsive disorder, posttraumatic stress disorder, social , generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse—related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those invoiving mutations to the Shank group of proteins), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus. {00365} In another aspect, provided is a method of evaluating or treating a mammal susceptible to or afflicted with a condition associated with brain excitability, which method comprises stering an ive amount of one or more of the pharmaceutical compositions described herein. {00366} In another aspect, provided is a method of inducing sedation or anesthesia. In another aspect, provided is a method of evaluating or treating a mammal susceptible to or afficted with a condition associated with adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic ers, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, pain, seizure disorders, stroke, traumatic brain injury, movement disorders and us.

} In yet another aspect, provided is the use of a compound of the present invention as a pharmaceutical, e.g., especially in the treatment or tion of the aforementioned conditions and diseases. {00368} In still yet another aspect, ed is a method of manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and {00369} In still yet r aspect, the present invention provides a method for preventing, treating, ameliorating or ng a disease or condition which comprises administering to a subject in need of such prevention, treatment, amelioration or management, a prophylactically or therapeutically ive amount of a compound of the present invention, or the pharmaceutical composition thereof. {00370} In yet another aspect, the t invention provides a use of a compound of the present invention for the manufacture of a medicament to treat a disease or condition associated with brain excitability. In one embodiment, the disease or condition is selected from depression, anxiety, phrenia, sleep ers, memory disorders, and mood disorders. {00371} In yet another aspect, the present invention provides a method of ent of a mammal, eg, a human being, to treat a disease associated with brain excitability, including WO 60441 treating said mammal with an effective amount of a compound of the present invention or composition thereof.

} In yet another aspect, the present ion provides a combination of a compound of the present invention and another phar‘macologically active agent. {00373} The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other . Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating stration, EXAlVIPLES {00374} In order that the invention described herein may be more fully understood, the following examples are set forth. The tic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical itions and methods provided herein and are not to be construed in any way as ng their scope.

Materials and Methods {00375} The compounds provided herein can be prepared from readily available starting als using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (116., on 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 ions can be determined by one skilled in the art by routine optimization. {00376} Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The 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 ting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. {00377} The nds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, or HPLC. The following s are presented with details as to the preparation of entative substituted biarylamides that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

} The enantiomerically pure compounds provided herein may be prepared according to any techniques known to those of skill in the art. For instance, they may be prepared by chiral or asymmetric synthesis from a suitable optically pure precursor or obtained from a racemate by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer. See, e.g., "Enantiomers, Racematcs and Resolutions," by J. Jacques, A. Collet, and SH. Wilen, (Wiley-Interscience, New York, 1981); SH. Wilen, A. , and J. Jacques, Tetrahedron, 2725 (1977); EL. Eliel Stereochemistty ofCarbon Compounds w-Hill, NY, 1962); and SH. Wilen Tables of Resolving Agents and Optical Resolutions 268 (EL. Eliel ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972, chemisttjy ofOrganic nds, Ernest L. Eliel, Samuel H.

Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc), and Stereosc/ective Synthesis A Practical Approach, Mihaly NOgradi (1995 VCH Publishers, Inc, NY, NY). {00379} In certain embodiments, an enantiomerically pure nd of the present invention may be obtained by on of the racemate with a suitable optically active acid or base. Suitable acids or bases include those bed in Bighley et al., 1995, Salt Farms of Drugs and tion, in Encyclopedia ofPharmaceittical Technology, vol. 13, Swarbrick & Boylan, eds, Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95:512; and CRC Handbook ofOptical Resolution via Diastereomcric Salt Formation, the ts of which are hereby incorporated by reference in their entireties. {00380} omerically pure compounds can also be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid omer used. The identity and optical purity of the particular compound so recovered can be determined by metry or other analytical methods known in the art. The diasteroisomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer regenerated by treatment with an appropriate base or acid. The other enantiomer may be obtained from the racemate in a similar manner or worked up from the liquors of the first separation.

In n embodiments, enantiomerically pure compound can be separated from racemic compound by chiral chromatography. Various chiral columns and eluents for use in the separation of the enantiomers are available and le conditions for the separation can be empirically determined by methods known to one of skill in the art. Exemplary chiral columns available for use in the separation of the enantiomers provided herein e, but are not limited to, CHIRALCEL® OB, CHIRALCEL® OB—H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF.‘ CHIRALCEL® 0G, CHIRALCEL® OJ and CHIRALCEL® OK.

Synthetic ures {00381} General processes for preparing compounds of the present invention are ed as further embodiments of the invention and are illustrated in generalized schemes l-l3 and Examples l-36. For the purpose of Scheme l-l3, if not defined, R’ is alkyl, R33 is 23c 3 T' 3 Z? Tb - - R l J or R2 b; and X1, L15 R1, R", R b, R ’3, and R are as described herein.

Scheme 1. Synthesis of bstituted-3 Q-hydroxy steroids debromination 19 R23 HO ; FQSa Scheme 2. Synthesis of 30t-Substituted-3 Q-hydroxy steroids 1 OH 23 Al—‘OH23 i) separation ii) Nu - (H', F', etc) 0 0 R23 R1 debromination R19 R23 2-2 (R33 = Me, CHzF, etc) 2_3 (R38 = Me, CHzF, etc) Scheme 3. Synthesis of 3B—Amino- and kylamino steroids R" R23 L1 +0Ac L1 +OH R19 R23 R19 R23 i) AcCl. Et3N ii) deprotect PG—O iii) 014380201, EtSN iv) 313.590. TMS-NS 3-2 Ph3P, H20, NaOH R1 < R23 L: +OH L1 +OH 0 R3b‘CHo ii) NaBHSCN Rab. HN 3-4 (R35 = alkyi) Scheme 4. Synthesis of Steroid sulfates L"#7OH H8030 /CL\R:§:L/' 4—1 4—2 SchemeSSynthesis of Steroid SB--ester and amide /R1 R1, R23 R23 fiiOH //\\ U‘.’OH R23 R19 R23 RWCOOH EDCL HOBt O \/ §\—X1 3'0‘ Raw = alkyl or -(CH2)25—COOH Scheme 6. Synthesis of 3—OX0 ds 4° 0 R19 OR' 1 1— n) Wittig p'o ii) Oxdn Br P‘O 1 1-2 DAST OH OH deprotection debromination PD 5 P'O Q33 R33 11-5 11-4 Scheme 12. Synthesis of 3a—Substituted-3B-hydroxy ds R19 OH W OR’ R19 OH 3) 3-OH protection HO \ HO ii) MeMgBr 12-1 12-2 12-3 I deprotection R19 OH 12—4 Scheme 13. Synthesis of 30L-Substituted-3B-hydroxy steroids R‘i / ii} debromination LA i) Separation? \/ HO g v ii) H- «F- R' Rv//: 13—3 13—6 (R" = Me) 13—4 (R" = Me) 13-? (R" = CHEF) 13—5 (R" = CHEF)‘ Example 1. Preparation of Compound STA-001 Ho/\/OH Bess-Martin —> —> PTSA, toluene, reflux HO O aq. HCI PPhacHgBr MeMgBr, MAD —> I —> THF/acetone , THF toluene O Pd/C, H2(1 atm) A_001_3 STA-001 {00382} Preparation of Compound 2: To a solution of ketone 1 (50.0 g. 0.17 mol. 1.0 eq) and ethylene glycol (62 mL) in toluene (600 mL) was added p-toluenesulfonic acid (1.4 g, 7.28 mmol). The reaction mixture was heated at reflux overnight with a Dean-Stark trap.

LCMS showed the ng material was consumed completely. The mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), and washed with saturated s sodium bicarbonate (300 mL x 2) and brine (300 mL x 2). The c phase was dried over sodium sulfate and concentrated in vacuum to afford crude t 2 (64.0 g, l00%) which was directly used in the next step without further purification. 1H NMR: (400 MHz CDClS) 5.35 (d. J=5.6 Hz, 1H), 3.97-3.82 (m, 4H), 3.59-3.47 (m, 1H), 2.34-2.21(m, 2H), 2.06-1.94 (m 2H), l.90—l.74 (m, 3H), 1.73-1.64 (m, 1H), 1.63-1.33 (m, 10H), 1.32-1.19 (m, lH), l.l4- 1.03 (m, 1H), 1.01 (s, 3H), 0.99-0.93 (m, 1H), 0.86 (s, 3H). {00383} Preparation of Compound 3: To a solution of compound 2 (32 g, 96 mmol. eq) in dry CHgClg (1200 mL) was added Bess-Martin (81 g, l92 mmol, 2.0 eq) in portions at 0 0C. Then the reaction mixture was stirred at room temperature for 3 h. TLC (PEzEA = 3: 1) showed the starting material was consumed completely. The mixture was quenched with saturated aqueous NaHCO3/N338303 = l13 (l L). The organic phase was washed with brine (500 mL) and dried over NagSOr and the solvent was evaporated to afford crude product 3 (33.0 g, 10 96), which was direct1y used in the next step without further purification. 1H NMR: (400 MHz, CDC13) 5 5.34 (d, J=5.2 Hz, 1H), 3.77-4.00 (m, 4H), 3.19- 3.39 (m, 1H). 2.83 (dd, J=16.44, 2.13 Hz, 1H), 2.38-2.59 (m, 1H), 2.21-2.37 (m, 1H), 1.95- 2.09 (m, 3H), 1.54-1.73 (m, 4H), 1.74-1.90 (m, 2H), 1.37-1.51 (m, 3H), 1.21-1.34 (m, 2H), 1.19 (s. 3H), 0.98-1.12 (m, 1H), 0.83-0.93 (m, 3H). {00384} Preparation of MAD: To a solution of compound 5 (96 g, 436 mmol, 1.0 eq) in toluene (300 mL) was added a solution ofA1Me3 (109 mL. 218 mmol. 0.5 eq, 2 M in hexane) at room temperature, at which time the methane gas was d immediately. The resulting e was stirred at room temperature for 1 h and used as a on ofMAD in toluene in the next step t any purification. {00385} Preparation of Compound 4: To a solution ofMAD (218 mmoi, 2.3 eq, freshly prepared) in toiuene (300 mL) was added dropwise a so1ution of compound 4 (33 g, 96 mmol, 1.0 eq) in toluene (100 mL) at -78 0C during a period of 1 h under en. Then the reaction mixture was d for 30 min, a solution of MeMgBr (205 mL, 288 mmol, 3 .0 eq, 1.4 M in toluene) was added dropwise at -78 OC. The reaction mixture was warmed to -40 °C and d at this temperature for 3 h. TLC (PE:EA = 3:1) showed that the starting material was consumed completely. The mixture was poured into saturated aqueous NH4C1 on (200 mL) and extracted with EA (150 mL x 2). The combined organic phases were dried over Na2804. and the solvent was evaporated to afford crude product. The crude product was purified by silica gei chromatography eluted with PE:EA (15: 1) to give the product (7.64 g, 22%) as white powder. 1H NMR: (400 MHz, CDC13) 5 5.30 (d, J=5.2 Hz, 1H), 3.75-4.04 (m. 4H), 2.42 (a, J=13.6 Hz, 1H), 1.88-2.12 (m, 3H). 1.73—1.86(1n.2H), 1.64-1.72 (m, 2H), .63 (m, 4H), 1.35- 1.51 (m, 4H). 1.19-1.32 (m, 1H), 1.12-1.18 (m, 1H), 1.10 (s, 3H). 0.99-1.03 (m, 3H), 0.92- 0.98 (m, 1H), 0.86 (s, 3H). {00386} Compound INT A: To a solution of compound 4 (6.0 g, 17.3 mmol. 1.0 eq) in THF (200 mL) was added s HC1 solution (35 1nL, 1 M) and acetone (35 mL). The reaction mixture was d at room temperature overnight. TLC (PE:EA = 3: 1) indicated that the reaction was complete. Then the reaction mixture was di1uted with EA (200 mL), washed with saturated aqueous NaHCO3 so1ution (200 1nL), dried over NaQSO4 and evaporated under reduced pressure to give the product (5.2 g, 99.2%). 1H NMR: (400 MHz.

CDCl3) 8 5.27 (d, J=6.8 HZ, 1H), 2.45-2.35 (m, 2H), 2.09-1.84 (m, 4 H), 1.82—1.57 (m, 6H), 1.50-1.35 (m, 4H), 1.26-1.08 (m, 4H), 1.05 (s, 3 H), 0.95 (s, 3 H), 0.86 (s, 3 H).

} Compound A_001_l: To a solution ofPPthHgBr (28.3 g, 79.35 mmol) in THF (50 mL) was added a solution of t-BuOK (8.96 g, 79.35 mmol) in THF (20 mL) at room temperature. After stirring for 1 11, INT A (4.0 g, 13.22 mmol) dissolved in THF (10 mL) was added dropwise. The reaction mixture was refluxed for 3 h. The on e was cooled to room temperature and ed with Sat. NH4C1, extracted with EA. The combined organic layer was washed with brine, dried and concentrated to give the crude product, which was purified by a flash column chromatography (PE/EA=15/l) to afford compound A_001_l (3.2 g, Y=80%) as a white solid. 1H NMR: (400 MHz, CDC13) 5 5.32 (d. J=5.2 Hz, 1H), 4.65-4.64 (m, 2H), 2.50-2.42 (m, 2H), 2.27-2.22 (m, 1H), 2.07-1.97 (m, 1H), 1.87-1.68 (m, 4H), .49 (m, 7H), 1.40-1.15 (m, 4H), 1.12 (s, 3H), 1.05 (s, 3H), 1.04-0.96 (m, 1H), 0.80 (s, 3H). {00388} Preparation of Compound A_001_2: To a solution of compound A_001_1 (300 mg, 1.0 mmol, 1.0 eq) and methyl propiolate (250 mg, 3.0 mmol, 3.0 eq) in CH3C12 (5 mL) was added dropwise EtgAlCl (4 mL, 4.0 mmol, 4.0 eq, 1 M in toluene) with stirring at 25 0C, then the reaction e was d overnight. TLC (PE/EA = 3/1) indicated that the ng material was consumed completely. The solution was washed with saturated aqueous , (5 mL), dried over NaZSOi and concentrated under reduced pressure to e the crude product which was purified by silica gel chromatography eluted with PEzEA (15:1) to give the desired product (200 mg, 52%) as a white powder. 1H NMR: (400 MHZ, CDCl3) 5 7.03-6.97 (m, 1H), 5.86 (dd, J1=1.2Hz, J;=15.6Hz, 1H), 5.35 (d, J=1.2Hz, 1H), 5.32 (d, J=5.2Hz, 1H), 3.72 (s, 3H), 2.87 (d. J=6.8 Hz, 2H), 2.42 (d. J=13.2 Hz, 1H), 2.13-1.95 (m, 3H), 2.00-1.40 (m, 11H), 1.40-1.20 (m, 4H), 1.11 (s, 3H), 1.06 (s, 3H), 0.90-0.82 (m, 3H), 0.78 (s, 3H). {00389} Preparation of Compound A_001_3: To a solution of compound A_001_2 (192 mg, 0.5 mmol, 1.0 eq) in BA (5 mL) was added Pd/C (5%, 40 mg) under N3. The suspension was degassed under vacuum and purged with H3 several times. Then the mixture was stirred under H; balloon at 30 0C for 1 h. TLC (PEzEA = 3: 1) showed that the reaction was complete. The suspension was filtered through a pad of celite and the pad was washed with EA (5 mL x 2). The combined filtrates were concentrated to dryness to give the product (185 mg, 95%) as a white powder. 1H NMR: (400 MHZ, CDC13) 5 5.31 (d, J=4.4Hz, 1H), 3.67 (s, 3H), 2.42 (d, J=13.2 Hz, 1H), 2.35-2.28 (m 2H), 2.02-1.92 (m, 2H), 1.90-1.60 (m, 6H). 1.55-1.30 (m, 6H), 1.30-1.13 (111,511), 1.12 (s, 3H), 1.02(s, 3H). 1.00-0.75 (m, 4H), 0.58 (s, 3H). {00390} Preparation of Compound ST—200-A-001: To a on of compound A_001_3 (150 mg, 0.3 86 mmol. 1.0 eq) in THF (5 mL) was added dropwise MeLi (2 mL, 3.200 mmoi, 8.3 eq, 1.6 M in THF) at -78 0C under nitrogen. After the addition the reaction mixture was warmed to -40 °C and stirred for 1 h. TLC (PE2EA = 3: 1) showed that the on was complete. The on mixture was quenched with saturated aqueous NH4C1 (10 1nL), extracted with EA (10 1nL x 2). The combined organic 1ayers were concentrated under reduced pressure to provide the crude product which was d by siiica gel chromatography eluted with PEzEA (10:1) to give product (91 mg, 60%) as a white powder. 1H NMR: (400 MHz. CDC13)8 5.31 (d. J=5.6Hz, 1H), 2.43 (d, J=13.2 Hz, 1H), 2.05-1.95 (m, 2H), 1.90-1.60(1n,6H), 1.21 (s, 6H). 1.12 (s, 3H), 1.11-1.04 (m, 1H), 1.03 (s, 3H), 1.01-0.92 (m, 2H), 0.58 (s, 3H).

Example 2. Preparation of Compound STA-003 Ph3PEtBr :0_ —> —> t-BuOK, THF EtZAICI, DCM JACS, 1981, 237 Pd/C, H2(1 atm) EtOAc MeLi STA-003 {00391} Preparation of Compound A_003_1 : To a solution of PthEtBr (12.25 g. 33.00 mmoi, 10.0 eq) in dry THF (15 mL) was added dropwise a solution of l-BuOK (3.70 g, 33.00 mmol. 10.0 eq) in dry THF (10 mL) under N; at 0 OC. The e was stirred at room temperature for 1.5 h. Then a solution of TNT A (1.00 g, 3.31 mmol. 1.0 eq) in THF (10 mL) was added dropwise and the resulting mixture was stirred at 70 °C for 4 h. TLC (PEzEA = 3:1) ted that the starting material was consumed completely. The reaction was quenched with ted aqueous NH4C1 solution (50 mL) and extracted with EA (30 mL x 2). The combined organic phases were dried over NaZSO4 and trated in vacuum. The residue was purified by column chromatography on silica gel (eluent: PE: EA = 12: 1) to give the product (900 mg, 90.9%) as a white powder. 1H NMR: (400 MHZ. CDC13) 6 5.32 (d, J=5.2Hz, 1H), 5.15-5.12 (m, 1H), .30 (m, 3H). 2.29-2.21 (m, 1H), 2.05-1.97 (m. 2H). 1.81-1.45 (m, 14H), 1.30-1.15 (m, 3 H), 1.12 (s, 3H), 1.02 (s, 3H), 0.95-1.01 (m, 1H), 0.90 (s, 3H). {00392} Preparation of Compound A_003_2 : To a solution of compound A_003_1 (1.00 g, 3.20 mmol, 1.0 eq) and methyl propiolate (0.67 g, 8.00 mmol, 2.5 eq) in dry DCM (15 mL) was added dropwise a solution of EtgAlCI (12.8 mL, 12.8 mmol, 4.0 eq, 1 M in toluene) with stirring at 0 0C. Then the reaction was warmed to room temperature and stirred overnight. TLC (PE:EA = 5:1) indicated that the starting material was consumed completely.

The mixture was quenched with saturated s NaHC03 solution (30 mL) and extracted with DCM (30 mL )1 2). The combined organic phases were dried over Na2804 and concentrated in vacuum. The e was purified by column chromatography on silica gel (eluent: PEzEA = 10:1) to give product (1.00 g, 78.7%) as white powder. 1H NMR: (400 MHZ. CDC13) 5 6.97-6.91 (m, 1 H) 5.82 (d,J=16 Hz, 1 H), .41 (m, 1H), 5.32 (d.

J=5.2Hz, 1H), 3.73 (s, 3 H), 3.04-3.00 (m, 1 H), 2.43 (d. J=12.8 Hz, 1H), 2.11-1.97 (m. 3H). .50 (m. lZH). l.40-l.20 (m, 3 H) l.21-l.26 (m, 1H), l.l8 (d, J=6.78 Hz, 3H). 1.12 (s. 3H), l.04 (s, 3H), 0.82 (s, 3H). {00393} ation of Compound A_003_3: To a solution of nd A_003_2 (160 mg, 0.40 mmol) in BA (15 1nL) was added Pd/C (30 mg, 5%). Then the reaction was stirred under 15 psi of H2 pressure at room temperature for 2 h. TLC (PE/EA = 3/1) showed that the starting material was consumed completely. And then the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the product (150 mg. 92.8%). 1H NMR: (400 MHz, CDCl3) 5 5.32 (d, J=5.2Hz, 1H), 3.67 (s, 3 H), 2.48-1.96 (m, 7H), .62 (m, 5H), 1.60-1.55 (m, 7H), 1.11 (s, 3H), 1.03-0.99 (m, 3 H). 0.95-0.93 (m, 2H), 0.70-0.66 (m, 2 H).

} Preparation of Compound STA-003: To a soiution of compound A_003_2 (100 mg, 0.25 mmol. 1.0 eq) in dry THF (1 mL) under N2 protection was added dropwise MeLi (1.56 mL, 2.50 mmol, 1.6 M in THF) at -78 OC and the mixture was stirred at this temperature for 30 min. TLC (PEzEA = 3:1) showed that the reaction was complete.

The reaction mixture was quenched with saturated aqueous NH4C1 (5 mL) and extracted with EA (5 mL x 2). The combined organic layers were concentrated under reduced re to provide the crude product, which was purified by silica gel chromatography eluted with PE:EA (10:1) to give the t (45 mg, 45%) as a white powder. 1H NMR: (400 MHZ, CDCl3) 5 5.30 (d, J=5.2HZ, 1H), 2.42 (d, J=12 HZ, 1 H), 2.02-1.98 (m, 3 H), 1.92-1.66 (m, 3 H), 1.61-1.56 (m, 2 H), 1.55-1.54(m.2H), .23 (m, 11 H). 1.20 (s. 6H), 1.10 (s. 3 H), 1.05 (s, 3H), 1.02 (s, 3 H), 0.95-0.90 (m, 3 H), 0.68 (s, 3 H).

Example 3. Preparation of Compound STA-007 Dess-Martin Ph3P=CHCOOMe Pd/C, H2(1 atm) —> —> toluene, reflux EtOAC STA-OO7 WO 60441 {00395} Preparation of Compound INT E: To a solution of 9-BBN (0.5 M in THE 133 mL, 66.6 mmol, 10.0 eq) under ice-bath, a solution ofA_001_1 (2.0 g, 6.66 mmol, 1.0 eq) in THF (10 1nL) was added dropwise. The reaction mixture was heated to 60 °C and stirred for 20 h. The mixture was cooled to 0 0C and 10% aqueous NaOH solution (20 1nL) followed by 30% aqueous H202 (30%, 10 mL) was added. The mixture was stirred for 2 11 at 0 0C and then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL). dried over Na2804 and concentrated in vacuum to give the cmde product, which was purified by a flash column chromatography eluted by PE/EA (10/1) to afford INT E (1.0 g, 47%) as a white solid. 1H NMR: (400 MHZ, CDClS) 5 5.30 (d, J=5.2Hz, 1H), 3.75- 3.71 (dd, J1=10.4HZ, J3=6.8HZ, 1H), 3.58-3.53 (dd, J1=10.4HZ, J;=7.6HZ, 1H), 2.43-2.41 (d, J=10.4Hz, 1H), 2.02-1.96 (m, 2H), 1.91 -1.75 (m, 3H), 1.72-1.44 (m, 10H), 1.33-1.20 (m, 5H), 1.18 (s, 3H), 1.06 (s, 3H), 1.04-0.99 (In, 1H), 0.67 (s, 3H). {00396} Preparation of nd INT B: To a solution of lNT E (100 mg, 0.314 mmol, 1.0 eq) in DCM (10 mL) under ice-bath. Dess—Martin reagent (265 mg, 0.628 mmol, 2.0 eq) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The e was poured into a solution 03 (4.5 g) and NaHC03 (1.5 g) in water (20 mL). extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 1nL), dried over NaZSO4 and concentrated in vacuum to give the crude product (100 mg, 100%) which was used directly in the next step without further purification. {00397} Preparation of Compound A_007_1: A mixture of lNT B (100 mg, 0.316 mmol, 1.0 eq) and Ph3P=CHCOOCH3 (634 mg, 1.89 mmol, 6.0 eq) in toluene (10 1nL) was stirred for 3 h at 80 0C and then concentrated in vacuum. The residue was purified by a flash column chromatography eluted by PE/EA (12/1) to afford product A_007_1 (65 mg, 55.2%) as a White solid. 1H NMR: (400 MHZ. CDCl3) 5 6.99-6.93 (dd. J1=l6 Hz, Jg=8.4Hz, 1H), .82-5.77 (dd, J1=15.6 Hz. Hz, 1H). 5.30 (d, J=5.2Hz, 1H), 3.73 (s, 3H), 2.42 (d, Hz, 1H), 2.14-2.11 (m, 1H), 2.05-1.99 (In 2H), 1.98-1.41 (in, 15H), 1.29-1.24 (m, 2H), 1.12-1.14011, 1H), 1.12 (s, 3H), 1.06 (s, 3H). 1.02-0.95 (m, 1H), 0.66 (s, 3H). {00398} Preparation of Compound A_007_2: A mixture of compound A_007_1 (65 mg, 0.174 mmol, 1.0 eq) and Pd/C (5%, 20 mg) in BA (5 1nL) was d for 2 h at room ature under H2 (1 atm). The mixture was filtered and the filtrate was concentrated in vacuum to give product A_007_2 (65 mg, 100%) which was used directly 111 the next step without further purification.

