Neurostimulatory steroids and methods of using the same

Abstract

(3α, 3β) disubstituted 17β steroid compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof are provided for the prevention and treatment of various CNS-related conditions. [Solution] In yet another aspect, a method is provided 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.

Description

Technical Field

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 61 / 779,735, filed on Mar. 13, 2013, which is hereby incorporated by reference in its entirety.

Background Art

[0002] Brain excitation is defined as the arousal level of an animal, is continuous from a coma state to a convulsion state, and is controlled by various neurotransmitters. Generally, neurotransmitters are responsible for controlling the conductance of ions through the nerve unit membrane. At rest, the nerve unit membrane has a potential (i.e., membrane potential) of about -70 mV, and the inside of the cell is negative with respect to the outside of the cell. This potential (voltage) is the result of the balance of ions (K+, Na+, Cl-, organic anions) passing through the semi-permeable nerve unit membrane. Neurotransmitters are stored in synaptic vesicles and are released as a result of the action potential of the nerve. When released into the synaptic cleft, depolarization of the membrane occurs (the potential changes from -70 mV to -50 mV) by an excitatory chemical transmitter such as acetylcholine. This effect is mediated by postsynaptic cell nicotinic receptors stimulated by acetylcholine, and the membrane permeability to Na+ ions increases. This decrease in membrane potential increases the likelihood of generating an action potential in the postsynaptic cell that enhances the excitability of the neuron.

[0003] NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission. When these receptors are activated, in certain situations, they cause synaptic plasticity, and in other situations, they cause excitation. These receptors are ligand-gated ion channels, and after the neurotransmitters glutamate and glycine bind, Ca 2+permits the passage and underlies excitatory neurotransmission and normal CNS function. The NMDA receptor is a heteromeric complex composed of NR1, NR2, and / or NR3 subunits and has distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. Positive modulators may be useful as therapeutic agents with potential clinical applications as recognition enhancers and in the treatment of mental disorders in which glutamatergic transmission is reduced or defective (see, for example, Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators may be useful as therapeutic agents (agenst) with potential clinical applications in the treatment of mental disorders in which glutamatergic transmission is pathologically increased (e.g., treatment-resistant depression).

[0004] Neurosteroids, such as pregnenolone sulfate (PS), have been shown to exert direct regulatory effects on several types of neurotransmitter receptors, such as GABAA, glycine, AMPA, kainate, and NMDA receptors. The NMDA receptor is positively regulated by PS, but the degree of regulation varies considerably, depending, for example, on the subunit composition of the receptor.

[0005] In addition to PS, several other 3β-hydroxy steroids have been shown to enhance NMDA receptors (see, for example, Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682). In recent years, a 3β-hydroxy-ergosta-5-ene steroid derivative (referred to as Org-1) has been reported to be a positive modulator of NMDA (NR1a / NR2A). Org-1 has been found to selectively regulate NMDA rather than GABAA (see, for example, 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).

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Summary of the Invention

Means for Solving the Problems

[0007] During the search for Org-1 analogs for NMDA modulation, the inventors of the present invention discovered a combination of some specific elements that provide an NMDA modulator with relatively excellent properties from a part of what is described in PCT / US2012 / 054261 incorporated herein by reference. For example, as shown in Table 1, compounds having a β-hydrogen at C5 are undesirable compared to compounds having an α-hydrogen at C5 or a double bond between C5 and C6 due to the lack of an enhancing effect on the NMDA receptor. The removal of the methyl at C 21 also results in a significant loss of the enhancing effect on the NMDA receptor. Disubstitution at C3 is expected to enhance the metabolic stability of these compounds and is thus a preferred feature of the present invention. C 17 Fluorination in the side chain has been shown to enhance the efficacy of the NMDA receptor and limit the maximum enhancing effect when tested with compounds at a concentration of about 1 μM. C 17Secondary or tertiary terminal alcohols in the side chain have been shown to enhance the efficacy of the NMDA receptor and limit the maximal enhancing effect when tested with compounds at a concentration of about 1 μM. Therefore, it is a preferred feature of the present invention that a bulkier group containing 2 to 3 carbons at the end, or a group containing a fluorine substituent, is preferred. Such properties are expected to limit the risk of inducing glutamate-induced neurotoxicity for compounds achieving a greater maximal enhancing effect on the NMDA receptor. The compounds of the present invention encompass various combinations of these specific features that provide excellent NMDA modulators. The present invention provides, for example, the following items. (Item 1) A compound of formula (I):

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[0008] Accordingly, in one aspect, a compound of formula (I): [Chemical formula] [Wherein, 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 -ORA2 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, R 3b is hydrogen or; alternatively R 3a and R 3b are connected 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 are connected to form a double bond; In each case, R 5a and R 5b are independently hydrogen or fluorine; R 6a is a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted carbocyclic groups, substituted and unsubstituted heterocyclic groups, substituted and unsubstituted aryl groups and substituted and unsubstituted heteroaryl groups, and the non-hydrogen group is optionally substituted with fluorine; R 6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine;

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

[0010] In yet another aspect, there is provided a method for treating or preventing a condition associated with the CNS related to 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 condition associated with the CNS 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 mood dysregulation disorder), schizophrenia or other mental disorders (including schizoaffective disorder), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including those associated with mutations in Shank family proteins), a neurodevelopmental disorder (including Rett syndrome), pain (including acute and chronic pain), a seizure disorder (including status epilepticus and monogenic epilepsy, such as Dravet syndrome and tuberous sclerosis complex (TSC)), stroke, 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 a sedative or anesthetic effect.

[0011] Other objects and advantages will be apparent to those skilled in the art upon consideration of the following detailed description, examples and claims.

Best Mode for Carrying Out the Invention

[0012] Definitions Chemical Definitions The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, 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 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 in the present invention may contain one or more asymmetric centers and thus 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 in the form of mixtures rich in racemic mixtures and one or more stereoisomers. The isomers may be isolated from the mixture 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 the 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 (E.L. Eliel, Ed., Univ. 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 recited, it is intended to include each value and sub-ranges within that range. For example, "C" 1~6 alkyl" includes 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 is intended to include alkyl.

[0015] The following terms are intended to have the meanings presented below and are useful for understanding the description of the invention and the intended scope of the invention. When describing the present invention, it may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions. The following terms, when present and unless otherwise indicated, have the following meanings. As described herein, any moiety defined below may be substituted with various substituents, and each definition is intended to include such substituted moieties within its scope as described below. Unless otherwise stated, the term "substituted" should be defined as shown below. Further, it should be understood that the terms "group" and "radical" can be considered interchangeable as 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 that article. By way of example, "an analogue" means one analogue, or more than one analogue.

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

[0017] "Alkyl" refers to a radical of a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 20 carbon atoms ("C 1~20 alkyl"). In certain embodiments, the alkyl group contains 1 to 12 carbon atoms ("C 1~12 alkyl"). In certain embodiments, the alkyl group contains 1 to 10 carbon atoms ("C 1~10 alkyl"). In certain embodiments, the alkyl group contains 1 to 9 carbon atoms ("C 1~9"alkyl"). In certain embodiments, the alkyl group contains 1 to 8 carbon atoms ("C 1~8 alkyl"). In certain embodiments, the alkyl group contains 1 to 7 carbon atoms ("C 1~7 alkyl"). In certain embodiments, the alkyl group contains 1 to 6 carbon atoms ("C 1~6 alkyl", also referred to herein as "lower alkyl"). In certain embodiments, the alkyl group contains 1 to 5 carbon atoms ("C 1~5 alkyl"). In certain embodiments, the alkyl group contains 1 to 4 carbon atoms ("C 1~4 alkyl"). In certain embodiments, the alkyl group contains 1 to 3 carbon atoms ("C 1~3 alkyl"). In certain embodiments, the alkyl group contains 1 to 2 carbon atoms ("C 1~2 alkyl"). In certain embodiments, the alkyl group contains 1 carbon atom ("C1 alkyl"). In certain embodiments, the 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-butanil (C5), tertiary amyl (C5) and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, in each case the alkyl group 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, the alkyl group is unsubstituted C 1~10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1~10It is alkyl. Abbreviations for common alkyls include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3) or i-Bu (-CH2CH(CH3)2).

[0018] As used herein, "alkylene", "alkenylene", and "alkynylene" each refer to a divalent radical of an alkyl group, an alkenyl group, and an alkynyl group, respectively. When a range or number of carbons is given for a particular "alkylene" group, "alkenylene" group, and "alkynylene" group, that range or number is understood to refer to the range or number of carbons in the divalent chain of straight-chain carbons. The "alkylene" group, "alkenylene" group, and "alkynylene" group may or may not be substituted with one or more substituents as described herein.

[0019] "Alkylene" refers to an alkyl group from which two hydrogens have been removed to give a divalent radical, which may or may not be substituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Exemplary substituted alkylene groups, such as 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)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0020] "Alkenyl" refers to a radical of a linear or branched hydrocarbon group containing 2 to 20 carbon atoms, including one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally including one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ( "C 2~20 alkenyl"). In certain embodiments, alkenyl does not contain any triple bonds. In one embodiment, the alkenyl group contains 2 to 10 carbon atoms ( "C 2~10 alkenyl"). In one embodiment, the alkenyl group contains 2 to 9 carbon atoms ( "C 2~9 alkenyl"). In one embodiment, the alkenyl group contains 2 to 8 carbon atoms ( "C 2~8 alkenyl"). In one embodiment, the alkenyl group contains 2 to 7 carbon atoms ( "C 2~7 alkenyl"). In one embodiment, the alkenyl group contains 2 to 6 carbon atoms ( "C 2~6 alkenyl"). In one embodiment, the alkenyl group contains 2 to 5 carbon atoms ( "C 2~5 alkenyl"). In one embodiment, the alkenyl group contains 2 to 4 carbon atoms ( "C 2~4 alkenyl"). In one embodiment, the alkenyl group contains 2 to 3 carbon atoms ( "C 2~3 alkenyl"). In one embodiment, the alkenyl group contains 2 carbon atoms ( "C2 alkenyl"). One or more carbon-carbon double bonds may 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. C 2~6 Examples of alkenyl groups include the above-described C 2~4Alkenyl groups and pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. can be mentioned. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatriene (C8), etc. Unless otherwise specified, the alkenyl group in each case is independently optionally substituted, that is, unsubstituted ( "unsubstituted alkenyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ( "substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2~10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2~10 alkenyl.

[0021] "Alkenylene" refers to an alkenyl group from which two hydrogens have been removed to give 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 (for example, -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, 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 (for example, -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)-), etc.

[0022] "Alkynyl" contains 2 to 20 carbon atoms, contains one or more carbon-carbon triple bonds (for example, 1, 2, 3 or 4 carbon-carbon triple bonds), and optionally contains one or more carbon-carbon double bonds (for example, 1, 2, 3 or 4 carbon-carbon double bonds), and refers to the radical of a straight-chain or branched-chain hydrocarbon group ( "C 2~20"alkynyl"). In certain embodiments, the alkynyl does not contain any double bonds. In some embodiments, the alkynyl group contains from 2 to 10 carbon atoms ("C 2~10 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 9 carbon atoms ("C 2~9 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 8 carbon atoms ("C 2~8 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 7 carbon atoms ("C 2~7 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 6 carbon atoms ("C 2~6 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 5 carbon atoms ("C 2~5 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 4 carbon atoms ("C 2~4 alkynyl"). In some embodiments, the alkynyl group contains from 2 to 3 carbon atoms ("C 2~3 alkynyl"). In some embodiments, the alkynyl group contains 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may 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. C 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 alkynyl groups and pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, in each case the alkynyl group 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, the alkynyl group is unsubstituted C 2~10 alkynyl. In certain embodiments, the alkynyl group is substituted C2~10 is alkynyl.

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

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

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

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

[0027] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" each refer to a divalent radical of an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a heteroalkenyl group, and a heteroalkynyl group, respectively. When a range or a number of carbons is given for a particular "alkylene" group, "alkenylene" group, "alkynylene" group, "heteroalkylene" group, "heteroalkenylene" group, or "heteroalkynylene" group, that range or number is understood to refer to the range or number of carbons in the divalent chain of straight-chain carbons. The "alkylene" group, "alkenylene" group, "alkynylene" group, "heteroalkylene" group, "heteroalkenylene" group, or "heteroalkynylene" group may or may not be substituted with one or more substituents as described herein.

[0028] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) cyclic radical of a 4n+2 aromatic ring system (e.g., containing 6π, 10π, or 14π electrons aligned in a ring and shared) containing 6 to 14 ring carbon atoms and 0 heteroatoms in the aromatic ring system (e.g., "C 6~14 aryl"). In certain embodiments, the aryl group contains 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In certain embodiments, the aryl group contains 10 ring carbon atoms ("C 10"Aryl"; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl). In certain embodiments, the aryl group contains 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracyl). "Aryl" also includes a ring system in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups and the linking radical or point of attachment is on the aryl ring, in which case the number of carbon atoms is consecutive as indicating the number of carbon atoms of the aryl ring system. Representative 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. In particular, aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise specified, the aryl group in each case is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C 6~14 aryl. In certain embodiments, the aryl group is substituted C 6~14 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] Examples of representative substituted aryls include [Chemical formula] include wherein, R 56 and R 57 one of which may be hydrogen, and R 56 and R 57 at least one of which is independently C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 COO alkyl, COO aryl, CONR 58 R 59 CONR 58 OR 59 NR 58 R 59 SO2NR 58 R 59 S-alkyl, SO alkyl, SO2 alkyl, S aryl, SO aryl, SO2 aryl; or R 56 and R 57 may combine to form a cyclic ring (saturated or unsaturated) of 5-8 atoms optionally containing one or more heteroatoms selected from the group of 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 aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl.

[0031] Other representative aryl groups containing a fused heterocyclyl group include the following,

Chemical formula

[0032] "Fused aryl" refers to an aryl containing two ring carbons that are commonly shared with a second aryl ring or heteroaryl ring, or a carbocyclic ring or heterocyclic ring.

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

[0034] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system that contains ring carbon atoms and 1 to 4 ring heteroatoms in an aromatic ring system, with each heteroatom independently selected from nitrogen, oxygen, and sulfur (e.g., containing 6π or 10π electrons arranged in a cyclic and shared manner) ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as permitted by the valence. The bicyclic ring system of heteroaryl may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups and the point of attachment is on the heteroaryl ring, and in such a case, the number of ring atoms is consecutive as indicating the number of ring atoms of the heteroaryl ring system. "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused to one or more aryl groups and the point of attachment is on the aryl ring or the heteroaryl ring, and in such a case, the number of ring atoms is consecutive as indicating the number of ring atoms of the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group 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., on the ring containing a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl).

