Neuroactive steroids and methods of use thereof

Abstract

To provide (3α,3β)-disubstituted 17β steroidal compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof for prevention and treatment of a variety of CNS-related conditions.SOLUTION: In another aspect, provided is a method for treating or preventing a CNS-related condition associated with NMDA modulation comprising administering, to a subject in need of the treatment or prevention of the CNS-related condition associated with NMDA modulation, an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority under U.S.C. §119(e) to U.S. Provisional Patent Application No. 61 / 779,735, filed March 13, 2013, which is incorporated herein by reference. [Background technology]

[0002] Brain arousal is defined as the level of an animal's alertness, ranging from coma to seizures, and is controlled by various neurotransmitters. Generally, neurotransmitters are responsible for controlling the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (i.e., membrane potential) of approximately -70 mV, meaning the inside of the cell is negative relative to the outside of the cell. This potential (voltage) is the result of the balance of ions (K+, Na+, Cl-, and organic anions) across the semipermeable neuronal membrane. Neurotransmitters are stored in synaptic vesicles and are released as a result of a neuronal action potential. Upon release into the synaptic cleft, excitatory chemical messengers such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV). This effect is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, increasing membrane permeability to Na+ ions. This decrease in membrane potential increases the likelihood of an action potential being generated in the postsynaptic cell, increasing neuronal excitability.

[0003] NMDA receptors are abundant in the CNS and are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some situations and to excitability in others. These receptors are ligand-gated ion channels that allow Ca ions to pass through after binding of the neurotransmitters glutamate and glycine. 2+NMDA receptors allow the passage of excitatory neurotransmission and underlie normal CNS function. NMDA receptors are heteromeric complexes composed of NR1, NR2, and / or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. Positive modulators would be useful as therapeutic agents with potential clinical applications as cognitive enhancers and in the treatment of psychiatric disorders in which glutamate transmission is reduced or defective (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators would be useful as therapeutic agents with potential clinical applications in the treatment of psychiatric disorders in which glutamate transmission is pathologically increased (e.g., treatment-resistant depression).

[0004] Neuroactive steroids, such as pregnenolone sulfate (PS), have been shown to exert direct modulatory effects on several neurotransmitter receptors, including GABAA, glycine, AMPA, kainate, and NMDA receptors. NMDA receptors are positively modulated by PS, although the degree of modulation varies considerably, depending, for example, on the subunit composition of the receptor.

[0005] In addition to PS, several other 3β-hydroxysteroids have been shown to potentiate NMDA receptors (see, e.g., Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682). Recently, a 3β-hydroxy-ergost-5-ene steroid derivative (called Org-1) was reported to be a positive modulator of NMDA (NR1α / NR2A). Org-1 has been shown to selectively modulate NMDA over GABAA (see, e.g., Madau et al., Program No. 613.2 / B87.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009; Connick et al., Program No. 613.1 / B86.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009; Paul et al., J. Neurosci. 2013, 33, 17290-17300). [ka] There is a need for new and improved neurostimulatory steroids that modulate brain excitation to prevent and treat CNS-related conditions. The compounds, compositions and methods described herein are directed to this end. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Horak et al., J.of Neuroscience, 2004, 24(46), 10318-10325 [Non-patent document 2] Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682 [Non-patent document 3] Madau et al., Program No. 613.2 / B87.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009 [Non-patent document 4] Connick et al., Program No. 613.1 / B86.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009 [Non-patent document 5] Paul et al., J.Neurosci.2013, 33, 17290-17300 Summary of the Invention [Means for solving the problem]

[0007] In the midst of their search for Org-1 analogs for NMDA modulation, the present inventors have discovered several specific combinations of elements that provide NMDA modulators with relatively superior properties, some of which are described in PCT / US2012 / 054261, incorporated herein by reference. For example, as shown in Table 1, compounds with a β-hydrogen at C5 are less desirable than compounds with an α-hydrogen at C5 or a double bond at C5-C6 due to their lack of potentiation of the NMDA receptor. 21 Removal of the methyl at C3 also results in a significant loss of NMDA receptor potentiation. Disubstitution at C3 is expected to increase the metabolic stability of these compounds and is therefore a preferred feature of the present invention. 17 Side chain fluorination has been shown to increase NMDA receptor potency and limit maximal potentiation when tested at compound concentrations as low as 1 μM. 17Secondary or tertiary terminal alcohols in the side chain have been shown to enhance NMDA receptor potency and limit maximum potentiation when tested at compound concentrations as low as 1 μM, and are therefore a preferred feature of the present invention. Bulkier groups containing 2-3 carbons at the terminals, or groups containing fluorine substituents, are preferred. These characteristics are expected to limit the risk of inducing glutamate-induced neurotoxicity for compounds achieving greater maximum potentiation of NMDA receptors. The compounds of the present invention encompass various combinations of these specific features that result in superior NMDA modulators. The present invention provides, for example, the following items. (Item 1) Compounds of formula (I): [ka] [In the formula, R 1 is a substituted or unsubstituted aliphatic; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted cyclopropyl or -OR A2 and R A2 is hydrogen or substituted or unsubstituted alkyl; R 3a is hydrogen or -OR A3 and R A3 is hydrogen or substituted or unsubstituted alkyl, and R 3b is hydrogen; or R 3a and R 3b connects to form an oxo (=O) group; R 4 is hydrogen, substituted or unsubstituted alkyl or halogen; X is -C(R X )2- or -O-, and R X is hydrogen or fluorine, or one R X Group and R 5b connect to form a double bond; R in each case 5a and R 5b are independently hydrogen or fluorine; R 6a is a non-hydrogen radical selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted carbocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups, wherein the non-hydrogen radical is optionally substituted with fluorine; R 6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; [ka] represents a single or double bond, provided that if a single bond is present, the hydrogen at C5 is in the alpha configuration; Furthermore, however, (1)R X , R 5a and R 5b at least one of is fluorine; or (2)R 6a and R 6b at least one of is a non-hydrogen group substituted with fluorine; or (3)R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. or a pharmaceutically acceptable salt thereof. (Item 2) R 1 But unsubstituted C 1~3 The compound according to item 1, wherein the aryl group is alkyl. (Item 3) R 1 is -CH3, -CH2CH3 or -CH2CH2CH3. (Item 4) R 2 The compound according to item 1, wherein is hydrogen. (Item 5) R 3a and R 3b and R are both hydrogen. (Item 6) R 4 The compound according to item 1, wherein is hydrogen. (Item 7) The compound is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof. (Item 8) The compound is a compound of formula (II-A): [ka] or a pharmaceutically acceptable salt thereof. (Item 9) The compound is a compound of formula (II-B): [ka] or a pharmaceutically acceptable salt thereof. (Item 10) R 1 10. The compound according to item 8 or 9, wherein is —CH3 or —CH2CH3. (Item 11) R 6b 10. The compound according to item 8 or 9, wherein is —CH3. (Item 12) R 5a and R 5b and R are both hydrogen. (Item 13) R 5a and R 5b10. The compound according to item 8 or 9, wherein at least one of is fluorine. (Item 14) R 5a and R 5b and R are both fluorine. (Item 15) R 6a 10. The compound according to item 8 or 9, wherein is a non-hydrogen group substituted with fluorine. (Item 16) R 6a 10. The compound according to item 8 or 9, wherein is —CF 3 . (Item 17) R 6a but one or more -OR A6 is a non-hydrogen group substituted with a group, R A6 10. The compound according to item 8 or 9, wherein is hydrogen or substituted or unsubstituted alkyl. (Item 18) R 6a But -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 Item 18. The compound according to item 17, wherein (Item 19) R 6a is substituted or unsubstituted C 2~4 Alkyl, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 2~3 The compound according to item 8 or 9, which is alkynyl or substituted or unsubstituted C3 carbocyclyl. (Item 20) R 6b 10. The compound according to item 8 or 9, wherein is hydrogen. (Item 21) R 6b 10. The compound according to item 8 or 9, wherein is —CH3 or —CF3. (Item 22) R 6a is -CF3 and R 6b is hydrogen or C 1~4 10. The compound according to item 8 or 9, wherein the alkyl is alkyl. (Item 23) R 6a is a non-hydrogen group substituted with fluorine, and R 6b 10. The compound according to item 8 or 9, wherein is —CH3. (Item 24) R 6a but one or more -OR A6 is substituted with an R A6 24. The compound according to item 23, wherein is hydrogen or substituted or unsubstituted alkyl. (Item 25) R 6a is substituted or unsubstituted C 2~4 Alkyl, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 2~3 alkynyl or substituted or unsubstituted C3 carbocyclyl, R 6b 10. The compound according to item 8 or 9, wherein is —CH3. (Item 26) R 6a But unsubstituted C 2~4 Alkyl, unsubstituted C 2~3 Alkenyl or unsubstituted C 2~3 alkynyl or unsubstituted C3 carbocyclyl, and R 6b 10. The compound according to item 8 or 9, wherein is —CH3. (Item 27) R 6a is a non-hydrogen group substituted with fluorine, and R 6b 10. The compound according to item 8 or 9, wherein is —CH3. (Item 28) R 1 C 1~3 alkyl, and R 6a is a non-hydrogen group substituted with fluorine, and R 6b 10. The compound according to item 8 or 9, wherein is —CH3. (Item 29) R 1 C 1~3 alkyl, and R 6a is a non-hydrogen group substituted with fluorine, and R 6b10. The compound according to item 8 or 9, wherein is hydrogen. (Item 30) R 1 C 1~3 alkyl, and R 6a is a non-hydrogen group selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted carbocyclyl; R 6b 10. The compound according to item 8 or 9, wherein is —CH3. (Item 31) R 6a is selected from the group consisting of substituted or unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl or unsubstituted carbocyclyl. (Item 32) R 6a 31. The compound according to item 30, wherein is selected from substituted or unsubstituted alkyl. (Item 33) R 1 33. The compound according to item 32, wherein is -CH3 or -CH2CH3. (Item 34) R 1 is -CH3 or -CH2CH3, and R 5a and R 5b At least one of R is fluorine, or 5a and R 5b and R are both hydrogen. (Item 35) R 1 is -CH3 or -CH2CH3, and R 6a is a non-hydrogen group substituted with fluorine, or one or more -OR A6 is a group, and R A6 10. The compound according to item 8 or 9, wherein is hydrogen or substituted or unsubstituted alkyl. (Item 36) R 1 is -CH3 or -CH2CH3, and R 6b is -CH3 or -CF3. (Item 37) R 6a 37. The compound according to item 36, wherein is selected from the group consisting of substituted or unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl or unsubstituted carbocyclyl. (Item 38) below: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof. (Item 39) A pharmaceutical composition comprising a compound according to any one of the preceding items or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. (Item 40) A method for treating or preventing a CNS-related condition, comprising administering an effective amount of a compound according to any one of items 1 to 39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject in need of such treatment or prevention. (Item 41) The CNS-related condition is an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer's disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other mental disorders (including schizoaffective disorder), a sleep disorder (including insomnia), a chemical-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including Tampa syndrome in the Shank group), The method of claim 40, wherein the compounds are selected from the group consisting of encephalopathy, ...

[0008] Thus, in one embodiment, a compound of formula (I): [ka] [In the formula, R 1 is a substituted or unsubstituted aliphatic; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted cyclopropyl or -OR A2 and R A2 is hydrogen or substituted or unsubstituted alkyl; R 3ais hydrogen or -OR A3 and R A3 is hydrogen or substituted or unsubstituted alkyl, and R 3b is hydrogen; or R 3a and R 3b connects to form an oxo (=O) group; R 4 is hydrogen, substituted or unsubstituted alkyl or halogen; X is -C(R X )2- or -O-, and R X is hydrogen or fluorine, or one R X Group and R 5b connect to form a double bond; R in each case 5a and R 5b are independently hydrogen or fluorine; R 6a is a non-hydrogen radical selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted carbocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups and substituted and unsubstituted heteroaryl groups, wherein the non-hydrogen radical is optionally substituted with fluorine; R 6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; [ka] represents a single or double bond, provided that if a single bond is present, the hydrogen at C5 is in the alpha configuration; Furthermore, however, (1)R X , R 5a and R 5b at least one of is fluorine; or (2)R 6a and R 6b at least one of is a non-hydrogen group substituted with fluorine; or (3)R6a is a non-hydrogen group containing 2 to 10 carbon atoms. and pharmaceutically acceptable salts thereof are provided.

[0009] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In yet another aspect, there is provided a method for treating or preventing a CNS-related condition associated with NMDA modulation, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the CNS-related condition is an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer's disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other mental disorders (including schizoaffective disorder), a sleep disorder (including insomnia), a chemical-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including those involving mutations to Shank group proteins), a neurodevelopmental disorder (including Rett syndrome), pain (including acute and chronic pain), a seizure disorder (including status epilepticus and monogenic forms of epilepsy, e.g., Dravet disease and tuberous sclerosis complex (TSC)), stroke, a traumatic brain injury, a movement disorder (including Huntington's disease and Parkinson's disease), and tinnitus. In certain embodiments, these compounds can be used to induce sedation or anesthesia.

[0011] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION

[0012] definition Chemical Definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry and specific functional moieties and reactivities are defined in accordance with the inside cover of the Ed., and specific functional groups are generally defined as described herein. Further, general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0013] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0014] When a range of values is listed, it is intended to encompass each value and sub-range within that range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C3~4 , C 4~6 , C 4~5 and C 5~6 Alkyl is intended to be included.

[0015] The following terms are intended to have the meanings presented below and are useful in describing the present invention and understanding its intended scope. In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it should also be understood that any moiety defined below may be substituted with various substituents, and that each definition is intended to encompass such substituted moieties within its scope as described below. Unless otherwise stated, the term "substituted" should be defined as set forth below. Furthermore, it should be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" may be used to refer to one or more than one (i.e., at least one) of the grammatical object of the article. As an example, "an analogue" means one analogue or more than one analogue.

[0016] "Aliphatic" refers to an alkyl group, alkenyl group, alkynyl group, or carbocyclyl group, as defined herein.

[0017] "Alkyl" refers to the radical of a straight or branched chain saturated hydrocarbon group containing from 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group contains 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group contains 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group contains 1 to 9 carbon atoms ("C 1~9In some embodiments, an alkyl group contains 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group contains 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group contains 1 to 6 carbon atoms ("C 1~6 In certain embodiments, an alkyl group contains 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group contains 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group contains 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group contains 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group contains 1 carbon atom ("C alkyl"). In some embodiments, an alkyl group contains 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, the alkyl group in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH) or i-Bu(-CHCH(CH)).

[0018] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to divalent radicals of alkyl, alkenyl, and alkynyl groups, respectively. When a range or number of carbons is given for a particular "alkylene," "alkenylene," or "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in a divalent linear chain of carbons. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more substituents as described herein.

[0019] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0020] "Alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group containing 2 to 20 carbon atoms and containing one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally containing one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, the alkenyl does not contain any triple bonds. In certain embodiments, the alkenyl group contains 2 to 10 carbon atoms ("C 2~10 In certain embodiments, an alkenyl group contains 2 to 9 carbon atoms ("C 2~9 In certain embodiments, an alkenyl group contains 2 to 8 carbon atoms ("C 2~8 In certain embodiments, an alkenyl group contains 2 to 7 carbon atoms ("C 2~7 In certain embodiments, an alkenyl group contains 2 to 6 carbon atoms ("C 2~6 In certain embodiments, an alkenyl group contains 2 to 5 carbon atoms ("C 2~5 In certain embodiments, an alkenyl group contains 2 to 4 carbon atoms ("C 2~4 In certain embodiments, an alkenyl group contains 2 to 3 carbon atoms ("C 2~3 In certain embodiments, an alkenyl group contains two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, the alkenyl group in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0021] "Alkenylene" refers to an alkenyl group from which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH-, -CH-CH=CH-). Exemplary substituted alkenylene groups, e.g., those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0022] "Alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group containing 2 to 20 carbon atoms and containing one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally containing one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, alkynyl groups contain 2 to 10 carbon atoms ("C 2~10 In certain embodiments, an alkynyl group contains 2 to 9 carbon atoms ("C 2~9 In certain embodiments, an alkynyl group contains 2 to 8 carbon atoms ("C 2~8 In certain embodiments, an alkynyl group contains 2 to 7 carbon atoms ("C 2~7 In certain embodiments, an alkynyl group contains 2 to 6 carbon atoms ("C 2~6 In certain embodiments, an alkynyl group contains 2 to 5 carbon atoms ("C 2~5 In certain embodiments, an alkynyl group contains 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group contains 2 to 3 carbon atoms ("C 2~3 In certain embodiments, an alkynyl group contains two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, the alkynyl group in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C2~10 It is alkynyl.

[0023] "Alkynylene" refers to a straight-chain alkynyl group, which may be substituted or unsubstituted, in which two hydrogens are removed to provide a divalent radical. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0024] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where one or more heteroatoms are inserted between a carbon atom and a parent atom, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group containing 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In certain embodiments, a heteroalkyl group is a saturated group containing 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In certain embodiments, a heteroalkyl group is a saturated group containing 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In certain embodiments, a heteroalkyl group is a saturated group containing 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In certain embodiments, a heteroalkyl group is a group containing 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In certain embodiments, a heteroalkyl group is a saturated group containing 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In certain embodiments, a heteroalkyl group is a saturated group containing 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4In certain embodiments, a heteroalkyl group is a saturated group containing 1 to 3 carbon atoms and one heteroatom ("heteroC 1~3 In certain embodiments, a heteroalkyl group is a saturated group containing 1 to 2 carbon atoms and one heteroatom ("heteroC 1~2 In certain embodiments, a heteroalkyl group is a saturated group containing 1 carbon atom and 1 heteroatom (a "heteroC1 alkyl"). In certain embodiments, a heteroalkyl group is a saturated group containing 2 to 6 carbon atoms and 1 or 2 heteroatoms (a "heteroC 2~6 Unless otherwise specified, each occurrence of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0025] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, further containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or wherein one or more heteroatoms are inserted between a carbon atom and a parent atom, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group containing 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2~10 In certain embodiments, a heteroalkenyl group contains 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In certain embodiments, a heteroalkenyl group contains 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8In certain embodiments, a heteroalkenyl group contains 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In certain embodiments, a heteroalkenyl group contains 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In certain embodiments, a heteroalkenyl group contains 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~5 In certain embodiments, a heteroalkenyl group contains 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~4 In certain embodiments, a heteroalkenyl group contains 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2~3 In certain embodiments, a heteroalkenyl group contains 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each occurrence of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0026] The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or wherein one or more heteroatoms are inserted between a carbon atom and a parent atom, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group refers to a group containing 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl"). 2~10 In certain embodiments, a heteroalkynyl group contains 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In certain embodiments, a heteroalkynyl group contains 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In certain embodiments, a heteroalkynyl group contains 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In certain embodiments, a heteroalkynyl group contains 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In certain embodiments, a heteroalkynyl group contains 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~5 In certain embodiments, a heteroalkynyl group contains 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~4 In certain embodiments, a heteroalkynyl group contains 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("heteroC 2~3 In certain embodiments, a heteroalkynyl group contains 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2~6 Unless otherwise specified, each occurrence of the heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0027] As used herein, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl groups, respectively. When a range or number of carbons is given for a particular "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbons in a divalent chain of linear carbons. An "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," or "heteroalkynylene" group can be substituted or unsubstituted with one or more substituents as described herein.

[0028] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., containing shared 6π, 10π, or 14π electrons arranged in a ring) radical containing 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group contains 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group contains 10 ring carbon atoms ("C 10aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group contains 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the bonding radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms is continued to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of the aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0029] In certain embodiments, an aryl group substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0030] Representative examples of substituted aryl include: [ka] are listed, In the formula, R 56 and R 57 may be hydrogen, and R 56 and R 57 At least one of the following is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl; or R 56 and R 57 may combine to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is an aryl, a 5- to 10-membered heteroaryl, or a substituted 5- to 10-membered heteroaryl.

[0031] Other representative aryl groups containing fused heterocyclyl groups include: [ka] where each W is C(R 66 )2, NR 66 , O, and S; each Y is selected from carbonyl, NR 66 , O and S; R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl.

[0032] "Fused aryl" refers to an aryl that contains two ring carbons that share a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0033] "Aralkyl" is a subset of alkyl and aryl, as defined herein, that refers to an alkyl group that is optionally substituted with an optionally substituted aryl group.

[0034] "Heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system containing ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (e.g., containing 6 or 10 shared π electrons arranged in a ring) ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in either or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring atoms is consecutive to indicate the number of ring atoms in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring atoms indicates the number of ring atoms in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.) and the point of attachment is on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0035] In certain embodiments, heteroaryl groups are 5-10 membered aromatic ring systems containing ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In certain embodiments, heteroaryl groups are 5-8 membered aromatic ring systems containing ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In certain embodiments, heteroaryl groups are 5-6 membered aromatic ring systems containing ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5-5 membered heteroaryl"). In certain embodiments, 5-6 membered heteroaryls contain 1-3 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl contains one to two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, a 5- to 6-membered heteroaryl contains one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of the heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0036] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0037] Representative examples of heteroaryls include: [ka] In the formula, each Y is a carbonyl, N, NR 65 , O and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl.