WO 60441 {00399} Preparation of Compound ST-ZOO-A-007: To a solution ofA_007_2 (65 mg, 0.17 mmo1, 1.0 eq) in THF (2 mL) at -78 °C, CH3Ll (1.6 M in THE 1 mL, 1.7 mmo1, 10.0 eq) was added dropwise under nitrogen. The on mixture was warmed to room temperature and stirred for 1 h. The e was quenched with saturated aqueous NH4Cl (10 mL) and then extracted with EA (5 mL x 2). The combined organic layers were washed with brine (5 rnL), dried over Na2$O4 and concentrated in vacuum to give the crude product, which was purified by a flash column chromatography (eluent: PE/EA = 8/ l) to afford ST—ZOO-A—007 (27 mg, 41%) as a white solid. 1H NMR: (400 MHz. CDC13)5 5.30 (d. J=5.2Hz. 1H), 2.42 (d, 2 Hz, 1H), 2.02-1.96 (m, 2H), l.86 -l.38 (m, l4H), .14 (m, 4H), 1.21 (s, 6H), 1.11 (s, 3H), 1.09—1.05 (1n, 2H) 1.02 (s, 3H), 1.01-0.94 (m, 3H), 0.61 (s. 3H).

Example 4. Preparation of Compound STA-011 CeCl3, NaBH4 STA-01 1 {00400} Preparation of Compound INT D: To a solution of TNTA (2.00 g, 6.58 mmol, 1.0 eq) in MeOH (30 mL) and THF (l5 mL) was added CeCl3.7H20 (2.45 g, 6.58 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 10 min. Then NaBH4 (0.50 g, 13.16 mmo'l. 2.0 eq) was slowly added and the i'esuitiiig mixture was stirred for 30 min at room temperature. TLC (PE/EA = 3/1) showed that the reaction was complete.

The reaction mixture was quenched by addition of saturated aqueous NH4Cl (50 mL) and extracted with BA (50 mL x 2). The combined organic layers were dried over NaQSO4 and evaporated to dryness to give the desired product (1.84 g, 91%) as a white solid. 1H NMR: (400 MHZ, CDCl3) 5 5.30 (d, J:5.2 Hz, 1H), 3.65 (t, J:8.6 Hz, lH), 2.43 (d, J:l3.2 HZ, lH), .97 (m, 3H), 1.97-1.68 (m, 3H), 1.64—1.38 (m, 5H), l.3l-l.20 (m, 2H), l.l9-l.l6 (m, 1H), 1.11 (s, 3H), 1.11-1.04 (m, 1H), 1.03 (s, 3H). 1.01-0.93 (m, 2H), .84 (m. 1H), 0.76 (s. 3H). {00401} Preparation of Compound A_011_l: To a solution of TNT D (500 mg, 1.63 mmol, 1.0 eq) in DCM (10 mL) was added methyl propiolate (325 mg, 3.30 mmol, 2.0 eq) and NMM (287 mg, 3.30 mmol. 2.0 eq) in turn. The reaction mixture was stirred at room temperature for two days. TLC (PE/EA = 3/1) showed that the reaction was complete. The reaction mixture was washed with saturated aqueous NaHC03 (20 mL) and brine (20 mL). dried over N32504 and evaporated to dryness to give the crude product. The e was d by silica gel chromatography eluted with PE: EA (15:1) to give the desired t (274 mg, 43%) as a white solid. in NMR: (400 MHz, CDCl3) 5 7.54 (d, J:12.8 Hz, 1H), 5. 29 ((1, 11:52 Hz, 1H). 5.24 (d, 11:12.8 Hz, 1H), 3.88 (t, J:8.2 HZ, lH), 3.68 (s, 3H), 2.42 (d.

J:13.2 Hz, 1H), 2.19-2.09 (m, 1H), 2.00-1.89 (m, 2H). .84 (m, 1H), .70 (m. 2H). 1.62-1.50 (m, 5H), 1.49-1.41 (m, 2H), 1.39-1.29 (m, 1H), 1.19-1.10 (m, 2H), 1.11 (s, 3H), 1.02 (5.311), 1.00-0.91 (m, 2H), 0.79 (s, 3H). {00402} ation of Compound A_011_2: To a solution of compound A_Ol l_l (50 mg, 0.128 mmol) in BA (5 mL) was added 5% Pd/C (50%. 25 mg) under argon. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 balloon at room temperature for 4 h. TLC (PE/EA = 3/1) showed that the starting material was consumed completely. Then the suspension was filtered through a pad of celite and the pad was washed with EA (5 mL x 3). The combined filtrates were trated to dryness to give the product (48 mg, 96%) as a white solid which was used directly in the next step without purification. 1H NMR: (400 MHz. CDCl3) 8 5.30 (d. J:5.2 Hz, 1H), 3.77-3.69 (m, 2H), 3.66 (s, 3H), 3.32 (t, J:8.4 Hz, 1H), 2.56 (t, J:6.4 Hz, 2H), 2.42 (d, J:12.4 Hz, 1H), 2.00-1.89 (m, 4H), 1.81-1.67 (m, 2H), 1.57-1.44 (m, 6H), 1.43-1.32 (m, 1H), 1.30-1.13 (m, 4H), 1.11 (s. 3H). 1.02 (s. 3H), 0.99-0.91 (m, 2H), 0.74 (s, 3H).

} Preparation of Compound ST—200-A-011: To a solution of compound A_011_2 (:60 mg. 0.16 mmol, 1.0 eq) in anhydrous THF (5 mL) was added dropwise MeLi (l mL, 1.60 mmol, 10.0 eq. 1.6 M in Eth) at -78 "C under N2. The reaction mixture was stirred at -78 0C for 30 min and then warmed to room ature for another 30 min. TLC (PE/EA = 3/1) showed that the starting al was consumed completeiy. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL). The resulting solution was extracted with EA (5 mL x 3). The combined organic layers were washed with brine (10 1nL), and dried over Na;SO4 and concentrated in . The residue was purified by silica gel chromatography eluted with PE: EA (10: 1) to give the target product (25 mg. 42%) as white solid. 1H NMR: (400 MHz. CDC13) 5 5.29 (d. J=4.8Hz. 1H). .62 (m, 2H), 3.27 (t.

J:8.4 Hz, 1H), 2.39 (d, J:13.2 Hz, 1H), 2.05-1.86 (m, 4H), 1.76-1.64 (m, 3H), 1.59-1.37 (m, 8H), 1.27-1.20 (m, 1H), 1.19 (s, 6H), 1.12-1.08 (m, 2H), 1.07 (s, 3H), 0.99 (s, 3H), 0.98-0.89 (m. 2H), 0.72 (s. 3H).

Example 5. Preparation of Compound STA-013 INT E STA-013 {00404} To a solution of TNT E (150 mg, 0.471 mmoi, 1.0 eq) in DMSO (1 mL) was added KOH (53 mg, 0.942 mmoi, 2.0 eq) and 2,2-dimethyloxirane (340 mg, 4.717 mmol, .0 eq). The reaction mixture was stirred at 50 0C for 16 h. TLC (PE/EA =3/l) showed the staiting material was consumed compietely. The mixture was cooled to room temperature. d with ethyl acetate (20 mL), and washed with saturated aqueous NH4C1 (10 1nL x 2) and water (10 mL x 2). The organic phase was dried over sodium e and concentrated in vacuum to afford the crude product which was purified by coiumn chromatography foilowed by prep-HPLC purification to afford pure product ST—200-A-013 (14 mg, 8%). 1H NMR (400MHz, CDCB) 5 5.30 (d, J=5.2HZ, 1H) 3.57-3.48 (m, 1H), 3.38-3.35 (‘m 1H), 3.20 (s, 2H), 2.42-2.40 (in, 1H), 2.03-1.85 (m, 3H), 1.76 (m, 4H), l.55-l.43 (m. 4H), 1.25 (s, 3H), 1.28-1.25 (m, 6H), 1.17-1.13 (m, 2H), 1.11 (s. 3H). 1.06-0.96 (m, 5H), 0.92-0.79 (m. 2H), 0.65 (s. 3H).

Example 6. Preparation of nd STA-017 INT D STA-017 {00405} To a solution of nd INT D (150 mg, 0.49 mmol, 1.0 eq) and 2, 2- dimethyloxirane (1.5 g, 20.8 mol, 42.0 eq) in DMSO (3 1nL) was added KOH (56 mg, 1.0 mmol, 2.0 eq), then the reaction mixture was stirred at 60 0C for 5 h. TLC (PE:EA= 3:1) indicated that the reaction was complete. The on was cooled to room ature, diluted with water (10 mL), extracted with EA (5 mL x 2). The combined organic layers were concentrated under reduced pressure to provide the crude product which was purified by pre- HPLC to give the product (6.6 mg, 3.5%) as a white powder. 1H NMR: (400 MHz, CDClg) 5 .30 (d, J=5.2Hz, 1H), 3.33 (t, J=8.0Hz. 1H), 3.29-3.22 (m, 2H). 2.40-2.50 (m, 2H), 2.05- 1.85 (m, 4H), 1.82-1.65 (m, 2H), 1.60-1.35 (m, 9H), 1.34- 1.22 (m, 1H), .15 (m, 6H). 1.14-1.11 (m, 1H). 1.12 (s, 3H). 1.05 (s, 3H). 0.90-1.00 (m, 2H), 0.79 (s, 3H).

Example 7. Preparation of Compound -A-021 A_001_3 STA-OZ1 {00406} To a solution of compound A_001_3 (150 mg, 0.39 mmol, 1.0 eq) in THF/HZO (4 mL, l/l). LiOH (90 mg. 2.20 mmol, 5.6 eq) was added. The reaction was d at room temperature overnight. TLC (PE/EA = 3/ 1) showed that compound A_001_3 was consumed completely. The mixture was diluted with water (3 mL), washed with MTBE (5 mL x 2) and then acidified to pH = 4 with l M s HCl. The precipitate was collected by filtration and dried in vacuum to give the product (54 mg, 37.3%). 1H NMR: (400 MHZ, CDCB) 5 .30 (0.11:5.2 112.211). 2.43-2.37 (m, 1H), 2.37-2.33 (m. 2H), 2.05-1.93 (m, 2H). 1.90-1.79 (m, 2H), 1.78-1.61 (m, 6H), 1.61-1.50 (m, 6H), 1.50-1.37 (m, 3H), 1.34-1.13 (m. 4 H), 1.12 (s, 3H), 1.02 (s, 3H), 0.93-1.01 (m. 3H). 0.61 (s. 3H). e 8. Preparation of nds STA-022 and STA-023 HOfOH artin PTSA. toluene CHZCIZ H0 0 reduction MeMgBr MAD, toluene SFC separation B220, pyridine. . sr-zoo-A-ozz sr-zoo-A-ozs Bz : benzoyl; -C(:O)C6H5 {00407} Preparation of Compound 7: To a solution of ketone 6 (16.7 g, 52.71 mmol, 1.0 eq) and ethylene glycol (20 mL) in toluene (450 mL) was added p—toluenesulfonic acid (418 mg, 2.20 mmol). The reaction mixture was heated at reflux ght with a Dean-Stark trap. LCMS showed the starting material was consumed completely. The mixture was cooled to room temperature, diluted with ethyl e (400 mL), and washed with saturated aqueous sodium bicarbonate (200 mL x 2) and brine (200 mL x 2). The organic phase was dried over sodium sulfate and concentrated in vacuum to afford crude product 7 (19.0 g, 100%) which was directly used in the next step without further purification. 1H NMR: (400 MHZ, CDCB) 5 5.34 (d, J=5.2 Hz. 2H). 4.00-3.85 (m, 4H), 3.53-3.5l (1n. 1H), 228-22201}, 2H). 2.12-2.00 (m, 1H), 1.99-1.95 (m, 1H), .73 (m, 5H). .44 (m, 8H), 1.29 (s, 3H), 1.08 (s, 3H), 1.07 (s, 3H). 1.06-0.92 (m, 1H), 0.77 (s, 3H). {00408} Preparation of Compound 8: To a on of compound 7 (19.0 g, 52.71 mmol, 1.0 eq) in dry CHZCi-z (700 mL) was added Dess-Martin (45.0 g. 105.42 mmol, 2.0 eq) in portions at O 0C. Then the reaction e was stirred at room temperature for 3 h. TLC (PE/EA = 3/1) showed the starting materiai was consumed completely. The mixture was quenched with ted aqueous NflHC03/Na28203 (l L. 113). The c phase was washed with brine (500 mL) and dried over NagSOr and the solvent was evaporated under reduced pressure to afford crude product 8 (19.0 g, 100%), which was directly used in the next step without further purification. 1H NMR: (400 MHz. CDC13) 5 5.33 (d, J=5.2 Hz, 2H), 4.01-3.85 (m, 4H), 3.34-3.21 (m, 1H), 2.82 (dd, 1. 2.01 Hz, 1H), 2.59-2.40 (m, 1H), 2.37-2.25 (m, 1H), 2.13-1.95 (m, 5H), 1.87-1.41 (m. 13H). 1.30 (s, 3H), 1.21-1.15 (m, 5H), 0.81 (s, 3H). {00409} Preparation of Compound 9: To a solution ofMAD (158 1nL, 158 mmol, 3.0 eq, 1 M in toluene, prepared via the method as described in the synthesis of ST—ZOO—A- 001) was added a on of compound 8 (19.0 g, 52.71 1nmo1, 1.0 eq) in toiuene at -78 0C under nitrogen. Then the reaction mixture was stirred at this temperature for 30 min. A solution ofMeMgBr (53 mL, 159 mmoi. 3.0 eq, 3 M in EtZO) was added dropwise at —78 0C.

The reaction mixture was warmed to -40 0C and stirred at this temperature for 3 h. TLC (PE:EA = 3:1) showed that the starting material was consumed completely. The mixture was poured into saturated aqueous NH4C1 solution (300 mL) and ted with EA (150 mL x 2).

The combined organic phases were dried over NaZSOr and the solvent was evaporated under reduced pressure to afford crude product. The crude product was purified by silica gel tography eluted with PEEA (15:1) to give the product (7.70 g. 39%) as a white powder. 1H NMR: (400 MHZ, CDC13) 5 5.31 (d, J=5.2 Hz, 2H), 4.01-3.85 (m. 4H), 2.42 (d, J=12 HZ, 1H) 2.04-1.96 (in, 1H), 1.96-1.95 (m 2H), 1.85-1.66011, 5H), 1.66-1.61 (m, 2H), 1.61 -1.36 (1n. 7H). 1.33 (s, 3H), 1.26-1.13 (m, 3H), 1.11 (s, 3H), 1.05 (s, 3 H). 0.91-1.00 (m, 2 H), 0.80 (s, 3 H). {00410} Preparation of nd INT C: To a solution of compound 9 (2.7 g, 7.21 mmol, 1.0 eq) in THF (20 mL) was added aqueous HCi solution (10 mL, 1 M) and acetone (10 mL). The reaction mixture was stirred at room temperature overnight. TLC (PEzEA = 3: 1) indicated that the reaction was complete. Then the reaction e was diiuted with EA (50 1nL), washed with saturated aqueous NaHC03 soiution (50 1nL x 2), dried over NaZSO4 and evaporated under reduced pressure to give the product (2.10 g, 88. %) as a white powder. 1H NMR: (400 MHZ, CDC13)5 5.31 (d, J=5.2 HZ, 2H), 2.55-2.50 (m, 1H), 2.40 (d J=l2HZ, 1H), 2.20 -2.19 (m, 1H), 2.15-2.10 (m, 3H), 2.08-1.94 (m, 3H), 1.83-1.76 (m, 1H), 1.74 -l.65 (111.3H), 1.62 (s. 3H), .39 (m, 7H), 1.30-1.13 (m, 4H), 1.12 (s, 3H), 1.01 (s, 3H), 0.61- 0.65 (m, 3H). {00411} Preparation of Compound A_022_1: To a solution of INT C (700 mg, 2.1 mmol, 1.0 eq) in MeOH (10 mL) and THF( 5 mL) was added NaBH4 (160 mg, 4.2 mmol, 2.0 feq) was added in five portions. The reaction mixture was stirred at room temperature for l h. TLC (PE/EA = 3/1) showed the starting material was consumed teiy. The mixture was quenched with saturated aqueous NH4C1 (50 mL) and extracted with EA (20 mL x 2).

The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuum to afford the desired product A_022_1 (600 mg, 86%). {00412} Preparation of Compounds ST—ZOO-A-OZZ and ST—ZOO-A-023: To solution ofA_022_1 (570 mmol, 1.717 mmol, 1.0 eq) in DCM (15 mL) was added TEA (867 mg, 8.585 mmo1, 5.0 eq) and DMAP (63 mg, 0.515 mmo1, 0.3 eq). Then BZCl (961 mg, 6.867 mmol, 4.0 eq) was added dropwise. The ing mixture was stirred at room temperature for 16 h and then neutralized by addition of l M aqueous HCl. The aqueous layer was ted and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated aqueous NaHC03 (:10 mL) and brine (10 mL), dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography eluted with PE: EA (15: 1) to give product (360 mg, 46.6%) as a write sohd which was applied to the SFC separation to afford the target ST—200—A-022 (100 mg) and ST—200-A-023(70 mg). IH NMR(ST—200-A-022): (400 MHZ, CDC13) 5 8.06 (d, J=7.2 HZ, 2H), 7.61-7.50 (m, 1H), 7.49— 7.40 (m, 2H). 5.30 (d, J=5.2 Hz, 2H), 5.19-5.08 (m, 1H), 2.40 (d. J=12HZ, 1H), 2.03-1.86 (m, 3H), 1.85—1.64 (m, 5H), .30 (m, 7H), 1.27 (d, J=6.0 HZ, 3H), 1.23-1.06 (m, 6H), 1.01- 0.83 (m, 5H), 0.68 (s, 3H). 1H NMR(ST—200—A—023): (400 MHZ, CDCB) 5 8.01 (d, Z, 2H), 7.58-7.50 (m, 1H), 7.47-7.39 (m, 2H), 5.31 (d, J=6.0 HZ, 2H), 5.24-5.14 (m, 1H), 2.43 (d,J=13.2Hz, 1H), 2.05-1.87 (m, 4H), .61 (m, 5H), 1.55-1.38 (m, 4H), 1.36 (d, J=6.0 HZ, 3H), .14 (m, 4H). 1.12 (5.311). 1.04-0.95 (m. 4H). 0.74 (s. 3H) Example 9. Preparation of Compound -C-001 Pd/C, SI) ethanol, 60 0C sr-zoo-A-om sr-zoo-c-om {00413} To a solution of compound ST—ZOO-A-OOl (65 mg. 0.167 mmol, 1.0 eq) in ethanol (10 mL) was added Pd/C (10%, 15 mg) under N3. The suspension was degassed under vacuum and purged with H; several times. Then the mixture was stirred under 50 psi ofhydrogen pressure at 60 0C for 24 h. TLC (PEzEA = 3: 1) showed that the reaction was complete. The suspension was filtered through a pad of celite and the pad was washed with l (5 mL x 2). The combined filtrates were concentrated to s to give the crude product, which was purified by silica gel chromatography eiuted with PE:EA (10:1) to give the product (28 mg, 43%) as a white powder. 1H NMR: (400 MHz CDCi3) 5 1.90-1.87 (m, 1H), 1.75-1.60 (m, 4H), 1.82-1.65 (m, 2H), 1.55-1.30 (m, 12H), 1.27-1.23 (m, 6H), 1.22 (s, 6H), 1.18-0.95 (m, 8H), 0.82 (s, 3H), 0.72 -0.65 (m, 1H), 0.55 (s, 3H).

Example 10. Preparation of Compounds STC-003 and STC-003A OH Pd/C, H2 (45 psi) ethanol STA-003 STC-003 STC-003A {00414} To a solution of compound ST—200-A-003 (40.0 mg, 0.10 mmol, 1.0 eq) in EtOH (30 mL) was added Pd/C (10 mg). The mixture was stirred at 60 oC overnight under 50 psi of hydrogen re. 1H NMR indicated that the reaction was complete. Then the mixture was filtered through a pad of celite and the fiitrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gei (eluent: PEzEA = 2:1) to afford the pure t -C-003 (12.0 mg, 29.8%) and ST—200-C-003A (0.8 mg, 2.3 "/E») as a White powder. 1H NMR (ST-ZOO-C-OOS): (400 MHZ, CDCIS) 5 1.97-1.83 (m, 2H), 1.65-1.55 (m, 7H), 1.55-1.42 (m, 4H), 141-12841 (m, 6H), 1.27-1.21 (m, 5H), 1.20 (s, 6H), 1.16-0.95 (m, 7H), 0.92 (d, J=6.27 Hz, 3 H), 0.81 (s, 3 H), 0.65 (s, 3 H). 1H NMR (ST- 200-C-003A): (400 MHz, CDC13) 5 1.98-1.79 (m, 4H), 1.64-1.53 (1n. 6H). 1.52 -1.29 (m. 7H), 1.25-1.22 (m, 6H), 1.22 (s, 3H), 1.20 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.91 (d. J=6.53 Hz, 3H), 0.86-0.80 (m, 2H), 0.65 (s, 3H).