[0035] In certain embodiments, the heteroaryl group comprises ring carbon atoms provided in an aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently being a 5- to 10-membered aromatic ring system selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl"). In certain embodiments, the heteroaryl group comprises ring carbon atoms provided in an aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently being a 5- to 8-membered aromatic ring system selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl"). In certain embodiments, the heteroaryl group comprises ring carbon atoms provided in an aromatic ring system and 1 to 4 ring heteroatoms, each heteroatom independently being a 5- to 6-membered aromatic ring system selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl"). In certain embodiments, the 5- to 6-membered heteroaryl contains 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl contains 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heteroaryl contains 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, in each case the heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0036] Exemplary 5-membered ring heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered ring heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered ring heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered ring heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered ring heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered ring heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered ring heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered ring 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, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, 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] Examples of representative heteroaryls include the following,

Chemical Structure

[0038] "Heteroalkyl" 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 "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group containing 3 to 10 ring carbon atoms ("C 3~10 carbocyclyl") and 0 heteroatoms. In certain embodiments, the carbocyclyl group contains 3 to 8 ring carbon atoms ("C 3~8 carbocyclyl"). In certain embodiments, the carbocyclyl group contains 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In certain embodiments, the carbocyclyl group contains 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In certain embodiments, the 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 (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3~8 carbocyclyl groups include, but are not limited to, the above-mentioned C 3~6Carbocyclic groups, and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. may be mentioned. Exemplary C 3~10 As the carbocyclic group, although not limited, the above-mentioned C 3~8 Carbocyclic groups, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), etc. may be mentioned. When showing the above examples, in a specific embodiment, the carbocyclic group is a monocyclic ring ("monocyclic carbocyclic"), or a fused ring system, a bridged ring system, or a spiro ring system, for example, a bicyclic system ("bicyclic carbocyclic"), and may be saturated or partially unsaturated. "Carbocyclic" also includes a ring system in which a carbocyclic ring as defined herein is fused with one or more aryl groups or heteroaryl groups, and the bonding point is on the carbocyclic ring. In such a case, the number of carbons is consecutive as indicating the number of carbons in the carbocyclic ring system. Unless otherwise specified, the carbocyclic group in each case is independently optionally substituted, that is, unsubstituted ("unsubstituted carbocyclic") or substituted with one or more substituents ("substituted carbocyclic"). In a specific embodiment, the carbocyclic group is an unsubstituted C 3~10 carbocyclic. In a specific embodiment, the carbocyclic group is a substituted C 3~10 carbocyclic.

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

[0041] "Heterocyclyl" or "heterocyclic ring" contains ring carbon atoms and 1 to 4 ring heteroatoms, and each heteroatom independently refers to a radical of a 3- to 10-membered non-aromatic ring system selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the bonding point may be a carbon atom or a nitrogen atom as long as the valence allows. The heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or include a fused ring system, a bridged ring system, or a spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The bicyclic heterocyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" refers to a ring system in which a heterocyclyl ring as defined herein is fused with one or more carbocyclic groups and the bonding point is on the carbocyclic ring or the heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined herein is fused with one or more aryl groups or heteroaryl groups and the bonding point is on the heterocyclyl ring. In such cases, the number of ring atoms is consecutive as indicating the number of ring atoms of the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl in each case 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, the heterocyclyl group comprises ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently being a 5- to 10-membered non-aromatic ring system selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In certain embodiments, the heterocyclyl group comprises ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently being a 5- to 8-membered non-aromatic ring system selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In certain embodiments, the heterocyclyl group comprises ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently being a 5- to 6-membered non-aromatic ring system selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In certain embodiments, the 5- to 6-membered heterocyclyl contains 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl contains 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclyl contains 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

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

[0044] Specific examples of the heterocyclic group are shown in the following specific examples,

Chemical formula

[0045] "Hetero" means that one or more carbon atoms of the compound or group are replaced by heteroatoms such as nitrogen, oxygen or sulfur when used to describe a compound or a group present on the compound. Hetero may be applied to any of the above hydrocarbyl groups, for example, alkyl containing 1 to 5, especially 1 to 3 heteroatoms, such as heteroalkyl, cycloalkyl, such as heterocyclyl, aryl, such as heteroaryl, cycloalkenyl, such as cycloheteroalkenyl, and the like.

[0046] "Acyl" refers to -C(O)R 20 a radical, and R 20 is, as defined herein, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. "Alkanoyl" is an acyl group in which R 20 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- to 10-membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclic), where t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic, C6-C 10 aryl, arylalkyl, 5- to 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" refers to -NR 22 C(O)R 23 a radical, where R 22 and R 23is, independently, as defined herein, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, 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. Particularly exemplary "acylamino" groups are -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 (4-10-membered heterocyclic), where t is an integer from 0 to 4, and each R 24 independently represents 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 heterocyclic, 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 heterocyclic, C6-C 10Aryl, arylalkyl, 5- to 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 which is other than H.

[0048] "acyloxy" refers to the -OC(O)R 27 radical, where R 27 is, as defined herein, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. 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- to 10-membered heterocyclic, C6-C 10 aryl, arylalkyl, 5- to 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" refers to the -OR 29 group, where R 29is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. In particular, alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. In particular, 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 one or more substituents selected from the group consisting of amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic, 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-, for example, 1 to 5 substituents, in particular, 1 to 3 substituents, in particular, a group containing 1 substituent. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl) and -O-(CH2) t(4- to 10-membered heteroaryl), where t is an integer from 0 to 4, and any aryl group, heteroaryl group, cycloalkyl group or heteroaryl group itself may 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 an amino group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, 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 is independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heteroaryl 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- to 10-membered heteroaryl), -(CH2) t (C3-C 10 cycloalkyl) or -(CH2) tSelected from (4- to 10-membered heterocyclyl), t is an integer from 0 to 8, each being unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or substituted with hydroxy; or both Rs 38 groups are connected 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- to 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 from 0 to 4, for example, 1 or 2, each R 39 independently represents H or C1-C8 alkyl; any alkyl group present itself may be substituted with halo, substituted or unsubstituted amino or hydroxy; any aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group present itself may 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. To avoid confusion, the term "substituted amino" includes alkylamino groups, substituted alkylamino groups, alkylarylamino groups, substituted alkylarylamino groups, arylamino groups, substituted arylamino groups, dialkylamino groups and substituted dialkylamino groups as defined below. Substituted amino includes both mono-substituted amino groups and di-substituted amino groups.

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

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

[0056] "Substituted carbamoyl" or "substituted amide" refers to the -C(O)N(R 62 )2 radical, where each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, and at least one of the Rs 62 is not hydrogen. In certain embodiments, R 62 is H, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic, 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 heterocyclic, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, 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; provided that at least one of the Rs 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 10(cycloalkyl) and -C(O)NR 64 -(CH2) t (a 4- to 10-membered heterocyclyl), t is an integer from 0 to 4, and each R 64 independently represents H or C1-C8 alkyl, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present per se may 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, the 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 by 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] "Heterocyclic alkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclic group. Typical heterocyclic alkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0065] "Cycloalkenyl" refers to a substituted or unsubstituted carbocyclic group containing 3 to 10 carbon atoms, including one cyclic ring or a plurality of fused rings, including fused ring systems and bridged ring systems, and containing at least one, particularly 1 to 2 sites of olefinic unsaturation. Examples of such cycloalkenyl groups include monocyclic structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[0066] "Fused cycloalkenyl" refers to a cycloalkenyl having 2 ring carbon atoms commonly shared with a second aliphatic or aromatic ring and having an olefinic unsaturation portion positioned to impart aromaticity to the cycloalkenyl ring.

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

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

[0069] "Ethynyl" refers to -(C≡C)-.

[0070] The "nitrogen-containing heterocyclyl" group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, and examples include, but are 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-alkylpiperazine, such as N-methylpiperazine. In particular, examples include azetidine, piperidone, and piperazone.

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

[0072] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, 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" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a given group (e.g., a carbon atom or a nitrogen atom) is replaced by an acceptable substituent, e.g., a substituent that results in a stable compound upon substitution, e.g., a compound that is not naturally subject to transformation by rearrangement, cyclization, elimination or other reactions. Unless otherwise indicated, a "substituted" group contains a substituent at one or more substitutable positions of that group, and when substituted at more than one position in a given structure, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all acceptable substituents of organic compounds, any of the substituents described herein that form stable compounds. The present invention contemplates any or all of such combinations to reach stable compounds. For the purposes of the present invention, a heteroatom, e.g., nitrogen, may have a hydrogen substituent and / or any suitable substituent as described herein that satisfies the valence of the heteroatom and forms a stable moiety.

[0073] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -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 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl and 5- to 14-membered heteroaryl, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; or alternatively, two geminal hydrogens on a carbon atom are replaced with a group of =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 groups; In each case, R aa is independently C 1~10 alkyl, C 1~10 perhaloalkyl, C 2~10Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclic, 3- to 14-membered heterocyclic, C 6~14 Selected from aryl and 5- to 14-membered heteroaryl, or two R aa groups are connected to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; In each case, R bb is independently 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 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 Carbocyclic, 3- to 14-membered heterocyclic, C 6~14 Selected from aryl and 5- to 14-membered heteroaryl, or two R bbThe group is connected to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; In each case, R cc is independently selected from hydrogen, C 1~10 alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups are connected to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; In each case, R dd is independently halogen, -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 Carbocyclic, 3 - to 10 - membered heterocyclic, C 6~10 Aryl, 5 - to 10 - membered heteroaryl, selected from, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents may be connected to form =O or =S; In each case, R ee is independently C 1~6 Alkyl, C1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclic, C 6~10 Selected from aryl, 3- to 10-membered heterocyclyl and 3- to 10-membered heteroaryl, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups; In each case, R ff is independently hydrogen, C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 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 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups; In each case, R gg is 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 1~6(alkyl), -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 1~6(alkyl), 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 (carbocyclic, C 6~10 (aryl, a 3- to 10-membered heterocyclic ring, or a 5- to 10-membered heteroaryl; or two geminal R gg (substituents may be connected to form =O or =S; X - (is a counterion.

[0074] (The term "counterion" or "anionic counterion" refers to 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 - (, OH - (, H2PO4 - (, HSO4 - (, SO4 -2 (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, ethanate ion, propionate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, etc.).

[0075] The nitrogen atom may be substituted or unsubstituted as long as its valence allows, and includes 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 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups connected to the nitrogen atom are connected to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R dd are as defined above.

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

[0077] Other definitions The term "pharmaceutically acceptable salt" refers to salts that are within the scope of sound medical judgment, have no excessive toxicity, irritation, allergic response, etc., have a reasonable benefit / risk ratio, and are suitable for use in contact with the tissues of humans and lower animals. 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 (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as 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, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4Examples of the (alkyl)4 salts include. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations made from suitable counterions (e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitric acid, lower alkyl sulfonates, and aryl sulfonates).

[0078] Examples of the "subject" for which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., teenagers, 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] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0080] As used herein and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate an operation (a "therapeutic treatment") that is performed while a subject is suffering from a particular disease, disorder, or condition and that reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition, and also contemplate an operation that is performed before a subject suffers from a particular disease, disorder, or condition (a "preventive 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 of skill in the art, the effective amount of the compounds of the invention will vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration and the age, health and condition of the subject. Effective amounts include therapeutic and prophylactic treatments.

[0082] As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to produce 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, alone or in combination with other therapeutic agents, means an amount of a therapeutic agent that produces a therapeutic effect in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids the cause of a symptom or 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 a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or to prevent its occurrence. A prophylactically effective amount of a compound, alone or in combination with other therapeutic agents, means an amount of a therapeutic agent that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis and enhances the prophylactic efficacy of another prophylactic agent.

[0084] DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION In the midst of the search for Org-1 analogs for NMDA modulation, the inventors of the present invention discovered, from among a part of what is described in PCT / US2012 / 054261 incorporated herein by reference, some specific combinations of elements that give NMDA modulators with relatively excellent properties. For example, as shown in Table 1, compounds having a β-hydrogen at C5 are undesirable compared to compounds having an α-hydrogen at C5 or a double bond between C5 and C6 due to the lack of an enhancing effect on the NMDA receptor. C 21 Removal of the methyl at C also results in a marked loss of the enhancing effect on the NMDA receptor. Disubstitution at C3 is expected to enhance the metabolic stability of these compounds and is thus a preferred feature of the present invention. C 17 Fluorination in the side chain has been shown to enhance the efficacy of the NMDA receptor and limit the maximum enhancing effect when tested with compounds at a concentration of about 1 μM. C 17 Secondary or tertiary terminal alcohols in the side chain have been shown to enhance the efficacy of the NMDA receptor and limit the maximum enhancing effect when tested with compounds at a concentration of about 1 μM and are thus a preferred feature of the present invention, and a bulkier group containing 2 to 3 carbons at the end or a group containing a fluorine substituent is preferred. Such properties are expected to limit the risk of inducing glutamate-induced neurotoxicity for compounds achieving a greater maximum enhancing effect on the NMDA receptor. The compounds of the present invention encompass various combinations of these specific features that give excellent NMDA modulators.

[0085] Compound In one aspect, a compound of formula (I): [Chemical formula] [wherein, R 1 is a substituted or unsubstituted aliphatic; R 2 is hydrogen, halogen, a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted cyclopropyl or -ORA2 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, R 3b is hydrogen or; or R 3a and R 3b are connected 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 are connected to form a double bond; In each case, R 5a and R 5b are independently hydrogen or fluorine; R 6a is a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted carbocyclic groups, substituted and unsubstituted heterocyclic groups, substituted and unsubstituted aryl groups and substituted and unsubstituted heteroaryl groups, and the non-hydrogen group is optionally substituted with fluorine; R 6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine;

Chemical formula

[0086] As generally described herein, compounds in which the C5 hydrogen is given in the β conformation show loss of the potentiating effect of NMDA compared to compounds in which the C5 hydrogen is α or compounds in which there is a double bond between C5-C6. Thus, the compounds of formula (I) are the compounds of formula (I-A) and (I-B)

Chemical formula

[0087] R 1 group As generally defined herein, R 1 is a substituted or unsubstituted aliphatic, i.e., a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl or a substituted or unsubstituted carbocyclic.

[0088] In certain embodiments, R 1 is a substituted or unsubstituted alkyl, e.g., a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted C 1~2 alkyl, a substituted or unsubstituted C 2~3 alkyl, a substituted or unsubstituted C 3~4 alkyl, a substituted or unsubstituted C 4~5 alkyl or a substituted or unsubstituted C 5~6 alkyl. Exemplary R 1 of C 1~6Examples of the alkyl group 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-butanil (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 alkyl (e.g., -CH2Cl, -CHCl2) and C substituted with an alkoxy group 1~6 alkyl (e.g., -CH2OCH3, -CH2OCH2CH3, -CH2O-cyclopropyl). In certain embodiments, R 1 is a substituted alkyl, for example, R 1 is a 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 an unsubstituted C 1~3 alkyl, for example, R 1 is -CH3, -CH2CH3 or -CH2CH2CH3.

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

[0091] In certain embodiments, R 1 is alkyl substituted with one or more -OR A1 groups, and R A1 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 1 is -CH2OR A1 where, for example, R A1 is hydrogen, -CH3, -CH2CH3 or -CH2CH2CH3.

[0092] In certain embodiments, R 1 is substituted or unsubstituted alkenyl, such as 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 alkenyl. In certain embodiments, R 1 is unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl or hydroxyl, and is ethenyl (C2), propenyl (C3) or butenyl (C4). In certain embodiments, R 1 is unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl or hydroxy, and is ethenyl, propenyl or butenyl. In certain embodiments, R 1 is ethenyl.