[0038] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an alkyl group optionally substituted by an optionally substituted heteroaryl group.

[0039] "Carbocyclyl" or "carbocycle" means a ring system containing 3 to 10 ring carbon atoms ("C 3~10 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group containing 3 to 8 ring carbon atoms ("C 3~8 In certain embodiments, a carbocyclyl group contains 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, a carbocyclyl group contains 3 to 6 ring carbon atoms ("C 3~6 In certain embodiments, a carbocyclyl group contains 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. Illustrating the above example, in certain embodiments, the carbocyclyl group is a single ring ("monocyclic carbocyclyl") or includes fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined herein, is fused to one or more aryl or heteroaryl groups and the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons is continued to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, the carbocyclyl group in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0040] In one embodiment, "carbocyclyl" is a monocyclic saturated carbocyclyl group containing 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group contains 3 to 8 ring carbon atoms ("C 3~8In some embodiments, a cycloalkyl group contains 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group contains 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group contains 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, the cycloalkyl group in each instance is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0041] "Heterocyclyl" or "heterocycle" refers to a radical of a 3- to 10-membered non-aromatic ring system containing ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or contain fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in either or both rings. "Heterocyclyl" includes ring systems in which a heterocyclyl ring, as defined herein, is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl ring or heterocyclyl ring, or in which a heterocyclyl ring, as defined herein, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such cases, the number of ring atoms is continued consecutively to indicate the number of ring atoms in the heterocyclyl ring system. Unless otherwise specified, the heterocyclyl in each instance is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0042] In certain embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system containing ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system containing ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In certain embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system containing ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In certain embodiments, a 5- to 6-membered heterocyclyl is a 1-3 ring heteroatom selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- or 6-membered heterocyclyl contains 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- or 6-membered heterocyclyl contains 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0043] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl group include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0044] Particular examples of heterocyclyl groups are illustrated by the following specific examples: [ka] In the formula, each W is CR 67 , C(R 67 )2, NR 67 , O, and S; each Y is selected from NR 67 , O and S; R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 and aryl and 5- to 10-membered heteroaryl. These heterocyclyl rings may optionally be substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. Substituents include carbonyl or thiocarbonyl, resulting in, for example, lactam and urea derivatives.

[0045] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms of the compound or group have been replaced with a heteroatom such as nitrogen, oxygen, or sulfur. Hetero may apply to any of the hydrocarbyl groups mentioned above, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl, etc., containing 1 to 5, especially 1 to 3, heteroatoms.

[0046] "Acyl" is -C(O)R 20 Refers to the radical, R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to a group of alkyl groups where R 20 is an acyl group where R is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6~C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3~C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl), where t is an integer of 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0047] "Acylamino" is -NR 22 C(O)R 23 In each case, R refers to the radical 22 and R 23are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, as defined herein, or R 22 is an amino-protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. A particularly exemplary "acylamino" group is -NR 24 C(O)-C1-C8 alkyl, -NR 24 C(O)-(CH2) t (C6~C 10 aryl), -NR 24 C(O)-(CH2) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH2) t (C3~C 10 cycloalkyl) and -NR 24 C(O)-(CH2) t (4- to 10-membered heterocyclyl), t is an integer of 0 to 4, and each R 24 independently represent H or C1-C8 alkyl. In certain embodiments, R 25 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; R 26 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl; provided that R 25 and R 26 At least one of is other than H.

[0048] "Acyloxy" is -OC(O)R 27 Refers to the radical, R 27 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 is C1-C8 alkyl substituted with halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0049] "Alkoxy" is -OR 29 R refers to the group 29is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particularly, alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particularly, alkoxy groups are lower alkoxy, i.e., alkoxy containing 1 to 6 carbon atoms. More particularly, alkoxy groups contain 1 to 4 carbon atoms.

[0050] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 A group containing one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent, selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl) and -O-(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any present aryl, heteroaryl, cycloalkyl, or heterocyclyl group may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0051] "Amino" refers to the -NH2 radical.

[0052] "Substituted amino" refers to a group of the formula -N(R 38 )2, and R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, and at least one R 38 is not hydrogen. In certain embodiments, each R 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 cycloalkyl) or -(CH2) t(4-10 membered heterocyclyl), t is an integer from 0 to 8, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups are joined to form an alkylene group.

[0053] Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl) and -NR 39 -(CH2) t (4- to 10-membered heterocyclyl), t is an integer of 0 to 4, for example, 1 or 2, and each R 39 independently represent H or C1-C8 alkyl; any alkyl group present may itself be substituted with halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0054] "Azide" refers to the -N3 radical.

[0055] "Carbamoyl" or "amido" refers to the -C(O)NH2 radical.

[0056] A "substituted carbamoyl" or "substituted amide" is a -C(O)N(R 62 )2 radicals, each R 62 independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 62 In certain embodiments, at least one of R 62 is H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, aralkyl, 5-10 membered heteroaryl and heteroaralkyl; or C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R 62 is other than H.

[0057] Exemplary "substituted carbamoyl" groups include, but are not limited to, -C(O)NR 64 -C1-C8 alkyl, -C(O)NR 64 -(CH2) t (C6~C 10 aryl), -C(O)N 64 -(CH2) t (5-10 membered heteroaryl), -C(O)NR 64 -(CH2) t (C3~C 10cycloalkyl) and -C(O)NR 64 -(CH2) t (4- to 10-membered heterocyclyl), t is an integer of 0 to 4, and each R 64 independently represent H or C1-C8 alkyl, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0058] "Carboxy" refers to the -C(O)OH radical.

[0059] "Cyano" refers to the -CN radical.

[0060] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0061] "Hydroxy" refers to the -OH radical.

[0062] "Nitro" refers to the -NO2 radical.

[0063] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0064] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0065] "Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl groups containing 3 to 10 carbon atoms and one cyclic ring or multiple fused rings, including fused and bridged ring systems, and containing at least one, and especially 1 to 2, sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[0066] "Fused cycloalkenyl" refers to a cycloalkenyl containing two ring carbon atoms which have in common a second aliphatic or aromatic ring and having olefinic unsaturation positioned so as to confer aromaticity to the cycloalkenyl ring.

[0067] "Ethenyl" refers to a substituted or unsubstituted -(C=C)-.

[0068] "Ethylene" refers to a substituted or unsubstituted --(CC)--.

[0069] "Ethynyl" refers to -(C≡C)-.

[0070] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines, such as N-methylpiperazine. Particular examples include azetidine, piperidone, and piperazone.

[0071] "Thioketo" refers to the =S group.

[0072] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted as defined herein (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that results in a stable compound upon substitution, e.g., a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group contains a substituent at one or more substitutable positions of the group, and when substituted at more than one position in a given structure, the substituents may be the same or different at each position. The term "substituted" is intended to include all permissible substituents of organic compounds, any substituents described herein that result in the formation of stable compounds. The present invention contemplates any and all such combinations to arrive at stable compounds. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0073] Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa, -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and aryl and 5- to 14-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd Is it substituted with a group? Or, two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc It is replaced by the group; R in each case aa independently, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R in each case bb are independently hydrogen, -OH, or -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bbgroups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R in each case cc are independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R in each case dd are independently halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(Rff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may be joined to form =O or =S; R in each case ee independently, C 1~6 Alkyl, C1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R in each case ff are independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R in each case gg are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be joined to form =O or =S; X - is the counter ion.

[0074] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2 Examples of the cations include sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate ion, ethanoate ion, propanoate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, etc.).

[0075] Nitrogen atoms may be substituted or unsubstituted, where valency allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined above.

[0076] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0077] Other definitions The term "pharmaceutically acceptable salt" refers to a salt that is within the scope of sound medical judgment, lacks undue toxicity, irritation, allergic response, etc., and is suitable for use in contact with the tissues of humans and lower animals, with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts obtained by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butanoate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and the like. + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, from counterions (e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates).

[0078] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., adolescents, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0079] Disease, disorder and condition are used interchangeably herein.

[0080] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a particular disease, disorder, or condition, either to lessen the severity of the disease, disorder, or condition or to slow or retard the progression of the disease, disorder, or condition ("therapeutic treatment"), and also to actions taken before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0081] Generally, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention will vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health and condition of the subject. The effective amount includes therapeutic and prophylactic treatments.

[0082] As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other therapeutic agents, provides a therapeutic effect in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0083] As used herein and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the occurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A prophylactically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other therapeutic agents, provides a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis and enhances the prophylactic efficacy of another prophylactic agent.

[0084] Detailed Description of Specific Embodiments of the Invention In the midst of their search for Org-1 analogs for NMDA modulation, the present inventors have discovered several specific combinations of elements that provide NMDA modulators with relatively superior properties, some of which are described in PCT / US2012 / 054261, incorporated herein by reference. For example, as shown in Table 1, compounds with a β-hydrogen at C5 are less desirable than compounds with an α-hydrogen at C5 or a double bond at C5-C6 due to their lack of potentiation of the NMDA receptor. 21 Removal of the methyl at C3 also results in a significant loss of NMDA receptor potentiation. Disubstitution at C3 is expected to increase the metabolic stability of these compounds and is therefore a preferred feature of the present invention. 17 Side chain fluorination has been shown to increase NMDA receptor potency and limit maximal potentiation when tested at compound concentrations as low as 1 μM. 17 Secondary or tertiary terminal alcohols in the side chain have been shown to enhance NMDA receptor potency and limit maximum potentiation when tested at compound concentrations as low as 1 μM, and are therefore a preferred feature of the present invention. Bulkier groups containing 2-3 carbons at the terminals, or groups containing fluorine substituents, are preferred. These characteristics are expected to limit the risk of inducing glutamate-induced neurotoxicity for compounds achieving greater maximum potentiation of NMDA receptors. The compounds of the present invention encompass various combinations of these specific features that result in superior NMDA modulators.

[0085] compound In one embodiment, the compound of formula (I): [ka] [In the formula, R 1 is a substituted or unsubstituted aliphatic; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted cyclopropyl or -OR A2 and RA2 is hydrogen or substituted or unsubstituted alkyl; R 3a is hydrogen or -OR A3 and R A3 is hydrogen or substituted or unsubstituted alkyl, and R 3b is hydrogen; or R 3a and R 3b connects to form an oxo (=O) group; R 4 is hydrogen, substituted or unsubstituted alkyl or halogen; X is -C(R X )2- or -O-, and R X is hydrogen or fluorine, or one R X Group and R 5b connect to form a double bond; R in each case 5a and R 5b are independently hydrogen or fluorine; R 6a is a non-hydrogen radical selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted carbocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryl groups and substituted and unsubstituted heteroaryl groups, wherein the non-hydrogen radical is optionally substituted with fluorine; R 6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; [ka] represents a single or double bond, provided that if a single bond is present, the hydrogen at C5 is in the alpha configuration; Furthermore, however, (1)R X , R 5a and R 5b at least one of is fluorine; or (2)R 6a and R6b at least one of is a non-hydrogen group substituted with fluorine; or (3)R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. and pharmaceutically acceptable salts thereof are provided herein.

[0086] As generally described herein, compounds in which the C5 hydrogen is in the β-configuration exhibit a loss of NMDA potentiation compared to compounds in which the C5 hydrogen is in the α-configuration or compounds in which a double bond is present at C5-C6. Thus, compounds of formula (I) are compounds of formulas (IA) and (IB) [ka] and pharmaceutically acceptable salts thereof.

[0087] R 1 base As generally defined herein, R 1 is a substituted or unsubstituted aliphatic, ie, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, or a substituted or unsubstituted carbocyclyl.

[0088] In certain embodiments, R 1 is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl or substituted or unsubstituted C 5~6 An exemplary R is alkyl. 1 C 1~6Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups. 1~6 alkyl (e.g., -CF3, -CH2F, -CHF2, difluoroethyl and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups 1~6 C substituted with alkyl (e.g., -CH2Cl, -CHCl2) and alkoxy groups 1~6 alkyl (e.g., —CH2OCH3, —CH2OCH2CH3, —CH2O-cyclopropyl). In certain embodiments, R 1 is a substituted alkyl, for example, R 1 is haloalkyl, alkoxyalkyl, or aminoalkyl. In certain embodiments, R 1 is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, methoxymethyl, methoxyethyl or ethoxymethyl.

[0089] In certain embodiments, R 1 is the unsubstituted C 1~3 alkyl, e.g., R 1 is -CH3, -CH2CH3 or -CH2CH2CH3.

[0090] In certain embodiments, R 1 is alkyl substituted with one or more fluorine atoms; for example, R 1 is -CH2F, -CHF2 or -CF3.

[0091] In certain embodiments, R 1 -OR means one or more A1 is an alkyl substituted with a group, and R A1 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 1 is -CH2OR A1 For example, R A1 is hydrogen, -CH3, -CH2CH3 or -CH2CH2CH3.

[0092] In certain embodiments, R 1 is a substituted or unsubstituted alkenyl, for example, a substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 3~4 Alkenyl, substituted or unsubstituted C 4~5 Alkenyl or substituted or unsubstituted C 5~6 In certain embodiments, R 1 is ethenyl (C2), propenyl (C3), or butenyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 1 is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R 1 is ethenyl.

[0093] In certain embodiments, R 1 is a substituted or unsubstituted alkynyl, for example, a substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4 Alkynyl, substituted or unsubstituted C 4~5 Alkynyl or substituted or unsubstituted C 5~6 alkynyl. Exemplary substituted or unsubstituted R 1Alkynyl groups include, but are not limited to, ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (e.g., CF), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R 1 is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. 1 is ethynyl (C2), propynyl (C3), or butynyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl. In certain embodiments, R 1 is ethynyl (C2), propynyl (C3), or butynyl (C4), substituted with a substituted phenyl. In certain embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amido. In certain embodiments, R 1 is ethynyl (C2), propynyl (C3) or butynyl (C4) substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl.

[0094] In certain embodiments, R 1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 1 is ethynyl or propynyl substituted with substituted or unsubstituted aryl. In certain embodiments, R 1is ethynyl or propynyl, unsubstituted or substituted with phenyl substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain embodiments, R 1 is ethynyl or propynyl substituted with a substituted or unsubstituted carbocyclyl. In certain embodiments, R 3a is ethynyl or propynyl substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 is ethynyl or propynyl substituted with substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is ethynyl or propynyl substituted with substituted or unsubstituted pyridinyl or pyrimidinyl. In certain embodiments, R 1 is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In certain embodiments, R 1 is ethynyl or propynyl substituted with a substituted or unsubstituted heterocyclyl. In certain embodiments, R 1 is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In certain embodiments, R 1 is propynyl or butynyl substituted with hydroxyl or alkoxy. In certain embodiments, R 1 is propynyl or butynyl substituted with methoxy or ethoxy. In certain embodiments, R 1 is ethynyl or propynyl substituted with chloro. In certain embodiments, R 1 is ethynyl or propynyl substituted with trifluoromethyl.

[0095] In certain embodiments, R 1is a substituted or unsubstituted carbocyclyl, for example, a substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 Carbocyclyl or substituted or unsubstituted C 5~6 In certain embodiments, R 1 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.

[0096] R 2 , R 3a , R 3b and R 4 base As generally defined herein, R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted cyclopropyl or -OR A2 and R A2 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halogen, for example, fluoro, chloro, bromo, or iodo. In certain embodiments, R 2 is fluoro or chloro. In certain embodiments, R 2 is a substituted or unsubstituted C 1~6 Alkyl, e.g., substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl or substituted or unsubstituted C 5~6 In certain embodiments, R 2 is -CH3, -CH2CH3, -CH2CH2CH3, or cyclopropyl. In certain embodiments, R 2 -OR A2 In certain embodiments, R A2 is hydrogen. In certain embodiments, R A2is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl or substituted or unsubstituted C 5~6 In certain embodiments, R A2 is hydrogen, -CH3, -CH2CH3 or -CH2CH2CH3, i.e., R of formula -OH, -OCH3, -OCH2CH3 or -OCH2CH2CH3 2 In certain embodiments, R 2 is a non-hydrogen substituent in the alpha conformation. In certain embodiments, R 2 is a non-hydrogen substituent in the β-configuration.

[0097] As generally defined herein, R 3a is hydrogen or -OR A3 and R A3 is hydrogen or substituted or unsubstituted alkyl, and R 3b is hydrogen or R 3a and R 3b are connected to form an oxo (=O) group.

[0098] In certain embodiments, R 3a and R 3b are both hydrogen.

[0099] In certain embodiments, R 3a and R 3b are connected to form an oxo (=O) group.

[0100] In certain embodiments, R 3a HA-OR A3 and R 3b is hydrogen. In certain embodiments, R 3a HA-OR A3 and R 3a is in the α or β conformation. In certain embodiments, R3a HA-OR A3 and R 3a is in the alpha conformation. In certain embodiments, R 3a HA-OR A3 and R 3a is in the β conformation. In certain embodiments, R A3 is hydrogen. In certain embodiments, R A3 is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl or substituted or unsubstituted C 5~6 In certain embodiments, R A3 is hydrogen, -CH3, -CH2CH3 or -CH2CH2CH3, i.e., R of formula -OH, -OCH3, -OCH2CH3 or -OCH2CH2CH3 3a It provides the foundation.

[0101] As generally defined herein, R 4 is hydrogen, substituted or unsubstituted alkyl, or halogen. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halogen, for example, fluoro. In certain embodiments, R 4 is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl or substituted or unsubstituted C 5~6 In certain embodiments, R 4 is C alkyl, e.g., —CH or —CF. In certain embodiments, R 4 is hydrogen, —CH or —F. In certain embodiments, [ka] represents a single bond, and R 4 is a non-hydrogen substituent in the alpha conformation. In certain embodiments, [ka] represents a single bond, and R 4 is a non-hydrogen substituent in the β-configuration.

[0102] X, R 5a , R 5b , R 6a and R 6b base As generally defined herein, X is —C(R X )2- or -O-, and R X is hydrogen or fluorine, or one R X Group and R 5b are connected to form a double bond; each R 5a and R 5b are independently hydrogen or fluorine; R 6a is a non-hydrogen radical selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl radicals, which non-hydrogen radicals are optionally substituted with fluorine; R 6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; provided that (1) R X , R 5a and R 5b at least one of R is fluorine; or (2) R 6a and R 6b at least one of R is a non-hydrogen group substituted with fluorine; or (3) R 6a is a non-hydrogen group containing 2 to 10 carbon atoms.

[0103] In certain embodiments, X is -O-. In certain embodiments, X is -CH2-. In certain embodiments, X is -CF2-.

[0104] In certain embodiments, R 5a and R 5b At least one of R is hydrogen. 5a and R 5b At least one of R is fluorine. 5a and R 5b are both hydrogen. In certain embodiments, R 5a and R 5b are both fluorine. In certain embodiments, R X and R 5b are connected to form a double bond, for example, a cis or trans double bond.

[0105] In certain embodiments, R 6a is a non-hydrogen group, as described herein, that is not substituted with fluorine. In certain embodiments, R 6a is substituted or unsubstituted alkyl (e.g., -CH, -CHCH, -CH(CH)), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl (e.g., isopropanol). In certain embodiments, R 6a is a non-hydrogen group, as described herein, substituted with fluorine.

[0106] In certain embodiments, R 6a is a non-hydrogen group as described herein, and R 6b is hydrogen. In certain embodiments, R 6a is a non-hydrogen group as described herein, and R 6b is a substituted or unsubstituted alkyl group, optionally substituted with fluorine. In certain embodiments, R 6b is an alkyl group that is not substituted with fluorine. In certain embodiments, R6a is a fluorine-substituted alkyl group.

[0107] In certain embodiments, R 6b is hydrogen. In certain embodiments, R 6b is a substituted or unsubstituted alkyl optionally substituted with fluorine, for example, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl or substituted or unsubstituted C 5~6 In certain embodiments, R 6b is C1 alkyl optionally substituted with fluorine, for example, -CH3 or -CF3.

