OXYSTEROLS AND METHODS OF USE THEREOF

Abstract

Compounds are provided according to Formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein A, R.sup.1, and R.sup.5 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

##STR00001##

Claims

1. A compound of Formula (I-A): ##STR00075## or a pharmaceutically acceptable salt thereof, wherein: A is carbocyclyl or heterocyclyl; R.sup.1 is C.sub.1-6 alkyl; R.sup.5 is absent or hydrogen; represents a single or double bond, wherein when one is a double bond, then the other is a single bond and R.sup.5 is absent.

2. A compound of Formula (I-B): ##STR00076## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.5 is absent or hydrogen; Z is —C(R.sup.A).sub.2—, —O—, or —S—; X is halogen, C.sub.1-6 alkyl, or —OR.sup.C; R.sup.A is hydrogen, halogen, or C.sub.1-6 alkyl; R.sup.B is hydrogen, C.sub.1-6 alkyl, —C(O)R.sup.C, —C(O)OR.sup.C, —C(O)N(R.sup.D).sub.2, or —S(O).sub.2R.sup.C; R.sup.C is hydrogen or C.sub.1-6 alkyl; each R.sup.D is independently hydrogen, C.sub.1-6 alkyl, aryl, or heteroaryl; m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 0, 1, 2, 3, 4, and 5; and represents a single or double bond, wherein when one is a double bond, then the other is a single bond and R.sup.5 is absent.

3. The compound of claim 2, wherein the compound is a compound of Formula (II-A), Formula (II-B), or Formula (II-C): ##STR00077##

4. The compound of claim 2, wherein p is an integer selected from 0, 1, or 2.

5. The compound of claim 2, wherein p is 0.

6. The compound of claim 2, wherein p is 1.

7. The compound of claim 2, wherein p is 1 and X is halogen.

8. The compound of claim 3, wherein the compound is of Formula (II-D), Formula (II-E), or Formula (II-F): ##STR00078##

9. The compound of claim 2, wherein R.sup.1 is C.sub.1-6 alkyl.

10. The compound of claim 9, wherein R.sup.1 is methyl or ethyl.

11. (canceled)

12. The compound of claim 2, wherein the compound is of Formula (II-G) or Formula (II-H): ##STR00079##

13. The compound of claim 2, wherein the compound is of Formula (II-I) or Formula (II-J): ##STR00080##

14. The compound of claim 2, wherein Z is —C(R.sup.A).sub.2—, —O—, or —NR.sup.B—.

15. The compound of claim 2, wherein R.sup.A is halogen.

16. The compound of claim 2, wherein Z is —CH.sub.2—, —CF.sub.2—, or —C(CH.sub.3).sub.2—.

17. The compound of claim 2, wherein Z is —O— or —NR.sup.B—.

18. The compound of claim 2, wherein Z is —NH—, —NMe-, or —NAc—.

19. The compound of claim 2, wherein Z is —CH.sub.2—.

20. The compound of claim 2, wherein Z is —C(CH.sub.3).sub.2—.

21. The compound of claim 2, wherein Z is —CF.sub.2—.

22. The compound of claim 2, wherein m is 1, n is 2, and Z is —O—.

23. The compound of claim 2, wherein m is 2 and n is 2.

24. The compound of claim 2, wherein m is 3 and n is 1.

25. The compound of claim 2, wherein m is 3, n is 1, and Z is —O—.

26. The compound of claim 2, wherein m is 2, n is 2, and Z is —O— or —NR.sup.B—.

27. A compound selected from: ##STR00081## ##STR00082## ##STR00083## ##STR00084##

28. A pharmaceutically acceptable salt of a compound selected from: ##STR00085## ##STR00086## ##STR00087## ##STR00088##

29. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.

30. A method of inducing sedation or anesthesia comprising administering to a subject an effective amount of a compound according to claim 1 or pharmaceutical composition thereof.

31. A method for treating or preventing a disorder described herein, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or pharmaceutical composition thereof; wherein the disorder is a gastrointestinal (GI) disorder, structural disorders affecting the GI, anal disorders, colon polyps, cancer, colitis, diabetes, a sterol synthesis disorder, a metabolic disorder.

32.-35. (canceled)

36. A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or pharmaceutical composition thereof.

37. The method according to claim 36, wherein the CNS-related condition is an adjustment disorder, anxiety disorder, cognitive disorder, dissociative disorder, eating disorder, mood disorder, bipolar disorder, dysthymic disorder, suicidality, schizophrenia or other psychotic disorder, sleep disorder, substance-related disorder, personality disorder, autism spectrum disorders, neurodevelopmental disorder, multiple sclerosis, sterol synthesis disorders, pain, encephalopathy secondary to a medical condition, seizure disorder, stroke, traumatic brain injury, movement disorder, vision impairment, hearing loss, and tinnitus.

38. (canceled)

39. A method for treating or preventing Smith-Lemli-Opitz Syndrome (SLOS), Desmosterolosis, Sitosterolemia, Cerebrotendinous xanthomatosis (CTX), Mevalonate Kinase Deficiency Syndromes (MKD), SC4MOL gene mutation (SMO Deficiency), Niemann-Pick disease, Autism Disorders Associated with Phenylketonuria, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 or pharmaceutical composition thereof.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0101] As generally described herein, the present invention provides new oxysterols useful for preventing and/or treating a broad range of disorders, including, but not limited to, NMDA-mediated disorders.

Compounds

[0102] In one aspect, provided herein are compounds according to Formula (I-A):

##STR00025##

or a pharmaceutically acceptable salt thereof, wherein: A is carbocyclyl or heterocyclyl (e.g., unsubstituted or substituted carbocyclyl or heterocyclyl, e.g., heterocyclyl substituted with at least one heteroatom (e.g., 1, 2, or 3 heteroatoms)); R.sup.1 is C.sub.1-6 alkyl (e.g., —CH.sub.3 or —CH.sub.2CH.sub.3); R.sup.5 is absent or hydrogen; represents a single or double bond, wherein when one is a double bond, then the other is a single bond and R.sup.5 is absent.

[0103] In one aspect, provided herein are compounds according to Formula (I-B):

##STR00026##

or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is hydrogen or C.sub.1-6 alkyl (e.g., —CH.sub.3 or —CH.sub.2CH.sub.3); R.sup.5 is absent or hydrogen; Z is —C(R.sup.A).sub.2—, —NR.sup.B—, —O—, or —S—; X is halogen, C.sub.1-6 alkyl, or —OR.sup.C; R.sup.A is hydrogen, halogen, or C.sub.1-6 alkyl; R.sup.B is hydrogen, C.sub.1-6 alkyl, —C(O)R.sup.C, —C(O)OR.sup.C, —C(O)N(R.sup.D).sub.2, or —S(O).sub.2R.sup.C; R.sup.C is hydrogen or C.sub.1-6 alkyl; each R.sup.D is independently hydrogen, C.sub.1-6 alkyl, aryl, or heteroaryl; m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 0, 1, 2, 3, 4, and 5; and represents a single or double bond, wherein when one is a double bond, then the other is a single bond and R.sup.5 is absent.

[0104] In some embodiments, the compound is a compound of Formula (II-A), Formula (II-B), or Formula (II-C):

##STR00027##

[0105] In some embodiments, p is an integer selected from 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 1 and X is halogen.

[0106] In some embodiments, the compound is of Formula (II-D), Formula (II-E), or Formula (II-F):

##STR00028##

[0107] In some embodiments, the compound is of Formula (II-G) or Formula (II-H):

##STR00029##

[0108] In some embodiments, the compound is of Formula (II-I) or Formula (II-J):

##STR00030##

[0109] In some embodiments, R.sup.1 is C.sub.1-6 alkyl. In some embodiments, R.sup.1 is methyl or ethyl. In some embodiments, R.sup.1 is —CH.sub.3, —CF.sub.3, —CH.sub.2CH.sub.3.

[0110] In some embodiments, Z is —C(R.sup.A).sub.2—, —O—, or —NR.sup.B—. Or, Z is —CH.sub.2—. Or, Z is O. Or, Z is —NR.sup.B—, wherein R.sup.B is —NH—, —N—(C.sub.1-C.sub.4 alkyl)-, or —NC(O)—(C.sub.1-C.sub.4 alkyl). In some embodiments, R.sup.A is halogen (e.g., —F). In some embodiments, Z is —CH.sub.2—, —CF.sub.2—, or —C(CH.sub.3).sub.2—.

[0111] In some embodiments, the compound is:

##STR00031##

[0112] In some embodiments, the compound is:

##STR00032##

[0113] In some embodiments, Z is —O— or —NR.sup.B—.

[0114] In some embodiments, the compound is:

##STR00033##

[0115] In some embodiments, the compound is:

##STR00034##

[0116] In some embodiments, the compound is:

##STR00035##

[0117] In some embodiments, Z is —NH—, —NMe-, or —NAc—.

[0118] In some embodiments, the compound is:

##STR00036##

[0119] In some embodiments, Z is —CH.sub.2—. In some embodiments, Z is —C(CH.sub.3).sub.2—. In some embodiments, Z is —CF.sub.2—. In some embodiments, m is 1, n is 2, and Z is —O—. In some embodiments, m is 2 and n is 2. In some embodiments, m is 3 and n is 1. In some embodiments, m is 3, n is 1, and Z is —O—. In some embodiments, m is 2, n is 2, and Z is —O— or —NR.sup.B—.

[0120] In some embodiments, the compound is:

##STR00037## ##STR00038## ##STR00039## ##STR00040##

[0121] In some embodiments, the compound is a pharmaceutically acceptable salt of:

##STR00041## ##STR00042## ##STR00043## ##STR00044##

Pharmaceutical Compositions

[0122] In another aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a effective amount of a compound as described herein (e.g., Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)).

[0123] When employed as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

[0124] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or topical carrier.

[0125] The present invention also relates to a compound as described herein (e.g., Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or pharmaceutical composition thereof for use as a pharmaceutical or a medicament.

[0126] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, 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 patient's symptoms, and the like.

[0127] 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.

[0128] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic 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 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0129] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0130] Injectable 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.

[0131] 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, preferably 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 paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0132] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0133] 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's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference.

[0134] 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's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0135] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0136] The present invention also relates to the pharmaceutically acceptable formulations of a compound of Formula (I). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β and γ-cyclodextrins consisting of 6, 7 and 8 α-1, 4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0137] The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of Formula (I). The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0138] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.

[0139] Exemplary Formulation 1—Tablets: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, 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.

[0140] Exemplary Formulation 2—Capsules: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

[0141] Exemplary Formulation 3—Liquid: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.

[0142] Exemplary Formulation 4—Tablets: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, 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.

[0143] Exemplary Formulation 5—Injection: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.

[0144] Exemplary Formulation 6—Tablets: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, 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.

[0145] Exemplary Formulation 7—Tablets: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, may be may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

[0146] Exemplary Formulation 8—Tablets: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, 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 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.

[0147] Exemplary Formulation 9—Tablets: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, 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 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

[0148] Exemplary Formulation 10—Tablets: A compound of Formula (I-A), or pharmaceutically acceptable salt thereof, 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 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

[0149] Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve 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.

[0150] 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 representative 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.

[0151] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0152] When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for 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.

Methods of Treatment and Use

[0153] Compounds of the present invention, e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), and pharmaceutically acceptable salts thereof, as described herein, are generally designed to modulate NMDA function, and therefore to act as oxysterols for the treatment and prevention of, e.g., CNS-related conditions in a subject. In some embodiments, the compounds described herein, e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), and pharmaceutically acceptable salts thereof, as described herein, are generally designed to penetrate the blood brain barrier (e.g., designed to be transported across the blood brain barrier). Modulation, as used herein, refers to, for example, the inhibition or potentiation of NMDA receptor function. In certain embodiments, the compound as described herein (e.g., Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or pharmaceutically acceptable salt thereof, may act as a negative allosteric modulator (NAM) of NMDA, and inhibit NMDA receptor function. In certain embodiments, the present invention, e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or pharmaceutically acceptable salt thereof, may act as positive allosteric modulators (PAM) of NMDA, and potentiate NMDA receptor function. In certain embodiments, the compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or pharmaceutically acceptable salt thereof, modulates NMDA function, but does not act as a negative allosteric modulator (NAM) or positive allosteric modulator (PAM) of NMDA.

[0154] In some embodiments, the disorder is cancer. In some embodiments, the disorder is diabetes. In some embodiments, the disorder is a metabolic disorder. In some embodiments, the disorder is a sterol synthesis disorder. In some embodiments, the disorder is a gastrointestinal (GI) disorder, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (TBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistula), colon polyps, cancer, colitis. In some embodiments, the disorder is inflammatory bowel disease.

[0155] In some embodiments, the disorder is Smith-Lemli-Opitz Syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disorder is Mevalonate Kinase Deficiency (MKD). In some embodiments, the disorder is SC4MOL gene mutation (SMO Deficiency). In some embodiments, the disorder is Niemann-Pick disease. In some embodiments, the disorder is autism spectrum disorder (ASD). In some embodiments, the disorder is associated with phenylketomuria.

[0156] Exemplary conditions related to NMDA-modulation includes, but are not limited to, gastrointestinal (GI) disorder, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistula), colon polyps, cancer, colitis, and CNS conditions, e.g., as described herein.

