Neuroactive steroids, compositions, and uses thereof

Abstract

Compounds according to Formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided wherein Z is a group of Formula (i), (ii), (iii), (iv) or (v), and wherein L1, L2, L3, X1, X2, Y, RZ4, RZ5, RZ6, n, R1, R2, R3a, R3b, R4a, R4b, R6a, R6b, R7a, R7b, R11a, R11b, R14, R17, R19, R20, R23a, R23b, and R24 are as defined herein. The compounds of the invention are contemplated to be useful for the prevention and treatment of a variety of CNS-related conditions in mammals. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202111105989.9, filed on September 7, 2012, entitled "Neuroactive Steroids, Compositions, and Uses Thereof".

[0002] Related applications

[0003] This application claims priority to U.S. Provisional Patent Application USSN 61 / 532,427, filed September 8, 2011, pursuant to 35 USC §119(e), which is incorporated herein by reference. Background Art

[0004] Brain excitability is defined as the level of arousal in an animal (a continuum ranging from coma to seizures) and is regulated by various neurotransmitters. Typically, neurotransmitters are responsible for regulating the conduction of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70 mV, with the intracellular portion being negative relative to the extracellular portion. Potential (voltage) is the amount of ion (K+) that can cross the semipermeable membrane of the neuron. + Na + Cl - This is a result of the balance of (organic anions). Neurotransmitters are stored in presynaptic vesicles and released due to the neuronal action potential. When released into the synaptic cleft, excitatory chemical neurotransmitters such as acetylcholine will cause membrane depolarization (a change in potential from -70mV to -50mV). This effect is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase Na+. + Membrane permeability of ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic potential.

[0005] NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, synaptic plasticity, and excitatory toxicity. These receptors accept Ca2+ after binding to the neurotransmitter glutamate. 2+ NMDA receptors are ligand-gated ion channels and are essential for excitatory neurotransmission and normal CNS function. NMDA receptors are heteromeric complexes composed of NR1, NR2, and / or NR3 subunits and have different recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. These modulators could be useful as therapeutic agents with potential clinical applications as cognitive enhancers and in the treatment of psychotic disorders in which glutamatergic transmission is reduced or impaired (see, for example, Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).

[0006] Neuroactive steroids (steroids) such as pregnenolone sulfate (PS) have been shown to have effects on several types of neurotransmitter receptors, such as GABA. A Glycine, AMPA-kainite, and NMDA receptors play direct regulatory roles. NMDA receptors are positively modulated by PS; however, the degree of regulation varies considerably.

[0007] Besides PS, several other 3β-hydroxy steroids have been shown to make NMDA receptors more potent (see, for example, Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682). Recently, a 3β-hydroxy-ergosterol-5-ene steroid derivative (1) has been reported as a positive regulator of NMDA (NR1a / NR2A). Compound (1) (also known as Org-1) was found to be effective against GABA. A Selective modulation of NMDA (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).

[0008]

[0009] There is a need for novel and improved neuroactive steroids that modulate brain excitability to prevent and treat CNS-related conditions. The compounds, compositions, and methods described herein target this objective. Summary of the Invention

[0010] The novel 3-α and 3β-hydroxysteroids described herein are potential NMDA receptor modulators and are therefore useful for the prevention and / or treatment of a wide range of CNS-related conditions, including but not limited to schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizophrenic disorder, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), depression (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., pain syndrome or disorder), sleep disorders, memory disorders, dementia, Alzheimer's disease, paroxysmal disorders (e.g., epilepsy), traumatic brain injury, stroke, addiction disorders (e.g., addiction to opiates, cocaine, and / or alcohol), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome, or tinnitus. These compounds are expected to exhibit improved in vivo potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, and / or safety.

[0011] In one aspect, compounds according to formula (I) are provided:

[0012]

[0013] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof;

[0014] in:

[0015] Z is a group of formula (i), (ii), (iii), (iv), or (v):

[0016]

[0017] L 1 、L 2 、L 3 、X 1 、X 2 Y, R Z4 、R Z5 、R Z6 n, R 1 、R 2 、R 3a 、R 3b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R14 、R 17 、R 19 、R 20 、R 23a 、R 23b and R 24 As defined herein; and the group -XR at the C3 position. 3b It can be α or β.

[0018] For example, in some embodiments, the compound of formula (I) is of formula (Iw):

[0019]

[0020] Or its pharmaceutically acceptable salt;

[0021] in:

[0022] Z is a group of formula (i), (ii), (iii), (iv), or (v):

[0023]

[0024]

[0025] L 1 and L 2 Selected from bonded, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkyne, substituted or unsubstituted hetero-C1-C6 alkylene, substituted or unsubstituted hetero-C2-C6 alkenyl, and substituted or unsubstituted hetero-C2-C6 alkyne.

[0026] L 3 It can be a substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkyne group, a substituted or unsubstituted hetero-C1-C6 alkylene group, a substituted or unsubstituted hetero-C2-C6 alkenyl group, or a substituted or unsubstituted hetero-C2-C6 alkyne group.

[0027] X 1 and X 2 Each case (instance) is independently -O-, -S-, or -NH-;

[0028] R 1 It is hydrogen or a substituted or unsubstituted alkyl group;

[0029] R 3b It is hydrogen;

[0030] R 3a It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

[0031] R 2 、R 11a and R 11b Each case is independently hydrogen or -OR B1 , where R B1 It is hydrogen or a substituted or unsubstituted alkyl group, or R 11a and R 11b They combine to form oxo (=O) groups;

[0032] R 6a and R 6b Each is independently hydrogen, halogen, or substituted or unsubstituted alkyl group, and Represents a single or double bond, provided that if a double bond exists, then R... 6a or R 6b One of them does not exist, and the condition is that if a single bond exists, then the hydrogen at C5 is in the α or β position;

[0033] R 19 and R 20 Each case is independently either hydrogen or -CH3;

[0034] And R 23a and R 23b Each case is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 23a and R 23b They combine to form substituted or unsubstituted C3-C6 cycloalkyl groups;

[0035] R 24 It is hydrogen or a substituted or unsubstituted alkyl group;

[0036] Y is -O-, -S-, or -NR Z5 -;

[0037] R Z4 Independently 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 Z5 、-SR Z5 、or -N(R Z5 )2;

[0038] R Z5 Each case is independently hydrogen or a substituted or unsubstituted alkyl group; and

[0039] R Z6 Each case is independently hydrogen or a substituted or unsubstituted alkyl group, or two R groups. Z6 Groups combine to form C 3-6 Carbon rings; and

[0040] The subscript n is 0 or 1;

[0041] The condition is that the following compounds are specifically excluded:

[0042]

[0043] In some embodiments, Z is a group of the following formula:

[0044]

[0045] In some implementations, L 3 Groups that are the following:

[0046]

[0047] Where p is 1, 2, or 3; and R Z7 and R Z8 Each case is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, or -OR Z5 .

[0048] In some implementations, L 3 Groups that are the following:

[0049]

[0050] Where w is 0 or 1 and p is 1, 2 or 3, or w is 1 and p is 0, 1, 2 or 3; and R Z7 and R Z8 Each case is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, or -OR Z5 .

[0051] In some implementations, L 3 Groups that are the following:

[0052]

[0053] In some implementations, L 3 Groups that are the following:

[0054]

[0055] In some implementations, L 3 Groups that are the following:

[0056]

[0057] In some implementations, Z is a formula

[0058] In some implementations, the group It is the following formula:

[0059]

[0060]

[0061] In some implementations, Z is a formula In some implementations, Y is -O- and L 3 It is an alkylene or heteroalkylene group. In some embodiments, the group... It is the following formula:

[0062]

[0063]

[0064] In some implementations, Z is a formula

[0065] In some implementations, Y is -O- and L 3 It is an alkylene or heteroalkylene.

[0066] In some implementations, the group It is the following formula:

[0067]

[0068] In some embodiments, the group -X 1 R 3b At the β position and R 3a At the α position. In some implementations, -X 1 R 3b It is -OH. In some embodiments, R 3a It is hydrogen. In some embodiments, R 3a It can be a substituted or unsubstituted alkyl group. In some embodiments, R 6b It is a halogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11b For hydrogen or -OR B1 And R 11a It is hydrogen. In some embodiments, R 11a and R 11b Together they form an oxo group. In some embodiments, This represents a single bond, and the hydrogen at C5 is in the α-position. In some embodiments, Represents a double bond. In some implementations, R 19 is -CH3.

[0069] In another aspect, a pharmaceutical composition is provided comprising the compounds of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the compounds of the present invention are provided in an effective amount. In some embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In some embodiments, the compounds of the present invention are provided in a preventatively effective amount.

[0070] In some aspects, the compounds of the present invention are provided as negative allosteric modulators (NAMs) of the NMDA receptor and are therefore useful for the prevention and / or treatment of a wide range of CNS conditions, including but not limited to schizophrenia, depression, bipolar disorder (I and II), schizophrenic disorder, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), depression (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), all pain syndromes and disorders, sleep disorders, memory disorders and dementia (including Alzheimer's disease, epilepsy and any paroxysmal disorder), traumatic brain injury (TBI), stroke, addiction disorders (including opiates and cocaine and alcohol), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome, or tinnitus. For example, in one aspect, a method of NMDA receptor modulation is provided, comprising administering (drugating) an effective amount of the compound of the present invention to a subject who requires the compound of the present invention. In another aspect, a method for modulating CNS activity is provided, comprising administering an effective amount of the compound of the present invention to a subject who requires the compound of the present invention. In yet another aspect, a method for modulating brain excitability is provided, comprising administering an effective amount of the compound of the present invention to a subject who requires the compound of the present invention.

[0071] Other objects and advantages will become apparent to those skilled in the art from the following detailed description, embodiments and claims.

[0072] definition

[0073] Chemical definition

[0074] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the CAS version of the periodic table inside the cover of the 75th edition of the Handbook of Chemistry and Physics, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as the descriptions of specific functional groups and reactivity, are found 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.

[0075] The compounds described herein may include one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (Ellie Liel, Ed., Univ. of Notre Dame Press, Notre Dame, 1972). The invention further includes the compounds described herein as single isomers substantially free of other isomers, or as mixtures of multiple isomers.

[0076] When listing a range of values, the intention is to include every value within that range and its subranges. For example, "C" 1–6 "Alkyl" is intended to include 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 、C 3–4 、C 4–6 、C 4–5 and C 5–6 alkyl.

[0077] The following terms are intended to have the meanings provided below and are useful in understanding the specification and intended scope of the invention. When describing the invention, which may include compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions, the following terms (if present) shall have the following meanings, unless otherwise stated. It should also be understood that, as described herein, any portion defined below may be substituted with various substituents, and the respective definitions are intended to include such substituted portions within their scope, as stated below. Unless otherwise stated, the term “substituted” will be defined as stated below. It should be further understood that the terms “base” and “group” are considered interchangeable when used herein. The article “a, an” may be used herein to refer to one or more of the grammatical objects of the article (i.e., at least one). As an example, “analyte” means one or more analogs.

[0078] "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1-20 carbon atoms. 1–20 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1-12 carbon atoms (“C”). 1–12 Alkyl group (“C”). In some embodiments, the alkyl group has 1-10 carbon atoms (“C”). 1–10 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1-9 carbon atoms (“C”). 1–9 Alkyl group”). In some embodiments, the alkyl group has 1-8 carbon atoms (C1-82 carbon atoms). 1–8 Alkyl group”). In some embodiments, the alkyl group has 1-7 carbon atoms (C1-72 carbon atoms). 1–7 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1-6 carbon atoms (“C”). 1–6 Alkyl group (also referred to herein as "lower alkyl group"). In some embodiments, the alkyl group has 1-5 carbon atoms ("C1-C5"). 1–5 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1-4 carbon atoms (“C”). 1–4 Alkyl group). In some embodiments, the alkyl group has 1-3 carbon atoms (“C13”). 1–3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1-2 carbon atoms (“C”). 1–2 Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2-6 carbon atoms (“C1 alkyl”). 2–6 Alkyl group). C 1–6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each alkyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents, such as 1-5 substituents, 1-3 substituents, or 1 substituent (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1. 1–10 Alkyl group (e.g., –CH3). In some embodiments, the alkyl group is a substituted C-molecule. 1–10 Alkyl. Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0079] As used herein, “alkylene,” “alkenylene,” and “ynylene” refer to the divalent groups of alkyl, alkenyl, and ynyl groups, respectively. When a range or number of carbon atoms is provided for a specific “alkylene,” “alkenylene,” and “ynylene,” it is understood that the range or number refers to the range or number of carbon atoms in a linear divalent carbon chain. “alkylene,” “alkenylene,” and “ynylene” may be substituted with one or more substituents as described herein or may be unsubstituted.

[0080] "Alkylene" refers to an alkyl group in which two hydrogens have been removed to provide a divalent group, and it may be substituted or unsubstituted. Unsubstituted alkylenes include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), etc. Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted 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.

[0081] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2-20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds), and no triple bonds. 2–20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-10 carbon atoms (“C”). 2–10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-9 carbon atoms (“C”). 2–9 Alkenyl group ("alkenyl"). In some embodiments, the alkenyl group has 2-8 carbon atoms ("(C")). 2–8 Alkenyl group ("alkenyl"). In some embodiments, the alkenyl group has 2-7 carbon atoms ("(C")). 2–7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-6 carbon atoms (“C”). 2–6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-5 carbon atoms (“C”). 2–5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-4 carbon atoms (“C”). 2–4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-3 carbon atoms (“C”). 2–3 The alkenyl group ("C2-alkenyl") has two carbon atoms. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2–4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2–6Examples of alkenyl groups include the C group mentioned above. 2–4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise specified, each alkenyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents, such as 1-5 substituents, 1-3 substituents, or 1 substituent (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C10 group. 2–10 Alkenyl group. In some embodiments, the alkenyl group is a substituted C group. 2–10 Alkenyl group.

[0082] "Alkenyl" refers to an alkenyl group in which two hydrogens have been removed to provide a divalent group, and it may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenyl groups include, but are not limited to, vinylidene (-CH=CH-) and propenylidene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted ethylidene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propyleneide (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0083] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2-20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds), and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds). 2–20 The alkynyl group ("alkynyl group"). An alkynyl group having one or more triple bonds and one or more double bonds is also called an "alkynyl" group. In some embodiments, the alkynyl group has 2-10 carbon atoms ("C"). 2–10 The alkynyl group (“Alynyl group”) is present in some embodiments. In some embodiments, the alkynyl group has 2-9 carbon atoms (“C…”). 2–9 The alkynyl group ("acetylinyl") has 2-8 carbon atoms in some embodiments. 2–8 The alkynyl group ("acetylinyl") has 2-7 carbon atoms in some embodiments. 2–7 The alkynyl group ("alkynyl group"). In some embodiments, the alkynyl group has 2-6 carbon atoms ("C"). 2–6 The alkynyl group ("alkynyl group"). In some embodiments, the alkynyl group has 2-5 carbon atoms ("C"). 2–5 The alkynyl group ("acetylinyl") has 2-4 carbon atoms in some embodiments.2–4 The alkynyl group ("acetylinyl group") has 2-3 carbon atoms in some embodiments. 2–3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. The one or more carbon-carbon triple bonds may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2–4 Examples of alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. 2–6 Examples of alkenyl groups include the C group mentioned above. 2–4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Additional examples of the alkynyl group include heptynyl (C7), octyynyl (C8), etc. Unless otherwise specified, each alkynyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents, such as 1-5 substituents, 1-3 substituents, or 1 substituent (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2–10 Alkynyl group. In some embodiments, the alkynyl group is a substituted C group. 2–10 Alkyne group.

[0084] "Imyynyl" refers to a linear ynyl group in which two hydrogens have been removed to provide a divalent group, which may be substituted or unsubstituted. Exemplary divalent ynyl groups include, but are not limited to, substituted or unsubstituted ethynyl groups, substituted or unsubstituted propynyl groups, etc.

[0085] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within a parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroalkyl group refers to a saturated group ("heteroalkyl") having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1–10 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1–9 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-8 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1–8 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-7 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1–7 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a group having 1-6 carbon atoms and 1, 2 or 3 heteroatoms (“heteroalkyl”).1–6 Alkyl group ("alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 1-5 carbon atoms and 1 or 2 heteroatoms ("heteroalkyl"). 1–5 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-4 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1–4 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-3 carbon atoms and 1 heteroatom (“heteroalkyl”). 1–3 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom (“heteroalkyl”). 1–2 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“heteroC1 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and one or two heteroatoms (“heteroC1 alkyl”). 2–6 Alkyl group (“Alkyl”). Unless otherwise specified, each case of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In some embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1–10 Alkyl group. In some embodiments, the heteroalkyl group is a substituted heteroC. 1–10 alkyl.

[0086] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroalkenyl group refers to a group having 2-10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl group"). 2–10 ("heteroalkenyl"). In some embodiments, the heteroalkenyl group has 2-9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2–9 ("alkenyl"). In some embodiments, the heteroalkenyl group has 2-8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("hetero-C"). 2–8 ("heterene"). In some embodiments, the heteroene group has 2-7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heterene"). 2–7 ("heterene"). In some embodiments, the heteroene group has 2-6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heterene"). 2–6 ("heterene"). In some embodiments, the heteroene group has 2-5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heterene"). 2–5("heteroalkenyl"). In some embodiments, the heteroalkenyl group has 2-4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroalkenyl"). 2–4 ("alkenyl"). In some embodiments, the heteroalkenyl group has 2-3 carbon atoms, at least one double bond, and 1 heteroatom ("hetero-C"). 2–3 ("heteroalkenyl"). In some embodiments, the heteroalkenyl group has 2-6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroalkenyl"). 2–6 (Alkenyl). Unless otherwise specified, each heteroalkenyl is independently unsubstituted (“unsubstituted heteroalkenyl”) or substituted with one or more substituents (“substituted heteroalkenyl”). In some embodiments, the heteroalkenyl is an unsubstituted heteroalkenyl. 2–10 Alkenyl. In some embodiments, the heteroalkenyl group is a substituted heteroC. 2–10 Alkenyl group.

[0087] As used herein, the term "heteroyne group" refers to an alkynyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroyne group refers to a group having 2-10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroyne group"). 2–10 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("Hydynyl group"). 2–9 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-8 carbon atoms, at least one triple bond, and 1, 2, 3 or 4 heteroatoms ("Hydynyl group"). 2–8 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-7 carbon atoms, at least one triple bond, and 1, 2, 3 or 4 heteroatoms ("Hydynyl group"). 2–7 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("Hydynyl group"). 2-6 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("Hydynyl group"). 2-5 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("Hydynyl group"). 2-4 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-3 carbon atoms, at least one triple bond, and 1 heteroatom ("Hydynyl group"). 2-3 ("Hydynyl group"). In some embodiments, the heteroynyl group has 2-6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("Hydynyl group").2-6 The xyrynyl group (“unsubstituted xyrynyl”) is, independently, either unsubstituted (“unsubstituted xyrynyl”) or substituted with one or more substituents (“substituted xyrynyl”). In some embodiments, the xyrynyl group is an unsubstituted xyrynyl group. 2-10 Alkynyl group. In some embodiments, the heteroyne group is a substituted hetero-C group. 2-10 Alkyne group.

[0088] As used herein, “alkylene,” “alkenylene,” “ynyneide,” “heteroalkylene,” “heteroalkenyl,” and “heteroynyne” refer to divalent groups of alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, and heteroynyne, respectively. When a range or number of carbon atoms is provided for a specific “alkylene,” “alkenylene,” “ynyneide,” “heteroalkylene,” “heteroalkenyl,” or “heteroynyne,” it is understood that the range or number refers to the range or number of carbon atoms in a linear divalent carbon chain. “alkylene,” “alkenylene,” “ynyneide,” “heteroalkylene,” “heteroalkenyl,” and “heteroynyne” may be substituted with one or more substituents as described herein or may be unsubstituted.

[0089] "Aryl" refers to a group ("C") that has a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) providing 6-14 ring carbon atoms and zero heteroatoms in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the group or linker is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from: benzo[a]acenaphthene, acenaphthene, acephenanthrylene, anthracene, etc. benzene, Aryl groups include phenyl, fluoranthene, fluorene, pentane, hexane, hexane, asymmetric indole, symmetric indole, indene, naphthalene, pentabenzene, octane, octane, oleophane, pentadiene, pentane, pentabenzene, pentane, perylene, phenanthene, phenanthrene, sepium, heptane, pyrene, pinane, rubidium, benzo[a]phenanthrene, and ternaphthalene. Specifically, aryl groups include phenyl, naphthyl, indole, and tetrahydronaphthyl. Unless otherwise specified, each aryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C[a][b]. 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0090] In some embodiments, the aryl group is substituted with one or more groups selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxyl, C1-C8 alkoxy and amino groups.

[0091] Representative examples of substituted aryl groups include the following:

[0092]

[0093] Where R 56 and R 57 One of them can be hydrogen, and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclic, 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, SO2alkyl, S-aryl, SO-aryl, SO2aryl; or R 56 and R 57 They can be combined to form cyclic rings (saturated or unsaturated) of 5-8 atoms, said cyclic rings optionally containing one or more heteroatoms selected from group N, O or S. R 60 and R 61 Independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, substituted C6-C 10 Aryl, 5-10 heteroaryl, or substituted 5-10 heteroaryl.

[0094] Other representative aryl groups with fused heterocyclic groups include the following:

[0095]

[0096] Each W is selected from C(R) 66 )2、NR 66 O and S; and each Y is selected from carbonyl, NR 66 O and S; and R 66 Independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl compounds.

[0097] "Fused aryl" refers to an aryl group that has two rings shared with a second aryl or heteroaryl ring or a carbocyclic or heterocyclic ring, and has a carbonyl or heterocyclic ring.

[0098] "Aryl group" is a subset of alkyl and aryl groups as defined herein, and refers to an alkyl group that is optionally substituted with an aryl group.

[0099] "Heteroaryl" refers to a 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having a 5-10 membered monocyclic or bicyclic ring providing a cyclic carbon atom and 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage may be a carbon or nitrogen atom, where the valence allows. The ring system of a heteroaryl bicyclic ring may include one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in such cases, the ring membership number continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in such cases, the ring member value continues to indicate the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom can have the connection point on the ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0100] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0101] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrole, furanyl, and thiophene groups. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, and... Azolyl, iso Azolyl, thiazolyl, and isothiazolyl groups. Exemplary five-membered heteroaryl groups comprising three heteroatoms include, but are not limited to, triazole groups. Diazolyl and thiadiazolyl. An exemplary 5-membered heteroaryl containing four heteroatoms non-limitingly includes a tetrazolyl. An exemplary 6-membered heteroaryl containing one heteroatom non-limitingly includes a pyridyl. An exemplary 6-membered heteroaryl containing two heteroatoms non-limitingly includes pyridazinyl, pyrimidinyl, and pyrazinyl. An exemplary 6-membered heteroaryl containing three or four heteroatoms non-limitingly includes a triazinyl and a tetraazinyl, respectively. An exemplary 7-membered heteroaryl containing one heteroatom non-limitingly includes a azirylyl. basic, oxygen thia The exemplary 5,6-bicyclic heteroaryl group includes, but is not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, and benzo[] azole group, benzo[a] Azolyl, benzo Diazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indene, and purine. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0102] Representative examples of heteroaryl groups include the following:

[0103]

[0104] Each Y is selected from carbonyl, N, and NR. 65 O and S; and R 65 Independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl compounds.

[0105] "Heteroaryl" is a subset of alkyl and heteroaryl groups as defined herein, and refers to an alkyl group that is optionally substituted by a heteroaryl group.

[0106] "Carbocyclic group" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group having 3-10 ring carbon atoms and zero heteroatoms in a non-aromatic ring system. 3-10 (Carbocyclic group). In some embodiments, the carbocyclic group has 3-8 cyclic carbon atoms ("C"). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3-6 cyclic carbon atoms (“C”). 3-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3-6 cyclic carbon atoms (“C”). 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5-10 cyclic carbon atoms ("C"). 5-10 (Carbocyclic group"). An example C 3-6 The carbocyclic group not limited to includes cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. An exemplary C 3-8 The carbocyclic group includes, without limitation, the C group described above. 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. An example C 3–10 The carbocyclic group includes, without limitation, the C group described above. 3–8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C10 ), octahydro–1H–indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or comprises a fused ring system, a bridged ring system, or a spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the carbon number continues to represent the number of carbons in the carbocyclic system. Unless otherwise specified, each case of a carbocyclic group is independently optionally substituted, i.e., unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3–10 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3–10 Carbon cyclic group.

[0107] In some embodiments, "carbocyclic group" is a monocyclic, saturated carbocyclic group having 3-10 ring carbon atoms. 3–10 cycloalkyl group”). In some embodiments, the cycloalkyl group has 3-8 cyclic carbon atoms” (C 3–8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3-6 cyclic carbon atoms (“C”). 3–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5-6 cyclic carbon atoms (“C”). 5–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5-10 cyclic carbon atoms (“C”). 5–10 cycloalkyl). C 5–6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3–6 Examples of cycloalkyl groups include the C4 ... 5–6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3–8 Examples of cycloalkyl groups include the C4 ... 3–6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3–10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C12 group. 3–10 Cycloalkyl.

[0108] "Heterocyclic group" or "heterocyclic" refers to a group comprising a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (3–10-membered heterocyclic group). In heterocyclic groups containing one or more nitrogen atoms, the bonding point may be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups may be monocyclic ("monocyclic heterocyclic group") or fused ring, bridged ring, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. A bicyclic heterocyclic system may include one or more heteroatoms in one or two rings. "Heterocyclic group" also includes ring systems in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring; or ring systems in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in such cases, the numerical value of the ring member continues to represent the number of ring members in the heterocyclic ring system. Unless otherwise specified, each case of heterocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3-10 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-10 membered heterocyclic group.

[0109] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has a cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0110] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but not limited to, acrylidinyl, ethylene oxide, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, butadiinyl, oxetaneyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-diketone. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but not limited to, dioxapentyl, oxasulfuranyl, disulfuranyl, and... 2-oxazolidinone. Exemplary 5-membered heterocyclic groups comprising three heteroatoms include, but are not limited to, triazolinyl groups. Diazolinyl 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, dithiohexacyclohexyl, and dioxaneyl. 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, hexacyclic heptyl, oxocyclic heptyl, and thiocyclic heptyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, hexacyclic octyl, oxocyclic octyl, and thiocyclic octyl. 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, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, and benzo[] Zolpidemone groups, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycles) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0111] Specific examples of heterocyclic groups are shown in the following illustrative examples:

[0112]

[0113] Each W is selected from CR 67 、C(R 67 )2、NR 67 O and S; and each Y is selected from NR 67 O and S; and R 67 Independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10Aryl, 5-10 membered heteroaryl. These heterocyclic rings may optionally be substituted with one or more groups selected from the following: acyl, amide, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amide), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, halogen, hydroxyl, ketone, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. Substituents include carbonyl or thiocarbonyl, which provide, for example, lactams and urea derivatives.

[0114] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur heteroatoms. "Hetero" can be applied to any hydrocarbon group described above, such as: alkyl, for example heteroalkyl; cycloalkyl, for example heterocyclic; aryl, for example heteroaryl; cycloalkenyl, for example cycloheterenyl, etc., having 1-5 and particularly 1-3 heteroatoms.