[0093] In certain embodiments, R 1 is substituted or unsubstituted alkynyl, such as 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 1Examples of the alkynyl group include, but are not limited to, unsubstituted or substituted ethynyl, propynyl or butynyl with alkyl, halo, haloalkyl (e.g., CF3), 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. In certain embodiments, R 1 is ethynyl (C2), propynyl (C3) or butynyl (C4) which is 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 carbocyclic and substituted or unsubstituted heterocyclic. In certain embodiments, R 1 is ethynyl (C2), propynyl (C3) or butynyl (C4) substituted with substituted phenyl. In certain embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino or amide. 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 which is 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 that is unsubstituted or substituted with phenyl that is unsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl or acyl. In certain embodiments, R 1 is ethynyl or propynyl that is substituted with substituted or unsubstituted carbocyclic. In certain embodiments, R 3a is ethynyl or propynyl that is substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In certain embodiments, R 1 is ethynyl or propynyl that is substituted with substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is ethynyl or propynyl that is substituted with substituted or unsubstituted pyridinyl or pyrimidinyl. In certain embodiments, R 1 is ethynyl or propynyl that is 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 that is substituted with substituted or unsubstituted heterocyclyl. In certain embodiments, R 1 is ethynyl or propynyl that is substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. In certain embodiments, R 1 is propynyl or butynyl that is substituted with hydroxyl or alkoxy. In certain embodiments, R 1 is propynyl or butynyl that is substituted with methoxy or ethoxy. In certain embodiments, R 1 is ethynyl or propynyl that is substituted with chloro. In certain embodiments, R 1 is ethynyl or propynyl that is substituted with trifluoromethyl.

[0095] In certain embodiments, R 1is a substituted or unsubstituted carbocyclic, e.g., a substituted or unsubstituted C 3~6 carbocyclic, a substituted or unsubstituted C 3~4 carbocyclic, a substituted or unsubstituted C 4~5 carbocyclic or a substituted or unsubstituted C 5~6 carbocyclic. In certain embodiments, R 1 is a substituted or unsubstituted cyclopropyl or a substituted or unsubstituted cyclobutyl.

[0096] R 2 , R 3a , R 3b and R 4 groups As generally defined herein, R 2 is hydrogen, halogen, a substituted or unsubstituted C 1~6 alkyl, a substituted or unsubstituted cyclopropyl or -OR A2 and R A2 is hydrogen or a substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halogen, e.g., 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., a substituted or unsubstituted C 1~2 alkyl, a substituted or unsubstituted C 2~3 alkyl, a substituted or unsubstituted C 3~4 alkyl, a substituted or unsubstituted C 4~5 alkyl or a substituted or unsubstituted C 5~6 alkyl. In certain embodiments, R 2 is -CH3, -CH2CH3, -CH2CH2CH3, or cyclopropyl. In certain embodiments, R 2 is -OR A2 . In certain embodiments, R A2 is hydrogen. In certain embodiments, R A2is a substituted or unsubstituted alkyl, for example, 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 alkyl. In certain embodiments, R A2 is hydrogen, -CH3, -CH2CH3 or -CH2CH2CH3, that is, R of the formula -OH, -OCH3, -OCH2CH3 or -OCH2CH2CH3 2 group. In certain embodiments, R 2 is a substituent that is not hydrogen in the α - conformation. In certain embodiments, R 2 is a substituent that is not hydrogen in the β - conformation.

[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 is -OR A3 and R 3b is hydrogen. In certain embodiments, R 3a is -OR A3 and R 3a is in the α - conformation or β - conformation. In certain embodiments, R3a is -OR A3 and R 3a is in the α - conformation. In certain embodiments, R 3a is -OR A3 and R 3a is in the β - conformation. In certain embodiments, R A3 is hydrogen. In certain embodiments, R A3 is substituted or unsubstituted alkyl, for example, 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 alkyl. In certain embodiments, R A3 is hydrogen, -CH3, -CH2CH3 or -CH2CH2CH3, that is, R 3a groups giving -OH, -OCH3, -OCH2CH3 or -OCH2CH2CH3.

[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 substituted or unsubstituted alkyl, for example, 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 alkyl. In certain embodiments, R 4 is C1 alkyl, for example, -CH3 or -CF3. In certain embodiments, R 4 is hydrogen, -CH3 or -F. In certain embodiments, [Chemistry] represents a single bond, and R 4 is a substituent that is not a hydrogen in the α - conformation. In certain embodiments, [Chemistry] represents a single bond, and R 4 is a substituent that is not a hydrogen in the β - conformation.

[0102] X, R 5a , R 5b , R 6a and R 6b groups As generally defined herein, X is -C(R X )2- or -O-, 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 is independently hydrogen or fluorine; R 6a is a non - hydrogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclic, substituted and unsubstituted heterocyclic, substituted and unsubstituted aryl and substituted and unsubstituted heteroaryl groups, and the non - hydrogen group is optionally substituted with fluorine; R 6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; provided that (1) at least one of R X , R 5a and R 5b is fluorine; or (2) at least one of R 6a and R 6b 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 which is hydrogen. In certain embodiments, R 5a and R 5b at least one of which is fluorine. In certain embodiments, R 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 group other than hydrogen as described herein and is not substituted with fluorine. In certain embodiments, R 6a is substituted or unsubstituted alkyl (e.g., -CH3, -CH2CH3, -CH(CH3)2), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted carbocyclic (e.g., isopropanol). In certain embodiments, R 6a is a group other than hydrogen as described herein and is substituted with fluorine.

[0106] In certain embodiments, R 6a is a group other than hydrogen as described herein, and R 6b is hydrogen. In certain embodiments, R 6a is a group other than hydrogen 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 not substituted with fluorine. In certain embodiments, R6a is an alkyl group substituted with fluorine.

[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, 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 alkyl. In certain embodiments, R 6b is a 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, 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 alkyl. Exemplary R 6a of C 1~6Examples of the alkyl group 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 iso-butyl (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-butanil (C5), substituted or unsubstituted tertiary amyl (C5), and substituted or unsubstituted n-hexyl (C6). In certain embodiments, R 6a is, as described above, alkyl substituted with one or more fluorines, for example, 1, 2, 3, 4, or more fluorines. In certain embodiments, R 6a is -CF3, -CH2F, -CHF2, difluoroethyl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl). In certain embodiments, R 6a is, as described above, alkyl substituted with one or more -OR A6 groups, where 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 optionally fluorine-substituted, substituted or unsubstituted alkenyl, for example, 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 5~6is alkenyl. In certain embodiments, R 6a is substituted or unsubstituted vinyl (C2) or substituted or unsubstituted allyl (C3).

[0110] In certain embodiments, R 6a is substituted or unsubstituted alkynyl, optionally substituted with fluorine, for example, 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. In certain embodiments, R 6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C3).

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

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

[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, a optionally substituted 5- to 6-membered heteroaryl.

[0115] In certain embodiments, R 6a is a group other than hydrogen containing 2 to 10 carbon atoms, for example, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms (including the boundary values). For example, in certain embodiments, R 6a is a substituted or unsubstituted C 2~3 alkyl, a substituted or unsubstituted C 2~3 alkenyl, a substituted or unsubstituted C 2~3 alkynyl or a substituted or unsubstituted C3 carbocyclic.

[0116] In certain embodiments, R X , R 5a and R 5b at least one of is fluorine; or R 6a and R 6b at least one of is a group other than hydrogen substituted with fluorine; R 6a is a substituted or unsubstituted C 1~3 alkyl, a substituted or unsubstituted C 1~3 alkenyl, a substituted or unsubstituted C 1~3 alkynyl or a substituted or unsubstituted C3 carbocyclic.

[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 the carbon to which R 6a is attached is in the (S) conformation or the (R) conformation. In certain embodiments, R 6aThe carbon to which it is attached is in the (S) conformation. In certain embodiments, R 6a The carbon to which it is attached is in the (R) conformation. In certain embodiments, R 6a is -CF3, and R 6b is hydrogen or C 1~4 alkyl. In certain embodiments, R 6a is a group other than hydrogen substituted with fluorine, and R 6b is -CH3. In certain embodiments, R 6a is substituted with one or more -OR A6 groups, and R A6 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, 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 carbocyclic, and R 6b is -CH3. In certain embodiments, R 6a is unsubstituted C 2~4 alkyl, unsubstituted C 2~3 alkenyl or unsubstituted C 2~3 alkynyl or unsubstituted C3 carbocyclic, and R 6b is -CH3. In certain embodiments, R 6a is a group other than hydrogen substituted with fluorine, and R 6b is -CH3.

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

[0119] For example, in certain embodiments, X is -CH2-, and R 5a and R 5b are both hydrogen, and the compound of formula (I-a)

Chemical formula

Chemical formula

Chemical formula

[0120] In certain embodiments, X is -CH2-, and R 5a and R 5b are both fluorine, and the compound of formula (I-b)

Chemical formula

Chemical formula

Chemical formula

[0121] In certain embodiments, X is -C(R X )2-, connecting one R X group and R 5b to form a trans double bond, and a compound of formula (I-c)

Chemical formula

[0122] In certain embodiments, the compound of formula (I) is a compound of formula (II): [Chemical formula] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6a is a non-hydrogen group containing 2 to 10 carbon atoms. In certain embodiments, R 6a and R 6b at least one of is a non-hydrogen group substituted with fluorine. In certain embodiments, R 6aThe carbon to which it is attached is in the (S) conformation. In certain embodiments, R 6a The carbon to which it is attached is in the (R) conformation. In certain embodiments, R 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 -CH3 or -CF3. In certain embodiments,

Chemical formula

Chemical formula

[0123] In certain embodiments, the compound of formula (I) is a compound of formula (II-A):

Chemical formula

[0124] In certain embodiments, the compound of formula (I) is a compound of formula (II-B):

Chemical formula

[0125] In certain embodiments, the compound of formula (I) is the following:

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[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 medicine, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and contain at least one active compound.

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

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

[0130] Generally, the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by the physician in view of relevant circumstances including the condition being treated, the route of administration selected, 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 a variety of 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 an injectable composition or an oral composition, for example, as an ointment, as a lotion, or as a patch for transdermal administration.

[0132] Compositions for oral administration may be in the form of a bulk liquid solution or suspension, or a bulk powder. However, more generally, the compositions are presented in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as a combined dosage for human subjects and other mammals, each unit containing a predetermined quantity of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. 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), and the remainder are various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0133] Suitable liquid forms for oral administration would include suitable aqueous or non-aqueous vehicles containing buffers, suspending and dispersing agents, coloring agents, flavoring agents, etc. Solid forms may, for example, contain any of the following components or compounds having similar properties. Binders such as microcrystalline cellulose, tragacanth gum or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primo Gel or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavor.

[0134] Injectable compositions typically are based on injectable sterile saline or phosphate buffered saline, or other injectable carriers known in the art. As before, the active compounds in such compositions typically are minor components, often about 0.05 to 10% by weight, with the remainder being, for example, injectable carriers.

[0135] Transdermal compositions typically are formulated as topical ointments or creams generally containing the active ingredient in an amount in the range of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient may typically be combined with a paraffinic or water miscible ointment base. Or, 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 contain additional components to enhance skin penetration of the active ingredient or formulation stability. All such known transdermal formulations and components are included within the scope provided herein.

[0136] The compounds provided herein also can be administered by transdermal devices. Thus, transdermal administration can be achieved using patches of containers or porous membranes, or patches of various solid matrices.

[0137] The above elements of an orally administrable composition, an injectable composition, or a locally administrable composition are merely representative examples. Other materials and processing techniques, etc., are described in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and are incorporated herein by reference.

[0138] The above elements of an orally administrable composition, an injectable composition, or a locally administrable composition are merely representative examples. Other materials and processing techniques, etc., are described in Part 8 of Remington’s The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, and are incorporated herein by reference.

[0139] The compounds of the present invention can also be administered in a sustained release form or can be administered from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0140] The present invention also relates to a pharmaceutically acceptable formulation of a compound of formula (I). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, optionally each containing one or more substituents on the linked sugar moiety, including but not limited to methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. 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. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more particular embodiment, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[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, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

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

[0143] Exemplary formulation 1 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. From this mixture, tablets of 240-270 mg are prepared using a tablet press (80-90 mg of active compound per tablet).

[0144] Exemplary formulation 2 - capsule: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a starch diluent in a weight ratio of about 1:1. This mixture is filled into 250 mg capsules (125 mg of the 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), and the resulting mixture is blended and passed through a U.S. No. 10 mesh sieve, and then may be mixed with an aqueous solution prepared in advance of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavoring agent and coloring agent are diluted with water and added with stirring. Then, sufficient water may be added to produce a product with a total volume of 5 mL.

[0146] Exemplary formulation 4 - tablet: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. From this mixture, tablets of 450 - 900 mg are prepared using a tablet press (150 - 300 mg of the active compound).

[0147] Exemplary formulation 5 - injection: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be dissolved or suspended in an aqueous injection medium of buffered physiological saline until a concentration of about 5 mg / mL is obtained.

[0148] Exemplary formulation 6 - tablet: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. From this mixture, tablets of 90 - 150 mg are prepared using a tablet press (30 - 50 mg of the active compound per tablet).

[0149] Exemplary formulation 7 - tablets: v may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. From this mixture, tablets of 30 - 90 mg are made with a tableting press (10 - 30 mg of the active compound per tablet).

[0150] Exemplary formulation 8 - tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. From this mixture, tablets of 0.3 - 30 mg are made with a tableting press (0.1 - 10 mg of the active compound per tablet).

[0151] Exemplary formulation 9 - tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. From this mixture, tablets of 150 - 240 mg are made with a tableting press (50 - 80 mg of the active compound per tablet).

[0152] Exemplary formulation 10 - tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. From this mixture, tablets of 270 - 450 mg are made with a tableting press (90 - 150 mg of the active compound per tablet).

[0153] The injection dosage is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour for all about 1 to about 120 hours, especially 24 to 96 hours. A pre - encapsulated bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve a sufficiently steady - state level. The maximum total dosage is expected not to exceed about 2 g / day in a 40 - 80 kg human patient.

[0154] For the prevention and / or treatment of a condition over a long period of time, the treatment plan usually extends over several months or years, in which case oral administration is preferred for patient convenience and acceptability. In the case of oral administration, oral administration 1 to 5 times a day, particularly 2 to 4 times a day, typically 3 times a day, is a representative plan. Using these dosing patterns, each dose provides a compound of about 0.01 to about 20 mg / kg provided herein, and the preferred dosages each provide about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0155] The transdermal dosage is generally selected to provide blood levels that are equal to or lower than those achieved using the injectable dosage.

[0156] When used to prevent the onset of CNS disorders, the compounds provided herein are typically administered at the dosages described above, based on the advice and supervision of a physician, to a subject at risk of progression of the condition. Subjects at risk of progression of a particular condition generally include those with a family history of the condition or those identified as particularly susceptible to the condition by genetic testing or screening.

[0157] Methods of Treatment and Use The compounds of formula (I) and their pharmaceutically acceptable salts are generally designed to modulate NMDA function as described herein and thus act as neuroactive 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 compound of formula (I) or its pharmaceutically acceptable salt may act as a negative allosteric modulator (NAM) of NMDA and may inhibit the function of the NMDA receptor. In certain embodiments, the compound of formula (I) or its pharmaceutically acceptable salt may act as a positive allosteric modulator (PAM) of NMDA and may enhance the function of the NMDA receptor.

[0158] Exemplary CNS conditions associated with the 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 mood-cycling disorders), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those with mutations in Shank family proteins), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy, such as Dravet syndrome and tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus. In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to induce a sedative or anesthetic effect. In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is useful for the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, 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 excitability in a subject predisposed to or suffering from a condition associated with brain excitability, 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 and another pharmacologically active agent. The compounds provided herein can be administered as a single active agent or in combination with other agents. Administration in a combined state can be carried out by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administrations.

Examples

[0161] To more fully understand the present invention described herein, the following examples are presented. 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 limiting the scope in any way.

[0162] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It is understood that typical or preferred processing conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given and other processing conditions can also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization.