[0157] Exemplary CNS conditions related to NMDA-modulation include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), 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 involving mutations to the Shank group of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, 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. In certain embodiments, the compound of the present invention, e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or pharmaceutically acceptable salt thereof, can be used to induce sedation or anesthesia. In certain embodiments, the compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or pharmaceutically acceptable salt thereof, is useful in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, sterol synthesis disorders, pain, seizure disorders, stroke, traumatic brain injury, movement disorders and vision impairment, hearing loss, and tinnitus.

[0158] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the present invention, e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof.

[0159] In yet another aspect, the present invention provides a combination of a compound of the present invention, e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or pharmaceutically acceptable salt thereof, and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

Diseases and Disorders

[0160] Described herein are methods of treating a sterol synthesis disorder. Exemplary disorders are described herein. The methods include administering to a subject, e.g., a subject suffering from a sterol synthesis disorder such as SLOS, a NMDA receptor modulating compound. Exemplary compounds are described herein.

Sterol Synthesis Disorders

[0161] In one aspect, described herein are methods for treating a sterol synthesis disorder. Cholesterol has an essential rule in growth and development. It is a membrance lipid and a precursor to many molecules that play important roles in cellular growth and diffierentiation, protein glycosylation, and signaling pathways. Biosynthesis of cholesterol involves a number of enzymes and intermediates. Disorders resulting from a deficiency in any of the enzymes involved in cholesterol biosynthesis lead to the accumulation of intermediates and imbalance in biomolecules, resulting in disorders including congenital skeletal malformations, dysmorphic facial features, psychomotor retardation, and failure to thrive. In an embodiment, a sterol synthesis disorder or symptom of a sterol synthesis disorder can be treated by administering to a subject suffering from a sterol synthesis disorder a compound described herein, such as a NMDA receptor modulating compound as described herein. Additional disorders are described below.

Smith-Lemli-Opitz Syndrome

[0162] In one aspect, described herein are methods for treating Smith-Lemli-Opitz Syndrome (or SLOS, or 7-dehydrocholesterol reductase deficiency). SLOS is an inborn error of cholesterol synthesis. In addition to microcephaly, moderate to severe intellectual disability, sensory hypersensitivity, stereotyped behaviors, dysmorphic facial features, and syndactyly of the second/third toes, a feature of the disease is reduced cerebrosterol (24(S)-hydroxycholesterol) levels. SLOS is an autosomal recessive genetic condition resulting from deficiency in the final enzyme of the cholesterol synthesis pathway, and causes low or low-normal plasma cholesterol levels and increased 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC) levels. Common therapies currently used include dietary cholesterol supplementation, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA reductase inhibitors, also known as statins), and treatment with agents that enhance cholesterol production and/or accretion; and to decrease the accumulation of 7DHC and 8DHC, the potentially toxic precursors of cholesterol.

Desmosterolosis

[0163] Desmosterolosis is a deficiency in desmosterol reductase and has a similar phenotype to SLOS. In one aspect, described herein are methods for treating desmosterolosis with compounds described herein.

Sitosterolemia

[0164] Sitosterolemia is a rare autosomal recessive disorder caused by mutations in two ATP-binding cassette (ABC) transporter genes (ABCG5 and ABCG8). Sitosterolemia enhances the absorption of plant sterols and cholesterol from the intestines. Patients typically present with tendon and tuberous xanthomas and premature coronary artery disease. In one aspect, described herein are methods for treating sitosterolemia with compounds described herein.

Cerebrotendinous Xanthomatosis (CTX)

[0165] In one aspect, described herein are methods for treating cerebrotendinous xanthomatosis (also referred to as cerebral cholesterosis, or Van Bogaert-Scherer-Epstein syndrome) with compounds described herein. CTX can be caused by a mutation in the CYP27A1 gene, which produces the sterol 27-hydroxylase enzyme. Sterol 27-hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid) that are important in the absorption of fats in the intestine. Enzyme dysfunction can lead to cholesterol accumulation in tissues. CTX is characterized by childhood diarrhea, cataracts, tendon xanthomas, reduced mental capability and abnormal movements in adults.

Mevalonate Kinase Deficiency Syndromes (MKD)

[0166] Mevalonate Kinase Deficiency (also referred to as mevalonic aciduria (a more severe form of MKD), or Hyper IgD Syndrome (HIDS, or hyperimmunoglobulinemia D) with period fever syndrome (a more benign form of MKD)) causes an accumulation of mevalonic acid in the urine as a result of insufficient activity of mevalonate kinase. MKD can result in developmental delay, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and overall failure to thrive. Mevalonic aciduria is characterized by delayed physical and mental development, failure to thrive, recurrent episodes of fever with vomiting and diarrhea, enlarged liver, spleen and lymph nodes, microcephaly (small head size), cataract, low muscle tone, short statute, distinctfacial features, ataxia, and anemia. HIDS is is characterized by recurrent episodes of fever associated with swollen lymph nodes, joint pain, gastrointestinal issues and skin rash. In one aspect, described herein are methods for treating MKD with the compounds described herein.

SC4MOL Gene Mutation (SMO Deficiency)

[0167] SC4MOL gene deficiency is a genetic disorder in the cholesterol biosynthesis pathway (e.g., mutations in the SC4MOL gene encoding a novel sterol oxidase). SC4MOL deficiency is characterized by the accumulation of dimethyl and monomethyl sterols that can be detected in blood, skin flakes or primary skin fibroblasts. In one aspect, described herein are methods for treating SMO deficiency with compounds described herein.

Niemann-Pick disease

[0168] Niemann-Pick disease is a lysosomal storage disease resulting from a genetic mutation that affects metabolism. Niemann-Pick disease leads to abnormal accumulation of cholesterol and other fatty substances (lipids) due to an inability of the body to transport the substances. The accumulation damages the affected areas.

Autism

[0169] In one aspect, described herein are methods for treating autism spectrum disorder or autism. Autism spectrum disorder (ASD) and autism refer to a group of complex disorders of brain development. Autism is typically characterized by difficulties in social interaction, for example in verbal and nonverbal communication. Repetitive behaviors are also often seen in individuals having autism. Autism can be associated with intellectual disability, difficulties in motor coordination and attention and physical health issues, e.g., sleep and gastrointestinal disturbances. Individuals having autism can also excel in visual skills, music, math and art. Autism can refer to autistic disorder, childhood disintegrative disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), and Asperger syndrome. Autism also refers to monogenetic causes of autism such as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome.

Disorders Associated with Phenylketonuria

[0170] In one aspect, described herein are methods for treating disorders associated with phenylketonuria (e.g., cognitive disorders) with compounds described herein. Phenylketonuria can lead to hypochesterolemia and lowered vitamin D status. Total and low-density cholesterols and 25-hydroxy vitamin D have been found to be decreased in subjects suffering from phenylketonuria as compared with subjects not suffering from phenylketonuria (Clin. Chim. Acta 2013, 416: 54-59). 24S-hydroxycholesterol and 27S-hydroxycholesterol and 7α-hydroxycholesterol (e.g., representing peripheral and hepatic cholesterol elimination, respectively) have been shown to be significantly decreased in subjects suffering from phenylketonuria, while 7β-hydroxycholesterol (e.g., reflecting oxidative stress) was increased significantly in subjects suffering from phenylketonuria. Changes in the levels of 24S-OHC and 7β-hydroxycholesterol correlate with phenylalanine level, and 27S-hydroxycholesterol levels may correlate with the 25-hydroxy vitamin D level in subjects suffering from phenylketonuria.

Alternative Embodiments

[0171] In an alternative embodiment, a compound described herein (e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)) may also comprise one or more isotopic substitutions. In some embodiments, hydrogen may be .sup.2H (D or deuterium), or .sup.3H (T or tritium). In some embodiments, carbon may be .sup.13C or .sup.14C. In some embodiments, oxygen may .sup.18O). In some embodiments, nitrogen may be .sup.15N. In a further embodiment, a compound may comprise one or more isotopic substiutions where the site of isotopic substitution is enriched with a particular isotope. For example, a compound described herein can comprise hydrogen enriched as .sup.2H or .sup.3H, carbon enriched as .sup.13C or .sup.14C, oxygen enriched as .sup.18O, or nitrogen enriched as .sup.15N.

EXAMPLES

[0172] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Materials and Methods

[0173] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.

[0174] 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 protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0175] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative neuroactive steroids 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. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0176] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH.sub.4HCO.sub.3) (30 L water, 24 g NH.sub.4HCO.sub.3, 30 mL NH.sub.3.H.sub.2O). Flow rate: 25 mL/min.

[0177] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH.sub.4HCO.sub.3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 C.

NMDA Potentiation

[0178] NMDA potentiation was assessed using the whole cell patch clamp of mammalian cells which expressed NMDA receptors.

Whole-Cell Patch Clamp of Mammalian Cells (Ionworks Barracuda (IWB)

[0179] The whole-cell patch-clamp technique was used to investigate the effects of compounds on GlunN1/GluN2A glutamate receptors expressed in mammalian cells. The results are shown in Table 1.

[0180] HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding the human GRIN1/GRIN2A genes. Stable transfectants were selected using G418 and Zeocin-resistance genes incorporated into the expression plasmid and selection pressure maintained with G418 and Zeocin in the medium. Cells were cultured in Dulbecco's Modified Eagle Medium/Nutrient Mixture (D-MEM/F-12) supplemented with 10% fetal bovine serum, 100 μg/ml penicillin G sodium, 100 mg/ml streptomycin sulphate, 100 μg/ml Zeocin, 5 μg/ml blasticidin and 500 μg/ml G418.

[0181] Test article effects were evaluated in 8-point concentration-response format (4 replicate wells/concentration). All test and control solutions contained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). The test article formulations were loaded in a 384-well compound plate using an automated liquid handling system (SciClone ALH3000, Caliper LifeScienses). The measurements were performed using Ion Works Barracuda platform following this procedure:

Electrophysiological Procedures:

[0182] a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl.sub.2, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH. [0183] b) Extracellular solution, HB-PS (composition in mM): NaCl, 137; KCl, 1.0; CaCl.sub.2, 5; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH (refrigerated until use). [0184] c) Holding potential: −70 mV, potential during agonist/PAM application: −40 mV.

Recording Procedure:

[0185] a) Extracellular buffer will be loaded into the PPC plate wells (11 μL per well). Cell suspension will be pipetted into the wells (9 μL per well) of the PPC planar electrode. [0186] b) Whole-cell recording configuration will be established via patch perforation with membrane currents recorded by on-board patch clamp amplifiers. [0187] c) Two recordings (scans) will be performed. First, during pre-application of test article alone (duration of pre-application—5 min) and second, during test articles and agonist (EC.sub.20 L-glutamate and 30 μM glycine) co-application to detect positive modulatory effects of the test article.

[0188] Test Article Administration: The first pre-application will consist of the addition of 20 μL of 2× concentrated test article solution and, second, of 20 μL of 1× concentrated test article and agonist at 10 μL/s (2 second total application time).

[0189] Synthetic Methods

Example 1

Synthesis of Intermediate A-6

[0190] ##STR00045## ##STR00046##

[0191] Step 1. Synthesis of Intermediate A-1. To a suspension of PPh.sub.3MeBr (2.13 kg, 5.97 mol) in THF (3000 mL) was added t-BuOK (688 g, 6.14 mol) at 20° C. The color of the suspension changed to yellow. After stirring at 50° C. for 1 h, Pregnenolone (630 g, 2.05 mol) was added at 50° C. and the reaction mixture was stirred at 50° C. for 2 h. After cooling to 20° C., the mixture was treated with NH.sub.4Cl (10% aq., 5 L) and heptane (3.5 L) and stirred for 15 minutes. The organic layer was separated and concentrated in vacuo to give the crude material as a thick oil, which was poured into MTBE (10 L) with vigorous stirring and allowed to stir at room temperature for 16 hours. The resulting off-white solid was collected by filtration and washed with MTBE (3 L). The combined filtrate was mixed with MeOH (10 L) and concentrated to 6 L in vacuo. The resulting off-white solid was collected by filtration, washed with MeOH (3 L), and air-dried to give 700 g of wet off-white solid. The combined MeOH filtrate was concentrated in vacuo to give a thick oil. The oil was poured into MTBE (3 L) with vigorous stirring and the mixture was allowed to stir for 3 hours. The resulting white solid was collected by filtration and washed with MTBE (1 L). The combined filtrate was mixed with MeOH (3 L) and concentrated to 1.5 L in vacuo. The resulting white solid was collected by filtration, washed with MeOH (500 mL) and air-dried to give 150 g of a wet off-white solid. The previous 700 g and 150 g batch were combined and vacuum-dried to give Intermediate A-1 (552 g, 88%) as an off-white solid.

[0192] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.40-5.30 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.60-3.50 (m, 1H), 2.36-2.18 (m, 2H), 2.08-1.96 (m, 2H), 1.92-1.78 (m, 3H), 1.76 (s, 3H), 1.73-1.48 (m, 9H), 1.38-1.03 (m, 4H), 1.01 (s, 3H), 1.00-0.91 (m, 1H), 0.58 (s, 3H).

[0193] Step 2. Synthesis of Intermediate A-2. To a solution of Intermediate A-1 (184 g, 585 mmol) in DCM (2000 mL) was added DMP (496 g, 1.17 mol) at 25° C. in portions, followed by water (42 mL). The mixture was stirred at 25° C. for 30 min. Water (1500 mL) and NaHCO.sub.3 (750 g) were added in portions (gas evolution was observed). The mixture was filtered through a pad of Celite and the solid was washed with DCM (500 mL). The organic layer in the filtrate was separated, washed with Na.sub.2S.sub.2O.sub.3 (1000 mL, saturated), dried over Na.sub.2SO.sub.4, filtered, concentrated in vacuo below 30° C. to give Intermediate A-2 (250 g, crude) as a light yellow gum. The crude was used in the next step directly without further purification or analysis.