[0115] "Acyl" refers to the group -C(O)R 20 , where R 20 "R" can be hydrogen, a substituted or unsubstituted alkyl group as defined herein, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. "Alkyl" is defined as R in this context. 20 Acyl groups are groups 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, and -C(O)-(CH2). t (C6-C 10 Aryl), -C(O)-(CH2) t (5-10 heteroaryl groups), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t (4-10-membered heterocyclic groups), where t is an integer from 0 to 4. In some implementations, R 21 It is a C1-C8 alkyl group substituted with halogen or hydroxyl group; or a C3-C4 alkyl group substituted with halogen or hydroxyl group. 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10Aryl, aralkyl, 5-10 heteroaryl or heteroaralkyl, each substituted with an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.

[0116] "Acylamino" refers to the -NR group. 22 C(O)R 23 , where R 22 and R 23 Each case independently consists of 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 The protecting group is an amino group. Exemplary "acylamino" includes, but is not limited to, formamide, acetamido, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoamide, and benzylcarbonylamino. A specific exemplary "acylamino" is –NR. 24 C(O)-C1-C8 alkyl, –NR 24 C(O)-(CH2) t (C6-C 10 aryl), –NR 24 C(O)-(CH2) t (5-10 aryl groups), –NR 24 C(O)-(CH2) t (C3-C 10 cycloalkyl) and –NR 24 C(O)-(CH2) t (4-10-membered heterocyclic bases), where t is an integer from 0 to 4, and each R 24 Independently represents H or C1-C8 alkyl. In some embodiments, R 25 H, C1-C8 alkyl groups substituted with halogens or hydroxyl groups; C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, aralkyl, 5-10-membered heteroaryl or heteroaralkyl, each substituted with an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and R 26 H, C1-C8 alkyl groups substituted with halogens or hydroxyl groups; C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10Aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each substituted with an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; the condition being R 25 and R 26 At least one of them is different from H.

[0117] "Acyloxy group" refers to the group -OC(O)R 27 , where R 27 The group can be hydrogen, a substituted or unsubstituted alkyl group as defined herein, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In some embodiments, R 28 C1-C8 alkyl groups substituted with halogens or hydroxyl groups; C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, aralkyl, 5-10 heteroaryl or heteroaralkyl, each substituted with an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl.

[0118] "Alkoxy" refers to the group –OR 29 , where R 29 The alkoxy group can be 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. Specific alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1-6 carbon atoms. More specifically, alkoxy groups have 1-4 carbon atoms.

[0119] In some implementations, R 29 A group having one or more substituents selected from the following, for example, 1-5 substituents, and particularly 1-3 substituents, particularly 1 substituent: amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10Cycloalkyl, 4-10 membered heterocyclic groups, halogens, 5-10 membered heteroaryl groups, hydroxyl groups, nitro groups, thioalkoxy groups, thioaryloxy groups, thiol groups, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary 'substituted alkoxy' groups include, but are not limited to, –O-(CH2). t (C6-C 10 Aryl), –O-(CH2) t (5-10 heteroaryl groups), –O-(CH2) t (C3-C 10 (cycloalkyl) and –O-(CH2) t (4-10 membered heterocyclic groups), where t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may be substituted by an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl group. Specific exemplary 'substituted alkoxy' groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0120] "Amino" refers to the group -NH2.

[0121] "Substituted amino group" refers to the formula -N(R 38 The amino group of )2, wherein R 38 It is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, wherein R 38 At least one of them is not hydrogen. In some embodiments, each R 38 Independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halogen or hydroxyl; C3-C8 alkenyl substituted with halogen or hydroxyl; C3-C8 alkynyl substituted with halogen or hydroxyl; or -(CH2). t (C6-C 10 Aryl), -(CH2) t (5-10 heteroaryl groups), -(CH2) t (C3-C 10 cycloalkyl), or -(CH2) t(4-10 membered heterocyclic groups), where t is an integer from 0 to 8, each of which is substituted by an unsubstituted C1-C4 alkyl group, a halogen, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, or an unsubstituted C1-C4 haloalkoxy group or a hydroxyl group; or two R groups. 38 Groups combine to form alkylene groups.

[0122] Exemplary “substituted amino” includes, but is not limited to, –NR 39 -C1-C8 alkyl, –NR 39 -(CH2) t (C6-C 10 aryl), –NR 39 -(CH2) t (5-10 aryl groups), –NR 39 -(CH2) t (C3-C 10 cycloalkyl) and –NR 39 -(CH2) t (4-10-membered heterocyclic bases), where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 Independently representing H or C1-C8 alkyl; and any alkyl group present may be substituted by itself with a halogen, a substituted or unsubstituted amino group, or a hydroxyl group; and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may be substituted by itself with an unsubstituted C1-C4 alkyl group, a halogen, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, or an unsubstituted C1-C4 haloalkoxy group or a hydroxyl group. For the avoidance of 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 groups include both monosubstituted and disubstituted amino groups.

[0123] "Azide group" refers to the group -N3.

[0124] "Carbamoyl" or "amide" refers to the group -C(O)NH2.

[0125] "Substituted carbamoyl" or "substituted amide" refers to the group -C(O)N(R) 62 )2, where each R 62 Independently comprising 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 amino protecting group, wherein R 62At least one of them is not hydrogen. In some embodiments, R 62 Selected from H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, aralkyl, 5-10 heteroaryl, and heteroaryl; or C1-C8 alkyl substituted with halogen or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, aralkyl, 5-10 heteroaryl, or heteroaryl, each substituted with an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R 62 Unlike H.

[0126] Exemplary “substituted carbamoyl group” includes, but is 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 heteroaryl groups), –C(O)NR 64 -(CH2) t (C3-C 10 cycloalkyl) and –C(O)NR 64 -(CH2) t (4-10-membered heterocyclic bases), where t is an integer from 0 to 4, and each R 64 Independently representing H or C1-C8 alkyl, and any aryl, heteroaryl, cycloalkyl or heterocyclic group present may be substituted by an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl group.

[0127] "Carboxy" refers to the group -C(O)OH.

[0128] "Cyano" refers to the radical -CN.

[0129] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is fluorine or chlorine.

[0130] "Hydroxy group" refers to the -OH group.

[0131] "Nitro" refers to the group –NO2.

[0132] "Cycloalkylalkyl" refers to an alkyl group in which the alkyl group is replaced 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.

[0133] "Heterocyclic alkyl" refers to an alkyl group in which the alkyl group is replaced by a heterocyclic group. Typical heterocyclic alkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, etc.

[0134] "Cycloalkenyl" refers to a substituted or unsubstituted carbocyclic group having 3-10 carbon atoms and a single cyclic ring or multiple fused rings (including fused ring systems and bridged ring systems) and having at least one and particularly 1-2 olefin unsaturated sites. Such cycloalkenyl groups include, for example, monocyclic structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, etc.

[0135] "Fused cycloalkenyl" refers to a cycloalkenyl group that has two carbon atoms in its ring shared with a second aliphatic or aromatic ring, and that makes its olefin unsaturated and oriented to impart aromaticity to the cycloalkenyl ring.

[0136] “Vinyl” refers to substituted or unsubstituted –(C=C)-.

[0137] "Ethylene" refers to substituted or unsubstituted –(CC)-.

[0138] "Ethyne group" refers to –(C≡C)-.

[0139] "Nitrogen-containing heterocyclic group" means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, and is not limited to, for example, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), acridine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine, such as N-methylpiperazine. Specific examples include acridine, piperidinone, and piperazineone.

[0140] "Thionyl group" refers to the group =S.

[0141] As defined herein, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl are optionally substituted (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). Generally, the term “substituted,” whether or not preceded by the term “optionally,” means that at least one hydrogen atom present in the group (e.g., carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, such as a compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, or other reactions. Unless otherwise stated, a “substituted” group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position are either the same or different. The term “substituted” is intended to include substitution with all permissible substituents of an organic compound (any substituents described herein that result in the formation of a stable compound). The present invention is designed (contemplated) to obtain any and all such combinations of stable compounds. For the purposes of the invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0142] Exemplary carbon atom substituents include, but are not limited to, halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, and –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 All-halogenated alkyl, C 2–10 Alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 Aryl and 5–14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0143] Or the two hydrogen-bearing groups on the carbon atom: =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 Substitute;

[0144] R aa Each case is independently selected from C. 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 Alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R aa The groups are combined to form a 3–14 membered heterocyclic group or a 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0145] R bb Each case is independently selected from 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 All-halogenated alkyl, C 2–10 Alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R bb The groups are combined to form a 3–14 membered heterocyclic group or a 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0146] R cc Each case is independently selected from hydrogen, C 1–10 Alkyl, C 1–10 All-halogenated alkyl, C 2–10 Alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl, or two R cc The groups are combined to form a 3–14 membered heterocyclic group or a 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0147] R dd The individual cases are independently selected from halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR ee –ON(R)ff )2、–N(R ff )2、–N(R ff )3 + X – 、–N(OR ee )R ff 、–SH、–SR ee 、–SSR ee 、–C(=O)R ee 、–CO2H、–CO2R ee 、–OC(=O)R ee 、–OCO2R ee 、–C(=O)N(R ff )2、–OC(=O)N(R ff )2、–NR ff C(=O)R ee 、–NR ff CO2R ee 、–NR ff C(=O)N(R ff )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)(ORee 2. C 1–6 Alkyl, C 1–6 All-halogenated alkyl, C 2–6 Alkenyl, C 2–6 alkynyl group, C 3–10 Carbocyclic groups, 3–10-membered heterocyclic groups, C 6–10 Aryl, 5–10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two geminal radicals dd Substituents can combine to form =O or =S;

[0148] R ee Each case is independently selected from C. 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 Aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0149] R ff Each case is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 All-halogenated alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 heteroaryl, or two R ff The groups are combined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and

[0150] R gg The cases are independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C) 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - -NH(C 1-6 Alkyl)2 + X - -NH2(C1-6 alkyl) + X - -NH3 + X - -N(OC) 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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 groups, -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 1-6alkyl)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 group, -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 All-halogenated alkyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two geminal Rs gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0151] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F...). - Cl - Br - I - NO3 - 、ClO4 - OH - H2PO4 - HSO4 - Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0152] Where the valence permits, the nitrogen atom may be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, hydrogen, -OH, and -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 All-halogenated alkyl, C 2-10 Alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 aryl and 5-14 heteroaryl groups, or two R groups attached to a nitrogen atom cc The groups are combined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa 、R bb 、R cc and R dd As defined above.

[0153] In some embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH and -OR. aa 、-N(R cc )2、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa 、-SO2R aa -C(=NR) cc )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 、C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aralkyl, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, wherein R aa 、R bb 、R cc and R dd As defined herein. Amino protecting groups are well-known in the art and are included in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd The ones described in detail in the edition, John Wiley & Sons, 1999, are incorporated herein by reference.

[0154] For example, amino protecting groups, such as amide groups (e.g., -C(=O)R), aa This includes, but is not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pyridine amide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetylacetamide, (N'-dithiobenzyloxyacetamide)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, 3-methyl-3-nitrobutyramide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0155] Amino protecting groups, such as urethane groups (e.g., -C(=O)OR), aaThis includes, but is not limited to, methyl carbamate, ethyl carbamate, 9-fluorenyl methyl carbamate (Fmoc), 9-(2-sulfonyl)fluorenyl methyl carbamate, 9-(2,7-dibromo)fluorenyl methyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl methyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl ethyl carbamate (Teoc), and other carbamates. 2-Phenylacetyl ester (hZ), 1-(1-adamantyl)-1-methyl ethyl ester of carbamate (Adpoc), 1,1-dimethyl-2-haloethyl ester of carbamate, 1,1-dimethyl-2,2-dibromoethyl ester of carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl ester of carbamate (TCBOC), 1-methyl-1-(4-biphenyl)ethyl ester of carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methyl ethyl ester of carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl ester of carbamate (Pyoc), ethyl 2-(N,N-dicyclohexylformamido)carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamic acid ester (Coc), 4-nitrocinnamic acid ester (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), amino p-Nitrobenzyl formate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylthionyl benzyl carbamate (Msz), 9-anthrayl methyl carbamate, diphenyl methyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonyl ethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithionyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphine carbamate 2-Triphenylphosphine carbamate (Peoc), 2-Triphenylphosphine carbamate 1,1-Dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzyl carbamate Azoxymethyl ester, 2-(trifluoromethyl)-6-chromone methyl ester (Tcroc), m-nitrobenzene carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl carbamate, p-decoxybenzyl carbamate, 2,2-dimethoxyyl vinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di( 2-Pyridyl)methyl ester, 2-furanylmethyl ester of carbamate, 2-iodoethyl ester of carbamate, isobornyl ester of carbamate, isobutyl ester of carbamate, isonicotinic ester of carbamate, p-(p'-methoxyphenylazo)benzyl ester of carbamate, 1-methylcyclobutyl ester of carbamate, 1-methylcyclohexyl ester of carbamate, 1-methyl-1-cyclopropylmethyl ester of carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl ester of carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl ester of carbamate, 1-methyl-1-phenylethyl ester of carbamate, 1-methyl-1-(4-pyridyl)ethyl ester of carbamate, phenyl ester of carbamate, p-(phenyl)benzyl ester of carbamate, 2,4,6-tri-tert-butylphenyl ester of carbamate, 4-(trimethylammonium)benzyl ester of carbamate, and 2,4,6-trimethylbenzyl ester of carbamate.

[0156] Amino protecting groups, such as sulfonamide groups (e.g., -S(=O)2R), are used to protect amino groups. aa This includes, but is not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilyl ethyl sulfonamide (SES), 9-anthracitesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethylsulfonamide.

[0157] Other amino protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3- Zolpidem-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldimethsilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N -(1-Isopropyl-4-nitro-2-oxo-3-pyrrololin-3-yl)amine, quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptaylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferroceneylmethylamino (Fcm), N-2-pyridinemethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylamine, N-p-methoxybenzylamine, N-diphenylmethyleneamine, N-[(2-pyridyl)] [N-methylamine], N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylethylenediamine, N-p-nitrobenzylamine, N-salicylamine, N-5-chlorosalicylamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid (borinic acid) Derivatives of acid, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphamide (Dpp), dimethylthiophosphamide (Mpt), diphenylthiophosphamide (Ppt), dialkyl aminophosphate, dibenzyl aminophosphate, diphenyl aminophosphate, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfinamide, and 3-nitropyridinesulfinamide (Npys).

[0158] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -R. aa 、-N(R bb )2、-C(=O)SR aa -C(=O)R aa -CO2R aa -C(=O)N(R) bb )2、-C(=NR bb )R aa -C(=NR) bb )OR aa -C(=NR) bb )N(R bb )2、-S(=O)R aa 、-SO2R aa 、-Si(R aa 3. -P(R) cc )2、-P(R cc 3. -P(=O)2R aa -P(=O)(R aa )2、-P(=O)(OR cc )2、-P(=O)2N(R bb )2 and -P(=O)(NR bb )2, where R aa 、R bb and R cc As defined herein, oxygen protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd The ones described in detail in the edition, John Wiley & Sons, 1999, are incorporated herein by reference.

[0159] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, and 2-methoxyethoxymethyl (ME). M), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiaranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiaranyl, 4-methoxytetrahydrothiaranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-di Alkyl-2-yl, tetrahydrofuranyl, tetrahydrothiaranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-bridged methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl 2-Trimethylsilylethyl, 2-(phenylselenoyl)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridinemethyl, 4-pyridinemethyl 3-Methyl-2-pyridinemethyl N-oxygen bridge (oxido), diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptanyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tris(p-methoxyphenyl)methyl, 4-(4′-bromobenzoylmethyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophenyliminoylphenyl)methyl, 4,4′,4″-tris(levulinoyl)oxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenemethyl, 9-anthrayl, 9-(9-phenyl) Tonyl, 9-(9-phenyl-10-oxo)anthrayl, 1,3-benzodithiacyclopentan-2-yl, benzisothiazolyl S,S-dioxobridge, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexyl(ethyl, thexyl)silyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl Alkyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxovalerate (acetylpropionate), 4,4-(ethylidene dithio)valerate (acetylpropionyl dithioacetal), neovalerate, adamantane, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate ( esters), alkyl methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphine)ethyl carbonate Alkyl ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, thioalkyl S-benzyl carbonate, 4-ethoxy-1-naphthyl carbonate, dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxy)methyl (e)benzoate, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, dichlorophenylacetic acid, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyyl)benzoate, α-naphthyl ester, nitrate, N,N,N',N'-tetramethyldiaminophosphate alkyl ester, N-phenylcarbamate alkyl ester, borate, dimethylphosphothio, alkyl 2,4-dinitrophenylsulfenic acid alkyl ester, sulfate, methanesulfonate (methanesulfonate), benzyl sulfonate and toluenesulfonate (Ts).

[0160] In some embodiments, the substituents present on the sulfur atom are sulfur protecting groups (also called thiol protecting groups). Sulfur protecting groups include, but are not limited to, –R aa –N(R) bb )2、–C(=O)SR aa –C(=O)R aa –CO2R aa –C(=O)N(R) bb )2、–C(=NR bb )R aa –C(=NR) bb )OR aa –C(=NR) bb )N(R bb )2、–S(=O)R aa –SO2R aa 、–Si(R aa 3. –P(R) cc )2、–P(R cc 3. –P(=O)2R aa –P(=O)(R aa )2、–P(=O)(OR cc )2、–P(=O)2N(R bb )2 and –P(=O)(NR bb )2, where Raa 、R bb and R cc As defined herein, sulfur protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd The ones described in detail in the edition, John Wiley & Sons, 1999, are incorporated herein by reference.

[0161] The terms “compounds of the present invention” and equivalent expressions are intended to include compounds as described above, and in particular any compound according to any of the formulas listed and / or described herein, including prodrugs, pharmaceutically acceptable salts, and solvates such as hydrates, when the context permits so. Similarly, references to intermediates, whether or not they themselves are claimed, are intended to include their salts and solvates, when the context permits so.

[0162] These and other exemplary substituents are described in more detail in the detailed description, embodiments, and claims. The invention is not intended to be limited in any way by the exemplary list of substituents above.

[0163] Other definitions

[0164] "Pharmaceutical acceptable" means approved or permitted by a federal or state government regulatory agency or by a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals and more specifically in humans.

[0165] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salt is non-toxic and may be an organic or inorganic acid addition salt and a base addition salt. In particular, such salt includes: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid. Salts formed from acids such as 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, and mucoconic acid; or (2) when the acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, or N-methylglucosamine. By way of example only, salts further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, further include salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cation counterion of an acidic functional group. Such cations are illustrated by examples of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc. (see, for example, Berge, et al., J. Pharm. Sci. 66(1):1-79 (Jan. 77).

[0166] "Pharmaceutically acceptable vehicle" means a diluent, adjuvant, excipient, or carrier used to administer the compounds of the present invention.

[0167] "Pharmaceutically acceptable metabolically cleavable group" refers to a group that cleaves in vivo to produce a parent molecule with the structure shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR, and –CH2OR groups, wherein R, each time it appears, is independently selected from alkyl, trialkylsilyl, carbocyclic aryl, or a carbocyclic aryl group substituted with one or more of an alkyl, halogen, hydroxyl, or alkoxy group. Representative examples of metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl.

[0168] "Prodrug" refers to a compound of the present invention having a cleavable group and being converted into a pharmaceutically active form in vivo by solvent decomposition or under physiological conditions. Such compounds include derivatives of the compounds of the present invention. Examples of such compounds include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, etc. Other derivatives of the compounds of the present invention are active in both their acidic and acid derivative forms, but often offer advantages in delayed release, tissue compatibility, or solubility in mammalian organisms in their acid-sensitive forms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives known to those skilled in the art, such as esters prepared by reaction of a parent acid with a suitable alcohol, or amides, or anhydrides, or mixed anhydrides prepared by reaction of a parent acid compound with a substituted or unsubstituted amine. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups dangling from the compounds of the present invention are specific prodrugs. In some cases, it is desirable to prepare diester-type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specifically, the compounds of the present invention are C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C 12 Substituted aryl and C7-C 12 Aryl esters.

[0169] A "solvent" refers to a compound in a form associated with a solvent or water (also called a "hydrate"), typically by solvent decomposition. This physical association includes hydrogen bonding. Common solvents include water, ethanol, acetic acid, etc. The compounds of this invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates such as hydrates, and also include both stoichiometric and non-stoichiometric solvates. In some cases, solvates can be separable, for example when one or more solvent molecules are introduced into the crystal lattice of a crystalline solid. A "solvent" includes both a solution phase and a separable solvate. Representative solvates include hydrates, ethanolates, and methanolates.

[0170] The term "subject" intended for administration includes, but is not limited to, humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0171] "Effective amount" refers to the amount of a compound that is sufficient to achieve such treatment or prevention when administered to a subject for the treatment or prevention of a disease. "Effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated. "Therapeutic effective amount" refers to an effective amount for therapeutic treatment. "Prophylactic effective amount" refers to an effective amount for preventative treatment.

[0172] "Prevention" or "preventive treatment" refers to the reduction of the risk of acquiring or developing a disease or condition (i.e., preventing at least one clinical symptom of the disease from developing in subjects who were susceptible to the disease or who were not exposed to the pathogen before the onset of the disease).

[0173] The term “prevention measures” relates to “prevention” and refers to measures or procedures whose purpose is to prevent, rather than treat or cure, a disease. Non-limiting examples of preventive measures may include administering vaccines; administering low molecular weight heparin to hospital patients at risk of thrombosis due to, for example, immobilization; and administering antimalarial agents such as chloroquine to geographical areas where malaria is endemic or where the risk of malaria infection is high before visiting.

[0174] In one embodiment, “treatment” or “therapeutic treatment” for any disease or condition means improving said disease or condition (i.e., preventing (suppressing) said disease or reducing at least one manifestation, extent, or severity of its clinical symptoms). In another embodiment, “treatment” means improving at least one physical parameter, which may not be identifiable to the subject. In yet another embodiment, “treatment” means physically (e.g., stabilizing identifiable symptoms), physiologically (e.g., stabilizing physical parameters), or both, regulating the disease or condition. In still another embodiment, “treatment” involves slowing the progression of the disease.

[0175] As used herein, the term "isotope variant" refers to a compound that contains isotopes in non-natural proportions at one or more sites of the atoms constituting the compound. For example, an "isotope variant" of a compound may contain one or more non-radioactive isotopes, such as deuterium (…). 2 H or D), carbon-13 (H or D), carbon-13 13 C), Nitrogen-15 ( 15 N), etc. It will be understood that in compounds in which such isotopic substitutions are performed, the following atoms, when present, can be changed such that, for example, any hydrogen can be... 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and arrangement of such atoms can be determined within the art. Similarly, in cases where the resulting compound can be used for drug and / or substrate tissue distribution studies, the invention may include the preparation of isotopic variants using radioactive isotopes. Given that the radioactive isotope tritium is... 3 H and carbon-14, i.e. 14 The ease of introducing C and readily available detection methods are particularly useful for this purpose. Furthermore, isotopes that emit positrons, for example... 11 C. 18 F. 15 O and 13 N-substituted compounds, which will be useful in positron emission tomography (PET) studies for examining matrix receptor occupancy. All isotopic variants (radioactive or non-radioactive) of the compounds provided herein are intended to be included within the scope of this invention.

[0176] It will also be understood that compounds with the same molecular formula but different in the nature or order of their atomic bonding or in the spatial arrangement of their atoms are called "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers".

[0177] Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R- and S-ordering rules of Cahn and Prelog, or by the plane of molecular rotational polarization, and are called dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0178] "Tautomers" are compounds that are interchangeable forms of a specific compound structure, altered by changes in the displacement of hydrogen atoms and electrons. Thus, the two structures are in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with an acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed through treatment with an acid or base. The tautomer form can be related to achieving optimal chemical reactivity and biological activity of the compound of interest.

[0179] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the “S” form of the compound is substantially free of the “R” form of the compound, and therefore in enantiomeric excess of the “R” form. The terms “enantiomeric pure” or “pure enantiomer” mean that the compound comprises more than 75 wt%, more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 91 wt%, more than 92 wt%, more than 93 wt%, more than 94 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, more than 98.5 wt%, more than 99 wt%, more than 99.2 wt%, more than 99.5 wt%, more than 99.6 wt%, more than 99.7 wt%, more than 99.8 wt%, or more than 99.9 wt% of the enantiomer. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0180] As used herein and unless otherwise stated, the term "enantiomerically pure R-compound" means at least about 80% by weight of the R-compound and at most about 20% by weight of the S-compound, at least about 90% by weight of the R-compound and at most about 10% by weight of the S-compound, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, at least about 99% by weight of the R-compound and at most about 1% by weight of the S-compound, at least about 99.9% by weight of the R-compound, or at most about 0.1% by weight of the S-compound. In some embodiments, the weights are based on the total weight of the compounds.

[0181] As used herein and unless otherwise stated, the term "enantiomerically pure S-compound" or "S-compound" means at least about 80% by weight of S-compound and at most about 20% by weight of R-compound, at least about 90% by weight of S-compound and at most about 10% by weight of R-compound, at least about 95% by weight of S-compound and at most about 5% by weight of R-compound, at least about 99% by weight of S-compound and at most about 1% by weight of R-compound, or at least about 99.9% by weight of S-compound and at most about 0.1% by weight of R-compound. In some embodiments, the weights are based on the total weight of the compounds.

[0182] In the compositions provided herein, enantiomerically pure compounds or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may include, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In some embodiments, the enantiomerically pure R-compound in such a composition may, for example, comprise at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound of the total weight of the compounds. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may include, for example, about 90% excipients and about 10% enantiomerically pure S-compound. In some embodiments, the enantiomerically pure S-compound in such a composition may, for example, comprise at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound of the total weight of the compounds. In some embodiments, the active ingredient may be formulated with very little excipient or carrier, or without any excipient or carrier.

[0183] The compounds of the present invention may have one or more asymmetric centers; such compounds may therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0184] Unless otherwise stated, the description or naming of specific compounds in the specification and claims is intended to include both individual enantiomers and mixtures thereof (racemic or vice versa). Methods for determining stereochemistry and isolating stereoisomers are well known in the art.

[0185] Those skilled in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically viable heterocycle (whether aromatic or non-aromatic) is determined by the ring size, degree of unsaturation, and valence of the heteroatoms. Typically, a heterocycle can have one to four heteroatoms, provided the heteroaromatic ring is chemically viable and stable. Detailed Implementation

[0186] In some respects, this article provides 3-α and 3β-hydroxysteroid compounds as NMDA receptor modulators and thus useful for the prevention and / or treatment of a wide range of CNS disorders, including schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizophrenic disorder, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), depression (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., pain syndrome or disorder), sleep disorders, memory disorders, dementia, Alzheimer's disease, paroxysmal disorders (e.g., epilepsy), traumatic brain injury, stroke, addiction disorders (e.g., addiction to opiates, cocaine, and / or alcohol), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome, or tinnitus. These compounds are expected to show improved in vivo potency, pharmacokinetic (PK) properties, oral bioavailability, reconstitutionability, stability, and / or safety.

[0187] Compound

[0188] In one aspect, compounds according to formula (I) are provided herein:

[0189]

[0190] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof;

[0191] in:

[0192] Z is a group of formula (i), (ii), (iii), (iv), or (v):

[0193]

[0194] L 1 and L 2 Selected from bonded, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkyne, substituted or unsubstituted hetero-C1-C6 alkylene, substituted or unsubstituted hetero-C2-C6 alkenyl, and substituted or unsubstituted hetero-C2-C6 alkyne.