[0163] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of appropriate protecting groups for specific 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 T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0164] The compounds provided in this specification 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). Along with the details regarding the preparation of representative substituted biaryl amides listed in this specification, the following schemes are presented. The compounds provided in this specification may be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided in this specification 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 instrument was equipped with a ChiralPak AD-10 μM, 200×50 mm ID and used for SFC purification. A mixture of carbon dioxide and methanol or ethanol (e.g., 20 - 35% methanol or ethanol and 0.1% ammonium hydroxide) was used and eluted at a flow rate of 55 - 200 mL / min, monitored at a wavelength of 220 nm, and the compounds were separated.

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

[0167] The conformations of the C-24 stereocenters of the 1-13 and 1-14 and 2-20 and 2-21 isomers of the steroid were determined by the Mosher method (Dale, J.A., Dull, D.L. and Mosher, H.S. (1969) J. Org. Chem. 34, 2543). Accordingly, for Examples 1-15 and 1-17, such intermediates were used and the C-24 conformations of the subsequent derivatives were assigned.

[0168] For all other types of diastereomers, the stereocenters at C-24 were not determined by the Mosher method. The diastereomer that eluted first from the SFC was tentatively assigned to have an (R) conformation at C-24, while the diastereomer that eluted second from the SFC was tentatively assigned to have an (S) conformation at C-24. This assignment was not clearly confirmed by the Mosher method or other techniques. Example 1 [Chemical formula] [Chemical formula]

[0169] Preparation of Compound 1-2. p-Toluenesulfonic acid (1.4 g, 7.28 mmol) was added to a toluene (600 mL) solution of ketone 1-1 (50.0 g, 0.17 mol) and ethylene glycol (62 mL). The reaction mixture was refluxed overnight in a Dean-Stark trap. The mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), and washed with saturated aqueous sodium bicarbonate solution (300 mL × 2) and brine (300 mL × 2). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product 1-2 (64.0 g, 100%), which was used directly in the next step without further purification. 11H NMR: (400 MHz, CDCl3) δ 5.35 (d, J = 5.6 Hz, 1H), 3.97 - 3.82 (m, 4H), 3.59 - 3.47 (m, 1H), 2.34 - 2.21 (m, 2H), 2.06 - 1.94 (m, 2H), 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 Compounds 1 - 3. To a dry CH2Cl2 (1200 mL) solution of Compound 1 - 2 (32 g, 96 mmol) was added Dess - Martin reagent (81 g, 192 mmol) portionwise at 0 °C. Then, the reaction mixture was stirred at room temperature for 3 h. TLC (petroleum ether:ethyl acetate = 3:1) indicated complete consumption of the starting material. The mixture was quenched with a saturated NaHCO3 / Na2S2O3 = 1:3 (1 L) aqueous solution. The organic phase was washed with brine (500 mL), dried over Na2SO4, 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 1H NMR: (400 MHz, CDCl3) δ 5.34 (d, J = 5.2 Hz, 1H), 3.77 - 4.00 (m, 4H), 3.19 - 3.39 (m, 1H), 2.83 (dd, J = 16.44, 2.13 Hz, 1H), 2.38 - 2.59 (m, 1H), 2.21 - 2.37 (m, 1H), 1.95 - 2.09 (m, 3H), 1.54 - 1.73 (m, 4H), 1.74 - 1.90 (m, 2H), 1.37 - 1.51 (m, 3H), 1.21 - 1.34 (m, 2H), 1.19 (s, 3H), 0.98 - 1.12 (m, 1H), 0.83 - 0.93 (m, 3H).

[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 an 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 without purification as a toluene solution of MAD.

[0172] Preparation of Compounds 1-4. To a solution of MAD (90 mmol, freshly prepared) in toluene (200 mL) was added dropwise a solution of Compounds 1-3 (10 g, 30 mmol) in toluene (80 mL) at -78 °C over 1 hour under nitrogen. The reaction mixture was then stirred for 30 minutes, and a CH3MgBr 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 hours. TLC (petroleum ether:ethyl acetate = 3:1) indicated complete consumption of the starting material. This mixture was poured into a saturated aqueous NH4Cl solution (200 mL) and extracted with EtOAc (150 mL × 2 times). 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 Compounds 1-4 (4 g, 38%) as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 1H), 3.75 - 4.04 (m, 4H), 2.42 (d, J = 13.6 Hz, 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 Compounds 1-5. To a solution of Compounds 1-4 (6.0 g, 17.3 mmol) in THF (200 mL) were added aqueous HCl solution (35 mL, 1 M) and acetone (35 mL). The reaction mixture was stirred at room temperature and 20 °C. TLC (petroleum ether:ethyl acetate = 3:1) indicated the completion of the reaction. The reaction mixture was then diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 solution (200 mL), dried over Na2SO4, evaporated under reduced pressure to give 1-5 (5.2 g, 99.2%). 1 1H NMR: (400 MHz, CDCl3) δ 5.27 (d, J = 6.8 Hz, 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) indicated the complete consumption of the starting material. The reaction was quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were 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. 11H NMR: (400 MHz, CDCl3) δ 5.32 (d, J = 5.2 Hz, 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 Compounds 1 - 7. To a dry CH2Cl2 (15 mL) solution of Compounds 1 - 6 (1.00 g, 3.20 mmol) and methyl propionate (0.67 g, 8.00 mmol), an Et2AlCl solution (12.8 mL, 12.8 mmol, 1 M in toluene) was added dropwise with stirring at 0 °C. Subsequently, the reaction mixture was warmed to room temperature and stirred for 20 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated complete consumption of the starting material. The mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with CH2Cl2 (30 mL × 2 times). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to obtain 1 - 7 (1.00 g, 78.7%) as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 6.97 - 6.91 (m, 1H) 5.82 (d, J = 16 Hz, 1H), 5.42 - 5.41 (m, 1H), 5.32 (d, J = 5.2 Hz, 1H), 3.73 (s, 3H), 3.04 - 3.00 (m, 1H), 2.43 (d, J = 12.8 Hz, 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 = 6.78 Hz, 3H), 1.12 (s, 3H), 1.04 (s, 3H), 0.82 (s, 3H).

[0176] Preparation of Compounds 1-8. To a solution of Compound 1-7 (1.75 g, 4.4 mmol) in dry THF (20 mL) was added dropwise DIBAL-H (1 M in THF, 22 mL, 22.0 mmol) at -78 °C under nitrogen. The reaction mixture was warmed to 30 °C and then stirred at 30 °C for 2 hours. H2O (2 mL) was added to quench the reaction, diluted with EtOAc (200 mL), dried over anhydrous Na2SO4, filtered through a Celite pad, and the pad was washed with EtOAc (50 mL × 3 times). 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 MnO2 (7.5 g, 86.0 mmol) in CH2Cl2 (50 mL) was stirred at 30 °C for 20 hours. The reaction mixture was filtered through a Celite pad, and the pad was washed with CH2Cl2 (50 mL × 3 times). The combined filtrate was concentrated until dry 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 = 7.6 Hz, 1H), 6.84 - 6.78 (dd, J1 = 15.6 Hz, J2 = 7.6 Hz, 1H), 5.54 - 5.49 (dd, J1 = 15.6 Hz, J2 = 7.6 Hz, 1H), 5.45 - 5.44 (m, 1H), 5.32 (d, J = 5.2 Hz, 1H), 3.19 - 3.12 (m, 1H), 2.42 (d, J = 12.8 Hz, 1H), 2.14 - 2.08 (m, 1H), 2.00 - 1.52 (m, 13H), 1.42 - 1.35 (m, 3H), 1.24 (d, J = 6.8 Hz, 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 20 °C under nitrogen at room temperature. TLC (petroleum ether:ethyl acetate = 3 / 1) indicated that the starting material was completely consumed. A 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 × 3 times), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12 / 1), and 1-10 (300 mg, 42%) was obtained as a white solid. 1 1H NMR: (400 MHz, CDCl3) δ 5.97 - 5.91 (dd, J1 = 15.6 Hz, J2 = 7.6 Hz, 1H), 5.54 - 5.49 (dd, J1 = 15.6 Hz, J2 = 6.8 Hz, 1H), 5.42 - 5.38 (m, 1H), 5.30 (d, J = 5.2 Hz, 1H), 4.44 - 4.36 (m, 1H), 2.97 - 2.94 (m, 1H), 2.42 (d, J = 12.0 Hz, 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 = 6.8 Hz, 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 30 °C for 2 h under a hydrogen pressure of 1 atm. The reaction mixture was filtered through a Celite pad, and the pad was washed with EA (10 mL × 3 times). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: PE / EA = 8 / 1), and 1-11 (20 mg, 50%) was obtained as a white solid. 11H NMR: (400 MHz, CDCl3) δ 5.31 (d, J = 5.2 Hz, 1H), 3.87 - 3.86 (m, 1H), 2.42 (d, J = 12.8 Hz, 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 = 6.6 Hz, 3H), 0.69 (s, 3H).

[0180] Preparation of Compounds 1 - 13 and 1 - 14. From 1 - 10 (300 mg, 0.814 mmol), 1 - 13 (120 mg, 40%) and 1 - 14 (120 mg, 40%) were obtained 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 H2 (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 × 3 times). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8 / 1), and 1 - 15 (70 mg, 59%) was obtained as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 1H), 4.00 - 3.90 (m, 1H), 2.42 (d, J = 13.2 Hz, 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 = 6.8 Hz, 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 H2 (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 × 3 times). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8 / 1), and 1-17 (71 mg, 59%) was obtained as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 5.27 (d, J = 5.6 Hz, 1H), 4.00 - 3.90 (m, 1H), 2.42 (d, J = 13.2 Hz, 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 = 6.4 Hz, 3H), 0.73 (s, 3H). Example 2

Chemical formula

Chemical formula

[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 an 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) indicated complete consumption of the starting material. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (150 mL × 2 times). 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: petroleum ether:ethyl acetate = 15:1), and the product 2-2 (2.0 g, 47.6%) was obtained as a white powder.1 1H NMR: (400 MHz, CDCl3) δ 5.28 (d, J = 5.2 Hz, 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 - 1.60 (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 = 6.8 Hz, 3H), 0.68 (s, 3H).

[0184] Preparation of 2 - 3. To a suspension of LiAlH4 (852.6 mg, 22.43 mmol) in THF (20 mL) was added 2 - 2 (2.0 g, 4.48 mmol) at - 78 °C. Then the solution was stirred at - 78 °C for 2 hours. The mixture was poured into saturated aqueous NaOH (2 mL) and extracted with EtOAc (50 mL × 2 times). 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: petroleum ether:ethyl acetate = 20:1) to give the product 2 - 3 (600 mg, 35%) as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 9.78 (s, 1H), 5.28 (d, J = 5.2 Hz, 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, 1H), 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 = 6.8 Hz, 3H), 0.68 (s, 3H).

[0185] Preparation of 2-4. TMSCF3 (1.2 mL, 7.8 mmol) was added 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), and the reaction mixture was stirred overnight at room temperature under nitrogen. TLC (petroleum ether:ethyl acetate = 3 / 1) indicated complete consumption of the starting material. A 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 (10 mL × 3 times), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1), and 2-4 (80 mg, 22%) was obtained as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 5.29 (d, J = 5.2 Hz, 1H), 3.87 - 3.84 (m, 1H), 2.36 (d, J = 13.2 Hz, 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 = 6.8 Hz, 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 at 50 °C for 36 h under H2 (50 psi). The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (20 mL × 3 times). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25 / 1), and 2-5 (25 mg, 35.7%) and 2-6 (20 mg, 28.6%) were obtained as white powders. 11H NMR (2-5): (400 MHz, 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 = 6.8 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.86 - 0.84 (m, 1H), 0.83 (s, 3H), 0.67 - 0.61 (m, 4H). 1 1H NMR (2-6): (400 MHz, 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. A solution of compound 2-13 (10 g, 30 mmol) in toluene (80 mL) was added dropwise to a solution of MAD (91 mmol, freshly prepared) in toluene (200 mL) at -78 °C over 1 hour under nitrogen. The reaction mixture was then stirred for 30 minutes, and an EtMgBr solution (91 mL, 91 mmol, 1.0 M in THF) was added at -78 °C. The reaction mixture was warmed to -40 °C and stirred at this temperature for 3 hours. TLC (petroleum ether:ethyl acetate = 3:1) indicated complete consumption of the starting material. 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, 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) were added aqueous HCl solution (35 mL, 1 M) and acetone (35 mL). The reaction mixture was stirred at room temperature (20 °C). TLC (petroleum ether:ethyl acetate = 3:1) indicated that the reaction was complete. The reaction mixture was then diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 solution (200 mL), dried over Na2SO4, evaporated under reduced pressure, and 2-15 (3 g, 88%) was obtained 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) at 0 °C under N2. 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) indicated that the starting material had been completely consumed. The reaction was quenched with saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (30 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1), and 2-16 (1.8 g, 64%) was obtained 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 CH2Cl2 (20 mL) was added dropwise a solution of Et2AlCl (22 mL, 22 mmol, 1 M in toluene) with stirring at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 20 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated complete consumption of the starting material. The mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with CH2Cl2 (30 mL × 2). The combined organic phases were dried over Na2SO4 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 1H NMR: (300 MHz, CDCl3) δ 6.99 - 6.92 (m, 1H) 5.84 (d, J = 10.5 Hz, 1H), 5.45 - 5.41 (m, 1H), 5.32 (d, J = 5.2 Hz, 1H), 3.75 (s, 3H), 3.06 - 2.99 (m, 1H), 2.38 (d, J = 12.6 Hz, 1H), 2.14 - 1.67 (m, 10H), 1.54 - 1.25 (m, 7H), 1.21 (d, J = 6.8 Hz, 3H), 1.15 - 0.99 (m, 5H), 0.87 (t, J = 7.2 Hz, 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 dropwise DIBAL-H (1 M in THF, 27 mL, 27.0 mmol) at -78 °C under nitrogen. The reaction mixture was warmed to 30 °C and then stirred at 30 °C for 2 h. Water (3 mL) was added to quench the reaction, and the mixture was diluted with EtOAc (200 mL), dried over anhydrous Na2SO4, filtered through a Celite pad, and the pad was washed with EtOAc (50 mL × 3). The combined filtrates were concentrated under reduced pressure to give 1.9 g of the 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 MnO2 (8.6 g, 98 mmol) in CH2Cl2 (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 × 3). The combined filtrates were 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: (400 MHz, 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 = 5.2 Hz, 1H), 3.15 - 3.14 (m, 1H), 2.36 (d, J = 13.2 Hz, 1H), 2.10 - 2.03 (m, 3H), 1.90 - 1.60 (m, 9H), 1.59 - 1.27 (m, 7H), 1.24 (d, J = 6.8 Hz, 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) indicated complete consumption of the starting material. A 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 × 3 times), 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. From 2-19 (650 mg, 1.44 mmol), 2-20 (210 mg, 32%) and 2-21 (210 mg, 32%) were obtained by SFC purification. The structures of 2-20 and 2-21 were confirmed by the Mosher method. 1 H NMR (2-20): (400 MHz, CDCl3) δ 5.92 (dd, J1 = 15.6 Hz, J2 = 7.2 Hz, 1H), 5.53 (dd, J1 = 15.6 Hz, J2 = 7.2 Hz, 1H), 5.40 - 5.37 (m, 1H), 5.30 (d, J = 5.2 Hz, 1H), 4.43 - 4.40 (m, 1H), 2.95 - 2.94 (m, 1H), 2.37 (d, J = 13.6 Hz, 1H), 2.09 - 1.98 (m, 4H), 1.87 - 1.18 (m, 18H), 1.16 (d, J = 6.8 Hz, 3H), 1.12 - 0.97 (m, 6H), 0.85 (t, J = 6.8 Hz, 3H), 0.78 (s, 3H). 11H NMR (2-21): (400 MHz, CDCl3) δ 5.95 (dd, J1 = 15.6 Hz, J2 = 7.2 Hz, 1H), 5.53 (dd, J1 = 15.6 Hz, J2 = 6.8 Hz, 1H), 5.39 - 5.36 (m, 1H), 5.30 (d, J = 5.2 Hz, 1H), 4.44 - 4.41 (m, 1H), 2.99 - 2.92 (m, 1H), 2.37 (d, J = 13.2 Hz, 1H), 2.10 - 1.98 (m, 4H), 1.87 - 1.25 (m, 18H), 1.16 (d, J = 6.8 Hz, 3H), 1.09 - 0.99 (m, 6H), 0.85 (t, J = 7.2 Hz, 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 at 30 °C for 72 h under H2 (1 atm). The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (10 mL × 3 times). The combined filtrates were 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 1H NMR (2-7): (400 MHz, CDCl3) δ 5.29 (d, J = 4.8 Hz, 1H), 3.90 - 3.80 (m, 1H), 2.36 (d, J = 13.6 Hz, 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 = 14.8 Hz, J2 = 7.2 Hz, 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 at 30 °C for 72 h under H2 (1 atm). The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (10 mL × 3 times). The combined filtrates were 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 1H NMR: (400 MHz, CDCl3) δ 5.29 (d, J = 4.8 Hz, 1H), 3.86 - 3.83 (m, 1H), 2.36 (d, J = 13.2 Hz, 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 = 6.8 Hz, 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 at 50 °C for 20 h under H2 (50 psi). The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (20 mL × 3). The combined filtrates were 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 1H NMR (2-10): (400 MHz, 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 = 6.8 Hz, 3H), 0.88 - 0.84 (m, 4H), 0.83 (s, 3H) 0.67 - 0.61 (m, 4H). 1 1H 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