[0108] In certain embodiments, R 6a is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 Alkyl or substituted or unsubstituted C 5~6 An exemplary R is alkyl. 6a C 1~6Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), substituted or unsubstituted isopropyl (C3), substituted or unsubstituted n-butyl (C4), substituted or unsubstituted tert-butyl (C4), substituted or unsubstituted sec-butyl (C4), substituted or unsubstituted isobutyl (C4), substituted or unsubstituted n-pentyl (C5), substituted or unsubstituted 3-pentanyl (C5), substituted or unsubstituted amyl (C5), substituted or unsubstituted neopentyl (C5), substituted or unsubstituted 3-methyl-2-butanyl (C5), substituted or unsubstituted tertiary amyl (C5), and substituted or unsubstituted n-hexyl (C6). In certain embodiments, R 6a is alkyl substituted with one or more fluorines, e.g., 1, 2, 3, 4, or more fluorines, as described above. In certain embodiments, R 6a is —CF, —CHF, —CHF, difluoroethyl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl). In certain embodiments, R 6a is one or more -OR as described above A6 is an alkyl substituted with a group, and R A6 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 6a is -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 , for example, -CH2OCH3, -CH2CH2OCH3 or -CH2CH2CH2OCH3.

[0109] In certain embodiments, R 6a is a substituted or unsubstituted alkenyl optionally substituted with fluorine, for example, a substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 3~4 Alkenyl, substituted or unsubstituted C 4~5 Alkenyl or substituted or unsubstituted C 5~6In certain embodiments, R 6a is a substituted or unsubstituted vinyl (C2) or a substituted or unsubstituted allyl (C3)

[0110] In certain embodiments, R 6a is a substituted or unsubstituted alkynyl optionally substituted with fluorine, for example, a substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4 Alkynyl, substituted or unsubstituted C 4~5 Alkynyl or substituted or unsubstituted C 5~6 In certain embodiments, R 6a is a substituted or unsubstituted ethynyl (C2) or a substituted or unsubstituted propargyl (C3).

[0111] In certain embodiments, R 6a is a substituted or unsubstituted carbocyclyl optionally substituted with fluorine, for example, a substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 Carbocyclyl or substituted or unsubstituted C 5~6 In certain embodiments, R 6a is a substituted or unsubstituted cyclopropyl.

[0112] In certain embodiments, R 6a is a substituted or unsubstituted heterocyclyl optionally substituted by fluorine, for example, a substituted or unsubstituted C 3~6 Heterocyclyl, substituted or unsubstituted C 3~4 Heterocyclyl, substituted or unsubstituted C 4~5 Heterocyclyl or substituted or unsubstituted C 5~6 It is a heterocyclyl.

[0113] In certain embodiments, R 6ais a substituted or unsubstituted aryl, optionally substituted with fluorine, for example, a substituted or unsubstituted phenyl.

[0114] In certain embodiments, R 6a is a substituted or unsubstituted heteroaryl optionally substituted with fluorine, for example, an optionally substituted 5- or 6-membered heteroaryl.

[0115] In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms, e.g., 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms (inclusive). For example, in certain embodiments, R 6a is a substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 2~3 It is an alkynyl or a substituted or unsubstituted C3 carbocyclyl.

[0116] In certain embodiments, R X , R 5a and R 5b at least one of R is fluorine; or R 6a and R 6b at least one of R is a non-hydrogen group substituted with fluorine; 6a is a substituted or unsubstituted C 1~3 Alkyl, substituted or unsubstituted C 1~3 Alkenyl, substituted or unsubstituted C 1~3 It is an alkynyl or a substituted or unsubstituted C3 carbocyclyl.

[0117] In certain embodiments, R 6a and R 6b are the same group. In certain embodiments, R 6a and R 6b are different groups, and R 6a The carbon to which R is attached is in the (S) or (R) configuration. 6ais in the (S) configuration. 6a The carbon to which is attached is in the (R) configuration. 6a is -CF3 and R 6b is hydrogen or C 1~4 In certain embodiments, R 6a is a non-hydrogen group substituted with fluorine, and R 6b is -CH3. In certain embodiments, R 6a -OR means one or more A6 is substituted with an R A6 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 6a is a substituted or unsubstituted C 2~4 Alkyl, substituted or unsubstituted C 2~3 Alkenyl, substituted or unsubstituted C 2~3 alkynyl or substituted or unsubstituted C3 carbocyclyl, and R 6b is -CH3. In certain embodiments, R 6a is the unsubstituted C 2~4 Alkyl, unsubstituted C 2~3 Alkenyl or unsubstituted C 2~3 alkynyl or unsubstituted C3 carbocyclyl, and R 6b is -CH3. In certain embodiments, R 6a is a non-hydrogen group substituted with fluorine, and R 6b is -CH3.

[0118] Various combinations of specific embodiments Various combinations of the specific embodiments are further contemplated herein.

[0119] For example, in certain embodiments, X is —CH— and R 5a and R 5b are both hydrogen, and the compound of formula (Ia) [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. 6a and R 6b At least one of R is a non-hydrogen group substituted with fluorine. 6a is in the (S) configuration. 6a The carbon to which is attached is in the (R) configuration. 6a is methyl (C1) optionally substituted with one or more fluorines, e.g., —CH3 or —CF3. In certain embodiments, R 6a is substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R 6a is -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 In certain embodiments, R 6a is substituted or unsubstituted vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R 6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R 6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R 6b is hydrogen. In certain embodiments, R 6b is —CH or —CF. In certain embodiments, [ka] represents a single bond and the hydrogen at C5 is alpha. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 1 is -CH3 or -CH2CH3. In certain embodiments, R 2 is hydrogen, —OH, —OCH, —OCHCH, —OCHCH, —CH, —CHCH, —CHCH, cyclopropyl, fluoro, or chloro. 2 is a non-hydrogen substituent in the alpha conformation. In certain embodiments, R 2 is a non-hydrogen substituent in the β-configuration. In certain embodiments, R 3a and R 3b In certain embodiments, R 3a and R 3b are connected to form =O (oxo). In certain embodiments, R 4 is hydrogen.

[0120] In certain embodiments, X is -CH- and R 5a and R 5b are both fluorine, and the compound of formula (Ib) [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. 6a and R 6b At least one of R is a non-hydrogen group substituted with fluorine. 6a The carbon to which R is attached is in the (S) configuration. 6a The carbon to which R is attached is in the (R) configuration. 6a is methyl (C1) optionally substituted with one or more fluorines, e.g., —CH3 or —CF3. In certain embodiments, R 6ais substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R 6a is -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 In certain embodiments, R 6a is substituted or unsubstituted vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R 6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R 6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R 6b is hydrogen. In certain embodiments, R 6b is —CH or —CF. In certain embodiments, [ka] represents a single bond and the hydrogen at C5 is alpha. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 1 is -CH3 or -CH2CH3. In certain embodiments, R 2 is hydrogen, —OH, —OCH, —OCHCH, —OCHCH, —CH, —CHCH, —CHCH, cyclopropyl, fluoro, or chloro. 2 is a non-hydrogen substituent in the alpha conformation. In certain embodiments, R 2 is a non-hydrogen substituent in the β-configuration. In certain embodiments, R 3a and R 3b are both hydrogen. In certain embodiments, R 3a and R 3bis connected to form =O (oxo). In certain embodiments, R 4 is hydrogen.

[0121] In certain embodiments, X is —C(R X )2- and one R X Groups and R 5b to form a trans double bond, and a compound of formula (Ic) [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. 6a and R 6b At least one of R is a non-hydrogen group substituted with fluorine. 6a The carbon to which R is attached is in the (S) configuration. 6a The carbon to which R is attached is in the (R) configuration. 6a is methyl (C1) optionally substituted with one or more fluorines, e.g., —CH3 or —CF3. In certain embodiments, R 6a is substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R 6a is -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 In certain embodiments, R 6a is substituted or unsubstituted vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R 6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R 6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R 6b is hydrogen. In certain embodiments, R6b is —CH or —CF. In certain embodiments, [ka] represents a single bond and the hydrogen at C5 is alpha. In certain embodiments, [ka] is a double bond. In certain embodiments, R 1 is -CH3 or -CH2CH3. In certain embodiments, R 2 is hydrogen, —OH, —OCH, —OCHCH, —OCHCH, —CH, —CHCH, —CHCH, cyclopropyl, fluoro, or chloro. 2 is a non-hydrogen substituent in the alpha conformation. In certain embodiments, R 2 is a non-hydrogen substituent in the β-configuration. In certain embodiments, R 3a and R 3b are both hydrogen. In certain embodiments, R 3a and R 3b are connected to form =O (oxo). In certain embodiments, R 4 is hydrogen.

[0122] In certain embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. 6a and R 6b At least one of R is a non-hydrogen group substituted with fluorine. 6aThe carbon to which R is attached is in the (S) configuration. 6a The carbon to which R is attached is in the (R) configuration. 6a is methyl (C1) optionally substituted with one or more fluorines, e.g., —CH3 or —CF3. In certain embodiments, R 6a is substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R 6a is -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 In certain embodiments, R 6a is substituted or unsubstituted vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R 6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R 6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R 6b is hydrogen. In certain embodiments, R 6b is —CH or —CF. In certain embodiments, [ka] represents a single bond and the hydrogen at C5 is alpha. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 1 is -CH3 or -CH2CH3.

[0123] In certain embodiments, the compound of formula (I) is a compound of formula (II-A): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. 6a and R 6b At least one of R is a non-hydrogen group substituted with fluorine. 6a The carbon to which R is attached is in the (S) configuration. 6a The carbon to which R is attached is in the (R) configuration. 6a is methyl (C1) optionally substituted with one or more fluorines, e.g., —CH3 or —CF3. In certain embodiments, R 6a is substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R 6a is -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 In certain embodiments, R 6a is substituted or unsubstituted vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R 6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R 6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R 6b is hydrogen. In certain embodiments, R 6b is —CH or —CF. In certain embodiments, R 1 is -CH3 or -CH2CH3.

[0124] In certain embodiments, the compound of formula (I) is a compound of formula (II-B): [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. 6a and R 6b At least one of R is a non-hydrogen group substituted with fluorine. 6a is in the (S) configuration. 6a is in the (R) configuration. 6a is methyl (C1) optionally substituted with one or more fluorines, e.g., —CH3 or —CF3. In certain embodiments, R 6a is substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R 6a is -CH2OR A6 , -CH2CH2OR A6 or -CH2CH2CH2OR A6 In certain embodiments, R 6a is substituted or unsubstituted vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R 6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3). In certain embodiments, R 6a is substituted or unsubstituted cyclopropyl. In certain embodiments, R 6b is hydrogen. In certain embodiments, R 6b is —CH or —CF. In certain embodiments, R 1 is -CH3 or -CH2CH3.

[0125] In certain embodiments, the compound of formula (I) is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts thereof.

[0126] Pharmaceutical Composition In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I).

[0127] When used as a pharmaceutical, the compounds provided herein are typically administered in the form of pharmaceutical compositions.Such compositions can be prepared in a manner well known in the pharmaceutical field and comprise at least one active compound.

[0128] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, an oral or a topical carrier.

[0129] The present invention also relates to a compound of formula (I) or a pharmaceutical composition for use as a medicament or pharmaceutical.

[0130] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of compound actually administered will typically be determined by a physician in view of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0131] The pharmaceutical compositions provided herein can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of administration, the compounds provided herein are preferably formulated as injectable or oral compositions, for example, as ointments, lotions, or as patches for transdermal administration.

[0132] Compositions for oral administration may be in the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as bulk dosages for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that serve to form the desired dosage form.

[0133] Liquid forms suitable for oral administration will include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. 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, Primo Gel, 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 flavor.

[0134] Injectable compositions are typically based on 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 about 0.05 to 10% by weight, with the remainder being the injectable carrier, etc.

[0135] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient in an amount generally ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, more 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 an ointment, the active ingredient may be combined with a compatible ointment base, typically a paraffinic or aqueous base. Alternatively, the active ingredient may be formulated in a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance dermal penetration of the active ingredient or stability of the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0136] The compounds provided herein can also be administered by a transdermal device. Thus, transdermal administration can be accomplished using a patch of reservoir or porous membrane, or a variety of solid matrix patches.

[0137] The above elements of orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0138] The above elements of orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described 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.

[0139] 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.

[0140] The present invention also relates to pharmaceutically acceptable formulations of compounds of Formula (I). In one embodiment, the formulation includes water. In another embodiment, the formulation includes 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, each optionally containing one or more substituents on the linked sugar moieties, including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation includes hexapropyl-β-cyclodextrin. In even more specific embodiments, the formulation includes hexapropyl-β-cyclodextrin (10-50% in water).

[0141] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of formula (I). Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, hydrogensulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.

[0142] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with the present invention, but the present invention is not limited to the following pharmaceutical compositions.

[0143] Exemplary Formulation 1—Tablets: A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in an approximately 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. This mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.

[0144] Exemplary Formulation 2—Capsules: A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a starch diluent in an approximately 1:1 weight ratio, and the mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

[0145] Exemplary Formulation 3—Liquid: The compound of Formula (I) or a pharmaceutically acceptable salt thereof (125 mg) may be mixed with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture may be blended, passed through a No. 10 mesh US sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added, with stirring. Sufficient water may then be added to produce a product with a total volume of 5 mL.

[0146] Exemplary Formulation 4—Tablets: A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in an approximately 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. This mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0147] Exemplary Formulation 5—Injection: A compound of formula (I) or a pharmaceutically acceptable salt thereof may be dissolved or suspended in an injectable aqueous medium of buffered saline to a concentration of about 5 mg / mL.

[0148] Exemplary Formulation 6—Tablets: A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in an approximately 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. This mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

[0149] Exemplary Formulation 7—Tablets: v may be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. This mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

[0150] Exemplary Formulation 8—Tablets: A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in an approximately 1:2 weight ratio. A small 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.

[0151] Exemplary Formulation 9—Tablets: A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in an approximately 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. This mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

[0152] Exemplary Formulation 10 - Tablets: A compound of Formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in an approximately 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. This mixture is formed into 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

[0153] Injection dosages range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour for about 1 to about 120 hours, particularly 24 to 96 hours in total. Pre-loaded boluses of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve sufficient steady-state levels. The maximum total dosage is expected to not exceed about 2 g / day for a 40-80 kg human patient.

[0154] For the prevention and / or treatment of long-term conditions, treatment regimens typically extend over several months or years, with oral administration being preferred for patient convenience and tolerance. For oral administration, oral administration 1 to 5 times daily, particularly 2 to 4 times daily, typically 3 times daily, is a typical regimen. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, with preferred dosages being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0155] Transdermal dosages are generally selected to provide blood levels equivalent to or less than those achieved with injection dosages.

[0156] When used to prevent the onset of CNS disorders, the compounds provided herein are typically administered in the dosages described above to subjects at risk of developing the condition under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include those who have a family history of the condition, or those who have been identified by genetic testing or screening as being particularly susceptible to the condition.

[0157] Methods of Treatment and Use The compounds of formula (I) and pharmaceutically acceptable salts thereof, as described herein, are generally designed to modulate NMDA function, thus acting as neurostimulant steroids for the treatment and prevention of CNS-related conditions in a subject. Modulation, as used herein, refers to the inhibition or enhancement of NMDA receptor function. In certain embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof may act as NMDA negative allosteric modulators (NAMs) and inhibit NMDA receptor function. In certain embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof may act as NMDA positive allosteric modulators (PAMs) and enhance NMDA receptor function.

[0158] Exemplary CNS conditions associated with modulation of NMDA include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic 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, bipolar disorder, and dysthymic disorder), schizophrenia or other psychiatric disorders (including schizoaffective disorder), sleep disorders (including insomnia), chemical-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to Shank group proteins), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy, e.g., Dravet 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 formula (I) or a pharmaceutically acceptable salt thereof can be used to induce sedation or anesthesia. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for treating or preventing adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychiatric disorders, sleep disorders, chemical-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, pain, seizure disorders, stroke, traumatic brain injury, movement disorders, and tinnitus.

[0159] In another aspect, there is provided a method of treating or preventing brain excitation in a subject susceptible to or afflicted with a condition associated with brain excitation, comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0160] In yet another aspect, the present invention provides a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof with another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or in combination with other agents. The administration of the combination can proceed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous and alternating administration. [Example]

[0161] 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 provided to illustrate the compounds, pharmaceutical compositions and methods provided herein, and should not be construed as in any way limiting their scope.

[0162] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, and it is understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0163] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesired reactions.The selection of suitable protecting groups for certain functional groups, and the conditions suitable for protection and deprotection are well known in the art.For example, many protecting groups and their introduction and removal are described in TW Greene and PG M Buts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0164] 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 for the preparation of representative substituted biaryl amides listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0165] General method for supercritical fluid chromatography (SFC): A Thar 200 preparative SFC system equipped with a ChiralPak AD-10 μM, 200 x 50 mm ID was used for SFC purification. Compounds were separated using a mixture of carbon dioxide and methanol or ethanol (e.g., 20-35% methanol or ethanol and 0.1% ammonium hydroxide) at flow rates of 55-200 mL / min, monitored at 220 nm.

[0166] After SFC chromatographic separation, one pure isomer was obtained, and two isomers were obtained with a diastereomeric ratio of ≥95:5 as determined by SFC chromatography.

[0167] The conformations of the steroid C-24 stereocenter of the 1-13 and 1-14 and 2-20 and 2-21 isomers were determined by the Mosher method (Dale, JA, Dull, DL, and Mosher, HS (1969) J. Org. Chem. 34, 2543). The C-24 conformations of subsequent derivatives using such intermediates for Examples 1-15 and 1-17 were therefore assigned.

[0168] For all other diastereomers, the stereocenter at C-24 was not determined by the Mosher method, and the first-eluting diastereomer from SFC was tentatively assigned to be connected in the (R) configuration at C-24, while the second-eluting diastereomer from SFC was tentatively assigned to be connected in the (S) configuration at C-24. This assignment was not definitively confirmed by the Mosher method or any other technique. Example 1 [ka] [ka]

[0169] Preparation of Compound 1-2. To a solution of ketone 1-1 (50.0 g, 0.17 mol) and ethylene glycol (62 mL) in toluene (600 mL) was added p-toluenesulfonic acid (1.4 g, 7.28 mmol). The reaction mixture was refluxed overnight with a Dean-Stark trap. The mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), and washed with saturated aqueous sodium bicarbonate (2 x 300 mL) and brine (2 x 300 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give crude product 1-2 (64.0 g, 100%), which was used directly in the next step without further purification. 1H NMR:(400MHz,CDCl3)δ 5.35(d,J=5.6Hz,1H),3.97-3.82(m,4H),3.59-3.47(m,1H),2.34-2.21(m,2H),2.06-1.94(m,2H),1.90-1.74(m,3H),1. 73-1.64(m,1H),1.63-1.33(m,10H),1.32-1.19(m,1H),1.14-1.03(m,1H),1.01(s,3H),0.99-0.93(m,1H),0.86(s,3H).

[0170] Preparation of Compound 1-3. To a solution of compound 1-2 (32 g, 96 mmol) in dry CHCl (1200 mL) was added Dess-Martin reagent (81 g, 192 mmol) in portions at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous NaHCO / NaSO = 1:3 (1 L). The organic phase was washed with brine (500 mL), dried over NaSO, and the solvent was evaporated to give crude product 1-3 (33.0 g, 100%), which was used directly in the next step without further purification. 1 H NMR:(400MHz,CDCl3)δ 5.34(d,J=5.2Hz,1H),3.77-4.00(m,4H),3.19-3.39(m,1H),2.83(dd,J=16.44,2.13Hz,1H),2.38-2.59(m,1H),2.21-2.37(m,1H),1.95-2 .09(m,3H),1.54-1.73(m,4H),1.74-1.90(m,2H),1.37-1.51(m,3H), 1.21-1.34(m,2H),1.19(s,3H),0.98-1.12(m,1H),0.83-0.93(m,3H).

[0171] Preparation of MAD. To a solution of 2,6-di-tert-butyl-4-methylphenol (40 g, 180 mmol) in toluene (200 mL) was added AlMe3 solution (45 mL, 90 mmol, 2 M in hexane) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and used in the next step as a toluene solution of MAD without further purification.

[0172] Preparation of Compound 1-4. To a solution of MAD (90 mmol, freshly prepared) in toluene (200 mL), a solution of compound 1-3 (10 g, 30 mmol) in toluene (80 mL) was added dropwise at −78°C over 1 h under nitrogen. The reaction mixture was then stirred for 30 min, and a CHClMgBr solution (30 mL, 90 mmol, 1.0 M in toluene) was added dropwise at −78°C. The reaction mixture was warmed to −40°C and stirred at this temperature for 3 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (150 mL × 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give compound 1-4 (4 g, 38%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),3.75-4.04(m,4H),2.42(d,J=13.6Hz,1H),1.88-2.12(m,3H),1.73-1.86(m,2H),1.64-1.72(m,2H),1.52-1. 63(m,4H),1.35-1.51(m,4H),1.19-1.32(m,1H),1.12-1.18(m,1H),1.10(s,3H),0.99-1.03(m,3H),0.92-0.98(m,1H),0.86(s,3H).