[0195] L 3 It can be a substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkyne group, a substituted or unsubstituted hetero-C1-C6 alkylene group, a substituted or unsubstituted hetero-C2-C6 alkenyl group, or a substituted or unsubstituted hetero-C2-C6 alkyne group.

[0196] X1 and X 2 The cases are independently -O-, -S-, -N(R) X )-, where R X Each of these cases 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 heteroalkyl, or amino protecting group.

[0197] R 1 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, halogen, -N3, -NO2, -SCN, -CN, -OR A1 、-SR A1 、-N(R A1 2. -N = NR A1 -N = C(R) A1 2. -N(OR) A1 (R) A1 -C(=O)R A1 -C(=O)OR A1 –C(=O)SR A1 –C(=O)N(R) A1 2. –C(=O)N(OR) A1 (R) A1 –OC(=O)R A1 –OC(=O)OR A1 –OC(=O)SR A1 –OC(=O)N(R) A1 )2、–NR A1 C(=O)R A1 ,–NR A1 C(=O)OR A1 ,–NR A1 C(=O)SR A1 ,–NR A1 C(=O)N(R A1 )2、–SC(=O)R A2 –SC(=O)OR A1 –SC(=O)SR A1 –SC(=O)N(R) A1 )2、–OS(=O)2R A2 –OS(=O)2OR A1 –S–S(=O)2R A2 –S–S(=O)2OR A1–S(=O)R A2 –SO2R A2 ,–NR A1 SO2R A2 、or –SO2N(R A1 )2, where R A1 It 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, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 Groups combine to form substituted or unsubstituted heterocycles; and R A2 The 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 A1 Groups and R A2 Groups combine to form substituted or unsubstituted heterocycles;

[0198] R 2 、R 4a 、R 4b 、R 7a 、R 7b 、R 11a and R 11b The individual cases are independently hydrogen, –OH, halogen, 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, –N3, –NO2, –SCN, –CN, –OR B1 –SR B1 –N(R) B1 2. –N = NR B1 –N=C(R) B1 2. –N(OR) B1 (R) B1 ), –C(=O)R B1 –C(=O)OR B1 –C(=O)SR B1 –C(=O)N(R) b1 2. –C(=O)N(OR) B1 (R) B1 –OC(=O)R B1 –OC(=O)OR B1 –OC(=O)SR B1 –OC(=O)N(R)B1 )2、–NR B1 C(=O)R B1 ,–NR B1 C(=O)OR B1 ,–NR B1 C(=O)SR B1 ,–NR B1 C(=O)N(R B1 )2、–SC(=O)R B2 –SC(=O)OR B1 –SC(=O)SR B1 –SC(=O)N(R) B1 )2、–OS(=O)2R B2 –OS(=O)2OR B1 –S–S(=O)2R B2 –S–S(=O)2OR B1 –S(=O)R B2 –SO2R B2 ,–NR B1 SO2R B2 、or –SO2N(R B1 )2, where R B1 It 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, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 Groups combine to form substituted or unsubstituted heterocycles; and R B2 The 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 B1 Groups and R B2 Groups combine to form substituted or unsubstituted heterocycles; or optionally R 4a and R 4b , and / or R 7a and R 7b , and / or R 11a and R 11b They combine to form oxo (=O) groups;

[0199] R 3aIt can be 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.

[0200] R 3b For hydrogen, -C(=O)R C1 -C(=O)OR C1 -C(=O)SR C1 -C(=O)N(R) C1 )2、-S(=O)2R C2 -S(=O)2OR C1 -P(=O)2R C2 -P(=O)2OR C1 -P(=O)(OR) C1 )2、-P(=O)(R C2 )2, or -P(=O)(R C2 )(OR C1 ), where R C1 It 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, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 Groups combine to form substituted or unsubstituted heterocycles; and R C2 It can be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0201] R 6a and R 6b Each is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, and Represents a single or double bond, provided that if a double bond exists in ring B, then R... 6a or R 6b One of them does not exist, and the condition is that if a single bond exists in ring B, then the hydrogen at C5 is in the α or β position;

[0202] R 14 It is hydrogen or a substituted or unsubstituted alkyl group;

[0203] R 17It can be hydrogen, halogen, 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 -OR D1 , where R D1 It can be 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 oxygen-protecting group.

[0204] R 18 、R 19 and R 20 Each case is independently hydrogen or a substituted or unsubstituted alkyl group;

[0205] And R 23a and R 23b Each case is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 23a and R 23b They combine to form substituted or unsubstituted C3-C6 cycloalkyl groups;

[0206] R 24 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, -C(=O)R E1 -C(=O)OR E1 -C(=O)SR E1 –C(=O)N(R) E1 )2、–S(=O)2R E2 –S(=O)2OR E1 –P(=O)2R E2 –P(=O)2OR E1 –P(=O)(OR E1 )2、–P(=O)(R E2 )2, or –P(=O)(R E2 )(OR E1 ), where R E1 It 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, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R E1 Groups combine to form substituted or unsubstituted heterocycles; and R E2It can be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0207] Y is –O–, –S–, or –NR Z5 –;

[0208] R Z4 Independently 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 Z5 –SR Z5 , or –N(R Z5 )2;

[0209] R Z5 Each of these cases independently consists of 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R groups. Z5 Groups combine to form substituted or unsubstituted heterocycles; and

[0210] R Z6 Each case is independently hydrogen or a substituted or unsubstituted alkyl group, or two R groups. Z6 Groups combine to form C 3–6 Carbon rings; and

[0211] The subscript n is 0, 1, 2 or 3.

[0212] In some implementations, when R 3a H, n is 1 and R 19 When it is Me, then R 1 Unlike H, alkyl, alkenyl, or alkynyl groups. In some embodiments, when R... 3a For H, R 3b For –COMe, R 19 When Me is 0 and n is 0, then R 1 For OH. In some embodiments, when R 3a H, n are 0 and R 20 When it is an alkyl group, then R 1 Unlike OH. In some implementations, when R 19 When it is Me, then R 1 Unlike H, alkyl, alkenyl, or alkynyl groups. In some embodiments, R 1For H; and R 19 Unlike Me. In some implementations, each R 1 and R 3a For H; and R 19 Unlike Me.

[0213] In some implementations, when R 3a When it is H, then R 1 Unlike H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some embodiments, when R 3a When it is H, then R 1 Substituted or unsubstituted carbocyclic groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, halogens, –N3, –NO2, –SCN, -CN, -OR A1 、-SR A1 、-N(R A1 2. -N = NR A1 -N = C(R) A1 2. -N(OR) A1 (R) A1 -C(=O)R A1 -C(=O)OR A1 -C(=O)SR A1 -C(=O)N(R) A1 )2、-C(=O)N(OR A1 (R) A1 -OC(=O)R A1 -OC(=O)OR A1 -OC(=O)SR A1 -OC(=O)N(R) A1 )2、-NR A1 C(=O)R A1 、-NR A1 C(=O)OR A1 、-NR A1 C(=O)SR A1 、-NR A1 C(=O)N(R A1 )2、-SC(=O)R A2 -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R) A1 )2、-OS(=O)2R A2 -OS(=O)2OR A1 -SS(=O)2R A2 -SS(=O)2OR A1-S(=O)R A2 、-SO2R A2 、-NR A1 SO2R A2 、or -SO2N(R A1 )2.

[0214] In some other embodiments, the following compounds are specifically excluded:

[0215]

[0216] And its pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, isotopic variants, or N-oxides, or combinations thereof.

[0217] R 3a Various implementation methods

[0218] As defined above, R 3a It can be 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. Generally understood, R... 3a It can be in the α (below) or β (above) position. In some implementations, R 3a Let α be α. In some implementations, R 3a Let it be β.

[0219] In some implementations, R 3a It is hydrogen.

[0220] In some implementations, R 3a For substituted or unsubstituted alkyl groups, for example, substituted or unsubstituted C4 groups. 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 group. Exemplary R 3a C 1–6 Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and C1 groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups.1–6 Alkyl groups (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 chlorine groups. 1–6 Alkyl groups (e.g., –CH2Cl, –CHCl2) and C groups substituted with alkoxy groups 1–6 Alkyl groups (e.g., –CH2OCH3 and –CH2OCH2CH3). In some embodiments, R 3a For substituted alkyl groups, for example, R 3a It is a haloalkyl, alkoxyalkyl, or aminoalkyl. In some embodiments, R 3a The derivatives are 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. In some embodiments, R... 3a For Me, Et, n-Pr, n-Bu, or i-Bu. In some implementations, R 3a It is methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, or ethoxyethyl. In some embodiments, R 3a It is a trifluoromethoxymethyl group. In some embodiments, R 3a It is fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl. In some embodiments, R 3a It is trifluoromethyl.

[0221] In some implementations, R 3a For substituted or unsubstituted alkenyl groups, 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 5–6 Alkenyl. In some embodiments, R 3a It is an unsubstituted vinyl (C2), propenyl (C3), or butenyl (C4) group, or substituted with one or more substituents selected from alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl groups. In some embodiments, R 3a It is an unsubstituted vinyl, propylene, or butenyl group, or a group substituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl groups. In some embodiments, R 3a It is vinyl.

[0222] In some implementations, R 3aFor substituted or unsubstituted alkynyl groups, for example, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-3 Alkyne group, substituted or unsubstituted C 3-4 Alkyne group, substituted or unsubstituted C 4-5 Alkyne group, or substituted or unsubstituted C 5-6 Alkyne group. Exemplary substituted or unsubstituted R 3a The alkynyl group includes, but is not limited to, unsubstituted or substituted ethynyl, propynyl, or butynyl groups, either alkyl, halogen, haloalkyl (e.g., CF3), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl-substituted. 3a The group is selected from trifluoroacetylene, cyclopropylacetylene, cyclobutylacetylene, propynyl, fluoropropynyl, and chloroacetylene. In some embodiments, R 3a The ethynyl (C2), propynyl (C3), or butynyl (C4) group is unsubstituted or substituted with one or more substituents selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, and substituted or unsubstituted heterocyclic groups. In some embodiments, R 3a The substituted phenyl group is an ethynyl (C2), propynyl (C3), or butynyl (C4) group. In some embodiments, the phenyl substituent is further substituted by one or more substituents selected from halogen, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amide. In some embodiments, R 3a For substituted or unsubstituted pyrrole, imidazole, pyrazol, azole group, thiazolyl group, iso- Azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl Diazolyl, thiadiazolyl, or tetrazolyl-substituted ethynyl (C2), propynyl (C3), or butynyl (C4).

[0223] In some implementations, R 3a It is an unsubstituted or substituted ethynyl, propynyl, or butynyl group, either alkyl, halogenated, haloalkyl, alkoxyalkyl, or hydroxylated. In some embodiments, R 3a The acetylene or propynyl group is substituted or unsubstituted with an aryl group. In some embodiments, R 3a It is an ethynyl or propynyl group substituted with an unsubstituted phenyl group or substituted with a halogen, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl group. In some embodiments, R 3a The acetylene or propynyl group is substituted or unsubstituted with a carbocyclic group. In some embodiments, R 3a The substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ethynyl or propynyl group is used. In some embodiments, R3a The ethynyl or propynyl group is substituted or unsubstituted with a heteroaryl group. In some embodiments, R 3a It can be a substituted or unsubstituted pyridyl group, or an acetylenic or propynyl group substituted with a pyrimidinyl group. In some embodiments, R 3a For substituted or unsubstituted pyrrole, imidazole, pyrazol, azole group, thiazolyl group, iso- Azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl Diazole, thiadiazole, tetrazolium-substituted ethynyl or propynyl groups. In some embodiments, R 3a The acetylene or propynyl group is substituted or unsubstituted with a heterocyclic group. In some embodiments, R 3a It is an acetylene or propynyl group substituted with or unsubstituted pyrrolidinyl, piperidinyl, piperazine, or morpholinyl groups. In some embodiments, R 3a It is a propynyl or butynyl group substituted with a hydroxyl or alkoxy group. In some embodiments, R 3a It is a propynyl or butynyl group substituted with methoxy or ethoxy. In some embodiments, R 3a It is an acetylene or propynyl group substituted with Cl. In some embodiments, R 3a It is an ethynyl or propynyl group substituted with trifluoromethyl.

[0224] In some implementations, R 3a For substituted or unsubstituted carbocyclic groups, for example, substituted or unsubstituted C 3-6 Carbocyclic, substituted or unsubstituted C 3-4 Carbocyclic, substituted or unsubstituted C 4-5 Carbocyclic group, or substituted or unsubstituted C 5-6 Carbon cyclic group.

[0225] In some implementations, R 3a The heterocyclic group may be substituted or unsubstituted, for example, a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted 3-4 membered heterocyclic group, a substituted or unsubstituted 4-5 membered heterocyclic group, or a substituted or unsubstituted 5-6 membered heterocyclic group.

[0226] In some implementations, R 3a The aryl group may be substituted or unsubstituted. In some embodiments, R 3a The phenyl group can be substituted or unsubstituted.

[0227] In some implementations, R 3a The heteroaryl group may be substituted or unsubstituted, for example, optionally substituted 5-6 membered heteroaryl groups.

[0228] R as a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted ynylic group 3a Another implementation is described below:

[0229]

[0230] Where R 3c The various cases are hydrogen, halogen, or -OR F1 , where R F1 For substituted or unsubstituted alkyl groups; and R 3d The various cases are hydrogen, halogen, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic.

[0231] In some implementations, at least one R 3c It is hydrogen. In some embodiments, at least two R... 3c It is hydrogen. In some embodiments, each R... 3c It is hydrogen. In some embodiments, at least one R 3c The halogen is a halogen (e.g., fluorine, chlorine, bromine, iodine). In some embodiments, at least two R... 3c It is a halogen (e.g., fluorine, chlorine, bromine, iodine). In some embodiments, each R... 3c It is a halogen (e.g., fluorine to provide the -CF3 group). In some embodiments, at least one R 3c For -OR F1 (e.g., OMe or OEt). In some implementations, at least two R 3c For -OR F1 (e.g., OMe or OEt). In some implementations, at least one R 3c It can be hydrogen, F, -OMe, or -OEt. In some embodiments, R 3c One of them is F, -OMe, or OEt; and the rest are H.

[0232] In some implementations, at least one R 3d It is hydrogen. In some embodiments, each R... 2c It is hydrogen. In some embodiments, at least one R 3d It is a halogen (e.g., fluorine, chlorine, bromine, iodine). In some embodiments, each R... 3d It is a halogen (e.g., fluorine, chlorine, bromine, iodine). In some embodiments, R 3d Each is an alkyl group, for example, R 2c Each is Me. In some implementations, R 3d One is an alkyl group; and the other is hydrogen, for example, R 3d One is Me; and the other is hydrogen. In some embodiments, R 3dOne is a substituted or unsubstituted carbocyclic group, such as cyclopropyl or cyclobutyl, and the other is hydrogen. In some embodiments, at least one R 3d It can be hydrogen, –F, –Br, –Cl, –I, –CH3, –CF3, cyclopropyl, or cyclobutyl. In some embodiments, R 3d The various cases are H. In some implementations, R 3d The various cases are halogens (e.g., fluorine, chlorine, bromine, iodine). In some embodiments, R 3d In various cases, the components are alkyl groups, such as –CH3, –CF3, –CH2CH2Cl. In some embodiments, R 3d The various cases involve substituted or unsubstituted carbocyclic groups, such as cyclopropyl or cyclobutyl. In some embodiments, R 3d The cyclopropyl group may be substituted or unsubstituted. In some embodiments, R 3d The various forms are hydrogen, –F, –Br, –Cl, –I, –CH3, –CF3, –CH2CH2Cl, cyclopropyl, or cyclobutyl. In some embodiments, R 3d For Me or Cl. In some implementations, R 3d A substituted or unsubstituted heterocyclic group.

[0233] –X 1 -R 3b Various implementation methods

[0234] As defined above, for the group –X 1 R 3b , X 1 Independently –O–, –S–, or –N(R) X )–, where R X Each of these cases independently comprises 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 heteroalkyl, or an amino protecting group; and R 3b For hydrogen, –C(=O)R C1 –C(=O)OR C1 –C(=O)SR C1 –C(=O)N(R) C1 )2、–S(=O)2R C1 –S(=O)2OR C1 –P(=O)2R C1 –P(=O)2OR C1 –P(=O)(OR C1 )2、–P(=O)(R C1 )2, or –P(=O)(R C1 )(ORC1 ), where R C1 It 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, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 Groups combine to form substituted or unsubstituted heterocycles. Generally understood, the group –X 1 -R 3b It can be at the α (below) or β (above) position. In some embodiments, the group –X 1 -R 3b For α. In some embodiments, the group –X 1 -R 3b Let it be β.

[0235] In some implementations, X 1 For –O–. In some implementations, X 1 For –S–. In some implementations, X 1 For –N(R) X In some implementations, R X It is an alkyl group. In some embodiments, R X For Me, Et, or i-Pr. In some implementations, R X Let H be the value of X, where X is the value of X. 1 It is –NH–.

[0236] In some implementations, R 3b It is hydrogen. For example, in some embodiments, the group –X 1 R 3b For –OH. In some embodiments, the –X group 1 R 3b For –SH. In some implementations, the group –X 1 R 3b For –NH2 or –NHR X .

[0237] In some implementations, R 3b For –C(=O)R C1 –C(=O)OR C1 –C(=O)SR C1 –C(=O)N(R) C1 )2、–S(=O)2R C1 –S(=O)2OR C1 –P(=O)2R C1 –P(=O)2ORC1 –P(=O)(OR C1 )2、–P(=O)(R C1 )2, or –P(=O)(R C1 )(OR C1 ).

[0238] In some implementations, R C1 At least one of these is a hydrogen or a protecting group, namely an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom. In some embodiments, R C1 At least one of them is hydrogen.

[0239] In some implementations, R C1 At least one of them is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C14 group. 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 group. Exemplary R C1 C 1–6 Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and C1 groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups. 1–6 Alkyl groups (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 chlorine groups. 1–6 Alkyl groups (e.g., –CH2Cl, –CHCl2) and C groups substituted with alkoxy groups 1–6 Alkyl groups (e.g., –CH2OCH3 and –CH2OCH2CH3).

[0240] In some implementations, R C1 At least one of them is a substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted C group. 2–6 alkenyl, substituted or unsubstituted C 2–3 alkenyl, substituted or unsubstituted C 3–4 alkenyl, substituted or unsubstituted C4–5 alkenyl, or substituted or unsubstituted C 5–6 Alkenyl group.

[0241] In some implementations, R C1 At least one of them is a substituted or unsubstituted alkynyl group, for example, a substituted or unsubstituted C group. 2–6 Alkyne group, substituted or unsubstituted C 2–3 Alkyne group, substituted or unsubstituted C 3–4 Alkyne group, substituted or unsubstituted C 4–5 Alkyne group, or substituted or unsubstituted C 5–6 Alkyne group.

[0242] In some implementations, R C1 At least one of them is a substituted or unsubstituted carbocyclic group, for example, a substituted or unsubstituted C 3–6 Carbocyclic, substituted or unsubstituted C 3–4 Carbocyclic, substituted or unsubstituted C 4–5 Carbocyclic group, or substituted or unsubstituted C 5–6 Carbon cyclic group.

[0243] In some implementations, R C1 At least one of them is a substituted or unsubstituted heterocyclic group, for example, a substituted or unsubstituted 3–6-membered heterocyclic group, a substituted or unsubstituted 3–4-membered heterocyclic group, a substituted or unsubstituted 4–5-membered heterocyclic group, or a substituted or unsubstituted 5–6-membered heterocyclic group.

[0244] In some implementations, R C1 At least one of them is a substituted or unsubstituted aryl group, for example, a substituted or unsubstituted phenyl group.

[0245] In some implementations, R C1 At least one of them is a substituted or unsubstituted heteroaryl group, for example, a optionally substituted 5–6-membered heteroaryl group.

[0246] In some implementations, two R C1 Groups combine to form substituted or unsubstituted heterocycles, such as substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, or substituted or unsubstituted morpholinyl rings.

[0247] In some implementations, R 3b For –C(=O)R C1 –C(=O)OR C1 –C(=O)N(R) C1 )2 or –C(=O)N(OR C1 (R) C1 ), where R C1 As defined in this article.

[0248] In some implementations, R 3b For –C(=O)R C1 For example, where R C1 For example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6). In some embodiments, R 3b It is –C(=O)CH3. In some implementations, R 3b For –C(=O)(CH2) m CO2H, where m is an integer from 2 to 5 (inclusive). In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, R 3b It is –C(=O)CH2CH2C(=O)OH.

[0249] In some implementations, R 3b -C(=O)OR C1 For example, where R C1 For example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6).

[0250] In some implementations, R 3b For –C(=O)SR C1 For example, where R C1 For example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6).

[0251] In some implementations, R 3b For –C(=O)N(R) C1 )2, for example, –C(=O)NH2 or –C(=O)NHR C1 , where R C1For example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6), or R 1 -C(=O)N(R) C1 )2, where two R C1 Groups combine to form substituted or unsubstituted heterocycles, such as substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, or substituted or unsubstituted morpholinyl rings.

[0252] In some implementations, R 3b is -S(=O)2R C1 or -S(=O)2OR C1 , where R C1 For example, hydrogen, or substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6), or substituted or unsubstituted phenyl. In some embodiments, R 3b is -S(=O)2R C1 In some implementations, R 3b -S(=O)2OR C1 For example, -SO3H.

[0253] In some implementations, R 3b -P(=O)2R C1 -P(=O)2OR C1 -P(=O)(OR) C1 )2、-P(=O)(R C1 )2, or -P(=O)(R C1 )(OR C1 ), where each R C1 For example, independently hydrogen, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6), or substituted or unsubstituted phenyl. In some embodiments, R 3b -P(=O)2RC1 In some implementations, R 1 -P(=O)2OR C1 In some implementations, R 3b -P(=O)(OR) C1 2. In some implementations, R 1 -P(=O)(R) C1 2. In some implementations, R 3b -P(=O)(R) C1 )(OR C1 ).

[0254] In each embodiment where Z is a group of formula (i) or (ii)

[0255] In some embodiments, Z is a group of formula (i):

[0256]

[0257] In another embodiment, Z is a group of formula (ii):

[0258]

[0259] As defined above, L 1 and L 2 It is a bond (i.e., in other words, it does not exist) or is a substituted or unsubstituted C1-C6 alkylene group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkyne group, a substituted or unsubstituted hetero C1-C6 alkylene group, a substituted or unsubstituted hetero C2-C6 alkenyl group, or a substituted or unsubstituted hetero C2–C6 alkyne group.

[0260] In some implementations, L 1 or L 2 For key.

[0261] In some implementations, L 1 or L 2 It is a substituted or unsubstituted C1–C6 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C1–C4 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C1–C3 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C1–C2 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C1 alkylene group. In some embodiments, L1 or L 2 It is a substituted or unsubstituted C2 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C3 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C4 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C5 alkylene group. In some embodiments, L 1 or L 2 It is a substituted or unsubstituted C6 alkylene group. In some embodiments, L 1 or L 2 The alkylene group described above is substituted with one or more substituents selected from substituted or unsubstituted alkyl groups and halogens. In some embodiments, L 1 or L 2 It can be -CH2-, -CHMe-, -CMe2-, -CH2-CH2-, -CF2-CH2-, -CH2-CMe2-, -CH2-CH2-CH2-, or -CH2-CH2-CMe2-.

[0262] In some implementations, L 1 or L 2 For substituted or unsubstituted C2–C6 alkenyl groups. In some embodiments, L 1 or L 2 For substituted or unsubstituted C2–C5 alkenyl groups. In some embodiments, L 1 or L 2 For substituted or unsubstituted C2–C4 alkenyl groups. In some embodiments, L 1 or L 2 For substituted or unsubstituted C2–C3 alkenyl groups. In some embodiments, L 1 or L 2 The C2-olefin group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C3-olefin group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C4 alkenyl group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C5-olefin group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C6-olefin group may be substituted or unsubstituted. In some embodiments, L 1 or L 2The as-described alkenyl group is substituted by one or more substituents selected from substituted or unsubstituted alkyl groups and halogens.

[0263] In some implementations, L 1 or L 2 The C2–C6 ynylene group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C2–C5 ynylene group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The group may be substituted or unsubstituted C2–C4 ynynoid. In some embodiments, L 1 or L 2 The C2–C3 ynylene group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C2-alkynyl group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C3 acetylinyl group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C4 acetylinyl group may be substituted or unsubstituted. In some embodiments, L 1 The C5-alkynyl group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The C6 acetylinyl group may be substituted or unsubstituted. In some embodiments, L 1 or L 2 The as-described ynylene group is substituted with one or more substituents selected from substituted or unsubstituted alkyl groups and halogens.

[0264] Furthermore, in some implementations, L 1 or L 2 For substituted or unsubstituted heterogeneous C 1–6 Alkylenes, for example, substituted or unsubstituted heterocarbons 1–2 Alkylene, substituted or unsubstituted heterocarbon 2–3 Alkylene, substituted or unsubstituted heterocarbon 3–4 Alkylene, substituted or unsubstituted heterocarbon 4–5 Alkylene, or substituted or unsubstituted heterocarbon 5–6 Alkylene. In some embodiments, L 1 or L 2 For substituted or unsubstituted heterogeneous C 2–6 alkenyl groups, for example, substituted or unsubstituted heterocyclic compounds. 2–3 alkenyl, substituted or unsubstituted heterocarbon 3–4 alkenyl, substituted or unsubstituted heterocarbon 4–5 alkenyl, or substituted or unsubstituted heterocyclic compounds 5–6Alkenyl group. In some embodiments, L 1 or L 2 For substituted or unsubstituted heterogeneous C 2–6 Alynyl groups, for example, substituted or unsubstituted heterocyclic compounds. 2–3 Hypo-alkynyl, substituted or unsubstituted hetero-C 3–4 Hypo-alkynyl, substituted or unsubstituted hetero-C 4–5 alkyne group, or substituted or unsubstituted heterocyclic group 5–6 Alynyl group. In any of the above cases, in some embodiments, L 1 or L 2 C is unsubstituted or halogenated (e.g., fluorine) or substituted or unsubstituted. 1–6 Alkyl-substituted heteroalkylene, heteroalkenyl, or heteroynyl.

[0265] As defined above, R 1 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, halogen, –N3, –NO2, –SCN, –CN, –OR A1 –SR A1 –N(R) A1 2. –N = NR A1 –N=C(R) A1 2. –N(OR) A1 (R) A1 ), –C(=O)R A1 –C(=O)OR A1 –C(=O)SR A1 –C(=O)N(R) A1 2. –C(=O)N(OR) A1 (R) A1 –OC(=O)R A1 –OC(=O)OR A1 –OC(=O)SR A1 –OC(=O)N(R) A1 )2、–NR A1 C(=O)R A1 ,–NR A1 C(=O)OR A1 ,–NR A1 C(=O)SR A1 ,–NR A1 C(=O)N(R A1 )2、–SC(=O)R A2 –SC(=O)OR A1 –SC(=O)SR A1–SC(=O)N(R) A1 )2、–OS(=O)2R A2 –OS(=O)2OR A1 –S–S(=O)2R A2 –S–S(=O)2OR A1 –S(=O)R A2 –SO2R A2 ,–NR A1 SO2R A2 、or –SO2N(R A1 )2, where R A1 It 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, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 Groups combine to form substituted or unsubstituted heterocycles; and R A2 The 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 A1 Groups and R A2 Groups combine to form substituted or unsubstituted heterocycles.

[0266] In some implementations, R 1 It is hydrogen.