Example 11. Preparation of Compound ST-ZOO-C-007 o/j) PTSA, toluene, reflux HO i 11 o/\‘ Dess-Martm. MeMgBr, MAD aq. HCI —> —> CH2C|2 THF THF/acetone l X I I - 9 HO Q-BBN, H202 aq, NaOH I1", Pd/C, H2(1 atm) Bess-Martin EtOAc CHZCIZ c_oo7_2 sr-zoo-c-oo7 {00415} Preparation of Compound 10: Amixture of compound 1 (28.0 g. 0.097mol, 1.0 eq) and Pd/C (3.5 g) in ethanoi (400 mL) was hydrogenated at room temperature overnight under 40 psi of hydrogen pressure. The sion was filtered through a pad of celite and the pad was washed with ethanol (20 mL x 3). The combined fiitrates were concentrated to dryness to give the product (28.0 g, 0.097 mol, 100%) as the white solid. 1H NMR (400 MHZ, CDC13) 5 3.63-3.53 (m, 1H), 2.42 (dd, 1:192, 8.4 HZ, 1H), 2.11-2.06 (m, 1H), .87(m, 1H) 1.83-1.09 (m, 18H) 1.04-0.91 (m, 2H) 0.85 (s, 3H) 0.82 (s, 3H). , , , , {00416} Preparation of Compound 11: To a soiution of compound 10 (28.0 g, 0.097 mol, 1.0 eq) and ethyiene glycol (30 mL) in toiuene (300 1nL) was added enesulfonic acid (0.7 g, 3.64 mmol). The reaction mixture was heated at reflux overnight with a Dean- Stark trap. LCMS showed the starting material was consumed completely. The mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with saturated aqueous sodium bicarbonate (100 mL x 2) and brine (100 mL x 2). The c phase was dried over sodium sulfate and concentrated in vacuum to afford crude product 11 (30.0 g, 0.090 mol. 93%) which was directly used in the next step without further ation. 1H NMR: (400 MHZ, CDC13) 5402-378 (m, 4H), 3.68-3.48 (m, 1H), .92 (m, 1H), 1.80- 1.54 (m, 8H) 1.46 -1.32 (m 5H), 1.31-1.19(m, 5H), 1.14—1.05 (m, 1H), 1.02-0.86 (m, 2H), 0.83 (s, 3 H). 0.80 (s. 3 H), 0.72-0.61 (m. 1 H). {00417} Preparation of Compound 12: To a solution of compound 11 (30.0 g, 0.090 mol, 1.0 eq) in dry DCM (300 mL) was added Dess-Martin oxidant (76.0 g, 0.180 mol, 2.0 eq) at 0 OC. The reaction e was stirred at 0 0C for 30 min and then at room temperature for 2 h. LCMS showed the starting material was consumed tely. The mixture was quenched with a mixed aqueous solution of saturated NaHCOg/Na3803 (200 mL, U3) and then diluted with DCM (250 mL). The c layer was washed with saturated aqueous sodium bicarbonate (100 1nL x 2) and brine (100 1nL x 2), dried over sodium sulfate and concentrated in vacuum to afford cmde product 12 (24.0 g, 0.072 mol, 80%) which was directiy used in the next step without further purification. {00418} Preparation of Compound 13: To a solution ofMAD (2.16 mol, 3.0 eq, prepared via the method as described in synthesis of ST—200-A-001) in dry toluene (300 mL) was added dropwise compound 12 (24.0 g, 0.072 mol, 1.0 eq) at —78 OC and the e was stirred at -78 0C for 30 min under nitrogen. Then MeMgBr (72 mL, 2.16 11101, 3.0 eq, 3 M in ether) was added dropwise at -78 0C and the resulting mixture was stirred at the same temperature for 2 h. LCMS showed the starting material was ed completely. The reaction mixture was poured into ted aqueous NH4C14 solution (400 mL) and exacted with EA (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography eluted with PE: EA (15:1) to give product 13 (16.0 g, 0.046 mol, 72%) as a white solid. 1H NMR: (400 MHZ, CDC13) 8 3.95-3.88 (m, 2 H), 3.87-3.82 (m, 2 H), 2.02- 1.92 (m, 1 H), 1.84-1.73 (m, 1 H), 1.71-1.50 (m, 9 H), 1.50-1.43 (m, 1 H) 1.33 (m, 4 H), 1.33—1.28 (m l H), 1.27-1.19 (m, 7 H) ,1.08-0.88 (m, 2 H) 0.83 (s, 3 H) ,0.81 , (s, 3 H). {00419} Preparation of Compound INT G: A mixture of nd 13 (16.0 g, 46.0 mmol, 1.0 eq) in 1 M aqueous HCl (60 mL), acetone (60 mL) and THF (350 mmL) was stirred at room temperature overnight, and then diluted with water (200 mL) and neutralized with solid NaHCO; until no C02 was evolved. The mixture was extracted with EA (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over sodium sulfate and concentrated in vacuum to afford product INT G (14.0 g, 46.0 mmol, 100%) as a white solid. 1H NMR: (400 MHZ, CDC13) 6 2.44 (dd, 0, 8.41 Hz, 1 H), 2.13-2.01 (m, 1 H) ,1.98- 1.89 (m, 1 H), 1.85-1.76 (m, 2 H), .60 (m, 3 H), 1.59-1.42 (m, 5 H) ,1.33-1.13 (m, 10 H), 1.08-0.94 (m, 2 H), 0.86 (s, 3 H), 0.84 (s, 3 H), 0.68-0.77 (m, 1 H). {00420} Preparation of Compound 14: To a solution OfPPll3CH3Bf (1.4 g, 3.94 mmol, 5.0 eq) in THF (10 mL) was added a on oft-B110K(442 mg, 3.94 mmol, 5.0 eq) in THF (5 mL) at room temperature. After stirring for 1 h, a solution of INT G (0.2 g, 0.657 mmol, 1.0 eq) in THF (5 mL) was added dropwise. The on mixture was refluxed for 3 h, then cooled room temperature and ed with saturated aqueous NH4C1 (50 mL), extracted with EA (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuum to give the crude product, which was purified by a flash column chromatography (eluent: PE/EA = 15/ l) to afford compound 14 (180 mg, 90%) as a white solid. 1H NMR: (400 MHZ, CDC13) 5 4.62 (d, J=6.4Hz, 2H), 2.51-2.44 (m, 1H), .22 (m, 1H), 1.82-1.78 (m, 1H), 1.75-1.30 (m, 9H), 1.29-1.11 (m, 11H), 1.03-0.95 (m, 3H), 0.83 (s, 3H), 0.77 (s, 3H), 0.72-0.68 (m, 1H). {00421} Preparation of Compound INT 1: To a solution of 9-BBN (0.5 M in THE, 50 mL. 25.00 mmol, 8.0 eq) under ice-bath. a solution of compound 14 (0.95 g. 3.14 mmol, 1.0 eq) in THF (10 mL) was added dropwise. The on mixture was heated to 60 OC and stirred for 20 h. The mixture was cooled to 0 0C and 10% aqueous NaOH solution (20 mL) followed by 30% aqueous H202 (10 mL) was added. The resulting mixture was stirred for 2 h at 0 0C and then extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuum to give the crude product, which was purified by a flash column chromatography (eluent: PE/EA = 10/1) to afford INT 1 (0.63 g, 63%) as a white solid. 1H NMR: (400 MHz, CDClg) 8 3.74-3.69 (dd, J;=10.4Hz, 12:6.8Hz, 1H), 3.56-3.52 (dd, J1=10.4Hz, J2=7.6Hz, 1H), 1.86-1.80 (m, 2H), 1.69-1.44 (m, 11H), 1.41-1.26 (m 4H) 1.25-1.21 (m, 5H), 1.19-0.99 (m, 5H), 0.93-0.91 (m, 5H), 0.81 (s. 3H), 0.74-0.68 (m, 1H), 0.64 (s, 3H). {00422} Preparation of Compound INT J : To a solution of INT 1 (500 mg, 1.56 mmol, 1.0 eq) in DCM (20 mL) under ice-bath, aitin reagent (1.3 g, 3.12 mmol, 2.0 eq) was added. The reaction mixture was warmed to room temperature and stirred for 2 h.

The mixture was poured into a solution ofNa8203 (5 g) and NaHC03 (1.5 g) in water ('20 mL), extracted with EA (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and trated in vacuum to give the crude product (500 mg, 100%), which was used directly in the next step without further purification. {00423} Preparation of Compound C_007_1: A mixture of INT J (500 mg. 1.57 mmol, 1.0 eq) and Ph3P=CHCOOCH3 (3.1 g, 8.27 mmol, 6.0 eq) in toluene (30 mL) was stirred for 3 h at 80 0C. The mixture was concentrated in vacuum and the residue was purified by a flash column chromatography (eluent: PE/EA=12/1) to afford product C_007_1 (188 mg, 32%) as a white solid.

} Preparation of Compound C_007_2: Amixture of compound C_007_1 (188 mg, 0.5 mmol. 1.0 eq) and Pd/C (5%, 60 mg) in EA (10 mL) was stirred for 2 h at room ature under H2 (1 atm). The e was filtered and the filtrate was concentrated in vacuum to give product C_007_2 (189 mg, 100%), which was used ly in the next step without further purification.

} Preparation of Compound -C-007: To a solution of nd C_007_2 (100 mg, 0.26 mmol, 1.0 eq) in THF (2 mL) at -78 0C, CH3Li (1.6 M in THE 1.6 mL, 2.6 mmol, 10.0 eq) was added dropwise under nitrogen. The reaction mixture was warmed to room temperature and stirred for l h. Saturated aqueous NH4C1 (10 mL) was added to quench the reaction and the mixture was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuum to give the crude product, which was purified by a flash column chromatography (eluent: PE/EA = 8/1) to afford the target ST—200-C-007 (32.7 mg, 32.7%) as a white solid. ‘H NMR: (400 MHZ. CDClg) 5 1.82-1.81 (m. 1H). .57 (m, 7H), 1.56- 1.26 (m, 10H), 1.24 (s, 3H), 1.20 (s, 6H), 1.18-0.83 (m. 10H). 0.81 (s. 3H). 0.71-0.66 (m, 1H), 0.58 (s, 3H).

Example 12. ation of Compound -C-Oll CeCl3, NaBH4 MeOH STC-01 1 {00426} Preparation of Compound INT H: To a solution of TNT G (1.00 g. 3.28 mmol, 1.0 eq) in MeOH (20 mL) and THF (8 mL) was added CBC13.7H30 (1.22 g. 3.28 mmol, 1.0 eq). Then NaBH4 (0.25 g, 6.56 mmol, 20 eq) was added in five po1tions and the mixture was stirred at room temperature for l h. The reaction slurry was quenched with saturated aqueous NH4Ci (50 mL) and extracted with BA (20 mL x 3). The combined c layers were washed with brine (30 mL). dried over sodium sulfate and concentrated in vacuum to give the desired product (0.97 g. 9 %) as a white solid. 1H NMR: (400MHz, CDC13)5 3.62 (1, J=8.4 Hz, 1H), 2.10-2.04 (m, 1H), 1.79-1.77 (m, 1H), 1.70-1.35 (m, 13H), 1.31-1.15 (m. 11H), .84 (m, 5H), 0.81 (s, 3H), 0.72 (s, 3H), 0.70-0.61 (m. 1H) } Preparation of Compound C_011_1: To a on of INT H (5.00 mg, 1.63 mmol, 1.0 eq) in DCM (20 mL), NMM (830 mg, 8.21 mmol, 5.0 eq) and methyl propiolate (690 mg, 8.21 mmol, 5.0 eq) were added. The mixture was stirred at room temperature for 16 h. then washed with water (30 1nL) and brine (30 mL). dried over sodium sulfate and concentrated in vacuum. The residue was purified by silica gel chromatography eluted with PE: EA (15:1) to give the product (500 mg, 78.6%) as a white solid. 1H NMR: z, CDCB) 5: 7.53 (d, J=12.4 HZ. 1H), 5.24 (d, J=l2.4 Hz, 1H) 3.86 (t, J=8.4 Hz, 1H), 3.68 (s, 3H), 2.18-2.06 (m, 1H), 1.84-1.81 (m, 1H), 1.70-0.85 (m, 30H), 0.81 (s, 3H), 0.78 (s, 3H), 0.72-0.64 (m, 1H). {00428} Preparation of Compound 2: To a soiution of C_01 l_1 (500 mg, 1.289 mmoi, 1.0 eq) in BA (20 mL) was added Pd/C (10%, 50 mg). The suspension was degassed under vacuum and purged with H; i times. The mixture was stirred at 30 0C for 16 h under 30 psi of hydrogen pressure. TLC (PE/EA = 3/ 1) showed the reaction was complete. The suspension was filtered through a pad of celite and the pad was washed with EA (20 mL x 5). The combined filtrates were concentrated in vacuum to give the product (430 mg, 85.5%) as a white solid. {00429} Preparation of nd ST—200-C-011: To a solution of C_011_2 (100 mg, 0.256 mmol. 1.0 eq) in dry THF (1 mL). MeLi (1.3 mL, 2.048 mmol, 8.0 eq) was added dropwise at -78 0C under N2. The resulting mixture was stirred at this temperature for 0.5 h, and then the temperature was allowed to warm to room temperature and stirred at this temperature for another 1 h. TLC (PE/EA = 3/1) showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl and extracted with BA (10 mL x 3).

The ed organic layers were washed with brine (10 mL), dried over sodium sulfate and trated in vacuum. The residue was purified by silica gel chromatography eluted with PE:EA (10:1) to give the product (30 mg. 3 %) as a white solid. 1H NMR (400MHz, CDC13) 53.86 (s, 1H), 3.78-3.61 (m 2H) 3.29 (t, J=8.3 Hz, 1H), 2.10-1.95 (m 1H), 1.90-1.81 (m, 1H), 1.74 (t, J=5.6 Hz, 2H), 1.69—1.61 (m, 3H), 1.55-1.28 (m, 9H), 1.24-1.22 (m, 9H). 1.22- 0.83 (m, 8H). 0.81 (s, 3H). 0.74 (s. 3H). 0.69-0.62 (m, 1H).

Example 13. Preparation of Compound -C-013 INT I STC-O13 {00430} To a solution of INT 1 (150 mg, 0.469 mmol, 1.0 eq) in DMSO (1 mL) was added KOH (53 mg. 0.937 mmoi, 2.0 eq) and 2,2-dimethyloxirane(337 mg, 4.687 mmol, 10.0 eq). The reaction mixture was d at 50 0C for 16 h. TLC (PE/EA: 10/1) showed the starting material was consumed completely. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with saturated aqueous NH4C1 (10 mL x 2) and water (10 mL x 2). The organic phase was dried over sodium sulfate and concentrated in vacuum to afford crude product which was purified by column chromatography followed by prep-HPLC to afford pure t.ST—200-C-013(26 mg, 15.8%). 1H NMR: (400 MHZ, CDCl3) 5 3.72 (dd, J=7.3, 9.3 Hz, 1H), 3.35 (dd, 11:6.8, 9.3 Hz, 1H), 3.21 (s, 2H), 2.34 (s, 1H), 1.84-1.80 (m, 1H), 1.79-1.63 (m, 5H), 1.54-1.27 (m, 8H), 1.25 (s, 3H), 1.19 (s, 6H), 1.18-0.83 (m, 7H), 0.81 (s, 3H), 0.74-0.65 (m, 1H), 0.63 (s, 3H) Example 14. ation of Compounds STC-017 and STC-017A O/k0" PdlC, H2 (50 psi) - —> g EtoH, so Dc sr-zoo-c-on STC-017A {00431} A on of ST—200-A-017 (60 mg, 0.159 mmol, 1.0 eq) and Pd/C (10 mg) in EtOH (:10 mL) was stirred at 50 0C under 50 psi of hydrogen pressure for 16 h. The reaction solution was ed through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography eluted by PEzEA (20:1) to give ST-ZOO-C— 017(21 mg) and ST—200-C-017A(4.6 mg) as a white solid. 1H NMR (STC-017): (400 MHz, CDC13) 5 3.73-3.71 (m, 1H), 3.31 (t, J=8.4Hz. 1H). 3.27-3.22 (m, 2H), 2.48 (s, 1H), 2.01-1.91 (m, 1H), .84(1n, 1H), 1.68-1.52 (m, 4H), 1.51-1.49 (m, 4H), 1.47-1.42 (1n. 1H), 1.31 — 1.24 (m, 7H), .83 (1n,6H), 1.15-1.10 (m, 1H), 1.03-0.95 (m, 2H), 0.90-0.85 (m. 1H), 0.81 (s. 3H), 0.65 (5,3H), 0.70-0.61 (m, 1H). 1H NMR (STC-017a): (400 MHz, CDC13) 5 3.33 (t, J=8.4Hz, 1H), 3.27-3.22 (m. 2H). 2.45 (s. 1H). 2.10-1.91 (m, 1H), 1.89- 1.78 (m, 3H), 1.69-1.61 (m, 1H), 1.58-1.51 (m, 1H), 1.50-1.30 (m, 7H), 1.29-1.24 (m, 5H), 1.20 (s. 3H), .10 (m, 8H), .01 (m, 1H), 0.98 (s, 3H), 0.75 (s, 3H).

Example 15. Preparation of nds 3-alpha-A2 and 3-beta-A2 4a,, OMe 44,, O .1 OH MeMgCl ACO HO 33-1 133-2 oxalyl chloride, DMSO, NEt3 CH2C|2, CHCI3 BB-Z 1313-3 MeLi 1‘ OH CeCI3 HOW A2 (Soc-OH) Imn. A2 (3/f-OH) {00432} Preparation of compound BB—Z: Under nitrogen a solution of BB-l (1.75 g, 4.06 mmol) in THF (35 Hi), prepared as described in Sieroids (2006) 71:18, was cooled to 0°C. Methylmagnesium chloride (22% (w/w) in THF, 19.5 mL, 58.1 mmol) was added dropwise. Stirring at 0"C was continued for 15 minutes and reaction mixture was allowed to warm to room temperature and stirring was ued for two hours. Saturated aqueous NHiC'l (5 mL) was added slowly. Precipitate formed and was dissolved by addition of water (10 mL). EtOAc (50 1nL) and brine (20 mL) were added. Layers were separated. Aqueous layer was extracted with EtOAc (2 X 50 mL). Combined organic layers were dried with N33804 and solvents were removed in vacuo. e was coevaporated with dichloromethane (50 niL). BB-2 (1.54 g, 3.95 mmol, 97%) was obtained as an off-white solid. 1HNMR (400 MHz CDC13): 5(ppm): 5.32 — 5.43 (1H. m), 3.46 — 3.61 (1H, m), 1.20 (3H, s), 1.19 (3H, S), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, S). {00433} Preparation of compound BB-S: Under nitrogen in an oven dried fiask a solution of oxa1y1 chloride (0.622 mL, 7.26 mmoi) in dichloromethane (19 mL) was coo1ed to —78°C. Dimethyl suifoxide (0.60 mL, 8.47 mmol) was added slowly. After 25 minutes a solution of BB-2 (0.470 g, 1.209 mmoi) in CHC13 (38 mL) was added dropwise over 25 minutes The solution was stirred at -78°C for 2.5 hours. Triethyi amine (3.36 ml, 24.19 mmol) was added dropwise at -78°C. Stirring was continued 15 minutes. Cooling bath was removed and stirring was continued for 10min. Aqueous ted NH4C1 (10 mL) was added and reaction mixture was stirred for 5 minutes. Dichloromethane (50 mL) and water (20 mL) were added. Layers were separated and c 1ayer was washed with water (20 mL). ed aqueous layers were diluted with brine (20 mL) and were extracted with EtOAc (2 x 75 mL). Combined organic 1ayers were dried with Na2804 and ts were removed in vacuo. Flash tography (heptane, 5% - 30% EtOAc) afforded BB-3 (238 mg, 0616 mmo1, 51%) as a white so1id. 1HNMR (400 MHz, CDC13)I 8(ppm): 5.31 — 5.38 (1H, m), 3.22 — 3.34 (1H, m), 2.83 (1H, dd, J =16.4 Hz, 2.1 HZ), 2.41 — 2.54 (1H, m), 2.25 — 2.34 (1H, m), 1.95 — 2.08 (3H, m), 1.82 -1.93 (1H, m), 1.21 (3H, s), 1.20 (3H, s), 1.19 (3H, s), 0.94 (3H, d, J = 6.5 Hz), 0.71 (3H, s). {00434} Preparation of compounds 3-a-0H A2 and 3~fl~0H A2: In a glove box in a flame dried flask. THF (degassed, 3 mL) was added to anhydrous ceriuin(111) chloride (0.319 g, 1.29 mmo1). The suspension was stirred at RT overnight. The white, fine suspension was taken out of the glove box. THF (dry, 1 mL) was added and thew mixture was stirred under argon for 15 s at RT. Under argon the white. fine suspension was cooled to - 78°C. At this temperature methyllithium, 1.6M in EtZO (0.79 mL, 1.27 mmoi) was added dropwise. A yeliow suspension formed and was d at -78°C for 1.511. A so1ution of BB-3 (0.100 g, 0.259 mmol) in THF (dry, 2mL) was added dropwise over 5min. The colour of the reaction mixture changed from yellow to brown. on mixture was stirred at -78°C for 45min. Cooiing bath was removed and reaction mixture was stirred for 10min. 5% aq. AcOH (2mL) was added. on mixture turned into a colour1ess, clear solution. EtOAc (l OmL) was added. Mixture was aliowed to warm to RT. Layers were separated and aq. layer was extracted with EtOAc (2x10mL). Combined org. layers were dried with sodium sulfate and solvents were removed in vacuo. Flash chromatography (H, 5%-20% EtOAc) afforded nd A2 (3 a—OH) (33 mg, 0.082 mmol; 63.5%) and compound A2 (3,B—OH) (13 mg. 0.032 mmoi; 25.0%). (3a—OH): 1H-NMR (400 MHZ, CDC13)I 5(ppm): 5.43 — 5.38 (m, 1H), 2.46 — 2.37 (m, 1H), 2.05 — 1.80 (m, 4H), 1.73 — 1.23 (m, 15H), 1.22 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 — 0.99 (m, 9H), 0.98 (s, 1H), 0.94 (d, J: 6.5 Hz, 3H), 0.68 (s, 3H). (33- OH): 1H-NMR (400 MHZ. CDC13)I : 5.34 — 5.28 (m, 1H), 2.47 — 2.38 (in. 1H), 2.07 — 1.92 (m, 3H), 1.91 — 1.66 (m, 3H), 1.63 — 1.24 (m, 13H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 — 1.12 (m, 3H), 1.11 (s, 3H), 1.10 — 1.02 (m, 2H), 1.01 (s, 3H), 1.00— 0.94 (m, 1H). 0.93 (d, J = 6.5 Hz, 3H), 0.91 — 0.82 (m, 1H), 0.68 (s, 3H). e 16. Preparation of Compounds 3-alpha-A28 and 3-beta-A28 MeLi " OH CeCI3 A28 (3a—OH) /Illn. A28 (Sfl-OH) } In a glove box in a flame dried flask THF (degassed, 1.5mL) was added to anhydrous cerium(111) chloride (0.207 g. 0.841 mmol). The suspension was stirred at RT overnight. The white, fine suspension was taken out of the glove box and stirred under argon for 15min. Under argon the white, fine suspension was cooled to —78°C. At this temperature ethyllithium, 0.5M in benzene/cyclohexane (1.68 mL, 0.841 mmol) was added dropwise. A yellow suspension formed and was d at -78°C for 30min. A so1ution of BB-3 (0.065 g, 0.168 mmoi) in THF (dry, 1.5mL) was added se over 3 min. The coiour of the reaction e changed from yel1ow to brown. on mixture was stirred at —78°C for 45min. A brown. milky suspension was obtained, TLC (H/E; 2: 1) showed complete conversion of the starting material and formation of a more polar spot. Cooling bath was removed and reaction mixture was stirred for 10min. 5% aq. AcOH (2mL) was added. After addition of brine (2mL), reaction mixture turned into a colourless, clear solution. EtOAc (SmL) was added.