[0173] Preparation of Compound 1-5. To a solution of compound 1-4 (6.0 g, 17.3 mmol) in THF (200 mL), aqueous HCl (35 mL, 1 M) and acetone (35 mL) were added. The reaction mixture was stirred at room temperature at 20 °C. TLC (petroleum ether: ethyl acetate = 3:1) showed that the reaction was complete. The reaction mixture was then diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO (200 mL), dried over NaSO, and evaporated under reduced pressure to give 1-5 (5.2 g, 99.2%). 1H NMR:(400MHz,CDCl3)δ 5.27(d,J=6.8Hz,1H),2.45-2.35(m,2H),2.09-1.84(m,4H),1.82-1.57(m,6H) ,1.50-1.35(m,4H),1.26-1.08(m,4H),1.05(s,3H),0.95(s,3H),0.86(s,3H).

[0174] Preparation of Compound 1-6. To a solution of Ph3PEtBr (12.25 g, 33.00 mmol) in dry THF (15 mL) was added dropwise a solution of t-BuOK (3.70 g, 33.00 mmol) in dry THF (10 mL) at 0 °C under N2. The mixture was stirred at room temperature for 1.5 h. Then, a solution of 1-5 (1.00 g, 3.31 mmol) in THF (10 mL) was added dropwise, and the resulting mixture was stirred at 70 °C for 4 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was completely consumed. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate=12:1) to give 1-6 (900 mg, 90.9%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.32(d,J=5.2Hz,1H),5.15-5.12(m,1H),2.44-2.30(m,3H),2.29-2.21(m,1H),2.05-1.97(m,2H) ,1.81-1.45(m,14H),1.30-1.15(m,3H),1.12(s,3H),1.02(s,3H),0.95-1.01(m,1H),0.90(s,3H).

[0175] Preparation of Compound 1-7. To a solution of compound 1-6 (1.00 g, 3.20 mmol) and methyl propionate (0.67 g, 8.00 mmol) in dry CHCl (15 mL) was added EtAlCl solution (12.8 mL, 12.8 mmol, 1 M in toluene) dropwise with stirring at 0 °C. The reaction was then warmed to room temperature and stirred for 20 h. TLC (petroleum ether:ethyl acetate = 5:1) showed complete consumption of the starting material. The mixture was quenched with saturated aqueous NaHCO (30 mL) and extracted with CHCl (2 x 30 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 1-7 (1.00 g, 78.7%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 6.97-6.91(m,1H)5.82(d,J=16Hz,1H),5.42-5.41(m,1H),5.32(d,J=5.2Hz,1H),3.73(s,3H),3.04-3.00(m,1H),2.43(d,J=12.8Hz,1H),2 .11-1.97(m,3H),1.88-1.50(m,12H),1.40-1.20(m,3H),1.21-1.26( m,1H),1.18(d,J=6.78Hz,3H),1.12(s,3H),1.04(s,3H),0.82(s,3H).

[0176] Preparation of Compound 1-8. To a solution of compound 1-7 (1.75 g, 4.4 mmol) in dry THF (20 mL) was added DIBAL-H (1 M in THF, 22 mL, 22.0 mmol) dropwise under nitrogen at −78° C. The reaction mixture was warmed to 30° C. and then stirred at 30° C. for 2 h. The reaction was quenched by adding HO (2 mL), diluted with EtOAc (200 mL), dried over anhydrous NaSO, filtered through a Celite pad, and the pad was washed with EtOAc (50 mL × 3). The combined filtrate was concentrated under reduced pressure to give crude product 1-8 (1.6 g, 98%), which was used directly in the next step without further purification.

[0177] Preparation of compound 1-9. A mixture of 1-8 (1.6 g, 4.3 mmol) and MnO (7.5 g, 86.0 mmol) in CHCl (50 mL) was stirred at 30 °C for 20 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with CHCl (50 mL x 3). The combined filtrate was concentrated to dryness to give crude product 1-9 (1.3 g, 82%), which was used directly in the next step without purification. 1 H NMR: (400 MHz, CDCl3) δ 9.54(d,J=7.6Hz,1H),6.84-6.78(dd,J1=15.6Hz,J2=7.6Hz,1H),5.54-5.49( dd,J1=15.6Hz,J2=7.6Hz,1H),5.45-5.44(m,1H),5.32(d,J=5.2Hz,1H),3.19- 3.12(m,1H),2.42(d,J=12.8Hz,1H),2.14-2.08(m,1H),2.00-1.52(m,13H),1. 42-1.35(m,3H),1.24(d,J=6.8Hz,3H),1.12(s,3H),1.05(s,3H),0.80(s,3H).

[0178] Preparation of Compound 1-10. To a suspension of 1-9 (600 mg, 1.63 mmol) and CsF (120 mg, 0.82 mmol) in toluene / THF (18 mL, 8 / 1) was added TMSCF3 (2.4 mL, 16.3 mmol), and the mixture was stirred at room temperature and 20 °C under nitrogen. TLC (petroleum ether:ethyl acetate = 3 / 1) showed that the starting material was completely consumed. TBAF solution (6.8 mL, 1 M in THF) was added, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with MTBE (200 mL), washed with saturated NaHCO3 solution (30 mL x 3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12 / 1) to give 1-10 (300 mg, 42%) as a white solid. 1H NMR:(400MHz,CDCl3)δ 5.97-5.91(dd,J1=15.6Hz,J2=7.6Hz,1H),5.54-5.49(dd,J1=15.6Hz,J2=6.8Hz,1H), 5.42-5.38(m,1H),5.30(d,J=5.2Hz,1H),4.44-4.36(m,1H),2.97-2.94(m,1H),2.42(d ,J=12.0Hz,1H),2.01-1.98(m,2H),1.88-1.64(m,6H),1.40-1.32(m,3H),1.26-1.21(m ,2H),1.17(d,J=6.8Hz,3H),1.12(s,3H),1.05(s,3H),1.00-0.95(m,2H),0.79(s,3H).

[0179] Preparation of Compound 1-11. A mixture of 1-10 (40 mg, 0.09 mmol) and 5% Pd / C (10 mg) in EA (10 mL) was hydrogenated at 1 atm hydrogen pressure at 30° C. for 2 hours. The reaction mixture was filtered through a Celite pad, and the pad was washed with EA (10 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: PE / EA = 8 / 1) to give 1-11 (20 mg, 50%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 5.31(d,J=5.2Hz,1H),3.87-3.86(m,1H),2.42(d,J=12.8Hz,1H),2.15-2.12(m,1H),2.05-1.96(m,3H),1.86-1. 41(m,16H),1.38-1.11(m,5H),1.11(s,3H),1.08-1.04(m,1H),1.01(s,3H),0.95(d,J=6.6Hz,3H),0.69(s,3H).

[0180] Preparation of Compounds 1-13 and 1-14. 1-13 (120 mg, 40%) and 1-14 (120 mg, 40%) were obtained from 1-10 (300 mg, 0.814 mmol) by SFC purification. The structures of 1-13 and 1-14 were confirmed by the Mosher method.

[0181] Preparation of Compound 1-15. A mixture of 1-13 (120 mg, 0.27 mmol) and 5% Pd / C (20 mg) in EtOAc (10 mL) was hydrogenated with H (1 atm) at room temperature for 20 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (10 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8 / 1) to give 1-15 (70 mg, 59%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),4.00-3.90(m,1H),2.42(d,J=13.2Hz,1H),2.02-1.29(m,18H ),1.28-1.08(m,6H),1.03(s,3H),1.02(s,3H),0.97(d,J=6.8Hz,3H),0.73(s,3H).

[0182] Preparation of Compound 1-17. A mixture of 1-14 (120 mg, 0.27 mmol) and 5% Pd / C (20 mg) in EtOAc (10 mL) was hydrogenated with H (1 atm) at room temperature for 20 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (10 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8 / 1) to give 1-17 (71 mg, 59%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.27(d,J=5.6Hz,1H),4.00-3.90(m,1H),2.42(d,J=13.2Hz,1H),2.03-1.28(m,19H ),1.25-1.03(m,5H),1.03(s,3H),1.02(s,3H),0.97(d,J=6.4Hz,3H),0.73(s,3H). Example 2 [ka] [ka]

[0183] Preparation of 2-2. Under nitrogen, a solution of 2-1 (4 g, 9.62 mmol) in toluene (20 mL) was added dropwise to a solution of MAD (28.87 mmol, freshly prepared) in toluene (20 mL) at −78°C over 1 h. The reaction mixture was then stirred for 30 min, and EtMgBr solution (29 mL, 28.87 mmol, 1.0 M in toluene) was added dropwise at −78°C. The reaction mixture was warmed to −40°C and stirred at this temperature for 3 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (150 mL × 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give product 2-2 (2.0 g, 47.6%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.28(d,J=5.2Hz,1H),3.69(s,3H),3.17(s,3H),2.45-2.34(m,3H),2.04-1.95(m,3H),1.94-1.61(m,4H),1.62-1.6 0(m,2H),1.53-1.26(m,10H),1.19-1.01(m,4H),1.10(s,3H),0.98-0.90(m,4H),0.85(t,J=6.8Hz,3H),0.68(s,3H).

[0184] Preparation of 2-3. 2-2 (2.0 g, 4.48 mmol) was added to a suspension of LiAlH (852.6 mg, 22.43 mmol) in THF (20 mL) at −78° C., and the solution was then stirred at −78° C. for 2 h. The mixture was poured into saturated aqueous NaOH (2 mL) and extracted with EtOAc (50 mL × 2). The combined organic phase was dried over NaSO, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to give product 2-3 (600 mg, 35%) as a white powder. 1H NMR:(400MHz,CDCl3)δ 9.78(s,1H),5.28(d,J=5.2Hz,1H),2.51-2.22(m,3H),2.03-1.91(m,3H),1.89-1.73(m,3H),1.67-1.61(m,2H),1.65-1.629(m,1) H),1.50-1.21(m,10H),1.19-1.06(m,4H),1.02(s,3H),1.01-0.99(m,1H),0.98-0.93(m,4H),0.87(t,J=6.8Hz,3H),0.68(s,3H).

[0185] Preparation of 2-4. To a mixture of 2-3 (0.3 g, 0.78 mmol) and CsF (0.06 g, 0.39 mmol) in toluene / THF (18 mL, 8 / 1) was added TMSCF3 (1.2 mL, 7.8 mmol), and the reaction mixture was stirred overnight at room temperature under nitrogen. TLC (petroleum ether:ethyl acetate = 3 / 1) showed complete consumption of the starting material. TBAF solution (7.8 mL, 7.8 mmol, 1 M in THF) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with tert-butyl methyl ether (30 mL), washed with saturated aqueous NaHCO3 (3 x 10 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to give 2-4 (80 mg, 22%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.29(d,J=5.2Hz,1H),3.87-3.84(m,1H),2.36(d,J=13.2Hz,1H),2.05-1.95(m,3H),1.86-1.61 (m,6H),1.54-1.06(m,17H),1.03(s,3H),1.02-0.91(m,5H),0.85(t,J=6.8Hz,3H),0.68(s,3H).

[0186] Preparation of 2-5 and 2-6. A mixture of 2-4 (0.07 g, 0.15 mmol) and 10% Pd / C (20 mg) in EtOAc (10 mL) was hydrogenated with H (50 psi) at 50 °C for 36 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (20 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 25 / 1) to give 2-5 (25 mg, 35.7%) and 2-6 (20 mg, 28.6%) as white powders. 1 H NMR(2-5):(400MHz,CDCl3)δ 3.87-3.82(m,1H),2.05-1.94(m,2H),1.86-1.58(m,6H),1.56-1.17(m,16H),1.13-0.96(m,6H), 0.93(d,J=6.8Hz,3H),0.88(t,J=6.8Hz,3H),0.86-0.84(m,1H),0.83(s,3H),0.67-0.61(m,4H). 1 H NMR(2-6):(400MHz,CDCl3)δ 3.83-3.76(m,1H),1.95-1.52(m,10H),1.43-0.98(m,22H),0.89(s,3H),0.88-0.82(m,6H),0.59(s,3H).

[0187] Preparation of 2-14. To a solution of MAD (91 mmol, freshly prepared) in toluene (200 mL) was added dropwise a solution of compound 2-13 (10 g, 30 mmol) in toluene (80 mL) at −78 °C under nitrogen over 1 h. The reaction mixture was then stirred for 30 min, and EtMgBr solution (91 mL, 91 mmol, 1.0 M THF) was added at −78 °C. The reaction mixture was warmed to −40 °C and stirred at this temperature for 3 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (150 mL × 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give compound 2-14 (4 g, 40%) as a white powder.

[0188] Preparation of 2-15. To a solution of 2-14 (4.0 g, 111 mmol) in THF (200 mL) was added aqueous HCl (35 mL, 1 M) and acetone (35 mL). The reaction mixture was stirred at room temperature at 20 °C. TLC (petroleum ether:ethyl acetate = 3:1) showed that the reaction was complete. The reaction mixture was then diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO (200 mL), dried over NaSO, and evaporated under reduced pressure to give 2-15 (3 g, 88%) as a white solid.

[0189] Preparation of 2-16. To a solution of Ph3PEtBr (15.8 g, 42.6 mmol) in dry THF (50 mL) was added dropwise a solution of t-BuOK (4.8 g, 42.6 mmol) in dry THF (20 mL) under N2 at 0 °C. The mixture was stirred at room temperature for 1.5 h. Then, a solution of 2-15 (2.7 g, 8.5 mmol) in THF (20 mL) was added dropwise, and the resulting mixture was stirred at 80 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1) showed that the starting material was completely consumed. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1) to give 2-16 (1.8 g, 64%) as a white solid.

[0190] Preparation of 2-17. To a solution of compound 2-16 (1.8 g, 5.5 mmol) and methyl propionate (1.1 g, 13.7 mmol) in dry CHCl (20 mL) was added EtAlCl solution (22 mL, 22 mmol, 1 M in toluene) dropwise with stirring at 0 °C. The reaction was then warmed to room temperature and stirred for 20 h. TLC (petroleum ether:ethyl acetate = 5:1) showed complete consumption of the starting material. The mixture was quenched with saturated aqueous NaHCO (30 mL) and extracted with CHCl (2 x 30 mL). The combined organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 2-17 (2.0 g, 88%) as a white powder. 1 H NMR:(300MHz,CDCl3)δ 6.99-6.92(m,1H)5.84(d,J=10.5Hz,1H),5.45-5.41(m,1H),5.32(d,J=5.2Hz,1H),3.75(s,3H),3.06-2.99(m,1H),2.38(d,J=1 2.6Hz,1H),2.14-1.67(m,10H),1.54-1.25(m,7H),1.21(d,J=6.8Hz,3H),1.15-0.99(m,5H),0.87(t,J=7.2Hz,3H),0.80(s,3H).

[0191] Preparation of 2-18. To a solution of compound 2-17 (2.2 g, 5.3 mmol) in dry THF (20 mL) was added DIBAL-H (1 M in THF, 27 mL, 27.0 mmol) dropwise at −78° C. under nitrogen. The reaction mixture was warmed to 30° C. and then stirred at 30° C. for 2 h. The reaction was quenched by adding water (3 mL), diluted with EtOAc (200 mL), dried over anhydrous NaSO, filtered through a Celite pad, and the pad was washed with EtOAc (50 mL x 3). The combined filtrate was concentrated under reduced pressure to give 1.9 g of crude product, which was used directly in the next step without further purification. A mixture of the crude product (1.9 g, 4.9 mmol) and MnO (8.6 g, 98 mmol) in CHCl (50 mL) was stirred at room temperature for 20 h. The reaction mixture was filtered through a Celite pad and the pad was washed with CH2Cl2 (50 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give 2-18 (1.5 g, 79%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 9.55-9.53(m,1H),6.84-6.78(m,1H),6.15-6.09(m,1H),5.45-5.41(m,1H),5.30(d,J=5.2Hz,1H),3.15-3.14(m,1H),2.36(d,J=13.2Hz) ,1H),2.10-2.03(m,3H),1.90-1.60(m,9H),1.59-1.27(m,7H),1.24(d,J=6.8Hz,3H),1.10-1.22(m,6H),0.87-0.83(m,4H),0.80(s,3H).

[0192] Preparation of 2-19. To a suspension of 2-18 (1.5 g, 3.92 mmol) and CsF (0.3 g, 1.96 mmol) in toluene / THF (22 mL, 9 / 1) was added TMSCF3 (5.8 mL, 39.2 mmol), and the mixture was stirred at room temperature for 20 h under nitrogen. TLC (petroleum ether:ethyl acetate = 3 / 1) showed complete consumption of the starting material. TBAF solution (39.2 mL, 39.2 mmol, 1 M in THF) was added, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with MTBE (200 mL), washed with saturated NaHCO3 solution (30 mL x 3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25 / 1) to give 2-19 (0.65 g, 37%) as a white solid.

[0193] Preparation of 2-20 and 2-21. 2-20 (210 mg, 32%) and 2-21 (210 mg, 32%) were obtained from 2-19 (650 mg, 1.44 mmol) by SFC purification. The structures of 2-20 and 2-21 were confirmed by the Mosher method. 1 H NMR(2-20):(400MHz,CDCl3)δ 5.92(dd,J1=15.6Hz,J2=7.2Hz,1H),5.53(dd,J1=15.6Hz,J2=7.2Hz,1H) ,5.40-5.37(m,1H),5.30(d,J=5.2Hz,1H),4.43-4.40(m,1H),2.95-2.94( m,1H),2.37(d,J=13.6Hz,1H),2.09-1.98(m,4H),1.87-1.18(m,18H),1.1 6(d,J=6.8Hz,3H),1.12-0.97(m,6H),0.85(t,J=6.8Hz,3H),0.78(s,3H). 1H NMR(2-21):(400MHz,CDCl3)δ 5.95(dd,J1=15.6Hz,J2=7.2Hz,1H),5.53(dd,J1=15.6Hz,J2=6.8Hz,1H) ,5.39-5.36(m,1H),5.30(d,J=5.2Hz,1H),4.44-4.41(m,1H),2.99-2.92( m,1H),2.37(d,J=13.2Hz,1H),2.10-1.98(m,4H),1.87-1.25(m,18H),1.1 6(d,J=6.8Hz,3H),1.09-0.99(m,6H),0.85(t,J=7.2Hz,3H),0.80(s,3H).

[0194] Preparation of 2-7. A mixture of 2-20 (200 mg, 0.44 mmol) and 5% Pd / C (50 mg) in EtOAc (20 mL) was hydrogenated with H (1 atm) at 30 °C for 72 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (10 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25 / 1) to give crude 2-7, which was purified by preparative HPLC to give 2-7 (64 mg, 52%) as a white powder. 1 H NMR(2-7):(400MHz,CDCl3)δ 5.29(d,J=4.8Hz,1H),3.90-3.80(m,1H),2.36(d,J=13.6Hz,1H),2.05-1.60(m,11H),1.53-1 .06(m,15H),1.03(s,3H),1.02-0.89(m,5H),0.85(t,J1=14.8Hz,J2=7.2Hz,3H),0.69(s,3H).

[0195] Preparation of 2-8. A mixture of 2-21 (200 mg, 0.44 mmol) and 5% Pd / C (50 mg) in EtOAc (20 mL) was hydrogenated with H (1 atm) at 30 °C for 72 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (10 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 25 / 1) to give 2-8 (105 mg, 52%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.29(d,J=4.8Hz,1H),3.86-3.83(m,1H),2.36(d,J=13.2Hz,1H),2.05-1.95(m,4H),1.86-1.60 (m,7H),1.54-1.08(m,15H),1.03(s,3H),1.01-0.90(m,5H),0.85(t,J=6.8Hz,3H),0.68(s,3H).

[0196] Preparation of 2-10 and 2-12. A mixture of 2-8 (30 mg, 0.067 mmol) and 10% Pd / C (10 mg) in EtOAc (10 mL) was hydrogenated with H (50 psi) at 50 °C for 20 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (20 mL × 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 25 / 1) to give 2-10 (11 mg, 37%) and 2-12 (7 mg, 23%) as white powders. 1 H NMR(2-10):(400MHz,CDCl3)δ 3.85-3.82(m,1H),2.04-1.93(m,2H),1.84-1.59(m,6H),1.56-1.20(m,14H),1.14-0 .96(m,7H),0.93(d,J=6.8Hz,3H),0.88-0.84(m,4H),0.83(s,3H)0.67-0.61(m,4H). 1 H NMR (2-12): (400 MHz, CDCl3) δ 3.89-3.80(m,1H),2.08-1.93(m,2H),1.91-1.66(m,6H),1.52-1.01(m,23H),0.97(s,3H),0.95-0.90(m,6H),0.66(s,3H). Example 3 [ka]

[0197] Preparation of 3-2. To a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene / THF (20 mL, 8 / 1) was added TMSCF3 (1.53 mL, 10.35 mmol), and the mixture was stirred at room temperature and 20 °C under nitrogen. TLC (petroleum ether:ethyl acetate = 3 / 1) showed that the starting material was completely consumed. TBAF solution (6.8 mL, 1 M in THF) was added, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with MTBE (200 mL), washed with saturated aqueous NaHCO3 (30 mL x 3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to give 3-2 (220 mg, 46%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 5.31(d,J=2.0Hz,1H),2.44-2.41(m,1H),2.04-1.96(m,3H),1.81-1.67(m,5H),1.65-1.39(m,11H),1.34-1.32 (m,3H),1.31-1.25(m,1H),1.21-1.10(m,3H),1.12-0.98(m,4H),0.96(s,3H),0.98-0.90(m,4H),0.68(s,3H).