Chemical Structure

[0197] Preparation of 3 - 2. TMSCF3 (1.53 mL, 10.35 mmol) was added to a suspension of 3 - 1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene / THF (20 mL, 8 / 1), and the mixture was stirred at room temperature and 20 °C under nitrogen. TLC (petroleum ether:ethyl acetate = 3 / 1) indicated that the starting material was completely consumed. A 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 × 3 times), 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 1H NMR: (400 MHz, CDCl3) δ 5.31 (d, J = 2.0 Hz, 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. Pd / C (20 mg) was added to a solution of compound 3-2 (220 mg, 0.569 mmol) in EtOAc (10 mL), and then the mixture was stirred with hydrogen (50 psi) at 50 °C overnight. The mixture was filtered through a pad of celite, 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 afford pure products 3-3 (100 mg, 38.5%) and 3-4 (51 mg, 19.3%) as white powders. 1 H NMR (3-3): (400 MHz, 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): (400 MHz, 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 afford products 3-5 (400 mg) and 3-6 (400 mg) as white powders (total yield: 66.7%). 1 H NMR (3-5): (400 MHz, CDCl3) δ 5.32 (d, J = 4.0 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.08 - 1.95 (m, 3H), 1.90 - 0.90 (m, 35H), 0.70 (s, 3H). 11H NMR (3 - 6): (400 MHz, CDCl3) δ 5.32 (d, J = 4.0 Hz, 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 N2. The suspension was degassed under reduced pressure and purged with H2 several times. Then, the mixture was stirred with H2 (50 psi) at 50 °C for 24 h. The suspension was filtered through a Celite pad and the pad was washed with EtOAc (50 mL × 2). The combined filtrates were 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 1H NMR: (3 - 7) (400 MHz, 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 1H NMR: (3 - 7A) (400 MHz, 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 N2. The suspension was degassed under reduced pressure and purged with H2 several times. Then the mixture was stirred with H2 (50 psi) at 50 °C for 24 h. The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (50 mL × 2). The combined filtrates were concentrated to dryness to afford 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 1H NMR: (3-8) (400 MHz, 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 1H NMR: (3-8A) (400 MHz, 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

Chemical formula

Chemical formula

[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 hour, and N,O-dimethylhydroxylamine hydrochloride (19.8 g, 203 mmol) was added. The mixture was stirred at room temperature for an additional 6 hours. The reaction mixture was concentrated, poured into water, extracted with EtOAc, washed with water, dried over Na2SO4, and concentrated to obtain 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 1H NMR: (300 MHz, CDCl3) δ: ppm 5.25 (d, J = 5.2 Hz, 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 = 6.4 Hz, 3H), 0.82 - 0.78 (m, 1H), 0.58 (s, 3H).

[0203] Preparation of Compound 4-3. Dess-Martin (28 g, 67.04 mmol, 2.0 eq) was added portionwise to a solution of Compound 4-2 (14 g, 33.52 mmol, 1.0 eq) in dry CH2Cl2 (600 mL) at 0 °C. Then the reaction mixture was stirred at room temperature for 6.5 hours. TLC (PE:EA = 3:1) indicated that the starting material was completely consumed. The mixture was quenched with saturated NaHCO3 / Na2S2O3 aqueous solution = 1:3 (800 mL). The organic phase was washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated to obtain the 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 a solution of Me3Al (50.5 mL, 101.00 mmol, 2 M in hexane) was added thereto. Then, a freshly prepared toluene solution of MAD (101 mmol, 3.0 eq) was added dropwise to this solution at -78 °C under nitrogen, and a solution of 4-3 (14.0 g, 33.7 mmol, 1.0 eq) in toluene (10 mL) was added dropwise thereto. Subsequently, the reaction mixture was 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) indicated that the starting material had been completely consumed. The mixture was poured into a saturated aqueous solution of NH4Cl (200 mL) and extracted with EtOAc (200 mL × 2 times). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 3:1) to obtain the pure target product (7.5 g, 52%) as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 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 dropwise MeMgBr solution (29 mL, 87 mmol, 5.0 eq, 3 M in THF) over 30 minutes under nitrogen at room temperature. The reaction mixture was then stirred at room temperature for 12 hours. TLC (PE:EA = 1:1) indicated that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (150 mL × 2 times). 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 afford Product 4-5 (5.2 g, 77%) as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 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 = 6.4 Hz, 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) was added dropwise EtMgBr solution (4.5 mL, 4.5 mmol, 6.0 eq, 1 M in THF) over 10 minutes under nitrogen at room temperature. The reaction mixture was then stirred at room temperature for 12 hours. TLC (PE:EA = 3:1) indicated that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL × 2 times). 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 afford Product 4-6 (200 mg, 62%) as a white powder. 11H NMR: (400 MHz, CDCl3) δ 5.23 (d, J = 5.6 Hz, 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 EtOAc (10 mL) 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 overnight under H2 (50 psi). The suspension was filtered through a Celite pad and the pad was washed with EA (20 mL × 3 times). The combined filtrates were 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 white powders. 1 1H NMR (4 - 7): (400 MHz, 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, 21H), 1.20 - 0.97 (m, 11H), 0.95 - 0.82 (m, 7H), 0.80 (s, 3H), 0.70 - 0.61 (m, 4H). 1 1H NMR (4 - 8): (400 MHz, 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), 1.32 - 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 EtOAc (20 mL) was added 10% Pd / C (20 mg) under N2. The suspension was degassed under reduced pressure and purged with H2 several times. Then, the mixture was stirred at 50 °C for 12 h under H2 (50 psi). The mixture was filtered through a Celite pad and the pad was washed with EtOAc (5 mL × 2). The combined filtrates were 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 afford 4-9 (40 mg, 50%) as a white powder. 1 1H NMR (4-9): (400 MHz, 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 EtOAc (20 mL) was added 10% Pd / C (20 mg) under N2. The suspension was degassed under reduced pressure and purged with H2 several times. Then, the mixture was stirred at 50 °C for 48 h under H2 (50 psi). The mixture was filtered through a Celite pad and the pad was washed with EtOAc (5 mL × 2). The combined filtrates were 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 afford 4-10 (40 mg, 50%) as a white powder. 1 1H NMR (4-10): (400 MHz, 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. From 4-6 (600 mg, 1.55 mmol), 4-11 (100 mg, 15.38%) and 4-12 (90 mg, 13.85%) were obtained by SFC purification. 11H NMR (Isomer 1): (400 MHz, CDCl3) δ 5.30 (m, 1H), 2.43 - 2.40 (d, J = 12.4 Hz, 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 1H NMR (Isomer 2): (400 MHz, CDCl3) δ 5.30 (m, 1H), 2.44 - 2.40 (d, J = 14 Hz, 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 [Chemical formula]

[0211] Preparation of Compound 5-2. To a solution of 5-1 (200 mg, 0.52 mmol) in toluene (5 mL) was added dropwise n-PrMgBr (1.3 mL, 2 M in THF, 2.6 mmol) at -78 °C. The mixture was gradually warmed to room temperature and stirred for 6 hours. The reaction mixture was quenched with aqueous NH4Cl solution 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. 11H NMR: (300 MHz, CDCl3) δ: ppm 5.30 (d, J = 4.8 Hz, 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. 10% Pd / C (100 mg) was added to a solution of compound 5-2 (400 mg, 0.93 mmol) in EtOAc (20 mL). The mixture was then stirred at 50 °C overnight under hydrogen (50 psi). The mixture was filtered through a pad of Celite 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 afford the pure products 5-3 (150 mg, 37.3%) and 5-4 (27 mg, 6.7%) as white powders. 1 1H NMR (5-3): (300 MHz, 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), 1.24 (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). 11H NMR (5-4): (300 MHz, 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, 3H), 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 dropwise n-PrMgBr 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) indicated the completion of the reaction. Saturated aqueous NH4Cl solution (5 mL) was slowly added to quench the reaction. The resulting solution was separated into EtOAc (30 mL × 3) and H2O (30 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column eluting with PE / EtOAc = 10 / 1 to give a mixture of diastereomer pairs (1.1 g) as a white powder. The diastereomer pair was 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 1H NMR (5-5): (400 MHz, CDCl3) δ 5.31 - 5.30 (m, 1H), 2.44 - 2.41 (d, 1H, J = 12.8 Hz), 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). 11H NMR (5 - 6): (400 MHz, CDCl3) δ 5.31 - 5.30 (m, 1H,), 2.44 - 2.41 (d, 1H, J = 12.4 Hz), 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 at 50 °C for 48 h under 50 psi of hydrogen. 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 by silica gel column eluting with PE / EtOAc = 20 / 1 to give 5 - 8 (111.3 mg, 55.4%) as a white solid. 1 1H NMR (5 - 8) (400 MHz, CDCl3), δ (ppm) 1.97 - 1.94 (d, 1H, J = 12.0 Hz), 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 1H NMR (5 - 8A) (400 MHz, CDCl3), δ (ppm) 1.98 - 1.95 (d, 1H, J = 11.2 Hz), 1.88 - 1.80 (m, 3H), 1.65 - 1.60 (m, 1H), 1.51 - 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 at 50 °C for 48 h under 50 psi of hydrogen. 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 by silica gel column eluting with PE / EtOAc = 20 / 1 to give 5-7 (118.5 mg, 59.0%) as a white solid. 1 H NMR (5-7) (400 MHz, CDCl3), δ (ppm) 1.97 - 1.94 (d, 1H, J = 12.8 Hz), 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) (400 MHz, CDCl3), δ (ppm) 1.98 - 1.95 (d, 1H, J = 11.2 Hz), 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

Chem.

Chem.

[0216] Preparation of 6-2. To a solution of 6-1 (150 mg, 0.39 mmol) in THF (4 mL) was added allylmagnesium bromide (2.34 mL, 2.34 mmol, 1 M in ether) at -78 °C. Subsequently, the reaction mixture was warmed to room temperature and stirred for 12 hours. The mixture was quenched with an 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: (400 MHz, CDCl3) δ 5.89 - 5.82 (m, 1H), 5.31 (d, J = 5.2 Hz, 2H), 5.15 - 5.09 (m, 2H), 2.43 - 2.40 (m, 1H), 2.22 - 2.20 (d, J = 7.6 Hz, 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 9-BBN solution (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 hours. The mixture was cooled to 0 °C, an aqueous NaOH (10%) solution (2 mL) was added, and then H2O2 (30%, 1 mL) was added. The mixture was stirred at 0 °C for 2 hours 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. 11H NMR: (300 MHz, CDCl3) δ: 5.30 (d, J = 5.2 Hz, 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 at 50 °C for 16 h under H2 (50 psi). The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (20 mL × 3 times). The combined filtrates were 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 dropwise C3H5MgBr (1.1 mL, 1.08 mmol) 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 solution 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 pure product 6-6 (40 mg, 51.9%) as a white powder. 1 1H NMR: (300 MHz, CDCl3) δ: ppm 5.92 - 5.79 (m, 1H), 5.15 (d, J = 4.2 Hz, 1H), 5.11 (d, J = 13.2 Hz, 1H), 2.21 (d, J = 7.5 Hz, 2H), 1.97 - 1.75 (m, 5H), 1.67 - 1.34 (m, 19H), 1.30 - 0.94 (m, 11H), 0.91 (d, J = 6.3 Hz, 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) (400 MHz, CDCl3), δ 5.90 - 5.81 (m, 1H), 5.31 (d, J = 5.2 Hz, 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) (400 MHz, CDCl3), δ 5.90 - 5.80 (m, 1H), 5.31 (d, J = 5.2 Hz, 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 dropwise BzCl (64.4 mg, 0.46 mmol) at room temperature. The reaction mixture was then stirred at 40 °C for 12 h. TLC indicated complete consumption of the starting material. The mixture was quenched with saturated aqueous solution and extracted with EtOAc. The combined organic phases were washed with 1 M HCl (30 mL) and brine, dried over anhydrous Na2SO4, 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 obtain 6-11-Bz (40 mg, 66%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 7.99 - 7.98 (d, J = 7.2 Hz, 2H), 7.53 - 7.49 (t, J = 7.2 Hz, 1H), 7.42 - 7.38 (t, J = 7.2 Hz, 2H), 2.22 - 2.20 (d, J = 7.6 Hz, 2H), 1.98 - 1.57 (m, 11H), 1.54 - 1.26 (m, 16H), 1.15 (s, 3H), 1.12 - 1.10 (m, 6H), 0.92 - 0.91 (d, J = 6.0 Hz, 3H), 0.80 (s, 3H), 0.64 - 0.60 (m, 4H).