Mixture was allowed to warm to RT. Layers were separated and aq. layer was extracted with EtOAc (2x5mL). Combined org. 1ayers were dried with sodium sulfate and so1vents were removed in vacuo. 60 mg of a white solid were obtained. Seperation on silicagel impregnated with AgNO; (H, 5%-20% EtOAc) afforded compound A28 (3 a—OH) (6 mg, 0.014 mmoi; 8.56%) and compound A28 (3fl-OH) (4 mg, 0.0096 mmol; 5.71%). (3 a—OH): 1H-NMR (400 MHz, CDClg): 5(ppm): 5.45 — 5.38 (m, 1H), 2.40 — 2.33 (m, 1H), 2.05 -1.93 (m, 2H), 1.92 — 1.80 (m, 2H), 1.75 — 1.23 (m, 15H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 — 0.98 (m, 7H), 0.97 (s, 3H), 0.96 — 0.90 (m. 6H), 0.89 — 0.81 (m, 2H), 0.68 (s, 3H). (3/9011): 1H-NMR (400 MHz, CDCI3): : 5.33 — 5.25 (m, 1H), 2.41 — 2.31 (m, 1H), 2.06 — 1.93 (m, 3H), 1.90 — 1.78 (m, 1H), 1.77 — 1.23 (11120111 1205,3111, 1.19 (s, 3H), 1.17 — 1.05 (m, 5H), 1.03 (s, 3H), 1.01 — 0.95 (m, 1H), 0.93 (d, J: 6.5 Hz, 3H), 0.92 — 0.88 (m, 1H), 0.84 (t, J: 7.4 Hz, 3H), 0.67 (s, 3H).

WO 60441 2014/026633 Example 17. Preparation of Compound 36 (CH3CO)ZO iodobenzene —)- —> HO pyridine AcO n-heptane Acros [8371 863 1) 03, pyridine, CHZCIQ AcO gr 2 CH COOH, Zn Br ) 3 Bab 36¢ OMe OMe (CH300)20 0.1N HCI (aq) —> —> pyridine acetone 35d 366 0 NaClOz, KHZPO4 2-methyl-2—butene tBuOH, THF, H20 1) l chloride DMF (cat), CHZCIZ 2) MeOH BGh BS {00436} Preparation of compound B6a. Acetic anhydride (15.36 mi, 164 mmol) was added to a suspension of Stigmasteroi (22.5 g, 54.5 mmol) in ne (90 ml) under nitrogen atmosphere and the mixture was incubated at room temperature for 42h.

TLC{heptane(2):ethyi acetate(1)] showed complete conversion to a higher eluting product after p-"inisaldehyde staining. Water (300 mi) was added to the reaction mixture to quench the excess acetic anhydride. After stirring for lh, the white solid was ed and thoroughly washed with water (9x 250 ml). The white solid was dried in a vacuum oven at 400C in presence of a beaker of sodium hydroxide over the weekend to obtain product 86a (2463 g, 54.2 mmol. Yie1d=99%) as white powder. B6a was used as such in the following experiment(s). 1HNMR (400 MHZ, CDCl3) 8(ppm): 5.38-5.37 (1H, m), 5.15 (1H, dd, J=15.1, 8.6 Hz), 5.01 (1H, dd, , 8.6 Hz), 4.64-4.56 (1H, m), 2.33-2.31 (2H, m). 2.03 (3H, s), 190-182 (2H, m), 1.75-1.65 (1H, m), 1.02 (6H, t, J=3.2 Hz) 0.86-0.78 (9H, m), 0.68 (3H, S). {00437} Preparation of compound 86b. e (1.754 ml, 34.l mmol) was added to a solution of iodobenzene (3.66 ml, 32.7 mmol) in n-heptane (100 ml) and the solution was coold to -5°C under nitrogen atmosphere. A solution of Stigmasteryl acetate B6a (13.5 g, 29.7 mmol) in n-heptane (700 ml) was also cooled to -50C under nitrogen atmosphere, d vigorously, and the on prepared above was added se over a period of 2.5h under a nitrogen atmosphere to in the solution a pale yellow color. The resulting solution was stirred overnight and then filtered. TLC{heptane(9):ethyl acetate(l)] showed complete conversion to a slightly lower eluting product after vanillin staining. The solution was trated under vacuum until dryness. The residue was purified by column (900 g) chromatography {heptane (95): diisopropyl ether(5)}. The pure product containing fractions were collected and evaporated under reduced pressure to obtain B6b (9.06 g, 14.7 mmol, Yield=50%) as a white . B6b was used as such in the following experiment(s). lHNMR (400 MHz, CDClg) 5(ppm): 5.48 (1H, sep, J=5.4 Hz), 5.15 (1H, dd, J=15.1, 8.6 Hz), .02 (lH, dd, J=15.l, 8.6 HZ), 4.84 (1H, brd), 2.05 (3H, s), 1.46 (3H, s), l.01 (3H, d, J=6.6 Hz), 0.90-0.79 (15H, m), 0.72 (3H. s). {00438} Preparation of compound Béc. A solution of 5(7.,68—Dibromostigmastan-3B— yl acetate B6b (8.11 g, 13.20 mmol) in molecular sieves dried dichloromethane (240 ml) and pyridine (3.05 ml, 37.7 mmol) was cooled in a liquid en / ethyl acetate bath. A stream of ozone rich oxygen was passed into the solution through a sintered glass sprayer for one hour. The color of reaction mixture turned slightly blue. TLC[heptane(9):ethyl acetate(1 )] showed complete conversion of the starting material under UV254. The ozonolysis reaction was d. The reaction mixture was immediately poured into a mixture of glacial acetic acid (33.2 ml, 581 mmol) and zinc, dust (21.57 g, 330 mmol) and stirred at room temperature overnight. The solution was filtered, washed successively with water (200 ml), 10% aqueous sodium hydrogen carbonate (200 ml), 5% aqueous sodium hydroxide (200 ml) and brine (200 ml), and then dried over anhydrous sodium sulfate. Evaporation of the solvent afforded crude t-S-en01a1 860 which was purified by flash column (300 g) Chromatography {heptane( 100=>90):et11y1 acetate(0=>10)}. The product containing fractions were collected and evaporated under reduced re to obtain Cholest—S-en—3B-ola1 860 (2.58 g, 6.93 mmol, 53%) as a white powder. B60 was used as such in the following experiment(s). 1HNMR (400 MHz, CDC13) 5(ppm); 9.57 (1H, <1, J=3.3 Hz), 5.38 (1H, brd), 4.65-4.56 (1H, m), 2.41-2.28 (3H, m). 2.04 (3H. s), 2.03-1.92 (2H, m), 1.91-1.81 (3H, m), 1.13 (3H, d. J=6.8 Hz). 1.03 (3H, s). 0.73 (3H, s).

} Preparation of nd 86d. To a soiution of (methoxymethyl)triphenyl- phosphonium chloride (0.789 g, 2.30 inmol) in dry THF (6.4 mL) at -10°C under an atmosphere of argon was added n—BuLi 1.6M in hexanes (1.342 mL, 2.15 mmol). The solution was stirred for 5 min at room ature. foilowed by addition of B6e (0.2 g, 0.54 inmol) in dry THF (1.3 1nL). The mixture was stirred for 30 min at room temperature. The reaction mixture was poured in saturated aqueous NHiCl (75 mL) and extracted twice with CHZCIZ (50 mL). The combined organic iayers were washed with brine dried on NaZSO4 and the crude product was purified by flash column chromatography (silica, heptane/ethylacetate, 1:0 -> 88:12) to afford B6d (103 mg, 0.29 mmol, yield = 5 %). B6d was obtained as 1:1 E/Z- mixture according to NMR. 1HNMR (400 MHZ, CDC13) 5(ppm): 6.24 (0.5H, d, J=l2.6 Hz), .74 (0.5H, d, J=6.2 Hz), 5.34 (1H, brd), 4.59 (0.5H, dd, J=12.5, 9.3 Hz). 4.17 (0.5H, dd.

J=9.8, 6.3 Hz), 3.58-3.46 (1H, m), 3.55 (1.5H, s), 3.47 (1.5H, s) 2.67-2.54 (0.5H, m) 2.33— 2.18 (2H. m), 2.04-1.78 (6H, m), 1.77-1.65 (1H. m), 1.114(1.5H,d,1=6.6 Hz). 1.01 (3H, s). 0.98 (1.5H, d, J=6.7 HZ), 0.72 (15H, s), 0.69 (1.5H, s). {00440} Preparation of compound Bée. Acetic anhydride (0.079 niL. 0.84 inmol) was added to a suspension of B6d (0.1 g, 0.279 mmol) in pyridine (3 mL) under nitrogen atmosphere, and the mixture was incubated at room temperature for 42h. Water (60 mL) was added to the reaction mixture to quench the excess acetic ide. After stirring for 111. the white solid was filtered and thoroughly washed with water (9x 250 1nL). The white solid was dried in a vacuum oven at 40°C ght to obtain product B6e (111 mg, 0.28 mmol.

Yie1d=99%). lHNMR (400 MHz, CDC13) 8(ppm): 6.24 (0.5H, d. J=12.6 Hz), 5.73 (0.5H, d, J=6.2 HZ), 5.37 (1H, brd), 4.66-4.55 (1H, m) 4.59 (0.5H, dd, J=12.5, 9.3 Hz), 4.17 (0.5H, dd, 1:98, 6.3 Hz), 3.55 (1.5H, s), 3.47 (15H, 5). 2.66-2.54 (0.5H, m), 2.35-2.28 (2H. m), 2.03 (3H, s). 2.02-1.91 (3H. m), .81 (2H, m). 1.77-1.66 (1H. m), 1.04 (15H, 6, J=6.6 Hz). 1.02 (3H, s), 0.99 (1.5H, d, J=6.6 Hz). 0.72 (15H, 5), 0.69 (1.5H, s). {00441} Preparation of compound 1361'. To a solution of B6e (0.111 g, 0.28 mmol) in acetone (9 mL) was added 0.1 M aqueous HC1 (1 mL, 0.10 mmo1). The resu1ting white suspension was d for 1h at room temperature, followed by 1h at 70°C and at room temperature overnight. The mixture heated at 70°C for 2h, cooled to room temperature and diluted with H20 (50 mL). The reaction mixture was evaporated until dryness, coevaporated with MeOH (50 mL) and CHgClg (10 mL). This seems to be a mixture of the desired product and the y1 . To a solution of this mixture (0.12 g, 0.28 mmol) in acetone (10 mL) was added 0.1 M aqueous HCl (1 mL, 0.10 mmol). The resulting white suspension was stirred for 2h at 70°C. 1,4-Dioxane (5 mL) was added, which caused the ble to ve.

The reaction mixture was heated to 70°C for another 2h, allowed to cool to room temperature and stirred over the weekend. The reaction mixture was di1tited with H20 (50 mL) and extracted with CH2Clg (3x50 mL). The combined organic layers were washed with brine, dried on Na;SO4 and the solvents evaporated. The crude product was coevaporated with CH2Clg (10 mL) to yield B6f(119 mg, 0.31 mmol, yield = 111%). lHNMR (400 MHZ, CDC13)5(ppm): 9.75 (1H, m), 5.37, (1H, brd), 4.66-454 (1H, m), 2.47 (1H, dd, J=15.8, 2.4 Hz), 2.36-2.28 (2H, m), 2.17 (1H, ddd, J=15.8, 9.3, 3.3 HZ), 2.03 (3H, s), 1.02 (3H, d, J=6.4 HZ), 1.02 (3H, s), 0.70 (3H, s).

} Preparation of compound B6g. Compound BGf(0. 11 g, 0.285 mmo1) was dissolved in t-butan01 (5 mL), dry THF (1 mL) and 2-methylbutene (0.512 mL, 4.84 mmol). The solution was stirred and cooled with an iced bath. A solution of NaClOZ (0.028 g, 0.313 mmoi) and K‘ZHPO4 (0.043 g, 0.313 mmol) in ralized Water (3 ml) was slowly added to the solution over a period of 5 minutes and the mixture was stirred 2 h at 0°C. The mixture was stirred at room ature overnight. Extra NaClOz (0.028 g, 0.313 mmol) and KQHPOa (0.043 g, 0.313 mmol) dissolved in H30 (3 mL) was added slowly to the reaction mixture and stirring was continued for 2h. The reaction mixture was poured into saturated aqueous NThCl (250 mL) and extracted three times with CHgClg (75 mL). The combined organic layers were dried over NagSO4, fi1tered and ated under reduced pressure. The white solid residue (2.26 g, 163%) was triturated in pet1‘01etiin ether 40-60 (10 mL). The white solid was filtered, washed twice with eum ether 40-60 (5 mL) and dried on air for 0.5h to obtain B6f(0.089 g, 0.22 mmol, Yield=78%). IHNMR (400 MHZ, CDC13) 5(ppm): .0 (1H, bs), 5.37 (1H, brd), 4.66-4.55 (1H, m), 2.53-2.44 (1H, m), 2.36-2.26 (2H, m), 2.04 (3H, s), 1.04 (3H, d, J=6.4 Hz), 1.02 (3H, s), 0.72 (3H, s). {00443} Preparation of compound 13611. To a soiution of B6g (0.09 g, 0.224 mmol) in CHzClg (10 mL) were added oxaiyi chloride (0.048 mL, 0.56 mmoi) and DMF (cat). The solution was stirred for 2h at room ature. The reaction mixture was diluted with dry MeOH (150 mL, 3703 mmol) and stirred at 40°C till all solids were ved. The reaction mixture was evaporated till dryness and the crude product was purified by flash column tography , heptane/ethyiacetate, 1:0 —> 95:5) and coevaporated with THF twice to afford B6h (85 mg. 0.20 mmol, yield = 91%). lHNMR (400 MHZ, CDCB) 5(pprn): 5.37 (1H, brd), 4.66-4.55 (1H. m), 3.66 (3H, s), 2.43 (1H, dd, J=i4.i. 2.9 Hz), 2.38-2.25 (2H, m), 2.04 (3H, s), 1.02 (3H, s), 0.99 (3H, d, J=6.2 Hz), 0.72 (3H, s). {00444} Preparation of compound Bé. A solution of B6h (0.085 g. 0.20 mmoi) in dry THF (3 mL) was cooled to 0°C under an atmosphere of argon. MeMgCl 3.0M in THF (0.68 mL, 204 mmoi) was added drop wise using a syringe. The reaction e was stirred for lh at 0°C, followed by 2h at room temperature. MeMgCl 3.0M in THF (0.68 mL, 204 mmol) was added again at room temperature and stirring was continued overnight. The reaction mixture was quenched with saturated aqueous NH4C1 (75 mL) and extracted three times with CH3C12 (3x50 mL).The combined organic layers were washed with brine dried on NaZSO4 and the crude product was purified by flash column chromatography (silica, heptane/ethylacetate, 1:0 -> 4: l) to afford B6 (45 mg, 0.12 mmol, yield = 59%) as a white fluffy solid. 1HNMR (400 MHz, CDC13) 5(ppm): 5.35 (1H, bi‘d), 3.53 (1H, sep, J=5.1 Hz), 2.34-2.17 (2H. In), 2.03 (1H, dt, J=12.6, 3.3 Hz), 2.01-1.94 (1H, m), 1.93-1.79 (3H, in), 1.23 (6H, s), 1.06 (3H, d. J=6.5 Hz), 1.01 (3H, s), 0.72 (3H. 5).

Example 18. Preparation of Compound B7 O o NaCIOz, KHQPO4 1) oxallyl chloride 2-methyl-2—butene H OH DMF (cat), CHQCIZ —> —> tBuOH, THF, H20 2) MeOH 36c 37d MeMgCl AcO HO B7e B7 {00445} Preparation of nd B7d: Cholest-S-en-3B-olal B7c (1.33 g. 3.57 mmol) was dissolved in t-butanol (75ml), tetrahydrofuran (dry) (15 m1) and 2-methyl butene (13.22 ml, 125 mmol). The on was stirred and cooled with an iced bath. A freshly prepared solution of sodium chlorite (0.355 g. 3.93 mmol) and potassium phosphate. monobasic, p.a. (0.534 g, 3.93 mmol) in ralized water (45 ml) was slowly added to the solution over a period of 30 minutes and the mixture was stirred 2 hour at 0°C. The ice bath was removed, the ature of the mixture was raised to room temperature, and stirred overnight. TLC{lieptane(2):etliyl acetate(l)] showed partial conversion to a lower eluting product after vanillin staining. Extra sodium chlorite (0.355 g, 3.93 mmol) and potassium phosphate, monobasic, p.a. (0.534 g, 3.93 mmol) dissolved in water (45 ml) was added slowly to the reaction mixture and stirring was continued for 2h. TLC [heptane(2):ethy1 acetate(l )] showed complete conversion to a lower eluting t after vanillin staining. The on mixture was poured into saturated aqueous ammonium chloride (250 ml) and extracted three times with dichloromethane (100 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced re. The residue was twice ed with toluene (50 m1) followed by dichloromethane (50 ml). The white solid residue (226 g, 163%) was triturated in petroleum ether 40-60 (10 ml) for 0.5h. The white solid was filtered. washed twice with petroleum ether 40-60 (10 ml) and dried on air (leaving the vacuum pump on) for 0.511 to obtain B7d (1.27 g, 3.26 mmol, Yield=9l%) as a white powder. B7d was used as such in the following ment(s). lHNMR (400 MHz, CDCl3) (ppm): 10.31 (1H, bs), 5.37 (1H. brd), 4.65-4.56 (lH. m), 2.47-2.39 (1H, in). 2.36—2.26 (2H, m), 2.04 (3H, s), 2.01-1.92 (2H, m), 1.90-1.76 (3H, m), 1.24 (3H, d, J=6.8 Hz), 1.02 (3H, s), 0.71 (3H, s). {00446} Preparation of compound B7e. Carboxylic acid B7d (0.1 g, 0.257 mmol) was dissolved in dichloromethane (l0 ml). Oxalyl chloride (0.044 mL, 0.515 mmol) and methylformamide (one drop) were added, and the reaction e was stirred for lh.

A sample of the reaction was poured out in methanol, evaporated until dryness. and anayzed on TLC[heptane(3):ethyl acetate(1)} which showed complete conversion to the methyl ester after vanillin staining. The reaction mixture was diluted with methanol (50 mL, 1234 mmol) (dried on mol. sieves), evaporated under reduced pressure, stripped with ous toluene, and dichloromethane. The residue was purified by flash column (4 g) chromatography {lieptane(99=>80):ethyl acetate(l=>20)]. The product containing fractions were collected and evaporated under reduced pressure to obtain B7e (0.104 g, 0.257 mmol, Yield=100%). B7e WO 60441 was stripped with toluene (2x 5 ml), dichloromethane (2x 5 ml) and anhydrous tetrahydrofuran (2x 5 ml) and used as such in the next reaction step. lHNMR (400 MHZ, CDCl3) 5(ppm): 5.37 (1H, brd), 4.65-4.56 (1H, m), 3.65 (3H. s), 2.47-2.38 (lH, m), 2.36- 2.26 (2H, m). 2.03 (3H, s). 2.01-1.92 (2H. m), 1.90-1.82 (2H, m). 1.19 (3H. d, J=6.8 Hz). 1.02 (3H, s), 0.69 (3H, s). {00447} Preparation of nd B7. Methyl ester B7e (0.104 g, 0.258 mmol) was dissolved in tetrahydrofuran (dry) (2.6 ml) and cooled in an ice bath under argon. After 20 s, methylmagnesium chloride 3.0M in THF (0.861 ml, 2.58 mmol) was added dropwise via a syringe. Some gas evolution was observed. After stirring the reaction mixture for 0.5h, the cooling bath was removed, and stirring was continued for 2h. TLC {heptane(3):ethyl e(l)] showed complete conversion of the starting material to two lower eluting products after vanillin staining. Stirring was continued for lh. The on mixture was poured out into saturated aqueous solution of ammonium chloride (75 ml) under stirring and extracted with dichloromethane (3x 50 ml). The extracts were combined, dried over sodium sulfate and evaporated. The residue was triturated in methanol (2 ml) for 0.511, the white solid was filtered, and the filter residue was washed with methanol (2 ml). Almost no material was left on the filter. most of it was present in the filtrate. Filtrate and filter residue were combined and purified by flash column chromatography [heptane (99=>70): ethyl acetate (l=>3 0)]. The product ning fractions were collected and evaporated under d re. The e was dried at 40°C in a vacuum oven overnight to obtain B7 (0.044 g, 0.122 mmol. Yield=47%) as a white solid. 1HNMR (400 MHZ. CDCl3) 6(ppm): .35 (1H. m), 3.53 (1H, sep. J=5.2 Hz), 2.34-2.19 (2H, m), 2.10 (1H, dt, J=l2.6. 3.4 Hz), 2.03-1.88 (2H. m), l.88-l.79 (2H, m), 1.20 (3H, s), 1.15 (3H, s), 1.00 (3H. s), 0.98 (3H. d, J=6.9 Hz), 0.73 (3H, s).

Example 19. ation of Compound BS EtO Toronto Research EtO- *1)/‘\n/0Et Chemicals Inc.

H [162246-79—9] O O TBDMSCI imidazole DMF OTBDMS OTBDMS 05F EtoigNOEtE o NaHMDS CHecooH (’3' THF o CH3CN {00448} Preparation of compound B8b. In a flame dried round bottom flask, a solution of NaHMDS (0.070 ml. 0.349 mmol) in tetrahydrofuran (dry) (1 ml) was added to a on of silyloxyphosphonate ester B8a (0.143 g, 0.403 mmol) in tetrahydrofuran (dry) (1 1111) at -78°C. The solution was stirred for 15 minutes at -78°C under argon atmosphere. Then a solution of t-S-en-3B-ol-ZZ-al B7c (0.1 g, 0.268 mmol) in tetrahydrofuran (dry) (1 ml) was slowiy added Via a syringe. The reaction mixture was slowiy warmed to room temperature and stirred for 20h. TLC[heptane(3):ethy1 acetate(1)] showed partial conversion to an higher eluting t after vanillin staining. The reaction mixture was quenched by the addition of aqueous saturated ammonium chloride (50 ml) and extracted with dichloromethane (3x 50 ml). The combined organic layers were washed with water (50 mi), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (4 g) chromatography [heptane(100=>90): diisopropyl ether (0=>10)]. The product containing fractions were ted and evaporated under reduced pressure to afford product B8b (0.117 g. 0.187 mmol, Yield=70%) as white powder. ing to NMR a 7:3 mixture of E- and Z-isomers was ed. 1HNMR (400 MHz. CDClg) 6(ppm): 5.70 (1H, d. J=10.4 Hz). 5.23 (1H, brd), 5.17-5.13 (1H, m). 4.51-4.40 (1H. m), 4.11-4.00 (2H, m), .07 (0.3H{Z-isorner}, In), 2.68-2.57 (0.7H{E-isomer}, m), 2.20-2.10 (2H, m), 1.89 (3H, s), 1.89- 1.77 (2H, m). 1.75-1.67 (2H. m), 0.89-0.85 (6H, m). 0.84-0.77 (lOH. m), 0.59 (0.9H[Z- isomer}, 5), 0.57 (2.1H[E-isomer}, s), 0.05-0.00 (6H, m). {00449} Preparation of compound BSc. Glacial acetic acid (0.060 mi, 1.047 mmol) and cesium fluoride (0.080 g, 0.524 mmol) were added to a suspension of B8’b (0.1 g, 0.175 mmol) in acetonitrile (anhydrous) (4 ml) under en atmosphere at 0°C. The ing mixture was stirred at 0°C for 30 min and at room temperature for 2h. LCMS-NQAD (acid) showed little conversion of the starting material to a product with unclear product mass.

Dichloromethane (2 ml) was added to the reaction mixture, and the reaction mixture immediately turned to a yellow clear solution. The reaction mixture was stirred overnight.