[0198] Preparation of 3-3 and 3-4. To a solution of compound 3-2 (220 mg, 0.569 mmol) in 10 mL of EtOAc was added Pd / C (20 mg), and the mixture was then stirred overnight at 50 °C under hydrogen (50 psi). The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to give the pure products 3-3 (100 mg, 38.5%) and 3-4 (51 mg, 19.3%) as white powders. 1 H NMR(3-3):(400MHz,CDCl3)δ 2.01-1.95(m,1H),1.89-1.75(m,2H),1.69-1.55(m,9H),1.52-1.43(m,5H),1.32-1.28(m,4H),1.27- 1.20(m,7H),1.17-1.08(m,4H),1.06-0.96(m,3H),0.96-0.91(m,3H),0.80(s,3H),0.68-0.49(m,4H). 1 H NMR(3-4):(400MHz,CDCl3)δ 2.01-1.95(m,1H),1.89-1.67(m,5H),1.66-1.60(m,2H),1.63-1.36(m,8H),1.35-1.31(m,4H), 1.29-1.24(m,4H),1.22(s,3H),1.28-1.06(m,6H),0.96(s,3H),0.95-0.92(m,3H),0.68(s,3H).

[0199] Preparation of 3-5 and 3-6. Compound 3-2 (1.2 g, 2.63 mmol) was separated by SFC to give products 3-5 (400 mg) and 3-6 (400 mg) as white powders (total yield: 66.7%). 1 H NMR(3-5):(400MHz,CDCl3)δ 5.32(d,J=4.0Hz,1H),2.50-2.40(m,1H),2.08-1.95(m,3H),1.90-0.90(m,35H),0.70(s,3H). 1H NMR(3-6):(400MHz,CDCl3)δ 5.32(d,J=4.0Hz,1H),2.50-2.40(m,1H),2.08-1.95(m,3H),1.90-0.92(m,35H),0.70(s,3H).

[0200] Preparation of 3-7. To a solution of compound 3-6 (300 mg, 0.66 mmol) in EtOAc (8 mL) was added Pd / C (10%, 200 mg) under N. The suspension was degassed under reduced pressure and purged with H several times. The mixture was then stirred at 50 °C under H (50 psi) for 24 h. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (50 mL x 2). The combined filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 3-7 (142 mg, 47%) as a white solid. 1 H NMR:(3-7)(400MHz,CDCl3)δ 1.96-1.92(m,1H),1.90-1.75(m,1H),1.70-1.57(m,5H),1.55-1.35(m,6H),1.30-1. 20(m,12H),1.20-1.06(m,12H),1.19-0.81(m,11H),0.80(s,3H),0.70-0.60(m,4H). 1 H NMR:(3-7A)(400MHz,CDCl3)δ 1.96-1.92(m,1H),1.90-1.75(m,3H),1.70-1.57(m,2H),1.55-1.25(m,13H),1.21-1.00(m,15H),0.96-0.86(m,8H),0.65(s,3H).

[0201] Preparation of 3-8. To a solution of compound 3-5 (300 mg, 0.66 mmol) in EtOAc (8 mL) was added Pd / C (10%, 200 mg) under N. The suspension was degassed under reduced pressure and purged with H several times. The mixture was then stirred at 50 °C under H (50 psi) for 24 h. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (50 mL × 2). The combined filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 3-8 (141.6 mg, 47%) as a white solid. 1 H NMR:(3-8)(400MHz,CDCl3)δ 1.96-1.92(m,1H),1.90-1.70(m,2H),1.69-1.57(m,5H),1.55-1.20(m,18H),1.19-0.81(m,10H),0.80(s,3H),0.70-0.60(m,4H). 1 H NMR:(3-8A)(400MHz,CDCl3)δ 1.97-1.70(m,6H),1.70-1.57(m,2H),1.50-1.30(m,13H),1.25-1.05(m,15H),1.00-0.86(m,7H),0.65(s,3H). Example 4 [ka] [ka]

[0202] Preparation of compound 4-2. To a solution of 4-1 (38 g, 101.5 mmol) in THF (400 mL) was added HATU (46.3 g, 121.8 mmol) and DIPEA (45.9 g, 355.2 mmol) at room temperature. The mixture was stirred for 1 h, and N,O-dimethylhydroxylamine hydrochloride (19.8 g, 203 mmol) was added. The mixture was stirred at room temperature for another 6 h. The reaction mixture was concentrated, poured into water, extracted with EtOAc, washed with water, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 3:1) to give the desired product 4-2 (24 g, 57%) as a white solid. 1 H NMR:(300MHz,CDCl3)δ:ppm 5.25(d,J=5.2Hz,1H),3.59(s,3H),3.46-3.37(m,1H),3.07(s,3H),2.70(s,1H),2.40-2.09(m,4H),1.92-1.63(m,6H),1. 44-1.33(m,6H),1.29-1.15(m,3H),1.11-0.93(m,5H),0.90(s,3H),0.85(d,J=6.4Hz,3H),0.82-0.78(m,1H),0.58(s,3H).

[0203] Preparation of Compound 4-3. To a solution of compound 4-2 (14 g, 33.52 mmol, 1.0 eq) in dry CHCl (600 mL) was added Dess-Martin (28 g, 67.04 mmol, 2.0 eq) in portions at 0 °C. The reaction mixture was then stirred at room temperature for 6.5 h. TLC (PE:EA = 3:1) showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous NaHCO / NaSO (1:3) (800 mL). The organic phase was washed with brine (500 mL), dried over NaSO, and the solvent was evaporated to give crude product 4-3 (14.0 g, 100%), which was used directly in the next step without further purification.

[0204] Preparation of Compound 4-4. A solution of 2,6-di-tert-butyl-4-methylphenol (44.4 g, 202 mmol) in toluene (200 mL) was stirred, and then a solution of MeAl (50.5 mL, 101.00 mmol, 2 M in hexane) was added. A freshly prepared solution of MAD (101 mmol, 3.0 eq) in toluene was stirred at room temperature for 1 hour. This solution was then added dropwise to a solution of 4-3 (14.0 g, 33.7 mmol, 1.0 eq) in toluene (10 mL) at −78°C under nitrogen. The reaction mixture was then stirred for 30 minutes, and a solution of MeMgBr (33.7 mL, 101 mmol, 3.0 eq, 3 M in ether) was added dropwise at −78°C. The reaction mixture was warmed to 25°C and stirred at this temperature for 12 hours. TLC (PE:EA = 3:1) showed complete consumption of the starting material. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 3:1) to give the pure target product (7.5 g, 52%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),3.69(s,3H),3.17(s,3H),2.50-2.30(m,3H),2.05-1.70(m,7H),1.52-1.30(m,9H),1.20-0.90(m,15H),0.68(s,3H).

[0205] Preparation of Compound 4-5. To a solution of compound 4-4 (7.5 g, 17.4 mmol, 1.0 eq) in THF (150 mL) was added MeMgBr solution (29 mL, 87 mmol, 5.0 eq, 3 M in THF) dropwise over 30 min at room temperature under nitrogen. The reaction mixture was then stirred at room temperature for 12 h. TLC (PE:EA = 1:1) showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl solution (200 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 4:1) to give product 4-5 (5.2 g, 77%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),2.50-2.30(m,3H),2.14(s,3H)2.03-1.93(m,3H),1.87-1.68(m,4H),1.60-1.18(m, 12H),1.12(s,3H),1.11-1.03(m,1H),1.01(s,3H),1.00-0.94(m,1H),0.91(d,J=6.4Hz,3H),0.68(s,3H).

[0206] Preparation of 4-6. To a solution of compound 4-5 (300 mg, 0.777 mmol, 1.0 eq) in toluene (5 mL), EtMgBr solution (4.5 mL, 4.5 mmol, 6.0 eq, 1 M in THF) was added dropwise over 10 min at room temperature under nitrogen. The reaction mixture was then stirred at room temperature for 12 h. TLC (PE:EA = 3:1) showed complete consumption of the starting material. The mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 8:1) to give product 4-6 (200 mg, 62%) as a white powder. 1H NMR:(400MHz,CDCl3)δ 5.23(d,J=5.6Hz,1H),2.40-2.30(m,1H),2.00-1.55(m,7H),1.50-1.98(m,25H),0.95(s,3H),0.94-0.80(m,8H),0.62(s,3H).

[0207] Preparation of 4-7 and 4-8. To a solution of compound 4-6 (175 mg, 0.42 mmol) in 10 mL of EtOAc was added 10% Pd / C (40 mg) under argon. The suspension was degassed under reduced pressure and purged with H2 several times. The mixture was stirred at 50 °C under H2 (50 psi) overnight. The suspension was filtered through a Celite pad, and the pad was washed with EA (20 mL x 3). The combined filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:EA = 8:1) to give 4-7 (84 mg, 48%) and 4-8 (25 mg, 14%) as a white powder. 1 H NMR(4-7):(400MHz,CDCl3)δ 1.98-1.92(m,1H),1.87-1.78(m,1H),1.70-1.60(m,2H),1.58-1.20(m,21 H),1.20-0.97(m,11H),0.95-0.82(m,7H),0.80(s,3H),0.70-0.61(m,4H). 1 H NMR(4-8):(400MHz,CDCl3)δ 2.00-1.78(m,4H),1.68-1.63(m,1H),1.57-1.55(m,1H),1.53-1.35(m,10H),1.3 2-1.12(m,16H),1.11-0.99(m,5H),0.97(s,3H),0.95-0.83(m,6H),0.67(s,3H).

[0208] Preparation of 4-9. To a solution of compound 10-12B (80 mg, 0.193 mmol) in 20 mL of EtOAc was added 20 mg of 10% Pd / C under N. The suspension was degassed under reduced pressure and purged with H several times. The mixture was then stirred at 50 °C under H (50 psi) for 12 h. The mixture was filtered through a Celite pad, and the pad was washed with EtOAc (5 mL x 2). The combined filtrate was concentrated to dryness to give the product, which was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 12:1 to 10:1) to give 4-9 (40 mg, 50%) as a white powder. 1 H NMR(4-9):(400MHz,CDCl3)δ 2.02-1.93(m,1H),1.92-1.80(m,1H),1.70-0.85(m,41H),0.82(s,3H),0.67(s,3H).

[0209] Preparation of 4-10. To a solution of compound 10-12A (80 mg, 0.193 mmol) in 20 mL of EtOAc was added 10% Pd / C (20 mg) under N. The suspension was degassed under reduced pressure and purged with H several times. The mixture was then stirred at 50 °C under H (50 psi) for 48 h. The mixture was filtered through a Celite pad, and the pad was washed with EtOAc (5 mL x 2). The combined filtrate was concentrated to dryness to give the product, which was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 12:1 to 10:1) to give 4-10 (40 mg, 50%) as a white powder. 1 H NMR(4-10):(400MHz,CDCl3)δ 2.02-1.93(m,1H),1.92-1.80(m,1H),1.70-0.85(m,41H),0.82(s,3H),0.67(s,3H).

[0210] Preparation of 4-11 and 4-12. 4-11 (100 mg, 15.38%) and 4-12 (90 mg, 13.85%) were obtained from 4-6 (600 mg, 1.55 mmol) by SFC purification. 1H NMR(Isomer 1):(400MHz,CDCl3)δ 5.30(m,1H),2.43-2.40(d,J=12.4Hz,1H),2.14-1.99(m,3H),1.96-1.68(m,3H),1.68-1.52(m,5H),1 .51-1.24(m,13H),1.19-1.09(m,8H),1.02(s,3H),0.96-0.93(m,3H),0.93-0.87(m,3H),0.69(s,3H). 1 H NMR(Isomer 2):(400MHz,CDCl3)δ 5.30(m,1H),2.44-2.40(d,J=14Hz,1H),2.17-1.96(m,3H),1.96-1.67(m,3H),1.67-1.18( m,18H),1.16-1.09(m,8H),1.06(s,3H),0.96-0.93(m,3H),0.93-0.87(m,3H),0.69(s,3H). Example 5 [ka]

[0211] Preparation of compound 5-2. To a solution of 5-1 (200 mg, 0.52 mmol) in toluene (5 mL) was added n-PrMgBr (1.3 mL, 2 M in THF, 2.6 mmol) dropwise at −78° C. The mixture was gradually warmed to room temperature and stirred for 6 h. The reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA=15:1) to give 5-2 (130 mg, 58%) as a white solid. 1H NMR: (300 MHz, CDCl3) δ: ppm 5.30(d,J=4.8Hz,1H),2.48-2.38(m,1H),2.02-1.95(m,3H),1.88-1.66(m ,3H),1.63-1.52(m,5H),1.52-1.46(m,4H),1.43-1.41(m,1H),1.41-1.35 (m,4H),1.30-1.22(m,3H),1.20-1.14(m,4H),1.13-1.08(m,4H),1.03(s, 3H),0.95-0.90(m,3H),0.90-0.87(m,3H),0.87-0.85(m,1H)0.68(s,3H).

[0212] Preparation of 5-3 and 5-4. To a solution of compound 5-2 (400 mg, 0.93 mmol) in EtOAc (20 mL) was added 10% Pd / C (100 mg). The mixture was then stirred overnight at 50 °C under hydrogen (50 psi). The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give the pure products 5-3 (150 mg, 37.3%) and 5-4 (27 mg, 6.7%) as white powders. 1 H NMR(5-3):(300MHz,CDCl3)δ 1.97-1.94(m,1H),1.93-1.77(m,1H),1.67-1.62(m,3H),1.56-1.51(m,6H),1.47-1.30(m,11H),1.2 4(s,6H),1.20(s,1H),1.13(s,5H),1.09-0.99(m,4H),0.94-0.90(m,6H),0.80(s,3H),0.65(s,3H). 1H NMR(5-4):(300MHz,CDCl3)δ 1.98-1.94(m,2H),1.91-1.78(m,5H),1.65-1.51(m,5H),1.47-1.46(m,3H),1.38-1.35(m,9H),1.32-1.30(m,2H),1.25(s,3 H),1.22(s,6H),1.16-1.10(m,4H),1.06-1.04(m,4H),0.98-0.94(m,4H),0.92-0.89(m,6H),0.86-0.83(m,1H),0.64(s,3H).

[0213] Preparation of 5-5 and 5-6. To a solution of compound 5-1 (1500 mg, 3.88 mmol) in dry THF (30 mL) was added n-PrMgBr solution (11.6 mL, 23.3 mmol) dropwise at 0 °C. The mixture was stirred at 40 °C for 16 h. TLC (PE / EtOAc = 2 / 1) showed that the reaction was complete. Saturated aqueous NH4Cl (5 mL) was slowly added to quench the reaction. The resulting solution was partitioned between EtOAc (30 mL × 3) and HO (30 mL). The combined organic layer was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 10 / 1 to give a mixture of diastereomeric pairs (1.1 g) as a white powder. The diastereomeric pairs were separated by preparative SFC to give 5-6 (380 mg, 22.8%) as a white solid and 5-5 (385 mg, 23.1%) as a white solid. 1 H NMR(5-5):(400MHz,CDCl3)δ 5.31-5.30(m,1H),2.44-2.41(d,1H,J=12.8Hz),2.01-1.96(m,3H),1.86-1.69(m,3H),1. 58-1.25(m,16H),1.14-1.08(m,11H),1.06-0.99(m,4H),0.94-0.91(m,6H),0.68(s,3H). 1H NMR(5-6):(400MHz,CDCl3)δ 5.31-5.30(m,1H,),2.44-2.41(d,1H,J=12.4Hz),2.02-1.96(m,3H),1.87-1.68(m,3H),1 .57-1.25(m,16H),1.18-1.08(m,10H),1.02-0.99(m,4H),0.94-0.91(m,6H),0.68(s,3H).

[0214] Preparation of 5-8. A mixture of 5-6 (200 mg, 0.464 mmol) and Pd / C (100 mg, catalytic amount) in EtOAc (30 mL) was hydrogenated under 50 psi of hydrogen at 50 °C for 48 h. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 20 / 1 to give 5-8 (111.3 mg, 55.4%) as a white solid. 1 H NMR(5-8)(400MHz,CDCl3),δ(ppm)1.97-1.94(d,1H,J=12.0Hz),1.83-1.78(m,1H),1.65-1.61(m ,3H),1.50-1.24(m,20H),1.13-1.00(m,11H),0.94-0.85(m,7H),0.80(s,3H),0.68-0.65(m,4H). 1 H NMR(5-8A)(400MHz,CDCl3),δ(ppm)1.98-1.95(d,1H,J=11.2Hz),1.88-1.80(m,3H),1.65-1.60(m,1H),1.5 1-1.47(m,1H),1.40-1.31(m,12H),1.28-1.20(m,8H),1.16-1.01(m,11H),0.96-0.80(m,10H),0.65(s,3H).

[0215] Preparation of 5-7. A mixture of 5-5 (200 mg, 0.464 mmol) and Pd / C (100 mg, catalytic amount) in EtOAc (30 mL) was hydrogenated under 50 psi of hydrogen at 50° C. for 48 hours. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 20 / 1 to give 5-7 (118.5 mg, 59.0%) as a white solid. 1 H NMR(5-7)(400MHz,CDCl3),δ(ppm)1.97-1.94(d,1H,J=12.8Hz),1.88-1.79(m,1H),1.71-1.61(m ,3H),1.51-1.24(m,20H),1.13-1.00(m,11H),0.94-0.85(m,7H),0.80(s,3H),0.68-0.65(m,4H). 1 H NMR(5-7A)(400MHz,CDCl3),δ(ppm)1.98-1.95(d,1H,J=11.2Hz),1.88-1.79(m,3H),1.65-1.59(m,1H),1.52-1.47(m ,1H),1.41-1.31(m,11H),1.27-1.22(m,9H),1.13-1.11(m,7H),1.06-1.01(m,4H),0.96-0.90(m,10H),0.65(s,3H). Example 6 [ka] [ka]

[0216] Preparation of 6-2. To a solution of 6-1 (150 mg, 0.39 mmole) in THF (4 mL) was added allylmagnesium bromide (2.34 mL, 2.34 mmole, 1 M in ether) at −78° C. The reaction mixture was then warmed to room temperature and stirred for 12 h. The mixture was quenched with NH4Cl (20 mL) solution and extracted with EtOAc (10 mL × 2). The organic phase was dried over Na2SO4 and purified by silica gel column chromatography (eluent: PE:EA = 10:1) to give 6-2 (100 mg, 59%). 1 H NMR:(400MHz,CDCl3)δ 5.89-5.82(m,1H),5.31(d,J=5.2Hz,2H),5.15-5.09(m,2H),2.43-2.40(m,1H),2.22-2.20(d,J=7.6Hz,2H),2.04-1.96(m,3H) ),1.95-1.57(m,3H),1.54-1.24(m,12H),1.19-1.11(m,5H),1.09-1.05(m,6H),1.03(s,3H),0.98-0.92(m,5H),0.68(s,3H).

[0217] Preparation of 6-3. To a solution of 9-BBN (3.2 mL, 1.6 mmol, 2 M in THF) was added dropwise a solution of 6-2 (70 mg, 0.16 mmol) in THF (2 mL) at 0 °C. The reaction mixture was heated at 60 °C and stirred for 12 h. The mixture was cooled to 0 °C, and an aqueous solution of NaOH (10%) (2 mL) was added, followed by H2O2 (30%, 1 mL). The mixture was stirred at 0 °C for 2 h and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to give 6-3 (30 mg, 42%) as a white solid. 1H NMR:(300MHz,CDCl3)δ:5.30(d,J=5.2Hz,1H),3.68-3.65(m,2H),2.43-2.39(m,1H),2.03-1.80(m,6H),1.79-1.62(m,6H),1. 47-1.36(m,5H),1.32-1.25(m,7H),1.17-1.13(m,4H),1.11-1.07(m,6H),10.5-0.98(m,4H),0.94-0.90(m,5H),0.68(s,3H).

[0218] Preparation of 6-4 and 6-5. A mixture of 6-1 (1.0 g, 2.59 mmol) and 10% Pd / C (140 mg) in EtOAc (30 mL) was hydrogenated under H (50 psi) at 50 °C for 16 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (20 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give 6-4 (500 mg, 49.5%) and 6-5 (200 mg, 19.8%) as white solids.