[0194] Step 3. Synthesis of Intermediate A-3. To a solution of BHT (769 g, 3.49 mol) in toluene (1500 mL) was added AlMe.sub.3 (870 mL, 2M in toluene, 1.74 mol) at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was cooled to −78° C. and a solution of Intermediate A-2 (250 g crude, theoretical mass: 182 g, 582 mmol) in toluene (1000 mL) was added. After stirring at −78° C. for 1 h, MeMgBr (580 mL, 3 M in ether, 1.74 mmol) was added and the mixture was stirred at −78° C. for another 1 h. The mixture was quenched by pouring into citric acid (4000 mL, 20% aq.) in portions (gas evolution was observed). Another two batches were conducted and combined. The mixture was extracted with EtOAc (10 L). The organic layer was separated, washed with brine (5 L, 10%), NaHCO.sub.3 (5 L, saturated aq.), brine (5 L, saturated), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE to EtOAc) to give Intermediate A-3 (440 g, impure, containing Intermediate A-1) as a light yellow solid. To a solution of impure Intermediate A-3 (440 g) in DCM (6 L) was added DMAP (24.4 g) and Ac.sub.2O (51 g). The mixture was stirred at 20° C. for 1 h. NaHCO.sub.3 (1 L, saturated aq.) was added and the mixture was stirred for 10 min. The organic layer was separated, concentrated in vacuo and the residue was triturated with PE (2 L). The solid was washed with PE (3×500 mL) and dried in vacuo to give A-3 (262 g) as an off-white solid. The combined filtrate was concentrated, purified by silica gel chromatography (PE/EtOAc=50/1 to 8/1) and triturated with PE (1 L) to give A-3 (30 g). Total yield for the two steps was 51%.

[0195] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.35-5.28 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.48-2.37 (m, 1H), 2.08-1.94 (m, 3H), 1.92-1.85 (m, 1H), 1.82-1.33 (m, 14H), 1.29-1.08 (m, 7H), 1.02 (s, 3H), 1.00-0.93 (m, 1H), 0.59 (s, 3H).

[0196] Step 4. Synthesis of Intermediate A-4. Intermediate A-3 (100 g, 304 mmol) was dissolved in 9-BBN (1.21 L, 0.5 M in THF, 608 mmol) at 0° C. under N.sub.2. The solution was heated and stirred at 65° C. for 1 hour and re-cooled to 10° C. to generate a off-white precipitate. Ethanol (279 g, 6080 mmol) and aqueous NaOH (304 mL, 5 M, 1520 mmol) were added dropwise below 10° C. to give a clear solution. Hydrogen peroxide (343 g, 30% in water, 3040 mmol) was added dropwise below 10° C. and the reaction mixture was heated and stirred at 75° C. for 1 hour. The mixture was cooled to 20° C. , and the resulting off-white precipitate was collected by filtration. The filter cake was washed with water (3×500 mL) and dried in vacuo to give an off-white solid, which was triturated with ethanol (1.5 L) at reflux to give Intermediate A-4 (92 g, 88%) as an off-white solid.

[0197] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.31-5.29 (m, 1H), 3.65-3.63 (m, 1H), 3.38-3.37 (m, 1H), 2.42 (d, J=12.4, 1H), 2.05-1.92 (m, 3H), 1.88-1.63 (m, 4H), 1.63-1.40 (m, 8H), 1.40-0.90 (m, 16H), 0.70 (s, 3H).

[0198] Step 5. Synthesis of Intermediate A-5. To a solution of Intermediate A-4 (124.5 g, 357 mmol) in chloroform (1 L) and pyridine (700 mL) was added TsCl (204 g, 1071 mmol) at 15° C. and the mixture was stirred at 15° C. for 2 hrs. The mixture was concentrated in vacuo to remove most of the chloroform. The pyridine mixture was poured into water (6 L) and the resulting off-white solid was collected by filtration, and the filter cake was washed with water (6×1 L). The off-white solid was dissolved in DCM (3.5 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give Intermediate A-5 (163 g, 92%) as an off-white solid.

[0199] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 5.29-5.28 (m, 1H), 3.96 (dd, J=3.2, 9.6 Hz, 1H), 3.79 (dd, J=6.4, 9.2 Hz, 1H), 2.45 (s, 3H), 2.41 (d, J=13.6 Hz, 1H), 1.99-1.91 (m, 3H), 1.77-1.39 (m, 11H), 1.26-0.86 (m, 16H), 0.64 (s, 3H).

[0200] Step 6. Synthesis of Intermediate A-6. To a solution of Intermediate A-5 (163 g, 325 mmol) in DMF (1.7 L) was added KI (258 g, 1560 mmol) at 15° C. The mixture was heated and stirred at 60° C. for 2 hours. Sodium benzenesulfinate (195 g, 975 mmol) was added and stirring was continued at 60° C. for 2 hours. The reaction mixture was cooled to 25° C. and combined with another batch of 83 g of Intermediate A-5. The combined mixture was poured into water (20 L) to give a yellow solid which was collected by filtration and washed with water (3×2 L). The resulting filter cake was dissolved in DCM (5 L), washed with water (2×1 L), brine (2×1 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a yellow solid residue, which was re-crystallized from toluene (2.5 L) to give Intermediate A-6 (150 g, 65%) as a light yellow solid. The re-crystallization filtrate was concentrated in vacuo to give crude Intermediate A-6 (30 g) as a yellow solid.

[0201] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.91 (d, J=7.2 Hz, 2H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 5.28-5.27 (m, 1H), 3.14 (d, J=14.0 Hz, 1H), 2.85 (dd, J=9.6, 14.0 Hz, 1H), 2.41 (d, J=12.8 Hz, 1H), 2.17-2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.81-1.65 (m, 3H), 1.60-1.32 (m, 8H), 1.25-0.85 (m, 15H), 0.65 (s, 3H). LCMS Rt=2.057 min in 3.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.29H.sub.41O.sub.2S [M+H−H.sub.2O].sup.+ 453, found 453.

Example 2

Synthesis of Intermediate B-4

[0202] ##STR00047##

[0203] Step 1. Synthesis of Intermediate B-1. To a solution of BHT (191 g, 866 mmol) in toluene (500 mL) was added AlMe.sub.3 (2 M in toluene, 216 mL, 433 mmol) at 10° C. and the solution was stirred for 1 h. To the mixture was added a solution of Intermediate A-2 (Theoretical Mass: 44.6 g) in DCM (100 mL) at −78° C. The mixture was stirred at −78° C. for 1 h. EtMgBr (141 mL, 426 mmol) was added at −78° C. and the mixture was stirred at −78° C. for 20 mins. Saturated citric acid (1 L) was added. The organic phase was separated, washed with brine (600 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc=50:1 to 30:1) to give Intermediate B-1 (27 g, 55%) as a yellow solid.

[0204] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.35-5.25 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.40-2.30 (m, 1H), 2.10-1.60 (m, 14H), 1.50-0.75 (m, 17H), 0.58 (s, 3H).

[0205] Step 2. Synthesis of Intermediate B-2. To 9-BBN (200 mL, 0.5 M in THF, 100 mL) was added Intermediate B-1 (13 g, 37.9 mmol) at 0° C. under N.sub.2. The mixture was heated and stirred at 65° C. for 2 hrs then cooled to 10° C. EtOH (46.5 g) was added, followed by aqueous NaOH (51 mL, 5 M) and H.sub.2O.sub.2 (57 g, 30% in water) and the resulting mixture was stirred at 75° C. for 1 h. The mixture was concentrated in vacuo to give a solution (100 mL), which was extracted with EtOAc (2×150 mL), washed with NH.sub.4Cl (2×300 mL) and brine (2×300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc=50:1 to 3:1) to give Intermediate B-2 (9.86 g, 72%) as an off-white solid.

[0206] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.31-5.29 (m, 1H), 3.70-3.60 (m, 1H), 3.40-3.30 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.75-1.65 (m, 1H), 1.65-1.55 (m, 2H), 1.50-1.26 (m, 6H), 1.25-0.95 (m, 15H), 0.90-0.75 (m, 6H), 0.70 (s, 3H).

[0207] Step 3. Synthesis of Intermediate B-3. To a solution of Intermediate B-2 (9.86 g, 27.3 mmol) in CHCl.sub.3 (100 mL) and pyridine (20 mL) was added TsCl (15.6 g, 81.9 mmol) at 15° C. The mixture was stirred at 15° C. for 1 h. The reaction mixture was concentrated in vacuo to give 60 mL of the mixture, which was poured into 600 mL of water to give an off-white precipitate. The mixture was filtered, the filter cake was washed with water, dissolved in DCM (150 mL), dried over Na.sub.2SO.sub.4, filtered, concentrated under vacuum to give Intermediate B-3 as an off-white solid (9.9 g, 70%).

[0208] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.78 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.30-5.20 (m, 1H), 4.00-3.90 (m, 1H), 3.80-3.70 (m, 1H), 2.45 (s, 3H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.75-1.60 (m, 6H), 1.55-1.30 (m, 5H), 1.25-0.95 (m, 13H), 0.90-0.80 (m, 5H), 0.65-0.50 (m, 3H).

[0209] Step 4. Synthesis of Intermediate B-4. To a solution of Intermediate B-3 (9.9 g, 19.2 mmol) in DMF (150 mL) was added KI (15.2 g, 92.1 mmol) at 15° C. The mixture was heated and stirred at 60° C. for 2 hrs. Sodium benzenesulfinate (9.43 g, 57.5 mmol) was added and the mixture was stirred at 60° C. for 2 hrs. The mixture was poured into water (200 mL) and the resulting yellow precipitate was collected by filtration. The filter cake was washed with water (2×100 L), dissolved in DCM (500 mL), washed with water (2×500 mL) and brine (2×1 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a yellow solid residue, which was purified by silica gel chromatography (0-35% EtOAc in PE) to give Intermediate B-4 (8 g, 89%).

[0210] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95-7.88 (m, 2H), 7.68-7.62 (m, 1H), 7.61-7.53 (m, 2H), 5.30-5.22 (m, 1H), 3.20-3.08 (m, 1H), 2.91-2.79 (m, 1H), 2.40-2.30 (m, 1H), 2.09-1.87 (m, 4H), 1.74-1.60 (m, 4H), 1.50-1.36 (m, 7H), 1.24-0.98 (m, 13H), 0.90-0.80 (m, 4H), 0.65 (s, 3H).

Example 3

Synthesis of Intermediate C-8

[0211] ##STR00048## ##STR00049##

[0212] Step 1. Synthesis of Intermediate C-1. To a solution of Intermediate A-1 (4 kg, 12.7 mol) in DCM (30 L) was added imidazole (1.72 kg, 25.4 mol) and TBSCl (2.86 kg, 19.0 mol) at 25° C. After stirring at 25° C. for 16 hrs, water (10 L) was added and the organic phase was separated and concentrated to give a residue which was triturated with MeOH (15 L) at reflux to give Intermediate C-1 (5.02 kg, 92%) as an off-white solid.

[0213] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.38-5.28 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.57-3.41 (m, 1H), 2.33-2.11 (m, 2H), 2.10-1.94 (m, 2H), 1.90-1.61 (m, 8H), 1.60-1.38 (m, 6H), 1.28-1.03 (m, 4H), 1.00 (s, 3H), 0.98-0.91 (m, 1H), 0.89 (s, 9H), 0.58 (s, 3H), 0.06 (s, 6H).

[0214] Step 2. Synthesis of Intermediate C-2. To a solution of Intermediate C-1 (1.69 kg, 3.94 mol) in THF (8 L) was added 9-BBN dimer (671 g, 2.75 mol) and the resulting mixture was stirred at 25° C. under N.sub.2 for 1 h (formation of an off-white precipitate was observed). Ethanol (2.26 L, 39.4 mol) and NaOH (3.94 L, 5 M, 19.7 mol) were added and the resulting clear solution was treated dropwise with H.sub.2O.sub.2 (3.94 L, 10 M, 39.4 mol) at 25° C. (the inner temperature raised to reflux). After addition was complete, the mixture was cooled to 25° C. and stirred for 16 hrs, followed by addition of Na.sub.2SO.sub.3 (2.5 L, 20% aq.) and water (5 L) at 25° C. After stirring for 1 hr, the mixture was allowed to settle to a clear lower layer and an upper suspension layer. The upper suspension layer was collected and treated with water (20 L). The mixture was stirred for 15 mins and filtered. The solid was washed with water to pH<9 to give the wet product, which was combined with two other batches of product from a previous synthesis. The wet product was dissolved in DCM (100 L) and the organic layer was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated to 20 L. The residue was used in the next step directly.

[0215] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.40-5.23 (m, 1H), 3.70-3.60 (m, 1H), 3.55-3.42 (m, 1H), 3.41-3.31 (m, 1H), 2.31-2.20 (m, 1H), 2.20-2.11 (m, 1H), 2.06-1.91 (m, 2H), 1.89-1.67 (m, 3H), 1.65-1.39 (m, 7H), 1.38-1.08 (m, 6H), 1.05 (d, J=6.4 Hz, 3H), 1.00 (s, 3H), 0.99-0.91 (m, 2H), 0.88 (s, 9H), 0.70 (s, 3H), 0.05 (s, 6H).