[0267] In some implementations, R 1 It can be a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some embodiments, R 1 The alkyl group may be substituted or unsubstituted, for example, Me, Et, or i-Pr. In some embodiments, R 1 The substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted vinyl group or a substituted or unsubstituted propenyl group. In some embodiments, R 1 The alkynyl group can be substituted or unsubstituted.

[0268] In some implementations, R 1 Selected from substituted or unsubstituted carbocyclic groups or substituted or unsubstituted heterocyclic groups.

[0269] In some implementations, R 1 The aryl group can be substituted or unsubstituted, for example, phenyl.

[0270] In some implementations, R 1The heteroaryl group may be substituted or unsubstituted, for example, substituted or unsubstituted heteroaryl groups selected from: pyrrole, imidazolyl, pyrazolyl, etc. azole group, thiazolyl group, iso- Azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl Diazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazonyl, quinoxalinyl, naphthidyl, indolyl, inzolyl, benzimidazolyl, pyrrolopyridyl, pyrrolopyrimidyl, pyridolopyrimidyl, or purine. In some embodiments, the heteroaryl group is substituted with one or more groups selected from: substituted or unsubstituted alkyl, haloalkyl, alkenyl, substituted or unsubstituted alkynyl, oxo, hydroxyl, halogen, alkoxy, -S-alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted -SO-alkyl, substituted or unsubstituted -SO2-alkyl, substituted or unsubstituted -SO-aryl, substituted or unsubstituted -SO2-aryl, substituted or unsubstituted -SO-heteroaryl, substituted or unsubstituted -SO2-heteroaryl, amino, cyano, and acyl. In some implementations, R 1 It is imidazole, pyrazol, 1,2,3-triazol, 1,2,4-triazol, Diazolyl, thiadiazolyl, or tetrazolyl; each being unsubstituted or independently substituted with one or two groups selected from: oxo, Me, F, Cl, -CN, and -CF3. In some embodiments, R 1 It is quinolinyl, isoquinolinyl, or purine; each is unsubstituted or independently substituted by one or two of the following groups: oxo, Me, F, Cl, -CN, and -CF3.

[0271] In some implementations, R 1 For -OR A1 In some implementations, R 1 The radical is -O-quinolinyl, -O-isoquinolinyl, or -O-purine, each being unsubstituted or substituted independently with one or two groups selected from the following: Me, F, Cl, -CN, and -CF3. In some embodiments, R 1 It is -OH or -O-CO-CH2-CH2-CO2H.

[0272] In some implementations, R 1 For -SR A1 In some implementations, R 1 It is an S-quinolinyl, -S-isoquinolinyl, or -S-purine group, each of which is unsubstituted or substituted independently with one or two groups selected from the following: Me, F, Cl, -CN, and -CF3. In some embodiments, R1 For -SH.

[0273] In some implementations, R 1 -OS(=O)2R A2 In some implementations, R 1 -OS(=O)2OR A1 For example, -O-SO3H. In some implementations, R 1 is -SS(=O)2R A2 In some implementations, R 1 -SS(=O)2OR A1 For example, -S-SO3H.

[0274] As defined above, R 20 Independently, it is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 20 It is hydrogen. In some embodiments, R 20 It is a substituted or unsubstituted alkyl group (e.g., -CH3).

[0275] As defined above, R 23a and R 23b Each case is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 23a and R 23b These are combined to form substituted or unsubstituted C3-C6 cycloalkyl groups. In some embodiments, R 23a and R 23b In each case, it is hydrogen. In some embodiments, R 23a and R 23b One of them is halogen, such as fluorine, and R 23a and R 23b The other is hydrogen, halogen, or a substituted or unsubstituted alkyl group. In some embodiments, R 23a and R 23b In some cases, R is a halogen, for example, fluorine. 23a and R 23b Each case is independently a substituted or unsubstituted alkyl group. In some embodiments, R 23a and R 23b Each is Me. In some implementations, R 23a and R 23b One of them is H. In some implementations, R 23a and R 23b One is H; and the other is a substituted or unsubstituted alkyl group. In some embodiments, R 23a and R 23b One is H; and the other is Me or Et. In some implementations, R23a and R 23b These are combined to form substituted or unsubstituted C3-C6 cycloalkyl groups. In some embodiments, R 23a and R 23b They combine to form substituted or unsubstituted cyclopropyl groups.

[0276] In some implementations, the group It is the following formula:

[0277]

[0278] As defined above, X 2 Independently -O-, -S-, or -N(R) X )-, where R X Each of these can be 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 heteroalkyl, or amino protecting group.

[0279] In some implementations, X 2 For –O–. In some implementations, X 2 For –S–. In some implementations, X 2 For –N(R) X In some implementations, R X It is an alkyl group. In some embodiments, R X For Me, Et, or i-Pr. In some implementations, R X It is hydrogen.

[0280] In some implementations, X 1 For –O– and X 2 For –O–. In some implementations, X 1 For –O– and X 2 For –S–. In some implementations, X 1 For –O– and X 2 For –N(R) X In some implementations, X 1 For –S– and X 2 For –O–. In some implementations, X 1 For –S– and X 2 For –S–. In some implementations, X 1 For –S– and X 2 For –N(R) X In some implementations, X 1 For –N(R) X )–and X 2For –O–. In some implementations, X 1 For –N(R) X )–and X 2 For –S–. In some implementations, X 1 For –N(R) X )–and X 2 For –N(R) X )–.

[0281] As defined above, R 24 H, 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, –C(=O)R E1 –C(=O)OR E1 –C(=O)SR E1 –C(=O)N(R) E1 )2、–S(=O)2R E2 –S(=O)2OR E1 –P(=O)2R E2 –P(=O)2OR E1 –P(=O)(OR E1 )2、–P(=O)(R E2 )2, or –P(=O)(R E2 )(OR E1 ).

[0282] In some implementations, R 24 It is hydrogen.

[0283] In some implementations, R 24 It can be a substituted or unsubstituted alkyl group. In some embodiments, R 24 It is an unsubstituted alkyl group substituted with one or more substituents selected from halogens or hydroxyl groups. In some embodiments, R 24 The alkenyl group may be substituted or unsubstituted. In some embodiments, R 24 The alkynyl group may be substituted or unsubstituted. In some embodiments, R 24 The substituted or unsubstituted carbocyclic group. In some embodiments, R 24 For substituted or unsubstituted heterocyclic groups. In some embodiments, R 24 The aryl group may be substituted or unsubstituted. In some embodiments, R 24 For substituted or unsubstituted heteroaryl groups.

[0284] In some implementations, R 24 For –C(=O)R E1 For example, R 24For –C(=O)(CH2) p CO2H, where p is an integer from 2 to 5 (inclusive). In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, R 24 -C(=O)OR E1 In some implementations, R 24 For –C(=O)SR E1 In some implementations, R 24 For –C(=O)N(R) E1 2. In some implementations, R 24 is –S(=O)2R E2 In some implementations, R 24 -S(=O)2OR E1 For example, -SO3H. In some implementations, R 24 For –P(=O)2R E2 In some implementations, R 24 -P(=O)2OR E1 In some implementations, R 24 For –P(=O)(OR) E1 2. In some implementations, R 24 -P(=O)(R) E2 2. In some implementations, R 24 -P(=O)(R) E2 )(OR E1 ).

[0285] As generally defined above, the subscript n is 0, 1, 2, or 3. In some implementations, n is 0. In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3.

[0286] In each embodiment where Z is a group of formula (iii), (iv), or (v)

[0287] In some embodiments, Z is a group of formula (iii), (iv), or (v):

[0288]

[0289] In some implementations, L 3 For substituted or unsubstituted C 1-6 Alkylenes, for example, substituted or unsubstituted C 1-2 Alkylene, substituted or unsubstituted C 2-3 Alkylene, substituted or unsubstituted C 3-4Alkylene, substituted or unsubstituted C 4-5 Alkylene, or substituted or unsubstituted C 5-6 Alkylene. In some embodiments, L 3 For substituted or unsubstituted C 2-6 alkenyl groups, for example, 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 group. In some embodiments, L 3 For substituted or unsubstituted C 2-6 Alynyl groups, for example, substituted or unsubstituted C 2-3 alkyne-based, substituted or unsubstituted C 3-4 alkyne-based, substituted or unsubstituted C 4-5 alkyne group, or substituted or unsubstituted C 5-6 Alynyl group. In any of the above cases, in some embodiments, L 3 C is unsubstituted or halogenated (e.g., fluorine), substituted or unsubstituted. 1-6 Alkyl, and / or -OR Z5 Substituted alkylene, alkenylene, or ynylene groups.

[0290] Furthermore, in some implementations, L 3 For substituted or unsubstituted heterogeneous C 1-6 Alkylenes, for example, substituted or unsubstituted heterocarbons 1-2 Alkylene, substituted or unsubstituted heterocarbon 2-3 Alkylene, substituted or unsubstituted heterocarbon 3-4 Alkylene, substituted or unsubstituted heterocarbon 4-5 Alkylene, or substituted or unsubstituted heterocarbon 5-6 Alkylene. In some embodiments, L 3 For substituted or unsubstituted heterogeneous C 2-6 alkenyl groups, for example, substituted or unsubstituted heterocyclic compounds. 2-3 alkenyl, substituted or unsubstituted heterocarbon 3-4 alkenyl, substituted or unsubstituted heterocarbon 4-5 alkenyl, or substituted or unsubstituted heterocyclic compounds 5-6 Alkenyl group. In some embodiments, L 3 For substituted or unsubstituted heterogeneous C 2-6 Alynyl groups, for example, substituted or unsubstituted heterocyclic compounds. 2-3 Hypo-alkynyl, substituted or unsubstituted hetero-C 3-4 Hypo-alkynyl, substituted or unsubstituted hetero-C 4-5 alkyne group, or substituted or unsubstituted heterocyclic group 5-6Alynyl group. In any of the above cases, in some embodiments, L 3 C is unsubstituted or halogenated (e.g., fluorine), substituted or unsubstituted. 1-6 Alkyl, and / or -OR Z5 Substituted heteroalkylene, heteroalkenyl, or heteroynyl.

[0291] In any of the above or below cases, in some embodiments, at least one R Z5 It is hydrogen.

[0292] In any of the above or below cases, in some implementations, R Z5 At least one of them is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C14 group. 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 group. Exemplary R Z5 C 1–6 Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and C1 groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups. 1–6 Alkyl groups (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 chlorine groups. 1–6 Alkyl groups (e.g., –CH2Cl, –CHCl2) and C groups substituted with alkoxy groups 1–6 Alkyl groups (e.g., –CH2OCH3 and –CH2OCH2CH3).

[0293] In any of the above or below cases, in some implementations, R Z5 At least one of them is a substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted C group. 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 group.

[0294] In any of the above or below cases, in some implementations, R Z5 At least one of them is a substituted or unsubstituted alkynyl group, for example, a substituted or unsubstituted C group. 2–6 Alkyne group, substituted or unsubstituted C 2–3 Alkyne group, substituted or unsubstituted C 3–4 Alkyne group, substituted or unsubstituted C 4–5 Alkyne group, or substituted or unsubstituted C 5–6 Alkyne group.

[0295] In any of the above or below cases, in some implementations, R Z5 At least one of them is a substituted or unsubstituted carbocyclic group, for example, a substituted or unsubstituted C 3–6 Carbocyclic, substituted or unsubstituted C 3–4 Carbocyclic, substituted or unsubstituted C 4–5 Carbocyclic group, or substituted or unsubstituted C 5–6 Carbon cyclic group.

[0296] In any of the above or below cases, in some implementations, R Z5 At least one of them is a substituted or unsubstituted heterocyclic group, for example, a substituted or unsubstituted 3–6-membered heterocyclic group, a substituted or unsubstituted 3–4-membered heterocyclic group, a substituted or unsubstituted 4–5-membered heterocyclic group, or a substituted or unsubstituted 5–6-membered heterocyclic group.

[0297] In any of the above or below cases, in some implementations, R Z5 At least one of them is a substituted or unsubstituted aryl group, for example, a substituted or unsubstituted phenyl group.

[0298] In any of the above or below cases, in some implementations, R Z5 At least one of them is a substituted or unsubstituted heteroaryl group, for example, a optionally substituted 5–6-membered heteroaryl group.

[0299] In any of the above or below cases, in some implementations, R Z5 For example, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, and a nitrogen protecting group when attached to a nitrogen atom.

[0300] In two of the R Z5 In some embodiments where the two R atoms are connected to nitrogen atoms, Z5 Groups combine to form substituted or unsubstituted heterocycles, such as substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, or substituted or unsubstituted morpholinyl rings.

[0301] Furthermore, in any of the above or below cases, in some implementations, R Z6 Each case is independently hydrogen, substituted or unsubstituted alkyl, or two R Z6 Groups combine to form C 3–6 Carbon ring.

[0302] In some implementations, R Z6 At least one of them is hydrogen.

[0303] In some implementations, R Z6 At least one of them is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C14 group. 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 group. Exemplary R Z4 C 1–6 Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and C1 groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups. 1–6 Alkyl groups (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 chlorine groups. 1–6 Alkyl groups (e.g., –CH2Cl, –CHCl2) and C groups substituted with alkoxy groups 1–6 Alkyl groups (e.g., –CH2OCH3 and –CH2OCH2CH3).

[0304] In some implementations, two R Z6 Groups combine to form C 3–6 Carbon rings, such as substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl rings.

[0305] In some implementations, R Z4 For substituted or unsubstituted alkyl groups, for example, substituted or unsubstituted C4 groups. 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C2–3 Alkyl, substituted or unsubstituted C 3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl group. Exemplary R Z4 C 1–6 Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and C1 groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups. 1–6 Alkyl groups (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 chlorine groups. 1–6 Alkyl groups (e.g., –CH2Cl, –CHCl2) and C groups substituted with alkoxy groups 1–6 Alkyl groups (e.g., –CH2OCH3 and –CH2OCH2CH3).

[0306] In some implementations, R Z4 For substituted or unsubstituted alkenyl groups, 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 5–6 Alkenyl group.

[0307] In some implementations, R Z4 For substituted or unsubstituted alkynyl groups, for example, substituted or unsubstituted C 2–6 Alkyne group, substituted or unsubstituted C 2–3 Alkyne group, substituted or unsubstituted C 3–4 Alkyne group, substituted or unsubstituted C 4–5 Alkyne group, or substituted or unsubstituted C 5–6 Alkyne group.

[0308] In some implementations, R Z4 For substituted or unsubstituted carbocyclic groups, for example, substituted or unsubstituted C 3–6 Carbocyclic, substituted or unsubstituted C 3–4 Carbocyclic, substituted or unsubstituted C 4–5 Carbocyclic group, or substituted or unsubstituted C 5–6Carbon cyclic group.

[0309] In some implementations, R Z4 The heterocyclic group may be substituted or unsubstituted, for example, a substituted or unsubstituted 3–6-membered heterocyclic group, a substituted or unsubstituted 3–4-membered heterocyclic group, a substituted or unsubstituted 4–5-membered heterocyclic group, or a substituted or unsubstituted 5–6-membered heterocyclic group.

[0310] In some implementations, R Z4 The aryl group is either substituted or unsubstituted, for example, a substituted or unsubstituted phenyl group.

[0311] In some implementations, R Z4 The heteroaryl group may be substituted or unsubstituted, for example, optionally substituted 5–6-membered heteroaryl groups.

[0312] In some implementations, R Z4 For –OR Z5 , where R Z5 As defined in this article, for example, R Z5 It can be hydrogen, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6).

[0313] In some implementations, R Z4 For –SR Z5 , where R Z5 As defined in this article, for example, R Z5 It can be hydrogen, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6).

[0314] In some implementations, R Z4 For –N(R) Z5 )2, for example, R Z4 For –NH2 or –NHR Z5 , where R Z5 As defined in this article, for example, R Z5It can be hydrogen, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), or n-hexyl (C6), or R Z4 -N(R Z5 )2, where two R Z5 Groups combine to form substituted or unsubstituted heterocycles, such as substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazine, or substituted or unsubstituted morpholinyl rings.

[0315] The L-shaped design in this article is particularly noteworthy. 3 Alkylene. For example, in some embodiments, L 3 For alkylene compounds of the following formula:

[0316]

[0317] Where p is 1, 2, or 3; and R Z7 and R Z8 Each case is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, or -OR Z5 In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3.

[0318] This article also features a special L design. 3 Alkenyl group. For example, in some embodiments, L 3 For the following formula, the sub-alkenyl group:

[0319]

[0320] Where q is 0, 1, or 2; and R Z7 and R Z8 Each case is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, or -OR Z5 In some implementations, q is 0. In some implementations, q is 1. In some implementations, q is 2.

[0321] This article also features a special L design. 3 Heteroalkylene compounds, for example, L in some embodiments 3 For heteroalkylene groups of the following formula:

[0322]

[0323] Where w is 0 or 1 and p is 1, 2 or 3, or w is 1 and p is 0, 1, 2 or 3; and RZ7 and R Z8 Each case is independently hydrogen, halogen, substituted or unsubstituted C. 1-6 Alkyl, or -OR Z5 .

[0324] In some implementations, p is 0. In some implementations, p is 1. In some implementations, p is 2. In some implementations, p is 3. In some implementations, w is 0. In some implementations, w is 1. In some implementations, w is 0 and p is 1. In some implementations, w is 0 and p is 2. In some implementations, w is 0 and p is 3. In some implementations, w is 1 and p is 1. In some implementations, w is 1 and p is 2. In some implementations, w is 1 and p is 3.

[0325] For example, in some implementations where w is 0, the following formula L is provided. 3 Heteroalkylene:

[0326]

[0327] Where p and R Z8 As defined in this article.

[0328] In some implementations where w is 1, the following formula L is provided. 3 Heteroalkylene:

[0329]

[0330] Where p, R 27 and R Z8 As defined in this article.

[0331] In some implementations, R Z7 At least one of the cases is hydrogen. In any of the above cases, in some embodiments, R Z7 At least one of the above is a halogen, for example, fluorine. In any of the above cases, in some embodiments, R Z7 At least one of the cases is substituted or unsubstituted C 1-6 Alkyl groups, for example, substituted or unsubstituted C4 groups 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 group. Exemplary R Z7 C 1-6Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and C1 groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups. 1-6 Alkyl groups (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 chlorine groups. 1-6 Alkyl groups (e.g., -CH2Cl, -CHCl2) and C groups substituted with alkoxy groups 1-6 Alkyl groups (e.g., -CH2OCH3 and -CH2OCH2CH3). In any of the above cases, in some embodiments, R Z7 At least one of the following is -CH3, -CF3, -CH2CH3(Et), or -CH(CH3)2(iPr). In any of the above cases, in some embodiments, R Z7 At least one of the cases is -OR Z5 For example, -OH.

[0332] In some implementations, R Z8 At least one of the cases is hydrogen. In any of the above cases, in some embodiments, R Z8 At least one of the above is a halogen, for example, fluorine. In any of the above cases, in some embodiments, R Z8 At least one of the cases is substituted or unsubstituted C 1-6 Alkyl groups, for example, substituted or unsubstituted C4 groups 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 group. Exemplary R Z8 C 1-6 Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), n-hexyl (C6), and C1 groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups.1-6 Alkyl groups (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 chlorine groups. 1-6 Alkyl groups (e.g., -CH2Cl, -CHCl2) and C groups substituted with alkoxy groups 1-6 Alkyl groups (e.g., -CH2OCH3 and -CH2OCH2CH3). In any of the above cases, in some embodiments, R Z8 At least one of the following is -CH3, -CF3, -CH2CH3(Et), or -CH(CH3)2(iPr). In any of the above cases, in some embodiments, R Z8 At least one of the cases is -OR Z5 For example, -OH.

[0333] Exemplary L 3 Alkyl groups include, but are not limited to:

[0334]

[0335] Exemplary L 3 Alkenyl groups include, but are not limited to:

[0336]

[0337] Exemplary L 3 Heteroalkylene compounds include, but are not limited to:

[0338]

[0339] In some implementations, where L 3 Groups that are alkylene or heteroalkylene It is the following formula:

[0340]

[0341]

[0342] In some implementations, Y is -O- and L 3 Groups that are alkylene or heteroalkylene It is the following formula:

[0343]

[0344] In some implementations, Y is -NH- and L 3 Groups that are alkylene or heteroalkylene It is the following formula:

[0345]

[0346]

[0347] In some implementations, Y is -O- and L 3 Groups that are alkylene or heteroalkylene It is the following formula:

[0348]

[0349] In some implementations, Y is -NH- and L 3 Groups that are alkylene or heteroalkylene It is the following formula:

[0350]

[0351] R 2 、R 11a and R 11b Various implementation methods

[0352] As defined above, R 2 、R 11a and R 11b The individual cases are independently H, -OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –N3, –NO2, –SCN, –CN, –OR B1 –SR B1 –N(R) B1 2. –N = NR B1 –N=C(R) B1 2. –N(OR) B1 (R) B1 ), –C(=O)R B1 –C(=O)OR B1 –C(=O)SR B1 –C(=O)N(R) b1 2. –C(=O)N(OR) B1 (R) B1 –OC(=O)R B1 –OC(=O)OR B1 –OC(=O)SR B1 –OC(=O)N(R) B1 )2、–NR B1 C(=O)R B1 ,–NR B1 C(=O)OR B1 ,–NRB1 C(=O)SR B1 ,–NR B1 C(=O)N(R B1 )2、–SC(=O)R B2 –SC(=O)OR B1 –SC(=O)SR B1 –SC(=O)N(R) B1 )2、–OS(=O)2R B2 –OS(=O)2OR B1 –S–S(=O)2R B2 –S–S(=O)2OR B1 –S(=O)R B2 –SO2R B2 ,–NR B1 SO2R B2 、or –SO2N(R B1 )2, and / or R 11a and R 11b They combine to form oxo (=O) groups.

[0353] In some implementations, R 2 For H. In some implementations, R 2 It can be a substituted or unsubstituted alkyl group. In some embodiments, R 2 The alkenyl group may be substituted or unsubstituted. In some embodiments, R 2 The alkynyl group may be substituted or unsubstituted. In some embodiments, R 2 For –OR B1 In some implementations, R 2 For –SR B1 In some implementations, R 2 For –N(R) B1 2. In some implementations, R 2 H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, –OR B1 –SR B1 , or –N(R B1 2. In some implementations, R 2 It can be F, Cl, Me, Et, n-Pr, methoxy, ethoxy, propoxy, butoxy, ethynyl, hydroxybutynyl, methoxypropynyl, chloroethynyl, or cyclopropynyl. In some embodiments, R 2 It is CF3, amino, or dimethylamino. In some embodiments, R 2 It is a non-hydrogen group at the α-position. In some embodiments, R 2 It is a non-hydrogen group at the β position.

[0354] In some implementations, R 11a and R 11b In each case, it is hydrogen. In some embodiments, R 11a and R 11b One of them is hydrogen. In some embodiments, R 11a and R 11b One is hydrogen; and the other is –OR B1 –SR B1 , or –N(R B1 2. In some implementations, R 11a and R 11b One is H; and the other is -OH, -OMe, amino, or dialkylamino. In some embodiments, R 11b It is a non-hydrogen group, and R 11a It is hydrogen. In some embodiments, R 11a It is a non-hydrogen group, and R 11b It is hydrogen.

[0355] In some implementations, R 11a and R 11b Together they form an oxo group.

[0356] R 4a 、R 4b 、R 6 、R 7a 、R 7b 、R 14 、R 17 、R 18 and R 19 Various implementation methods

[0357] As defined above, R 4a 、R 4b 、R 7a and R 7b The individual cases are independently hydrogen, –OH, halogen, 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, –N3, –NO2, –SCN, –CN, –OR B1 –SR B1 –N(R) B1 2. –N = NR B1 –N=C(R) B1 2. –N(OR) B1 (R) B1 ), –C(=O)R B1 –C(=O)OR B1 –C(=O)SR B1-C(=O)N(R) b1 )2、-C(=O)N(OR B1 (R) B1 -OC(=O)R B1 -OC(=O)OR B1 -OC(=O)SR B1 -OC(=O)N(R) B1 )2、-NR B1 C(=O)R B1 、-NR B1 C(=O)OR B1 、-NR B1 C(=O)SR B1 、-NR B1 C(=O)N(R B1 )2、-SC(=O)R B2 -SC(=O)OR B1 -SC(=O)SR B1 -SC(=O)N(R) B1 )2、-OS(=O)2R B2 -OS(=O)2OR B1 -SS(=O)2R B2 -SS(=O)2OR B1 -S(=O)R B2 、-SO2R B2 、-NR B1 SO2R B2 、or -SO2N(R B1 )2, where R B1 It 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, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 Groups combine to form substituted or unsubstituted heterocycles; and R B2 The 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 B1 Groups and R B2 Groups combine to form substituted or unsubstituted heterocycles; or optionally R 4a and R 4b , and / or R 7a and R 7b They combine to form oxo (=O) groups.

[0358] In some implementations, R 4a and R 4b In each case, it is hydrogen. In some embodiments, R 4a and R 4b One of them is hydrogen. In some embodiments, R 4a and R 4b One is hydrogen; and the other is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In some embodiments, R 4a and R 4b One is hydrogen; and the other is Me, Et, vinyl, ethynyl, propynyl, or propynyl. In some embodiments, R 4a and R 4b Each is independently a substituted or unsubstituted alkyl group. In some embodiments, R 4a and R 4b Each is Me.

[0359] In some implementations, R 7a and R 7b The various cases are all hydrogen.

[0360] As defined above, R 6a and R 6b Each is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, and Represents a single or double bond, provided that if a double bond exists in ring B, then R... 6a or R 6b One of them does not exist, and the condition is that if a single bond exists in ring B, then the hydrogen at C5 is at the α or β position.

[0361] In it In some implementations representing a single bond, R 6a and R 6b In each case, it is hydrogen. In some embodiments, R 6a and R 6b The various cases are halogens, for example, fluorine.

[0362] In it In some implementations representing a single bond, R 6a It is hydrogen, and R 6b It can be a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. In some embodiments, R 6a It is hydrogen, and R 6b It is a halogen (e.g., fluorine). In some embodiments, R 6a It is hydrogen, and R 6bFor substituted or unsubstituted alkyl groups, for example, substituted or unsubstituted C4 groups. 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 groups, such as methyl, ethyl, propyl, or isopropyl. In some embodiments, R 6a It is hydrogen, and R 6b The alkenyl group may be substituted or unsubstituted. In some embodiments, R 6a It is hydrogen, and R 6b The alkynyl group can be substituted or unsubstituted.

[0363] In it In some implementations representing a single bond, R 6b It is hydrogen, and R 6a It can be a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group. In some embodiments, R 6b It is hydrogen, and R 6a It is a halogen (e.g., fluorine). In some embodiments, R 6b It is hydrogen, and R 6a For substituted or unsubstituted alkyl groups, for example, substituted or unsubstituted C4 groups. 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 groups, such as methyl, ethyl, propyl, or isopropyl. In some embodiments, R 6b It is hydrogen, and R 6a The alkenyl group may be substituted or unsubstituted. In some embodiments, R 6b It is hydrogen, and R 6a The alkynyl group can be substituted or unsubstituted.

[0364] In it In some implementations representing double bonds, R 6a It is hydrogen. In it In some implementations representing double bonds, R 6a For example, halogens, such as fluorine. In which... In some implementations representing double bonds, R 6a For substituted or unsubstituted alkyl groups, for example, substituted or unsubstituted C4 groups. 1-6 Alkyl, substituted or unsubstituted C 1-2Alkyl, 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 groups, such as methyl, ethyl, propyl, or isopropyl. In which... In some implementations representing double bonds, R 6a The substituted or unsubstituted alkenyl group. In which... In some implementations representing double bonds, R 6a The alkynyl group can be substituted or unsubstituted.