Extra cesium fluoride (0.080 g. 0.524 mmol) was added to the reaction mixture and ng was continued for 24h. Extra cesium fluoride (0.080 g, 0.524 mmol) was added to the reaction mixture again and stirring was continued for 4h. Although TLC {heptane(3):ethyl acetate(1)] showed still a little bit of starting material present in the reaction mixture, the reaction mixture was diluted with dichloromethane (75 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic layer was dried over sodium sulfate and concentrated under d pressure. The residue was d by flash column (25 g) chromatography ne(100=>90):ethyl e(0=>10)] to remove the remaining starting material (only visible on TLC). The product containing fractions were collected and evaporated under reduced pressure to afford product BSc (0.051 g, 0.111 mmol, Yield=64%). 1HNMR (400 MHz. CDClg) 5(ppm): 5.37 (1H, brd), 4.65-4.55 (1H. m), 4.31, (2H, q, J=7.1 Hz), 2.89 (1H, dd, J=16.8, 3.0 Hz), 2.57 (1H, dd, , 9.9 Hz), 2.37-2.25 (2H, m), 2.04 (3H, s), 2.09-1.9l (2H, m), l.90-l.77 (3H, m), 1.37 (3H, t, J=7.l HZ), 1.02 (3H, s), 0.97 (3H, d. J=6.5 Hz), 0.72 (3H. s). {00450} Preparation of compound 38d. A solution of B8c (0.05l g, 0.111 mmol) in romethane (1 ml) was cooled in an ice bath under nitrogen atmosphere for 0.5h. laminosulfur trilluoride (DAST) (0.027 ml. 0.222 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred overnight. Extra diethylaminosulfur trifluoride (DAST) (0.027 mi, 0.222 mmol) was added and stirring was continued for 20h. ptane(3):ethyl acetate( 1)] showed still no complete consumption of the starting material after vanillin staining. LCMS-ELSD (base): 4 % product at rt= 3.43 with m«’z(+)= 421, corresponds to desired product were acetate group is eliminated [M- CH3COOH+H]+. The reaction mixture was diluted with romethane (50 ml) and washed with saturated sodium hydrogen carbonate (50 ml). The aqueous layer was separated and twice extracted with dichloromethane (50 ml). The extracts were ed with the former c layer. dried over sodium sulfate and evaporated under reduced pressure. The residue was d by flash column chromatography {heptane(100=>90):ethyl acetate(0=>90)]. The product containing fractions were coliected, evaporated under d pressure and stripped with dichloromethane (5 mi) to afford product B8d (0.027 g, 0.056 mmol. Yieid=5 l%).

IHNMR (400 MHZ. CDCl3)5(ppH’1)I 5.37 (lH, brd). 4.65-4.55 (1H. m), 4.32, (2H, (1, J=7.1 Hz), 2.37-2.28 (2H, m), 2.27-2.09 (1H, m), 2.03 (3H, s), 2 (2H, m), .81 (3H, m), 1.35 (3H, t. J=7.1 Hz), 1.06 (3H.d,1=6.1 Hz). 1.02 (3H. s). 0.88 (6H, t, J=6.8 Hz), 0.70 (3H, s). {00451} ation of compound BS. Compound B8d (0.027 g, 0.056 mmol) was dissolved in tetrahydrofuran (dry) (1 mi) under argon here. The mixture was cooled in an ice bath for 15 minutes and lithium ium hydride, 2.4M in THF (0.047 mi. 0.112 mmol) was added gradually. Some gas evolution was observed. The reaction mixture was cooled and stirred for 111. TLC[heptane(3):ethyl acetate(l)] showed complete conversion to mainly one lower eluting product after vanilhn staining. The ice bath was removed and stirring was continued for lh. The reaction mixture was ed with saturated aqueous ammonium chloride (50 ml) and extracted three times with dichloromethane (50 ml). The combined extracts were dried over sodium sulfate and evaporated under reduced pressure.

The residue was purified by flash column (4 g silica) chromatography {heptane(100=>85):ethyl e(0=>15)}. The product containing fractions were collected and evaporated under reduced pressure. The residue was transfered to a Vial (4 ml) with methanol and the methanol was evaporated at 37°C under a stream of nitrogen. The residue was dried at 40°C in a vacuum oven overnight to afford product BS (0011 g. 0.028 mmol, Yield=49%).1HNMR (400 MHz. CDClg) 5(ppm): 5.35 (1H, m), 3.71 (2H, t, J=12.8 Hz), 3.58-3.48 (1H, m), 2.35-2.18 (2H, m), 2.15-1.93 (3H, m), 1.92-1.73 (5H, m). 1.70-1.40 (9H. m). 1.08 (3H. d, J=6.5 Hz). 1.01 (3H, s). 0.72 (3H. 5).

Example 20. Preparation of Compound BIO .11\H 133-1 AcO HO } In a flame dried flask under argon a solution of BB-i (100 mg, 0.23 mmoi) and titanium (IV) isopropoxide (0.07 mL, 0.23 mmol) in THF (dry, 2 mL) was cooled to 0°C.

Ethylmagnesium bromide (l.0M in THF. l.i6 mL) was added dropwise. Reaction mixture was stirred at 0°C for 15 minutes, TLC (H03; 2: 1) showed starting material and two new spots. Reaction e was allowed to warm to RT and stirring was continued for 1h, Reaction e was then cooled to 0°C and ethylmagnesium bromide (1.0M in THF, 1.16 mL) was added dropwise. Reaction mixture was stirred at 0°C for 15 minutes. TLC (H/E; 2: 1) showed complete conversion and a single new spot. The reaction mixture was d with EtzO (2mL). Aq. sat. NH4C1 (2 mL) and H30 (2 mL) were added at 0°C. Solids were filtered off over cotton and the filter cake was washed with Eth (10 mL). The colourless layers were separated and the aq. layer was extracted with Eth (20 mL) and a mixture of Eth and EtOAc (20 mL; 1:1). Org. layers were dried with Na2804 and solvents were removed in vacuo. 125 mg of a white solid were obtained. Flash chromatography (lieptane, 5%-30% EtOAc) afforded compound B 10 (37 mg, 0.096 mmol; 41.2%). 1H-NMR (400 MHZ, CDClg) 6(ppm): 5.36-5.35 (m, 1H), 3.58 — 3.46 (m, 1H). 2.32 — 2.21 (m, 2H), 2.03 — 1.93 (m. 2H). 1.91 — 1.80 (m, 3H) 1.77 (s. 1H), 1.69 — 1.37 (m, 10H), 1.34 — 0.82 (m. 9H), 1.01 (s, 3H), 0.93 (d, J: 6.6 HZ, 3H), 0.75 — 0.71 (m, 2H), 0.69 (s, 3H) 0.46 — 0.39 (m, 2H).

Example 21. Preparation of Compounds 314 LiAIH4 K2003 ‘20 THF {00453} Preparation of compound 3133. To a solution of BB-2 (762 mg, 1.961 mmol) in Pyridine (15 ml) at 0°C was added acetic anhydride (0.185 ml. 1.961 mmol) and DMAP (23.95 mg, 0.196 mmol) (a slightly yellowish suspension which slowly dissolves).

The mixture was d at RT overnight. TLC (Heptane / EtOAc 2: 1) showed full conversion. The RM was diluted with EtOAc (100 ml) and water (100 m1) and the layers were separated. The water layer was extracted with EtOAc (2x). The organic layers were combined and washed with water (3x) and brine, dried with Na2SO4 and concentrated. The obtained solid was co—evaporated three times with toluene, EtOH and DCM. The material was purified by flash chromatography (40 gr silica, 4-40% EtOAc in heptane, loaded with DCM). Compound B13a (687 mg, 1.595 mmol; 81%) was obtained as a white solid. 1HNMR 2,CDC13): 5(ppm): 5.37 (1H, d, 5.1 Hz), 4.60 (1H, m), 1.99 (3H, s), 1.20 (6H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s). {00454} ation of compound 3131). To a on of compound Bl3a (687 mg, 1.595 mmol) in Dichioromethane (8.5 ml) under nitrogen, was added TMS-Ng, (0.233 ml, 1.755 mmol), followed by BF3.OEt3 (0.842 ml, 3.19 mmol). The mixture was stirred at RT for 2 hours. TLC showed almost complete conversion into a higher eluting spot. Impurities present. Stirred for another 30 minutes after which the RM was diluted with 2M NaOH (25 ml) and DCM (25 ml). The layers were separated. The water layer was extracted with DCM (2x). The organic layers were combined and washed with brine, dried over Na3804 and concentrated and purified by flash chromatgraphy (40 gr silica, 4-40% EtOAc in heptane, loaded with DCM to give compound B13b (660 mg, 1.376 mmol; 86%). IH1\11\1R(3001V1Hz, CDClg): 5(ppm): 5.37 (1H, d, 4.8 HZ), 4.60 (1H, m), 2.03 (3H, s), 1.20 (6H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s).

} Preparation of compound 1313. To a solution of compound B13b (660 mg, 1.448 mmol) in l ether (dry) (1 5 m1) at 0°C under argon, was added LiAlH4 in Et20 (0.797 ml, 3.19 mmol) (white suspension was formed). The e was stirred for 30 minutes at 0°C and for 1 hour at RT, after which TLC showed complete conversion of the SM into a low eluting spot (amine). The mixture was cooled to 0°C again and WATER (0.057 ml, 3.19 mmol) and NaOH, 4M solution in water (0.797 ml, 3.19 mmol) were added. Stirred for minutes at RT and filtered over Celite with diethyl ether and THF. The organic layer was dried with Na2SO4 and the t evaporated. The crude product was purified by gravity column chromatography (100 gr silica, loaded with DCM). First, the column was eluted with DCM:MeOH (95:5), to flush off all the impurities. Then, the column was eluted with DCM:7M NH3 in MeOH (95:5), to obtain compound B13 (400 mg, 1.032 mmol; 71.2%). 1HNMR (300MHz, CDClg): : 5.35 (1H, d, 5.1 Hz), 3.51 (1H, m), 1.07 (6H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s). {00456} Preparation of compound 314. Compound B13 (50 mg, 0.129 mmol) was dissolved in Tetrahydrofuran (dry) (2 ml) by slightly heating, then Mel (8.07 ul, 0.129 mmol) (1 mL from a stock solution of 81 iter Mel in 10 mL of THF) and K2CO3 (21.39 mg, 0.155 mmol) were added. Stirring overnight at rt. The solid was filtered off, washed with water and dried. The mixture was purified on a 12g pre-packed flash column (GraceResolveTM) run in DCM/7N NH3 in MeOH 975/25 15 ml/min, 1 min. fractions.

Compound B14 (18 mg, 0.045 mmol, 34.7%) was thus obtained. 1HNMR z, CDClg): (ppm): 5.35 (1H, d, 4.8 Hz), 3.53 (1H, m). 2.30 (3H, s), 1.02 (9H. s), 0.93 (3H. d. J = 6.6 Hz), 0.68 (3H, 3).

Example 22. Preparation of Compound Bl7 MeHNOMe.HCI EDCI, HOAt Eth, CH20|2 TCI {52554} B17a MeMgBr NaBH4 # —> THF EtOH {00457} Preparation of compound B17a. 1-(3-Dimethylaminopropyl) ethylcarbodiimide hydrochloride (EDCI) (0.282 g, 1.468 mmol), and 1-hydroxy azabenzotriazole (HOAt) (0.018 g, 0.133 mmol) were added at 0°C to a solution of SB- hydroxy cholenic acid (0.5 g, 1.335 mmol), N,O-dimethylhydroxylamine hydrochloride (0.143 g, 1.468 mmol), and N,N—diisopropylethylamine (0.256 ml, 1.468 mmol) in dichloromethane (15 ml) under nitrogen atmosphere. The reaction e was allowed to warm to room temperature over the weekend. Extra in1ethylaminopropyl) ethylcarbodi‘imide hydrochloride (EDCl) (0.282 g, 1.468 mmol) and 1-hydroxy azabenzotriazole (HOAt) (0.018 g, 0.133 mmol) were added and stirring was continued for 2h. The reaction was diluted with dichloromethane (100 ml), washed with 0.5N s potassium hydrogen sulfate (75 ml), and ted aqueous sodium hydrogen ate (75 ml), dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column (4 g silica) chromatography{heptane(80=>66):ethyl acetate(20=>3 3)]. The product containing fractions were collected and evaporated under reduced pressure. The residue was stripped with methanol and dried at 40°C overnight to afford Bl7a (0.495 g, 1.185 mmol, Yield=89%) as a white . 1HNMR (400 MHz, CDC13)5(ppm): 5.36-5.35 (1H, m). 3.69 (3H. s). 3.58-3.48 (1H, m), 3.18 (3H, s), 2.49-2.41 (1H, m), 2.37-2.20 (3H, m), .96 (2H, m), 1.96-1.75 (4H. m), 1.01 (3H, s), 0.95 (3H, d.

J=6.5 Hz), 0.69 (3H, s). {00458} Preparation of compound 1317!). Under argon here, Bl7a (0.2 g, 0.479 mmoi) was dissolved in Tetrahydrofuran (dry) (5 m1) and cooled to -75°C.

Methylmagnesium e 3.0M in diethyiether (0.798 ml, 2.394 mmoi) was added dropwise (exothermic, temperature raised to —40°C). After the addition, the reaction mixture d down to -75°C. The cooiing bath was removed and the reaction mixture was allowed to warm to room temperature over a period of 20 minutes, and stirred 5h. ptane(2):ethy1 e(l)] showed te conversion to a higher eluting product after vaniiiin staining. The reaction mixture was quenched by addition of a saturated aqueous ammonium chioride (75 m1) and extracted with dichloromethane (2x 75 ml). The combined extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified via flash column (4 g) chromatography ne (80=>66):ethy1 acetate (20=>33)]. The product containing fractions were collected and evaporated under reduced pressure. The e was stripped with methanol and dried at 40°C overnight to afford Bl7b (0.117 g, 0.314 mmol, Yie1d=66%) as a white solid. The product was used as such in the next step. 1HNMR (400 MHz, CDCig) 5(ppm): .34 (1H, m), 3.56-3.48 (1H, m), 2.50-2.30 (2H, m) 2.30-2.19 (2H, m), 2.14 (3H. s), 202-194 (2H, m), 1.90-1.81 (3H. m), 1.01 (311.5), 0.91 (3H, d, J=6.5 Hz) 0.67 (3H, s). {00459} ation of compound Bl7. Compound Bl7b (0.117 g, 0.314 mmoi) was dissolved in ethanol (Abs) (5 n11) under nitrogen atmosphere and cooled to 0°C. Sodium borohydride (0.018 g, 0.471 mmol) was added in one n (beware for foaming) and the reaction mixture was allowed to warm slowiy to room temperature. After stirring for 3h, TLC{heptane(2):ethy1 acetate( 1)] showed complete consumption of the starting material after vanillin staining. Excess sodium borohydride was decomposed with a saturated aqueous solution of ammonium chloride (50 ml). The reaction mixture was extracted with dichloromethane (3x 50ml). The extracts were combined, dried over sodium sulfate and evaporated under reduced pressure. The residue was dried at 400C in a vacuum oven overnight to afford 817 (0. l05 g, 0.280 mmoi, Yield=89%) as a white solid. lHNMR (400 MHZ, CDCB) 5(ppm): .34 (1H, 1n), 3.75 (1H, q, J=5.8 Hz), 3.53 (1H, sep, J=5.5 Hz), 2.32-2.20 (2H, m), 2.02-1.95 (2H, m), 1.90-1.79 (3H, m), 1.19 (3H, dd, 1:61. 2.1 Hz), 1.01 (3H, s), 0.93 (3H, d, J=5.5 Hz), 0.68 (3H, s).

Example 23. Preparation of Compound BIS LiAIH4 TCI [525541 B18 {00460} 3B-hydroxy cholenic acid (0.1 g. 0.267 mmol) was suspended in tetrahydrofuran (dry) (5 ml) under argon atmosphere. Lithium aluminium hydride, 2.4M in THF (0.222 ml. 0.534 mmol) was added gradually. Some gas ion was observed. The reaction e was heated to 60°C and stirred overnight. TLC [heptane(2):ethyl acetate(1)] showed complete conversion to a higher eluting product after molybdenum staining. Ethyl acetate (50 ml) and water (50 ml) were added carefully to destroy the excess reagent. The insoluble was filtered and washed with ethyl e (3x 5 ml). The washings were combined with the filtrate and the organic phase was separated. The aqueous phase was twice more extracted with ethyl acetate (25 ml). and the ed extracts were washed with brine (75 ml), dried over sodium sulfate and evaporated under reduced pressure to afford product B18 (0.032 g, 0.089 mmol. 33%) as white powderlHNMR (400 MHZ, CDC13) 8(ppm): .36-5.35 (1H, m), 3.65-3.58 (2H, bs). 3.57-3.48 (1H. m), .20 (2H, m). 2.03-1.93 (2H, m), 1.89-1.79 (3H, m). 1.01 (3H. s), 0.94 (3H. d. J=6.5 Hz). 0.68 (3H. 5).

Example 24. Preparation of C12, C32, and C33 H Al(O—iPr)3 ./ MeMgCI N—Me piperidone AcO Tin-W _ toluene 0 C "' rt c122 Pd/C ElOH (’1' /\,/2 H E ’\ MeMgCl AcO 5 THF H 0" C :- ’t 032a H C33b K-selectride cs?» (17%) C33 (83%) {00461} Preparation of compound C12. Compound C12e (300 mg, 0.720 mmol) was dissolved in Tetrahydrofuran (dry) (7 m1) and cooied to 4°C under Argon. Then, Methyhnagnesium de, 3M in THF (2.400 ml, 7.20 mmol) was added via a syringe at such a speed that the temperature did not exceed 7°C. ng at 4°C for 20 min and then at rt. After 2h, TLC revealed complete reaction. The ix was dropped onto a stirred ted solution of NH4C1 and extracted with EtOAc (2x). Some MeOH was added to assure that all the product ves in the organic iayer. The extract was dried . NaQSO4) and evaporated. The residue was stirred in a little MeOH (~5 ml) and the white solid was filtered off and dried: Compound C12 (168 mg, 0.448 mmoi; 62.3%).1HNMR (400MHz, G): (ppm): 5.36 (L1H, d, 4.6 Hz), 4.61 (1H, d, J=4.3 Hz), 4.03 (1H, s), 3.26 (1H, m). 2.32 (1H. m), 1.03 (6H, s), 0.87 (3H, d, J=6.6 Hz), 0.65 (3H, s). {00462} Preparation of compound C3221. Compound C 12e (74 mg, 0.178 mmol) was dissolved in Ethanoi (Abs) (10 ml) and Palladium, 10% On Charcoal (18.90 mg, 0.018 mmol) was added. The rx was flushed with nitrogen and consecutively with hydrogen. It was stirred vigorously at rt. LCMS after 2h ted complete sion whereas TLC did not show any change. The rx was again flushed with nitrogen and the Pd/C was filtered off through a fritted tube (3 frits). Stili Pd/C in the filtrate. The EtOH was evaporated and the residue was dissolved in DCM and filtered through a smali cotton plug. This gave a clear soiution. DCM was evaporated to give compound C32a (68 mg, 0.162 mmol; 91% yieid). Used as such without further purification. IHNMR z, CDClg): 5(ppm): 4.68 (1H, m), 3.66 (3H, s), 2.02 (3H, s), 0.91 (3H, d, J=6.6 Hz), 0.66 (3H, s). {00463} Preparation of compound C32. Compound C32a (68 mg, 0.162 mmol) was dissolved in Tetrahydrofuran (dry) (1.5 m1) and cooied to 0°C under argon. Then, Methylmagnesium chloride (0.541 mL, 1.624 mmoi) was added. Vigorous gas evolution is seen. Stirring at 0°C and after 3 min. at rt. A iittie more methyimagnesium chloride (0.1 mL, 0.300 minoi) was added after 2 hours. Stirring overnight at rt. Next day, the 1x was poured into 50 m1 of sat. aq. NH4C1 and extracted 3x with EtOAc. EtOAc dried , sulfate) and evaporated. The residue was purified by coiumn chromatography: The crude mixture was dissolved in DCM with a few drops MeOH to aid dissolution and applied to a pre-packed flash siiica column. It was eluted 30 ml/min fractions of 30 sec. with: 5 min 100% heptane; min 0 => 20% EtOAc/heptane and 20 min 20% EtOAc/Heptane isocratic. The product fractions were combined, the solvent evaporated and the white solid residue was triturated in Et20, filtered off and dried to give compound C32 (25 mg, 0.063 mg; 38.8% yield). IHNMR (400MHz, CDCl3): 6(ppmf): 3.58 (1H, m), 1.19 (6H, s). 0.91 (3H, d, J=6.6 Hz), 0.66 (3H, s). {00464} Preparation of compound C33a. Compound C 12 (110 mg, 0.294 mmol) was suspended in Toluene (dry) (7 ml) and 1-methy1—4-piperidone (1.666 mg, 0.015 mmol) and Aluminium isopropoxide (93 mg, 1.028 mmol) were added. Stirring at reflux temp. for 4h.

TLC: still s.m. present. More Aluminium isopropoxide (100 mg. 0.884 mmol) was added.

Continue reflux. After 2 h, more Aluminium isopropoxide (100 mg, 0.884 mmol) was added.

Continue reflux for 3h. Then the last amount ofAluminiuni isopropoxide (100 mg, 0.884 mmol) was added. Reflux for 2h more. Then the rx was d to cool to rt. diluted with EtOAc and extracted with 1N HCl to remove the 3. The -colored aqueous layer was extracted 2x with EtOAc. The combined EtOAc fractions was washed with 1N HCl (3x), dried (brine, sulfate) and evaporated. The residue was stripped with DIPE to leave behind a white powder. This crude mixture was purified on a 40 g pre-packed flash column (GraceResolveTM) applied in CHCl3 with a little MeOH; run in a gradient 30 ml/min: 2 min 100% Heptane; 38 min 0 => 20% Heptane/EtOAc; 10 min 20% e/EtOAc; fraction size sec. Product C33a (84 mg, 0.225 mmol; 77%) was thus obtained. lHNMR (400MHz.

CDClg): D(ppm): 5.82 (1H, s). 1.20 (6H, s). 0.93 (3H, d, J=6.5 Hz). 0.73 (3H, s). {00465} Preparation of compound C33b. Compound C33a (84 mg, 0.225 mmol) was dissolved in Ethanol (25 ml) and flushed with nitrogen. Then, Palladium on calcium ate, (~10% as Pd; 23.99 mg, 0.023 mmol. 10 %) was added and the rx was again flushed with nitrogen. Then the rx was flushed with hydrogen and usly stirred under hydrogen. After 3h. TLC indicated completion of the reaction. It was again flushed with nitrogen and the catalyst was filtered off over hyllo. the EtOH evaporated. The mixture was ed on a 12g clred flash column (GraceResolveTM) run tic in Heptane/EtOAc 9/1; sample applied in DCM; 15 ml/min 1 min fraction-size; t C33b (40 mg, 0.107 mmol; 47.4%) was thus obtained. 1HNMR (400MHz, CDC13): 8(ppm): 2.60 (1H, t. J=14.4 Hz), 1.20 (6H, s), 0.93 (3H, d, J=6.5 Hz), 0.70 (3H, s). {00466} Preparation of compound C33. Compound C33b (5 mg, 0.013 mmol) was dissolved in Tetrahydrofuran (dry) (1 ml) and cooled to -78OC. Then, K—Selectride (0.020 mmol, 0.020 ml) was added and the on mixture was stirred for 6 hours under nitrogen.

The reaction was stopped by the addition of a 10% NaOH solution (0.1 mL) followed by the addition of 30% hydrogen peroxide solution (0.2 mL). The reaction mixture was warmed to room temperature and stirring was continued for 30 minutes. The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na2$04, filtered and evaporated. The crude product was purified by flash column chromatography using 2:l Heptane/EtOAc. Compound C33 (2.2 mg, 0.00502 mmol; 37.6%) was thus obtained. LCMS: 83% pure. contains 17% of the 3 a—OH isomer. lHNMR (400MHz, CDClg): (ppm): 4.12 (1H, t. J=2.7 Hz). 1.20 (6H. 5). 0.92 (3H. d, J=6.6 Hz), 0.67 (3H. 8). e 25. ation of D15 MeLi D1 5 (25.05%) {00467} Compound C33b (40 mg, 0.107 mmol) was dissolved in tetrahydrofuran (dry) (1 ml) under argon and cooled to -78°C. Then, Methyllithium 1,6M (0.320 mmol, 0.200 ml) was added. Stirring at -78CC. TLC after 2h: still much s.m. t. The rx was allowed to reach r.t. slowly. TLC after 1h: still much sm. present and a thick precipitate t. more Tetrahydrofuran (dry) (1 mL) was added to aid dissolution. After 30 min; the rx was almost completely dissolved. Continue stirring for 1h. TLC: s.m. still present but 90+% conversion.