[0216] Step 3. Synthesis of Intermediate C-3. To a solution of Intermediate C-2 (theoretical mass: 5.2 kg, 11.6 mol) in DCM (15 L) was added N-methyl-imidazole (1.37 L, 17.4 mol) and TEA (3.2 L, 23.2 mol) at 25° C. TsCl (2.53 kg, 13.3 mol) was added portionwise to the above solution, maintaining the inner temperature between 25˜30° C. The reaction mixture was stirred at 25° C. for 1 h. To the mixture was added water (10 L), citric acid (20%, 1 L) and HCl (1 M) to adjust the pH to ˜3. The organic layer was separated, washed with water (2×10 L), NaHCO.sub.3 (saturated aq. 5 L) and brine (5 L), dried over Na.sub.2SO.sub.4, filtered and concentrated to give Intermediate C-3 (6.63 kg, 95% for 2 steps) as an off-white solid.

[0217] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6 7.78 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 5.37-5.25 (m, 1H), 3.96 (dd, J=2.8, 9.2 Hz, 1H), 3.79 (dd, J=6.4, 9.2 Hz, 1H), 3.53-3.41 (m, 1H), 2.45 (s, 3H), 2.32-2.20 (m, 1H), 2.20-2.11 (m, 1H), 2.01-1.88 (m, 2H), 1.84-1.61 (m, 4H), 1.56-1.31 (m, 6H), 1.23-1.02 (m, 5H), 1.02-0.95 (m, 7H), 0.93-0.90 (m, 1H), 0.88 (s, 9H), 0.63 (s, 3H), 0.05 (s, 6H).

[0218] Step 4. Synthesis of Intermediate C-4. To a suspension of Intermediate C-3 (2.69 kg, 4.47 mol) in DMF (25 L) was added KI (1.48 g, 8.94 mol) at 70° C. and the mixture was stirred at 70° C. for 1 h. PhSO.sub.2Na (2.19 kg, 13.4 mol) was added and stirring was continued at 70° C. for 1 h. The mixture was poured into water (50 L) and filtered. The filter cake was washed with water (2×10 L) to give the wet product, which was combined with two other batches from previous syntheses. Half of the wet product was triturated with MeCN (20 L) at 80° C. and cooled to 30° C. The heating and cooling process was repeated two more times and the residue was collected by filtration and further triturated with MeCN/toluene (20 L, 10:1) at 80° C., filtered, washed with MeCN (3×5 L), dried in vacuo to give Intermediate C-4 (2.21 kg) as a white solid. Another half of the wet product was triturated with MeCN (20 L) at 80° C. and cooled to 50° C. The heating and cooling process was repeated two more times and the precipitate was collected by filtration to give Intermediate C-4 (1.92 kg) as an off-white solid. Totally 4.13 kg of the product was obtained (67% yield).

[0219] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.00-7.82 (m, 2H), 7.69-7.61 (m, 1H), 7.60-7.49 (m, 2H), 5.37-5.20 (m, 1H), 3.57-3.39 (m, 1H), 3.14 (d, J=14.0 Hz, 1H), 2.85 (dd, J=9.6, 14.0 Hz, 1H), 2.35-2.05 (m, 3H), 2.02-1.88 (m, 2H), 1.85-1.62 (m, 3H), 1.61-1.32 (m, 7H), 1.29-0.91 (m, 12H), 0.88 (s, 9H), 0.65 (s, 3H), 0.05 (s, 6H).

[0220] Step 5. Synthesis of Intermediate C-5. To a suspension of Intermediate C-4 (2.21 kg, 3.87 mol) in THF (10 L) was added TBAF.3H.sub.2O (1.87 kg, 5.92 mol). The mixture was heated and stirred at 65° C. for 1 h to give a clear solution, which was treated with water (25 L) and stirred at 80° C. for 2 h. After cooling, the mixture was filtered and the filter cake was washed with water (3×10 L) and air-dried to give Intermediate C-5 (1.83 kg, crude) as an off-white solid.

[0221] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.98-7.88 (m, 2H), 7.69-7.61 (m, 1H), 7.60-7.51 (m, 2H), 5.40-5.28 (m, 1H), 3.58-3.44 (m, 1H), 3.14 (d, J=13.2 Hz, 1H), 2.85 (dd, J=9.6, 14.0 Hz, 1H), 2.36-2.18 (m, 2H), 2.18-2.04 (m, 1H), 2.03-1.90 (m, 2H), 1.89-1.79 (m, 2H), 1.78-1.68 (m, 1H), 1.62-1.48 (m, 6H), 1.38-0.84 (m, 14H), 0.65 (s, 3H).

[0222] Step 6. Synthesis of Intermediate C-6. To a solution of Intermediate C-5 (50 g, 109 mmol) in THF (500 mL) was added Pd/C (wet, 10%, 11.7 g, 10.9 mmol) under Ar. After degassing three times with N.sub.2, the reaction mixture was purged three times with H.sub.2. The reaction mixture was stirred for 72 h at 25° C. under a hydrogen atmosphere (50 Psi). Formation of the desired product and consumption of starting material was confirmed by NMR. The catalyst was removed by filtration and the filtrate was concentrated to give Intermediate C-6 (39 g, crude) as an off-white solid, which was used in next step directly without further purification.

[0223] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.85-7.82 (m, 2H), 7.58-7.55 (m, 1H), 7.52-7.47 (m, 2H), 3.54-3.47 (m, 1H), 3.09-3.04 (m, 1H), 2.80-2.74 (m, 1H), 2.03-1.83 (m, 2H), 1.63-1.46 (m, 2H), 1.30-1.21 (m, 8H), 1.20-1.17 (m, 7H), 1.16-1.10 (m, 6H), 1.09-0.92 (m, 2H), 0.72 (s, 3H), 0.60-0.48 (m, 4H).

[0224] Step 7. Synthesis of Intermediate C-7. To a solution of Intermediate C-6 (196 g, 427 mmol) in DCM (2 L) was added PCC (137 g, 640 mmol) and the reaction mixture was stirred at 25° C. for 2 h, then filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography (DCM) to give Intermediate C-7 (145 g, 74%) as an off-white solid.

[0225] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95-7.85 (m, 2H), 7.70-7.60 (m, 1H), 7.60-7.50 (m, 2H), 3.20-3.10 (m, 1H), 2.90-2.80 (m, 1H), 2.45-2.20 (m, 3H), 2.15-1.90 (m, 4H), 1.75-1.60 (m, 2H), 1.55-1.00 (m, 16H), 0.99 (s, 3H), 0.95-0.70 (m, 2H), 0.66 (s, 3H).

[0226] Step 8. Synthesis of Intermediate C-8. To a solution of BHT (499 g, 2.27 mmol) in anhydrous toluene (1 L) under N.sub.2 at 0° C. trimethylaluminum (2 M in toluene, 525 mL, 1.05 mmol) was added dropwise. The mixture was stirred at 25° C. for 1 hour and cooled to −70° C. Intermediate C-7 (160 g, 350 mmol) in toluene (500 mL) was added maintaining the temperature below −60° C. The resulting mixture was stirred at −70° C. for 1 hour. Ethylmagnesium bromide (350 mL, 3.0 M in diethyl ether, 1.05 mmol) was added dropwise maintaining the temperature below −60° C. and stirring was continued at −70° C. for another 1 hour. The reaction mixture was quenched with saturated citric acid (2 L) at −70° C., warmed slowly to 25° C., and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (0%˜30% EtOAc in PE) to afford Intermediate C-8 (153 g, 90%) as an off-white solid. A small sample of this material (300 mg) was purified by re-crystallization from MeCN (2 mL) to give Intermediate C-8 (200 mg) as an off-white solid.

[0227] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95-7.85 (m, 2H), 7.70-7.60 (m, 1H), 7.60-7.50 (m, 2H), 3.20-3.10 (m, 1H), 2.90-2.80 (m, 1H), 2.15-2.05 (m, 1H), 1.95-1.85 (m, 1H), 1.75-1.60 (m, 3H), 1.55-1.40 (m, 6H), 1.40-1.15 (m, 11H), 1.15-0.95 (m, 7H), 0.88 (t, J=7.2 Hz, 3H), 0.81 (s, 3H), 0.65-0.55 (m, 4H).

[0228] LCMS Rt=1.194 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.30H.sub.48O.sub.4S[M+H.sub.2O].sup.+ 504, found 504.

Example 4

Synthesis of Compound 1

[0229] ##STR00050##

[0230] Step 1. Synthesis of Intermediate 1-2. To a suspension of Me.sub.3SI (3.93 g, 19.3 mmol) in THF (20 mL) was added a solution of t-BuOK (3.33 g, 29.8 mmol) in THF (10 mL) under N.sub.2 at 15° C. and the resulting suspension was stirred at 15° C. for 30 mins. A solution of Intermediate 1-1 (2 g, 14.9 mmol) in THF (5 mL) was added dropwise at 15° C. and the mixture was stirred at 15° C. for 16 hrs. The mixture was quenched with saturated NH.sub.4Cl (50 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, and concentrated to give Intermediate 1-2 (1.8 g, 82%) as a brown solid.

[0231] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.72 (s, 2H), 2.20-1.85 (m, 8H).

[0232] Step 2. Synthesis of Intermediate 1-3. To a flask containing THF (5 mL) was added n-BuLi (2.5 M, 1.59 mmol, 0.636 mL) under N.sub.2 at −70° C. A suspension of A-6 (0.637 mmol, 300 mg) in THF (4 mL) was added dropwise to give a light yellow suspension. After stirring at −70° C. for 30 mins, a solution of Intermediate 1-2 (0.764 mmol, 113 mg) in THF (1 mL) was added dropwise and the reaction was stirred at 15° C. for 12 hrs. The reaction was quenched with saturated NH.sub.4Cl (30 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give Intermediate 1-3 (400 mg, crude) as light yellow solid, which was used directly for the next step.

[0233] Step 3. Synthesis of Compound 1. To a solution of Intermediate 1-3 (400 mg, 0.646 mmol) in MeOH (5 mL) was added Mg powder (930 mg, 38.76 mmol) at 60° C. and the mixture was stirred at 60° C. for 16 hrs. The reaction was quenched with HCl (50 mL, 1N) and extracted with DCM (2×30 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, concentrated and the residue was purified by silica gel chromatography (0-10% EtOAc in PE) to give 50 mg impure product, which was purified by SFC (column: AD(250 mm*30 mm, 5 um), gradient: 0-40% B (A=0.05% NH.sub.3/H.sub.2O, B=MeOH); FlowRate (mL/min): 60) to give Compound 1 (32 mg, 10%) as an off-white solid.

[0234] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.31-5.29 (m, 1H), 2.43-2.40 (m, 1H), 2.20-2.02 (m, 4H), 2.00-1.73 (m, 5H), 1.72-1.61 (m, 5H), 1.60-1.46 (m, 10H), 1.45-1.22 (m, 3H), 1.21-1.06 (m, 8H), 1.05-0.96 (m, 3H), 0.95-0.90 (m, 5H), 0.68 (s, 3H). LCMS Rt=1.256 min in 2.0 min chromatography, 30-90AB_ELSD, purity 100%, MS ESI calcd. for C.sub.30H.sub.45F.sub.2 [M+H−2H.sub.2O].sup.+443, found 443.

Example 5

Synthesis of Compound 2

[0235] ##STR00051##

[0236] Step 1. Synthesis of Intermediate 2-2. To a solution of Me.sub.3SI (13.4 g, 66.1 mmol) in DMSO (100 mL) was added NaH (2.63 g, 66.1 mmol, 60%) in portions at 0° C. After stirring at 25° C. for 30 min, a solution of Intermediate 2-1 (5 g, 50.9 mmol) in 50 ml of DMSO was added dropwise and the mixture was stirred at 25° C. for 1 h, poured into ice-water (300 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc=10/1) to afford Intermediate 2-2 (0.6 g, 10%) as a colorless oil.

[0237] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.59 (s, 2H), 1.78-1.71 (m, 4H), 1.59-1.51 (m, 6H).

[0238] Step 2. Synthesis of Intermediate 2-3. To a flask containing THF (4 mL) under N.sub.2 at −70° C. was added n-BuLi (2.5 M, 3.17 mmol, 1.26 mL, 2.5 eq.) followed by dropwise addition of a suspension of A-6 (600 mg, 1.27 mmol) in THF (6 mL). After stirring at −70° C. for 30 min, a solution of Intermediate 2-2 (227 mg, 2.03 mmol) was added. The reaction was stirred at 25° C. for 16 hours, poured into ice-water (100 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc=5/1) to afford Intermediate 2-3 (400 mg, impure) as a light yellow solid. LCMS Rt=1.066 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.36H.sub.53O.sub.3S [M+H−H.sub.2O].sup.+ 565, found 565.

[0239] Step 3. Synthesis of Compound 2. To a solution of Intermediate 2-3 (400 mg, 0.69 mmol) in 10 mL of dry methanol, magnesium turnings (492 mg, 20.5 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl.sub.2 (44.4 mg, 0.34 mmol) were added under N.sub.2 and the reaction was stirred at 50° C. for 1 h. The reaction was quenched at 10° C. by dropwise addition of 2M HCl (50 mL) until the complete dissolution of all solids. The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with saturated NaHCO.sub.3 (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=10/1) to afford Compound 2 (42 mg, 14%) as an off-white solid.

[0240] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.31-5.30 (m, 1H), 2.44-2.41 (m, 1H), 2.02-1.93 (m, 3H), 1.86-1.58 (m, 6H), 1.52-1.36 (m, 16H), 1.32-1.25 (m, 3H), 1.18-1.07 (m, 9H), 1.03-0.92 (m, 8H), 0.68 (s, 3H). LCMS Rt=1.353 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.30H.sub.47 [M+H−2H.sub.2O].sup.+ 407, found 407.