[0365] As defined above, R 17 It can be hydrogen, halogen, 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 -OR D1 In some implementations, R 17 It is hydrogen. In some embodiments, R 17 It is a halogen. In some embodiments, R 17 It can be a substituted or unsubstituted alkyl group. In some embodiments, R 17 The alkenyl group may be substituted or unsubstituted. In some embodiments, R 17 The alkynyl group may be substituted or unsubstituted. In some embodiments, R 17 The substituted or unsubstituted carbocyclic group. In some embodiments, R 17 For substituted or unsubstituted heterocyclic groups. In some embodiments, R 17 The aryl group may be substituted or unsubstituted. In some embodiments, R 17 For substituted or unsubstituted heteroaryl groups. In some embodiments, R 17 For -OR D1 (e.g., -OH).

[0366] As defined above, R 14 It is H or a substituted or unsubstituted alkyl group. In some embodiments, R 14 For H. In some implementations, R 14 It is a substituted or unsubstituted alkyl group (e.g., -CH3).

[0367] As defined above, R 18 Independently, it is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 18 It is hydrogen. In some embodiments, R 18 It is a substituted or unsubstituted alkyl group (e.g., -CH3).

[0368] As defined above, R 19 Independently, it is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 19 It is hydrogen. In some embodiments, R 19 It is a substituted or unsubstituted alkyl group (e.g., -CH3).

[0369] In some implementations, R 14 For hydrogen, R 18 It is -CH3 and R 19 It is -CH3.

[0370] In some implementations, R 14 For hydrogen, R 18 It is -CH3 and R 19 It is hydrogen.

[0371] Additional implementation of formula (I)

[0372] This document further designs various combinations of the above embodiments. For example, in some embodiments, the compound of formula (I) is of formula (Iw):

[0373]

[0374] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3b It is hydrogen. In some embodiments, the group -X at the C3 position... 1 R 3b For β. In some implementations, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is a methyl group.

[0375] In some embodiments, the compound of formula (I) is of formula (Ix):

[0376]

[0377] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, the -OH group at the C3 position is β. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is a methyl group.

[0378] In some embodiments, the compound of formula (I) is of formula (Iy):

[0379]

[0380] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, the -OH group at the C3 position is β. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -ORB1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine.

[0381] In some embodiments, the compound of formula (I) is of formula (Iz):

[0382]

[0383] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, the -OH group at the C3 position is β. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine.

[0384] In some embodiments, the compound of formula (I) is of formula (I-a1), (I-a2), or (I-a3):

[0385]

[0386] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3b It is hydrogen. In some embodiments, the group -OR at the C3 position 3b For β. In some implementations, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine.

[0387] In some embodiments, the compound of formula (I) is of formula (I-b1), (I-b2), or (I-b3):

[0388]

[0389] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3b It is hydrogen. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine.

[0390] In some embodiments, the compound of formula (I) is of formula (I-c1), (I-c2), or (I-c3):

[0391]

[0392] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3b It is hydrogen. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a For hydrogen and R 11b For hydrogen or -OR B1 In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine.

[0393] In some embodiments, the compound is of formula (Id):

[0394]

[0395] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3b It is hydrogen. In some embodiments, the group -X at the C3 position... 1 R 3b For β. In some implementations, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is methyl. In some embodiments, each R Z6 It can be hydrogen or methyl on its own.

[0396] In some embodiments, the compound is of formula (Ie):

[0397]

[0398] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is methyl. In some embodiments, each R Z6 It can be hydrogen or methyl on its own.

[0399] In some embodiments, the compound is of formula (If):

[0400]

[0401] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3b It is hydrogen. In some embodiments, the -X group is located at the C3 position. 1 R 3b For β. In some implementations, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is methyl. In some embodiments, each R Z6 Independently, it is either hydrogen or methyl. In some embodiments, R Z5 It can be hydrogen or methyl.

[0402] In some embodiments, the compound is of formula (Ig):

[0403]

[0404] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6aIt is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is methyl. In some embodiments, each R Z6 Independently, it is either hydrogen or methyl. In some embodiments, R Z5 It can be hydrogen or methyl.

[0405] In some embodiments, the compound is of formula (Ih):

[0406]

[0407] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3b It is hydrogen. In some embodiments, the group -X at the C3 position... 1 R 3b For β. In some implementations, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is methyl. In some embodiments, R Z6It is isopropyl.

[0408] In some embodiments, the compound is of formula (Ii):

[0409]

[0410] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof. In some embodiments, R 3a It is hydrogen or a substituted or unsubstituted alkyl group. In some embodiments, R 2 For hydrogen or -OR B1 In some implementations, R 11a It is hydrogen and R 11b For hydrogen or -OR B1 In some implementations, Represents a single bond, R 5 For α (below) and R 6a It is hydrogen. In some embodiments, Represents a double bond. In some implementations, R 6a and R 6b Both are hydrogen. In some implementations, R 6a It is a halogen, such as fluorine or an alkyl group. In some embodiments, R 6b It is a halogen, such as fluorine or alkyl, and R 6a It is hydrogen. In some embodiments, R 6a and R 6b Both are halogens, for example, fluorine. In some embodiments, R 19 It is methyl. In some embodiments, R Z6 It is isopropyl.

[0411] Additional embodiments of formula (I) include compounds of the following formula:

[0412]

[0413]

[0414]

[0415]

[0416]

[0417] In some embodiments, the compound is any one of the following compounds:

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof.

[0425] In some embodiments, the compound is any one of the following compounds:

[0426]

[0427]

[0428]

[0429]

[0430] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof.

[0431] In some embodiments, the compound is any one of the following compounds:

[0432]

[0433] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof.

[0434] In some embodiments, the compound is any one of the following compounds:

[0435]

[0436]

[0437] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof.

[0438] In some embodiments, the compound is any one of the following compounds:

[0439]

[0440] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof.

[0441] In some embodiments, the compound is any one of the following compounds:

[0442]

[0443] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof.

[0444] In some embodiments, the compound is any one of the following compounds:

[0445]

[0446] Or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotope variant, or N-oxide, or a combination thereof.

[0447] In some embodiments, the compounds of the present invention are pharmaceutically acceptable salts.

[0448] Pharmaceutical composition

[0449] 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).

[0450] When used as pharmaceuticals, the compounds described herein are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared in ways known in the pharmaceutical field and include at least one active compound.

[0451] In one embodiment, the carrier of the pharmaceutical composition is a parenteral carrier, an oral carrier, or a topical carrier.

[0452] This invention also relates to the use of compounds of this invention or pharmaceutical compositions thereof as medicines or pharmaceutical agents.

[0453] Typically, the compounds described herein are administered in therapeutically effective amounts. The actual amount of compound administered will typically be determined by the physician based on relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0454] The pharmaceutical compositions provided herein can be administered via a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds provided herein are preferably formulated as injectable or oral compositions or as ointments, lotions, or patches (all for transdermal administration).

[0455] Compositions intended for oral administration may be in bulk liquid solutions or suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for accurate dosing. The term "unit dose form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance, calculated in conjunction with suitable pharmaceutical excipients, to produce the desired therapeutic effect. Typical unit dose 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 typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various media or carriers useful for forming the desired dose dosing form, as well as processing aids.

[0456] Liquid forms suitable for oral administration may include appropriate aqueous or non-aqueous media, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0457] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As previously mentioned, in such compositions the active compound is typically a small component, often about 0.05-10% by weight, with the remainder being the injectable carrier, etc.

[0458] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient, usually in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with a paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and typically include additional ingredients to enhance skin penetration and improve the stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0459] The compounds described herein can also be administered via transdermal devices. Therefore, transdermal administration can be achieved using reservoir or porous membrane-type or solid matrix-type patches.

[0460] The above-described components for use in oral, injectable, or topical compositions are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0461] The above-described components for use in oral, injectable, or topical compositions are merely representative. Other materials and processing techniques are described in Part 8 of Remington's *The Science and Practice of Pharmacy*, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0462] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0463] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. 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, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally comprising one or more substituents at the linked sugar moieties, including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfonyl ether substitutions. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as... See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0464] This invention also relates to pharmaceutically acceptable acid addition salts of the compounds of this invention. The 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 hydrochlorides, hydroiodides, hydrobroms, nitrates, sulfates, hydrogen sulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, p-toluenesulfonates, etc.

[0465] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0466] Exemplary Formulation 1 – Tablets: The compounds of the present invention can be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then compressed in a tableting machine into 240-270 mg tablets (80-90 mg of active compound per tablet).

[0467] Exemplary Formulation 2 – Capsules: The compounds of the present invention can be mixed as a dry powder with a starch diluent at a weight ratio of about 1:1. The mixture is then filled into 250 mg capsules (125 mg of active compound per capsule).

[0468] Exemplary Formulation 3 – Liquid: The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a US sieve of No. 10 mesh, and then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavoring agent, and coloring agent are diluted with water and added with stirring. Sufficient water can then be added to produce a total volume of 5 mL.

[0469] Exemplary Formulation 4 – Tablets: The compounds of the present invention can be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then shaped into 450-900 mg tablets (150-300 mg of active compound) in a tableting machine.

[0470] Exemplary Formulation 5 – Injection: The compounds of the present invention can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg / mL.

[0471] Exemplary Formulation 6 – Tablets: The compounds of the present invention can be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 90-150 mg tablets (30-50 mg of active compound per tablet) using a tableting machine.

[0472] Exemplary Formulation 7 – Tablets: The compounds of the present invention can be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tableting machine.

[0473] Exemplary Formulation 8 – Tablets: The compounds of the present invention may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then shaped into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) using a tableting machine.

[0474] Exemplary Formulation 9 – Tablets: The compounds of the present invention may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then compressed in a tableting machine into 150-240 mg tablets (each tablet containing 50-80 mg of the active compound).

[0475] Exemplary Formulation 10 – Tablets: The compounds of the present invention may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then shaped into 270-450 mg tablets (90-150 mg of active compound per tablet) using a tableting machine.

[0476] Injectable dosage levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all for about 1–120 hours, especially 24–96 hours. Preloading boluses (large pills) of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve appropriate steady-state levels. For patients weighing 40–80 kg, a maximum total dose exceeding about 2 g / day is not expected.

[0477] For the prevention and / or treatment of long-term conditions, treatment regimens typically run for many months or years; therefore, oral dosing is preferred for patient convenience and tolerability. For oral dosing, one to five times daily, and especially two to four times daily, and typically three times daily, are representative regimens. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of the compounds described herein, with preferred doses each providing about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg.

[0478] Transdermal doses are typically chosen to provide similar or lower blood levels (serum concentrations) as achieved with injectable doses.

[0479] When used to prevent the onset of CNS disorders, the compounds described herein are administered to subjects at risk of developing the condition, typically under the advice and supervision of a physician, at the dosage levels described above. Subjects at particular risk of developing the condition typically include those with a family history of the condition or those who have been identified by genetic testing or screening as particularly susceptible to developing the condition.

[0480] Treatment and usage methods

[0481] Early studies (see, for example, Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) demonstrated that some 3α-hydroxylated steroids are orders of magnitude more potent as GRC modulators than others previously reported (see, for example, Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. and Harrison et al. taught that 3α-hydroxylated 5-reduced steroids can achieve much lower levels of efficacy. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids allows them to be therapeutically useful in the regulation of brain excitability via the GRC (see, for example, Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(l):65-71 (1995)).

[0482] Various synthetic steroids have also been formulated as neuroactive steroids. See, for example, U.S. Patent No. 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, paroxysmal disorders, and mood disorders acted upon by GRC-activators, such as depression, in a therapeutically beneficial manner. Moreover, these steroids have previously been shown to interact at unique sites on the GRC, which are distinct from other known interacting sites (e.g., barbiturates, benzodiazepines). (and GABA), previously shown to have beneficial therapeutic effects on stress, anxiety, sleep, mood disorders, and paroxysmal disorders at the other known interacting sites (see, for example, Gee, K.W. and Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders", Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K.G. and Morselli, PL, "Psychopharmacology of GABAergic Drugs", Psychopharmacology: The Third Generation of Progress, HY Meltzer, ed., Raven Press, NY (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable due to their duration of action, potency, and oral activity (as well as other forms of administration).

[0483] Therefore, the compounds and pharmaceutical compositions provided herein are found to be useful as therapies for the prevention and / or treatment of CNS conditions in mammals, including humans and non-human mammals. Thus, and as previously stated, the invention encompasses and extends within its scope to the described treatment methods, compounds for such methods, and the use of such compounds in the preparation of pharmaceutical agents useful for such methods. The novel 3α- and 3β-hydroxysteroids of the present invention are anticipated to be useful as negative allosteric modulators (NAMs) of NMDA receptors and therefore for the prevention and / or treatment of a wide range of CNS conditions.

[0484] In one aspect, the compounds of the present invention are designed as therapeutic agents, for example, for the treatment of CNS disorders in mammals, such as schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizophrenic disorder, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), mild depression, social anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., pain syndrome or disorder), sleep disorders, memory disorders, dementia, Alzheimer's disease, paroxysmal disorders (e.g., epilepsy), traumatic brain injury (TBI), stroke, addiction disorders (e.g., addiction to opiates, cocaine, and / or alcohol), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome, or tinnitus. In some embodiments, the compounds of the present invention are useful in the treatment of depression, anxiety, mood disorders, sleep disorders, memory disorders, traumatic brain injury, stroke, epilepsy, and schizophrenia.

[0485] In another aspect, a method is provided for treating mammals susceptible to or tormented by conditions related to brain excitability, the method comprising administering an effective amount of one or more of the pharmaceutical compositions described herein.

[0486] In another aspect, the compounds of the present invention are provided as medicines, for example, particularly as medicines for the treatment or prevention of the aforementioned conditions and diseases.

[0487] In another aspect, a method for manufacturing a medicine for the treatment or prevention of one of the aforementioned symptoms and diseases is provided.

[0488] In another aspect, the present invention provides a method for preventing, treating, improving or controlling a disease or condition, comprising administering to a subject who requires such prevention or treatment an effective amount of the compound of the present invention or a pharmaceutical composition thereof.

[0489] In another aspect, the present invention provides the use of the compounds of the invention in the manufacture of a medicament for treating diseases or conditions related to brain excitability. In one embodiment, the disease or condition is selected from depression, anxiety, schizophrenia, sleep disorders, memory disorders, and mood disorders.

[0490] In another aspect, the present invention provides a method for treating mammals, such as humans, for diseases related to brain excitability, comprising treating said mammals with an effective amount of the compounds of the present invention or compositions thereof.

[0491] In another aspect, the present invention provides a combination of the compounds of the invention with additional pharmacologically active agents.

[0492] The compounds provided herein may be applied as the sole active agent or in combination with other agents. Combination application may be performed by any technique known to those skilled in the art, including, for example, single, sequential, simultaneous, and alternating application.

[0493] Example

[0494] To provide a fuller understanding of the invention described herein, the following embodiments are set forth. The synthetic and biological embodiments described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as limiting their scope in any way.

[0495] Raw materials and methods

[0496] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be understood that where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may 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 through conventional optimization.

[0497] 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 suitable protecting groups for specific functional groups and the appropriate conditions for protection and deprotection are well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0498] The compounds provided herein can be isolated and purified using known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, or HPLC. The following schemes are presented in detail regarding the preparation of representative substituted diaryl amides listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis using known or commercially available starting materials and reagents.

[0499] The enantiomerically pure compounds provided herein can be prepared using any technique known to those skilled in the art. For example, they can be prepared from suitable optically pure precursors via chiral or asymmetric synthesis, or from racemic compounds via any conventional technique, such as chromatographic separation using a chiral column, TLC, or by preparation of diastereomers, their separation, and regeneration of the desired enantiomers. See, for example, J. Jacques, A. Collet and SH Wilen, "Enantiomers, Racemates and Resolutions" (Wiley-Interscience, New York, 1981); SH Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); EL Eliel Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and SH Wilen Tables of Resolving Agents and Optical Resolutions 268 (ELElieled., Univ. of Notre Dame Press, Notre Dame, IN, 1972, Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihály Nógrádi (1995 VCH Publishers, Inc., NY, NY).

[0500] In some embodiments, the enantiomerically pure compounds of the present invention can be obtained by reacting a racemic compound with a suitable optically active acid or base. Suitable acids or bases include those described in: Bighley et al., 1995, Salt Forms of Drugs and Adsorption, Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; Ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50: 4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95: 512; and CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, the entire contents of which are incorporated herein by reference.

[0501] Depending on the specific acid resolving agent used and the solubility properties of the enantiomers of the specific acid used, enantiomerically pure compounds can also be obtained from crystallized diastereomers or from the mother liquor. The identity and optical purity of the specific compounds thus obtained can be determined by polarimetry or other analytical methods known in the art. The diastereomers can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomers can be regenerated by treatment with a suitable base or acid. Other enantiomers can be obtained in a similar manner from racemates or by establishing a workup from the mother liquor of the first separation.

[0502] In some embodiments, enantiomerically pure compounds can be separated from racemic compounds by chiral chromatography. Various chiral columns and eluents used for the separation of enantiomers are available, and suitable conditions for separation can be empirically determined by methods known to those skilled in the art. Exemplary chiral columns that can be used for the separation of enantiomers provided herein include, but are not limited to, [list of columns]. OB OB-H, OD, OD-H, OF OG, OJ and OK.

[0503] Synthesis program

[0504] The general method for preparing the compounds of the present invention is provided as a further embodiment of the invention and is described in general embodiments 1-13 and examples 1-36. For embodiments 1-13, R' is an alkyl group unless otherwise defined. 23 For R 23a or R 23b And X 1 、L 1 、R 1 、R 3a 、R 3b 、R 23a and R 23b As described in this article.

[0505] Scheme 1. Synthesis of 3α-substituted 3β-hydroxy steroids

[0506]

[0507] Scheme 2.3 Synthesis of α-substituted 3β-hydroxy steroids

[0508] Scheme 3. Synthesis of 3β-amino- and 3β-alkylamino steroids

[0509]

[0510] Option 4. Synthesis of Steroid Sulfates

[0511] Scheme 5. Synthesis of steroid 3β-esters and amides

[0512]

[0513] Scheme 6.3 Synthesis of oxosteroids

[0514]

[0515] Scheme 7.21 Synthesis of heteroaryl-3β-hydroxysteroids

[0516]

[0517] Scheme 8.3 Synthesis of α-substituted 3β-hydroxy steroids

[0518]

[0519] Scheme 9.3 Synthesis of α-substituted 3β-hydroxy steroids

[0520] Scheme 10.3 Synthesis of α-substituted 3β-hydroxy steroids

[0521]

[0522] Scheme 11.3 Synthesis of α-substituted 3β-hydroxy steroids

[0523] Scheme 12.3 Synthesis of α-substituted 3β-hydroxy steroids

[0524] Scheme 13.3 Synthesis of α-substituted 3β-hydroxy steroids

[0525]

[0526] Example 1. Preparation of compound ST-200-A-001

[0527]

[0528]

[0529] Preparation of Compound 2: p-Toluenesulfonic acid (1.4 g, 7.28 mmol) was added to a solution of ketone 1 (50.0 g, 0.17 mol, 1.0 eq) and ethylene glycol (62 mL) in toluene (600 mL). The reaction mixture was heated under reflux overnight using a Dean-Stark trap. LCMS showed that the starting material was completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), and washed with saturated sodium bicarbonate aqueous solution (300 mL × 2) and brine (300 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain crude product 2 (64.0 g, 100%), which was used directly in the next step without further purification. 1 H NMR: (400MHz, CDCl3) δ5.35 (d, J=5.6Hz, 1H), 3.97-3.82 (m, 4H), 3.59-3.47 (m, 1H), 2.34-2.21 (m, 2H), 2.06-1.94 (m, 2H), 1.90-1.7 4(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).

[0530] Preparation of Compound 3: Dess-Martin reagent (81 g, 192 mmol, 2.0 eq) was added fractionally to a solution of Compound 2 (32 g, 96 mmol, 1.0 eq) in 1200 mL of dry CH2Cl2 at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. TLC (PE:EA = 3:1) showed complete consumption of the starting material. The mixture was quenched with a saturated aqueous solution of NaHCO3 / Na2S2O3 (1:3) (1 L). The organic phase was washed with brine (500 mL) and dried over Na2SO4, and the solvent was evaporated to obtain crude product 3 (33.0 g, 100%), which was used directly in the next step without further purification. 1 H NMR: (400MHz, CDCl3) δ5.34 (d, J=5.2Hz, 1H), 3.77-4.00 (m, 4H), 3.19-3.39 (m, 1H), 2.83 (dd, J=16.44, 2.13Hz, 1H), 2.38-2.59 (m, 1H), 2.21-2.37 (m, 1 H), 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).

[0531] Preparation of MAD: An AlMe3 solution (109 mL, 218 mmol, 0.5 eq, in hexane, 2 M) was added to a solution of compound 5 (96 g, 436 mmol, 1.0 eq) in toluene (300 mL) at room temperature, immediately releasing methane gas. The resulting mixture was stirred at room temperature for 1 hour and used as the MAD solution in toluene in the next step without any purification.

[0532] Preparation of Compound 4: Compound 4 (33 g, 96 mmol, 1.0 eq) in toluene (100 mL) was added dropwise to a solution of MAD (218 mmol, 2.3 eq, freshly prepared) in toluene (300 mL) over a period of 1 hour at -78 °C under nitrogen. The reaction mixture was then stirred for 30 minutes, and a MeMgBr solution (205 mL, 288 mmol, 3.0 eq, 1.4 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 (PE:EA = 3:1) showed that the starting material was completely consumed. The mixture was poured into a saturated aqueous NH4Cl solution (200 mL) and extracted with EA (150 mL × 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to obtain a crude product. The crude product was purified by silica gel chromatography eluting with PE:EA (15:1) to give the product (7.64 g, 22%) as a white powder.

[0533] 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 3.75-4.04 (m, 4H), 2.42 (d, J=13.6Hz, 1H), 1.88-2.12 (m, 3H), 1.73-1.86 (m, 2H), 1.64-1.72 (m, 2H) ), 1.52-1.63(m, 4H), 1.35-1.51(m, 4H), 1.19-1.32(m, 1H), 1.12-1.18( m, 1H), 1.10 (s, 3H), 0.99-1.03 (m, 3H), 0.92-0.98 (m, 1H), 0.86 (s, 3H).

[0534] Compound INT A: To a solution of compound 4 (6.0 g, 17.3 mmol, 1.0 eq) in THF (200 mL), an aqueous solution of HCl (35 mL, 1 M) and acetone (35 mL) were added. The reaction mixture was stirred overnight at room temperature. TLC (PE:EA = 3:1) indicated that the reaction was complete. The reaction mixture was then diluted with EA (200 mL), washed with a saturated aqueous solution of NaHCO3 (200 mL), dried over Na2SO4, and evaporated under reduced pressure to give the product (5.2 g, 99.2%). 1H NMR: (400MHz, CDCl3) δ5.27 (d, J=6.8Hz, 1H), 2.45-2.35 (m, 2H), 2.09-1.84 (m, 4H), 1.82- 1.57(m, 6H), 1.50-1.35(m, 4H), 1.26-1.08(m, 4H), 1.05(s, 3H), 0.95(s, 3H), 0.86(s, 3H).

[0535] Compound A_001_1: At room temperature, a solution of t-BuOK (8.96 g, 79.35 mmol) in THF (20 mL) was added to a solution of PPh3CH3Br (28.3 g, 79.35 mmol) in THF (50 mL). After stirring for 1 hour, INT A (4.0 g, 13.22 mmol) dissolved in THF (10 mL) was added dropwise. The reaction mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature and quenched with saturated NH4Cl, and extracted with EA. The combined organic layers were washed with brine, dried, and concentrated to give a crude product, which was purified by rapid column chromatography (PE / EA = 15 / 1) to obtain compound A_001_1 (3.2 g, Y = 80%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ5.32 (d, J=5.2Hz, 1H), 4.65-4.64 (m, 2H), 2.50-2.42 (m, 2H), 2.27-2.22 (m, 1H), 2.07-1.97 (m, 1 H), 1.87-1.68(m, 4H), 1.68-1.49(m, 7H), 1.40-1.15(m, 4H), 1.12(s, 3H), 1.05(s, 3H), 1.04-0.96(m, 1H), 0.80(s, 3H).

[0536] Preparation of compound A_001_2: Et2AlCl (4 mL, 4.0 mmol, 4.0 eq, in toluene 1 M) was added dropwise to a solution of compound A_001_1 (300 mg, 1.0 mmol, 1.0 eq) and methyl propynate (250 mg, 3.0 mmol, 3.0 eq) in CH2Cl2 (5 mL) under stirring at 25 °C, and the reaction mixture was stirred overnight. TLC (PE / EA = 3 / 1) indicated that the starting material was completely consumed. The solution was washed with saturated NaHCO3 aqueous solution (5 mL), dried over Na2SO4, and concentrated under reduced pressure to provide a crude product, which was purified by silica gel chromatography eluting with PE:EA (15:1) to give the desired product (200 mg, 52%) as a white powder. 1H NMR: (400MHz, CDCl3) δ7.03-6.97 (m, 1H), 5.86 (dd, J1=1.2Hz, J2=15.6Hz, 1H), 5.35 (d, J=1.2Hz, 1H), 5.32 (d, J=5.2Hz, 1H), 3.72 (s, 3H), 2.87 (d, J=6. 8Hz, 2H), 2.42 (d, J=13.2Hz, 1H), 2.13-1.95 (m, 3H), 2.00-1.40 (m, 11H), 1. 40-1.20 (m, 4H), 1.11 (s, 3H), 1.06 (s, 3H), 0.90-0.82 (m, 3H), 0.78 (s, 3H).

[0537] Preparation of compound A_001_3: Pd / C (5%, 40 mg) was added to a solution of compound A_001_2 (192 mg, 0.5 mmol, 1.0 eq) in EA (5 mL) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was then stirred at 30 °C under an H2 balloon (cylinder) for 1 hour. TLC (PE:EA = 3:1) showed that the reaction was complete. The suspension was filtered through a diatomaceous earth pad and the pad was washed with EA (5 mL × 2). The combined filtrates were concentrated to dryness to give the product (185 mg, 95%) as a white powder. 1 H NMR: (400MHz, CDCl3) δ5.31 (d, J=4.4Hz, 1H), 3.67 (s, 3H), 2.42 (d, J=13.2Hz, 1H), 2.35-2.28 (m, 2H), 2.02-1.92 (m, 2H ), 1.90-1.60(m, 6H), 1.55-1.30(m, 6H), 1.30-1.13(m, 5H), 1.12(s, 3H), 1.02(s, 3H), 1.00-0.75(m, 4H), 0.58(s, 3H).

[0538] Preparation of compound ST-200-A-001: MeLi (2 mL, 3.200 mmol, 8.3 eq, in 1.6 M THF) was added dropwise to a solution of compound A_001_3 (150 mg, 0.386 mmol, 1.0 eq) in THF (5 mL) at -78 °C under nitrogen. After the addition, the reaction mixture was warmed to -40 °C and stirred for 1 hour. TLC (PE:EA = 3:1) showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL) and extracted with EA (10 mL × 2). The combined organic layers were concentrated under reduced pressure to provide a crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product (91 mg, 60%) as a white powder.1 H NMR: (400MHz, CDCl3) δ5.31 (d, J=5.6Hz, 1H), 2.43 (d, J=13.2Hz, 1H), 2.05-1.95 (m, 2H), 1.90-1.60 (m, 6H), 1.21 (s, 6H), 1.12 (s, 3H), 1.11-1.04 (m, 1H), 1.03 (s, 3H), 1.01-0.92 (m, 2H), 0.58 (s, 3H).