The rx was stirred 30 min. longer and then quenched. Sat. aq. NH4C1 was added and the t was extracted with DCM (3x). 32 mg yield (crude). Tha aq. layer was ted with NaCl and extracted again this time with EtOAc (3x). Now 36 mg crude product. The mixture was purified on a 12g pre-packed flash column (GraceResolveTM) run in a nt l5 ml/min: 2 min 100% Heptane; 28 min 0 => 15% Heptane/EtOAc; 20 min 15% Heptane/EtOAc; fraction size 60 sec. The product D15 (ll mg, 0.027 mmol; 25.05%) was thus obtained. 1HNMR (400MHz. CDC13): 5(ppm): 1.21 (3H. s), 1.20 (6H. s), 0.92 (3H. d.

J=6.5 Hz), 0.67 (3H, s).

Example 26. Preparation of D10 and D16 CHCI3 MAD/MeLi tolune/EtZO F30 Q D16 H) D16 (315-011) D16 (3p-0H) + D16 (sot-0H) 29.6% {00468} Preparation of 3-alpha—D16 nd. Compound D10a (68 mg, 0.182 mmol) was dissolved in Tetrahydrofuran (dry) (2 ml) under argon and cooled to 0°C. Then, Methylmagnesium chloride (0.605 ml, 1.815 mmol) was added. After ‘10 min, the rx was stirred at rt for 3h. The I‘X was then added to 100 mL of sat. aq. NH4C1, rX vessel rinsed with THF and DCM, and stirred for 0.5h with DCM. The product was extracted twice more with DCM. DCM dried (brine. sulfate) and evaporated and Purification on a silica column run in ml/min fractions 30 sec. Grandient: 5 min 100% e; 25 min 100/0 H/EtOAc => 80/20 heptane/EtOAc; 20 min 80/20 heptane/EtOAc. Compound D16 (3 a—OH) (21 mg, 0.054 mmol; 29.6%) was thus obtained. 1HNMR (400MHz. CDClg): 5(ppm): 1.19 (9H. s), 0.91 (3H, d, J=6.6 Hz), 0.66 (3H, s). {00469} Preparation of 3-beta-D16 compound. Compound D10a (57 mg, 0.152 mmol) was dissolved in Toluene (dry) (1 ml) under argon and cooled to -78°C. Then, MAD, 0.4 M solution in toluene (1.141 ml, 0.456 mmol) was added. After 10 min. stirring at -78°C, Methyllithium, 1.6 M solution in diethyl ether (0.285 ml, 0.456 mmol) was added. ng for 2h at -780C under argon. After 211 at that temperature. the reaction was allowed to stir and warm to rt. After 2 additional hour it was quenched by adding it to saturated NH4C1. The D: vessel was rinsed with EtOAc. t extracted with EtOAc (2X). EtOAc dried (brine.

NaZSO4) and evaporated. The e was purified on a 12g pre-packed flash column (GraceResolveTM) applied in DCM and run in a gradient 30 ml/min: 5 min 100% Heptane; 25 min 0 => 15% Heptane/EtOAc; 20 min 15% e/EtOAc; fraction size 30 sec. Product D16 (3fl-OH) (35 mg. 00901an1; 58.8%) was thus obtained. lHNMR (400MHz. CDCIS): 6(ppm): 1.23 (3H, s), 1.20 (6H, s), 0.91 (3H, d, J=6.6 Hz). 0.66 (3H, s). {00470} ation of compound D10a. nd C32 (222 mg, 0.589 mmoi) was dissolved in Chloroform (dry) (15 ml) by slightly heating. Then the solution was cooled in a water bath (did not crystallize upon cooiing) and FCC (191 mg, 0.884 mmol) was added.

Stirring while still in the water-bath. TLC after 1h: ~60-70% conversion. Stirring overnight.

The soiution was then transferred to a separatory funnel and the deposit was extensively washed with DCM and added to the separatory funnei. Washing with 0.5N KHSO4. The aq. phase was washed with DCM, org. phase combined and dried over N212804 (no brine) and evaporated. The mixture was purified on a 12g pre-packed flash column (GraceResoiveTM) run in a gradient 30 : 5 min 100% H; 25 min 0 => 15% H/EA; 20 min 15% H/EA; fraction size 30 sec. 100 tubes. Coumpound D10a (132 mg, 0.352 mmol; 59.8%) was thus obtained. 1HNMR (400MHz, CDCl3): 5(ppm): 1.20 (6H, s), 0.92 (3H, d, J=6.6 Hz), 0.69 (3H, } ation of nd D10. Compound D10a (73 mg, 0.195 mmoi) was dissolved in tetrahydrofuran (dry) (2 m1) under argon and trifluoromethyitrimethylsilane (0.086 ml, 0.585 mmol) and Cesium fluoride (2.96 mg. 0.019 mmol) were added. Stirring at rt. The soiution became slightly yellow slowly. TLC after 311: fiiil conversion. The 1x was diluted with DCM and ted with water. No phase tion. Brine (equal volume) was added. Good separation. The aq. layer was again extracted with DCM; DCM combined and dried (Na2’SO4) and evaporated. 103 mg crude product (102%). Flash coiumn on a 12g pre- packed column run in 30 min. gradient from 0 => 2.5% DIPE in e. The impure TMS- intermediate was thus obtained as an impure mixture of the 3 a— and 3fl—OH products and used as such: The intermediate was dissolved in 1,4-Dioxane (4 ml) and 1N HCi (1 mL, 1.000 mmoi) is added. Stirring at rt. TLC after 1h: s.m. gone. Water was added and the product was extracted with DCM 3x and dried over 1\a2804 and evaporated. The crude product was purified on a C l 8-cohmm run in a gradient ofMeCN/water 95/5 => 0/100 12 min then 12 min isocratic 100% water. Compound D10 (14 mg, 0.030 mmoi'. 22.9%) was thus Obtained. lHNMR (400MHz, CDC13): 6(ppm): 1.19 (6H, s), 0.91 (3H, d, J=6.6 HZ), 0.67 (3H, s).

Example 27. Preparation of Compound D1 OH OH TMS—CF3 THF How. 0 F30 H H {00472} In a flame dried tube a colorless clear solution of compound D13a (97 mg, 0.250 mmol) and Trifluoromethyltrimethylsilane (0.119 ml, 0.749 mmol) in THF (dry, linL) was cooled to 0°C under argon. Cesium fluoride (20 mg, 0.132 mmol) was added. on mixture stayed colorless and was d at 0°C for 5 min. Cooling bath was removed and stirring was continued at RT for 1.511. Reaction mixture had turned brown-yellow, TLC (Heptane/EtOAc. 1:1) complete conversion. Reaction mixture was left standing at RT overnight. H20 (lmL) and EtOAc (SmL) were added. Layers were ted and aq. layer was extracted with EtOAc (ZXSmL). Combined org. layers were dried with Na2SO4 and solvents were removed in vacuo. Flash cinematography (Heptane, 5%—20% EtOAc) afford the impure 3-OTMS intermediate. This was used as such: Aq. HCl (1N, lmL) was added to a solution of the 3-OTMS intermediate in THF . Reaction mixture was stirred at RT overnight. TLC (H/E; 1:1) complete conversion. Solvents were removed in vacuo. A yellow solid was ed, Purification by flash chromatography (Heptane; l5%-35% EtOAc) afforded compound D1 (36 mg, 0.078 mmoi; 31.4%). 1H-NMR (400 MHZ, CDCl3)I C(ppm): 1.20 (6H. S), 0.96 (3H. s), 0.89 (3H. d. J=10.6 Hz). 0.65 (3H. 5).

Example 28. Preparation of DZa-DZ compounds 1) NaOMe, MeOH 2) oxallyl chloride DMF (cat), CH20|2 3) MeOH 4) resolution 1:12 (fi-OH) {00473} Preparation of compound DZa. Under an atmosphere of argon, compound BB—la (1 g, 2.57 mmol) was dissolved in ol (25 ml), and palladium, 10% on activated carbon (0.137 g, 0.129 mmol) was added. The argon atmosphere was replaced by hydrogen (balloon) and the reaction mixture was vigorously stirred at room temperature overnight. The reaction e was filtered over hyilo and the filter residue was washed with methanol (50 m1) and dichloromethane (2x 50 ml). The filtrate and gs were combined and evaporated under reduced pressure to afford t D2a (1.01 g, 2.57 mmol, Yie1d=100%) as white powder. 1HNMR (400 MHZ, CDC13) 5(ppm): 3.66 (3H, s), 3.59 (1H, oct, J=5.1 Hz), 2.35 (1H, ddd, 1:154. 10.3, 5.1 Hz). 2.21 (1H, ddd, 1:158, 9.5, 6.3 Hz), 1.94 (1H. d1, 1:124, 3.3 Hz), 0.91 (3H, d, J=6.4 Hz), 0.65 (3H, s), 0.62 (1H, ddd, 1:14.23, 8.1, 4.1 Hz). {00474} Preparation of compound D21). A suspension ofpyridinium chlorochromate (PCC) (0.969 g. 4.49 mmol) in dichloromethane (10 ml) (dried over molecular sieves) was cooled to 0°C under nitrogen atmosphere. A solution ofD2a (0.585 g, 1.498 mmol) in dichloromethane (5 ml) (dried over molecular sieves) was added gradually. After ng for 1h, a color change from orange to dark brown was observed. The ice bath was removed and stirring was continued for 35h. TLC[heptane(2):ethy1 acetate(1)} showed complete clean conversion to a higher eluting product after vanillin staining. The reaction mixture was diluted with a 2:1 mixture of e/ethyl acetate (15 ml), eluted over a short pad of silica (30 g) and the pad was twice rinsed with heptane/etliyl acetate/dichloromethane 2:1 :1 (60 ml). The elute was washed with 0.5N s potassium hydrogen sulfate (90 ml). The washing was back ted with dicliioromethane (90 m1) and this extract was combined with the former organic layer, dried over sodium suifate, d and evaporated under reduced pressure. The residue was stripped twice with dichloromethane to afford D2b (0.555 g, 1.428 mmol, Yield=95°/0) as a white solid. 1HNMR (400 MHZ, CDClg) 5(ppm): 3.66 (3H, s), 2.04-1.94 (2H, m), 1.91-1.74 (2H. m), 1.73-1.66 (1H, m), 1.01 (3H, s), 0.92 (3H, d, J=6.4 Hz). 0.64 (3H, s). {00475} ation of compound D2c. Under an atmosphere of argon, di’bromomethane (1.268 ml, 18.01 mmol) was added to a stirred suspension of zinc (3.99 mi, 57.9 mmo1) in ydrofuran (dry) (30 m1) (slightly exothermic). The e was cooled to -40°C in a dry ice / acetonitrile bath and stirring for 10 minutes. Titanium(IV) chloride (1.533 ml, 13.90 mmol) was added gradually at such a rate that the temperature did not exceed - °C (very exothermic). The dry ice itri1e bath was removed and the mixture was stirred in an ice bath for 4h at an internal temperature between 06°C. Part of the b1acl< sion (~3 ml) was added at room temperature to a solution of D2b (0.1 g, 0.257 mmol) in tetrahydrofuran (dry) (10 ml). The mixture was stirred for 10 minutes. TLC {Heptane (2) : ethyl acetate (1)] showed mainly staiting material present in the reaction mixture after molybdenum staining. Another part of the suspension (~3 mi) was added and stirring was ued for 5 minutes. TLC{Heptane(2):ethyl acetate(l)} showed still mainly starting material present in the reaction mixture after molybdenum ng. The rest of the suspension was added and after stirring for 5 minutes, TLC [Heptane(2):ethy1 acetate( 1)] showed complete conversion of the starting material to main‘iy one very apoiar product after molybdenum staining. The on mixture was poured out in saturated aqueous sodium hydrogen carbonate (100 mi) (beware for foaming) and extracted three times with ethyl acetate (100 ml). The combined extracts were washed with brine (150 ml), dried over sodium sulfate and evaporated under reduced pressure. The e was chromatographed on sihca gel (12 g flash column) using an eluent with gradient of 0—5% diisopropyl ether in heptane to provide D2c (0.058 g, 0.150 mmol, Yie1d=58%) as a white soiid product. lHNMR (400 MHZ, CDC13) 5(ppm): 4.55 (211.0111), 3.66 (3H, s), 2.35 (1H, ddd, J=15.4, 10.3, 5.1 Hz), 2.21 (1H, ddd, J=15.8, 9.7, 6.4 HZ), 2.19-2.09 (2H, m), 2.06-1.71 (6H, m), 1.69-1.6l (1H, m), 0.91 (3H, d, J=6.4 Hz), 0.85 (3H, s), 0.69-0.60 (1H, m), 0.65 (3H, s). {00476} Preparation of compound D2d. To a on of D20 (0058 g. 0.150 mmoi) in dry dich1oromethane (2 ml) (dried on molsieves) was added potassium carbonate (anhydrous) (0.027 g, 0.195 mmol) under nitrogen atmosphere. The ing mixture was cooled in an ice/water bath, and solid 3-chloroperoxybenzoic acid (70-75%) (mCPBA) (0.039 g, 0.158 mmol) was added in a one portion. The reaction mixture was stirred overnight.

TLC{heptane(9):ethyi acetate(1)] showed partiai clean conversion after vanillin staining.

Extra potassium carbonate (anhydrous) (0.027 g, 0.195 mmol) and roperoxybenzoic acid (70-75%) (m—CPBA) (0.039 g, 0.158 mmol) was added and stirring was continued for 2h. ptane(9):ethyl acetate(l)} showed te sion after vanillin staining. The reaction mixture was filtered and the precipitated benzoate salt was washed with dichloromethane (2x Sml). The solvent was removed in vac-2.10 to afford D2d (0.060 g, 0.149 mmol, Yield=99%) as a white solid residue. According to NMR a 2:1 e of d-O— and B- O-diastereoisomers was ed. IHNMR (400 MHz. CDC13) 5(ppm): 3.66 (3H, s), 2.62 {d—diastereoisomer], d, J=4.8 Hz), 2.61 (0.33H[d-diastereoisomer], d, J=4.9 Hz), 2.57 (0.33H{B-diastereoisomer], bs), 2.35 (1H, ddd,J=15.4, 10.3, 5.1 Hz), 2.21 (1H, ddd, J=15.7, 9.4, 6.3 HZ) 2.i0—l.99 (1H. m), 1.99-1.92 (1H, m), 0.91 (3H. d, J=6.4 Hz). 0.86 (THUS- diastereoisomer], 5,), 0.84 (2H[d-diastereoisomer}, s), 0.66 (3H, s). {00477} Preparation of nd D2e (tr-OH and B-OH). A mixture of D2d (0.055 g. 0. i37 mmol) in methanol (extra dry) (5.5 mi) was heated until a clear colorless solution was obtained. The solution was allowed to cool to room temperature under a nitrogen atmosphere and sodium methoxide, 5.4M (30 wt.%) soiution in methanoi (0.239 mmol, 0.080 ml) was added. The reaction mixture was heated to reflux and stirred overnight.

TLC{heptane(4):ethyi acetate(i )] showed complete conversion after vaniliin staining, product not visible. The reaction mixture was poured out in a saturated aqueous solution of ammonium chioride (50 mi) and three times extracted with dichioromethane (50 ml). The combined extracts were dried over sodium sulfate and evaporated. According to TLC, a very poiar product was formed. The methyl ester moiety was hydrolyzed to the carboxyiic acid due to presence of water in the reaction mixture. The e was dissolved in dichloromethane (10 mi). Oxalyl chioride (0.078 g, 0.612 mmol, 0.053 ml) and N,N— ylformamide (cat) were added, and the reaction mixture was d for 2h. A sample was poured out in methanol, evaporated until dryness, and analyzed on TLC {dichloromethane(98):methanol(2)] which showed compiete conversion to the methyl ester after molybdenum staining. The reaction mixture was diluted with methanol (150 ml) (dried on moi. ), and evaporated under reduced pressure at 40°C. The residue was purified by flash coiumn (12 g) chromatography [heptane (100=>80) : ethyi acetate(0=>20)]. Two product fractions were obtained, which were separately collected and evaporated under reduced pressure to afford D2e ((Z-OH) (0.035 g, 0.081 mmol, Yield=33%) and D2e (B-OH) (0.032 g, 0.074 mmol, Yield=30%) as white solids. D2e (tr-OH) and D2e (B-OH) were used as such in the following mentDZe (or—OH): 1HNMR (400 MHZ, CDCl3) 8(ppm): 3.66 (3H, s), 3.38 (3H, s), 3.18 (2H, s), 2.35 (1H, ddd, 1:154, 10.3, 5.1 Hz), 2.21 (1H. ddd, 1:157. 94, 6.3 Hz), 2.02 (1H. bs), 1.94 (1H, dt, 1:123, 3.0 Hz), .73 (2H. m), 0.91 (3H, d, J=6.4 Hz), 0.74 (3H, s), 0.65 (3H, s).D2e (B-OH): IHNMR (400 MHZ, CDClg) (ppm): 3.66 (3H, s), 3.39 (3H, s), 3.37 (2H, d, J=4.3 Hz), 2.54 (1H, bs), 2.35 (1H, ddd, J=15.4, 10.3, 5.1 HZ), 2.21 (1H, ddd, 1:158, 9.5, 6.3 Hz), 1.95 (1H, dt, 1:125, 3.0 Hz), 1.90- 1.73 (2H, m), 0.91 (3H, c1. J=6.4 Hz), 0.83 (3H. s), 0.65 (3H. s).

} Preparation of compound D2 (or-OH). In a flame dried round bottom flask (100 ml), D2e (CL-OH) (0.035 g, 0.081 mmol) was dissolved in tetrahydrofuran (dry) (1 ml) and cooled in an ice bath under argon for 0.5h. Methylmagnesium chloride 3.0M in THF (0.805 mmol, 0.268 ml) was added via a syringe. Some gas evolution was observed. After stirring the reaction mixture for 2h, TLC[heptane(l )zethyl acetate(l )} showed complete conversion of the starting material to a lower eluting product after enum staining. The reaction mixture was ioned between a ted aqueous solution of ammonium de (20 ml) and dichloromethane (20 ml) and left for two days. The organic layer was separated and the aqueous layer was twice more extracted with dichloromethane (20 ml). The extracts were combined, dried over sodium sulfate and evaporated. The residue was purified by flash column (12 g) chromatography [heptane(100=>80):ethyl e(0=>20)]. The product containing fractions were collected and ated under reduced pressure at 40°C. The e was transferred to a vial as a solution in dichloromethane ./ methanol and evaporated at 370C under a stream of nitrogen. The white solid residue was dried at 45 °C in a vacuum oven overnight to afford D2 (or-OH) (0.025 g, 0.055 mmol. Yield=68%) as white powder. lHNMR (400 MHz. CDC13) 5(ppm); 3.38 (3H. s), 3.18 (2H, s), 1.98 (1H, bs), 1.95 (1H, dt, J=12.5, 3.2 Hz), .79 (1H, m), 1.68-1.61 (1H, m), 1.20 (3H, s), 1.19 (3H, s), 0.91, (3H, d, J=6.5 Hz), 0.74 (3H. s), 0.65 (3H. s). {00479} Preparation of compound D2 (B-OH). In a flame dried round bottom flask (100 ml), D26 (LB-0H) (0.035 g, 0.081 mmol) was dissolved in tetrahydrofuran (dry) (1 ml) and cooled in an ice bath under argon for 0.5h. Methylmagnesium chloride 3.0M in THF (0.805 mmol. 0.268 ml) was added via a syringe. Some gas evolution was obseived. After stirring the reaction mixture for 2h, TLC[heptane(1):ethyl acetate(1)} showed complete sion of the starting material to a lower eluting t after molybdenum staining. The reaction mixture was partitioned between a saturated aqueous on of ammonium de (20 mi) and dichloromethane (20 ml) and left for two days. The organic layer was separated and the aqueous layer was twice more extracted with dichloromethane (20 ml). The extracts were combined, dried over sodium e and evaporated. The residue was purified by flash column (12 g) chromatography [heptane (100=>80): ethyl acetate (0=>20)]. The product containing fractions were collected and evaporated under reduced pressure at 40°C. The residue was transferred to a vial as a solution in dichloromethane methanol and evaporated at 370C under a stream of nitrogen. The white solid residue was dried at 450C in a vacuum oven overnight to afford D2 (B-OH) (0.018 g, 0.039 mmol. Yield=53%) as white powder. 1HNMR (400 MHz. CDC13) 5(ppm): 3.40 (3H. s), 3.39 (1H. d. J=9.2 Hz), 3.36 (1H. d. J=9.2 Hz), 2.51 (1H, bs), 1.96 (1H, dt, J=12.4, 3.1 Hz). 1.89-1.77 (1H, m), 1.20 (6H, s), 0.91, (3H, d. J=6.5 Hz), 0.83 (3H. s), 0.65 (3H. 5).

Example 29. ation of 3-alpha-D3 and 3-beta-D6 D3 (ct-OH) {00480} ation of compound D6a. To a solution of lS—crown—6 (0.315 g. 1.192 mmol) and KHFZ (0.233 g, 2.98 mmol) in dry DMF (7.5 mL) under an argon atmosphere was added D50 (0.3 g, 0.745 mmol) The reaction mixture was heated till 150°C overnight. More KHF; (0.233 g, 2.98 mmol) was added and heating was continued for 8 h. The mixture was cooled to room ature poured out in H20 (150 mL) and stin‘ed with EtOAc (100 mL) for 30 min. The aqueous layer was extracted twice with EtOAc (200 mL). The combined organic layers were washed with brine (2x) dried over N32 804, filtered and evaporated under reduced pressure. The crude product was ed by flash column chromatography (silica, heptane/ethylacetate, 1:0 -> 85:15) to afford product D6a (71 mg, 0.17 mmol. yield=23%).

WO 60441 2014/026633 According to NMR D6a was obtained as a 3:1 cis/trans mixture. 1HNMR (400 MHz. CDCl3) 6(ppm): 4.18 (1.5H {cis-isomer (B-OH)], d, J: 47.8 Hz), 4.15 (0.5H {trans-isomer (d-OH)], d, J: 48 Hz), 3.66 (3H, s), 2.35 (1H, ddd, J=15.4 ,10.3, 5.2 Hz), 2.21 (1H. ddd, 1:158, 95, 6.3 HZ), 0.98 (3H, s), 0.91 (3H, d, J=6.4 HZ), 0.65 (3H, S). {00481} Preparation of compound D6 (B-OH) and D3 ((L-OH). Compound D621 (0.071 g, 0.168 mmol) was coevaporated with toluene (50 mL) and dissolved in dry THF (2 mL) under an atmosphere of argon and cooled to 00C. MeMgC l 3.0M in THF (0.560 mL. 1680 nimo1,) was added using a syringe. The reaction mixture was stirred for 2 h at 00C. The reaction mixture was quenched with ted aqueous NH4C1 (50 mL) and extracted three times with CHZCIZ (100 mL).The combined organic layers were washed with brine dried on NaZSO4 and the cmde product was purified by flash co1umn tography (silica, heptane/ethylacetate, 1:0 -> 85:15) to afford D6 (B-OH) (23 mg, 0.05 mmol, yield = 32%) and D3 ((X-OH) (8 mg, 0.007 mmol, yie1d = 4%). D6 (Ii-OH): lHNMR (400 MHZ, CDCl3) (ppm): 4.19 (2H, d. J: 47.8 Hz), 2.00-1.94 (1H, m), 1.76-1.69 (1H, m), 1.20 (6H, s), 0.98 (3H, s), 0.91 (3H, d, J=6.5 Hz), 0.65 (3H, 5). D3 (Qt-OH): 1HNMR (400 MHZ, CDCl3) (ppm); 4.15 (2H, d, J: 47.8 Hz), 1.96 (1H, dt, J=12.4, 3.2 Hz), 1.89-1.78 (111,111). 1.20 (3H, s), 1.19 (3H, s), 0.92 (3H, d, J=6.5 Hz), 0.76 (3H, s), 0.65 (3H, 5).