Example 6

Synthesis of Compound 3

[0241] ##STR00052##

[0242] Step 1. Synthesis of Intermediate 3-2. To a mixture of trimethylsulfoxonium iodide (47.1 g, 231 mmol) in 100 mL of DMSO was added NaH (9.23 g, 60% in mineral oil, 231 mmol) portionwise at 10° C. under N.sub.2. The mixture was stirred at 10° C. for 30 mins. Intermediate 3-1 (15 g, 178 mmol) in DMSO (50 mL) was added dropwise below 15° C. and the reaction mixture was stirred at 15° C. for 20 hrs. The reaction was quenched at 10° C. with water (200 mL) and extracted with MTBE (2×300 mL). The combined organic phases were washed with water (2×400 mL), brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (DCM) to give Intermediate 3-2 (11 g, impure) as a colorless oil.

[0243] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.83 (s, 2H), 1.95-1.77 (m, 4H), 1.74-1.60 (m, 4H).

[0244] Step 2. Synthesis of Intermediate 3-3. To a flask containing THF (4 mL) under N.sub.2 at −70° C. was added n-BuLi (2.5 M, 5.30 mmol, 2.11 mL), followed by dropwise addition of a suspension of A-6 (2.12 mmol, 1 g) in THF (10 mL). After stirring at −70° C. for 30 mins, a solution of Intermediate 3-2 (4.24 mmol, 416 mg) in THF (4 mL) was added and the reaction was stirred at −70° C. for 10 mins and at 25° C. for 16 hrs. The reaction was quenched with water (10 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give Intermediate 3-3 (1.2 g, crude) as a yellow solid. LCMS Rt=1.161 min & 1.222 min in 2.0 min chromatography, 30-90 AB, 28%, MS ESI calcd. for C.sub.35H.sub.52O.sub.4SNa [M+Na].sup.+ 591, found 591.

[0245] Step 3. Synthesis of Compound 3. To a solution of Intermediate 3-3 (1.2 g, 2.10 mmol) in 50 mL of dry MeOH and 25 mL of THF, magnesium turnings (3.06 g, 126 mol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl.sub.2 (54.4 mg, 0.42 mmol) were added under N.sub.2 at 50° C. to initiate continuous hydrogen generation. The reaction was quenched at 10° C. by addition of 1 M HCl (200 mL) until the complete dissolution of all solids. The mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with saturated NaHCO.sub.3 (500 mL), brine (500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give Compound 3 (600 mg, crude), which was purified by column chromatography on silica gel (PE/EtOAc=5/1) to give a product (150 mg, impure) as an off-white solid. The impure product was purified by SFC (Column: AD(250 mm*30 mm, 5 um); Condition: Base-ETOH, 40% B; FlowRate(ml/min): 60 mL/min) to give 30 mg of the product. The product was washed with n-hexane (5 mL) to give Compound 3 (3 mg, 0.3%).

[0246] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.34-5.28 (m, 1H), 2.46-2.35 (m, 1H), 2.05-1.93 (m, 3H), 1.89-1.59 (m, 12H), 1.53-1.24 (m, 11H), 1.21-0.99 (m, 13H), 0.96-0.89 (m, 4H), 0.68 (s, 3H).

[0247] LCMS Rt=1.161 min & 1.295 min in 2.0 mm chromatography, 30-90 AB_E, MS ESI calcd. for C.sub.29H.sub.45 [M+H−2H.sub.2O].sup.+393, found 393.

Example 7

Synthesis of Compound 4

[0248] ##STR00053##

[0249] Step 1. Synthesis of Intermediate 4-2. To a solution of Intermediate 4-1 (1 g, 14.6 mmol) in DCM (30 mL) was added m-CPBA (3.77 g, 21.9 mmol) and the mixture was stirred at 25° C. for 16 hrs. The reaction mixture was filtered, and the filtrate was distilled in vacuo to give a solution of Intermediate 4-2 in DCM. The solution was distilled under normal pressure to give a solution of Intermediate 4-2 (5 g, 2% solution in DCM calculated from .sup.1H NMR, 8% yield calculated from HNMR).

[0250] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.67 (s, 2H), 2.54-2.43 (m, 2H), 2.30-2.20 (m, 2H), 1.89-1.72 (m, 2H).

[0251] Step 2. Synthesis of Intermediate 4-3. To a solution of n-BuLi (2.5 M in hexane, 1.1 mL, 2.65 mmol) in anhydrous THF (8 mL) under nitrogen at −78° C., A-6 (500 mg, 1.06 mmol) was added in one portion and the mixture was stirred at −78° C. for 0.5 hr. A solution of Intermediate 4-2 (5 g, 2% in DCM, 1.18 mmol) was added dropwise to the above mixture and the reaction was gradually warmed to 15° C. After stirring for 16 hrs the reaction was quenched with saturated NH.sub.4Cl (20 mL) and extracted with EtOAC (3×30 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc=9:1) to give Intermediate 4-3 (100 mg, 17%) as an off-white solid. LCMS Rt=1.131 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.34H.sub.49O.sub.3S [M+H−H.sub.2O].sup.+ 537, found 537.

[0252] Step 3. Synthesis of Compound 4. To a solution of Intermediate 4-3 (100 mg, 0.180 mmol) in anhydrous MeOH (5 mL) under nitrogen was added magnesium powder (260 mg, 10.7 mmol). The mixture was stirred at 60° C. for 2 hrs, cooled to room temperature, neutralized with 1 M HCl and extacted with EtOAc (4×20 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc=10:1) to afford a residue, which was triturated with n-hexane to give Compound 4 (23 mg, 31%) as an off-white solid.

[0253] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.34-5.26 (m, 1H), 2.46-2.37 (m, 1H), 2.09-1.57 (m, 14H), 1.54-1.23 (m, 11H), 1.21-1.05 (m, 8H), 1.04-0.90 (m, 8H), 0.69 (s, 3H). LCMS Rt=1.230 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.43 [M+H−2H.sub.2O].sup.+ 379, found 379.

Example 8

Synthesis of Compound 5

[0254] ##STR00054##

[0255] Step 1. Synthesis of Intermediate 5-2. To a mixture of trimethylsulfoxonium iodide (28.3 g, 139 mmol) in DMSO (60 mL) was added NaH (5.55 g, 60% in mineral oil, 139 mmol) in portions at 5° C. under N.sub.2 and the mixture was stirred at 5° C. for 30 mins. Dihydrofuran-3(2H)-one (10 g, 116 mmol) in DMSO (40 mL) was added dropwise while maintaining the temperature below 15° C. and the resulting mixture was stirred at 15° C. for 20 hrs. The reaction was quenched at 10° C. with water (200 mL) and extracted with MTBE (2×200 mL). The combined organic phases were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated and the residue was purified by silica gel chromatography (0%˜40% EtOAc in PE) to afford Intermediate 5-2 (100 mg, 1%) as a colorless oil.

[0256] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.12-3.93 (m, 3H), 3.68 (d, J=10.4 Hz, 1H), 3.05 (d, J=4.4 Hz, 1H), 2.96 (d, J=4.4 Hz, 1H), 2.37-2.25 (m, 1H), 2.02-1.92 (m, 1H).

[0257] Step 2. Synthesis of Intermediate 5-3. To a flask containing THF (2 mL) under N.sub.2 at −78° C. was added n-BuLi (0.9 mL, 2.22 mmol, 2.5 M) followed by a suspension of A-6 (300 mg, 0.637 mmol) in THF (4 mL), giving a light yellow suspension. After stirring at −78° C. for 30 mins, a solution of Intermediate 5-2 (100 mg, 1.01 mmol) in THF (2 mL) was added and the reaction was stirred at −78° C. for 10 mins and at 15° C. for 16 hrs. The reaction was quenched with saturated NH.sub.4Cl (20 mL), extracted with EtOAc (3×20 mL) and the combined organic phases were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give crude Intermediate 5-3 (300 mg) as a yellow solid, which was used directly in next step.

[0258] LCMS Rt=0.907 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C.sub.34H.sub.49O.sub.4S [M+H−H.sub.2O].sup.+ 553, found 553.

[0259] Step 3. Synthesis of Compound 5. To a solution of Intermediate 5-3 (300 mg, 0.525 mmol) in 20 mL of dry MeOH under N.sub.2, magnesium turnings (127 mg, 5.24 mmol) (activated with 0.5% aqueous HCl, water, dry EtOH, and MTBE) and NiCl.sub.2 (13.6 mg, 0.10 mmol) were added with stirring at 55° C. to initiate continuous hydrogen generation. After four batches of 127 mg of magnesium turnings were added most of the starting material was consumed. The reaction was quenched by adding 2M HCl (50 mL) until the complete dissolution of all solids. The mixture was extracted with DCM (3×20 mL) and the combined organic phases were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (0%˜50% EtOAc in PE) to afford Compound 5 (34 mg, 15%) as an off-white solid.

[0260] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.37-5.24 (m, 1H), 4.08-3.98 (m, 1H), 3.94-3.84 (m, 1H), 3.74-3.65 (m, 1H), 3.59-3.51 (m, 1H), 2.48-2.37 (m, 1H), 2.06-1.67 (m, 9H), 1.66-1.38 (m, 13H), 1.34-1.07 (m, 8H), 1.06-0.90 (m, 7H), 0.68 (s, 3H). LCMS Rt=1.111 min in 2 min chromatography, 30-90AB_E, MS ESI calcd. for C.sub.30H.sub.49O.sub.3NNa [M+MeCN+Na].sup.+ 494, found 494.

Example 9

Preparation of Compound 5-A and 5-B

[0261] ##STR00055##

[0262] Racemic Compound 5 (1.4 g) was purified by SFC (Column: AD (250 mm*30 mm, 5 um)); Condition: 0.1% NH.sub.3H.sub.2O IPA; Gradient 40% B; Gradient Time(min):30; FlowRate(ml/min): 60.) to afford Compound 5-A (350 mg, 15%) as an off-white solid and Compound 5-B (310 mg, 14%) as a an off-white solid.

[0263] Compound 5-A

[0264] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.33-5.28 (m, 1H), 4.10-4.00 (m, 1H), 3.93-3.85 (m, 1H), 3.69 (d, J=9.2 Hz, 1H), 3.54 (d, J=9.2 Hz, 1H), 2.46-2.38 (m, 1H), 2.04-1.88 (m, 5H), 1.87-1.56 (m, 9H), 1.53-1.23 (m, 7H), 1.21-1.09 (m, 7H), 1.08-0.89 (m, 9H), 0.68 (s, 3H).

[0265] LCMS Rt=1.091 min in 2 min chromatography, 30-90AB_E, purity 100%, MS ESI calcd. for C.sub.28H.sub.46O.sub.3Na [M+Na].sup.+ 453, found 453.

[0266] Compound 5-B

[0267] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.32-5.28 (m, 1H), 4.10-4.00 (m, 1H), 3.93-3.85 (m, 1H), 3.70 (d, J=9.2 Hz, 1H), 3.55 (d, J=9.2 Hz, 1H), 2.45-2.39 (m, 1H), 2.04-1.83 (m, 6H), 1.81-1.63 (m, 4H), 1.61-1.54 (m, 5H), 1.52-1.37 (m, 6H), 1.26-1.08 (m, 8H), 1.05-0.92 (m, 8H), 0.68 (s, 3H).

[0268] LCMS Rt=1.093 min in 2 min chromatography, 30-90AB_E, purity 100%, MS ESI calcd. for C.sub.28H.sub.43O [M+H−2H.sub.2O].sup.+ 395, found 395.

Example 10

Synthesis of Compound 6

[0269] ##STR00056##

[0270] Step 1. Synthesis of Intermediate 6-2. To a mixture of trimethylsulfoxonium iodide (12.2 g, 59.8 mmol) in DMSO (40 mL) at 5° C. under N.sub.2, NaH (2.38 g, 60% in mineral oil, 59.8 mmol) was added portionwise and the mixture was stirred at 5° C. for 30 mins. Intermediate 6-1 (5 g, 49.9 mmol) in DMSO (40 mL) was added dropwise maintaining the temperature below 15° C. and the reaction mixture was stirred at 15° C. for 20 hrs. The reaction was quenched at 10° C. with water (200 mL) and extracted with MTBE (2×200 mL). The combined organic phases were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated and the resulting residue was purified by silica gel chromatography (0%˜50% EtOAc in PE) to afford Intermediate 6-2 (1.5 g, 26%) as colorless oil.

[0271] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.93-3.76 (m, 4H), 2.69 (s, 2H), 1.94-1.81 (m, 2H), 1.58-1.48 (m, 2H).

[0272] Step 2. Synthesis of Intermediate 6-3. To a flask containing THF (5 mL) under N.sub.2 at −78° C., n-BuLi (2.96 mL, 7.42 mmol, 2.5 M) was added, followed by dropwise addition of a suspension of A-6 (1 g, 2.12 mmol) in THF (10 mL) to give a light yellow suspension. After stirring at −78° C. for 30 mins, a solution of Intermediate 6-2 (483 mg, 4.24 mmol) in THF (5 mL) was added and the reaction was stirred at −78° C. for 10 min and at 15° C. for 16 hrs. The reaction was quenched with saturated NH.sub.4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give crude Intermediate 6-3 (1 g) as a yellow solid, which was used directly in next step. LCMS Rt=2.423 min in 3.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.35H.sub.52O.sub.5SNa [M+Na].sup.+ 607, found 607.