[0539] Example 2. Preparation of compound ST-200-A-003

[0540]

[0541] Preparation of compound A_003_1: A solution of t-BuOK (3.70 g, 33.00 mmol, 10.0 eq) in dry THF (15 mL) was added dropwise to a solution of Ph3PEtBr (12.25 g, 33.00 mmol, 10.0 eq) 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 INTA (1.00 g, 3.31 mmol, 1.0 eq) in THF (10 mL) was added dropwise, and the resulting mixture was stirred at 70 °C for 4 h. TLC (PE:EA = 3:1) indicated that the starting material was completely consumed. The reaction was quenched with saturated NH4Cl aqueous solution (50 mL) and extracted with EA (30 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (elution: PE:EA = 12:1) to give the product as a white powder (900 mg, 90.9%). 1 H NMR: (400MHz, CDCl3) δ5.32 (d, J=5.2Hz, 1H), 5.15-5.12 (m, 1H), 2.44-2.30 (m, 3H), 2.29-2.21 (m, 1H), 2.05-1 .97(m, 2H), 1.81-1.45(m, 14H), 1.30-1.15(m, 3H), 1.12(s, 3H), 1.02(s, 3H), 0.95-1.01(m, 1H), 0.90(s, 3H).

[0542] Preparation of compound A_003_2: At 0 °C with stirring, Et2AlCl solution (12.8 mL, 12.8 mmol, 4.0 eq, in toluene 1 M) was added dropwise to a solution of compound A_003_1 (1.00 g, 3.20 mmol, 1.0 eq) and methyl propynate (0.67 g, 8.00 mmol, 2.5 eq) in dry DCM (15 mL). The reaction was then warmed to room temperature and stirred overnight. TLC (PE:EA = 5:1) indicated that the starting material was completely consumed. The mixture was quenched with a saturated aqueous solution of NaHCO3 (30 mL) and extracted with DCM (30 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: PE:EA = 10:1) to give the product (1.00 g, 78.7%) as a white powder. 1 H NMR: (400MHz, CDCl3) δ6.97-6.91(m, 1H) 5.82(d, J=16Hz, 1H), 5.42-5.41(m , 1H), 5.32 (d, J=5.2Hz, 1H), 3.73 (s, 3H), 3.04-3.00 (m, 1H), 2.43 (d, J=12. 8Hz, 1H), 2.11-1.97 (m, 3H), 1.88-1.50 (m, 12H), 1.40-1.20 (m, 3H), 1.21-1 .26(m, 1H), 1.18(d, J=6.78Hz, 3H), 1.12(s, 3H), 1.04(s, 3H), 0.82(s, 3H).

[0543] Preparation of compound A_003_3: Pd / C (30 mg, 5%) was added to a solution of compound A_003_2 (160 mg, 0.40 mmol) in EA (15 mL). The reaction was then stirred at room temperature for 2 hours under 15 psi H2 pressure. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure to give the product (150 mg, 92.8%). 1 H NMR: (400MHz, CDCl3) δ5.32 (d, J=5.2Hz, 1H), 3.67 (s, 3H), 2.48-1.96 (m, 7H), 1.90-1.62 (m, 5 H), 1.60-1.55 (m, 7H), 1.11 (s, 3H), 1.03-0.99 (m, 3H), 0.95-0.93 (m, 2H), 0.70-0.66 (m, 2H).

[0544] Preparation of compound ST-200-A-003: A solution of compound A_003_2 (100 mg, 0.25 mmol, 1.0 eq) in dry THF (1 mL) was added dropwise to MeLi (1.56 mL, 2.50 mmol, 1.6 M in THF) under N2 protection at -78 °C, and the mixture was stirred at this temperature for 30 min. TLC (PE:EA = 3:1) showed that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution (5 mL) and extracted with EA (5 mL × 2). The combined organic layers were concentrated under reduced pressure to provide a crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product (45 mg, 45%) as a white powder. 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 2.42 (d, J=12Hz, 1H), 2.02-1.98 (m, 3H), 1.92-1.66 (m, 3H), 1.61-1.56 (m, 2H), 1.55-1.54(m, 2H), 1.53-1.23(m, 11H), 1.20(s, 6H), 1.10(s, 3H), 1.05(s, 3H), 1.02(s, 3H), 0.95-0.90(m, 3H), 0.68(s, 3H).

[0545] Example 3. Preparation of compound ST-200-A-007

[0546]

[0547] Preparation of compound INTE: A solution of A_001_1 (2.0 g, 6.66 mmol, 1.0 eq) in 10 mL THF was added dropwise to a 9-BBN solution (0.5 M in THF, 133 mL, 66.6 mmol, 10.0 eq) in 10 mL THF. The reaction mixture was heated to 60 °C and stirred for 20 h. The mixture was cooled to 0 °C and 20 mL of 10% NaOH aqueous solution was added, followed by 10 mL of 30% H2O2 aqueous solution. The mixture was stirred at 0 °C for 2 h and then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give a crude product, which was purified by rapid column chromatography eluting with PE / EA (10 / 1) to obtain INTE (1.0 g, 47%) as a white solid. 1H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 3.75-3.71 (dd, J1=10.4Hz, J2=6.8Hz, 1H), 3.58-3.53 (dd, J1=10.4Hz, J2=7.6Hz, 1H), 2.43-2.41 (d, J= 10.4Hz, 1H), 2.02-1.96(m, 2H), 1.91-1.75(m, 3H), 1.72-1.44(m, 10H), 1. 33-1.20 (m, 5H), 1.18 (s, 3H), 1.06 (s, 3H), 1.04-0.99 (m, 1H), 0.67 (s, 3H).

[0548] Preparation of compound INT B: Dysmart reagent (265 mg, 0.628 mmol, 2.0 eq) was added to a solution of INT E (100 mg, 0.314 mmol, 1.0 eq) in DCM (10 mL) under ice bath conditions. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was poured into a solution of NaS₂O₃ (4.5 g) and NaHCO₃ (1.5 g) in water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum to give a crude product (100 mg, 100%), which was used directly in the next step without further purification.

[0549] Preparation of compound A_007_1: A mixture of INT B (100 mg, 0.316 mmol, 1.0 eq) and Ph3P=CHCOOCH3 (634 mg, 1.89 mmol, 6.0 eq) in toluene (10 mL) was stirred at 80 °C for 3 h, and then concentrated under vacuum. The residue was purified by rapid column chromatography eluting with PE / EA (12 / 1) to obtain product A_007_1 (65 mg, 55.2%) as a white solid. 1HNMR: (400MHz, CDCl3) δ6.99-6.93 (dd, J1=16Hz, J2=8.4Hz, 1H), 5.82-5.77 (dd, J1=15.6Hz, J2=1.2Hz, 1H), 5.30(d, J=5.2Hz, 1H), 3.73(s, 3H), 2.42(d, J=12.4Hz , 1H), 2.14-2.11(m, 1H), 2.05-1.99(m, 2H), 1.98-1.41(m, 15H), 1.29-1.24(m, 2 H), 1.12-1.14(m, 1H), 1.12(s, 3H), 1.06(s, 3H), 1.02-0.95(m, 1H), 0.66(s, 3H).

[0550] Preparation of compound A_007_2: A mixture of compound A_007_1 (65 mg, 0.174 mmol, 1.0 eq) and Pd / C (5%, 20 mg) in EA (5 mL) was stirred at room temperature for 2 hours under H2 (1 atm). The mixture was filtered and the filtrate was concentrated under vacuum to give product A_007_2 (65 mg, 100%), which was used directly in the next step without further purification.

[0551] Preparation of compound ST-200-A-007: CH3Li (1.6M, 1mL, 1.7mmol, 10.0eq in THF) was added dropwise to a solution of A_007_2 (65mg, 0.17mmol, 1.0eq) at -78℃ in THF (2mL) under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was quenched with saturated NH4Cl aqueous solution (10mL) and then extracted with EA (5mL × 2). The combined organic layers were washed with brine (5mL), dried over Na2SO4, and concentrated under vacuum to give a crude product, which was purified by rapid column chromatography (elution: PE / EA = 8 / 1) to obtain ST-200-A-007 (27mg, 41%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 2.42 (d, J=15.2Hz, 1H), 2.02-1.96 (m, 2H), 1.86-1.38 (m, 14H), 1.25-1.14(m, 4H), 1.21(s, 6H), 1.11(s, 3H), 1.09-1.05(m, 2H) 1.02(s, 3H), 1.01-0.94(m, 3H), 0.61(s, 3H).

[0552] Example 4. Preparation of compound ST-200-A-011

[0553]

[0554]

[0555] Preparation of compound INT D: CeCl3·7H2O (2.45 g, 6.58 mmol, 1.0 eq) was added to a solution of INT A (2.00 g, 6.58 mmol, 1.0 eq) in MeOH (30 mL) and THF (15 mL). The reaction mixture was stirred at room temperature for 10 min. Then, NaBH4 (0.50 g, 13.16 mmol, 2.0 eq) was slowly added and the resulting mixture was stirred at room temperature for 30 min. TLC (PE / EA = 3 / 1) showed that the reaction was complete. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were dried over Na2SO4 and evaporated to dryness to give the desired product (1.84 g, 91%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 3.65 (t, J=8.6Hz, 1H), 2.43 (d, J=13.2Hz, 1H), 2.09-1.97 (m, 3H), 1.97-1.68 (m, 3H), 1.64-1.38 ( m, 5H), 1.31-1.20 (m, 2H), 1.19-1.16 (m, 1H), 1.11 (s, 3H), 1.11-1.04 ( m, 1H), 1.03 (s, 3H), 1.01-0.93 (m, 2H), 0.88-0.84 (m, 1H), 0.76 (s, 3H).

[0556] Preparation of compound A_011_1: Methyl propargyl ester (325 mg, 3.30 mmol, 2.0 eq) and NMM (287 mg, 3.30 mmol, 2.0 eq) were added sequentially to a solution of INT D (500 mg, 1.63 mmol, 1.0 eq) in DCM (10 mL). The reaction mixture was stirred at room temperature for two days. TLC (PE / EA = 3 / 1) showed that the reaction was complete. The reaction mixture was washed with saturated aqueous NaHCO3 solution (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated to dryness to give a crude product. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to give the desired product (274 mg, 43%) as a white solid. 1H NMR: (400MHz, CDCl3) δ7.54 (d, J=12.8Hz, 1H), 5.29 (d, J=5.2Hz, 1H), 5.24 (d, J=12.8Hz, 1H ), 3.88 (t, J=8.2Hz, 1H), 3.68 (s, 3H), 2.42 (d, J=13.2Hz, 1H), 2.19-2.09 (m, 1H), 2.00-1.8 9(m, 2H), 1.88-1.84(m, 1H), 1.80-1.70(m, 2H), 1.62-1.50(m, 5H), 1.49-1.41(m, 2H), 1.39 -1.29 (m, 1H), 1.19-1.10 (m, 2H), 1.11 (s, 3H), 1.02 (s, 3H), 1.00-0.91 (m, 2H), 0.79 (s, 3H).

[0557] Preparation of compound A_011_2: 5% Pd / C (50%, 25 mg) was added to a solution of compound A_011_1 (50 mg, 0.128 mmol) in EA (5 mL) under argon atmosphere. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at room temperature under an H2 balloon for 4 hours. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The suspension was then filtered through a diatomaceous earth pad and the pad was washed with EA (5 mL × 3). The combined filtrates were concentrated to dryness to give the product (48 mg, 96%) as a white solid, which was used directly in the next step without purification. 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 3.77-3.69 (m, 2H), 3.66 (s, 3H), 3.32 (t, J=8.4Hz, 1H), 2.56 (t, J=6.4Hz, 2H), 2.42 (d, J=12.4Hz, 1H), 2.0 0-1.89(m, 4H), 1.81-1.67(m, 2H), 1.57-1.44(m, 6H), 1.43-1.32(m, 1H), 1. 30-1.13 (m, 4H), 1.11 (s, 3H), 1.02 (s, 3H), 0.99-0.91 (m, 2H), 0.74 (s, 3H).

[0558] Preparation of compound ST-200-A-011: MeLi (1 mL, 1.60 mmol, 10.0 eq, in Et2O, 1.6 M) was added dropwise to a solution of compound A_011_2 (60 mg, 0.16 mmol, 1.0 eq) in anhydrous THF (5 mL) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 30 min, then warmed to room temperature for another 30 min. TLC (PE / EA = 3 / 1) showed complete consumption of the starting material. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (5 mL). The resulting solution was extracted with EA (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (10:1) to give the target product (25 mg, 42%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ5.29 (d, J=4.8Hz, 1H), 3.80-3.62 (m, 2H), 3.27 (t, J=8.4Hz, 1H), 2.39 (d, J=13.2Hz, 1H), 2.05-1.86 (m, 4H), 1.76-1. 64(m, 3H), 1.59-1.37(m, 8H), 1.27-1.20(m, 1H), 1.19(s, 6H), 1.12-1 .08 (m, 2H), 1.07 (s, 3H), 0.99 (s, 3H), 0.98-0.89 (m, 2H), 0.72 (s, 3H).

[0559] Example 5. Preparation of compound ST-200-A-013

[0560]

[0561] KOH (53 mg, 0.942 mmol, 2.0 eq) and 2,2-dimethylethylene oxide (340 mg, 4.717 mmol, 10.0 eq) were added to a solution of INTE (150 mg, 0.471 mmol, 1.0 eq) in DMSO (1 mL). The reaction mixture was stirred at 50 °C for 16 h. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with saturated NH4Cl aqueous solution (10 mL × 2) and water (10 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by column chromatography followed by preparative-HPLC (prep-HPLC) to obtain a pure product ST-200-A-013 (14 mg, 8%). 1H NMR (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 3.57-3.48 (m, 1H), 3.38-3.35 (m, 1H), 3.20 (s, 2H), 2.42-2.40 (m, 1H), 2.03-1.85 (m, 3H), 1.76 (m , 4H), 1.55-1.43(m, 4H), 1.25(s, 3H), 1.28-1.25(m, 6H), 1.17-1.13(m , 2H), 1.11 (s, 3H), 1.06-0.96 (m, 5H), 0.92-0.79 (m, 2H), 0.65 (s, 3H).

[0562] Example 6. Preparation of compound ST-200-A-017

[0563]

[0564] KOH (56 mg, 1.0 mmol, 2.0 eq) was added to a solution of compound INT D (150 mg, 0.49 mmol, 1.0 eq) and 2,2-dimethylethylene oxide (1.5 g, 20.8 mol, 42.0 eq) in DMSO (3 mL), and the reaction mixture was stirred at 60 °C for 5 h. TLC (PE:EA = 3:1) indicated that the reaction was complete. The solution was cooled to room temperature, diluted with water (10 mL), and extracted with EA (5 mL × 2). The combined organic layers were concentrated under reduced pressure to provide a crude product, which was purified by preparative-HPLC to give the product as a white powder (6.6 mg, 3.5%). 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 3.33 (t, J=8.0Hz, 1H), 3.29-3.22 (m, 2H), 2.40-2.50 (m, 2H), 2.05-1.85 (m, 4H), 1.82-1.65 (m, 2H), 1.60-1.35(m, 9H), 1.34-1.22(m, 1H), 1.20-1.15(m, 6H), 1.14-1 .11 (m, 1H), 1.12 (s, 3H), 1.05 (s, 3H), 0.90-1.00 (m, 2H), 0.79 (s, 3H).

[0565] Example 7. Preparation of compound ST-200-A-021

[0566]

[0567] LiOH (90 mg, 2.20 mmol, 5.6 eq) was added to a solution of compound A_001_3 (150 mg, 0.39 mmol, 1.0 eq) in THF / H2O (4 mL, 1 / 1). The reaction was stirred overnight at room temperature. TLC (PE / EA = 3 / 1) showed that compound A_001_3 was completely consumed. The mixture was diluted with water (3 mL), washed with MTBE (5 mL × 2), and then acidified to pH = 4 with 1 M HCl aqueous solution. The precipitate was collected by filtration and dried under vacuum to give the product (54 mg, 37.3%). 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 2H), 2.43-2.37 (m, 1H), 2.37-2.33 (m, 2H), 2.05-1.93 (m, 2H), 1.90-1.79 (m, 2H), 1.78- 1.61 (m, 6H), 1.61-1.50 (m, 6H), 1.50-1.37 (m, 3H), 1.34-1.13 (m, 4H), 1.12 (s, 3H), 1.02 (s, 3H), 0.93-1.01 (m, 3H), 0.61 (s, 3H).

[0568] Example 8. Preparation of compounds ST-200-A-022 and ST-200-A-023

[0569]

[0570] Preparation of Compound 7: p-Toluenesulfonic acid (418 mg, 2.20 mmol) was added to a solution of ketone 6 (16.7 g, 52.71 mmol, 1.0 eq) and ethylene glycol (20 mL) in toluene (450 mL). The reaction mixture was heated under reflux overnight using a Dean-Stark separator. LCMS showed that the starting material was completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and washed with saturated sodium bicarbonate aqueous solution (200 mL × 2) and brine (200 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain crude product 7 (19.0 g, 100%), which was used directly in the next step without further purification. 1H NMR: (400MHz, CDCl3) δ5.34 (d, J=5.2Hz, 2H), 4.00-3.85 (m, 4H), 3.53-3.51 (m, 1H), 2.28-2.22 (m, 2H), 2.12-2.00 (m, 1H), 1.9 9-1.95 (m, 1H), 1.86-1.73 (m, 5H), 1.71-1.44 (m, 8H), 1.29 (s, 3H), 1.08 (s, 3H), 1.07 (s, 3H), 1.06-0.92 (m, 1H), 0.77 (s, 3H).

[0571] Preparation of Compound 8: A solution of Compound 7 (19.0 g, 52.71 mmol, 1.0 eq) in dry CH₂Cl₂ (700 mL) was added fractionally to a solution of Compound 7 (19.0 g, 52.71 mmol, 1.0 eq) at 0 °C with Dys-Martin reagent (45.0 g, 105.42 mmol, 2.0 eq). The reaction mixture was then stirred at room temperature for 3 h. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The mixture was quenched with a saturated aqueous solution of NaHCO₃ / Na₂S₂O₃ (1 L, 1 / 3). The organic phase was washed with brine (500 mL) and dried over Na₂SO₄, and the solvent was evaporated under reduced pressure to obtain crude product 8 (19.0 g, 100%), which was used directly in the next step without further purification. 1 HNMR: (400MHz, CDCl3) δ5.33 (d, J=5.2Hz, 2H), 4.01-3.85 (m, 4H), 3.34-3.21 (m, 1H), 2.82 (dd, J=16.31, 2.01Hz, 1H), 2. 59-2.40 (m, 1H), 2.37-2.25 (m, 1H), 2.13-1.95 (m, 5H), 1.87-1.41 (m, 13H), 1.30 (s, 3H), 1.21-1.15 (m, 5H), 0.81 (s, 3H).

[0572] Preparation of Compound 9: A solution of Compound 8 (19.0 g, 52.71 mmol, 1.0 eq) in toluene was added to a MAD solution (158 mL, 158 mmol, 3.0 eq, 1 M in toluene, prepared by the method described in the synthesis of ST-200-A-001) at -78 °C under nitrogen. The reaction mixture was then stirred at this temperature for 30 min. A MeMgBr solution (53 mL, 159 mmol, 3.0 eq, 3 M in Et2O) was added dropwise at -78 °C. The reaction mixture was warmed to -40 °C and stirred at this temperature for 3 h. TLC (PE:EA = 3:1) showed that the starting material was completely consumed. The mixture was poured into a saturated aqueous NH4Cl solution (300 mL) and extracted with EA (150 mL × 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography eluting with PE:EA (15:1) to give the product as a white powder (7.70 g, 39%). 1 H NMR: (400MHz, CDCl3) δ5.31 (d, J=5.2Hz, 2H), 4.01-3.85 (m, 4H), 2.42 (d, J=12Hz, 1H ), 2.04-1.96(m, 1H), 1.96-1.95(m, 2H), 1.85-1.66(m, 5H), 1.66-1.61(m, 2H), 1.61 -1.36 (m, 7H), 1.33 (s, 3H), 1.26-1.13 (m, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.91-1.00 (m, 2H), 0.80 (s, 3H).

[0573] Preparation of compound INT C: An aqueous solution of HCl (10 mL, 1 M) and acetone (10 mL) were added to a solution of compound 9 (2.7 g, 7.21 mmol, 1.0 eq) in THF (20 mL). The reaction mixture was stirred overnight at room temperature. TLC (PE:EA = 3:1) indicated that the reaction was complete. The reaction mixture was then diluted with EA (50 mL), washed with saturated aqueous solution of NaHCO3 (50 mL × 2), dried over Na2SO4, and evaporated under reduced pressure to give the product (2.10 g, 88.2%) as a white powder. 1H NMR: (400MHz, CDCl3) δ5.31 (d, J=5.2Hz, 2H), 2.55-2.50 (m, 1H), 2.40 (d, J=12Hz, 1H), 2.20 -2.19(m, 1H), 2.15-2.10(m, 3H), 2.08-1.94(m, 3H), 1.83-1.76(m, 1H), 1.74 -1.65 (m, 3H), 1.62 (s, 3H), 1.61-1.39 (m, 7H), 1.30-1.13 (m, 4H), 1.12 (s, 3H), 1.01 (s, 3H), 0.61-0.65 (m, 3H).

[0574] Preparation of compound A_022_1: NaBH4 (160 mg, 4.2 mmol, 2.0 feq) was added in five batches to a solution of INT C (700 mg, 2.1 mmol, 1.0 eq) in MeOH (10 mL) and THF (5 mL). The reaction mixture was stirred at room temperature for 1 hour. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated under vacuum to obtain the desired product A_022_1 (600 mg, 86%).

[0575] Preparation of compounds ST-200-A-022 and ST-200-A-023: TEA (867 mg, 8.585 mmol, 5.0 eq) and DMAP (63 mg, 0.515 mmol, 0.3 eq) were added to a solution of A_022_1 (570 mmol, 1.717 mmol, 1.0 eq) in DCM (15 mL). BzCl (961 mg, 6.867 mmol, 4.0 eq) was then added dropwise. The resulting mixture was stirred at room temperature for 16 hours and then neutralized by adding 1 M HCl aqueous solution. The aqueous layer was separated and extracted with DCM (10 mL × 3). The combined organic layers were washed with saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to give the product (360 mg, 46.6%) as a white solid, which was then used for SFC separation to obtain the targets ST-200-A-022 (100 mg) and ST-200-A-023 (70 mg). 1H NMR (ST-200-A-022): (400MHz, CDCl3) δ8.06 (d, J=7.2Hz, 2H), 7.61-7.50 (m, 1H), 7.49-7.40 (m, 2H), 5.30 (d, J=5.2Hz, 2H), 5.19-5.08 (m, 1H), 2.40 (d, J=12Hz, 1H), 2.03-1.86(m, 3H), 1.85-1.64(m, 5H), 1.58-1.30(m, 7H), 1.27 (d, J=6.0Hz, 3H), 1.23-1.06 (m, 6H), 1.01-0.83 (m, 5H), 0.68 (s, 3H). 1 H NMR (ST-200-A-023): (400MHz, CDCl3) δ8.01 (d, J=8.4Hz, 2H), 7.58-7.50 (m, 1H), 7.47-7.39 (m, 2H), 5.31 (d, J=6.0Hz, 2H), 5.24-5.14 (m, 1H), 2.43 (d, J=1 3.2Hz, 1H), 2.05-1.87(m, 4H), 1.82-1.61(m, 5H), 1.55-1.38(m, 4H), 1.36(d, J=6.0Hz, 3H), 1.29-1.14(m, 4H), 1.12(s, 3H), 1.04-0.95(m, 4H), 0.74(s, 3H)

[0576] Example 9. Preparation of compound ST-200-C-001

[0577]

[0578] Pd / C (10%, 15 mg) was added to a solution of compound ST-200-A-001 (65 mg, 0.167 mmol, 1.0 eq) in ethanol (10 mL) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was then stirred at 60 °C for 24 h at 50 psi hydrogen pressure. TLC (PE:EA = 3:1) showed that the reaction was complete. The suspension was filtered through a diatomaceous earth pad and the pad was washed with ethanol (5 mL × 2). The combined filtrates were concentrated to dryness to give a crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product as a white powder (28 mg, 43%). 1HNMR: (400MHz, CDCl3) δ1.90-1.87(m, 1H), 1.75-1.60(m, 4H), 1.82-1.65(m, 2H), 1.5 5-1.30 (m, 12H), 1.27-1.23 (m, 6H), 1.22 (s, 6H), 1.18-0.95 (m, 8H), 0.82 (s, 3H), 0.72 -0.65(m,1H),0.55(s,3H).

[0579] Example 10. Preparation of compounds ST-200-C-003 and ST-200-C-003A

[0580]

[0581] Add Pd / C (10 mg) to a solution of compound ST-200-A-003 (40.0 mg, 0.10 mmol, 1.0 eq) in EtOH (30 mL). Stir the mixture overnight at 60 °C under a hydrogen pressure of 50 psi. 1 HNMR indicated that the reaction was complete. The mixture was then filtered through a diatomaceous earth pad and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (elution: PE:EA = 2:1) to obtain pure products ST-200-C-003 (12.0 mg, 29.8%) and ST-200-C-003A (0.8 mg, 2.3%) as white powders. 1 H NMR (ST-200-C-003): (400MHz, CDCl3) δ1.97-1.83 (m, 2H), 1.65-1.55 (m, 7H), 1.55-1.42 (m, 4H), 1.41-1.2841 (m, 6H), 1.27-1.21 (m, 5H), 1.20 (s, 6H), 1.16-0.95 (m, 7H), 0.92 (d, J=6.27Hz, 3H), 0.81 (s, 3H), 0.65 (s, 3H). 1 H NMR (ST-200-C-003A): (400MHz, CDCl3) δ1.98-1.79 (m, 4H), 1.64-1.53 ​​(m, 6H), 1.52 -1.29 (m, 7H), 1.25-1.22 (m, 6H), 1.22 (s, 3H), 1.20 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.91 (d, J=6.53Hz, 3H), 0.86-0.80 (m, 2H), 0.65 (s, 3H).

[0582] Example 11. Preparation of compound ST-200-C-007

[0583]

[0584] Preparation of Compound 10: A mixture of Compound 1 (28.0 g, 0.097 mol, 1.0 eq) and Pd / C (3.5 g) in ethanol (400 mL) was hydrogenated overnight at room temperature under hydrogen pressure at 40 psi. The suspension was filtered through a diatomaceous earth mat and the mat was washed with ethanol (20 mL × 3). The combined filtrates were concentrated to dryness to give the product (28.0 g, 0.097 mol, 100%) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.63-3.53 (m, 1H), 2.42 (dd, J=19.2, 8.4Hz, 1H), 2.11-2.06 (m, 1H ), 19.6-1.87(m, 1H), 1.83-1.09(m, 18H), 1.04-0.91(m, 2H), 0.85(s, 3H), 0.82(s, 3H).