[0219] Preparation of 6-6. To a solution of 6-4 (70 mg, 0.18 mmol) in dry THF (2 mL) was added C3H5MgBr (1.1 mL, 1.08 mmol) dropwise at −78 °C under N2. The mixture was gradually warmed to room temperature and stirred for 12 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give the pure product 6-6 (40 mg, 51.9%) as a white powder. 1 H NMR: (300 MHz, CDCl3) δ: ppm 5.92-5.79(m,1H),5.15(d,J=4.2Hz,1H),5.11(d,J=13.2Hz,1H),2.21(d,J=7.5Hz,2H),1.97-1.75(m ,5H),1.67-1.34(m,19H),1.30-0.94(m,11H),0.91(d,J=6.3Hz,3H),0.80(s,3H),0.69-0.61(m,4H).

[0220] Preparation of 6-7 and 6-8. Compound 6-2 (400 mg, 0.849 mmol) was separated by SFC to give 6-7 (96 mg) and 6-8 (162 mg) as white powders (total yield: 65%). 1 H NMR(6-7)(400MHz,CDCl3),δ 5.90-5.81(m,1H),5.31(d,J=5.2Hz,1H),5.20-5.09(m,2H),2.45-2.35(m,1H),2.25-2.15(m,2H),2.04-0.90(m,36H),0.68(s,3H). 1 H NMR(6-8)(400MHz,CDCl3),δ 5.90-5.80(m,1H),5.31(d,J=5.2Hz,1H),5.21-5.09(m,2H),2.45-2.34(m,1H),2.25-2.15(m,2H),2.04-0.89(m,36H),0.68(s,3H).

[0221] Preparation of 6-6-Bz. To a solution of 6-6 (100 mg, 0.23 mmol) in pyridine (3 mL) was added BzCl (64.4 mg, 0.46 mmol) dropwise at room temperature. The reaction mixture was then stirred at 40 °C for 12 h. TLC showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous solution and extracted with EtOAc. The combined organic phase was washed with 1 M HCl (30 mL) and brine, dried over anhydrous NaSO, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 6-8-Bz (60 mg, 48%) as a white solid.

[0222] Preparation of 6-11-Bz: Compound 6-6-Bz (60 mg, 0.11 mmol) was separated by SFC to give 6-11-Bz (40 mg, 66%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 7.99-7.98(d,J=7.2Hz,2H),7.53-7.49(t,J=7.2Hz,1H),7.42-7.38(t,J=7.2Hz,2H),2.22-2.20(d,J=7.6Hz,2H),1.98-1.5 7(m,11H),1.54-1.26(m,16H),1.15(s,3H),1.12-1.10(m,6H),0.92-0.91(d,J=6.0Hz,3H),0.80(s,3H),0.64-0.60(m,4H).

[0223] Preparation of 6-11. To a solution of compound 6-11-Bz (40 mg, 0.075 mmol) in a mixture of THF (2 mL) and MeOH (1 mL) was added a solution of LiOH (90 mg, 3.75 mmol) in HO (1 mL). The mixture was stirred at 40 °C for 3 days. TLC showed that the starting material was completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaSO, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 6-11 (23 mg, 71%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 5.86-5.84(m,1H),5.13-5.09(m,2H),2.21-2.19(d,J=7.6Hz,2H),1.84-1.25(m,19H),1.24(s,3 H),1.14(s,3H),1.13-1.09(m,7H),0.91-0.90(d,J=6.8Hz,3H),0.80(s,3H),0.64-0.60(m,4H). Example 7 [ka]

[0224] Preparation of Compound 7-2. To a solution of 7-1 (193 mg, 0.5 mmol, 1.0 eq) in dry THF (3 mL) was added n-BuLi (1.6 mL, 4 mmol, 8.0 eq) dropwise at −78° C. The resulting mixture was stirred at this temperature for 0.5 h, then warmed to room temperature and stirred at this temperature for an additional 18 h. TLC (PE / EA=5 / 1) indicated that the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=20:1) to give product 7-2 (85 mg, 38.6%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.31(d,J=5.2Hz,1H),2.41(d,J=13.2Hz,1H),2.10-1.95(m,3H),1.94-1.62(m,42H),1.52-1.22(m,17H),1 .22-1.20(m,1H),1.15(s,3H),1.10(s,3H),1.05(s,3H),1.04-1.00(m,3H),1.00-0.85(m,9H),0.67(s,3H).

[0225] Preparation of Compound 7-3. A mixture of 7-2 (100 mg, 2.59 mmol) and 10% Pd / C (140 mg) in EtOAc (30 mL) was hydrogenated under H (50 psi) at 50 °C for 16 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (20 mL x 3). The combined filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give 7-3 (35 mg, 35%) and 7-3A (19 mg, 19%) as a white powder. 1 H NMR(7-3):(400MHz,CDCl3)δ 2.02-1.92(m,1H),1.90-1.77(m,1H),1.70-1.38(m,14H),1.36-1.29(m,6H),1.28-1.20(m,8 H),1.20-1.08(m,6H),1.07-0.96(m,4H),0.96-0.84(m,7H),0.82(s,3H),0.70-0.60(m,4H). 1 H NMR(7-3A):(400MHz,CDCl3)δ 1.98-1.80(m,4H),1.67-1.48(m,6H),1.45-1.33(m,9H),1.32-1.23(m,10H),1.22-1.18( m,4H),1.17-1.10(m,6H),1.10-0.97(m,4H),0.94(s,3H),0.93-0.87(m,6H),0.64(s,3H).

[0226] Preparation of 7-4 and 7-5. To a solution of compound 7-1 (1.5 g, 3.88 mmol) in dry THF (15 mL) was added n-BuLi (12.5 mL, 31 mmol, 2.5 M in THF) dropwise at −78° C. The resulting mixture was stirred at this temperature for 0.5 h, then warmed to room temperature and stirred at this temperature for an additional 18 h. TLC (PE / EA=5 / 1) indicated that the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=20:1) to give 7-2 (800 mg, 46.4%) as a white powder, which was separated by SFC to give 7-4 (207 mg) and 7-5 (360 mg) as white powders. 1 H NMR(7-4):(400MHz,CDCl3)δ 5.38-5.29(m,1H),2.44(d,1H,J=12.5Hz),2.04-1.69(m,6H),1.57-1.25(m,18H),1.20-0.89(m,23H),0.70(s,3H). 1H NMR(7-5):(400MHz,CDCl3)δ 5.32(s,1H),2.44(d,1H,J=12.3Hz),2.08-1.68(m,6H),2.55-1.25(m,17H),2.22-0.85(m,24H),0.70(s,3H).

[0227] Preparation of 7-6. To a solution of 7-4 (0.17 g, 0.38 mmol) in 15 mL of EtOH, Pd / C (100 mg) was added, and the reaction mixture was then stirred under hydrogen (50 psi) at 50 °C for 24 h. The resulting solution was filtered and concentrated. The product was purified by silica gel column chromatography eluted with (PE:EA = 20:1) to give 7-6 (40 mg, yield: 23.42%) as a white solid. 1 H NMR(7-6)(400MHz,CDCl3),δ 1.97-1.94(m,1H),1.88-1.76(m,1H),1.71-1.59(m,3H),1.56-1.23(m,21H),1.23-0.86(m,19H),0.81(s,3H),0.65(s,3H).

[0228] Preparation of 7-7. To a solution of 7-5 (0.23 g, 0.52 mmol) in 15 mL of EtOH, Pd / C (200 mg) was added, and the reaction mixture was then stirred under hydrogen (50 psi) at 50° C. for 24 hours. The resulting solution was filtered and concentrated. The product was purified by silica gel column chromatography eluted with (PE:EA=20:1) to give 7-7 (70 mg, yield: 30.3%) as a white solid. 1 H NMR(7-7)(400MHz,CDCl3),δ(ppm)1.99-1.92(m,1H),1.88-1.78(m,1H),1.70- 1.52(m,6H),1.46-1.20(m,21H),1.18-0.87(m,20H),0.81(s,3H),0.65(s,3H). Example 8 [ka] [ka]

[0229] Preparation of 8-2. To a solution of compound 8-1 (100 mg, 0.25 mmol) in toluene (8 mL) was added i-PrMgBr solution (1.5 mL, 1.5 mmol, 1 M in THF) dropwise over 10 min at room temperature under nitrogen. The reaction mixture was then stirred at room temperature for 12 h. TLC showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to give product 8-2 (66 mg, 59.46%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),2.43-2.40(m,1H),2.04-1.55(m,3H),1.88-1.66(m,5H),1.58-1.13(m,1 5H),1.11(s,3H),1.08(s,3H),1.01(s,3H),0.96-0.90(m,6H),0.90-0.86(m,3H),0.68(s,3H).

[0230] Preparation of 8-3 and 8-4. To a solution of compound 8-2 (60 mg, 0.14 mmol) in 15 mL of EtOAc was added 10% Pd / C (20 mg) under argon. The suspension was degassed under reduced pressure and purged with H2 several times. The mixture was stirred at 50 °C under H2 (50 psi) overnight. The suspension was filtered through a Celite pad, and the pad was washed with EA (20 mL x 3). The combined filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give 8-3 (27 mg, 45%) and 8-4 (9 mg, 15%) as a white powder. 1H NMR(8-3):(400MHz,CDCl3)δ 1.97-1.94(m,1H),1.85-1.78(m,2H),1.74-1.42(m,12H),1.48-1.20(m,12H),1.18-1.09(m,3H) ,1.07(s,3H),1.02-0.98(m,2H),0.93-0.88(m,6H),0.88-0.86(m,3H),0.80(s,3H),0.63(s,3H). 1 H NMR(8-4):(400MHz,CDCl3)δ 1.98-1.95(m,1H),1.89-1.79(m,3H),1.75-1.54(m,7H),1.48-1.24(m,16H),1.23(s,3H),1. 19-1.11(m,4H),1.08(s,4H),0.95(s,3H),0.94-0.88(m,6H),0.88-0.86(m,3H),0.63(s,3H).

[0231] Preparation of 8-7 and 8-8. To a solution of compound 8-1 (1500 mg, 3.88 mmol) in dry THF (30 mL) was added i-PrMgCl solution (11.6 mL, 23.3 mmol) at 0 °C. The mixture was stirred at 40 °C for 16 h. TLC (PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction was quenched by slowly adding saturated aqueous NH4Cl (5 mL). The resulting solution was partitioned between EtOAc (30 mL x 3) and H2O (30 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 10 / 1 to give a mixture of diastereomeric pairs (800 mg) as a white powder. The diastereomeric pairs were separated by preparative SFC to give 8-8 (317 mg, 19.0%) and 8-7 (250 mg, 15.0%) as a white solid. 1 H NMR(8-8):(400MHz,CDCl3)δ 5.30(s,1H),2.42(d,J=12.4Hz,1H),2.01-1.99(m,3H),1.89-1.65(m,4H),1.59-1.58(m,1H) ,1.51-1.26(m,9H),1.20-1.05(m,12H),1.04-0.99(m,4H),0.94-0.88(m,10H),0.68(s,3H).1 H NMR(8-7):(400MHz,CDCl3)δ 5.30(d,J=3.6Hz,1H),2.42(d,J=12.4Hz,1H),2.00-1.97(m,3H),1.89-1.68(m,4H),1.5 8-1.25(m,10H),1.19-1.08(m,10H),1.03-0.98(m,4H),0.95-0.88(m,10H),0.68(s,3H).

[0232] Preparation of 8-6. A mixture of 8-8 (200 mg, 0.464 mmol) and Pd / C (100 mg, catalytic amount) in EtOAc (30 mL) was hydrogenated under 50 psi of hydrogen at 50° C. for 48 hours. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 20 / 1 to give 8-6 (85.9 mg, 42.8%) as a white solid and 8-6A (17.6 mg, 8.8%) as a white solid. 1 H NMR(8-6)(400MHz,CDCl3),δ(ppm)1.97-1.94(d,1H,J=12.8Hz),1.88-1.79(m,1H),1.71-1.61(m,3H),1.54 -1.45(m,3H),1.36-1.19(m,13H),1.16-0.96(m,12H),0.92-0.87(m,10H),0.80(s,3H),0.68-0.65(m,4H). 1 H NMR(8-6A)(400MHz,CDCl3),δ(ppm)1.98-1.95(d,1H,J=10.8Hz),1.88-1.79(m,3H),1.71-1.59(m,3H), 1.53-1.48(m,2H),1.42-1.31(m,6H),1.27-0.96(m,20H),0.92-0.87(m,12H),0.80(s,3H),0.64(s,3H).

[0233] Preparation of 8-5. A mixture of 8-7 (150 mg, 0.348 mmol, 1.0 eq) and Pd / C (75 mg, catalytic amount) in EtOAc (20 mL) was hydrogenated under 50 psi of hydrogen at 50 °C for 48 h. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 20 / 1 to give 8-5 (89.0 mg, 44.3%) as a white solid and 8-5A (4.6 mg, 2.3%) as a white solid. 1 H NMR(8-5)(400MHz,CDCl3),δ(ppm)1.97-1.94(d,1H,J=12.8Hz),1.88-1.79(m,1H),1.71-1.61(m,3H),1.54 -1.45(m,3H),1.36-1.19(m,13H),1.16-0.96(m,12H),0.92-0.87(m,10H),0.80(s,3H),0.68-0.65(m,4H). 1 H NMR(8-5A)(400MHz,CDCl3),δ(ppm)1.98-1.95(d,1H,J=10.8Hz),1.91-1.79(m,3H),1.7 2-1.64(m,2H),1.54-1.50(m,1H),1.46-1.00(m,28H),0.96-0.87(m,12H),0.64(s,3H). Example 9 [ka]

[0234] Preparation of 9-2. To a solution of compound 9-1 (100 mg, 0.25 mmol) in THF (2 mL) was added cyclopropylmagnesium bromide solution (2.5 mL, 2.5 mmol, 1 M in THF) dropwise over 10 min at room temperature under nitrogen. The reaction mixture was then stirred at room temperature for 12 h. TLC showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give product 9-2 (33 mg, 30%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ:5.31(d,J=5.2Hz,1H),2.42(d,J=12.8Hz,1H),2.08-1.93(m,3H),1.90-1.65(m,3H ),1.62-1.27(m,13H),1.22-1.08(m,11H),1.01(s,3H),1.00-0.85(m,6H),0.68(s,3H),0.40-0.25(m,4H).

[0235] Preparation of 9-3 and 9-4. Compound 9-2 (200 mg, 0.46 mmol) was separated by SFC to give 9-3 (90 mg) and 9-4 (100 mg) as white solids (total yield: 95%). 1 H NMR:(9-3)(400MHz,CDCl3)δ 5.31-5.30(m,1H),2.44-2.41(m,1H),2.02-1.99(m,3H),1.95-1.60(m,3H),1.50-1 .25(m,9H),1.20-1.05(m,11H),1.02-0.93(m,11H),0.68(s,3H),0.35-0.28(m,4H). 1 H NMR:(9-4)(400MHz,CDCl3)δ 5.31-5.30(m,1H),2.44-2.41(m,1H),2.02-1.95(m,3H),1.93-1.60(m,3H),1.50-1. 25(m,10H),1.20-1.05(m,11H),1.02-0.93(m,11H),0.68(s,3H),0.36-0.24(m,4H).

[0236] Preparation of 9-7. To a solution of compound 9-3 (100 mg, 0.23 mmol) in EtOAc (8 mL) was added Pd / C (10%, 200 mg) under N. The suspension was degassed under reduced pressure and purged with H several times. The mixture was then stirred at 50 °C under H (50 psi) for 24 h. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (30 mL x 2). The combined filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 9-7 (27.8 mg, 27.8%) as a white solid. 1 H NMR:(9-7)(400MHz,CDCl3)δ 1.97-1.94(m,1H),1.90-1.80(m,1H),1.64-1.57(m,3H),1.54-1.30(m,7H ),1.28-0.85(m,25H),0.80(s,3H),0.65-0.60(m,4H),0.36-0.33(m,4H). 1 H NMR:(9-7A)(400MHz,CDCl3)δ 1.95-1.83(m,4H),1.70-1.57(m,1H),1.45-1.11(m,22H),1.05-0.85(m,17H),0.65(s,3H),0.36-0.34(m,4H).

[0237] Preparation of 9-8. To a solution of compound 9-4 (100 mg, 0.23 mmol) in EtOAc (8 mL) was added Pd / C (10%, 200 mg) under N. The suspension was degassed under reduced pressure and purged with H several times. The mixture was then stirred at 50 °C under H (50 psi) for 24 h. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (30 mL x 2). The combined filtrate was concentrated to dryness to give the crude product, which was purified by HPLC to give 9-8 (18.3 mg, 18%) as a white solid. 1H NMR:(9-8)(400MHz,CDCl3)δ 1.97-1.94(m,1H),1.90-1.80(m,1H),1.60-1.57(m,3H),1.54-1.20(m,16 H),1.19-0.82(m,16H),0.80(s,3H),0.65-0.60(m,4H),0.36-0.28(m,4H). Example 10 [ka] [ka] [ka] [ka]

[0238] Preparation of 10-2. To a solution of compound 10-1 (100 mg, 0.25 mmol) in toluene (8 mL) was added ethynylmagnesium bromide solution (4 mL, 2.0 mmol, 0.5 M in THF) dropwise over 10 min at room temperature under nitrogen. The reaction mixture was then stirred at 50 °C overnight. TLC showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (25 mL x 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give product 10-2 (80 mg, 74.98%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),2.43-2.40(m,2H),2.06-1.81(m,5H),1.80-1.67(m,3H),1.67-1.59(m,2H),1.49(s, 3H),1.48-1.42(m,2H),1.40-1.24(m,4H),1.20-1.13(m,2H),1.10(s,3H),0.96-0.92(m,3H),0.69(s,3H).

[0239] Preparation of 10-3 and 10-4. Compound 10-2 (350 mg, 0.849 mmol) was separated by SFC to give 10-3 (82 mg) and 10-4 (94 mg) as white powders (total yield: 50%). 1 H NMR (a10-3) (400MHz, CDC l3),δ 5.29(d,J=5.2Hz,1H),2.43-2.40(m,2H),2.05-0.95(m,38H),0.68(s,3H). 1 H NMR(10-4)(400MHz,CDCl3),δ5.29(d,J=5.2Hz,1H),2.43-2.40(m,2H),2.05-0.95(m,38H),0.68(s,3H).

[0240] Preparation of 10-5. To a solution of compound 10-1 (3.0 g, 7.76 mmol) in a mixture of EtOAc (20 mL) and EtOH (10 mL), Pd / C (33%, 1.0 g) was added under N. The suspension was degassed under reduced pressure and purged with H several times. The mixture was then stirred at 50 °C under H (50 psi) for 6 days. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (100 mL x 3). The combined filtrate was concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 10-5 (1.7 g, 56%) as a white solid. 1H NMR:(400MHz,CDCl3)δ 2.48-2.44(m,1H),2.43-2.40(m,1H),2.13(s,3H),1.95-1.25(m,20H),1.23(s,3H) ),1.22-1.00(m,8H),0.90-0.88(d,J=6.4Hz,3H),0.80(s,3H),0.63-0.60(m,4H).

[0241] Preparation of 10-6. To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 mL) was added ethynylmagnesium bromide (28.2 mL, 14.1 mmol) dropwise at 0 °C under N. The reaction mixture was then stirred at room temperature for 12 h. TLC showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous NH.sub.4Cl (80 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 10-6 (380 mg, 64%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 2.42(s,1H),1.97-1.48(m,14H),1.47(s,3H),1.29-1.26(m,7H),1.24(s,3H), 1.23-0.94(m,7H),0.93-0.92(d,J=6.4Hz,3H),0.80(s,3H),0.65-0.62(m,4H).

[0242] Preparation of 10-6-Bz. To a solution of 10-6 (250 mg, 0.60 mmol) in pyridine (3 mL) was added BzCl (168 mg, 1.2 mmol) dropwise at room temperature. The reaction mixture was then stirred at 45 °C for 12 h. TLC showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous solution and extracted with EtOAc. The combined organic phase was washed with 1 M HCl (20 mL) and brine, dried over anhydrous NaSO, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 10-6-Bz (200 mg, 64%) as a white solid.

[0243] Preparation of 10-8-Bz and 10-9-Bz. Compound 10-6-Bz (200 mg, 0.39 mmol) was separated by SFC to give 10-8-Bz (80 mg, 40%) and 10-9-Bz (70 mg, 35%) as white solids. 1 H NMR:(10-8-Bz)(400MHz,CDCl3)δ 7.99-7.98(d,J=7.6Hz,2H),7.51-7.49(d,J=7.2Hz,1H),7.42-7.38(t,J=7.2Hz,2H),2.42(s,1H),2.05-1.68(m,8H),1.6 5(s,3H),1.60-1.49(m,7H),1.48(s,3H),1.45-1.11(m,16H),0.94-0.92(d,J=6.4Hz,3H),0.87(s,3H),0.66-0.62(m,4H). 1 H NMR:(10-9-Bz)(400MHz,CDCl3)δ 7.99-7.98(d,J=7.6Hz,2H),7.51-7.49(d,J=7.2Hz,1H),7.42-7.38(t,J=7.6Hz,2H),2.43(s,1H),2.05-1.67(m,8H),1.65(s,3H) ,1.60-1.48(m,5H),1.47(s,3H),1.45-1.20(m,11H),1.19-0.95(m,9H),0.94-0.92(d,J=6.8Hz),0.87(s,3H),0.66-0.62(m,4H).