[0223] Preparation of 6-11. A solution of compound 6-11-Bz (40 mg, 0.075 mmol) dissolved in a mixed solvent of THF (2 mL) and MeOH (1 mL) was added to a solution of LiOH (90 mg, 3.75 mmol) in H2O (1 mL). The mixture was stirred at 40 °C for 3 days. TLC indicated that the starting material was completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain 6-11 (23 mg, 71%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.86 - 5.84 (m, 1H), 5.13 - 5.09 (m, 2H), 2.21 - 2.19 (d, J = 7.6 Hz, 2H), 1.84 - 1.25 (m, 19H), 1.24 (s, 3H), 1.14 (s, 3H), 1.13 - 1.09 (m, 7H), 0.91 - 0.90 (d, J = 6.8 Hz, 3H), 0.80 (s, 3H), 0.64 - 0.60 (m, 4H). Example 7

Chemical Structure

[0224] Preparation of Compound 7-2. To a dry THF (3 mL) solution of 7-1 (193 mg, 0.5 mmol, 1.0 eq) 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 the temperature was 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 × 3 times). 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 the product 7-2 (85 mg, 38.6%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.31 (d, J = 5.2 Hz, 1H), 2.41 (d, J = 13.2 Hz, 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 at 50 °C for 16 h under H2 (50 psi). The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (20 mL × 3 times). 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 white powders. 1 H NMR(7-3): (400 MHz, 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, 8H), 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 1H NMR(7-3A): (400 MHz, 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 dropwise n-BuLi (12.5 mL, 31 mmol, 2.5 M in THF) at -78 °C. The resulting mixture was stirred at this temperature for 0.5 h, then the temperature was warmed to room temperature and stirred at this temperature for an additional 18 h. TLC (PE / EA = 5 / 1) indicated the completion of the reaction. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (30 mL × 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 1H NMR(7-4): (400 MHz, CDCl3) δ 5.38 - 5.29 (m, 1H), 2.44 (d, 1H, J = 12.5 Hz), 2.04 - 1.69 (m, 6H), 1.57 - 1.25 (m, 18H), 1.20 - 0.89 (m, 23H), 0.70 (s, 3H). 11H NMR (7-5): (400 MHz, CDCl3) δ 5.32 (s, 1H), 2.44 (d, 1H, J = 12.3 Hz), 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. Pd / C (100 mg) was added to a 15 mL EtOH solution of 7-4 (0.17 g, 0.38 mmol), and then the reaction mixture was stirred at 50 °C for 24 h under hydrogen (50 psi). The resulting solution was filtered and concentrated. The product was purified by silica gel column chromatography eluting with (PE:EA = 20:1) to give 7-6 (40 mg, yield: 23.42%) as a white solid. 1 1H NMR (7-6) (400 MHz, 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. Pd / C (200 mg) was added to a 15 mL EtOH solution of 7-5 (0.23 g, 0.52 mmol), and then the reaction mixture was stirred at 50 °C for 24 h under hydrogen (50 psi). The resulting solution was filtered and concentrated. The product was purified by silica gel column chromatography eluting with (PE:EA = 20:1) to give 7-7 (70 mg, yield: 30.3%) as a white solid. 1 1H NMR (7-7) (400 MHz, 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

Chemical Structure

Chemical Structure

[0229] Preparation of 8-2. To a solution of compound 8-1 (100 mg, 0.25 mmol) in toluene (8 mL) was added dropwise i-PrMgBr solution (1.5 mL, 1.5 mmol, 1 M in THF) under nitrogen at room temperature over 10 minutes. The reaction mixture was then stirred at room temperature for 12 hours. TLC indicated that the starting material had been completely consumed. The mixture was poured into saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (50 mL × 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: petroleum ether:ethyl acetate = 8:1) to afford product 8-2 (66 mg, 59.46%) as a white powder. 1 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 1H), 2.43 - 2.40 (m, 1H), 2.04 - 1.55 (m, 3H), 1.88 - 1.66 (m, 5H), 1.58 - 1.13 (m, 15H), 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 EtOAc (15 mL) 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 overnight under H2 (50 psi). The suspension was filtered through a Celite pad and the pad was washed with EA (20 mL × 3). The combined filtrates were concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford 8-3 (27 mg, 45%) and 8-4 (9 mg, 15%) as white powders. 11H NMR (8-3): (400 MHz, 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 1H NMR (8-4): (400 MHz, 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) indicated that the reaction was complete. Saturated aqueous NH4Cl solution (5 mL) was slowly added to quench the reaction. The resulting solution was separated into EtOAc (30 mL × 3) and H2O (30 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column eluting with PE / EtOAc = 10 / 1 to give a mixture of diastereomer pairs (800 mg) as a white powder. The diastereomer pair was separated by preparative SFC to give 8-8 (317 mg, 19.0%) and 8-7 (250 mg, 15.0%) as white solids. 1 1H NMR (8-8): (400 MHz, CDCl3) δ 5.30 (s, 1H), 2.42 (d, J = 12.4 Hz, 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 1H NMR (8-7): (400 MHz, CDCl3) δ 5.30 (d, J = 3.6 Hz, 1H), 2.42 (d, J = 12.4 Hz, 1H), 2.00 - 1.97 (m, 3H), 1.89 - 1.68 (m, 4H), 1.58 - 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 at 50 °C for 48 h under 50 psi of hydrogen. 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 by silica gel column eluting 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 1H NMR (8-6) (400 MHz, CDCl3), δ (ppm) 1.97 - 1.94 (d, 1H, J = 12.8 Hz), 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 1H NMR (8-6A) (400 MHz, CDCl3), δ (ppm) 1.98 - 1.95 (d, 1H, J = 10.8 Hz), 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 at 50 °C for 48 h under 50 psi of hydrogen. 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 by silica gel column eluting 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 1H NMR (8-5) (400 MHz, CDCl3), δ (ppm) 1.97 - 1.94 (d, 1H, J = 12.8 Hz), 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 1H NMR (8-5A) (400 MHz, CDCl3), δ (ppm) 1.98 - 1.95 (d, 1H, J = 10.8 Hz), 1.91 - 1.79 (m, 3H), 1.72 - 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

Chemical Structure

[0234] Preparation of 9-2. To a solution of compound 9-1 (100 mg, 0.25 mmol) in THF (2 mL) was added dropwise a solution of cyclopropylmagnesium bromide (2.5 mL, 2.5 mmol, 1 M in THF) over 10 minutes under nitrogen at room temperature. The reaction mixture was then stirred at room temperature for 12 hours. TLC indicated that the starting material had been completely consumed. The mixture was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL × 2 times). 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: petroleum ether:ethyl acetate = 10:1) to afford product 9-2 (33 mg, 30%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ: 5.31 (d, J = 5.2 Hz, 1H), 2.42 (d, J = 12.8 Hz, 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) (400 MHz, 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) (400 MHz, 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 N2. The suspension was degassed under reduced pressure and purged with H2 several times. Then, the mixture was stirred at 50 °C for 24 h under H2 (50 psi). The suspension was filtered through a Celite pad and the pad was washed with EtOAc (30 mL × 2). The combined filtrates were 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 1H NMR: (9-7) (400 MHz, 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 1H NMR: (9-7A) (400 MHz, 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 N2. The suspension was degassed under reduced pressure and purged with H2 several times. Then, the mixture was stirred at 50 °C for 24 h under H2 (50 psi). The suspension was filtered through a Celite pad and the pad was washed with EtOAc (30 mL × 2). The combined filtrates were 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. 11H NMR: (9 - 8)(400 MHz, 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, 16H), 1.19 - 0.82 (m, 16H), 0.80 (s, 3H), 0.65 - 0.60 (m, 4H), 0.36 - 0.28 (m, 4H). Example 10

Chem.

Chem.

Chem.

Chem.

[0238] Preparation of 10 - 2. To a solution of compound 10 - 1 (100 mg, 0.25 mmol) in toluene (8 mL), a solution of ethynylmagnesium bromide (4 mL, 2.0 mmol, 0.5 M in THF) was added dropwise under nitrogen at room temperature over 10 minutes. Subsequently, the reaction mixture was stirred at 50 °C overnight. TLC indicated that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (25 mL × 2 times). The combined organic phases were dried over Na2SO4 and the solvent was evaporated to obtain 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. 11H NMR: (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 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 obtain 10 - 3 (82 mg) and 10 - 4 (94 mg) as white powders (total yield: 50%). 1 1H NMR (a10 - 3) (400 MHz, CDC l3), δ 5.29 (d, J = 5.2 Hz, 1H), 2.43 - 2.40 (m, 2H), 2.05 - 0.95 (m, 38H), 0.68 (s, 3H). 1 1H NMR (10 - 4) (400 MHz, CDCl3), δ 5.29 (d, J = 5.2 Hz, 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) dissolved in a mixed solvent of EtOAc (20 mL) and EtOH (10 mL), Pd / C (33%, 1.0 g) was added under N2. The suspension was degassed under reduced pressure and purged with H2 several times. Then, the mixture was stirred at 50 °C for 6 days under H2 (50 psi). The suspension was filtered through a Celite pad, and the pad was washed with EtOAc (100 mL × 3 times). The combined filtrates were concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 10 - 5 (1.7 g, 56%) as a white solid. 11H NMR: (400 MHz, 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 = 6.4 Hz, 3H), 0.80 (s, 3H), 0.63 - 0.60 (m, 4H).

[0241] Preparation of 10 - 6. Ethynylmagnesium bromide (28.2 mL, 14.1 mmol) was added dropwise to a solution of 10 - 5 (550 mg, 1.41 mmol) in dry THF (10 mL) at 0 °C under N2. Subsequently, the reaction mixture was stirred at room temperature for 12 h. TLC indicated that the starting material had been completely consumed. The mixture was quenched with saturated aqueous NH4Cl (80 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, 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 1H NMR: (400 MHz, 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 = 6.4 Hz, 3H), 0.80 (s, 3H), 0.65 - 0.62 (m, 4H).

[0242] Preparation of 10 - 6 - Bz. BzCl (168 mg, 1.2 mmol) was added dropwise to a solution of 10 - 6 (250 mg, 0.60 mmol) in pyridine (3 mL) at room temperature. Subsequently, the reaction mixture was stirred at 45 °C for 12 h. TLC indicated that the starting material had been completely consumed. The mixture was quenched with saturated aqueous solution and extracted with EtOAc. The combined organic phases were washed with 1 M HCl (20 mL) and brine, dried over anhydrous Na2SO4, 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 obtain 10-8-Bz (80 mg, 40%) and 10-9-Bz (70 mg, 35%) as white solids. 1 H NMR: (10-8-Bz) (400 MHz, CDCl3) δ 7.99 - 7.98 (d, J = 7.6 Hz, 2H), 7.51 - 7.49 (d, J = 7.2 Hz, 1H), 7.42 - 7.38 (t, J = 7.2 Hz, 2H), 2.42 (s, 1H), 2.05 - 1.68 (m, 8H), 1.65 (s, 3H), 1.60 - 1.49 (m, 7H), 1.48 (s, 3H), 1.45 - 1.11 (m, 16H), 0.94 - 0.92 (d, J = 6.4 Hz, 3H), 0.87 (s, 3H), 0.66 - 0.62 (m, 4H). 1 H NMR: (10-9-Bz) (400 MHz, CDCl3) δ 7.99 - 7.98 (d, J = 7.6 Hz, 2H), 7.51 - 7.49 (d, J = 7.2 Hz, 1H), 7.42 - 7.38 (t, J = 7.6 Hz, 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 = 6.8 Hz), 0.87 (s, 3H), 0.66 - 0.62 (m, 4H).

[0244] Preparation of 10-8. A solution of compound 10-8-Bz (80 mg, 0.15 mmol) dissolved in a mixed solvent of THF (3 mL) and MeOH (1.5 mL) was added to a solution of LiOH (180 mg, 7.5 mmol) in H2O (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC indicated that the starting material had been completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain 10-8 (57 mg, 92%) as a white solid. 11H NMR: (400 MHz, 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 = 6.4 Hz, 3H), 0.80 (s, 3H), 0.65 - 0.62 (m, 4H).

[0245] Preparation of 10 - 9. A solution of compound 10 - 9 - Bz (70 mg, 0.14 mmol) dissolved in a mixed solvent of THF (3 mL) and MeOH (1.5 mL) was added to a solution of LiOH (168 mg, 7.0 mmol) in H2O (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC indicated that the starting material had been completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain 10 - 9 (53 mg, 91%) as a white solid. 1 1H NMR: (400 MHz, 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 = 6.4 Hz, 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 N2. The reaction mixture was then stirred at room temperature for 12 hours. TLC indicated that the starting material had been completely consumed. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain 10 - 7 (300 mg, 51%) as a white solid. 11H NMR: (400 MHz, CDCl3) δ 5.93 - 5.86 (m, 1H), 5.20 - 5.16 (d, J = 17.6 Hz, 1H), 5.05 - 5.02 (d, J = 10.8 Hz, 1H), 1.96 - 1.93 (m, 1H), 1.60 - 1.57 (m, 4H), 1.51 - 1.20 (m, 20H), 1.19 - 1.00 (m, 8H), 0.91 - 0.89 (d, J = 6 Hz, 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 dropwise BzCl (150 mg, 1.06 mmol) at room temperature. Then, the reaction mixture was stirred at 40 °C for 12 h. TLC indicated that the starting material was completely consumed. The mixture was quenched with saturated aqueous solution and extracted with EtOAc. The combined organic phases were washed with 1 M HCl (30 mL) and brine, dried over anhydrous Na2SO4, 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 1H NMR: (10 - 10 - Bz) (400 MHz, CDCl3) δ 7.99 - 7.97 (d, J = 7.2 Hz, 1H), 7.51 - 7.49 (d, J = 7.6 Hz, 1H), 7.42 - 7.38 (t, J = 8.0 Hz, 2H), 5.93 - 5.86 (dd, J1 = 11.2 Hz, J2 = 17.2, 1H), 5.21 - 5.16 (d, J = 17.6 Hz, 1H), 5.05 - 5.02 (d, J = 10.4 Hz, 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, 6.0 Hz, 3H), 0.86 (s, 3H), 0.70 - 0.64 (m, 4H). 1 1H NMR: (10 - 11 - Bz) (400 MHz, CDCl3) δ 7.99 - 7.97 (d, J = 7.2 Hz, 1H), 7.51 - 7.49 (d, J = 7.6 Hz, 1H), 7.42 - 7.38 (t, J = 8.0 Hz, 2H), 5.93 - 5.86 (dd, J1 = 10.8 Hz, J2 = 17.6, 1H), 5.20 - 5.16 (d, J = 17.2 Hz, 1H), 5.05 - 5.02 (d, J = 10.4 Hz, 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, 6.4 Hz, 3H), 0.86 (s, 3H), 0.70 - 0.64 (m, 4H).