[0273] Step 3. Synthesis of Compound 6 To a solution of Intermediate 6-3 (1 g, 1.70 mmol) in 20 mL of anhydrous MeOH under N.sub.2, magnesium turnings (410 mg, 16.9 mmol) (activated with 0.5% aqueous HCl, water, anhydrous ethanol, and MTBE) and NiCl.sub.2 (44.0 mg, 0.34 mmol) were added with stirring at 55° C. to initiate continuous hydrogen generation. After four batches of magnesium turnings (410 mg overall) were added, the reaction was quenched at 10° C. by dropwise addition of 2M HCl (80 mL) until the complete dissolution of all solids. The mixture was extracted with DCM (3×50 mL) and the combined organic phases were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (0%˜70% EtOAc in PE) to afford Compound 6 (200 mg, 26%) as an off-white solid.

[0274] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 5.24-5.15 (m, 1H), 4.34 (s, 1H), 4.02 (s, 1H), 3.64-3.47 (m, 4H), 2.30-2.23 (m, 1H), 2.00-1.75 (m, 5H), 1.70-1.24 (m, 14H), 1.20-0.83 (m, 18H), 0.63 (s, 3H). LCMS Rt=2.043 min in 3.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.29H.sub.45O [M+H−2H.sub.2O].sup.+ 409, found 409.

Example 11

Synthesis of Compound 7

[0275] ##STR00057##

[0276] Step 1. Synthesis of Intermediate 7-2. To a solution of trimethylsulfoxonium iodide (26.5 g, 130 mmol) in 50 mL of DMSO at 10° C. under N.sub.2, NaH (5.18 g, 60% in mineral oil, 130 mmol) was added portionwise and the mixture was stirred at 10° C. for 30 mins. Intermediate 7-1 (20 g, 100 mmol) in DMSO (50 mL) was added dropwise maintaining the temperature below 15° C. and stirring was continued at 15° C. for 20 hrs. The reaction was quenched at 10° C. with water (200 mL) and extracted with MTBE (2×300 mL). The combined organic phases were washed with water (2×400 mL), brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE:EtOAc=6:1) to give Intermediate 7-2 (15 g, 70%) as an off-white solid.

[0277] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.77-3.66 (m, 2H), 3.43 (m, 2H), 2.69 (s, 2H), 1.86-1.72 (m, 2H), 1.52-1.39 (m, 11H).

[0278] Step 2. Synthesis of Intermediate 7-3. To a solution of n-BuLi (2.5 M in hexane, 4.2 mL, 10.6 mmol) in anhydrous THF (20 mL) at −70° C. under nitrogen A-6 (2 g, 4.24 mmol) was added in one portion and the mixture was stirred at −70° C. for 30 mins. Intermediate 7-2 (1.80 g, 8.48 mmol) was added and the resulting mixture was gradually warmed to 15° C. and stirred for an additional 16 hours. The reaction was quenched with saturated NH.sub.4Cl (30 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:THF=5:1) to give Intermediate 7-3 (2.3 g, 79%) as an off-white solid.

[0279] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.96-7.87 (m, 2H), 7.72-7.55 (m, 3H), 5.31-5.24 (m, 1H), 4.00-3.83 (m, 2H), 3.43-3.32 (m, 1H), 3.30-3.06 (m, 2H), 2.44-2.24 (m, 2H), 1.99-1.87 (m, 3H), 1.80-1.50 (m, 11H), 1.49-1.42 (m, 12H), 1.40-1.25 (m, 4H), 1.18-0.80 (m, 15H), 0.43 (s, 3H).

[0280] Step 3. Synthesis of Intermediate 7-4. To a solution of Intermediate 7-3 (2.3 g, 3.36 mmol) and nickel(II) chloride (435 mg, 3.36 mmol) in anhydrous MeOH (30 mL) and THF (10 mL) under nitrogen at 45° C. was added a single portion of magnesium turnings (3.25 g, 134 mmol). The internal temperature rose to 60° C. and vigorous gas evolution was observed. The mixture was stirred at 60° C. for 3 hrs, cooled to room temperature, quenched with 1 M HCl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated NaHCO.sub.3 (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:THF=6:1) to give Intermediate 7-4 (1.1 g, 60%) as an off-white solid.

[0281] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.34-5.27 (m, 1H), 3.91-3.66 (m, 2H), 3.23-3.07 (m, 2H), 2.47-2.38 (m, 1H), 2.03-1.91 (m, 3H), 1.88-1.65 (m, 4H), 1.60-1.54 (m, 4H), 1.47-1.42 (m, 12H), 1.38-1.24 (m, 4H), 1.20-0.97 (m, 14H), 0.97-0.77 (m, 7H), 0.68 (s, 3H).

[0282] Step 4. Synthesis of Compound 7. To a solution of Intermediate 7-4 (1 g, 1.83 mmol) in EtOAc (8 mL) and DCM (8 mL) were added ethanol (843 mg, 18.3 mmol) and acetyl chloride (1.43 g, 18.3 mmol). The mixture was stirred at 15° C. for 16 hrs. The precipitated solid was collected by filtration and dried in vacuo to afford crude product (720 mg), which was triturated with methanol to give the hydrochloride of Compound 7 (260 mg, 30%) as an off-white solid.

[0283] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.70-8.38 (m, 1H), 5.24-5.15 (m, 1H), 4.52-4.24 (m, 2H), 3.11-2.94 (m, 4H), 2.35-2.25 (m, 1H), 1.98-1.77 (m, 4H), 1.71-1.50 (m, 8H), 1.47-1.31 (m, 7H), 1.28-0.98 (m, 8H), 0.97-0.86 (m, 10H), 0.65 (s, 3H). LCMS Rt=1.054 min in 2.0 min chromatography, 10-80 AB, MS ESI calcd. for C.sub.29H.sub.50NO.sub.2 [M+H].sup.+ 444, found 444.

Example 12

Synthesis of Compound 8

[0284] ##STR00058##

[0285] To a suspension of Compound 7 hydrochloride (50 mg, 0.104 mmol) in DCE (4 mL) were added Et.sub.3N (21.0 mg, 0.208 mmol), paraformaldehyde (18.7 mg, 0.208 mmol) and NaBH.sub.3CN (16.3 mg, 0.260 mmol) and the mixture was stirred at 25° C. for 16 hrs. The reaction mixture was neutralized with 1 M HCl and purified by preparative HPLC (Column: DuraShell 150*25 mm*5 um. Mobile phase: A: Water (0.1% TFA), B: ACN. Gradient: 35-60% B, 25 Min. Flow rate: 30 mL/min) to give Compound 8 (3 mg, 6%) as an off-white solid.

[0286] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.34-5.26 (m, 1H), 3.44-3.32 (m, 2H), 3.19-3.04 (m, 2H), 2.78 (d, J=4.0 Hz, 3H), 2.48-2.37 (m, 1H), 2.16-1.92 (m, 5H), 1.86-1.56 (m, 9H), 1.51-1.35 (m, 7H), 1.31-1.04 (m, 10H), 1.04-0.87 (m, 8H), 0.67 (s, 3H). LCMS Rt=0.748 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.30H.sub.52NO.sub.2 [M+H].sup.+ 458, found 458.

Example 13

Synthesis of Compound 9

[0287] ##STR00059##

[0288] To a suspension of Compound 7 hydrochloride (50 mg, 0.104 mmol) in DCM (4 mL) were added Et.sub.3N (31.5 mg, 0.312 mmol) and AcCl (16.3 mg, 0.208 mmol) and the mixture was stirred at 25° C. for 16 hrs. The reaction mixture was neutralized with 1 M HCl and purified by preparative HPLC (Column: DuraShell 150*25 mm*5 um. Mobile phase: A: Water (0.1% TFA), B: ACN. Gradient: 51-76% B, 25 Min. Flow rate: 30 mL/min) to give Compound 9 (15 mg, 30%) as an off-white solid.

[0289] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.35-5.25 (m, 1H), 4.43-4.27 (m, 1H), 3.65-3.38 (m, 2H), 3.12-2.94 (m, 1H), 2.48-2.37 (m, 1H), 2.11 (s, 11H), 1.89-1.57 (m, 6H), 1.52-1.21 (m, 9H), 1.20-1.03 (m, 8H), 1.03-0.89 (m, 8H), 0.68 (s, 3H). LCMS Rt=1.036 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for C.sub.31H.sub.52NO.sub.3 [M+H].sup.+ 486, found 486.

Example 14

Synthesis of Compound 10

[0290] ##STR00060##

[0291] Step 1. Synthesis of Intermediate 10-2. To a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) was added Me.sub.3SI (4.18 g, 20.5 mmol) under N.sub.2 and the suspension was stirred at 15° C. for 30 min. A solution of Intermediate 10-1 (2 g, 15.8 mmol) in 10 ml of THF was added dropwise and stirring was continued at 15° C. for 16 hrs. The reaction was quenched with saturated NH.sub.4Cl (100 mL) and extracted with EtOAc (3×150 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give Intermediate 10-2 (1.8 g, 81%) as a yellow liquid.

[0292] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.58 (s, 2H), 1.90-1.80 (m, 1H), 1.70-1.55 (m, 2H), 1.54-1.45 (m, 3H), 1.40-1.30 (m, 2H), 1.00-0.90 (m, 6H).

[0293] Step 2. Synthesis of Intermediate 10-3. To a flask containing THF (0.5 mL) under N.sub.2 at −70° C. was added n-BuLi (1.05 mL, 2.5 M, 2.65 mmol), followed by dropwise addition of a suspension of Intermediate A-6 (500 mg, 1.06 mmol) in THF (1 mL) to give a light yellow suspension. After stirring at −70° C. for 30 min, a solution of Intermediate 10-2 (178 mg, 1.27 mmol) in THF (1 mL) was added dropwise and the reaction was stirred at 15° C. for 12 hrs. The reaction was quenched with saturated NH.sub.4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give Intermediate 10-3 (500 mg, crude) as a yellow solid, which was used directly for the next step.

[0294] Step 3. Synthesis of Compound 10. To a solution of Intermediate 10-3 (500 mg, 0.818 mmol) and nickel (II) chloride (26.4 mg, 0.204 mmol) in dry methanol under N.sub.2 (20 mL) was added magnesium powder (794 mg, 32.7 mmol) with stirring at 50° C. to initiate continuous hydrogen generation. After stirring at 60° C. for 1 hour the reaction was quenched at 10° C. by dropwise addition of 2M HCl (100 mL) until the complete dissolution of all solids. After extraction with EtOAc (2×150 mL), the combined organic layers were washed with sat. NaHCO.sub.3 aq.(300 mL), brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a yellow solid, which was purified by silica gel chromatography (PE/THF=4/1) to give 150 mg of white solid. 72 mg of the solid was purified by SFC (column: AD(250 mm*30 mm, 10 um)), gradient: 55-55% B (A=0.1% NH.sub.3/H.sub.2O, B=EtOH), flow rate: 80 mL/min) to give Compound 10 (39 mg) as an off-white solid.

[0295] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.35-5.30 (m, 1H), 2.45-2.40 (m, 2H), 2.10-1.95 (m, 3H), 1.90-1.65 (m, 7H), 1.60-1.40 (m, 14H), 1.39-1.10 (m, 11H), 1.09-1.00 (m, 4H), 0.09-0.88 (m, 6H), 0.87 (s, 3H), 0.67 (m, 3H).

[0296] LCMS Rt=1.481 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.32H.sub.51 [M+H−2H.sub.2O].sup.− 435, found 435.

Example 15

Synthesis of Compound 11

[0297] ##STR00061##

[0298] Step 1. Synthesis of Intermediate 11-2. To a mixture of trimethylsulfoxonium iodide (12.2 g, 59.8 mmol) in DMSO (40 mL) was added NaH (2.38 g, 60% in mineral oil, 59.8 mmol) portionwise at 5° C. under N.sub.2 and the mixture was stirred at 5° C. for 30 mins. Intermediate 11-1 (5 g, 49.9 mmol) in DMSO (40 mL) was added dropwise maintaining the temperature below 15° C. and stirring was continued at 15° C. for 20 hrs. The reaction was quenched at 10° C. with water (200 mL) and extracted with DCM (2×200 mL). The combined organic phases were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by silica gel chromatography (0%˜50% EtOAc in PE) to afford Intermediate 11-2 (2 g, 35%) as a colorless oil.

[0299] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.81-3.60 (m, 3H), 3.49 (d, J=12.0 Hz, 1H), 2.73-2.65 (m, 2H), 2.03-1.82 (m, 2H), 1.81-1.62 (m, 2H).

[0300] Step 2. Synthesis of Intermediate 11-3. To a flask containing THF (3 mL) under N.sub.2 at −78° C. was added n-BuLi (1.48 mL, 3.71 mmol, 2.5 M), followed by dropwise addition of a suspension of Intermediate A-6 (500 mg, 1.06 mmol) in THF (5 mL) to give a light yellow suspension. After stirring at −78° C. for 30 min, a solution of Intermediate 11-2 (362 mg, 3.18 mmol) in THF (2 mL) was added and the reaction was stirred at −78° C. for 10 min and at 15° C. for 16 hrs. The reaction was quenched with aq. NH.sub.4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude Intermediate 11-3 (500 mg) as a yellow solid, which was used directly in next step.