[0244] Preparation of 10-8. To a solution of compound 10-8-Bz (80 mg, 0.15 mmol) in a mixture of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH (180 mg, 7.5 mmol) in HO (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC showed that the starting material was completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-8 (57 mg, 92%) as a white solid. 1H NMR:(400MHz,CDCl3)δ 2.42(s,1H),1.93-1.49(m,11H),1.48(s,3H),1.35-1.20(m,16H),1.19- 0.94(m,5H),0.93-0.92(d,J=6.4Hz,3H),0.80(s,3H),0.65-0.62(m,4H).

[0245] Preparation of 10-9. To a solution of compound 10-9-Bz (70 mg, 0.14 mmol) in a mixture of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH (168 mg, 7.0 mmol) in HO (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC showed that the starting material was completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaSO, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-9 (53 mg, 91%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 2.42(s,1H),1.93-1.49(m,11H),1.48(s,3H),1.29-0.94(m,21H),0.93-0.92(d,J=6.4Hz,3H),0.80(s,3H),0.65-0.62(m,4H).

[0246] Preparation of 10-7. To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 mL) was added vinylmagnesium bromide (9.87 mL, 9.87 mmol) dropwise at 0 °C under N. The reaction mixture was then stirred at room temperature for 12 h. TLC showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous NH.sub.4Cl (30 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 10-7 (300 mg, 51%) as a white solid. 1H NMR:(400MHz,CDCl3)δ 5.93-5.86(m,1H),5.20-5.16(d,J=17.6Hz,1H),5.05-5.02(d,J=10.8Hz,1H),1.96-193(m,1H),1.60-1.5 7(m,4H),1.51-1.20(m,20H),1.19-1.00(m,8H),0.91-0.89(d,J=6Hz,3H),0.80(s,3H),0.64-0.60(m,4H).

[0247] Preparation of 10-7-Bz. To a solution of 10-7 (220 mg, 0.53 mmol) in pyridine (3 mL) was added BzCl (150 mg, 1.06 mmol) dropwise at room temperature. The reaction mixture was then stirred at 40 °C for 12 h. TLC showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous solution and extracted with EtOAc. The combined organic phase was washed with 1 M HCl (30 mL) and brine, dried over anhydrous NaSO, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:1) to give 10-7-Bz (150 mg, 54%) as a white solid.

[0248] Preparation of 10-10-Bz and 10-11-Bz. Compound 10-7-Bz (190 mg, 0.37 mmol) was separated by SFC to give 10-10-Bz (75 mg, 39%) and 10-11-Bz (70 mg, 37%) as white solids. 1 H NMR:(10-10-Bz)(400MHz,CDCl3)δ 7.99-7.97(d,J=7.2Hz,1H),7.51-7.49(d,J=7.6Hz,1H),7.42-7.38(t,J=8.0Hz,2H),5.93-5.86(dd,J1=11.2Hz,J2=17.2,1H), 5.21-5.16(d,J=17.6Hz,1H),5.05-5.02(d,J=10.4Hz,1H),2.05-1.75(m,8H),1.65-1.27(m,19H),1.26(s,3H),1.25-0.93(m,10 H),0.91-0.90(d,6.0Hz,3H),0.86(s,3H),0.70-0.64(m,4H). 1 H NMR:(10-11-Bz)(400MHz,CDCl3)δ 7.99-7.97(d,J=7.2Hz,1H),7.51-7.49(d,J=7.6Hz,1H),7.42-7.38(t,J=8.0H z,2H),5.93-5.86(dd,J1=10.8Hz,J2=17.6,1H),5.20-5.16(d,J=17.2Hz,1H),5 .05-5.02(d,J=10.4Hz,1H),2.05-1.75(m,8H),1.65-1.27(m,10H),1.26(s,3H) ,1.25-0.93(m,10H),0.91-0.90(d,6.4Hz,3H),0.86(s,3H),0.70-0.64(m,4H).

[0249] Preparation of 10-10. To a solution of compound 10-10-Bz (75 mg, 0.14 mmol) in a mixture of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH (168 mg, 7.0 mmol) in HO (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC showed that the starting material was completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaSO, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-10 (55 mg, 94%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 1.96-1.92(m,1H),1.90-1.70(m,2H),1.69-1.57(m,5H),1.55-1.20(m,18H),1.19-0.81(m,10H),0.80(s,3H),0.70-0.60(m,4H).

[0250] Preparation of 10-11-Bz. To a solution of compound 10-11-Bz (70 mg, 0.13 mmol) in a mixture of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH (168 mg, 7.0 mmol) in HO (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC showed that the starting material was completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaSO, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-11 (49 mg, 91%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 1.96-1.92(m,1H),1.90-1.70(m,2H),1.69-1.57(m,5H),1.55-1.20(m,18H),1.19-0.81(m,10H),0.80(s,3H),0.70-0.60(m,4H).

[0251] Preparation of 10-22 and 10-23. To a solution of 10-14 (550 mg, 1.27 mmol) in THF (10 mL) was added NaH (254 mg, 6.36 mmol) at 0 °C and stirred at the same temperature for 30 min. Then, CHCl (127 mg, 0.770 mmol) was added dropwise to the mixture. The reaction was monitored by TLC. After 1 h, 127 mg of CHCl was added in two portions. After stirring at room temperature for 1.5 h, the reaction mixture was quenched with aqueous NHCl (20 mL), extracted with EtOAc (20 mL x 3), dried over NaSO, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 10-14 as a white powder. The diastereomeric pair (340 mg) was separated by preparative SFC to give 10-22 (130 mg, 22.9%) as a white powder and 10-23 (135 mg, 23.8%) as a white powder. 1H NMR(10-22):(400MHz,CDCl3)δ 5.30(s,1H),3.65-3.53(m,2H),3.35(s,3H),3.04(br,1H),2.44-2.40(d,1H,J=13.6Hz),2.02-1.95(m,3H),1.86-1.64(m, 5H),1.62-1.58(m,1H),1.52-1.23(m,9H),1.17-1.05(m,11H),1.04-0.98(m,4H),0.95-0.93(d,4H,J=6.8Hz),0.68(s,3H). 1 H NMR(10-23):(400MHz,CDCl3)δ 5.30(s,1H),3.61(t,2H,J=6.0Hz),3.35(s,3H),3.04(br,1H),2.44-2.40(d,1H,J=12.8Hz) ,2.02-1.95(m,3H),1.86-1.64(m,5H),1.57-1.25(m,12H),1.16-0.93(m,17H),0.68(s,3H).

[0252] Preparation of 10-17. A mixture of 10-22 (100 mg, 0.224 mmol) and Pd / C (50 mg, catalytic amount) in EtOAc (10 mL) was hydrogenated under 50 psi of hydrogen at 50 °C for 48 h. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 15 / 1 to give 10-17 (68.4 mg, 68.1%) as a white solid. 1 H NMR(10-17)(400MHz,CDCl3),δ 3.62-3.58(m,2H),3.35(s,3H),3.07(br,1H),1.97-1.93(d,1H,J=12.8Hz),1.83-1.74(m,2H),1.69-1.55(m,5H),1. 50-1.43(m,3H),1.37-1.23(m,12H),1.16-0.97(m,10H),0.93-0.91(d,1H,J=6.0Hz),0.80(s,3H),0.68-0.64(m,3H).

[0253] Preparation of 10-19. A mixture of 10-23 (100 mg, 0.224 mmol) and Pd / C (50 mg, catalytic amount) in EtOAc (10 mL) was hydrogenated under 50 psi of hydrogen at 50 °C for 48 h. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (40 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 15 / 1 to give 10-19 (68.6 mg, 68.3%) as a white solid. 1 H NMR(10-19)(400MHz,CDCl3),δ 3.60(t,2H,J=6.0Hz),3.35(s,3H),3.07(br,1H),1.97-1.94(d,1H,J=12.8Hz),1.81-1.57(m,6H),1.54-1.43 (m,4H),1.36-1.22(m,12H),1.16-0.97(m,10H),0.92-0.91(d,1H,J=6.0Hz),0.80(s,3H),0.68-0.61(m,3H).

[0254] Preparation of 10-7. A solution of 10-6 (60 mg, 0.14 mmol) in 2 mL of EtOAc was added to Lindlar's catalyst (24 mg). The mixture was then stirred at room temperature under hydrogen (1 atm) for 1.5 h. The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to give the pure product 10-7 (26 mg, 43.0%) as a white powder. 1 H NMR:(400MHz,CDCl3)δ 5.93-5.85(m,1H),5.20-5.16(d,J=17.2Hz,1H),5.05-5.02(d,J=10.8Hz,1H),1.96-1. 93(m,1H),1.79-1.67(m,1H),1.66-1.57(m,4H),1.55-1.36(m,11H),1.35-1.27(m,9H) ,1.26-0.97(m,8H),0.96-0.89(m,3H),0.81(s,3H),0.68-0.62(m,4H).

[0255] Preparation of Compound 10-12. To a solution of 10-1 (50 mg, 0.13 mmol) in THF (2 mL) was added vinylmagnesium bromide solution (1 mmol, 1 M in THF, 1 mL) dropwise at -50 °C. The reaction mixture was warmed to room temperature and stirred at room temperature for 16 h. TLC (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15 / 1) to give 10-12 (27 mg, 54%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.94-5.86(m,1H),5.30(d,J=5.2Hz,1H),5.19(d,J=17.2Hz,1H),5.04(d,J =10.4Hz,1H),2.42(d,J=12.8Hz,1H),2.01-1.95(m,3H),1.80-1.61(m,4H), 1.56-1.37(m,10H),1.27(s,3H),1.18-1.13(m,3H),1.11(s,3H),1.10-1.04 (m,3H),1.01(s,3H),1.00-0.95(m,2H),0.92(d,J=6.4Hz,3H),0.67(s,3H).

[0256] Preparation of 10-12A and 10-12B. Compound 10-12 (350 mg, 0.84 mmol) was separated by SFC to give 10-12A (160 mg) and 10-12B (110 mg) as white solids (total yield: 77%). 1 H NMR(10-12-A):(400MHz,CDCl3)δ 5.94-5.86(m,1H),5.30(d,J=5.2Hz,1H),5.19(d,J=17.2Hz,1H),5.04(d,J=10.4Hz,1H),2.50-2.40(m,1H),2.05-0.85(m,36H),0.67(s,3H). 1H NMR(10-12-B):(400MHz,CDCl3)δ 5.94-5.86(m,1H),5.30(d,J=5.2Hz,1H),5.19(d,J=17.2Hz,1H),5.04(d,J=10.4Hz,1H),2.50-2.40(m,1H),2.05-0.85(m,36H),0.67(s,3H).

[0257] Preparation of compound 10-13. To a solution of 10-12 (500 mg, 1.21 mmol) in THF (5 mL) was added 9-BBN (24.2 mL, 12.1 mmol) slowly under N protection at 0 °C. The mixture was stirred at 60 °C for 16 h. The reaction mixture was then cooled to 0 °C, and 10% aqueous NaOH (10 mL) and 30% HO (5 mL) were added. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with aqueous NaSO (10 mL), extracted with EtOAc (10 mL x 3), dried over NaSO, and concentrated to give the crude product. The crude product was purified by preparative HPLC to give 10-13 (100 mg, 19.2%) as a white solid. 1 H NMR:(300MHz,CD3OD)δ 5.32(d,J=5.2Hz,1H),3.70(d,J=6.4Hz,2H),2.51-2.35(m,1H),2.14-1.84(m,4H),1.8 2-1.26(m,16H),1.24-1.10(m,7H),1.08-1.00(m,7H),1.00-0.93(m,4H),0.73(s,3H).

[0258] Preparation of compound 10-14. To a solution of 10-13 (50 mg, 0.11 mmol) in THF (5 mL) was added NaH (13.2 mg, 0.55 mmol) at 0 °C and stirred at the same temperature for 30 minutes. Then, CHCl (78 mg, 0.55 mmol) was added dropwise to the mixture. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous NHCl (10 mL), extracted with EtOAc (10 mL × 3), dried over NaSO, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 10-14 (13 mg, 25.2%) as a white powder.1 H NMR:(300MHz,CDCl3)δ 5.23(d,J=5.2Hz,1H),3.54(d,J=6.4Hz,2H),3.29(s,3H),2.38-2.34(m,1H),1.95-1.88(m,3H),1.74-1.58(m,5H),1.52-1. 19(m,14H),1.10(s,3H),1.09-1.05(m,1H),1.04(s,3H),1.02-0.94(m,2H),0.91(s,3H),0.87(d,J=6.4Hz,3H),0.61(s,3H).

[0259] Preparation of 10-20 and 10-21. The crude product 10-13 was washed with EtOAc (30 mL) to give a diastereomeric pair (900 mg, 53.9%) as a white solid. The mixture (400 mg) was separated by SFC to give 10-20 (30 mg, 4.0%) as a white solid and 10-21 (68 mg, 9.2%) as a white solid. 1 H NMR(10-20):(400MHz,Methaol-d4)δ 5.28(s,1H),3.69(t,2H,J=7.2Hz),2.42-2.39(d,1H,J=11.6Hz),2.04-1.90(m,5H) ,1.78-1.28(m,17H),1.17-1.02(m,12H),0.95-0.93(d,4H,J=6.8Hz),0.71(s,3H). 1 H NMR(10-21):(400MHz,Methaol-d4)δ 5.28(s,1H),3.68(t,2H,J=7.2Hz),2.42-2.39(d,1H,J=11.6Hz),2.04-1.90(m,5H) ,1.78-1.28(m,16H),1.18-0.98(m,13H),0.95-0.93(d,4H,J=7.0Hz),0.71(s,3H).

[0260] Preparation of 10-16. A mixture of 10-20 (20 mg, 0.046 mmol) and Pd / C (20 mg, catalytic amount) in EtOAc (5 mL) was hydrogenated under 50 psi of hydrogen at 50 °C for 48 h. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 5 / 1 to give 10-16 (7.6 mg, 39.3%) as a white solid. 1 H NMR(10-16)(400MHz,Methaol-d4),δ 3.70(t,2H,J=7.2Hz),2.01-1.98(d,1H,J=12.4Hz),1.93-1.82(m,1H),1.72-1.57(m,5H),1.53 -1.39(m,5H),1.35-0.99(m,22H),0.96-0.94(d,4H,J=6.4Hz),0.84(s,3H),0.70-0.66(m,4H).

[0261] Preparation of 10-18. A mixture of 10-21 (40 mg, 0.092 mmol, 1.0 eq) and Pd / C (20 mg, catalytic amount) in EtOAc (5 mL) was hydrogenated under 50 psi of hydrogen at 50 °C for 48 h. The reaction mixture was filtered through a Celite pad. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column eluted with PE / EtOAc = 5 / 1 to give 10-18 (12.9 mg, 32.1%) as a white solid. 1 H NMR(10-18)(400MHz,Methaol-d4),δ 3.68(t,2H,J=7.2Hz),1.99-1.96(d,1H,J=12.4Hz),1.92-1.82(m,1H),1.68-1.58(m,5H),1.52 -1.41(m,5H),1.37-0.97(m,22H),0.94-0.92(d,4H,J=6.4Hz),0.82(s,3H),0.67-0.65(m,4H). Example 11 [ka] [ka]

[0262] Preparation of Compound 11-2. To a solution of crude compound 11-1 (30 g, 77 mmol) in dichloromethane (200 mL), imidazole (10.4 g, 154 mmol) and tert-butylchlorodimethylsilane (13.8 g, 92 mmol) were added. The mixture was then stirred at 15 °C for 16 h. The mixture was washed with water, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 150:1 to 80:1) to give crude product 11-2 (38 g, 98%) as a white solid.

[0263] Preparation of Compound 11-3. To a solution of diisopropylamine (34.3 g, 340 mmol) in THF (1 L) was added butyllithium (136 mL, 340 mmol, 2.5 M in hexane) under a nitrogen atmosphere at −78° C. The mixture was then stirred at −78° C. for 10 minutes, then at 25° C. for 10 minutes, and finally at −78° C. for 10 minutes. A solution of crude Compound 11-2 (34 g, 68 mmol) in THF (100 mL) was then added and stirred at −78° C. for 1 hour. Triethyl phosphite (22.6 g, 136 mmol) was then added to the mixture, and the mixture was stirred under an oxygen atmosphere at −78° C. for 3 hours, then at 25° C. for 16 hours. Ammonium chloride (aqueous solution) was then added to the mixture. The organic layer was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) to give the crude product of 11-3 (10 g, 28%) as a yellow solid.

[0264] Preparation of Compound 11-4. To a solution of crude 11-3 (10 g, 19 mmol) in dichloromethane (100 mL) was added Dess-Martin reagent (16 g, 38 mmol) at 0 °C under a nitrogen atmosphere. The mixture was then stirred at 30 °C for 3 h. An aqueous solution of sodium bicarbonate and sodium thiosulfate was then added to the mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 11-4 (5.9 g, 59%) as a white solid.

[0265] Preparation of compound 11-5. To a solution of crude 11-4 (5.9 g, 11 mmol) in THF (60 mL) was added hydrogen chloride (aqueous, 6 mL, 6 mmol, 1 M). The mixture was stirred at 15 °C for 16 h. To this mixture was then added sodium bicarbonate (aqueous). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 11-5 (3.2 g, 70% yield) as a white solid.

[0266] Preparation of Compound 11-6. To a solution of crude 11-5 (3.2 g, 7.9 mmol) in pyridine (50 mL) was added dropwise acetyl chloride (1.5 g, 19 mmol) at 0 °C until the reaction was complete as monitored by TLC. Water was then added to the mixture and concentrated under reduced pressure. Water was added to the residue and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:1) to give crude 11-6 (2.8 g, 79%) as a white solid.

[0267] Preparation of Compound 11-7. Diethylaminosulfur trifluoromethane (8 g, 50 mmol) was added dropwise to a solution of crude 11-6 (2.8 g, 6.3 mmol) in dichloromethane (10 mL) at 0 °C. The mixture was then stirred at 30 °C for 16 h. The mixture was added to sodium bicarbonate (aqueous solution). The organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100:1 to 33:1) to obtain crude 11-7 (2 g, 68%) as a white solid.

[0268] Preparation of compound 11-8. To a solution of crude 11-7 (2 g, 4.2 mmol) in THF (10 mL), a solution of lithium hydroxide monohydrate (900 mg, 21 mmol) in water (10 mL) was added, followed by the addition of methanol (5 mL). The mixture was then stirred at 30 °C for 16 hours. The mixture was then concentrated under reduced pressure. Water was added to the residue, and the mixture was filtered. The solid was washed with water and dried under reduced pressure to give 11-8 (1.5 g, 85%) as a white solid. 1 H NMR:(400MHz,Methanol-d4)δ 5.34(d,J=5.2Hz,1H),3.45-3.35(m,1H),2.30-2.10(m,3H),2.10-1.68(m,7H),1.68 -1.44(m,6H),1.35-1.28(m,2H),1.28-1.12(m,3H),1.12-0.98(m,8H),0.74(s,3H).

[0269] Preparation of compound 11-9. To a solution of 11-8 (1 g, 2.4 mmol) in methanol (15 mL) was added hydrogen chloride (5 mL, 4 M in methanol). The mixture was stirred at 30 °C for 15 min. Sodium bicarbonate (aqueous solution) was added until pH = 7. The mixture was then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to give 11-9 (970 mg, 93%) as a white solid. 1 H NMR:(400MHz,CDCl3)δ 5.34(d,J=5.2Hz,1H),3.87(s,3H),3.60-3.48(m,1H),2.32-2.15(m,2H),2.10-1. 95(m,2H),1.95-1.70(m,5H),1.65-1.40(m,8H),1.30-0.90(m,13H),0.70(s,3H).

[0270] Preparation of compound 11-10. To a solution of 11-9 (0.97 g, 2.3 mmol) in dichloromethane (50 mL) was added Dess-Martin reagent (2.3 g, 5.4 mmol) at 0 °C under a nitrogen atmosphere. The mixture was then stirred at 30 °C for 3 hours. An aqueous solution of sodium bicarbonate and sodium thiosulfate was then added to the mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 11-10 (1 g, 100%) as a yellow oil.