[0585] Preparation of Compound 11: p-Toluenesulfonic acid (0.7 g, 3.64 mmol) was added to a solution of Compound 10 (28.0 g, 0.097 mol, 1.0 eq) and ethylene glycol (30 mL) in toluene (300 mL). The reaction mixture was heated under reflux overnight using a Dean-Stark separator. LCMS showed that the starting material was completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with saturated sodium bicarbonate aqueous solution (100 mL × 2) and brine (100 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain crude product 11 (30.0 g, 0.090 mol, 93%), which was used directly in the next step without further purification. 1 H NMR: (400MHz, CDCl3) δ4.02-3.78(m, 4H), 3.68-3.48(m, 1H), 2.04-1.92(m, 1H), 1.80-1.54(m, 8H), 1.46 -1.32 (m, 5H), 1.31-1.19 (m, 5H), 1.14-1.05 (m, 1H), 1.02-0.86 (m, 2H), 0.83 (s, 3H), 0.80 (s, 3H), 0.72-0.61 (m, 1H).

[0586] Preparation of Compound 12: A solution of Compound 11 (30.0 g, 0.090 mol, 1.0 eq) in dry DCM (300 mL) was added to a solution of Compound 11 at 0 °C with Dys-Martin oxidant (76.0 g, 0.180 mol, 2.0 eq). The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 2 h. LC-MS showed complete consumption of the starting material. The mixture was quenched with a saturated aqueous solution of NaHCO3 / Na2SO3 (200 mL, 1 / 3) and then diluted with DCM (250 mL). The organic layer was washed with saturated aqueous solutions of sodium bicarbonate (100 mL × 2) and brine (100 mL × 2), dried over sodium sulfate, and concentrated under vacuum to obtain crude product 12 (24.0 g, 0.072 mol, 80%), which was used directly in the next step without further purification.

[0587] Preparation of Compound 13: Compound 12 (24.0 g, 0.072 mol, 1.0 eq) was added dropwise to a solution of MAD (2.16 mol, 3.0 eq, prepared by the method described in the synthesis of ST-200-A-001) in dry toluene (300 mL) at -78 °C, and the mixture was stirred at -78 °C for 30 min under nitrogen. Then, MeMgBr (72 mL, 2.16 mol, 3.0 eq, 3 M in ether) was added dropwise at -78 °C, and the resulting mixture was stirred at the same temperature for 2 h. LC-MS showed that the starting material was completely consumed. The reaction mixture was poured into a saturated aqueous solution of NH4Cl4 (400 mL) and extracted with EA (300 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to give product 13 (16.0 g, 0.046 mol, 72%) as a white solid. 1 HNMR: (400MHz, CDCl3) δ3.95-3.88(m, 2H), 3.87-3.82(m, 2H), 2.02-1.92(m, 1H), 1.8 4-1.73(m,1H),1.71-1.50(m,9H),1.50-1.43(m,1H),1.42-1.33(m,4H),1.33-1.28(m 1H), 1.27-1.19(m, 7H), 1.08-0.88(m, 2H), 0.83(s, 3H), 0.81(s, 3H).

[0588] Preparation of compound INT G: A mixture of compound 13 (16.0 g, 46.0 mmol, 1.0 eq) in 1 M HCl aqueous solution (60 mL), acetone (60 mL), and THF (350 mL) was stirred overnight at room temperature, then diluted with water (200 mL) and neutralized with solid NaHCO3 until no CO2 was released. The mixture was extracted with EA (300 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over sodium sulfate, and concentrated under vacuum to obtain product INT G (14.0 g, 46.0 mmol, 100%) as a white solid.

[0589] 1 H NMR: (400MHz, CDCl3) δ2.44 (dd, J=19.20, 8.41Hz, 1H), 2.13-2.01 (m, 1H), 1.98-1.89 (m, 1H), 1.85-1.76 (m, 2H), 1.69 -1.60 (m, 3H), 1.59-1.42 (m, 5H), 1.33-1.13 (m, 10H), 1.08-0.94 (m, 2H), 0.86 (s, 3H), 0.84 (s, 3H), 0.68-0.77 (m, 1H).

[0590] Preparation of compound 14: A solution of t-BuOK (442 mg, 3.94 mmol, 5.0 eq) in THF (5 mL) was added to a solution of PPh3CH3Br (1.4 g, 3.94 mmol, 5.0 eq) in THF (10 mL) at room temperature. After stirring for 1 h, a solution of INT G (0.2 g, 0.657 mmol, 1.0 eq) in THF (5 mL) was added dropwise. The reaction mixture was refluxed for 3 h, then cooled to room temperature and quenched with saturated NH4Cl aqueous solution (50 mL), and extracted with EA (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum to give a crude product, which was purified by rapid column chromatography (elution buffer: PE / EA = 15 / 1) to obtain compound 14 (180 mg, 90%) as a white solid. 1 HNMR: (400MHz, CDCl3) δ4.62 (d, J=6.4Hz, 2H), 2.51-2.44 (m, 1H), 2.24-2.22 (m, 1H), 1.82-1.78 (m, 1H), 1.75-1.30 (m, 9H), 1.29-1.11 (m, 11H), 1.03-0.95 (m, 3H), 0.83 (s, 3H), 0.77 (s, 3H), 0.72-0.68 (m, 1H).

[0591] Preparation of compound INT I: A solution of compound 14 (0.95 g, 3.14 mmol, 1.0 eq) in 10 mL of THF was added dropwise to a 9-BBN solution (0.5 M, 50 mL, 25.00 mmol, 8.0 eq) in THF. The reaction mixture was heated to 60 °C and stirred for 20 h. The mixture was cooled to 0 °C and 20 mL of 10% NaOH aqueous solution was added, followed by 10 mL of 30% H2O2 aqueous solution. The resulting mixture was stirred at 0 °C for 2 h and then extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum to give a crude product, which was purified by rapid column chromatography (elution: PE / EA = 10 / 1) to obtain INT I (0.63 g, 63%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ3.74-3.69 (dd, J1=10.4Hz, J2=6.8Hz, 1H), 3.56-3.52 (dd, J1=10.4Hz, J2=7.6Hz, 1H), 1.86-1.80 (m, 2H), 1.69-1 .44 (m, 11H), 1.41-1.26 (m, 4H), 1.25-1.21 (m, 5H), 1.19-0.99 (m, 5H), 0.93-0.91 (m, 5H), 0.81 (s, 3H), 0.74-0.68 (m, 1H), 0.64 (s, 3H).

[0592] Preparation of compound INT J: Desmond-Martin reagent (1.3 g, 3.12 mmol, 2.0 eq) was added to a solution of INT I (500 mg, 1.56 mmol, 1.0 eq) in DCM (20 mL) under ice bath conditions. The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was poured into a solution of NaS₂O₃ (5 g) and NaHCO₃ (1.5 g) in water (20 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum to give a crude product (500 mg, 100%), which was used directly in the next step without further purification.

[0593] Preparation of compound C_007_1: A mixture of INT J (500 mg, 1.57 mmol, 1.0 eq) and Ph3P=CHCOOCH3 (3.1 g, 8.27 mmol, 6.0 eq) in toluene (30 mL) was stirred at 80 °C for 3 hours. The mixture was concentrated under vacuum and the residue was purified by rapid column chromatography (elution buffer: PE / EA = 12 / 1) to obtain product C_007_1 (188 mg, 32%) as a white solid.

[0594] Preparation of compound C_007_2: A mixture of compound C_007_1 (188 mg, 0.5 mmol, 1.0 eq) and Pd / C (5%, 60 mg) in EA (10 mL) was stirred at room temperature for 2 hours under H2 (1 atm). The mixture was filtered and the filtrate was concentrated under vacuum to give product C_007_2 (189 mg, 100%), which was used directly in the next step without further purification.

[0595] Preparation of compound ST-200-C-007: CH3Li (1.6M, 1.6mL, 2.6mmol, 10.0eq in THF) was added dropwise to a solution of compound C_007_2 (100mg, 0.26mmol, 1.0eq) at -78℃ in THF (2mL) under nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 1 hour. A saturated aqueous solution of NH4Cl (10mL) was added to quench the reaction and the mixture was extracted with EA (10mL × 2). The combined organic layers were washed with brine (10mL), dried over sodium sulfate, and concentrated under vacuum to give a crude product, which was purified by rapid column chromatography (elution: PE / EA = 8 / 1) to obtain target ST-200-C-007 (32.7mg, 32.7%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ1.82-1.81(m, 1H), 1.75-1.57(m, 7H), 1.56-1.26(m, 10H), 1.24 (s, 3H), 1.20 (s, 6H), 1.18-0.83 (m, 10H), 0.81 (s, 3H), 0.71-0.66 (m, 1H), 0.58 (s, 3H).

[0596] Example 12. Preparation of compound ST-200-C-011

[0597]

[0598] Preparation of compound INT H: CeCl3·7H2O (1.22 g, 3.28 mmol, 1.0 eq) was added to a solution of INT G (1.00 g, 3.28 mmol, 1.0 eq) in MeOH (20 mL) and THF (8 mL). NaBH4 (0.25 g, 6.56 mmol, 2.0 eq) was then added in five portions, and the mixture was stirred at room temperature for 1 hour. The reaction slurry was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum to give the desired product (0.97 g, 97%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ3.62 (t, J=8.4Hz, 1H), 2.10-2.04 (m, 1H), 1.79-1.77 (m, 1H), 1.70-1.35 (m, 13H), 1.31-1.15 (m, 11H), 1.14-0.84 (m, 5H), 0.81 (s, 3H), 0.72 (s, 3H), 0.70-0.61 (m, 1H).

[0599] Preparation of compound C_011_1: NMM (830 mg, 8.21 mmol, 5.0 eq) and methyl propynate (690 mg, 8.21 mmol, 5.0 eq) were added to a solution of INT H (500 mg, 1.63 mmol, 1.0 eq) in DCM (20 mL). The mixture was stirred at room temperature for 16 hours, then washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to give the product (500 mg, 78.6%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ=7.53 (d, J=12.4Hz, 1H), 5.24 (d, J=12.4Hz, 1H), 3.86 (t, J=8.4Hz, 1H), 3.68 (s, 3H ), 2.18-2.06(m, 1H), 1.84-1.81(m, 1H), 1.70-0.85(m, 30H), 0.81(s, 3H), 0.78(s, 3H), 0.72-0.64(m, 1H).

[0600] Preparation of compound C_011_2: Pd / C (10%, 50 mg) was added to a solution of C_011_1 (500 mg, 1.289 mmol, 1.0 eq) in EA (20 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 30 °C for 16 h under a hydrogen pressure of 30 psi. TLC (PE / EA = 3 / 1) showed that the reaction was complete. The suspension was filtered through a diatomaceous earth pad and the pad was washed with EA (20 mL × 5). The combined filtrates were concentrated under vacuum to give the product (430 mg, 85.5%) as a white solid.

[0601] Preparation of compound ST-200-C-011: MeLi (1.3 mL, 2.048 mmol, 8.0 eq) was added dropwise to a solution of C_011_2 (100 mg, 0.256 mmol, 1.0 eq) in dry THF (1 mL) at -78 °C under N2. The resulting mixture was stirred at this temperature for 0.5 h, then warmed to room temperature and stirred at this temperature for another 1 h. TLC (PE / EA = 3 / 1) showed that the reaction was complete. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product (30 mg, 30%) as a white solid. 1 HNMR (400MHz, CDCl3) δ3.86 (s, 1H), 3.78-3.61 (m, 2H), 3.29 (t, J=8.3Hz, 1H), 2.10-1.95 (m, 1H), 1.90-1.81 (m, 1H), 1.74 (t, J=5.6 Hz, 2H), 1.69-1.61 (m, 3H), 1.55-1.28 (m, 9H), 1.24-1.22 (m, 9H), 1.22-0.83 (m, 8H), 0.81 (s, 3H), 0.74 (s, 3H), 0.69-0.62 (m, 1H).

[0602] Example 13. Preparation of compound ST-200-C-013

[0603]

[0604] KOH (53 mg, 0.937 mmol, 2.0 eq) and 2,2-dimethylethylene oxide (337 mg, 4.687 mmol, 10.0 eq) were added to a solution of INT I (150 mg, 0.469 mmol, 1.0 eq) in DMSO (1 mL). The reaction mixture was stirred at 50 °C for 16 h. TLC (PE / EA = 10 / 1) showed that the starting material was completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with saturated NH4Cl aqueous solution (10 mL × 2) and water (10 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain a crude product, which was purified by column chromatography and subsequent preparative-HPLC to obtain a pure product ST-200-C-013 (26 mg, 15.8%). 1 H NMR: (400MHz, CDCl3) δ3.72 (dd, J=7.3, 9.3Hz, 1H), 3.35 (dd, J=6.8, 9.3Hz, 1H), 3.21 (s, 2H), 2.34 (s, 1H), 1.84-1.80 (m, 1H), 1 .79-1.63(m, 5H), 1.54-1.27(m, 8H), 1.25(s, 3H), 1.19(s, 6H), 1.18-0.83(m, 7H), 0.81(s, 3H), 0.74-0.65(m, 1H), 0.63(s, 3H)

[0605] Example 14. Preparation of compounds ST-200-C-017 and ST-200-C-017A

[0606]

[0607] A solution of ST-200-A-017 (60 mg, 0.159 mmol, 1.0 eq) and Pd / C (10 mg) in EtOH (10 mL) was stirred at 50 °C and 50 psi hydrogen pressure for 16 h. The reaction solution was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography with PE:EA (20:1) elution to give ST-200-C-017 (21 mg) and ST-200-C-017A (4.6 mg) as white solids. 1H NMR (ST-200-C-017): (400MHz, CDCl3) δ3.73-3.71 (m, 1H), 3.31 (t, J=8.4Hz, 1H), 3.27- 3.22(m, 2H), 2.48(s, 1H), 2.01-1.91(m, 1H), 1.88-1.84(m, 1H), 1.68-1.52(m, 4H), 1.5 1-1.49(m, 4H), 1.47-1.42(m, 1H), 1.31-1.24(m, 7H), 1.20-1.83(m, 6H), 1.15-1.10(m, 1H), 1.03-0.95(m, 2H), 0.90-0.85(m, 1H), 0.81(s, 3H), 0.65(s, 3H), 0.70-0.61(m, 1H). 1 HNMR (ST-200-C-017a): (400MHz, CDCl3) δ3.33 (t, J=8.4Hz, 1H), 3.27-3.22 (m, 2H), 2.45 (s, 1H), 2.10-1.91 (m, 1H), 1.89-1.78 (m, 3H), 1.69-1.6 1(m, 1H), 1.58-1.51(m, 1H), 1.50-1.30(m, 7H), 1.29-1.24(m, 5H), 1.20 (s, 3H), 1.29-1.10 (m, 8H), 1.09-1.01 (m, 1H), 0.98 (s, 3H), 0.75 (s, 3H).

[0608] Example 15. Preparation of compounds 3-α-A2 and 3-β-A2

[0609]

[0610]

[0611] Preparation of compound BB-2: A solution of BB-1 (1.75 g, 4.06 mmol) prepared as described in Steroids (2006) 71:18 was cooled to 0 °C under nitrogen in 35 mL of THF. Methylmagnesium chloride (22% (w / w) in THF, 19.5 mL, 58.1 mmol) was added dropwise. Stirring was continued at 0 °C for 15 min, and the reaction mixture was warmed to room temperature and stirred for 2 h. A saturated aqueous solution of NH4Cl (5 mL) was slowly added. A precipitate formed, which was dissolved by adding water (10 mL). EtOAc (50 mL) and brine (20 mL) were added. Layer separation was performed. The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried with Na2SO4 and the solvent was removed under vacuum. The residue was coevaporated with dichloromethane (50 mL). BB-2 was obtained as a grayish-white solid (1.54 g, 3.95 mmol, 97%). 1 HNMR (400MHz, CDCl3): δ (ppm): 5.32-5.43 (1H, m), 3.46-3.61 (1H, m), 1.20 (3H, s), 1.19 (3H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6Hz), 0.68 (3H, s).

[0612] Preparation of compound BB-3: A solution of oxaloyl chloride (0.622 mL, 7.26 mmol) in dichloromethane (19 mL) was cooled to -78 °C in an oven-dried flask under nitrogen. Dimethyl sulfoxide (0.60 mL, 8.47 mmol) was slowly added. After 25 minutes, a solution of BB-2 (0.470 g, 1.209 mmol) in CHCl3 (38 mL) was added dropwise over a 25-minute period. The solution was stirred at -78 °C for 2.5 hours. Triethylamine (3.36 mL, 24.19 mmol) was added dropwise at -78 °C. Stirring was continued for 15 minutes. The cooling bath was removed and stirring was continued for 10 minutes. A saturated aqueous solution of NH4Cl (10 mL) was added and the reaction mixture was stirred for 5 minutes. Dichloromethane (50 mL) and water (20 mL) were added. The layers were separated, and the organic layer was washed with water (20 mL). The combined aqueous layers were diluted with brine (20 mL) and extracted with EtOAc (2 × 75 mL). The combined organic layers were dried with Na₂SO₄ and the solvent was removed under vacuum. Rapid chromatography (heptane, 5%–30% EtOAc) yielded BB-3 as a white solid (238 mg, 0.616 mmol, 51%). 1H NMR (400MHz, CDCl3): δ (ppm): 5.31-5.38 (1H, m), 3.22-3.34 (1H, m), 2.83 (1H, dd, J = 16.4Hz, 2.1Hz), 2.41-2.54 (1H, m), 2.25- 2.34(1H,m), 1.95-2.08(3H,m), 1.82-1.93(1H,m), 1.21(3H,s), 1.20(3H,s), 1.19(3H,s), 0.94(3H,d,J=6.5Hz), 0.71(3H,s).

[0613] Preparation of compounds 3-α-OH A2 and 3-β-OH A2: In a flame-dried flask in a glove box, degassed THF (3 mL) was added to anhydrous cerium(III) chloride (0.319 g, 1.29 mmol). The suspension was stirred overnight at room temperature. A white, fine suspension was removed from the glove box. 1 mL of dried THF was added, and the mixture was stirred at room temperature under argon for 15 minutes. The white, fine suspension was cooled to -78 °C under argon. At this temperature, 1.6 M methyllithium (0.79 mL, 1.27 mmol) in Et2O was added dropwise. A yellow suspension formed, and the mixture was stirred at -78 °C for 1.5 hours. A solution of BB-3 (0.100 g, 0.259 mmol) in 2 mL of dried THF was added dropwise over 5 minutes. The color of the reaction mixture changed from yellow to brown. The reaction mixture was stirred at -78 °C for 45 minutes. The cooling bath was removed, and the reaction mixture was stirred for 10 minutes. A 5% aqueous solution of AcOH (2 mL) was added. The reaction mixture became a colorless, transparent solution. Add EtOAc (10 mL). Warm the mixture to room temperature. Separate the layers, and extract the aqueous layer with EtOAc (2 × 10 mL). Dry the combined organic layers with sodium sulfate and remove the solvent under vacuum. Rapid chromatography (H, 5%–20% EtOAc) yielded compound A2(3α-OH) (33 mg, 0.082 mmol; 63.5%) and compound A2(3β-OH) (13 mg, 0.032 mmol; 25.0%). (3α-OH): 1 H-NMR (400MHz, CDCl3): δ (ppm): 5.43-5.38 (m, 1H), 2.46-2.37 (m, 1H), 2.05-1.80 (m, 4H), 1.73-1.23 (m, 15H) , 1.22 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18-0.99 (m, 9H), 0.98 (s, 1H), 0.94 (d, J=6.5Hz, 3H), 0.68 (s, 3H). (3β-OH): 1H-NMR (400MHz, CDCl3): δ (ppm): 5.34-5.28 (m, 1H), 2.47-2.38 (m, 1H), 2. 07-1.92(m, 3H), 1.91-1.66(m, 3H), 1.63-1.24(m, 13H), 1.20(s, 3H), 1.19 (s, 3H), 1.18-1.12 (m, 3H), 1.11 (s, 3H), 1.10-1.02 (m, 2H), 1.01 (s, 3H), 1.00-0.94 (m, 1H), 0.93 (d, J=6.5Hz, 3H), 0.91-0.82 (m, 1H), 0.68 (s, 3H).

[0614] Example 16. Preparation of compounds 3-α-A28 and 3-β-A28

[0615]

[0616] In a flame-dried flask in a glove box, THF (degassed, 1.5 mL) was added to anhydrous cerium(III) chloride (0.207 g, 0.841 mmol). The suspension was stirred overnight at room temperature. The white fine suspension was removed from the glove box and stirred under argon for 15 min. The white fine suspension was cooled to -78 °C under argon. At this temperature, 0.5 M ethyllithium (1.68 mL, 0.841 mmol) in benzene / cyclohexane was added dropwise. A yellow suspension formed and was stirred at -78 °C for 30 min. A solution of BB-3 (0.065 g, 0.168 mmol) in THF (dried, 1.5 mL) was added dropwise over 3 min. The color of the reaction mixture changed from yellow to brown. The reaction mixture was stirred at -78 °C for 45 min. A brown emulsion suspension was obtained, and TLC (H / E; 2:1) showed complete conversion of the starting material and the formation of more polar points. The cooling bath was removed and the reaction mixture was stirred for 10 min. Add 5% AcOH aqueous solution (2 mL). After adding brine (2 mL), the reaction mixture becomes a colorless and transparent solution. Add EtOAc (5 mL). Warm the mixture to room temperature. Perform layer separation and extract the aqueous layer with EtOAc (2 × 5 mL). Dry the combined organic layers with sodium sulfate and remove the solvent under vacuum. 60 mg of white solid is obtained. Separation on silica gel impregnated with AgNO3 (H, 5%–20% EtOAc) yields compound A28(3α-OH) (6 mg, 0.014 mmol; 8.56%) and compound A28(3β-OH) (4 mg, 0.0096 mmol; 5.71%). (3α-OH): 1H-NMR (400MHz, CDCl3): δ (ppm): 5.45–5.38 (m, 1H), 2.40–2.33 (m, 1H), 2.05 -1.93(m, 2H), 1.92–1.80(m, 2H), 1.75–1.23(m, 15H), 1.20(s, 3H), 1.19(s, 3H), 1 .18–0.98 (m, 7H), 0.97 (s, 3H), 0.96–0.90 (m, 6H), 0.89–0.81 (m, 2H), 0.68 (s, 3H). (3β-OH): 1 H-NMR (400MHz, CDCl3): δ (ppm): 5.33–5.25 (m, 1H), 2.41–2.31 (m, 1H), 2.06–1.93 (m, 3H), 1.90–1.78 (m, 1H), 1.77–1.23 (m, 20H), 1.20 (s, 3H), 1.19(s, 3H), 1.17–1.05(m, 5H), 1.03(s, 3H), 1.01–0.95(m, 1H), 0.93( d, J=6.5Hz, 3H), 0.92–0.88 (m, 1H), 0.84 (t, J=7.4Hz, 3H), 0.67 (s, 3H).

[0617] Example 17. Preparation of compound B6

[0618]

[0619] Preparation of compound B6a. Acetic anhydride (15.36 mL, 164 mmol) was added to a suspension of stigmasterol (22.5 g, 54.5 mmol) in pyridine (90 mL) under a nitrogen atmosphere, and the mixture was incubated at room temperature for 42 h. TLC [heptane (2): ethyl acetate (1)] showed complete conversion to the higher elution product after staining with p-methoxybenzaldehyde. Water (300 mL) was added to the reaction mixture to quench excess acetic anhydride. After stirring for 1 h, the white solid was filtered and thoroughly washed with water (9 × 250 mL). The white solid was dried over the weekend in a vacuum oven at 40 °C in the presence of a sodium hydroxide beaker to obtain product B6a (24.63 g, 54.2 mmol, yield = 99%) as a white powder. B6a was used as is in the following experiments. 1H NMR (400MHz, CDCl3) δ (ppm): 5.38-5.37 (1H, m), 5.15 (1H, dd, J = 15.1, 8.6Hz), 5.01 (1H, dd, J = 15.1, 8.6Hz), 4.64-4.56 (1H, m) , 2.33-2.31 (2H, m), 2.03 (3H, s), 1.90-1.82 (2H, m), 1.75-1.65 (1H, m), 1.02 (6H, t, J = 3.2Hz), 0.86-0.78 (9H, m), 0.68 (3H, s).

[0620] Preparation of compound B6b. Bromine (1.754 mL, 34.1 mmol) was added to a solution of iodobenzene (3.66 mL, 32.7 mmol) in n-heptane (100 mL), and the solution was cooled to -5 °C under a nitrogen atmosphere. A solution of stigmasterol acetate B6a (13.5 g, 29.7 mmol) in n-heptane (700 mL) was also cooled to -5 °C under a nitrogen atmosphere, stirred vigorously, and the solution prepared above was added dropwise over a period of 2.5 hours under a nitrogen atmosphere to maintain the solution as pale yellow. The resulting solution was stirred overnight and then filtered. TLC [heptane (9): ethyl acetate (1)] showed complete conversion to a slightly lower eluent after staining with vanillin. The solution was concentrated under vacuum until dry. The residue was purified by column chromatography (900 g) [heptane (95): diisopropyl ether (5)]. The fraction containing pure product was collected and evaporated under reduced pressure to obtain B6b as a white powder (9.06 g, 14.7 mmol, yield = 50%). B6b was used as is in the following experiments. 1 H NMR (400MHz, CDCl3) δ (ppm): 5.48 (1H, sep, J = 5.4Hz), 5.15 (1H, dd, J = 15.1, 8.6Hz), 5.02 (1H, dd, J = 15.1, 8.6Hz), 4.84 (1H, brd), 2.05 (3H, s), 1.46 (3H, s), 1.01 (3H, d, J=6.6Hz), 0.90-0.79 (15H, m), 0.72 (3H, s).

[0621] Preparation of compound B6c. A solution of 5α,6β-dibromostigmasteryl ester B6b (8.11 g, 13.20 mmol) in dichloromethane (240 mL) dried over a molecular sieve and pyridine (3.05 mL, 37.7 mmol) was cooled in a liquid nitrogen / ethyl acetate bath. An ozone-rich oxygen stream was introduced into the solution through a sintered glass injector for 1 hour. The reaction mixture turned slightly blue. Under UV light... 254Complete conversion of the starting material was shown by TLC [heptane (9): ethyl acetate (1)]. The ozone decomposition reaction was stopped. The reaction mixture was immediately poured into a mixture of glacial acetic acid (33.2 mL, 581 mmol) and zinc powder (21.57 g, 330 mmol) and stirred overnight at room temperature. The solution was filtered, washed successively with water (200 mL), 10% sodium bicarbonate aqueous solution (200 mL), 5% sodium hydroxide aqueous solution (200 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. Evaporation of the solvent provided crude cholester-5-en-3β-ol-22-al B6c, which was purified by rapid column (300 g) chromatography [heptane (100 => 90): ethyl acetate (0 => 10)]. The fraction containing the product was collected and evaporated under reduced pressure to obtain cholester-5-en-3β-ol-22-al B6c (2.58 g, 6.93 mmol, yield = 53%) as a white powder. B6c was used as is in the following experiments. 1 H NMR (400MHz, CDCl3) δ (ppm): 9.57 (1H, d, J = 3.3Hz), 5.38 (1H, brd), 4.65-4.56 (1H, m), 2.41-2.28 (3H, m ), 2.04 (3H, s), 2.03-1.92 (2H, m), 1.91-1.81 (3H, m), 1.13 (3H, d, J = 6.8Hz), 1.03 (3H, s), 0.73 (3H, s).