Example 30. Preparation of nd D4 omen2 BB-3 1N HCI (aq) 1.4-dioxane {00482} Preparation of compound D4a. BB—3 (0.448 g, 1.153 mmol) was suspended in EtOH (abs) (12 mL) and MeOH (6 mL) under an atmosphere of argon and pal1adium, 10% on activated carbon (0.012 g. 0.012 mmol) was added. The argon here was replaced by en (atmospheric) and the reaction mixture was vigorously stirred at room temperature for 2h. Stirring was continued for 3 days. The reaction mixture was filtered over liyflo and evaporated till dryness. The residue was suspended in acetic acid (5 mL). EtOAc (5 mL) and 1,4-dioxane (5 mL) and heated till a clear solution was obtained. The reaction mixture was cooled to room temperature and palladium. 10% on ted carbon (0.012 g. 0.012 mmol) was added under an Argon atmosphere. The argon atmosphere was replaced by hydrogen (atmospheric) and the reaction mixture was vigorously d at room temperature overnight. The reaction mixture was filtered over hyflo and washed with MeOH (2x50 mL) and CHgClg (50 mL). The ts were evaporated and the residue triturated with ted aqueous NaHCO3, filtered off and dried in a vacuum oven at 40°C overnight to afford D4a (385 mg. 0.99 mmol, yield = 85%) as a white solid. 1HNMR (400 MHZ, CDCl3) 5(ppm): 3.59 (lH, sep. J=5.3 HZ), 1.96 (lH. dt. J=9.3, 3.l HZ) l.98-l.75 (2H, m). 1.7l (lH, dt. J=l3.2. 3.4 Hz). 1.65 (1H, dq, 1:130, 3.4 Hz). 1.19 (6H. s). 0.91, (3H. d. J=6.5 Hz), 0.80 (3H. s), 0.65 (3H. s). {00483} Preparation of compound D4b. To an ice cooled solution of pyridinium chlorochromate (PCC) (0.248 g. l. l 52 mmol) in dry CH2C12 (4 mL) under a nitrogen atmosphere was added a suspension of D4a (0.3 g. 0.768 mmol) in dry CH2C12 (4 mL). The solid material was added drop wise redissolved as a solution in dry CHC13 (41nL). The reaction mixture was stirred for 30 min at 0°C, followed by 2h at room temperature. Again pyridinium chlorochromate (PCC) (0248 g. l.l52 mmol) was added in one portion at room ature. and the reaction mixture was stirred overnight. The reaction mixture was eluted over a short pad of sand. silica (5 g) and hyflo. and the pad was rinsed with CHQClg (l00 mL).

The elute was washed twice with aqueous 0.5N KHSO4 (100 ml). The combined washings were extracted once with CH2C12 (100 mL). and the combined organic layers were dried over Na3804, filtered and evaporated under d pressure to afford D41) (306 mg, 0.79 mmol. yield = 103%) an orange/brown solileNMR (400 MHz, CDCl3) 5(ppm): 2.38 (1H. td, 1:145. 6.4 Hz), 2.32-2.21 (2H, m). 2.15-1.93 (3H. m), 1.90-1.79 (1H. m). 1.75-1.65 (1H, m). 1.20 (6H, s). 1.01 (3H, s). 0.92 (3H. d, J=6.4 Hz). 0.78-0.64 (1H. m), 0.68 (3H. s). {00484} Preparation of compound D4c. In a flame dried reaction tube. a solution of D4b (0.1 g, 0.257 mmol) and (trifluoromethyl)trimethylsilane (0.053 mL. 0.34 mmol) in dry THF (2.5 mL) was cooled to 0°C under argon. CsF (spatula tip) was added and the on mixture was stirred at 0°C for 5 minutes. The cooling bath was d and stirring was continued at room temperature overnight. Extra (trifluoromethyl)trimethylsilane (0.053 ml. 0.34 mmol) and CsF la tip) were added to the reaction mixture and stirring under argon atmosphere was continued for 3h. H20 (50 mL) and EtOAc (50 mL) were added. Layers were ted after stirring for 30 minutes. The aqueous layer was extracted twice with EtOAc (50 mL). The combined organic layers were dried with Na2804 and solvents were removed in vacuo. D4c (163 mg, 0.31 mmol, yield = 119%) was obtained as a light yellow oil. 1HNMR (400 MHZ, CDCl3) 5(ppm): 2.04-1.92 (1H, m), l.90-l.68 (2H, m), 1.09 (3H. s), 1.08 (3H. s), 0.80 (3H. s), 0.73 (3H. s), 0.55 (3H. s), 0.03 (12H. m). {00485} Preparation of nd D4. To a solution ofD4c (0.137 g, 0.258 mmol) in 1,4-dioxane (8 mL) was added 1 M s HCl (2 mL, 2.0 mmol). The yellow solution was stirred for 311 at room temperature. The on mixture was diluted with H20 (50 mL) and extracted with CH2Cl3 (3x50 mL). The combined organic layers were washed with saturated aqueous NaHCOg, brine, dried on Na;SO4 and the solvents evaporated. The crude product was purified by flash column chromatography (silica, heptane/EtOAc, 1:0 -> 4: l) and crystallized from CH2Clg to afford D4 (44 mg, 0.10 mmol, yield = 37%) as a white solid. 1HNMR (400 MHz, CDCl3) 5(ppm): 2.09-2.02 (1H, m), 1.98 (1H, s), 1.96 (1H, dt, J=12.8, 3.4 Hz), 1.88—1.77 (2H, m), l.72-l.6l (3H, m), l.20 (3H, s), l.l9 (3H, s), 0.92 (3H, d, J=6.6 Hz), 085(3H, s), 0.65 (3H, s).

Example 31. ation of compound D5 OMe (iPrO)3AI 1-methyl-4—piperidone Pd/Caco3 EtOH {00486} Preparation of compound DSa. To a solution BB—1 (2 g, 5.15 mmol) and A1(I?PrO)3 (3.68 g, 18.01 mmol) in dry e (80 mL) was added 1-methylpiperidone (29.1 g, 257 mmol, 29.7 mL). The solution was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with aqueous 0.5 M HCl (80 mL), brine (80 mL) and 13th (120 mL). The c layer was extracted with EtOAc (3x100 mL). The combined organic layers were dried with NagSO4, filtered and the solvents were removed in vacuo. The e was diluted with aqueous 1 M HCl (250 mL) and extracted with EtOAc (2x250 mL).

The organic solvents were washed with brine, dried with NaZSO4 and evaporated till dryness.

The crude product was purified by flash column chromatography (silica, heptane/ethylacetate, 1:0 —> 9:1) and coevaporated with CHgClg to afford D5a (1.27 g, 3.27 mmol, yield = 64%). IHNlVIR (400 MHZ, CDCl3) 5(ppm): 5.72 (1H, s), 3.67 (3H, s), 2.48- 2.17 (6H, m), 2.02 (1H, dt, 1:9.6, 3.8 Hz), .75 (3H, m), 1.69 (1H, td, J=14.0, 4.7 Hz), 1.18 (3H, s), 0.92 (3H, d, J=6.4 HZ), 0.71 (3H, s). {00487} Preparation of compound D5b. A suspension of D5a (1.26 g, 3.26 mmol) in absolute EtOH (150 mL) was heated till the starting material was dissolved. The solution was cooled to room temperature and made under an argon here. Palladium on calcium carbonate, 10% (w/w) (cat) was added, and hydrogen pheric) was flushed through the on mixture for 15 minutes. The reaction mixture was stirred at room temperature under hydrogen atmosphere ght. The reaction mixture was flushed with argon, the solids were filtered over Celite/silica gel. and the filter was washed with EtOH (75 ml). The solvents were d in vacuo and the crude product was purified by flash column chromatography (silica, heptane/ethylacetate, l:0 —> 9: 1) to obtain product D5b (l.12 g. 2. l6 mmol, Yield=75%). According to NMR D5b was obtained as a 3:1 cis/trans mixturelHNMR (400 MHZ. CDCl3) 5(ppm): 3.67 (3H. s), 2.70 (1H, t, J=l4.2 Hz). 1.02 (2H[cis-isomer}, s), 1.00 (lH[trans-isomer}, s). 0.92 (3H, d, J=6.4 Hz). 0.68 (3H, s). {00488} Preparation of compound D5c. To a solution of trimethylsulfoxonium iodide (0.747 g, 3.39 mmol) in dry DMSO (10 mL) under an nitrogen atmosphere was added NaH (60% dispersion in mineral oil) (0.075 g, 3.13 mmol) in 1 portion. The on mixture was stirred for 30 min and a on of D5b (1.014 g, 2.61 mmol) in dry THF (10 mL) was added. The reaction mixture was stirred for 1h, followed by the addition of extra trimethylsulfoxonium iodide (0.747 g. 3.39 mmol) and NaH (60% dispersion in mineral oil) (0.075 g. 3.13 mmol). The mixture stirred for 2 h. The reaction mixture was partitioned between saturated aqueous NH4C1 (150 mL) and CHzClg (150 mL). The aqueous layer extracted with CHZClg (100 mL) and the combined organic layers were washed with brine. dried on Na2804 and evaporated till s. The crude product was purified by flash column chromatography (silica. heptane/ethylacetate, 1:0 -> 88:12) to afford product D5c (1 g, 2.48 mmol, Yield=75%). According to NMR D5c was obtained as a cis/trans mixture. 1HNMR (400 MHz, CDCl3) 5(ppm): 3.67 (3H, s), 2.64-2.60 (2H, m), 2.42-2.30 (2H, m), 2.27-2.16 (1H, m), 0.99 (3H, s), 0.92 (3H, d, J=6.4 Hz), 0.66 (3H, s). {004891 Preparation of compound D5d. To a suspension of DSC (0.1 g. 0.248 mmol) in MeOH (2.5 mL) under a nitrogen atmosphere was added KOtBu (0.056 g. 0.497 mmol) in one portion. The reaction mixture was heated till reflux for 3 hours and cooled to room temperature overnight. The e was diluted with CH3Clg (5 mL) and poured out in saturated aqueous NH4Cl (25 mL). The aqueous layer was extracted with CHZClg (3x 25 mL).

The combined c layers were dried over NaZSO4, filtered and evaporated under reduced pressure. The crude product was purified by flash column chromatography (silica, e/ethylacetate. 1:0 -> 9: 1) and coevaporated with CHzClZ (5 mL) to afford product D5d (0.08 g, 0.18 mmol, 74%). According to NMR D5d was obtained as a ~2:l cis/trans mixture. lHNMR (400 MHZ, CDCl3) 5(ppm): 3.66 (3H, s), 3.39 (2H [cis-isomer (B-OH)], s), 3.38 (1H [trans—isomer (u-OHH, s), 3.24-3.12 (2H [cis-isomer (By-OH) trans—isomer (u—OH)], m). 2.35 (1H, ddd, J=l5.4. 10.3, 5.1 Hz), 2.21 (1H, ddd, 1:158, 95, 6.3 Hz), 2.04 (1H, bs). 1.98—1.92 (1H, m), 1.92-1.75 (3H, m), 0.96 (3H, s), 0.91 (3H, d, J=6.4 HZ), 0.64 (3H, s). {00490} Preparation of compound D5. In a flame dried round bottom flask (100 mL) D5d (0.080 g, 0.184 mmol) was dissolved in dry THF (3 mL) under an atmosphere of nitrogen and cooled to 0°C. MeMgCl 3.0M in THF (0614 mL. 1.841 mmol) was added using a syringe The reaction mixture was stirred for 1.5 h at 0°C. The reaction mixture was quenched with ted aqueous NH4C1 (20 mL) and extracted three times with CHgC-l3 (3x20 e combined organic layers were washed with brine dried on NaZSO4 and the crude product was ed by flash column chromatography (silica, heptane/ethylacetate, 1:0 -> 85:15) to afford D5 (36 mg, 0.08 mmol, yield = 45%). lHNMR (400 MHZ, CDCl3) (ppm): 3.39 (3H, s), 3.22 (1H, d. J=9.0 Hz), 3.20 (1H, d. 9.0 Hz), 1.20 6H, s), 0.97 (3H, s), 0.91 (3H, d, J=6.5 Hz), 0.65 (3H, s).

Example 32. Preparation of C3-alpha-Dl3 and C3-beta-D13 compounds MeLi 0H " OH "0’0 D13 (Ba-OH) "10,, H0 D13 (3/3—OH) {00491} Under argon at 0°C methyllitliium, 1.6M in diethyl ether (0.26 mL, 0.412 mmol) was added dropwise to a solution of Dl3a (0.080 g, 0.206 mmol) in THF (dry, lmL).

A white precipitate formed upon addition. THF (dry, SmL) was added. Stirring at 0°C was continued for 10min. on e was alllowed to warm to RT and stirring was ued for 1h, TLC (H/E,l : l) showed starting material and two more polar spots.

Methyllithium, l.6M in diethyl ether (0.39 mL. 0.618 mmol) was added at RT under argon.

Stirring was continued overnight. Reaction mixture had turned into a yellow solution. Solvent was removed in vacuo. THF (dry, lmL) was added under argon at RT. Methyllithium, 1.6M in diethyl ether (0.26 mL, 0.412 mmol) was added dropwise and reaction mixture was d at RT for 3h. Aq. sat. ammonium chloride (lOmL). H20 (SmL) and diethyl ether (20mL) were added. Layers were separated and aq. layer was extracted with diethyl ether (2x25mL).

Combined org. layers were dried with sodium sulfate and ts were removed in vacuo.

Flash tography (H, 5%-25% EtOAc) afforded 13 mg of the 3beta-hydroxy diastereoisomer and 12 mg of the 3alpha—hydroxy diastereoisomer. Compound D13 (3 a—OH) (12 mg, 0.030 mmol; 14.4%) and compound Dl3 (Sfl-OH) (13 mg, 0.032 mmol; 15.6%). (3 a—OH): 1H-NMR (400 MHz, CDCl3): 6(ppm); 2.03 — 1.92 (m, 2H), 1.90 — 1.79 (m. 2H). 1.78 — 1.70011. 1H). 1.63 — 0.99 (m, 25H), 1.25 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 0.93 (s, 3H), 0.91 (d, J: 6.5 Hz, 3H), 0.64 (s, 3H). (3fl-OH): ‘H-NMR (400 MHZ, CDClg): 6(ppmf): 2.00 — 1.78 (1n. 4H). 1.67 — 0.99 (m, 25H), 1.22 (s, 3H), 1.20 (s, br, 6H), 0.96 (s, 3H), 0.94 — 0.86 (m, 4H). 0.65 (s, 3H).

Example 33. Preparation of compounds ha and C3-beta D14 D14 (on-OH) MeMQC, D14 (gs-0H) {00492} In a flame dried reaction tube (.20 mL) D4b (0.1 g, 0.257 mmol) was dissolved in dry THF (3 mL) under an here of argon and cooled to -100C. MeMgCl 3.0M in THF (0.86 mL, 2.57 mmol) was added drop wise using a syringe MeMgCl 3.0M in THF (0.68 mL, 2.04 mmol). The reaction mixture was coming up to room temperature during 1.5 h and stirred for 2h at room temperature. The reaction mixture was poured into a stirred solution of saturated aqueous NH4C1 (100 mL) and extracted three times with CH3C12 (3x75 e combined c layers were washed with brine dried on NaZSO4 and the crude product was purified by flash column chromatography (silica, heptane/ethylacetate, 1:0 -> 4:1) to afford D14 (oz-OH) (28 mg, 0.07 mmol, yield = 27%) and D14 (B-OH) (21 mg. 0.05 mmol, yield = 20%) both as a white solid. D14 (or-OH): 1HNMR (400 MHZ, CDClg) 5(ppm): 1.95 (1H, dt, J=12.3, 3.1Hz), 1.89-1.77 (1H, m) 1.65 (1H, dq, J=12.7, 3.3 HZ), 1.20 (9H, s), 0.92 (3H, d, J=6.5 Hz), 0.75 (3H, s), 0.78-0.69 (1H, m), 0.65 (3H, 5). D14 (B-OH)‘. lHNMR (400 MHz. CDClg) 5(ppm): 1.96 (1H. dt, 1:125, 3.3 Hz). 1.89-1.77 (1H. m), 1.25 (311,5), 1.20 (3H, s), 1.19 (3H, s), 0.92 (3H, d, J=6.5 Hz), , s), 0.65 (3H, s), 0.70-0.61 (1H, 111).

Example 34. Synthesis of 6-difluoro analogs (3) H2804, MeOH, reflux overnight, 97%; (b) Jones reagent, acetone, 0°C 30 min, 60%; (c) HCI, MeOH, rt overnight, 44%; (d) A020, pyridine, 70°C, overnight, 92%; (e) DAST(neat), 40°C, 4 days, 42%; (f) HCI, MeOH, THF, rt overnight; (9) Bess-Martin periodinane, CH2C|2, rt ght; (h) MeMgBr, THF, 0°C.

Example 35. Synthesis of 5,6-alkenylmonofluoro analogs 2014/026633 (a) H2504, MeOH, reflux overnight, 97%; (b) Jones reagent, acetone, 0°C 30 min, 60%; (c) HCI, MeOH, rt overnight, 44%; (d) A020, pyridine, 70°C, overnight, 92%; (e) DAST(neat), cat. fuming H2804; (f) HCI, MeOH, THF, rt overnight; (9) Bess-Martin periodinane. CHZCIZ, rt overnight; (h) MeMgBr, THF, 0°C.

Example 36. Synthesis of 6-beta-methyl analogs (a) Ethane-1,2-diol, cat.TsOH, toluene, reflux overnight; (b) A020, pyridine, rt ght; (0) 8H3, THF, NaOH/ H202, 0°C then rt; (d) Bess-Martin periodinane, CHzclz, rt overnight; (e) triphenylphosphonium bromide, potassium tert—butoxide, THF, room temperature; (f) TCDI, DMAP, CHZCIZ, 40 °C; (9) PhSSnH, AIBN, toluene, 110 "C; (h) potassium carbonate, MeOH,rt overnight; (i) MeMgBr, THF, 0 °C. 10a, (it-OH 11a, or-OH 10b, B-OH 11b, B-OH 13 14 15 (a) 3M HCI, acetone; (b)(ethy|)-tripheny|phosphonium bromide, t-BuOK, THF, 65°C; (e) methylacrylate, EtAICIZ, DCM, rt; (1’) 10% Pd/C, H2, EtOAc; (g) MeMgBr, THF. 0 "C.

Assay Methods } nds of the present invention can be evaluated using various in vitro and in viva assays described in the literature; examples of which are described below. {00494} The following examples are offered to illustrate the ical activity of the compounds, pharmaceutical itions, and methods provided herein and are not to be construed in any way as limiting the scope thereof.

MMDA modulation activity assay {00495} The compounds of the ion are or can be tested for their NMDA modulation activity using the assay described by Paul at (1]., in J. Pharm. and Exp. Ther. 1994, 271, 677-682. The assay protocol is reproduced below. (1) Cell culture {00496} Hippocampal s from i9-day-old Sprague-Dawley rat embryos are maintained in primary culture, as described previously (Segal, J. NeurophysioL 50 1249- 1264, I983). Briefly, hippocampal tissue is dissected and mechanically disrupted and the cell suspension is plated onto poly—L—lysine (Sigma, St. Louis, MO)-coated, glass-bottom, 35-mm culture dishes that contained modified Eagle’s medium with Earle’s salts supplemented with l0% fetal bovine serum, l0% horse serum and 2 mM glutamine (Sigma). N3 serum supplement ied from Guthrie et 01., Brain Res. 420 313-323, 1987) consisted of: bovine serum n, 0.001%; transferrin, 20 mg/liter; insulin, l0 trig/liter; selenium, 60 nM; corticosterone, 40 rig/liter; othyronine, 20 er; progesterone, 40 nM; and putrescine, 200 till/I, which is added to the media. Cells are incubated in a humidified atmosphere that contained l0% CO; and 90% air. Culture media that lacked fetal bovine serum is added every 7 days after plating. The cells are used after 7 to 14 days in culture. (2) Measurement of intracellular Ca++ } Cultures are washed three times with buffer that contained (in millimolar quantities) the following: NaCl, 145; KCl, 2.5; HEPES. 10; CaClg. l; and glucose, 10 (adjusted to pH 7.4 with NaOH and to an osmolality of 315-325 mOsm with sucrose). The cultures are then incubated with fura-2 acetoxymethyl ester 2 to 5 ttM for 30 to 45 min in the dark at 37°C. After the incubation period, the cultures are again ished three times with buffer and allowed to stand for 2 15 mm to permit complete hydrolysis of the ester. The neuron of interest is perfused with buffer at a rate of approximately 250 ul/min (37 0C). The perfusion device consisted of a water-jacketed array of 10 tubes that emptied into a common tip oned approximately 500 pm from the cell. All ons contained 0.5 uM tetrodotoxin to eliminate voltage-sensitive Na+ ts and 2 to 5 uM glycine to saturate the strychnine— insensitive glycine site on NMDA receptors. {00498} [Call] is measured by microspectrofluorimetry with the Ca++ sensitive indicator fura-2 (Groden at 61]., Cell Calcium 12: 279-287, 1991). The neurons are illuminated on a Nikon ed cope with a dual-wavelength illumination—photometry system (SPEX-DM3000 AR-CM, SPEX Industries, Edison, NJ). {00499} Excitation of fura-2 occurred at 340 and 380 nm with emitted light monitored at 510 nm. The neurons are visualized by phase—contrast copy and are easily identified by their characteristic morphology. Light reaching the photomultiplier is limited to that emitted by the cell of interest by a pinhole. The photon counts are stored in digital form for subsequent analysis. Calibration is carried out as described by Grynkiewicz et at. (J. Biol.

Chem. 280, 34440-3450, 1985). The fluorescence ratio at saturating Ca++ (Rum) is determined in situ by bathing the cells in buffer that contained (in millimolar quantities) the following: KCl, 130; NaCl, 17; HEPES, 10; glucose, 10; CaClg, 2; and ionomycin, 0.015 (pH 7.2, 370C.

Some ation buffers contained 10 uM carbonyl cyanide-m-chlorophenyl-hydrazone to le mitochondrial oxidatiVe phosphorylation. For the determination of the fluorescence ratio at zero Ca++ (Rmm), the buffer is modified so that 3 mM EGTA and 80 uM EGTA acetoxymethyl ester is substituted for C3Clg. An nt K; of 285 nM (Groden e: at, 1991) is used for {Calm calculations.

Electrophysiology assay {00500} The compounds of the invention are or can be tested in electrophysiology assay as described by Petrovic er £11., in J. Neuroscience 160 (2009) 616—628. The assay protocol is reproduced below. (l) Hippocampal cultures } Primary dissociated hippocampal cultures are prepared from l—to 2—day-old postnatal rats. Animals are tated, and the hippocampi are dissected. Trypsin digestion, followed by mechanical dissociation, is used to e cell suspension. Single cells are plated at a density of 500,000 cells/cm2 on 31- or 12-min polylysine-coated glass coverslips.