[0301] LCMS Rt=0.939 min in 1.5 min chromatography, 5-95 AB, purity 79%, MS ESI calcd. for C.sub.35H.sub.51O.sub.4S [M+H−H.sub.2O].sup.+ 567, found 567.

[0302] Step 3. Synthesis of Compound 11. To a solution of Intermediate 11-3 (500 mg, 0.85 mmol) in 20 ml, of dry MeOH under N.sub.2, magnesium turnings (828 mg, 34.1 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl.sub.2 (22 mg, 0.17 mmol) were added with stirring at 55° C. to initiate continuous hydrogen generation. After two batches of magnesium turnings (828 mg) were added, most of the starting material was consumed. The reaction mixture was quenched at 10° C. by addition of 2M HCl (40 mL) until the complete dissolution of all solids. The resulting solution was extracted with DCM (3×50 mL) and the combined organic phases were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (0%˜20% MeOH in DCM) to afford the crude product, which was recrystallized from MeCN (20 mL) to afford Compound 11 (150 mg, 40%) as a white solid.

[0303] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.25-5.22 (m, 1H), 3.84-3.75 (m, 1H), 3.50-3.40 (m, 1H), 3.36-3.21 (m, 2H), 2.39-2.32 (m, 1H), 2.19-2.14 (m, 1H), 1.96-1.86 (m, 3H), 1.85-1.51 (m, 6H), 1.49-1.40 (m, 3H), 1.44-1.26 (m, 8H), 1.25-1.14 (m, 2H), 1.13-0.97 (m, 8H), 0.96-0.82 (m, 8H), 0.61 (s, 3H).

[0304] LCMS Rt=1.226 min in 2 min chromatography, 30-90AB_E, purity 100%, MS ESI calcd. for C.sub.29H.sub.45O [M+H−2H.sub.2O].sup.+ 409, found 409.

Example 16

Synthesis of Compound 12

[0305] ##STR00062##

[0306] Step 1. Synthesis of Intermediate 12-1. To a flask containing THF (5 mL) was added BuLi (4.12 mL, 2.5 M in hexane, 10.3 mmol) and the solution was cooled to −70° C. and treated with a solution of Intermediate B-4 (2 g, 4.12 mmol) in THF (10 mL). The mixture was stirred at −70° C. for 1 h and treated with a solution of Intermediate 1-2 (1.89 g, 6.18 mmol, 50% purity) in THF (5 mL) at −70° C. The reaction was warmed to 25° C. and allowed to stir for 16 hrs. NH.sub.4Cl (40 mL, saturated aq.) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was separated, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0˜25% EtOAc in PE) to give Intermediate 12-1 (150 mg, 6%) as an off-white solid.

[0307] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.96-7.90 (m, 2H), 7.70-7.62 (m, 1H), 7.62-7.55 (m, 2H), 5.30-5.26 (m, 1H), 3.58 (m, 1H), 2.40-2.28 (m, 3H), 2.10-2.00 (m, 2H), 1.99-1.76 (m, 6H), 1.75-1.58 (m, 7H), 1.56-1.31 (m, 8H), 1.30-1.15 (m, 4H), 1.14-1.03 (m, 3H), 1.01 (s, 3H), 0.96-0.75 (m, 8H), 0.58 (s, 3H).

[0308] Step 2. Synthesis of Compound 12. To a solution of Intermediate 12-1 (170 mg, 0.268 mmol) in MeOH (15 mL) was added Mg powder (256 mg, 10.7 mmol) at 55° C. After stirring at 60° C. for 16 hrs., the reaction was quenched by addition of HCl (50 mL, 1 N) until the reaction became clear and the resulting solution was extracted with DCM (2×30 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by silica gel chromatography (0-10% EtOAc in PE) to give Compound 12 (50 mg, 38%) as an off-white solid.

[0309] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.30-5.26 (m, 1H), 2.38-2.31 (m, 1H), 2.18-1.76 (m, 8H), 1.75-1.58 (m, 8H), 1.56-1.41 (m, 9H), 1.40-1.20 (m, 3H), 1.18-1.05 (m, 5H), 1.02 (s, 3H), 1.00-0.90 (m, 6H), 0.88-0.80 (m, 3H), 0.68 (s, 3H).

[0310] LCMS Rt=1.268 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.31H.sub.47F.sub.2 [M+H−2H.sub.2O].sup.+ 457, found 457.

Example 17

Synthesis of Compound 13

[0311] ##STR00063##

[0312] Step 1. Synthesis of Intermediate 13-1. To a solution of diisopropylamine (526 mg,5.20 mmol) in THF (1 mL) was added n-BuLi (1.93 mL, 2.5 M in hexane, 4.84 mmol) under N.sub.2 at −70° C. and the mixture was allowed to warm to 25° C. After cooling to −70° C., a suspension of Intermediate B-4 (588 mg, 1.21 mmol) in THF (5 mL) was added dropwise under N.sub.2 and stirring was continued at −70° C. for 30 min. Intermediate 10-2 (339 mg, 2.42 mmol) was added at −70° C. and the reaction was allowed to slowly warm to 25° C. After stirring for 16 hours, the reaction was quenched with saturated aqueous NH.sub.4Cl (15 mL) and the resulting mixture was extracted with EtOAc (2×15 mL). The combined organic phases were washed with brine (2×20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give Intermediate 13-1 (840 mg, crude) as a yellow oil which was used directly for next step without further purification.

[0313] Step 2. Synthesis of Compound 13. A solution of Intermediate 13-1 (840 mg, 1.34 mmol) in MeOH (40 mL) was heated to 65° C. NiCl.sub.2 (34.2 mg, 268 mmol) and Mg powder (1.28 g, 53.6 mmol) were added in one portion and the mixture was allowed to stir at 65° C. for 1 h. After cooling, the mixture was quenched by addition of HCl (40 mL, 2N) until the reaction became clear and the resulting solution was extracted with DCM (2×40 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by silica gel chromatography (0-10% EtOAc in PE) to give Compound 13 (240 mg, 37%) as an off-white solid.

[0314] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.31-5.26 (m, 1H), 2.42-2.31 (m, 1H), 2.07-1.92 (m, 3H), 1.92-1.78 (m, 1H), 1.77-1.68 (m, 1H), 1.68-1.58 (m, 3H), 1.52-1.44 (m, 10H), 1.44-1.34 (m, 4H), 1.34-1.23 (m, 3H), 1.22-1.14 (m, 3H), 1.14-1.05 (m, 5H), 1.04-0.96 (m, 5H), 0.96-0.89 (m, 7H), 0.89-0.82 (m, 6H), 0.68 (s, 3H).

[0315] LCMS Rt=1.475 min in 2 min chromatography, 30-90AB, purity 100%, MS ESI calcd. For C.sub.33H.sub.53 [M+H−2H.sub.2O].sup.+ 449, found 449.

Example 18

Synthesis of Compound 14

[0316] ##STR00064##

[0317] Step 1. Synthesis of Intermediate 14-1. To a flask containing THF (3 mL) under N.sub.2 at −78° C. was added n-BuLi (1.44 mL, 3.60 mmol, 2.5 M), followed by dropwise addition of a suspension of Intermediate B-4 (500 mg, 1.03 mmol) in THF (5 mL) to give a light yellow suspension. After stirring at −78° C. for 30 min, a solution of Intermediate 6-2 (352 mg, 3.09 mmol) in THF (2 mL) was added, and the reaction was stirred at −78° C. for 10 min at 15° C. for 16 hours. The reaction was quenched with saturated NH.sub.4Cl (50 mL) and extracted with DCM (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude Intermediate 14-1 (500 mg) as a yellow solid, which was used directly in next step.

[0318] LCMS Rt=0.953 min in 1.5 min chromatography, 5-95 AB, purity 36%, MS ESI calcd. for C.sub.36H.sub.54O.sub.5SNa [M+Na].sup.+ 621, found 621.

[0319] Step 2. Synthesis of Compound 14. To a solution of Intermediate 14-1 (500 mg, 0.834 mmol) in 20 mL of anhydrous MeOH under N.sub.2, magnesium turnings (809 mg, 33.3 mmol) (activated with 0.5% aqueous HCl, water, anhydrous EtOH, and MTBE) and NiCl.sub.2 (21.5 mg, 0.17 mmol) were added with stirring at 55° C. to initiate continuous hydrogen generation. After two batches of 809 mg of magnesium turnings were added, most of the starting material was consumed. The reaction mixture was quenched at 10° C. by addition of 2M HCl (40 mL) until the complete dissolution of all solids and the resulting solution was extracted with DCM (3×50 mL). The combined organic phases were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (0%˜20% MeOH in DCM), to afford the crude product, which was recrystallized from MeCN (20 mL) to afford Compound 14 (150 mg, 39%) as an off-white solid.

[0320] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.26-5.18 (m, 1H), 3.78-3.61 (m, 4H), 2.34-2.25 (m, 1H), 2.02-1.85 (m, 4H), 1.83-1.71 (m, 1H), 1.69-1.49 (m, 7H), 1.47-1.35 (m, 9H), 1.27-1.15 (m, 4H), 1.12-0.96 (m, 9H), 0.90-0.77 (m, 7H), 0.61 (s, 3H).

[0321] LCMS Rt=1.227 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.30H.sub.47O [M+H−2H.sub.2O].sup.+ 423, found 423.

Example 19

Synthesis of Compound 15

[0322] ##STR00065##

[0323] Step 1. Synthesis of Intermediate 15-1. To a flask containing THF (3 mL) under N.sub.2 at −78° C. was added n-BuLi (1.44 mL, 3.60 mmol, 2.5 M), followed by dropwise addition of a suspension of Intermediate B-4 (500 mg, 1.03 mmol) in THF (5 mL) to give a light yellow suspension. After stirring at −78° C. for 30 min, a solution of Intermediate 11-2 (352 mg, 3.09 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 10 mins and at 15° C. for 16 hrs. The reaction was quenched with aq. NH.sub.4Cl (50 mL) and extracted with DCM (3×50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude Intermediate 15-1 (500 mg) as a yellow solid, which was used directly in next step.

[0324] LCMS Rt=0.973 min in 1.5 min chromatography, 5-95 AB, purity 47%, MS ESI calcd. for C.sub.36H.sub.53O.sub.4S [M+H−H.sub.2O].sup.+ 581, found 581.

[0325] Step 2. Synthesis of Compound 15. To a solution of Intermediate 15-1 (500 mg, 0.834 mmol) in 20 mL of dry MeOH under N.sub.2, magnesium turnings (809 mg, 33.3 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl.sub.2 (21.5 mg, 0.17 mmol) were added with stirring at 55° C. to initiate continuous hydrogen generation. After two batches of magnesium turnings (809 mg) were added, most of the starting material was consumed. The reaction mixture was quenched at 10° C. by addition of 2M HCl (40 mL) until the complete dissolution of all solids. The resulting solution was extracted with DCM (3×50 mL) and the combined organic phases were washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (0%˜20% MeOH in DCM) to provide the product which was recrystallized from MeCN (20 mL) to afford Compound 15 (150 mg, 39%) as an off-white solid.

[0326] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 5.25-5.18 (m, 1H), 3.84-3.74 (m, 1H), 3.50-3.41 (m, 1H), 3.35-3.21 (m, 2H), 2.33-2.26 (m, 1H), 2.20-2.12 (m, 1H), 2.00-1.64 (m, 7H), 1.63-1.47 (m, 6H), 1.44-1.31 (m, 9H), 1.26-1.14 (m, 3H), 1.10-0.94 (m, 8H), 0.89-0.75 (m, 7H), 0.61 (s, 3H).

[0327] LCMS Rt=1.284 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.30H.sub.47O [M+H−2H.sub.2O].sup.+ 423, found 423.

Example 20

Synthesis of Compound 16

[0328] ##STR00066##

[0329] To a solution of Compound 1 (300 mg, 0.626 mmol) in MeOH (20 mL) was added Pd(OH).sub.2 (100 mg, dry). The mixture was hydrogenated at 50° C., 50 Psi for 48 hrs. The mixture was filtered, washed with DCM (100 mL) and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (0-15% Et0Ac in PE) to give Compound 16 (114 mg, 38%) as an off-white solid.

[0330] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.20-2.00 (m, 2H), 1.99-1.75 (m, 4H), 1.70-1.60 (m, 5H), 1.59-1.42 (m, 8H), 1.41-1.23 (m, 6H), 1.22-1.16 (m, 6H), 1.15-0.96 (m, 8H), 0.95-0.82 (m, 4H), 0.80 (s, 3H), 0.70-0.60 (m, 4H).

[0331] LCMS Rt=1.275 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.30H.sub.47F.sub.2 [M+H−2H.sub.2O].sup.+ 445, found 445.

Example 21

Synthesis of Compound 17

[0332] ##STR00067##

[0333] To a solution of Compound 5-A (100 mg, 0.232 mmol) in MeOH (10 mL) was added dry Pd/C (100 mg) at 15° C. The mixture was degassed and purged several times with H.sub.2 and was allowed to stir under 50 psi H.sub.2 at 55° C. for 48 hrs. The reaction mixture was filtered to remove the Pd/C and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (0%˜30%) EtOAc in PE/DCM (v/v=1/1)) to afford Compound 17 (30 mg, 30%) as an off-white solid.

[0334] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.06-3.98 (m, 1H), 3.93-3.85 (m, 1H), 3.69 (d, J=9.2 Hz, 1H), 3.54 (d, J=9.2 Hz, 1H), 1.99-1.75 (m, 4H), 1.74-1.58 (m, 5H), 1.55-1.37 (m, 7H), 1.35-1.18 (m, 10H), 1.17-0.95 (m, 7H), 0.94-0.83 (m, 4H), 0.80 (s, 3H), 0.70-0.60 (m, 4H).