[0622] Preparation of compound B6d. (Methoxymethyl)triphenyl chloride was prepared by reacting the compound with an argon atmosphere at -10°C. A solution of 1.6Mn-BuLi (1.342 mL, 2.15 mmol) in dry THF (6.4 mL) was added to hexane. The solution was stirred at room temperature for 5 min, followed by the addition of B6c (0.2 g, 0.54 mmol) in dry THF (1.3 mL). The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (75 mL) and extracted twice with CH2Cl2 (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and the crude product was purified by rapid column chromatography (silica, heptane / ethyl acetate, 1:0 -> 88:12) to obtain B6d (103 mg, 0.29 mmol, yield = 54%). B6d was obtained as a 1:1 E / Z mixture according to NMR. 1HNMR (400MHz, CDCl3) δ (ppm): 6.24 (0.5H, d, J = 12.6Hz), 5.74 (0.5H, d, J = 6.2Hz), 5.34 (1H, brd) , 4.59 (0.5H, dd, J = 12.5, 9.3Hz), 4.17 (0.5H, dd, J = 9.8, 6.3Hz), 3.58-3.46 (1H, m), 3.55 (1.5H, s), 3.47 (1.5H, s), 2.67-2.54 (0.5H, m), 2.33-2.18 (2H, m), 2.04-1.78 (6H, m), 1.77-1.65 (1H, m) ), 1.04 (1.5H, d, J = 6.6Hz), 1.01 (3H, s), 0.98 (1.5H, d, J = 6.7Hz), 0.72 (1.5H, s), 0.69 (1.5H, s).

[0623] Preparation of compound B6e. Acetic anhydride (0.079 mL, 0.84 mmol) was added to a suspension of B6d (0.1 g, 0.279 mmol) in pyridine (3 mL) under a nitrogen atmosphere, and the mixture was incubated at room temperature for 42 hours. Water (60 mL) was added to the reaction mixture to quench excess acetic anhydride. After stirring for 1 hour, the white solid was filtered and thoroughly washed with water (9 × 250 mL). The white solid was dried overnight in a vacuum oven at 40 °C to obtain product B6e (111 mg, 0.28 mmol, yield = 99%). 1 H NMR (400MHz, CDCl3) δ (ppm): 6.24 (0.5H, d, J = 12.6Hz), 5.73 (0.5H, d, J = 6.2Hz), 5.37 (1H, brd), 4.66-4 .55 (1H, m), 4.59 (0.5H, dd, J = 12.5, 9.3Hz), 4.17 (0.5H, dd, J = 9.8, 6.3Hz), 3.55 (1.5H, s), 3.47 (1.5H, s ), 2.66-2.54 (0.5H, m), 2.35-2.28 (2H, m), 2.03 (3H, s), 2.02-1.91 (3H, m), 1.90-1.81 (2H, m), 1.77-1.6 6 (1H, m), 1.04 (1.5H, d, J = 6.6Hz), 1.02 (3H, s), 0.99 (1.5H, d, J = 6.6Hz), 0.72 (1.5H, s), 0.69 (1.5H, s).

[0624] Preparation of compound B6f. A solution of B6e (0.111 g, 0.28 mmol) in acetone (9 mL) was supplemented with 0.1 M HCl aqueous solution (1 mL, 0.10 mmol). The resulting white suspension was stirred at room temperature for 1 hour, followed by stirring at 70 °C for 1 hour and then at room temperature overnight. The mixture was heated at 70 °C for 2 hours, cooled to room temperature, and diluted with H₂O (50 mL). The reaction mixture was evaporated until dry, co-evaporated with MeOH (50 mL) and CH₂Cl₂ (10 mL). This appeared to be a mixture of the desired product and dimethylacetal. A solution of this mixture (0.12 g, 0.28 mmol) in acetone (10 mL) was supplemented with 0.1 M HCl aqueous solution (1 mL, 0.10 mmol). The resulting white suspension was stirred at 70 °C for 2 hours. 1,4-Dioxane (5 mL) was added, which caused the insoluble matter to dissolve. The reaction mixture was heated to 70 °C for another 2 hours, cooled to room temperature, and stirred overnight. The reaction mixture was diluted with H₂O (50 mL) and extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and the solvent was evaporated. The crude product was then reacted with CH₂Cl₂. 2( 10 mL) co-evaporated to obtain B6f (119 mg, 0.31 mmol, yield = 111%). 1 H NMR (400MHz, CDCl3) δ (ppm): 9.75 (1H, m), 5.37, (1H, brd), 4.66-.454 (1H, m), 2.47 (1H, dd, J=15.8, 2.4Hz), 2.36 -2.28 (2H, m), 2.17 (1H, ddd, J = 15.8, 9.3, 3.3Hz), 2.03 (3H, s), 1.02 (3H, d, J = 6.4Hz), 1.02 (3H, s), 0.70 (3H, s).

[0625] Preparation of compound B6f. Compound B6f (0.11 g, 0.285 mmol) was dissolved in tert-butanol (5 mL), dry THF (1 mL), and 2-methyl-2-butene (0.512 mL, 4.84 mmol). The solution was stirred and cooled in an ice bath. A solution of NaClO2 (0.028 g, 0.313 mmol) and K2HPO4 (0.043 g, 0.313 mmol) in softened water (3 mL) was slowly added over 5 minutes, and the mixture was stirred at 0 °C for 2 hours. The mixture was stirred overnight at room temperature. Additional NaClO2 (0.028 g, 0.313 mmol) and K2HPO4 (0.043 g, 0.313 mmol) dissolved in H2O (3 mL) were slowly added to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was poured into a saturated NH4Cl aqueous solution (250 mL) and extracted three times with CH2Cl2 (75 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The white solid residue (2.26 g, 163%) was ground in petroleum ether 40-60 (10 mL). The white solid was filtered, washed twice with petroleum ether 40-60 (5 mL), and air-dried for 0.5 h to obtain B6f (0.089 g, 0.22 mmol, yield = 78%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.0 (1H, bs), 5.37 (1H, brd), 4.66-4.55 (1H, m), 2.53-2.44 (1H, m), 2.36-2.26 (2H, m), 2.04 (3H, s), 1.04 (3H, d, J = 6.4Hz), 1.02 (3H, s), 0.72 (3H, s).

[0626] Preparation of compound B6h. Oxaloyl chloride (0.048 mL, 0.56 mmol) and DMF (catalyst) were added to a solution of B6 g (0.09 g, 0.224 mmol) in CH2Cl2 (10 mL). The solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with dry MeOH (150 mL, 3703 mmol) and stirred at 40 °C until all solids dissolved. The reaction mixture was evaporated to dryness and the crude product was purified by rapid column chromatography (silica, heptane / ethyl acetate, 1:0 -> 95:5) and co-evaporated twice with THF to obtain B6h (85 mg, 0.20 mmol, yield = 91%). 1H NMR (400MHz, CDCl3) δ (ppm): 5.37 (1H, brd), 4.66-4.55 (1H, m), 3.66 (3H, s), 2.43 (1H, dd, J=1 4.1, 2.9Hz), 2.38-2.25 (2H, m), 2.04 (3H, s), 1.02 (3H, s), 0.99 (3H, d, J = 6.2Hz), 0.72 (3H, s).

[0627] Preparation of compound B6. A solution of B6 (0.085 g, 0.20 mmol) in dry THF (3 mL) was cooled to 0 °C under an argon atmosphere. 3.0 M MeMgCl (0.68 mL, 2.04 mmol) was added dropwise to THF using a syringe. The reaction mixture was stirred at 0 °C for 1 h, followed by stirring at room temperature for 2 h. 3.0 M MeMgCl (0.68 mL, 2.04 mmol) was added again to THF at room temperature, and stirring continued overnight. The reaction mixture was quenched with saturated NH4Cl aqueous solution (75 mL) and extracted three times with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and the crude product was purified by rapid column chromatography (silica, heptane / ethyl acetate, 1:0 -> 4:1) to obtain B6 as a white, fluffy solid (45 mg, 0.12 mmol, yield = 59%). 1 H NMR (400MHz, CDCl3) δ (ppm): 5.35 (1H, brd), 3.53 (1H, sep, J = 5.1Hz), 2.34-2.17 (2H, m), 2.03 (1H, dt, J = 12.6 , 3.3Hz), 2.01-1.94 (1H, m), 1.93-1.79 (3H, m), 1.23 (6H, s), 1.06 (3H, d, J=6.5Hz), 1.01 (3H, s), 0.72 (3H, s).

[0628] Example 18. Preparation of compound B7

[0629]

[0630] Preparation of compound B7d: Cholesterol-5-en-3β-ol-22-aldehyde B7c (1.33 g, 3.57 mmol) was dissolved in tert-butanol (75 mL), tetrahydrofuran (dried) (15 mL), and 2-methyl-2-butene (13.22 mL, 125 mmol). The solution was stirred and cooled in an ice bath. During a 30-minute period, a solution of freshly prepared sodium chlorite (0.355 g, 3.93 mmol) and potassium dihydrogen phosphate (0.534 g, 3.93 mmol) in softened water (45 mL) was slowly added to the solution, and the mixture was stirred at 0 °C for 2 hours. The ice bath was removed, the mixture was heated to room temperature, and stirred overnight. TLC [heptane (2): ethyl acetate (1)] showed partial conversion to the lower (lower) elution product after vanillin staining. Additional sodium chlorite (0.355 g, 3.93 mmol) and potassium dihydrogen phosphate (0.534 g, 3.93 mmol) dissolved in water (45 mL) were slowly added to the reaction mixture, and stirring was continued for 2 hours. TLC [heptane (2): ethyl acetate (1)] showed complete conversion to the lower eluent after vanillin staining. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (250 mL) and extracted three times with dichloromethane (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was stripped twice with toluene (50 mL) followed by dichloromethane (50 mL). The white solid residue (2.26 g, 163%) was ground in petroleum ether 40-60 (10 mL) for 0.5 hours. The white solid was filtered, washed twice with 40-60 (10 mL) of petroleum ether, and air-dried (with the vacuum pump running) for 0.5 hours to obtain B7d as a white powder (1.27 g, 3.26 mmol, yield = 91%). B7d was used as is in the following experiments. 1 H NMR (400MHz, CDCl3) δ (ppm): 10.31 (1H, bs), 5.37 (1H, brd), 4.65-4.56 (1H, m), 2.47-2.39 (1H, m), 2.36-2.26 (2H, m), 2.04 (3H, s), 2.01-1.92 (2H, m), 1.90-1.76 (3H, m), 1.24 (3H, d, J=6.8Hz), 1.02 (3H, s), 0.71 (3H, s).

[0631] Preparation of compound B7e. Carboxylic acid B7d (0.1 g, 0.257 mmol) was dissolved in dichloromethane (10 mL). Oxaloyl chloride (0.044 mL, 0.515 mmol) and N,N-dimethylformamide (one drop) were added, and the reaction mixture was stirred for 1 hour. The reaction sample was poured into methanol, evaporated to dryness, and analyzed by TLC [heptane (3): ethyl acetate (1)], which showed complete conversion to methyl ester after staining with vanillin. The reaction mixture was diluted with methanol (50 mL, 1234 mmol) (dried through a molecular sieve), evaporated under reduced pressure, and stripped with anhydrous toluene and dichloromethane. The residue was purified by rapid column chromatography (4 g) [heptane (99 => 80): ethyl acetate (1 => 20)]. The fraction containing the product was collected and evaporated under reduced pressure to obtain B7e (0.104 g, 0.257 mmol, yield = 100%). B7e was stripped with toluene (2 × 5 mL), dichloromethane (2 × 5 mL), and anhydrous tetrahydrofuran (2 × 5 mL) and used as is in the next reaction step. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.37 (¹H, brd), 4.65–4.56 (¹H, m), 3.65 (³H, s), 2.47–2.38 (¹H, m), 2.36–2.26 (²H, m), 2.03 (³H, s), 2.01–1.92 (²H, m), 1.90–1.82 (²H, m), 1.19 (³H, d, J = 6.8 Hz), 1.02 (³H, s), 0.69 (³H, s).

[0632] Preparation of compound B7. Methyl ester B7e (0.104 g, 0.258 mmol) was dissolved in tetrahydrofuran (dried) (2.6 mL) under argon atmosphere and cooled in an ice bath. After 20 minutes, 3.0 M methyl magnesium chloride (0.861 mL, 2.58 mmol) was added dropwise to THF via syringe. Some gas release was observed. After stirring the reaction mixture for 0.5 h, the cooling bath was removed and stirring was continued for 2 h. TLC [heptane (3): ethyl acetate (1)] showed complete conversion of the starting material to two lower elution products after vanillin staining. Stirring was continued for 1 h. The reaction mixture was poured into a saturated ammonium chloride aqueous solution (75 mL) under stirring and extracted with dichloromethane (3 × 50 mL). The extracts were combined, dried over sodium sulfate and evaporated. The residue was ground in methanol (2 mL) for 0.5 h, the white solid was filtered, and the filtrate was washed with methanol (2 mL). Almost no substance remained on the filter, most of which was present in the filtrate. The filtrate and the residue were combined and purified by rapid column chromatography [heptane (99 => 70): ethyl acetate (1 => 30)]. The fraction containing the product was collected and evaporated under reduced pressure. The residue was dried overnight in a vacuum oven at 40 °C to obtain B7 as a white solid (0.044 g, 0.122 mmol, yield = 47%). 1 H NMR (400MHz, CDCl3) δ (ppm): 5.35 (1H, m), 3.53 (1H, sep, J = 5.2Hz), 2.34-2.19 (2H, m), 2.10 (1H, dt, J = 12.6, 3.4Hz) , 2.03-1.88(2H,m), 1.88-1.79(2H,m), 1.20(3H,s), 1.15(3H,s), 1.00(3H,s), 0.98(3H,d,J=6.9Hz), 0.73(3H,s).

[0633] Example 19. Preparation of compound B8

[0634]

[0635] Preparation of compound B8b. A solution of NaHMDS (0.070 mL, 0.349 mmol) in tetrahydrofuran (dried) (1 mL) was added to a solution of silyloxyphosphonate B8a (0.143 g, 0.403 mmol) in tetrahydrofuran (dried) (1 mL) at -78 °C in a flame-dried round-bottom flask. The solution was stirred at -78 °C for 15 min under an argon atmosphere. Then, a solution of cholester-5-en-3β-ol-22-aldehyde B7c (0.1 g, 0.268 mmol) in tetrahydrofuran (dried) (1 mL) was slowly added via syringe. The reaction mixture was slowly warmed to room temperature and stirred for 20 h. TLC [heptane (3): ethyl acetate (1)] showed partial conversion to the higher eluent after vanillin staining. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with water (50 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by rapid column chromatography (4 g) [heptane (100 => 90): diisopropyl ether (0 => 10)]. The fraction containing the product was collected and evaporated under reduced pressure to obtain product B8b (0.117 g, 0.187 mmol, yield = 70%) as a white powder. A 7:3 mixture of E- and Z-isomers was obtained according to NMR. 1 ¹H NMR (400MHz, CDCl₃) δ (ppm): 5.70 (¹H, d, J = 10.4Hz), 5.23 (¹H, brd), 5.17–5.13 (¹H, m), 4.51–4.40 (¹H, m), 4.11–4.00 (²H, m), 3.16–3.07 (0.3H [Z-isomer], m), 2.68–2.57 (0.7H [E-isomer]). , m), 2.20-2.10 (2H, m), 1.89 (3H, s), 1.89-1.77 (2H, m), 1.75-1.67 (2H, m), 0.89-0.85 (6H, m), 0.84-0.77 (10H, m), 0.59 (0.9H [Z-isomer], s), 0.57 (2.1H [E-isomer], s), 0.05-0.00 (6H, m).

[0636] Preparation of compound B8c. Glacial acetic acid (0.060 mL, 1.047 mmol) and cerium fluoride (0.080 g, 0.524 mmol) were added to a suspension of B8b (0.1 g, 0.175 mmol) in anhydrous acetonitrile (4 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h. LCMS-NQAD (acid) showed minimal conversion of the starting material to the product, with unclear product material. Dichloromethane (2 mL) was added to the reaction mixture, which immediately turned into a yellow, clear solution. The reaction mixture was stirred overnight. Additional cerium fluoride (0.080 g, 0.524 mmol) was added to the reaction mixture, and stirring continued for 24 h. Additional cerium fluoride (0.080 g, 0.524 mmol) was added to the reaction mixture again, and stirring continued for 4 h. Although TLC [heptane (3): ethyl acetate (1)] showed a small amount of starting material remaining in the reaction mixture, the reaction mixture was diluted with dichloromethane (75 mL) and washed with saturated sodium bicarbonate aqueous solution (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid column chromatography (25 g) [heptane (100 => 90): ethyl acetate (0 => 10)] to remove the remaining starting material (visible only on TLC). The fraction containing the product was collected and evaporated under reduced pressure to obtain product B8c (0.051 g, 0.111 mmol, yield = 64%). 1 H NMR (400MHz, CDCl3) δ (ppm): 5.37 (1H, brd), 4.65-4.55 (1H, m), 4.31, (2H, q, J=7.1Hz), 2.89 (1H, dd, J=16.8, 3.0Hz), 2.57 (1H, dd, J=16.8, 9.9Hz ), 2.37-2.25(2H, m), 2.04(3H, s), 2.09-1.91(2H, m), 1.90-1.77(3H, m) , 1.37 (3H, t, J = 7.1Hz), 1.02 (3H, s), 0.97 (3H, d, J = 6.5Hz), 0.72 (3H, s).

[0637] Preparation of compound B8d. A solution of B8c (0.051 g, 0.111 mmol) in dichloromethane (1 mL) was cooled in an ice bath under a nitrogen atmosphere for 0.5 h. Diethylaminosulfonium trifluoride (DAST) (0.027 mL, 0.222 mmol) was added, and the reaction mixture was warmed to room temperature and stirred overnight. Additional diethylaminosulfonium trifluoride (DAST) (0.027 mL, 0.222 mmol) was added, and stirring was continued for 20 h. TLC [heptane (3): ethyl acetate (1)] still showed incomplete consumption of the starting material after vanillin staining. LCMS-ELSD (base): 47% of product at room temperature = 3.43, where m / z(+) = 421, corresponding to the desired product with the acetate group eliminated [M-CH3COOH+H]. + The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate (50 mL). The aqueous layer was separated and extracted twice with dichloromethane (50 mL). The extracts were combined with the preceding organic layer, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by rapid column chromatography [heptane (100 => 90): ethyl acetate (0 => 90)]. The fraction containing the product was collected, evaporated under reduced pressure, and stripped with dichloromethane (5 mL) to obtain product B8d (0.027 g, 0.056 mmol, yield = 51%). 1 H NMR (400MHz, CDCl3) δ (ppm): 5.37 (1H, brd), 4.65-4.55 (1H, m), 4.32, (2H, q, J = 7.1Hz), 2.37-2.28 (2H, m), 2.27-2.09 (1H, m), 2.03 (3H, s), 2.04-1.92 (2H, m), 1.90-1.81 (3H, m), 1.35 (3H, t, J = 7.1Hz), 1.06 (3H, d, J = 6.1Hz), 1.02 (3H, s), 0.88 (6H, t, J = 6.8Hz), 0.70 (3H, s).

[0638] Preparation of compound B8. Compound B8d (0.027 g, 0.056 mmol) was dissolved in tetrahydrofuran (dry) (1 mL) under an argon atmosphere. The mixture was cooled in an ice bath for 15 min and 2.4 M lithium aluminum hydride (0.047 mL, 0.112 mmol) in THF was added stepwise. Some gas release was observed. The reaction mixture was cooled and stirred for 1 h. TLC [heptane (3): ethyl acetate (1)] showed complete conversion to a major lower product after staining with vanillin. The ice bath was removed and stirring was continued for 1 h. The reaction mixture was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted three times with dichloromethane (50 mL). The combined extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by rapid column chromatography (4 g silica) [heptane (100 => 85): ethyl acetate (0 => 15)]. The fraction containing the product was collected and evaporated under reduced pressure. The residue was transferred to a vial containing methanol (4 mL) and the methanol was evaporated at 37 °C under a nitrogen stream. The residue was dried overnight in a vacuum oven at 40 °C to obtain product B8 (0.011 g, 0.028 mmol, yield = 49%). 1 H NMR (400MHz, CDCl3) δ (ppm): 5.35 (1H, m), 3.71 (2H, t, J = 12.8Hz), 3.58-3.48 (1H, m), 2.35-2.18 (2H, m), 2 .15-1.93(3H,m), 1.92-1.73(5H,m), 1.70-1.40(9H,m), 1.08(3H,d,J=6.5Hz), 1.01(3H,s), 0.72(3H,s).

[0639] Example 20. Preparation of compound B10

[0640]

[0641] A solution of BB-1 (100 mg, 0.23 mmol) and titanium isopropoxide (IV) (0.07 mL, 0.23 mmol) in THF (dry, 2 mL) was cooled to 0 °C under argon atmosphere in a flame-dried flask. Ethyl magnesium bromide (1.0 M, 1.16 mL in THF) was added dropwise. The reaction mixture was stirred at 0 °C for 15 min, and TLC (H / E; 2:1) showed the starting material and two new spots. The reaction mixture was warmed to room temperature and stirred for 1 h, then cooled to 0 °C and ethyl magnesium bromide (1.0 M, 1.16 mL in THF) was added dropwise. The reaction mixture was stirred at 0 °C for 15 min, and TLC (H / E; 2:1) showed complete conversion and a single new spot. The reaction mixture was diluted with Et₂O (2 mL). A saturated aqueous solution of NH₄Cl (2 mL) and H₂O (2 mL) were added at 0 °C. The solids were filtered off through cotton wool, and the filter cake was washed with Et₂O (10 mL). The colorless layer was separated and the aqueous layer was extracted with Et₂O (20 mL) and a mixture of Et₂O and EtOAc (20 ...

Claims

1. A compound of the formula: or a pharmaceutically acceptable salt thereof; in: Z is a group of formula (i), (ii), (iii), (iv) or (v): L 1 and L 2 is selected from a bond, a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C2-C6 alkenylene, a substituted or unsubstituted C2-C6 alkynylene, a substituted or unsubstituted heteroC1-C6 alkylene, a substituted or unsubstituted heteroC2-C6 alkenylene, and a substituted or unsubstituted heteroC2-C6 alkynylene; L 3 is substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, substituted or unsubstituted heteroC1-C6 alkylene, substituted or unsubstituted heteroC2-C6 alkenylene, or substituted or unsubstituted heteroC2-C6 alkynylene; X 1 and X 2 Each instance of is independently -O-, -S-, or -NH-; R 1 is hydrogen or substituted or unsubstituted alkyl; R 3b is hydrogen; R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 2 , R 11a and R 11b Each instance of is independently hydrogen or -OR B1 , where R B1 is hydrogen or substituted or unsubstituted alkyl, or R 11a and R 11b Combine to form an oxo (=O) group; R 6a and R 6b are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, and represents a single bond or a double bond, provided that if a double bond exists, then R 6a or R 6b one of is not present, and provided that if a single bond is present, the hydrogen at C5 is in the alpha or beta position; R 19 and R 20 Each instance of is independently hydrogen or -CH3; And R 23a and R 23b Each instance of is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 23a and R 23b Combined together to form a substituted or unsubstituted C3-C6 cycloalkyl group; R 24 is hydrogen or substituted or unsubstituted alkyl; Y is -O-, -S-, or -NR Z5 -; R Z4 are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR Z5 、-SR Z5 , or -N(R Z5 )2; R Z5 Each instance of is independently hydrogen or substituted or unsubstituted alkyl; and R Z6 Each instance of is independently hydrogen or substituted or unsubstituted alkyl, or two R Z6 The groups combine to form C 3-6 Carbon rings; and Subscript n is 0 or 1; Provided that the following compounds are specifically excluded:

2. The compound of claim 1, wherein Z is a group of the formula:

3. The compound of claim 2, wherein L 3 A group of the formula: Where p is 1, 2 or 3; and R Z7 and R Z8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, or -OR Z5 .

4. The compound of claim 2, wherein L 3 A group of the formula: wherein w is 0 or 1 and p is 1, 2 or 3, or w is 1 and p is 0, 1, 2 or 3; and R Z7 and R Z8 Each instance of is independently hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, or -OR Z5 .

5. The compound of claim 2, wherein L 3 A group of the formula:

6. The compound of claim 2, wherein L 3 A group of the formula:

7. The compound of claim 2, wherein L 3 A group of the formula:

8. The compound of claim 1, wherein Z is of the formula 9. The compound of claim 8, wherein the group Is the following formula:

10. The compound of claim 1, wherein Z is of the formula 11. The compound of claim 10, wherein Y is -O- and L 3 is an alkylene group or a heteroalkylene group.

12. The compound of claim 11, wherein the group Is the following formula:

13. The compound of claim 1, wherein Z is of the formula 14. The compound of claim 13, wherein Y is -O- and L 3 is an alkylene group or a heteroalkylene group.

15. The compound of claim 14, wherein the group Is the following formula:

16. The compound of claim 1, wherein the group -X 1 R 3b In the β position, and R 3a In the α position.

17. The compound of claim 1, wherein -X 1 R 3b It is -OH.

18. The compound of claim 1, wherein R 3a For hydrogen.

19. The compound of claim 1, wherein R 3a is a substituted or unsubstituted alkyl group.

20. The compound of claim 1, wherein represents a double bond and R 6a is halogen or substituted or unsubstituted alkyl.

21. The compound of claim 1, wherein R 6b is halogen or substituted or unsubstituted alkyl.

22. The compound of claim 1, wherein R 2 For hydrogen.

23. The compound of claim 1, wherein R 2 For-OR B .

24. The compound of claim 1, wherein R 11b is hydrogen or -OR B , and R 11a For hydrogen.

25. The compound of claim 1, wherein R 11a and R 11b Together they form an oxo group.

26. The compound of claim 1, wherein represents a single bond, and the hydrogen at C5 is in the alpha position.

27. The compound of claim 1, wherein Represents a double bond.

28. The compound of claim 1, wherein R 19 It is -CH3.

29. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

30. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

31. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

32. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

33. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

34. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

35. The compound of claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of the preceding claims.

37. A method for preventing, treating, ameliorating or controlling a disease or condition, comprising administering to a subject in need of such prevention, treatment, amelioration or control a preventively or therapeutically effective amount of a compound or pharmaceutical composition according to any one of the preceding claims.

38. The method according to claim 37, wherein the disease or condition is schizophrenia, depression, bipolar disorder (I and II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (minor depression), social anxiety disorder, obsessive-compulsive disorder (OCD), all pain syndromes and disorders, sleep disorders, memory disorders and dementia including Alzheimer's disease, epilepsy and any seizure disorder, traumatic brain injury (TBI), stroke, addictive disorders including opiates and cocaine and alcohol, autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome, or tinnitus.

39. The method according to claim 38, wherein the disease or disorder is schizophrenia.

40. The method according to claim 38, wherein the disease or condition is traumatic brain injury (TBI).

41. The method according to claim 38, wherein the disease or condition is stroke.

42. An intermediate compound selected from the following compounds 2, 3, 4, INT A, A_001_1, A_001_2 and A_001_3:

43. A hanging wire test comprising the following steps: a) The hanging wire test uses a custom-made apparatus consisting of a metal wire (2 mm diameter) suspended horizontally (25 cm) above the padded surface; b) mice were secured by the base of the tail with their front paws placed in contact with the wire and then released; c) the animal is required to have both hind paws in contact with the line within 5 seconds to be scored as a pass; and d) Process the results counter-intuitively.

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