[0249] Preparation of 10 - 10. A solution of compound 10 - 10 - Bz (75 mg, 0.14 mmol) dissolved in a mixed solvent of THF (3 mL) and MeOH (1.5 mL) was added to a solution of LiOH (168 mg, 7.0 mmol) in H2O (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC indicated that the starting material was completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), and 10 - 10 (55 mg, 94%) was obtained as a white solid. 1 1H NMR: (400 MHz, 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. A solution of compound 10-11-Bz (70 mg, 0.13 mmol) dissolved in a mixed solvent of THF (3 mL) and MeOH (1.5 mL) was added to a solution of LiOH (168 mg, 7.0 mmol) in H2O (1.5 mL). The mixture was stirred at 40 °C for 3 days. TLC indicated that the starting material had been completely consumed. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1), and 10-11 (49 mg, 91%) was obtained as a white solid. 1 1H NMR: (400 MHz, 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 the mixture was stirred at the same temperature for 30 minutes. Then, CH3I (127 mg, 0.770 mmol) was added dropwise to this mixture. The reaction was monitored by TLC. After 1 hour, 127 mg of CH3I was added in two portions. After stirring at room temperature for 1.5 hours, the reaction mixture was quenched with an aqueous NH4Cl solution (20 mL), extracted with EtOAc (20 mL × 3 times), dried over Na2SO4, concentrated, and the crude product was obtained. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1), and 10-14 was obtained as a white powder. The diastereomeric pair (340 mg) was separated by preparative SFC, and 10-22 (130 mg, 22.9%) was obtained as a white powder and 10-23 (135 mg, 23.8%) was obtained as a white powder. 11H NMR (10 - 22): (400 MHz, 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 = 13.6 Hz), 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 = 6.8 Hz), 0.68 (s, 3H). 1 1H NMR (10 - 23): (400 MHz, CDCl3) δ 5.30 (s, 1H), 3.61 (t, 2H, J = 6.0 Hz), 3.35 (s, 3H), 3.04 (br, 1H), 2.44 - 2.40 (d, 1H, J = 12.8 Hz), 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 at 50 °C for 48 h under 50 psi of hydrogen. 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 by silica gel column eluting with PE / EtOAc = 15 / 1 to give 10 - 17 (68.4 mg, 68.1%) as a white solid. 1 1H NMR (10 - 17) (400 MHz, CDCl3), δ 3.62 - 3.58 (m, 2H), 3.35 (s, 3H), 3.07 (br, 1H), 1.97 - 1.93 (d, 1H, J = 12.8 Hz), 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 = 6.0 Hz), 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 at 50 °C for 48 h under 50 psi of hydrogen. 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 by silica gel column eluting with PE / EtOAc = 15 / 1 to give 10-19 (68.6 mg, 68.3%) as a white solid. 1 H NMR (10-19) (400 MHz, CDCl3), δ 3.60 (t, 2H, J = 6.0 Hz), 3.35 (s, 3H), 3.07 (br, 1H), 1.97 - 1.94 (d, 1H, J = 12.8 Hz), 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 = 6.0 Hz), 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 EtOAc (2 mL) was added to Lindlar's catalyst (24 mg). The mixture was then stirred at room temperature for 1.5 h under hydrogen (1 atm). 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: (400 MHz, CDCl3) δ 5.93 - 5.85 (m, 1H), 5.20 - 5.16 (d, J = 17.2 Hz, 1H), 5.05 - 5.02 (d, J = 10.8 Hz, 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 Compounds 10-12. To a solution of 10-1 (50 mg, 0.13 mmol) in THF (2 mL) was added dropwise a vinylmagnesium bromide solution (1 mmol, 1 M in THF, 1 mL) 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) indicated the completion of the reaction. The reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL), and then extracted with EtOAc (10 mL × 3 times). The combined organic layers were washed with brine (10 mL × 2 times), 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 obtain 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 = 5.2 Hz, 1H), 5.19 (d, J = 17.2 Hz, 1H), 5.04 (d, J = 10.4 Hz, 1H), 2.42 (d, J = 12.8 Hz, 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 = 6.4 Hz, 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 obtain 10-12A (160 mg) and 10-12B (110 mg) as white solids (total yield: 77%). 1 H NMR (10-12-A): (400 MHz, CDCl3) δ 5.94 - 5.86 (m, 1H), 5.30 (d, J = 5.2 Hz, 1H), 5.19 (d, J = 17.2 Hz, 1H), 5.04 (d, J = 10.4 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.05 - 0.85 (m, 36H), 0.67 (s, 3H). 11H NMR (10-12-B): (400 MHz, CDCl3) δ 5.94 - 5.86 (m, 1H), 5.30 (d, J = 5.2 Hz, 1H), 5.19 (d, J = 17.2 Hz, 1H), 5.04 (d, J = 10.4 Hz, 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 gradually added 9-BBN (24.2 mL, 12.1 mmol) at 0 °C under N2 protection. The mixture was stirred at 60 °C for 16 h. Then, the reaction mixture was cooled to 0 °C, and 10% aqueous NaOH solution (10 mL) and 30% H2O2 (5 mL) were added. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with aqueous Na2S2O3 solution (10 mL), extracted with EtOAc (10 mL × 3), dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to give 10-13 (100 mg, 19.2%) as a white solid. 1 1H NMR: (300 MHz, CD3OD) δ 5.32 (d, J = 5.2 Hz, 1H), 3.70 (d, J = 6.4 Hz, 2H), 2.51 - 2.35 (m, 1H), 2.14 - 1.84 (m, 4H), 1.82 - 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 the mixture was stirred at the same temperature for 30 min. Then, CH3I (78 mg, 0.55 mmol) was added dropwise to this mixture. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with aqueous NH4Cl solution (10 mL), extracted with EtOAc (10 mL × 3), dried over Na2SO4, and concentrated to obtain 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 1H NMR: (300 MHz, CDCl3) δ 5.23 (d, J = 5.2 Hz, 1H), 3.54 (d, J = 6.4 Hz, 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 = 6.4 Hz, 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 afford the 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 1H NMR (10 - 20): (400 MHz, Methanol - d4) δ 5.28 (s, 1H), 3.69 (t, 2H, J = 7.2 Hz), 2.42 - 2.39 (d, 1H, J = 11.6 Hz), 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 = 6.8 Hz), 0.71 (s, 3H). 1 1H NMR (10 - 21): (400 MHz, Methanol - d4) δ 5.28 (s, 1H), 3.68 (t, 2H, J = 7.2 Hz), 2.42 - 2.39 (d, 1H, J = 11.6 Hz), 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 = 7.0 Hz), 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 at 50 °C for 48 h under 50 psi of hydrogen. The reaction mixture was filtered through a pad of Celite. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column eluting with PE / EtOAc = 5 / 1 to afford 10-16 (7.6 mg, 39.3%) as a white solid. 1 H NMR (10-16) (400 MHz, Methaol-d4), δ 3.70 (t, 2H, J = 7.2 Hz), 2.01 - 1.98 (d, 1H, J = 12.4 Hz), 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 = 6.4 Hz), 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 at 50 °C for 48 h under 50 psi of hydrogen. The reaction mixture was filtered through a pad of Celite. The pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column eluting with PE / EtOAc = 5 / 1 to afford 10-18 (12.9 mg, 32.1%) as a white solid. 1 H NMR (10-18) (400 MHz, Methaol-d4), δ 3.68 (t, 2H, J = 7.2 Hz), 1.99 - 1.96 (d, 1H, J = 12.4 Hz), 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 = 6.4 Hz), 0.82 (s, 3H), 0.67 - 0.65 (m, 4H). Example 11

Chemical Structure

[0262] Preparation of Compound 11-2. To a solution of crude Compound 11-1 (30 g, 77 mmol) in dichloromethane (200 mL) were added imidazole (10.4 g, 154 mmol) and tert-butyldichlorodimethylsilane (13.8 g, 92 mmol). The mixture was then stirred at 15 °C for 16 h. The mixture was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 150:1 - 80:1) to give the crude product of 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 n-butyllithium (136 mL, 340 mmol, 2.5 M in hexane) at -78 °C under a nitrogen atmosphere. The mixture was then stirred at -78 °C for 10 min, then at 25 °C for 10 min, and finally at -78 °C for 10 min. Then, a solution of crude Compound 11-2 (34 g, 68 mmol) in THF (100 mL) was added, and the mixture was stirred at -78 °C for 1 h. Then, triethyl phosphite (22.6 g, 136 mmol) was added to this mixture, and the mixture was stirred at -78 °C for 3 h under an oxygen atmosphere and then at 25 °C for 16 h. Ammonium chloride (aqueous solution) was then added to this mixture. The organic layer was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 - 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 product 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 hours. Subsequently, an aqueous solution of sodium hydrogen carbonate and sodium thiosulfate was added to this mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and crude compound 11-4 (5.9 g, 59%) was obtained as a white solid.

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

[0266] Preparation of Compound 11-6. To a solution of crude product 11-5 (3.2 g, 7.9 mmol) in pyridine (50 mL) was added acetyl chloride (1.5 g, 19 mmol) dropwise at 0 °C until the reaction was complete as monitored by TLC. Water was then added to this mixture and it was concentrated under reduced pressure. Water was added to this residue and it was 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), and crude product 11-6 (2.8 g, 79%) was obtained as a white solid.

[0267] Preparation of Compound 11-7. To a solution of crude product 11-6 (2.8 g, 6.3 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (8 g, 50 mmol) dropwise at 0 °C. The mixture was then stirred at 30 °C for 16 hours. The mixture was added to sodium hydrogen carbonate (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), and crude product 11-7 (2 g, 68%) was obtained as a white solid.

[0268] Preparation of Compound 11-8. A solution of lithium hydroxide monohydrate (900 mg, 21 mmol) in water (10 mL) was added to a solution of crude product 11-7 (2 g, 4.2 mmol) in THF (10 mL), and then methanol (5 mL) was added. 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 filtered. The solid was washed with water and dried under reduced pressure to obtain 11-8 (1.5 g, 85%) as a white solid. 1 H NMR: (400 MHz, Methanol-d4) δ 5.34 (d, J = 5.2 Hz, 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. Hydrogen chloride (5 mL, 4 M in methanol) was added to a solution of 11-8 (1 g, 2.4 mmol) in methanol (15 mL). The mixture was stirred at 30 °C for 15 minutes. Sodium hydrogen carbonate (aqueous solution) was added until pH = 7. The mixture was then concentrated under reduced pressure. Water was added to the residue and 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 - 5:1) to obtain 11-9 (970 mg, 93%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.34 (d, J = 5.2 Hz, 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. Then, an aqueous mixed solution of sodium hydrogen carbonate and sodium thiosulfate was added to this mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude compound of 11-10 (1 g, 100%) was obtained 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 Me3Al (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. Then, methylmagnesium bromide (2.4 mL, 7.2 mmol, 3 M in ether) was added at -78 °C. The mixture was then stirred at -78 °C for 1 hour. Then, ammonium chloride (aqueous solution) was added to this mixture and 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), and 240 mg of crude 11-11 (yield: 28%) and 210 mg of crude 11-12 (yield: 25%) were obtained. 1 H NMR (400 MHz, 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: (400 MHz, 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 Compounds 11 - 13. Sodium borohydride (100 mg, 2.6 mmol) was added to a solution of 11 - 12 (70 mg, 0.16 mmol) in ethanol (2 mL) at 15 °C. The mixture was stirred at 15 °C for 30 minutes. Then, ammonium chloride (aqueous solution) was added to this mixture, and it was concentrated under reduced pressure. Water was added to the residue, and it 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 - 8:1) to obtain 11 - 13 (40 mg, 57%) as a white solid. 1 H NMR: (400 MHz, 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 = 6.0 Hz, 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 diastereomer mixture 11 - 13 (30 mg, 0.071 mmol) was separated by SFC to obtain 11 - 15 (12.2 mg) and 11 - 16 (14.7 mg) as white powders (total yield: 90%). 1 H NMR (11 - 15): (400 MHz, MeOD) δ 5.32 (d, J = 5.2 Hz, 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): (400 MHz, MeOD) δ 5.32 (d, J = 5.2 Hz, 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 Compounds 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 minutes. Then, ammonium chloride (aqueous solution) was 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 obtain 11-19 (39 mg, 55%) as a white solid. 1 H NMR: (400 MHz, 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 = 6.4 Hz, 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

Chemical Structure

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

[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 gradually added. The precipitated solid was filtered off and washed with water (100 mL × 2 times). The crude solid was purified by silica gel column (PE / EtOAc = 8 / 1) to obtain compound 0 - 4 (40 g, yield of two steps 34.3%) as a white solid. 1 1H NMR (400 MHz, 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 - 2.04 (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 dry CH2Cl2 (700 mL) solution of Compound 0-4 (33 g, 85 mmol, 1.0 eq) was added Dess-Martin reagent (72 g, 170 mmol, 2.0 eq) portionwise at 0 °C. The reaction mixture was then stirred at room temperature for 1 h. TLC (PE:EA = 3:1) indicated complete consumption of the starting material. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 / Na2S2O3 = 1:3 (250 mL). The organic phase was washed with brine (200 mL × 2), dried over Na2SO4, the solvent was evaporated to give the desired product (35 g, unpurified), which was used in the next step without further purification.

[0279] Preparation of 0-6. A solution of Me3Al (210 mL, 0.42 mmol, 2 M in hexane) was added to a stirred toluene (200 mL) solution of 2,6-di-tert-butyl-4-methylphenol (185 g, 0.84 mol), and then the resulting freshly prepared solution of MAD (0.42 mol, 3.0 eq) in toluene was stirred at room temperature for 1 h. 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. 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) indicated complete consumption of the starting material. The mixture was poured into a saturated aqueous solution of NH4Cl (100 mL) and extracted with EtOAc (300 mL × 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 eluting with PE:EA = 10:1 to give the pure target (30 g, 53%) as a white powder. 11H NMR: (400 MHz, 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 - 1.68 (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 / H2O (800 mL, 1 / 1) was added LiOH·H2O (17.51 g, 417.28 mmol). The reaction mixture was stirred at room temperature for 18 h. TLC (PE / EA = 2 / 1) indicated the complete consumption of Compound 0 - 6. 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, unpurified) as an off - white solid. 1 1H NMR: (400 MHz, 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), 1.61 - 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 Et3N (46.0 mL, 329.40 mmol) in 500 mL of anhydrous CH2Cl2 was stirred at room temperature for 18 h. TLC indicated that the reaction was complete. Then, CH2Cl2 was added to this mixture, and the resulting solution was washed with water, saturated aqueous NaHCO3 solution of 1N HCl and brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel (PE:EtOAc = 10:1~3:1) to obtain the target compound 0-8 (17.0 g, yield: 47.8%) as an off-white solid. 1 1H NMR: (400 MHz, 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, 7H), 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 the key intermediate 0-9. To a 300 mL anhydrous THF solution of Compound 0-8 (17.0 g, 39.38 mmol) was added MeMgBr (65.6 mL, 196.92 mmol, 3M in ether) dropwise at 0 °C under N2. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. TLC indicated that the reaction was complete. Then, saturated aqueous NH4Cl solution was slowly added to the mixture at 0 °C, then the mixture was poured into water and extracted with EtOAc (200 mL × 2 times). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel (PE:EtOAc = 20:1~6:1) to obtain the target compound 0-9 (11.0 g, yield: 72%) as a white solid. 11H NMR: (400 MHz, 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 various in vitro assays and in vivo assays described in the literature, examples of which are described below.

[0284] The following examples are provided 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 way.

[0285] NMDA enhancing effect The NMDA enhancing effect was evaluated using whole-cell patch-clamp of mammalian cells expressing the NMDA receptor or two-electrode voltage-clamp (TEVC) of Xenopus Laevis oocytes expressing the NMDA receptor.

[0286] Whole-cell patch-clamp of mammalian cells Using the whole-cell patch-clamp technique, the effects of the compounds (0.1 mM and 1.0 mM) on the NMDA receptor (GRIN1 / GRIN2A subunits) expressed in HEK cells were observed. NMDA / glycine peak and steady-state currents were recorded from stably transfected cells expressing the NMDA receptor, and the control effects of the test substances 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 with GRIN2A cDNA and CD8(pLeu) antigen cDNA (Lipofectamine™). Approximately 24 to 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 to 80% confluence. Cells were seeded onto poly-L-lysine-coated coverslips covered with complete culture medium in 35 mm culture dishes. Clusters of confluent cells were electrically coupled (Pritchett et al., Science (1988), 242:1306-8). Responses in separated cells are not adequately voltage-clamped, and there is uncertainty about the degree of coupling (Verdoorn et al., Neuron (1990), 4:919-28), so cells were cultured at a density at which a single cell (not visibly connected to adjacent cells) could be measured. Cells were incubated at 37 °C in a 5% CO2, high humidity atmosphere (relative humidity approximately 95%). Cells were maintained continuously and passaged into sterile culture flasks containing a 1:1 mixture of Dulbecco's modified Eagle's medium and nutrient mixture F-12 (1X D-MEM / F-12, liquid, containing L-glutamine), supplemented with 9% fetal bovine serum and 0.9% penicillin / streptomycin solution. 3.0 μg / ml puromycin was added to the complete medium.