Neuronal es are maintained in NeurobasalTM-A (Invitrogen, Carlsbad, CA, USA) medium supplemented with glutamine (0.5 mM) and B27 Serum-Free Supplement rogen). (2) Transfection and maintenance of HEK293 cells {00502} HEK293 cells can Type Culture Collection, ATTC No. CRL1573, Roclwille, MD, USA) are cultured in Opti—MEM® 1 (Invitrogen) with 5% fetal bovine serum at 37 OC and transfected with NRl-la/NR28/green fluorescent protein (GFP) plasmids as prexuously (Cais er (1]., Neuroscience l51: 8, 2008). Briefly, equal amounts (0.3 ug) of cDNAs coding for NR1, NR2 and GFP (pQB125, Takara, Otsu, Shiga, Japan) are mixed with 0.9 til Matra-A Reagent (TBA, Gottingen, Germany) and added to confluent HEK293 cells on a 24-well plate. After tiypsinization, the cells are resuspended in EM® 1 containing 1% fetal bovine serum supplemented with 20mM MgCl2,1 mM D,Lamino phosphonopentanoic acid and 3 mM l MMDA binding in vitro } Compounds can be screened to determine their potential as modulators of NMDA binding in vitm. These assays are or can be performed in accordance with the above discussed procedures.

WO 60441 In vivo Pharmacology {00506} Male NSA mice weighing between 15-20 g are Obtained from Harlan Sprague- Dawley (San Diego. CA). Upon arrival they are housed in standard rbonate cages (4 per cage) containing a sterilized bedding material in a room of constant temp (23.00 i 2.5 0C) with a 12 h (07.00-19.00 light) light/dark cycle. Food d LM 485) and water are freely available. Mice are acclimated a minimum of 4 days prior to mentation.

Hanging Wire Test {00507} The hanging—wire test used a custom-built apparatus that consisted of a metal wire (2 mm diameter) suspended horizontally above a padded surface (25 cm). Mice are held by the base of the tail. their ws placed in contact with the wire, and then ed.

Animals are required to bring both hindpaws in contact with the wire Within 5 sec in order to be scored as a pass. Results are treated lly.

Drug Metabolism and Pharmacokinefics: HERG assay {00508} HEK 293 cells which stably express the HERG potassium channel are used for electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found elsewhere (Zhou et 61]., Biophvs. J. 74:41, 1998). Before the day of experimentation, the cells are harvested from culture flasks and plated onto glass coverslips in a standard Minimum Essential Medium (MEM) medium with 10% Fetal Calf Serum (FCS). The plated cells are stored in an incubator at 37 °C ined in an here of 95%02/5%C02. Cells are studied n 15-28 hrs after harvest. {00509} HERG currents are studied using standard patch clamp techniques in the whole-cell mode. During the experiment the cells are superfused with a standard external solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl;. 2; MgClg, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole-cell recordings are made using a patch clamp amplifier and patch es which have a resistance of l-3 MOhm when filled with the standard internal solution of the following composition (mM); KCl, 130; MgATP, 5; MgClg, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 15 MOhm and seal resistances >lGOhrn are accepted for further experimentation. Series resistance compensation was applied up to a maximum of 80%. No leak subtraction is done. However, acceptable access resistance depended on the size of the recorded currents and the level of series resistance compensation that can safely be used. 2014/026633 {00510} Following the achievement of whole cell configuration and sufficient time for cell dialysis with pipette solution (>5 min), a standard voltage protocol is applied to the cell to evoke membrane currents. The voltage protocol is as follows. The membrane is depolarized from a holding potential of -80 mV to +40 mV for 1000ms. This was followed by a descending voltage ramp (rate 0.5 mV msec-l) back to the holding potential. The voltage protocol is applied to a cell continuously throughout the experiment every 4 seconds (0.25 Hz). The amplitude of the peak t elicited around -40mV during the ramp is measured. Once stable evoked current responses are obtained in the external solution, vehicle (0.5% DMSO in the standard al solution) is applied for 10-20 min by a peristalic pump. ed there were l s in the amplitude of the evoked current response in the vehicle control condition, the test compound of either 0.3, l, 3, or l0 mM is d for a l0 min period. The l0 min period included the time which supplying on was passing through the tube from solution reservoir to the recording chamber via the pump.

Exposing time of cells to the compound solution was more than 5 min after the drug concentration in the chamber well reached the attempting concentration. There is a subsequent wash period of a 10-20 min to assess reversibility. Finally, the cells is exposed to high dose of dofetilide (5 mM), a specific IKr blocker, to evaluate the itive endogenous current. {00511} All experiments are performed at room temperature (23 :: lQC). Evoked membrane currents were recorded on—line on a computer, filtered at 500—1 KHz (Bessel -3dB) and sampled at l-2 KHz using the patch clamp amplifier and a specific data analyzing software. Peak current amplitude, which occurred at around -40 mV, is measured off line on the computer. {00512} The arithmetic mean of the ten values of amplitude is calculated under vehicle control conditions and in the presence of drug. Percent decrease of IN in each ment was ed by the normalized current value using the following formula: IN = (l- ID/IC )xlOO, where ID is the mean current value in the presence of drug and 1C is the mean current value under control ions. Separate experiments are performed for each drug concentration or time-matched control, and arithmetic mean in each experiment is defined as the result of the study.

WO 60441 Drug [Metabolism and cokinefz‘cs: Half-life in human liver microsomes (HLM) {00513} Test compounds (1 uM) are incubated with 3.3 mM MgCl2 and 0.78 mg/mL HLM (HLlOl) in 100 mM potassium ate buffer (pH 7.4) at 37 °C on the 96—deep well plate. The reaction e is split into two groups. a non-P450 and a P450 group. NADPH is only added to the reaction mixture of the P450 group. An aliquot of samples of P450 group is collected at 0, l0, 30, and 60 min time point, where 0 min time point indicated the time when NADPH was added into the reaction e of P450 group. An aliquot of samples of 50 group is collected at -lO and 65 min time point. Collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, l5 min). The compound concentration in supernatant is measured by LC/MS/MS system. The half-life value is obtained by plotting the natural logarithm of the peal< area ratio of nds/ internal standard versus time. The slope of the line of best fit through the points yields the rate of lism (k), and is converted to a half-life value using following equation: Half-life = ln 2 / k. e 37. NMDA potentiation data {00514} The whole-cell patch—clamp technique was used to investigate the effects of compounds (0.1 mM and LO mM) on the NlVTDA receptor (GRlNl / GRINZA subunits) expressed in HEK cells. NMDA Glycine peak and steady-state currents were recorded from stably transfected cells expressing the NMDA receptor and the modulatory effects of the test items on these currents were investigated. {00515} Cells were stably transfected (LipofectamineTM) with human GRlNl (variant NRl-3). These cells were ently transfected with GRlNzA cDNA and CD8 (pLeu) antigene (DNA. About 24—72 hours ing transfection 1 ul Dynabeads M-45 CD8 was added to identify successfiilly transfected cells (Jurman er a[., Biotechmques (l994) 17:876— 881). Cells were passaged to a confluence of 50-80%. Whole cell currents were measured with HEKA EPC—IO amplifiers using PatchMaster software. Cell culture dishes for recordings were placed on the dish holder of the microscope and continuously perfused (l ml/min) with bath solution. All solutions applied to cells including the pipette solution were maintained at room temperature (19°C - 30°C). After formation of a Gigaohm seal between the patch electrodes and transfected individual HEK 293 cells (pipette resistance range: 2.5 MW - 6.0 MW; seal resistance rangez>l GW) the cell membrane across the pipette tip was ruptured to assure ical access to the cell interior (whole-cell patch-configuration). Once a stable seal could be ished NMDA inward currents were measured upon application of MM NMDA (and 5.0 MM Glycine) to patch-clamped cells (2 applications) for 5 s. The cells were voltage clamped at a holding potential of -80 mV.

Compound I (Org-1) ,x 74 171 C26H4202 WO 60441 WO 60441 WO 60441 C27H45F302 WO 60441 WO 60441 ?????????????????????????????? ???????????????????????????????? ???????? ???????????????????????????????????? ?????????????????!?T?q?e?C?1?q?-?N?’?E?O?c?q?’?]?e?E?-?M?1?c?q?c?j?-?C?q?’?c?q???’?????q???’?T?????q?’?U?/?q???e?C?1???q?O?’?p?q?O?1?’?T?q?W?U?1?q?W?]?q?O?W?]?1?q?e?C?’?U?q ?W?T?1?q?j?T?M?1?c?c?q?F?T?0?E?-?’?e?1?0?q?e?W?q?e?C?1?q?-?W?T?e?]?’?]?p?q?W?]?q?W?e?C?1?]?m?E?c?1?q?1?l?F?0?1?T?e?q???W?P?q?e?C?1?q?-?W?T?e?1?o?e???q???M?’?F?O?c?q?W?]?q ?0?1?c?-?]?E?Z?e?E?W?T?c?q?e?C?’?e?q?F?T?-?M?j?0?1?q???W?^???q?+?1?e?m?1?1?T?q?W?T?1?q?W?^?q?O?W?]?1?q?O?1?O?+?1?]?c?q?W?4?q?’?q?A?]?W?j?Z?q?’?]?1?q?-?W?T?c?E?/?1?]?1?/?q ?c?’?e?F?c?7?I?1?/?q?F?4?q?W?U?1???q?O?W?^?1?q?e?C?’?T?q?W?T?1???q?W?^?q?’?M?M?q?W?4?q?e?C?1?q?A?^?W?k?Z?q?O?1?O?+?1?]?c?q?’?]?1?q?Z?^?1?c?1?U?e?q?F?U???q?1?O?[?M?W?p?1?/?q?F?U???q?W?]?q ?1?^?m?F?c?1?q?]?1?M?1?l?’?T?e?q?e?W?q?’?q?A?E?l?1?U?q?Z?]?W?0?j?-?e?q?W?^?q?Z?^?W?-?1?c?c?q?j?T?N?1?c?c?q?E?T?/?E?-?(?e?1?0?q?e?W?q?e?C?1?q?-?W?U?h?]?’?^?p?q?W?^?q?W?e?C?1?^?m?E?c?1?q ?1?l?F?0?1?T?e?q?@?W?O?q?e?C?1?q?-?W?T?e?1?o?e???q?#?C?1?q?F?T?l?1?T?e?F?W?T?q?F?U?-?M?j?0?1?c?q?1?O?,?W?0?F?O?1?T?e?c?q?F?T?q?m?C?E?-?C?q?1?o?’?-?e?M?p?q?W?T?1?q?O?1?O?,?1?]?q ?W?4?q?e?C?1?q?A?]?X?j?Z?q?E?c?q?Z?]?1?c?1?T?e?q?F?T???q?1?O?Z?N?W?p?1?/?q?E?T???q?W?]?q?W?e?C?1?]?m?F?c?1?q?^?1?M?1?l?’?T?f?q?e?W?q?’?q?A?F?l?1?T?q?Z?^?W?0?j?-?e?q?W?]?q?Z?^?W?-?1?c?c???q ?$?C?1?q?F?U?l?1?T?e?E?W?T?q?E?T?-?M?k?/?1?c?q?1?O?,?W?0?F?O?1?U?e?c?q?F?U?q?m?C?F?-?C?q?O?W?]?1?q?e?C?’?T?q?W?U?1???q?W?]?q?’?N?M?q?W?4?q?e?C?1?q?A?]?W?j?[?q?O?1?O?,?1?]?c?q?’?^?1?q ?Z?]?1?c?1?U?e?q?E?T???q?1?O?Z?M?W?p?1?/?q?F?U???q?W?]?q?W?e?C?1?^?m?F?c?1?q?]?1?M?1?l?’?U?e?q?e?W?q?’?q?A?E?l?1?U?q?Z?]?W?0?j?-?e?q?W?^?q?Z?^?W?-?1?c?c???q ???????????????? ? ?k?]?h?C?1?^?O?W?]?1???q?e?C?1?q?F?T?l?1?T?e?F?W?U?q?1?U?-?W?O?Z?’?c?c?1?c?q?’?M?M?q?l?’?]?F?’?e?F?W?T?c???q?-?W?O?+?E?T?’?e?F?W?U?c???q?’?T?0?q ?Z?1?_?O?j?e?’?e?F?W?T?c?q?F?U?q?m?C?F?-?C?q?W?U?1?q?W?^?q?O?W?^?1?q?M?F?O?E?e?’?e?F?W?U?c???q?1?M?1?O?1?U?e?c???q?-?N?’?k?c?1?c???q?’?T?0?q?/?1?c?-?]?F?Z?e?F?l?1?q?e?1?]?O?c?q???W?O?q ?W?U?1?q?W?^?q?O?W?^?1?q?W?4?q?e?C?1?q?M?F?c?e?1?/?q?-?M?’?E?O?c?q?E?c?q?F?U?i?W?/?j?-?1?/?q?E?T?e?W?q?’?T?W?e?C?1?]?q?-?M?)?J?????q? ?W?]?q?1?o?*?S?Z?M?1???q?’?T?p?q?-?M?’?J???q?e?C?’?e?q ?E?c?q?0?1?Z?1?T?0?1?T?e?q?W?T?q?’?T?W?e?C?1?^?q?-?M?’?F?O?q?-?’?T?q?+?1?q?O?W?0?E??j?T?0?q?E?T?q ?’?U?p?q?W?e?C?1?]?q?-?N?’?E?O?q?e?C?’?e?q?E?c?q?0?1?Z?1?T?0?1?U?e?q?W?U?q?e?C?1?q?c?’?O?1?q?,?’?c?1?q?-?M?’?F?O???q?&?D?1?]?1?q?1?M?1?O?1?T?e?c?q?’?]?1?q?Z?]?1?c?1?U?e?1?0?q?’?c?q ?N?F?c?e?c???q?????????????F?U?q?"?’?]?L?j?c?C?q?B?^?W?k?Z?q?6?Y?^?O?’?e???q?1?’?-?C?q?c?j?+?A?^?W?k?Z?q?W?4?q?e?C?1?q?1?M?1?O?1?U?e?c?q?F?c?q?’?N?c?W?q?0?F?c?-?N?W?c?1?0???q?’?T?0?q?’?T?p?q ?1?M?1?O?1?T?e???c???q?-?’?T?q?+?1?q?]?1?O?W?l?1?0?q?8?b?W?O?q?e?C?1?q?B?^?W?k?Z???q?!?e?q?c?C?W?j?M?/?q?F?e?q?+?1?q?k?V?/?1?]?c?e?W?W?0?q?e?C?’?e???q?F?T?q?A?1?T?1?]?’?M???q?m?C?1?]?1?q ?q?E?T?l?1?U?e?F?W?U???q?W?^?q?’?c?Z?1?-?e?c?q?W?4?q?e?C?1?q?E?T?l?1?U?e?F?W?T???q?E?c???’?]?1?q?]?1?6?3?]?]?1?/?q?e?W?q?’?c?q?-?W?O?Z?]?F?c?F?U?A?q?Z?’?]?e?E?-?j?M?’?]?q?1?M?1?O?1?T?e?c?q ?’?T?/???W?]?q?4?1?’?e?j?]?1?c???q?-?1???G?’?F?T?q?1?O?,?W?0?F?O?1?U?e?c?q?W?4?q?e?C?1?q?F?U?l?1?T?e?F?W?T?q?W?^?q?’?c?\?1?-?e?c?q?W?4?q?e?C?1?q?E?T?l?1?U?e?F?W?U?q?-?W?U?c?F?c?e???q?W?]?q ?-?W?T?c?E?c?e?q?1?c?c?1?U?e?F?’?M?M?p?q?W?5???q?c?j?-?C?q?1?M?1?O?1?T?e?c?q?’?T?0???W?]?q?6?3?’?e?k?]?1?c???q? ?W?]?q?Z?k?‘?Z?W?c?1?c?q?W?4?q?c?E?O?[?M?E?-?E?e?p???q?e?C?W?c?1?q ?1?O?+?W?/?F?O?1?T?e?c?q?C?’?l?1?q?T?W?e?q?,?1?1?T?q?c?Z?1?-?F?7?I?-?’?M?N?p?q?c?1?e?q?>?]?e?C?q?????????????????????????????C?1?]?1?E?T???q?!?e?q?F?c?q?’?M?c?W?q?T?W?e?1?/?q?e?C?’?e?q ?e?C?1?q?e?1?Q???c?q???-?W?O?Z?]?E?c?F?T?A???q?’?T?/?q???-?W?U?e?’?F?U?E?T?A???q?’?^?1?q?F?T?e?1?U?0?1?/?q?e?W?q?+?1?q?W?[?1?T?q?’?T?/?q?Z?1?]?O?E?e?c?q?e?C?1?q?F?U?-?M?j?c?F?W?U?q?W?4?q ?’?0?/?E?e?F?W?U?’?M?q?1?M?1?O?1?T?e?c?q?W?^?q?c?e?1?Z?c???q?&?C?1?]?1?q?]?’?U?A?1?c?q?’?^?1?q?A?E?l?1?T???q?1?T?/?Z?X?F?U?e?c?q?’?^?1?q?E?T?-?M?k?/?1?0???q? ?k?^?e?C?1?^?O?W?]?1???q ?j?T?M?1?c?c?q?W?e?C?1?^?m?E?c?1?q?E?T?0?F?-?’?e?1?/?q?W?^?q?W?e?C?1???n?F?c?1?q?1?l?E?/?1?T?e?q???W?O?q?e?C?1?q?-?W?U?e?1?o?e?q?’?T?0?q?k?T?/?1?]?c?e?’?T?/?F?T?A?q?W?4?q?W?T?1?q?W?4?q ?W?]?0?F?T?’?]?p?q?c?L?E?N?M?q?F?U?q?e?C?1?q?’?]?e???q?l?’?M?j?1?c?q?e?C?’?e?q?’?]?1?q?1?o?Z?^?1?c?c?1?/?q?’?c?q?]?’?T?A?1?c?q?-?’?T?q?’?c?c?j?O?1?q?’?U?p?q?c?Z?1?-?F?6?H?-?q?l?’?M?j?1?q?W?]?q ?c?j?,???]?’?U?A?1?q?m?F?e?C?F?U?q?e?C?1?q?c?e?’?e?1?/?q?^?’?T?A?1?c?q?E?T?q?/?E?;?1?^?1?T?e?q?1?O?+?W?/?E?O?1?T?e?c?q?W?4?q?e?C?1?q?E?T?l?1?U?e?F?W?U???q?e?W?q?e?C?1?q?e?1?U?e?C?q?W?4?q ?q?k?T?F?e?q?W?4?q?e?C?1?q?M?W?m?1?^?q?M?E?O?E?e?q?W?4?q?e?C?1?q?^?’?T?A?1???q?k?T?M?1?c?c?q?e?C?1?q?-?W?T?e?1?o?e?q?-?M?2?’?^?M?p?q?/?E?-?e?’?e?1?c?q?W?e?C?1?]?m?E?c?1???q ?????????????????%?C?F?c?q?’?Z?Z?N?F?-?’?e?F?W?T?q?]?1?:?]?c?q?e?W?q?l?’?^?E?W?j?c?q?F?c?c?j?1?0?q?Z?’?e?1?U?e?c???q?Z?j?+?M?F?c?C?1?0?q?Z?’?e?1?T?e?q?’?Z?Z?M?F?-?’?e?F?W?U?c???q ?K?W?j?]?U?’?M?q?’?]?e?E?-?M?1?c???q?’?U?0?q?W?e?C?1?^?q?Z?j?+?M?F?-?’?e?F?W?U?c???q?’?M?M?q?W?4?q?m?C?E?-?C?q?’?^?1?q?F?T?-?W?‘?Z?W?^?’?e?1?/?q?C?1?^?1?F?T?q?,?p?q?^?1?4?1?^?1?T?-?1???q?!?4?q ?e?C?1?^?1?q?E?c?q?’?q?-?W?T?=?F?-?e?q?+?1?e?m?1?1?T?q?’?T?p?q?W?4?q?e?C?1?q?E?T?-?W?^?[?W?^?’?e?1?0?q?^?1?4?1?^?1?T?-?1?d?q?’?U?/?q?e?C?1?q?E?T?c?e?’?T?e?q?c?Z?1?-?E?6?H?-?’?e?E?W?T???q?e?C?1?q ?c?Z?1?-?E? Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made t departing from the spirit or scope of the present invention, as defined in the following claims.

The term "comprise" and variants of the term such as "comprises" or ising" are used herein to denote the ion of a stated integer or stated integers but not necessarily to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common l knowledge.

Claims (8)

We claim:

1. Use of a compound of Formula (I-w) or pharmaceutically acceptable salt thereof in the manufacture of a ment for treating a central nervous system (CNS) e or disorder related to NMDA or modulation in a t having an alteration in the level of 24(S)- hydroxycholesterol in a sample from the patient compared to a reference standard from a treatment and/or diagnosis guideline; wherein the compound of Formula (I-w) has the structure: R11a Z R11b R3b X1 R6a R6b or a ceutically acceptable salt thereof; wherein: Z is a group of the a (iii), (iv), or (v): L3 O L3 RZ6 L3 RZ6 YRZ5 RZ4 RZ6 or YRZ5 (iii), (iv), (v) L3 is a substituted or unsubstituted C1–C6 alkylene, a substituted or unsubstituted C2–C6 alkenylene, substituted or unsubstituted C2–C6 alkynylene, a substituted or unsubstituted hetero C1–C6 alkylene, a substituted or unsubstituted hetero C2–C6 alkenylene, or a substituted or unsubstituted hetero C2–C6 alkynylene; X1 is –O–, –S–, or –NH–; R3b is hydrogen; R3a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; each instance of R2, R11a, and R11b is independently hydrogen or –ORB1, wherein wherein RB1 is hydrogen or substituted or unsubstituted alkyl, or R11a and R11b are joined to form an oxo (=O) group; each of R6a and R6b is independently hydrogen, halo, or substituted or unsubstituted alkyl, and represents a single or double bond, provided if a double bond is present, then one of R6a or R6b is , and provided if a single bond is present, then the hydrogen at C5 is in the alpha or beta position; R19 is hydrogen or –CH3; Y is –O–, –S–, or –NRZ5–; RZ4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted yclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, –ORZ5, –SRZ5, or –N(RZ5)2; each instance of RZ5 is independently hydrogen or substituted or unsubstituted alkyl; each instance of RZ6 is independently en, or two RZ6 groups are joined to form a C3–6 carbocyclic ring; wherein each of said substituted C1–C6 alkylene, substituted C2–C6 lene, substituted C2–C6 alkynylene, substituted hetero C1–C6 alkylene, substituted hetero C2–C6 alkenylene, substituted hetero C2–C6 alkynylene, substituted alkyl, substituted alkenyl and substituted l is independently substituted with one or more halogen, C1-10 alkyl, -OH, ORaa, -N(Rbb)2; n Raa is C1-10 alkyl; and each Rbb is ndently hydrogen or C1-10 alkyl.

2. The use according to claim 1, wherein the CNS condition or disorder is selected from schizophrenia, depression, bipolar disorder, schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, compulsive disorders, post-traumatic stress disorder , Autism spectrum disorder (ASD), dysthymia, social anxiety disorder, obsessive compulsive disorder (OCD), pain, sleep disorders, memory disorder, ia, Alzheimer's Disease, a seizure disorder, traumatic brain injury, stroke, ive disorders, autism, Huntington's Disease, insomnia, Parkinson's disease, withdrawal syndromes, or tinnitus.

3. The use ing to claim 2, wherein the memory disorder is memory impairment.

4. The use according to claim 2, wherein the addictive disorder is a drug overdose.

5. The use according to claim 2, wherein the er is cognitive disorder.

6. The use according to claim 2, wherein the disorder is dementia.

7. The use according to claim 2, wherein the disorder is Alzheimer’s disease.

8. The use according to any one of claims 1 to 7, wherein the patient sample is selected from a fluid sample, a blood , plasma, serum, cerebrospinal fluid, circulating, interstitial fluid, a biopsy, a brain , isolate, or a surgical specimen. SAGE THERAPEUTICS INC. By the Attorneys for the Applicant SPRUSON & FERGUSON Per: