Lymphatic system targeting compounds

Abstract

This disclosure provides a lymphoid targeting compound of formula (I) and pharmaceutically acceptable salts thereof, a pharmaceutical composition thereof, and a method for treating various conditions related to NMDA receptor modulation. The use of a pharmaceutical composition containing the compound of formula (I) for the manufacture of a pharmaceutical for the treatment of a disease or condition related to NMDA receptor modulation is also described in this disclosure. A pharmaceutical composition containing the compound of formula (I) for use in the treatment of a disease or condition related to NMDA receptor modulation is further described in this disclosure.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 463,540, filed 2 May 2023, and U.S. Provisional Patent Application No. 63 / 631,365, filed 8 April 2024, the disclosures of each thereof being incorporated in their entirety by reference herein. [Background technology]

[0002] NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some situations and excitotoxicity in others. These receptors bind to the neurotransmitters glutamate and glycine after Ca2+12+ 2+ NMDA receptors are ligand-gated ion channels that add ions and are fundamental to excitatory neurotransmission and normal CNS function. NMDA receptors are heteromeric complexes consisting of NR1, NR2, and / or NR3 subunits, possessing distinct recognition sites for exogenous and endogenous ligands. These recognition sites include glycine binding sites, as well as glutamate agonists and regulators. Positive regulators may be useful as therapeutic agents with potential clinical applications as cognitive enhancers and in the treatment of mental disorders characterized by reduced or deficient glutamatergic transmission (see, e.g., Horak et al., J. Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative regulators may be useful as therapeutic agents with potential clinical applications in the treatment of mental disorders characterized by pathologically increased glutamatergic transmission (e.g., treatment-resistant depression).

[0003] The lymphatic system is a network of blood vessels, organs (e.g., bone marrow, thymus, lymph nodes, and spleen), and tissues distributed throughout the body that work together to return lymph fluid to the circulatory system. The lymphatic system has several important functions, including the transport of immune cells, the collection of excess fluid from the body's tissues and its return to the bloodstream, filtering of waste and abnormal cells, the absorption of dietary lipids, and tumor metastasis. Because of these characteristics of the lymphatic system, it has become a preferred approach for improving drug delivery to target organs. For example, drug delivery via the lymphatic system has several key advantages, including avoiding first-pass metabolism in the liver and targeting drugs to tissues via the lymphatic system (e.g., certain types of cancer and human immunodeficiency virus). Lipid-based therapeutics possess unique characteristics that make them promising candidates for enhanced lymphatic delivery. Therefore, there remains a need to develop therapeutic agents that promote the delivery of NMDA receptor modulators via the lymphatic system to treat CNS conditions. The compounds, compositions, and methods described herein are for this purpose. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Horak et al., J. Neuroscience, 2004, 24(46), 10318-10325 [Overview of the project]

[0005] Compounds of formula (I), pharmaceutical compositions containing them, and methods of use thereof are described in this disclosure. The use of pharmaceutical compositions containing compounds of formula (I) for the manufacture of pharmaceuticals for the treatment of diseases or conditions related to NMDA receptor modulation is also described in this disclosure. Pharmaceutical compositions containing compounds of formula (I) for use in the treatment of diseases or conditions related to NMDA receptor modulation. However, this disclosure will provide further details.

[0006] In one embodiment, the present disclosure relates to a compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof.

[0007] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

[0008] In another aspect, the disclosure provides a method for modulating NMDA receptors in a subject, the method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0009] In another aspect, the Disclosure provides a method for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject, the method comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0010] In another embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in modulating NMDA receptors in a subject.

[0011] In another embodiment, the present disclosure provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in modulating NMDA receptors in a subject.

[0012] In another embodiment, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of diseases, disorders, or conditions requiring allosteric NMDA receptor modulation.

[0013] In another embodiment, the present disclosure provides compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of diseases, disorders, or conditions requiring allosteric NMDA receptor modulation.

[0014] In another aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for allosterically modulating an NMDA receptor.

[0015] In another aspect, the disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical product for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation. [Modes for carrying out the invention]

[0016] General definition The term "Disclosure" refers to the entire application.

[0017] Unless otherwise defined in this disclosure, scientific and technical terms used in this application shall have the meanings generally understood by those skilled in the art to which this disclosure pertains. The nomenclature used in connection with the compounds, compositions, and methods described herein is well known and commonly used in the art.

[0018] Any embodiment described in this disclosure, including those described in different embodiments of this disclosure and different parts of this disclosure (including embodiments described only in the Examples), can be combined with one or more other embodiments of this disclosure, unless expressly excluded or inappropriate. The combination of embodiments is not limited to any particular combination claimed through multiple dependent claims. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same basic claim. If elements are listed, for example, presented in Markush group form, each subgroup of elements is also disclosed, and any element can be excluded from the group.

[0019] Throughout this disclosure, the terms “comprise,” or variations such as “comprises” or “comprising,” should be understood to mean that they include the described complete entity (or component) or group of complete entities (or components), but do not exclude any other complete entity (or component) or group of complete entities (or components).

[0020] Throughout this disclosure, where a composition is described as having, containing, or including (or a variation thereof) certain components, it is assumed that the composition may also consist essentially of the listed components or comprise them. Similarly, where a method or process is described as having, containing, or including certain process steps, the process may also consist essentially of the listed processing steps or comprise them. The composition may also be of the form. Furthermore, it will be understood that the order of steps or the order in which to perform a particular action is not important, as long as the composition and method described herein remain operational. Furthermore, two or more steps or actions can be performed simultaneously.

[0021] Where used in this disclosure, the term “including” means “including, but not limited to.” “Including” and “including, but not limited to” are used interchangeably. Thus, these terms should be understood to mean that they include the described completes (or components) or groups of completes (or components), but not exclude any other completes (or components) or groups of completes (or components).

[0022] Where used in this disclosure, “about” or “approximately” means within an acceptable margin of error for a particular value as determined by a person skilled in the art, which depends in part on how the value is measured or determined, i.e., the limits of the measuring system.

[0023] The terms “a,” “an,” and “the,” as well as similar demonstrative pronouns, in contexts describing elements (particularly in the context of the following claims), should be interpreted as encompassing both singular and plural forms unless otherwise indicated in this disclosure or unless explicitly contradicted by the context.

[0024] Where used in this disclosure, the term “or” should be understood to mean “and / or” unless the context explicitly indicates otherwise.

[0025] The enumeration of value ranges in this disclosure is intended merely as a concise way of referring individually to each distinct value, including the endpoint, within that range, unless otherwise suggested in this disclosure, and each distinct value is incorporated into this disclosure as if it were individually enumerated hereof. All methods described in this disclosure may be performed in any suitable order, unless otherwise indicated in this disclosure or unless it is clearly inconsistent with the context. Any and all embodiments or use of exemplary language (e.g., "etc.") provided in this disclosure is intended merely to better describe the embodiments and does not imply any limitation on the claims unless otherwise stated. Nothing in this disclosure should be construed as indicating any non-claim element as essential.

[0026] All publications, patents, and published patent applications referenced in this application are incorporated specifically by reference into this disclosure. In the event of any conflict, the disclosure containing the specific definitions thereof shall prevail. Furthermore, any particular embodiment of this disclosure contained in the prior art may be expressly excluded from one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly stated in this disclosure, as they are considered to be publicly known to those skilled in the art. Any particular embodiment of this disclosure may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0027] chemical definition Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Furthermore, not only general principles of organic chemistry but also specific functional parts and reactivity are discussed in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, and 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 This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0028] The compounds described herein may contain one or more chiral centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers, including a racemic mixture and a mixture rich in one or more stereoisomers. Isomers, such as stereoisomers, can be isolated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. For example, see 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 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further, The compounds described herein are included as individual isomers substantially free from other isomers, and alternatively as mixtures of various isomers.

[0029] Compounds having the same molecular formula but differing in the nature or arrangement of their atomic bonds, or in the spatial arrangement of their atoms, are called "isomers." Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposed mirror images of each other are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center, described by the Kahn and Prelog R-sequencing rules and S-sequencing rules, or by the rotation of the plane of polarized light on which the molecule rotates, and are designated as dextrorotatory or left-rotatory (i.e., as (+) 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."

[0030] As used in this disclosure, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., it is in an enantiomer-rich state). In other words, an "S" form of a compound that is substantially free of the "R" form is in an enantiomer-rich state of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight, or a mixture of enantiomers. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound. As used in this disclosure, the term “diastereomer purity” refers to the amount of the compound having the illustrated absolute stereochemistry, expressed as a percentage of the total amount of the illustrated compound and its diastereomers. The term “diastereomerically pure” indicates that the compound contains more than 75% by weight, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9%. Methods for determining diastereomer purity and enantiomer purity are well known in the art. The diastereomer purity can be determined by any analytical method capable of quantitatively distinguishing a compound from its diastereomers, such as high-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).

[0031] In the compositions provided by the present disclosure, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure (R)-position / center / carbon compound can contain, for example, about 90% excipient and about 10% enantiomerically pure (R) compound. In certain embodiments, the enantiomerically pure (R) compound in such a composition can contain, for example, at least about 95% by weight of the (R) compound and up to about 5% by weight of the (S) compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure (S) compound can contain, for example, about 90% excipient and about 10% enantiomerically pure (S) compound. In certain embodiments, the enantiomerically pure (S) compound in such a composition can contain, for example, at least about 95% by weight of the (S) compound and up to about 5% by weight of the (R) compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated without substantially or entirely containing an excipient or carrier and can be formulated without substantially or entirely containing an excipient or carrier.

[0032] The compounds described in the present disclosure may also contain one or more isotope substitutions. For example, H can be 1 H, 2 H (D or deuterium), and 3 H (T or tritium) in any isotopic form, C can be 12 C, 13 C, and 14 C in any isotopic form, O can be 16 O and 18 O in any isotopic form, and the like.

[0033] When ranges of values are listed, each value and subrange within the range is intended to be included. For example, "C 1-6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6, C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to include alkyl groups.

[0034] The following terms are intended to have the meanings set forth below and are useful in understanding the description and intended scope of this disclosure. Where described in this disclosure, any part defined herein may be substituted with various substituents, and it should be understood that each definition is intended to include such substituted parts within its scope, as set forth below. Unless otherwise stated, the term “substitution” should be defined as set forth below. Furthermore, naturally, where used in this disclosure, the terms “group” and “radical” may be considered interchangeable.

[0035] "Aliphatic" means an alkyl group, alkenyl group, alkynyl group, or carbocyryl group as defined in this disclosure. "Divalent aliphatic" means a divalent radical of an alkyl (i.e., alkylene), alkenyl (i.e., alkenylene), alkynyl (i.e., alkynylene), or carbocyryl group.

[0036] "Alkyl" refers to a group of 1 to 50 carbon atoms ("C"). 1-50 This refers to a linear or branched saturated hydrocarbon radical containing an alkyl group. In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has one to two carbon atoms ("C1 alkyl"). 1-2 The alkyl group has 1 to 3 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1-3 The alkyl group has 1 to 4 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 The alkyl group has 1 to 5 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5The alkyl group has 1 to 6 carbon atoms ("C"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6 It has an alkyl group. 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Unless otherwise specified, each example of an alkyl group can be independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 4 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0037] As used in this disclosure, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," "heteroalkylynylene," and "heteroalkylynylene" are respectively alkyl, alkenyl, alkynyl, heteroalkyl, and heteroalkyl. This refers to the divalent radicals of roalkenyl and heteroalkynyl groups. When a range or number of carbon atoms is provided for a particular "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," or "heteroalkynylene" group, the range or number is understood to refer to a range or number of carbon atoms in a linear divalent carbon chain. The "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," "heteroalkynylene," and "heteroalkynylene" groups may be substituted with one or more substituents described herein, or they may be unsubstituted.

[0038] "Alkylene" or "alkylene group" refers to an alkyl group that may be substituted or unsubstituted, in which two hydrogen atoms are removed to provide a divalent radical. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). For example, exemplary substituted alkylene groups substituted with one or more halo, -NO2, -OH, C1-C6 alkoxy, or C1-C6 alkyl (e.g., methyl) groups include 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-, Alkilen abbreviations include, but are not limited to, (CH(CH3))-, -(CH(CH2CH3))-, -(CH(CH2CH2CH3))-, -(CH(CH2CH2CH2CH3))-, -(CH2CH(CH2CH2CH2CH3))-, -(CH2CH2CH(CH2CH2CH2CH3))-, -(CH(CH3)CH2)-, -(CH(CH3)CH2CH2)-, -(CH(CH3)CH2CH2CH2)-, -(CH2CH(CH3)CH2)-, This includes, but is not limited to, -(CH2CH(CH3)CH2CH2)- and (CH2CH2CH(CH3)CH2CH2)-.

[0039] "Alkenyl" is defined as having 2 to 50 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-50"Alkenyl" refers to a linear or branched hydrocarbon radical containing an alkenyl group. In certain embodiments, the alkenyl does not contain any triple bond. In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). In some embodiments, the alkenyl group has two to three carbon atoms ("C2 alkenyl"). 2-3 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2-10 Alkenyl). One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 Alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Examples include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified, each example of an alkenyl group can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl").

[0040] "Alkenylene" refers to an alkenyl group that may be substituted or unsubstituted, where two hydrogen atoms are removed to provide a divalent radical. Examples of unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene. (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). For example, exemplary substituted alkenylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-) and substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, Examples include -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-, etc.

[0041] "Alkynnyl" is a molecule consisting of 2 to 50 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-50 Refers to a linear or branched hydrocarbon radical containing an alkynyl group. In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). In some embodiments, the alkynyl group has two to three carbon atoms ("C2 alkynyl"). 2-3 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2-7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8("Alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 In some embodiments, the alkynyl group consists of 2 to 10 carbon atoms ("C"). 2-10 It has an "alkynyl" bond. In certain embodiments, the alkynyl bond does not contain any double bonds. One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 An example of an alkenyl group is the aforementioned C 2-4 Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyls include heptynyl (C7) and octinyl (C8). Unless otherwise specified, each example of an alkynyl group can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 2-10 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkinyl.

[0042] "Alkynylene" refers to a linear alkynyl group that provides a divalent radical by removing two hydrogen atoms, and which may be substituted or unsubstituted. Examples of divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene and substituted or unsubstituted propynylene.

[0043] As used in this disclosure, the term “heteroalkyl” means an alkyl group as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain, and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between bonding sites. In certain embodiments, the heteroalkyl group comprises 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero-C"). 1-10 This refers to a saturated group containing an alkyl group. In some embodiments, a heteroalkyl group contains 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (hetero C 1-9 A saturated group containing an alkyl group. In some embodiments, a heteroalkyl group contains 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (hetero C 1-8 A saturated group containing an alkyl group. In some embodiments, a heteroalkyl group contains 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (hetero C 1-7 A saturated group containing an alkyl group. In some embodiments, a heteroalkyl group contains 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (hetero C 1-6 A group containing an alkyl group. In some embodiments, a heteroalkyl group is a saturated group containing 1 to 5 carbon atoms and 1 or 2 heteroatoms (heteroC 1-5 A heteroalkyl group is an alkyl group. In some embodiments, a heteroalkyl group consists of 1 to 4 carbon atoms and 1 or 2 heteroatoms (hetero C 1-4 A saturated group containing an alkyl group. In some embodiments, a heteroalkyl group has 1 to 3 carbon atoms and 1 heteroatom (hetero C 1-3 A saturated group containing an alkyl group. In some embodiments, a heteroalkyl group contains one to two carbon atoms and one heteroatom (hetero C 1-2A saturated group containing an alkyl group. In some embodiments, a heteroalkyl group is a saturated group containing one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group contains two to six carbon atoms and one or two heteroatoms ("heteroC1 alkyl"). 2-6 A saturated group containing an alkyl group. Unless otherwise specified, each example of a heteroalkyl group is independently either unsubstituted ("unsubstituted heteroalkyl group") or substituted with one or more substituents ("substituted heteroalkyl group"). In certain embodiments, the heteroalkyl group is an unsubstituted hetero-C group. 1-10 It is alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is alkyl.

[0044] Where used in this disclosure, the term “heteroalkenyl” means an alkenyl group as defined in this disclosure, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), one or more heteroatoms inserted between adjacent carbon atoms in the parent carbon chain, and / or one or more heteroatoms inserted between carbon atoms and the parent molecule, i.e., between bond points. In certain embodiments, the heteroalkenyl group comprises 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2-10 The term "heteroalkenyl" refers to a group containing an "alkenyl" atom. In some embodiments, the heteroalkenyl group consists of 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2-9 The heteroalkenyl group has 2 to 8 carbon atoms, at least 1 double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). In some embodiments, the heteroalkenyl group has 2 to 8 carbon atoms, at least 1 double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2-8 The heteroalkenyl group has 2 to 7 carbon atoms, at least 1 double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). In some embodiments, the heteroalkenyl group has 2 to 7 carbon atoms, at least 1 double bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2-7The heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("hetero C"). In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("hetero C"). 2-6 The heteroalkenyl group has 2 to 5 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms ("hetero C"). In some embodiments, the heteroalkenyl group has 2 to 5 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms ("hetero C"). 2-5 The heteroalkenyl group has 2 to 4 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms ("hetero C"). In some embodiments, the heteroalkenyl group has 2 to 4 carbon atoms, at least 1 double bond, and 1 or 2 heteroatoms ("hetero C"). 2-4 It has an "alkenyl" (in some embodiments). In some embodiments, it has a heteroalkenyl The group consists of 2-3 carbon atoms, at least one double bond, and one heteroatom ("heteroC"). 2-3 The heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("hetero C"). In some embodiments, the heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("hetero C"). 2-6 The heteroalkenyl group has an "alkenyl" ( ). Unless otherwise specified, each example of a heteroalkenyl group is independently either unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, the heteroalkenyl group is an unsubstituted hetero C 2-10 It is an alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is Alkenil.

[0045] Where used in this disclosure, the term “heteroalkynyl” means an alkynyl group as defined in this disclosure, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), one or more heteroatoms inserted between adjacent carbon atoms in the parent carbon chain, and / or one or more heteroatoms inserted between carbon atoms and the parent molecule, i.e., between bond points. In certain embodiments, the heteroalkynyl group comprises 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("hetero C"). 2-10refers to a group containing an alkynyl group. In some embodiments, the heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (hetero C 2-9 alkynyl). In some embodiments, the heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (hetero C 2-8 alkynyl). In some embodiments, the heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (hetero C 2-7 alkynyl). In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (hetero C 2-6 alkynyl). In some embodiments, the heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (hetero C 2-5 alkynyl). In some embodiments, the heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (hetero C 2-4 alkynyl). In some embodiments, the heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (hetero C 2-3 alkynyl). In some embodiments, the heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (hetero C 2-6 alkynyl). Unless otherwise specified, each example of the heteroalkynyl group is independently unsubstituted (unsubstituted heteroalkynyl) or substituted with one or more substituents (substituted heteroalkynyl). In certain embodiments, the heteroalkynyl group is unsubstituted hetero C 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is substituted hetero C 2-10 alkynyl.

[0046] "Aryl" refers to an aromatic ring system (C 6-14Refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system containing 6 to 14 ring carbon atoms and zero heteroatoms, provided in the "aryl") (e.g., having 6, 10, or 14 π electrons shared in a cyclic array). In some embodiments, the aryl group has 6 ring carbon atoms (C6 aryl, e.g., phenyl). Aryl also includes a ring system, and the aryl ring is fused to one or more carbocyclic or heterocyclic groups as defined in the present disclosure, and the radical or point of attachment is on the aryl ring. In such examples, the number of carbon atoms continues to indicate the number of carbon atoms within the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each example of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C aryl. In certain embodiments, the aryl group is substituted C 6-14 aryl. 6-14 is aryl.

[0047] In certain embodiments, the aryl group is substituted with one or more of the groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino. 一つ is substituted with.

[0048] Examples of representative substituted aryls include the following. [ka] In the formula, R 56 and R 57 One of them may be hydrogen, R 56 and R 57 At least one of these is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR. 58 COR 59 , NR 58 SOR 59 , NR 58 SO2R 59 COOalkyl, COOaryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59 Selected from S-alkyl, SOalkyl, SO2alkyl, S-aryl, SOaryl, SO2aryl, or R 56 and R 57 These may bond to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, and optionally contain one or more heteroatoms selected from the N, O, or S groups, or R 60 and R 61 These are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl substitution C6~C 10 It is an aryl, a 5- to 10-membered heteroaryl, or a substituted 5- to 10-membered heteroaryl.

[0049] A "fusion aryl" refers to an aryl ring that has two of its ring carbons in common with a second aryl ring or heteroaryl ring, or with a carbocykyl ring or heterocycline ring.

[0050] "Aralkyl" is a subset of alkyl and aryl groups as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group.

[0051] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in the cyclic arrangement) having a ring carbon atom and 1-4 ring heteroatoms located on the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, as long as the valence allows. A heteroaryl bicyclic ring system may be a configuration in which one or both rings contain one or more heteroatoms. A heteroaryl includes a ring system, where the heteroaryl ring is fused with one or more carbocykryl or heterocyclyl groups as defined above, and the bond site is on the heteroaryl ring, even in such cases the number of ring members The number of ring members indicates the number of ring members in the heteroaryl ring system. A heteroaryl also includes a ring system, where the heteroaryl ring is fused with one or more aryl groups as defined above, and the bond site is either an aryl ring or a heteroaryl ring, in which case the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site may be on either ring, i.e., a ring supporting a heteroatom (e.g., 2-indolyl) or a ring not containing a heteroatom (e.g., 5-indolyl).

[0052] In some embodiments, the heteroaryl group is a 5-10 member aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 member aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 member aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 member heteroaryl"). In some embodiments, the 5-6 member heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 member heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each example of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0053] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively.

[0054] Typical examples of heteroaryl compounds include the following: [ka] In the formula, each Z is a carbonyl, N, or NR. 65 Selected from , O, and S, R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryl compounds.

[0055] "Heteroaralkyl" is a subset of alkyl and heteroaryl groups as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted heteroaryl group.

[0056] "Carbocyclyl," "carbocyclic," or "carbocyclic" refers to a ring of 3-10 carbon atoms ("C").3-10 The term "carbocyrill" refers to a radical of a non-aromatic cyclic hydrocarbon group containing zero heteroatoms within a non-aromatic ring system. In some embodiments, the carbocyrill group has 3 to 8 ring carbon atoms ("C"). 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Exemplary C 3-6 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-8 The carbocyclyl group is not limited to the aforementioned C 3-6 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). Exemplary C 3-10 The carbocyclyl group is not limited to the aforementioned C 3-8 Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10Examples include the above. As illustrated by the examples above, in certain embodiments, the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or contain condensed, crosslinked, or spirocyclic systems such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which the carbocyclyl ring is fused with one or more aryl or heteroaryl groups, as defined above, and the bonding site is on the carbocyclyl ring, and in such examples as well, the number of carbons indicates the number of carbons in the carbocyclic system. Unless otherwise specified, each example of a carbocyclyl group may be independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3-10 It is carbocyclyl.

[0057] In some embodiments, "carbocykrill," "carbocyclic formula," or "carbocyclic" refers to a ring of 3 to 10 carbon atoms ("C"). 3-10 This refers to a monocyclic saturated carbocyclyl group containing a cycloalkyl group. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3-8 It has a cycloalkyl group. In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3-6 It has a cycloalkyl group. In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C"). 5-6 It has a cycloalkyl group. In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5-10 It has a cycloalkyl (C) 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include, as mentioned earlier, C 5-6 Examples include cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8Examples of cycloalkyl groups include, as mentioned earlier, C 3-6 Examples include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each example of a cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3-10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3-10 It is a cycloalkyl group.

[0058] "Heterocyclyl," "heterocyclic," or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system containing a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the bond sites can be carbon or nitrogen atoms, as long as the valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or bicyclic ("bicyclic heterocyclyl") systems, which may be condensed, bridged, or spirocyclic systems, and may be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. Furthermore, "heterocyclyl" includes a ring system, where the heterocyclyl ring is fused with one or more carbocykyl groups as described above, and the bond site is on either the carbocykyl ring or the heterocyclyl ring, or includes a ring system, where the heterocyclyl ring is fused with one or more aryl or heteroaryl groups as described above, and the bond site is on the heterocyclyl ring, in which case the number of ring members indicates the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each example of heterocyclyl can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0059] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system containing a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system containing a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system containing a ring carbon atom and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl is It has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0060] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxylanil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianyl, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl, and thiokanyl. Examples of five-membered heterocyclyl groups condensed to a C6 aryl ring (also referred to in this disclosure as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinol.Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to in this disclosure as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0061] 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 are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the aforementioned hydrocarbyl groups, such as alkyl groups, e.g., heteroalkyl groups; cycloalkyl groups, e.g., heterocyclyl groups; aryl groups, e.g., heteroaryl groups; cycloalkenyl groups, e.g., cycloheteralkenyl groups, which contain 1 to 5 heteroatoms, and especially 1 to 3 heteroatoms.

[0062] "Acyl" is a radical-C(O)R 20 It refers to, and in the formula, R 20 This includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl as defined in this disclosure.

[0063] "Alkanoil" is R 20 The group other than hydrogen is the acyl group. Representative acyl groups include 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 member heteroaryl), -C(O)-(CH2) t (C3~C 10 Cycloalkyl, and -C(O)-(CH2) t (4-10 member heterocyclyl) is one example, but it is not limited to this, formula In this case, t is an integer from 0 to 4. In a particular embodiment, R 20 This refers to C1-C8 alkyl groups substituted with a halo or hydroxyl group, or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The compounds are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0064] "Alkoxy" is R 29 However, it is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, -OR 29 This refers to the group. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy groups, i.e., have 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0065] In a particular embodiment, R 29 is amino, substituted amino, C6~C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10A group having one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent, selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Examples of "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 member heteroaryl), -O-(CH2) t (C3~C 10 Cycloalkyl, and -O-(CH2) t The formula includes a (4-10 membered heterocyclyl), where t is an integer from 0 to 4 and any aryl group, and the heteroaryl, cycloalkyl, or heterocyclyl group may be present and itself may be substituted with an unsubstituted C1-C4 alkyl group, such as halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary substituted alkoxy groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0066] "Amino" refers to the radical -NH2.

[0067] "Substituting amino" is defined by the formula -N(R 38 ) refers to the amino group of 2, and in the formula, R 38 R is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 38 At least one of them is not hydrogen. In a particular embodiment, each R 38These are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C6-C 10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxyl; C3-C8 alkenyl substituted with halo or hydroxyl; C3-C8 alkynyl substituted with halo or hydroxyl, or -(CH2) t (C6~C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl, or -(CH2) t Selected from (4-10 member heterocyclyl), where t is an integer from 0 to 8, each being an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, or unsubstituted C1-C4 hydroxyl Droxyalkyl, or substituted with unsubstituted C1-C4 haloalkoxy or hydroxyl groups, or both R groups 38 The groups bond together to form an alkylene group.

[0068] Examples of "substituted amino groups" include, but are not limited to, -NR 39 -C1~C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3~C 10 Cycloalkyl, and -NR 39 -(CH2) t Examples include (4-10 member heterocyclyls), where t is an integer from 0 to 4, for example, 1 or 2, each R 39'' independently represents H or C1-C8 alkyl; and any alkyl group present may itself be substituted with a halo, substituted or unsubstituted amino, or hydroxyl; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. To avoid any doubt, the term "substituted amino" encompasses the group of alkylaminos, substituted alkylaminos, alkylarylaminos, substituted alkylarylaminos, arylaminos, substituted arylaminos, dialkylaminos, and substituted dialkylaminos as defined below. A substituted amino includes both monosubstituted and disubstituted amino groups.

[0069] "Carboxylate" refers to the radical -C(O)OH.

[0070] "Cyano" refers to the radical -CN.

[0071] "Halo" or "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I). In certain embodiments, the halo group is either fluoro or chloro.

[0072] "Hydroxy" refers to the radical -OH.

[0073] "Nitro" refers to the radical NO2.

[0074] "Cycloalkylalkyl" refers to an alkyl radical in which an alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0075] "Heterocyclylalkyl" refers to an alkyl radical in which an alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, and morpholinylethyl.

[0076] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, and includes, but is not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine such as N-methylpiperazine. A specific example is azetidine. Examples include thidine, piperidone, and piperazone.

[0077] "Thioketo" refers to the group = S.

[0078] "Wavy bond" or " [ka] " refers to the bonding point of the base.

[0079] The alkyl, alkenyl, alkynyl, carbocyrill, heterocyclyl, aryl, and heteroaryl groups as defined in this disclosure are optionally substituted (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyrill, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or unsubstituted heteroaryl groups). In general, the term “substituted” means that at least one hydrogen present on the group (e.g., a carbon or nitrogen atom) is substituted with an acceptable substituent, e.g., a substituent that results in a stable compound upon substitution, e.g., a compound that does not spontaneously undergo transformation by recombination, cyclization, removal, or other reactions, whether “optionally selected.” Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions of the group, and if multiple positions in any given structure are substituted, the substituents are either identical or different at each position. The term “substituted” includes substitution with all acceptable substituents of an organic compound, and it is assumed that any of the substituents described in this disclosure results in the formation of a stable compound. This disclosure assumes any and all such combinations to arrive at a stable compound. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0080] Examples of carbon atom substituents include 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 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Examples include aryls and 5-14 member heteroaryls, but are not limited to these, and each alkyl and alkeni R, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl can be independently 0, 1, 2, 3, 4, or 5 R dd Is it substituted by the base? Alternatively, two geminal hydrogen atoms on a carbon atom are =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb , or =NOR cc Replaced under the basis of; R aa Each example is independent of C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C6-14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by the base; R bb Each example is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R bb The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring (each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups). dd It is replaced by the base; R cc Each example independently involves hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring (each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups). dd It is replaced by the base; R dd Each instance of is independent of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+X-, -N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(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)(OR ee )2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 membered heteroaryls (each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with or two R groups dd Substituents can bond to form =O or =S; R ee Each example is independent of C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, C 6-10Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls (each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg (Substituted by the base), R ff Each example is independent of hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring (each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups). gg Replaced by the base); and R gg Each of these examples is independent of halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OC. 1-6 Alkyl, -ON(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)2,-N(C 1-6 Alkyl)3+X-,-NH(C 1-6 Alkyl)2+X-,-NH2(C 1-6 Alkyl)+X-, -NH3+X-, -N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl), -CO2H, -CO2(C 1-6 Alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl), -C(=O)NH2, -C(=O)N(C 1-6Alkyl)2,-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 Alkyl)2,-NHC(=O)NH(C 1-6 Alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl),-OC(=NH)(C 1-6 Alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2,-C(=NH)NH(C 1-6 Alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2,-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3,-OSi(C 1-6 Alkyl)3,-C(=S)N(C 1-6 Alkyl)2, C(=S)NH(C 1-6 Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 Alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Carbocyclyl, C 6-10 Selected from aryl, 3-10 member heterocyclyl, 5-10 member heteroaryl, or two geminal R gg Substituents can bond to form =O or =S (where X - (This is the counterion).

[0081] A "counterion" or "anion counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electron neutrality. Examples of counterions include halide ions (e.g., F - Cl - , Br - , I - ), NO 3- ClO4 - , OH - H2PO4 - HSO4 - SO4 -2 Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphoresulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethaneate, propaneate, benzoate, Examples include glycerolates, lactates, tartrates, glycolates, etc.

[0082] Nitrogen atoms may be substituted or unsubstituted, as long as their valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include 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(=NRbb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, 3-14 member heterocyclyl, C 6-14 Aryls, and 5-14 member heteroaryls, or two Rs bonded to a nitrogen atom cc The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc , and R dd This is as defined above.

[0083] Other definitions "Pharmacologically acceptable" means approved or appropriable by a federal or state regulatory authority or corresponding agency listed in a country other than the United States, or in the United States Pharmacopeia or any pharmacopoeia generally accepted for use in animals, more specifically in humans.

[0084] "Pharmacologically acceptable salt" means a salt of a compound disclosed herein that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are nontoxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, these salts include (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and similar substances, or 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, 4-toluenesulfonic acid, camphorsulfonic acid, 4- Examples include acid addition salts formed with organic acids such as methylbicyclo[2.2.2]-octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthic acid, salicylic acid, stearic acid, muconic acid, and similar substances, or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., alkali metal ions, alkaline earth ions, or aluminum ions), or when combined with an organic base such as ethanolamine (e.g., diethanolamine, triethanolamine, N-methylglucamine). Salts further include, for illustrative purposes only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. The term "pharmaceutically acceptable cation" refers to an acceptable cation counterion of an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium cations.For example, see Berge, et al., J. Pharm. Sci. (1977) 66(1): 1~79.

[0085] "Pharmacologically acceptable carrier" refers to compositions, carriers, diluents, and reagents that are pharmaceutically acceptable materials that can be administered to or to a subject. A pharmaceutically acceptable carrier may be involved in transporting or delivering a target active substance from one organ or part of the body to another organ or part of the body. Carriers may be in the form of solids, semi-solids, or liquid diluents, creams, or capsules. The active ingredient may be mixed with excipients that are pharmaceutically acceptable, compatible with the active ingredient, and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol, or similar substances, and combinations thereof.

[0086] "Isotope variant" means a compound disclosed herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than those commonly found in nature. Examples of isotopes that may be incorporated into the compounds of this application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 18 F, and 37 Examples include, but are not limited to, Cl. Compounds disclosed herein that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this disclosure. Specific isotopic variants of the compounds of this application, for example, radioactive isotopes (e.g., 3 H and 14Isotope variants incorporating C) may be useful in drug and / or substrate distribution assays. Furthermore, heavier isotopes (e.g., 2 Substitution at H) can result in certain therapeutic benefits arising from greater metabolic stability, such as an increased in vivo half-life or reduced dosing requirements, and may therefore be preferable in some situations. The isotopic variants of the compounds disclosed herein and their pharmaceutically acceptable salts can generally be prepared by substituting readily available isotopic labeling reagents for non-isotopic labeling reagents by performing the procedures disclosed in the schemes and / or examples.

[0087] The “subjects” to which the administration is intended include, but are not limited to, human subjects (i.e., males or females 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 including primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably in this disclosure.

[0088] Diseases, disorders, and conditions are used interchangeably in this disclosure.

[0089] Where used in this disclosure, the terms “to treat,” “to treat,” or “treatment” include reversing, reducing, or cessating the symptoms, clinical signs, and underlying pathology of a condition in which the condition is improved or stabilized. As used in this disclosure and as similarly understood in the art, “treatment” is an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, reduction, improvement, reduction in severity, or delay of one or more symptoms or progression of a condition, whether detectable or undetectable; reduction in the degree of disease; stabilization of the disease state (i.e., no worsening); delay or slowing of disease progression; improvement or mitigation of the disease state; and remission (whether partial or total). “Treatment” may also mean an extension of survival compared to expected survival without treatment.

[0090] As used in this disclosure, and unless otherwise specified, the terms “preventive,” “preventive,” and variations thereof are intended to describe actions that occur before the subject begins to suffer from a specified disease, disorder, or condition.

[0091] Generally, the “effective dose” of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective dose of a compound in this disclosure may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and factors such as the age, weight, health, and condition of the subject. The effective dose encompasses both therapeutic and prophylactic treatments.