[0335] LCMS Rt=1.114 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.28H.sub.45O [M+H−2H.sub.2O].sup.+ 397, found 397.

Example 22

Synthesis of Compound 18

[0336] ##STR00068##

[0337] To a solution of Compound 6 (100 mg, 0.224 mmol) in MeOH (10 mL) was added dry Pd/C (100 mg) at 15° C. The mixture was degassed and purged several times with H.sub.2 and was allowed to stir under 50 psi H.sub.2 at 50° C. for 48 hrs. The reaction mixture was filtered to remove the Pd/C and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (0%˜30% EtOAc in PE/DCM (v/v=1/1)) to afford Compound 18 (32 mg, 32.0%) as an off-white solid.

[0338] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.75-3.61 (m, 4H), 1.92-1.84 (m, 1H), 1.81-1.70 (m, 1H), 1.66-1.49 (m, 7H), 1.48-1.36 (m, 7H), 1.34-1.22 (m, 5H), 1.20-1.12 (m, 7H), 1.09-0.98 (m, 5H), 0.96-0.77 (m, 6H), 0.81 (s, 3H), 0.64-0.53 (m, 4H).

[0339] LCMS Rt=1.216 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.29H.sub.47O [M+H−2H.sub.2O].sup.+ 411, found 411.

Example 23

Synthesis of Compound 19

[0340] ##STR00069##

[0341] To a solution of Compound 11 (100 mg, 0.224 mmol) in MeOH (10 mL) was added dry Pd/C (100 mg) at 15° C. The mixture was degassed and purged several times with H.sub.2 and was allowed to stir under 50 psi H.sub.2 at 50° C. for 48 hrs. The reaction mixture was filtered to remove the Pd/C and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (0%˜30% EtOAc in PE/DCM (v/v=1/1)) to afford Compound 19 (35.0 mg, 35%) as an off-white solid.

[0342] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.84-3.74 (m, 1H), 3.49-3.42 (m, 1H), 3.35-3.20 (m, 2H), 2.18-2.14 (m, 1H), 1.93-1.71 (m, 3H), 1.68-1.49 (m, 5H), 1.47-1.34 (m, 7H), 1.33-1.21 (m, 4H), 1.21-1.10 (m, 8H), 1.10-0.89 (m, 7H), 0.88-0.68 (m, 7H), 0.63-0.52 (m, 4H).

[0343] LCMS Rt=1.249 min in 2 min chromatography, 30-90AB_E, purity 100%, MS ESI calcd. for C.sub.29H.sub.47O [M+H−2H.sub.2O].sup.+ 411, found 411.

Example 24

Synthesis of Compound 20

[0344] ##STR00070##

[0345] Step 1. Synthesis of Intermediate 20-1. To a solution of 2, 6-di-tert-butyl-4-methylphenol (14.4 mg, 65.4 mmol) in toluene (100 mL) was added AlMe3 (16.3 mL, 32.7 mmol, 2 M in toluene) dropwise at 0° C. The mixture was stirred at 25° C. for 1 h to give a MAD solution. A solution of Intermediate C-7 (5 g, 10.9 mmol) in toluene (50 mL) was added dropwise to the MAD (116 ml, 0.28 M in toluene) reaction mixture at −65° C. After stirring at −65° C. for 1 h, MeMgBr (10.8 mL, 32.6 mmol, 3M in ethyl ether) was added dropwise at −65° C. and the resulting solution was stirred at −65° C. for 1 hr. The reaction was quenched at −65° C. with saturated aqueous NH.sub.4Cl (100 mL) and the mixture was allowed to warm to 25° C. After stirring for 10 min, the resulting suspension was filtered through a Celite pad and the pad was washed with EtOAc (100 mL). The combined organic layers were separated, washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford Intermediate 20-1 (4.5 g crude) as an off-white solid.

[0346] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.95-7.83 (m, 2H), 7.66-7.60 (m, 1H), 7.58-7.51 (m, 2H), 3.17-3.08 (m, 1H), 2.88-2.68 (m, 1H), 2.15-2.03 (m, 1H), 1.94-1.86 (m, 1H), 1.73-1.40 (m, 9H), 1.40-0.90 (m, 19H), 0.90-0.80 (m, 1H), 0.79 (s, 3H), 0.62 (s, 3H).

[0347] Step 2. Synthesis of Intermediate 20-2. To a solution of n-BuLi (504 μL, 2.5 M in hexane, 1.26 mmol) in THF (1 mL) at −65° C. under N.sub.2, a suspension of Intermediate 20-1 (200 mg, 0.423 mmol) in THF (3 mL) was added dropwise. After stirring for 30 minutes at −65° C., a solution of diisopropylamine (127 mg, 1.26 mmol) was added dropwise, followed by the dropwise addition of a solution of Intermediate 10-2 (176 mg, 1.26 mmol). The mixture was stirred for another 30 min at −65° C. and then gradually warmed to 25° C. and allowed to stir for 16 hours. The reaction was quenched with saturated aqueous NH.sub.4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give Intermediate 20-2 (270 mg, crude), which was used directly for the next step.

[0348] Step 3. Synthesis of Compound 20. A solution of Intermediate 20-2 (270 mg, 0.44 mmol) in MeOH (50 mL) was heated to 60° C. One portion of NiCl.sub.2 (2.83 mg, 0.022 mmol) was added, followed by four portions of Mg (420 mg, 17.5 mmol). After stirring at 60° C. for 1 h, the reaction was quenched by addition of HCl (10 mL, 2 M) until a clear solution was obtained and the solution was extracted with DCM (2×20 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by silica gel chromatography (0-20% EtOAc in PE) to give Compound 20 (100 mg, 48%). The product was dissolved in MeCN (25mL), vacuum concentrated at 70° C., triturated with water (5 mL), filtered and concentrated to give Compound 20 as an off-white solid (56 mg).

[0349] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.00-1.91 (m, 1H), 1.89-1.78 (m, 1H), 1.70-1.51 (m, 3H), 1.51-1.19 (m, 13H), 1.19-1.04 (m, 13H), 1.18-1.06 (m, 5H), 1.06-0.96 (m, 3H), 0.95-0.86 (m, 10H), 0.82-0.79(m, 3H), 0.70-0.60 (m, 4H).

[0350] LCMS Rt=1.442 mm in 2 min chromatography, 30-90AB_2MIN_E, purity 100%, MS ESI calcd. for C.sub.32H.sub.53 [M+H−2H.sub.2O].sup.+ 437, found 437.

Example 25

Synthesis of Compound 21

[0351] ##STR00071##

[0352] Step 1. Synthesis of Intermediate 21-1. To a solution of diisopropylamine (173 mg, 1.72 mmol) in THF (0.5 mL) cooled to −70° C. was added butyllithium (0.616 mL, 1.54 mmol, 2.5 M in n-hexane) and the mixture was stirred at −70° C. for 30 minutes. A solution of Intermediate C-8 (300 mg, 0.616 mmol) in THF (3 mL) was added and the mixture was stirred at −70° C. for 30 minutes. Intermediate 1-2 (182 mg, 1.23 mmol) was added at −70° C. and the mixture was warmed to 25° C. and stirred at this temperature for 17 hours. The mixture was quenched with saturated NH.sub.4Cl (30 mL), extracted with EtOAc (3×10 mL), washed with brine (2×30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give Intermediate 21-1 (350 mg) as a yellow solid, which was used directly in the next step.

[0353] Step 2. Synthesis of Compound 21. A solution of Intermediate 21-1 (350 mg, 0.551 mmol) in MeOH (15 mL) was heated to 55° C., treated with one portion of Mg powder (547 mg, 22.8 mmol) and heated to reflux for 1 h. The reaction was quenched with HCl (50 mL, 1N) and the resulting clear solution was extracted with DCM (2×30 mL). The combined organic phases were dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by silica gel chromatography (0-10% EtOAc in PE) to give impure Compound 21 (120 mg, 44% yield, containing 22,23-olefin) as an off-white solid. The 120 mg of impure sample was dissolved in THF (5 mL) and treated with Pd/C (100 mg, wet). The mixture was hydrogenated (15 Psi, 25° C.) for 2 hrs, filtered, concentrated and purified by silica gel chromatography (0-15% EtOAc in PE) to give Compound 21 (86 mg, 72%) as an off-white solid.

[0354] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.20-2.01 (m, 2H), 1.98-1.72 (m, 4H), 1.70-1.58 (m, 10H), 1.56-1.41 (m, 6H), 1.40-1.30 (m, 5H), 1.29-1.18 (m, 4H), 1.17-1.05 (m, 4H), 1.04-0.96 (m, 3H), 0.95-0.80 (m, 10H), 0.68-0.58 (m, 4H).

[0355] LCMS Rt=1.325 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.31H.sub.49F.sub.2 [M+H−2H.sub.2O].sup.+ 459, found 459.

Example 26

Synthesis of Compound 22

[0356] ##STR00072##

[0357] To a solution of Compound 13 (160 mg, 0.391 mmol) in MeOH (15 mL) and THF (15 mL) was added Pd(OH).sub.2/C (dry, 350 mg) under N.sub.2. The suspension was degassed and purged with H.sub.2 three times. The mixture was stirred under H.sub.2 (50 psi) at 50° C. for 48 hours to give a black suspension. The reaction mixture was filtered through a pad of Celite, washed with THF (3×20 mL) and the filtrate was concentrated in vacuo to give Compound 22 (12 mg, 8%) as an off-white solid.

[0358] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 2.00-1.91 (m, 1H), 1.91-1.73 (m, 1H), 1.69-1.56 (m, 5H), 1.54-1.44 (m, 9H), 1.44-1.41 (m, 1H), 1.41-1.32 (m, 4H), 1.32-1.15 (m, 9H), 1.15-1.04 (m, 5H), 1.04-0.95 (m, 3H), 0.95-0.91 (m, 5H), 0.91-0.89 (m, 2H), 0.89-0.85 (m, 6H), 0.85-0.79 (m, 3H), 0.69-0.60 (m, 4H)

[0359] LCMS Rt=1.515 min in 2 min chromatography, 30-90AB, purity 100%, MS ESI calcd. For C.sub.33H.sub.55 [M+H−2H.sub.2O].sup.+ 451, found 451.

Example 27

Synthesis of Compound 23

[0360] ##STR00073##

[0361] To a solution of Compound 14 (100 mg, 0.217 mmol) in MeOH (10 mL) was added dry Pd/C (100 mg) at 15° C. The mixture was degassed and purged with H.sub.2 several times and was stirred under 50 psi H.sub.2 at 55° C. for 48 hrs. The reaction mixture was filtered to remove the Pd/C, the filtrate was concentrated and the residue was purified by silica gel chromatography (0%˜30% EtOAc in PE/DCM (v/v=1/1)) to afford Compound 23 (36.0 mg, 36%) as an off-white solid.

[0362] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.82-3.69 (m, 4H), 1.99-1.91 (m, 1H), 1.87-1.75 (m, 1H), 1.73-1.57 (m, 7H), 1.55-1.42 (m, 7H), 1.40-1.17 (m, 10H), 1.16-0.95 (m, 8H), 0.94-0.84 (m, 7H), 0.82 (s, 3H), 0.70-0.55 (m, 4H).

[0363] LCMS Rt=1.208 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.30H.sub.49O [M+H−2H.sub.2O].sup.+ 425, found 425.

Example 28

Synthesis of Compound 24

[0364] ##STR00074##

[0365] To a solution of Compound 15 (100 mg, 0.217 mmol) in MeOH (10 mL) was added dry Pd/C (100 mg) at 15° C. The mixture was degassed and purged with H.sub.2 several times and stirred under 50 psi H.sub.2 at 50° C. for 48 hours. The reaction mixture was filtered to remove the Pd/C, the filtrate was concentrated and the residue was purified by silica gel chromatography (0%˜30% EtOAc in PE/DCM (v/v=1/1)) to afford Compound 24 (27 mg, 27%) as a white solid.

[0366] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 3.89-3.81 (m, 1H), 3.55-3.48 (m, 1H), 3.43-3.25 (m, 2H), 2.25-2.20 (m, 1H), 1.99-1.77 (m, 3H), 1.73-1.57 (m, 6H), 1.54-1.41 (m, 7H), 1.40-1.18 (m, 10H), 1.15-0.96 (m, 7H), 0.93-0.80 (m, 10H), 0.70-0.57 (m, 4H).

[0367] LCMS Rt=1.270 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calcd. for C.sub.30H.sub.49O [M+H−2H.sub.2O].sup.+ 425, found 425.

TABLE-US-00001 TABLE 1 NMDA Potentiation GluN2A PCA IWB Ephys % potentiation Compound at 3 μM 1 C 2 C 3 C 4 B 5 C 5-A B 5-B C 6 B 7 B 8 A 9 C 10 A 11 C 12 C 13 A 14 C 15 C 16 A 17 C 18 C 19 C 20 A 21 C 22 A 23 C 24 C For Table 1, “A” indicates 10 to 100%, “B” indicates potentiation of >100% to 150%; and “C” indicates potentiation of >150%.

[0368] The data in Table 1 demonstrate the ability of the exemplified compounds to modulate the NMDA receptor as positive allosteric modulators (PAMs).

Other Embodiments

[0369] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0370] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0371] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0372] 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 without departing from the spirit or scope of the present invention, as defined in the following claims.