[0288] Whole-cell currents were measured using a HEKA EPC-10 amplifier and PatchMaster software. The cell culture dish for recording was placed in the dish holder of the microscope, and the "bath solution" (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, MgCl2 Cells were continuously perfused with 1 mM, 10 mM HEPES, 10 mM D-glucose, pH (NaOH) 7.4 (1 ml / min). All solutions applied to the pipette solution containing cells were maintained at room temperature (19 °C to 30 °C). After creating a Gigaohm seal between the patch electrode and individual transfected HEK 293 cells (pipette resistance range: 2.5 MΩ to 6.0 MΩ; seal resistance range: >1 GΩ), the cell membrane at the tip of the pipette was ruptured to ensure the flow of electricity into the cell (whole-cell patch configuration). At this point, the bath solution was switched to "NMDA bath solution" (137 mM NaCl, 4 mM KCl, 2.8 mM CaCl2, 10 mM HEPES, 10 mM D-glucose, 0.02% Cremophore, pH (NaOH) 7.4). 30 μM NMDA (and 5.0 μM glycine) was applied to the patch-clamped cells for 5 seconds (applied twice), and the current inside NMDA was measured. The cells were clamped at a voltage of -80 mV holding potential. For the analysis of the test substance, after sequential pre-incubation while increasing the concentration of the test substance, the NMDA receptor was stimulated with 30 μM NMDA and 5.0 μM glycine. The pre-incubation period was 30 seconds. The stimulation period was 5 seconds. The test substance was dissolved in DMSO to prepare 0.1 mM and 1 mM stock solutions. The test substance was diluted to 0.1 μM and 1 μM with "NMDA bath solution". Test substances at both concentrations were tested on each cell. The same concentration was applied at least 3 times or until an amplification of the steady-state current was recorded. Every day, one cell was tested with 50 μM PREGS (positive control) using the same application protocol to test whether the cell was successfully transfected with the NMDA receptor.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0289] Oocyte To observe the effect of a compound (10 μM) on the NMDA receptor (GRIN1 / GRIN2A) expressed in Xenopus oocytes, the two - electrode voltage - clamp (TEVC) technique was used. Glutamate / glycine peak and steady - state currents were recorded from oocytes expressing the NMDA receptor, and the control effect of the test substance on these currents was observed. The results are shown in Table 2.

[0290] Ovaries were collected from Xenopus Laevis females deeply anesthetized by cooling to 4°C and immersing in tricaine methanesulfonate (MS-222 at a concentration of 150 mg / L) in sodium bicarbonate (300 mg / L). Once anesthetized, the animals' necks were severed and the animals were given a medullary puncture in accordance with the rules regarding animal rights in the canton of Geneva. The remaining parts were maintained at 4°C in a sterile Barth solution containing, in mM, 88 NaCl, 1, KCl, 2.4 NaHCO3, 10 HEPES, 0.82 MgSO4·7H2O, 0.33 Ca(NO3)2·4H2O, 0.41 CaCl2.6H2O, to which 20 μg / ml of kanamycin, 100 units / ml of penicillin and 100 μg / ml of streptomycin were added, while small pieces of ovaries were isolated for immediate preparation. All recordings were made at 18°C and the cells were superfused with a medium containing, in mM, 82.5 NaCl, 2.5 KCl, 5 HEPES, 1 CaCl2·2H2O, 6H2O, pH 7.4.

[0291] Using an automated injection device with exclusive rights (Hogg et al., J. Neurosci. Methods, (2008) 169:65 - 75), oocytes were injected with cDNA encoding either the human GRIN1 or GRIN2A subunit. At least two days later, electrophysiology was used to evaluate receptor expression. The ratio of cDNA injection for GRIN1 and GRIN2A was 1:1. Electrophysiological recordings were made using an automated process with standard TEVC, and data were collected and analyzed using data acquisition and analysis software that runs on Matlab (Mathworks Inc.) and has exclusive rights. Throughout the experiment, the membrane potential of the oocytes was maintained at -80 mV. To examine the effect of the compound with exclusive rights, currents were induced by applying 3 μM glutamate and 10 μM glycine for 10 seconds. Then, after washing the oocytes for 90 seconds, they were exposed to the test substance at a concentration of 10 μM for 120 seconds. Thereafter, 3 μM glutamate and 10 μM glycine were immediately reapplied for 10 seconds. The enhancing effects on peak current and steady-state current were evaluated. For statistical analysis, values were computed 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] Glutamate was prepared as a concentrated stock aqueous solution (10 -1 M) and diluted in the recording medium to obtain the desired test concentration. Glycine was prepared as a 1 M stock aqueous solution. The compound was prepared as a stock DMSO solution (10 -2 M) and then diluted in the recording medium to obtain the desired test concentration. The remaining DMSO did not exceed a concentration of 1%, which has been shown not to affect the function of Xenopus oocytes. [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

[0293] As shown in Table 1, compounds having a β-hydrogen at C5 are undesirable because the enhancing effect on the NMDA receptor is lost compared to compounds having an α-hydrogen at C5 or a double bond at C5-C6. This is shown by Comparative Compounds 5 vs. 4-6 and 4-7. C 21 Even when the methyl group of C is removed and measured at a concentration of 0.1 μM, the enhancing effect of Comparative Compound 4, for example, is reduced to one-fifth compared to Comparative Compound 3, and the NMDA enhancing effect is significantly reduced. Therefore, the compounds of this selection have a methyl group at C 21 and have a double bond at C5-C6 or an α-hydrogen at C5. In addition, the compounds of this selection exhibit excellent efficacy, and when tested with a compound at a concentration of 1 μM (for example, Comparative Compound 2 vs. 4-6 and 1-11), the maximum enhancing effect on the NMDA receptor is limited. Such characteristics are expected to limit the risk of inducing glutamate-induced neurotoxicity compared to compounds that achieve a greater maximum enhancing effect on the NMDA receptor.

[0294] Other embodiments In the articles of the claims, for example, "a", "an", and "the" will mean one or more than one unless the contrary is indicated or is not apparent from the context. A claim or description that includes "or" between one or more members of a group will be considered satisfied if one, more than one, or all of the members of the group are present in, used in, or otherwise related to a given product or process, unless the contrary is indicated or is not apparent from the context. The present invention, in fact, includes embodiments in which one member of the group is present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all of the members of the group are present in, used in, or otherwise related to a given product or process.

[0295] Furthermore, the present invention encompasses all modifications, combinations, and exchanges in which one or more recited claims have had one or more limitations, elements, clauses, and descriptive terms introduced from another claim. For example, any claim that depends on another claim can be changed to include one or more limitations found in any other claim that depends on the same underlying claim. When elements exist 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 this group. Generally, when the present invention or an aspect of the present invention is described as including a particular element and / or feature, it should be understood that a particular embodiment of the present invention or an aspect of the present invention consists of or consists essentially of such element and / or feature. For the sake of simplicity, these embodiments are not specifically shown as such herein. 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. When a range is given, the endpoints are included. Furthermore, unless otherwise indicated or not apparent from the context and the understanding of those skilled in the art, values expressed as ranges are, unless explicitly stated otherwise in the text, to be presumed to be specific values or sub-ranges within the ranges described for different embodiments of the present invention, to the extent of one tenth of the unit of the lower limit of the range.

[0296] This application references various published patents, published patent specifications, magazines and other publications, all of which are incorporated herein by reference. In the event of any conflict between the incorporated cited references and this specification, the content of this specification shall govern. In addition, any particular embodiment of the invention that is within the prior art will be explicitly excluded from one or more of any of the claims. Such embodiments are considered to be known to those of ordinary skill in the art and will be excluded even if not explicitly shown to be excluded herein. Any particular embodiment of the invention can be excluded from any claim for any reason, whether or not it is related to the existence of the prior art.

[0297] Those of ordinary skill in the art will be able to recognize or confirm many equivalents to the particular embodiments described herein using no more than routine experimentation. 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 of ordinary skill 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

A composition for use in modulating NMDA receptor activity, characterized in that the composition is for oral administration, and the composition comprises a compound of formula (I): 【Chemical 101】 [Wherein, 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 wherein R Ａ２ is hydrogen or substituted or unsubstituted alkyl; R ３ａ is hydrogen or -OR Ａ３ wherein 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; 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 are connected to form a double bond; R in each case ５ａ and R ５ｂ is, independently, hydrogen or fluorine; R ６ａ is a group other than hydrogen selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted carbocyclic groups, substituted and unsubstituted heterocyclic groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups, and the group other than hydrogen is optionally substituted with fluorine; R ６ｂ is a hydrogen atom or a substituted or unsubstituted alkyl group optionally substituted with fluorine; 【Chemical 102】 represents a single bond or a double bond, provided that when a single bond is present, the hydrogen at C5 is in the α conformation; Further provided that, (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 which is a non-hydrogen group substituted with fluorine; or (3) R ６ａ is a group containing 2 to 10 carbon atoms and not hydrogen] or a pharmaceutically acceptable salt thereof. A composition. Claim 2 R １ is unsubstituted C １～３ alkyl, a composition for use according to claim 1. Claim 3 R １ is -CH ３ , -CH ２ CH ３ or -CH ２ CH ２ CH ３ and is the composition for use according to claim 2. Claim 4 R ２ The composition for use according to claim 1, wherein R is hydrogen. Claim 5 R ３ａ and R ３ｂ are both hydrogen, a composition for use according to claim 1. Claim 6 R ４ The composition for use according to claim 1, wherein R is hydrogen. Claim 7 The compound is a compound of formula (II-A): 【Chemical 103】 Or a pharmaceutically acceptable salt thereof. A composition for use according to claim 1. Claim 8 The compound is a compound of formula (II-B): 【Chemical 104】 Or a pharmaceutically acceptable salt thereof. A composition for use according to claim 1. Claim 9 R １ is -CH ３ or -CH ２ CH ３ A composition for use according to claim 7 or 8, wherein it is Claim 10 R ６ｂ is - CH ３ A composition for use according to claim 7 or 8, wherein it is Claim 11 R ５ａ and R ５ｂ A composition for use according to claim 7 or 8, wherein both are hydrogen. Claim 12 R ５ａ and R ５ｂ A composition for use according to claim 7 or 8, wherein at least one of them is fluorine. Claim 13 R ５ａ and R ５ｂ A composition for use according to claim 7 or 8, wherein both are fluorine. Claim 14 R ６ａ The composition for use according to claim 8 or 9, wherein R is a group other than hydrogen substituted with fluorine. Claim 15 R ６ａ is -CF ３ A composition for use according to claim 7 or 8, wherein it is. Claim 16 R ６ａ is a group other than hydrogen substituted with one or more -OR Ａ６ groups, and R Ａ６ is hydrogen or a substituted or unsubstituted alkyl, a composition for use according to claim 7 or 8. Claim 17 R ６ａ is -CH ２ OR Ａ６ 、 -CH ２ CH ２ OR Ａ６ or -CH ２ CH ２ CH ２ OR Ａ６ and the composition for use according to claim 16. Claim 18 R ６ａ is a substituted or unsubstituted C ２～４ alkyl, a substituted or unsubstituted C ２～３ alkenyl, a substituted or unsubstituted C ２～３ alkynyl or a substituted or unsubstituted C ３ carbocyclic, a composition for use according to claim 7 or 8. Claim 19 R ６ｂ The composition for use according to claim 7 or 8, wherein R is hydrogen. Claim 20 R ６ｂ is -CH ３ or -CF ３ and is a composition for use according to claim 7 or 8. Claim 21 R ６ａ is -CF ３ and R ６ｂ is hydrogen or C １～４ alkyl, a composition for use according to claim 7 or 8. Claim 22 R ６ａ is a group other than hydrogen substituted with fluorine, R ６ｂ is -CH ３ The composition for use according to claim 7 or 8, wherein is Claim 23 R ６ａ is a substituted or unsubstituted C ２～４ alkyl, a substituted or unsubstituted C ２～３ alkenyl, a substituted or unsubstituted C ２～３ alkynyl or a substituted or unsubstituted C ３ carbocyclic, and R ６ｂ is -CH ３ for use according to claim 7 or 8, a composition. Claim 24 R ６ａ is unsubstituted C ２～４ alkyl, unsubstituted C ２～３ alkenyl or unsubstituted C ２～３ alkynyl or unsubstituted C ３ carbocyclic, and R ６ｂ is -CH ３ for use according to claim 7 or 8, a composition. Claim 25 R ６ａ is a group other than hydrogen substituted with fluorine, R ６ｂ is -CH ３ The composition for use according to claim 7 or 8, wherein is Claim 26 R １ is C １～３ alkyl, and R ６ａ is a non-hydrogen group substituted with fluorine, and R ６ｂ is -CH ３ is a composition for use according to claim 7 or 8. Claim 27 R １ is C １～３ an alkyl, and R ６ａ is a non-hydrogen group substituted with fluorine, and R ６ｂ is hydrogen, a composition for use according to claim 7 or 8. Claim 28 R １ is C １～３ alkyl, and R ６ａ is a group other than hydrogen selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted carbocyclic, and R ６ｂ is -CH ３ A composition for use according to claim 7 or 8, wherein is Claim 29 R ６ａ The composition for use according to claim 28, wherein R is selected from the group consisting of substituted or unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl or unsubstituted carbocyclic. Claim 30 R ６ａ The composition for use according to claim 28, wherein R is selected from substituted or unsubstituted alkyl. Claim 31 R １ is -CH ３ or -CH ２ CH ３ and the composition for use according to claim 30. Claim 32 R １ is -CH ３ or -CH ２ CH ３ and at least one of R ５ａ and R ５ｂ is fluorine, or both R ５ａ and R ５ｂ are hydrogen, a composition for use according to claim 7 or 8. Claim 33 R １ is -CH ３ or -CH ２ CH ３ and R ６ａ is a group other than hydrogen substituted with fluorine, or is one or more -OR Ａ６ groups, and R Ａ６ is hydrogen or a substituted or unsubstituted alkyl, a composition for use according to claim 7 or 8. Claim 34 R １ is -CH ３ or -CH ２ CH ３ and R ６ｂ is -CH ３ or -CF ３ A composition for use according to claim 7 or 8, wherein Claim 35 R ６ａ is a composition for use according to claim 34 selected from the group consisting of substituted or unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl or unsubstituted carbocyclic. Claim 36 The compound is as follows: 【Chemical 105】 【Chemical 106】 【Chemical 107】 【Chemical 108】 【Chemical 109】 【Chemical 110】 【Chemical 111】 【Chemical 112】 【Chemical 113】 【Chemical 114】 And a composition for use according to claim 1, selected from the group consisting of pharmaceutically acceptable salts thereof. Claim 37 The compound is 【Chemical 115】 A composition for use according to claim 36. Claim 38 The compound is as follows: 【Chemical 116】 A pharmaceutically acceptable salt thereof. A composition for use according to claim 36. Claim 39 The compound is as follows: 【Chemical 117】 A composition for use according to claim 36. Claim 40 The compound is as follows: 【Chemical 118】 A pharmaceutically acceptable salt thereof. A composition for use according to claim 36. Claim 41 The compound is as follows: 【Chemical 119】 A composition for use according to claim 36. Claim 42 The compound is as follows: 【Chemical 120】 A pharmaceutically acceptable salt thereof. A composition for use according to claim 36. Claim 43 The compound is as follows: 【Chemical 121】 A composition for use according to claim 36. Claim 44 The compound is as follows: 【Chemical Formula 122】 A pharmaceutically acceptable salt thereof. A composition for use according to claim 36. Claim 45 The compound is as follows: 【Chemical 123】 A composition for use according to claim 36. Claim 46 The compound is as follows: 【Chemical 124】 The composition for use according to claim 36, which is a pharmaceutically acceptable salt thereof.

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