[0271] Preparation of Compounds 11-11 and 11-12. To a solution of butylated hydroxytoluene (3.1 g, 14.2 mmol) in toluene (20 mL) was added MeAl (3.6 mL, 7.2 mmol, 2 M in toluene) at 15 °C. The mixture was then stirred at 15 °C for 30 minutes. A solution of 11-11 (0.9 g, 2.4 mmol) in toluene (5 mL) was added at -78 °C. The mixture was then stirred at -78 °C for 1 hour. Methylmagnesium bromide (2.4 mL, 7.2 mmol, 3 M in ether) was then added at -78 °C. The mixture was then stirred at -78 °C for 1 hour. Ammonium chloride (aqueous solution) was then added to the mixture, which was then filtered. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1 to 10:1) to give 240 mg of crude 11-11 (yield: 28%) and 210 mg of crude 11-12 (yield: 25%). 1 H NMR (400MHz, CDCl3): δ 5.33-5.25(m,1H),3.87(s,3H),2.50-0.75(m,33H),0.70(s,3H). 1 H NMR:(400MHz,CDCl3)δ 5.35-5.27(m,1H),2.50-2.37(m,1H),2.32(s,3H),2.20-0.75(m,32H),0.70(s,3H).

[0272] Preparation of Compound 11-13. To a solution of 11-12 (70 mg, 0.16 mmol) in ethanol (2 mL) was added sodium borohydride (100 mg, 2.6 mmol) at 15°C. The mixture was stirred at 15°C for 30 minutes. Ammonium chloride (aqueous solution) was then added to the mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 8:1) to give 11-13 (40 mg, 57%) as a white solid. 1 H NMR:(400MHz,methanol-d4)δ 5.35-5.28(m,1H),3.88-3.68(m,1H),2.49-2.37(m,1H),2.18-1.22(m,20H),1.19(d,J=6.0Hz,3H ),1.18-1.14(m,1H),1.11-1.08(m,3H),1.06(s,3H),1.04(s,3H),1.02-0.95(m,1H),0.76(s,3H).

[0273] Preparation of Compounds 11-15 and 11-16. The diastereomeric mixture 11-13 (30 mg, 0.071 mmol) was separated by SFC to give 11-15 (12.2 mg) and 11-16 (14.7 mg) as white powders (total yield: 90%). 1 H NMR(11-15):(400MHz,MeOD)δ 5.32(d,J=5.2Hz,1H),3.85-3.72(m,1H),2.50-2.40(m,1H),2.20-1.57(m,11H),1.52-0.85(m,23H),0.78(s,3H). 1 H NMR(11-16):(400MHz,MeOD)δ 5.32(d,J=5.2Hz,1H),3.85-3.72(m,1H),2.50-2.40(m,1H),2.20-1.45(m,15H),1.40-0.85(m,20H),0.78(s,3H).

[0274] Preparation of Compound 11-19. To a solution of 11-12 (70 mg, 0.16 mmol) in THF (2 mL) was added methylmagnesium bromide (1 mL, 3 mmol, 3 M in ether) at -78 °C. The mixture was stirred at 15 °C for 30 min. Ammonium chloride (aqueous solution) was then added to the mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 8:1) to give 11-19 (39 mg, 55%) as a white solid. 1 H NMR:(400MHz,Methanol-d4)δ 5.33-5.28(m,1H),2.48-2.38(m,1H),2.12-1.70(m,17H),1.23(s,6H),1.20-1.12(m, 3H),1.10(d,J=6.4Hz,3H),1.06(s,3H),1.04(s,3H),1.03-0.91(m,2H),0.76(s,3H).

[0275] Example 12. Preparation of Intermediate 0-9 [ka] Preparation of 0-2. To a solution of compound 0-1 (100 g, 255 mmol, 1.0 eq) in dry MeOH (500 mL) was added concentrated H2SO4 (14 mL). The mixture was heated to reflux overnight and then cooled to room temperature. The mixture was quenched with saturated aqueous NaHCO3 (0.5 L) and then evaporated to remove MeOH. The residual mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated to give the product (100 g crude, 96%) as an off-white powder. 1H NMR:(400MHz,CDCl3)δ 4.09-4.02(m,1H),3.66(s,3H),3.63-3.58(m,1H),2.39-2.31(m,1H),2.25-2.15(m,1H),1 .97-1.91(m,1H),1.91-1.55(m,10H),1.52-1.02(m,14H),0.95-0.88(m,6H),0.62(s,3H).

[0276] Preparation of 0-3. To a solution of compound 0-2 (250 g, 615 mmol, 1.0 eq) in dry pyridine (0.8 L) was added a solution of TsCl (352 g, 1844 mmol, 3.0 eq) in dry pyridine (200 mL). The mixture was stirred at room temperature for 18 hours. Ice chips were slowly added to the mixture, and the precipitated solid was filtered, washed with 10% aqueous HCl (400 mL x 3) and water (400 mL x 2), and then evaporated to dryness to obtain the crude product (500 g, crude) as an off-white powder, which was used directly in the next step.

[0277] Preparation of 0-4. A mixture of compound 0-3 (250 g, crude), CH3COOK (24 g, 245 mmol, 0.77 eq), water (150 mL), and DMF (900 mL) was heated to reflux for 24 h. The solution was cooled to room temperature, and ice chips were slowly added. The precipitated solid was filtered and washed with water (100 mL x 2). The crude solid was purified on a silica gel column (PE / EtOAc = 8 / 1) to give compound 0-4 (40 g, 34.3% yield for two steps) as a white solid. 1 H NMR(400MHz,CDCl3)δ 5.32-5.38(m,1H),3.66(s,3H),3.47-3.57(m,1H),2.16-2.41(m,4H),1.93-2.0 4(m,2H),1.74-1.92(m,4H),1.30-1.59(m,9H),0.90-1.19(m,12H),0.68(s,3H).

[0278] Preparation of 0-5. To a solution of compound 0-4 (33 g, 85 mmol, 1.0 eq) in dry CHCl (700 mL) was added Dess-Martin reagent (72 g, 170 mmol, 2.0 eq) in portions at 0 °C. The reaction mixture was then stirred at room temperature for 1 h. TLC (PE:EA = 3:1) showed that the starting material was completely consumed. The reaction mixture was quenched with a saturated aqueous solution of NaHCO / NaSO = 1:3 (250 mL). The organic phase was washed with brine (200 mL x 2), dried over NaSO, and the solvent was evaporated to give the desired product (35 g, crude), which was used in the next step without further purification.

[0279] Preparation of 0-6. A solution of compound 0-5 (54 g, 0.14 mol, 1.0 eq) in toluene (200 mL) was added dropwise at −78°C under nitrogen to a freshly prepared solution of MAD (0.42 mol, 3.0 eq) in toluene (200 mL) prepared by adding MeAl solution (210 mL, 0.42 mmol, 2 M in hexane) to a stirred solution of 2,6-di-tert-butyl-4-methylphenol (185 g, 0.84 mol) in toluene (200 mL) and stirring at room temperature for 1 h. The reaction mixture was then stirred for 30 min, and a solution of MeMgBr (140 mL, 0.42 mol, 3.0 eq, 3 M in ether) was added dropwise at −78°C. The reaction mixture was warmed to −40°C and stirred at this temperature for 3 h. TLC (PE:EA = 3:1) showed complete consumption of the starting material. The mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (300 mL x 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography eluted with PE:EA = 10:1 to give the pure target (30 g, 53%) as a white powder. 1H NMR:(400MHz,CDCl3)δ 5.31-5.29(m,1H),3.66(s,3H),2.39-2.33(m,2H),2.24-2.22(m,1H),1.99-1.95(m,3H),1.85-1.6 8(m,4H),1.59-1.40(m,8H),1.31-1.26(m,2H),1.17-1.01(m,11H),0.93-0.91(m,4H),0.67(s,3H).

[0280] Preparation of 0-7. To a solution of compound 0-6 (30.0 g, 74.51 mmol) in THF / HO (800 mL, 1 / 1) was added LiOH·HO (17.51 g, 417.28 mmol). The reaction was stirred at room temperature for 18 h. TLC (PE / EA = 2 / 1) showed that compound 0-6 was completely consumed. The mixture was concentrated under reduced pressure, diluted with water (2 L), and then acidified to pH = 4 with 1 M aqueous HCl. The precipitate was collected by filtration and dried under reduced pressure to give the product, compound 0-7 (33 g, crude), as an off-white solid. 1 H NMR:(400MHz,CDCl3)δ 5.31-5.30(m,1H),2.44-2.36(m,2H),2.29-2.24(m,1H),2.01-1.95(m,3H),1.87-1.71(m,5H),1.6 1-1.56(m,2H),1.50-1.32(m,8H),1.17-1.09(m,7H),1.01(s,3H),0.95-0.93(m,4H),0.68(s,3H).

[0281] Preparation of 0-8. A mixture of compound 0-7 (32.0 g, 82.35 mmol), N,O-dimethylhydroxylamine (16.07 g, 164.70 mmol), HATU (37.57 g, 98.82 mmol), and EtN (46.0 mL, 329.40 mmol) in 500 mL of anhydrous CHCl was stirred at room temperature for 18 h. TLC indicated the reaction was complete. CHCl was then added to the mixture, and the resulting solution was washed with water, 1 N HCl, saturated aqueous NaHCO, and brine, dried over anhydrous NaSO, filtered, concentrated, and purified by silica gel (PE:EtOAc = 10:1 to 3:1) to give the target compound 0-8 (17.0 g, yield: 47.8%) as an off-white solid. 1 H NMR:(400MHz,CDCl3)δ 5.31-5.29(m,1H),3.69(s,3H),3.17(s,3H),3.03(s,2H),2.47-2.29(m,3H),2.04-1.68(m,7 H),1.60-1.43(m,7H),1.38-1.30(m,2H),1.20-1.08(m,6H),1.03-0.91(m,8H),0.68(s,3H).

[0282] Preparation of Key Intermediate 0-9. To a solution of compound 0-8 (17.0 g, 39.38 mmol) in 300 mL of anhydrous THF, MeMgBr (65.6 mL, 196.92 mmol, 3 M in ether) was added dropwise at 0 °C under N . After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. TLC showed that the reaction was complete. Saturated aqueous NH Cl was then slowly added to the mixture at 0 °C. The mixture was then poured into water and extracted with EtOAc (200 mL × 2). The organic layer was washed with brine, dried over anhydrous Na SO , filtered, concentrated, and purified on silica gel (PE: EtOAc = 20:1 to 6:1) to give the target compound 0-9 (11.0 g, yield: 72%) as a white solid. 1H NMR:(400MHz,CDCl3)δ 5.31-5.30(m,1H),2.50-2.30(m,3H),2.17(s,2H),2.14(s,3H),2.02-1.94(m,3H),1.88-1.67(m,4H),1. 61-1.58(m,1H),1.56-1.49(m,5H),1.47-1.41(m,2H),1.31-1.11(m,7H),1.08-0.91(m,8H),0.68(s,3H).

[0283] Assay Method The compounds of the present invention can be evaluated using a variety of in vitro and in vivo assays described in the literature, examples of which are described below.

[0284] The following examples are presented to illustrate the biological activity of the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting the scope of the invention in any manner.

[0285] NMDA potentiation NMDA potentiation was assessed using whole-cell patch clamp on mammalian cells expressing NMDA receptors or two-electrode voltage clamp (TEVC) on Xenopus Laevis oocytes expressing NMDA receptors.

[0286] Whole-cell patch clamping of mammalian cells Using the whole-cell patch clamp technique, we observed the effects of compounds (0.1 mM and 1.0 mM) on NMDA receptors (GRIN1 / GRIN2A subunits) expressed in HEK cells. NMDA / glycine peak and steady-state currents were recorded from stably transfected cells expressing NMDA receptors, and the regulatory effects of the test compounds on these currents were observed. The results are shown in Table 1.

[0287] Cells were stably transfected with human GRIN1 (variant NR1-3). These cells were transiently transfected (Lipofectamine™) with GRIN2A cDNA and CD8 (pLeu) antigen cDNA. Approximately 24-72 hours after transfection, 1 μl of Dynabead M-45 CD8 was added to identify successfully transfected cells (Jurman et al., Biotechniques (1994) 17:876-881). Cells were passaged until they reached 50-80% confluence. Cells were seeded onto poly-L-lysine-coated coverslips in 35 mm culture dishes covered with complete culture medium. Confluent cell clusters were electrically connected (Pritchett et al., Science (1988) 242:1306-8). Because responses from distant cells are not adequately voltage-clamped and there is uncertainty about the degree of coupling (Verdoorn et al., Neuron (1990), 4:919-28), cells were cultured at a density that allowed measurements of single cells (with no visible connection to neighboring cells). Cells were incubated at 37°C in a humid atmosphere (approximately 95% relative humidity) with 5% CO2. Cells were continuously maintained and passaged into sterile culture flasks containing a 1:1 mixture of Dulbecco's modified Eagle's medium and nutrient mixture F-12 (D-MEM / F-12 1x, liquid, with L-glutamine), supplemented with 9% fetal bovine serum and 0.9% penicillin / streptomycin solution. The complete medium was supplemented with 3.0 μg / ml puromycin.

[0288] Whole-cell currents were measured using a HEKA EPC-10 amplifier and PatchMaster software. Cell culture dishes for recording were placed in the microscope dish holder and filled with "bath solution" (NaCl 137 mM, KCl 4 mM, CaCl 1.8 mM, MgCl 2 mM). The cells were continuously perfused (1 ml / min) with NMDA bath solution (NaCl 137 mM, KCl 4 mM, CaCl2 2.8 mM, HEPES 10 mM, D-glucose 10 mM, pH (NaOH) 7.4). All solutions applied to the cell-containing pipette were maintained at room temperature (19°C-30°C). After creating a gigahertz seal between the patch electrode and an individual transfected HEK 293 cell (pipette resistance range: 2.5 MΩ-6.0 MΩ; seal resistance range: >1 GΩ), the cell membrane at the pipette tip was disrupted to ensure electrical flow to the cell interior (whole-cell patch configuration). At this point, the bath solution was switched to "NMDA bath solution" (NaCl 137 mM, KCl 4 mM, CaCl2 2.8 mM, HEPES 10 mM, D-glucose 10 mM, Cremophore 0.02%, pH (NaOH) 7.4). 30 μM NMDA (and 5.0 μM glycine) was applied to patch-clamped cells for 5 seconds (applied twice), and NMDA inward currents were measured. Cells were voltage-clamped at a holding potential of -80 mV. For test article analysis, NMDA receptors were stimulated with 30 μM NMDA and 5.0 μM glycine after sequential preincubation with increasing concentrations of test article. The preincubation period was 30 seconds. The stimulation period was 5 seconds. Test articles were dissolved in DMSO to make 0.1 mM and 1 mM stock solutions. Test articles were diluted to 0.1 μM and 1 μM in "NMDA bath solution." Both concentrations of test article were tested on each cell. The same concentration was applied at least three times, or until steady-state current amplitudes were recorded. Each day, one cell was tested using the same application protocol with 50 μm PREGS (positive control) to test whether the cells were successfully transfected with NMDA receptors. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] In Table 1, "A" indicates an enhancement effect of 10 to 75%, "B" indicates an enhancement effect of more than 75% up to 150%, "C" indicates an enhancement effect of more than 150% up to 250%, and "D" indicates an enhancement effect of more than 250%.

[0289] oocyte To observe the effects of compounds (10 μM) on NMDA receptors (GRIN1 / GRIN2A) expressed in Xenopus oocytes, we used the two-electrode voltage clamp (TEVC) technique. Glutamate / glycine peak and steady-state currents were recorded from oocytes expressing NMDA receptors, and the regulatory effects of test compounds on these currents were observed. The results are shown in Table 2.

[0290] Ovaries were collected from deeply anesthetized Xenopus laevis females by immersion in tricaine methanesulfonate (MS-222 at a concentration of 150 mg / L) in sodium bicarbonate (300 mg / L) cooled to 4°C. Once anesthetized, the animals were decapitated and medullary puncture was performed in accordance with the Geneva Cantonal Animal Rights Regulations. Small pieces of ovaries were isolated for immediate preparation while the remaining parts were kept at 4°C in sterile Barth's solution containing, in mM, NaCl 88, KCl 1, NaHCO3 2.4, HEPES 10, MgSO4 7H2O 0.82, Ca(NO3)2 4H2O 0.33, and CaCl2 6H2O 0.41, pH 7.4, supplemented with 20 μg / ml kanamycin, 100 units / ml penicillin, and 100 μg / ml streptomycin. All recordings were made at 18°C, and cells were made superconfluent in medium containing, in mM, NaCl 82.5, KCl 2.5, HEPES 5, CaCl2·2H2O·6H2O 1, pH 7.4.

[0291] Oocytes were injected with cDNA encoding either the human GRIN1 or GRIN2A subunit using a proprietary automated injection device (Hogg et al., J. Neurosci. Methods, (2008) 169:65-75), and receptor expression was assessed using electrophysiology at least two days later. The cDNA injection ratio for GRIN1 and GRIN2A was 1:1. Electrophysiological recordings were performed using a standard automated TEVC process, and data were collected and analyzed using proprietary data acquisition and analysis software running in Matlab (Mathworks Inc.). The membrane potential of oocytes was maintained at -80 mV throughout the experiment. To examine the effects of proprietary compounds, currents were evoked by applying 3 μM glutamate and 10 μM glycine for 10 seconds. Oocytes were then washed for 90 seconds and then exposed to a 10 μM concentration of the test compound for 120 seconds. This was followed immediately by re-application of 3 μM glutamate and 10 μM glycine for 10 seconds. Potentiation of peak and steady-state currents was assessed. For statistical analysis, values were calculated by computer using Excel (Microsoft) or Matlab (Mathworks Inc.). All experiments were performed using at least three cells to obtain the mean of measurements with standard deviation.

[0292] Concentrated stock aqueous solution (10 -1 Glutamate was prepared as a 1 M stock in water and diluted in media to obtain the desired test concentration. Glycine was prepared as a 1 M stock in water. Compounds were prepared as stock DMSO solutions (10 -2 The solution was prepared as a DMSO solution (as described in Example 1) and then diluted with recording medium to obtain the desired test concentration. Residual DMSO did not exceed 1%, a concentration that has been shown not to affect Xenopus oocyte function. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] In Table 2, "A" indicates an enhancement effect of 10 to 50%, "B" indicates an enhancement effect of more than 50% up to 100%, and "C" indicates an enhancement effect of more than 100%.

[0293] As shown in Table 1, compounds with a β-hydrogen at C5 are undesirable due to their loss of potentiation of the NMDA receptor compared to compounds with an α-hydrogen at C5 or a double bond at C5-C6. This is illustrated by the comparison of compounds 5 vs. 4-6 and 4-7. 21Even when the methyl group was removed, the potentiation effect of Comparative Compound 4 was reduced to one-fifth of that of Comparative Compound 3 when measured at a concentration of 0.1 μM, and the NMDA potentiation effect was significantly reduced. Therefore, this compound was 21 The compounds in this selection exhibited excellent potency and limited maximal NMDA receptor potentiation when tested at 1 μM (e.g., comparative compounds 2 vs. 4-6 and 1-11). These properties are expected to limit the risk of inducing glutamate-induced neurotoxicity compared to compounds that achieve greater maximal NMDA receptor potentiation.

[0294] Other embodiments In the claim articles, for example, "a," "an," and "the" shall mean one or more than one unless otherwise indicated or apparent from the context. A claim or description including "or" between one or more members of a group is deemed to be satisfied when one, more than one, or all group members are present in, employed in, or in some way relevant to a given product or process, unless otherwise indicated or apparent from the context. The invention includes embodiments in which one member of the group is actually present in, employed in, or in some way relevant to a given product or process. The invention includes embodiments in which more than one or all group members are present in, employed in, or in some way relevant to a given product or process.

[0295] Furthermore, the present invention encompasses all modifications, combinations, and permutations of one or more limitations, elements, clauses, and descriptive terms from one or more recited claims introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same base claim. Where elements are presented as a list (e.g., in the form of a Markush group), each subset of the elements is also disclosed, and any element may be excluded from the group. In general, when the invention or aspects of the invention are described as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For simplicity, these embodiments have not been specifically set forth in this specification. It is also noted that the terms "comprising" and "containing" are intended to be inclusive and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Additionally, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values expressed as ranges can be presumed to be specific values or subranges within the ranges set forth in different embodiments of the present invention, down to one-tenth of the unit of the lower limit of that range, unless expressly indicated otherwise in the context.

[0296] This application references various published patents, published patent specifications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between an incorporated reference and this specification, the present specification controls. Additionally, any particular embodiment of the present invention that falls within the prior art would be expressly excluded from any one or more claims. Such embodiments would be excluded even if not expressly set forth herein because they are deemed known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0297] 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 embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit and scope of the invention, as defined in the following claims.

Claims

[Claim 1] A device as described in this specification.

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