[0092] The terms “pharmaceutical effective dose,” “therapeutic effective dose,” and “therapeutic effective dose” are used interchangeably in this disclosure and refer to an amount sufficient to treat a patient’s disease, for example, to bring about a beneficial and / or desirable change in the health of a patient suffering from the disease, to treat, cure, inhibit or improve a physiological response or condition, to delay or minimize one or more symptoms associated with the disease, disorder, or condition, etc. The complete therapeutic effect is not necessarily produced by a single dose, but may only occur after a series of doses have been administered. Thus, a therapeutic effective dose may be administered in one or more doses. The exact effective dose required for a subject depends, for example, the size of the subject, their health and age, the nature and severity of the disease, the therapeutic agent or combination of therapeutic agents selected for administration, and the mode of administration. Those skilled in the art can readily determine the effective dose for a given situation by routine experimentation. The terms “pharmaceutical effective dose,” “therapeutic effective dose,” or “therapeutic effective dose” also refer to the amount required to improve a patient’s clinical symptoms. The therapeutic effective dose of a compound also refers to a certain amount of a therapeutic agent, either alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term therapeutically effective dose can encompass an amount that improves the overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0093] As used in this disclosure, and unless otherwise specified, “preventive effective dose” of a compound means an amount sufficient to prevent or prevent the recurrence of one or more symptoms associated with a disease, disorder, or condition, or a disease, disorder, or condition. “Preventive effective dose” of a compound means a certain amount of the therapeutic agent, either alone or in combination with other agents, that provides a preventive benefit in the prevention of a disease, disorder, or condition. The term “preventive effective dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0094] As used in this disclosure, and unless otherwise specified, pharmacokinetics may be defined as the study of the absorption, distribution, metabolism, and excretion of a drug into the body. "Pharmacokinetics" may be defined as the characteristic interactions between an active substance and the body in terms of its absorption, distribution, metabolism, and excretion, or the branch of pharmacology relating to how an active substance is taken into the body, moves around, and is eliminated from the body.

[0095] The “administration” of a substance, compound, or active agent to a target, or the “administration,” can be carried out using one of various methods known to those skilled in the art. For example, a compound or active agent can be administered intravenously, intra-arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, subocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., via the skin canal). The compound or active agent can also be appropriately introduced by a rechargeable or biodegradable polymer device or other device, e.g., a patch and pump, or a formulation, that provides sustained release, sustained release, or controlled release of the compound or active agent. Administration can also be carried out, for example, once, multiple times, and / or over one or more long periods. In some embodiments, administration includes direct administration, including self-administration, and the active agent This includes both direct and indirect administration, including the act of prescribing the substance. For example, as used in this disclosure, a physician who instructs a patient to self-administer an active substance or to administer another active substance, and / or provides a patient with a prescription for an active substance, administers the active substance to the patient. If this method is part of a therapeutic regimen that includes multiple active substances or therapeutic modalities, this disclosure assumes that the active substances may be administered at the same or different times and via the same or different routes of administration. The appropriate method of administering a substance, compound, or active substance to a subject also depends, for example, on the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject has cognitive impairment at the time of administration, the degree of impairment, and the chemical and biological properties of the compound or active substance (e.g., solubility, digestibility, bioavailability, stability, and toxicity).

[0096] As used in this disclosure, the term “lipid” refers to natural and unnatural hydrophobic and / or lipophilic fats, oils, polymers, hydrocarbons, and other such materials. In some embodiments, preferred lipids, when incorporated into a compound, are processed or metabolized in the same way as triglycerides in the gastrointestinal tract, or mimic such processing or metabolism. The term “glyceride” refers to glycerol esters (1,2,3-propanetriols) having acyl radicals of fatty acids or other lipids, also known as acylglycerols. A “monoglyceride” is a glycerol molecule in which only one position of the molecule is esterified with a fatty acid. A “diglyceride” is a glycerol molecule in which two positions of the molecule are esterified with fatty acids. A “simple glyceride” is one in which all esterified positions contain the same fatty acid. A “mixed glyceride” is one in which different fatty acids are present at the esterified positions. The carbon atoms in the glycerol skeleton are designated as sn-1, sn-2, and sn-3, with sn-2 being in the center and sn-1 and sn-3 being at the ends of the glycerol.

[0097] The term "cleavable portion" refers to a chemical portion that can be cleaved via hydrolysis, reduction, or enzymatic reactions. Cleavable portions include, but are not limited to, acid-unstable portions, hydrolyzable portions, enzymatically cleavable portions, reduction-unstable portions, and self-destructive portions.

[0098] As used in this disclosure, the term “self-destructing moiety” means a divalent chemical moiety comprising a covalent bond, a cleavable bond, and a stable covalent bond with a therapeutic agent as one of its divalent bonds, the bond with the therapeutic agent becoming unstable upon cleavage of the cleavable bond. A self-destructing group may be any such group known to those skilled in the art. Examples of self-destructing moieties include, but are not limited to, disulfide groups, hydrazones, acetal self-destructing moieties, carboxyacetal self-destructing moieties, carboxy(methylacetal) self-destructing moieties, para-hydroxybenzylcarbonyl self-destructing moieties, inverted ester self-destructing moieties, and trimethylloc or 2-hydroxyphenylcarbamate (2-HPC) self-destructing moieties. Other suitable self-destructing parts are known in the art, as described, for example, in C. Blencowe et al., Polym. Chem. 2011, 2, 773-790 and Kratz et al., ChemMedChem. 2008, 3(1), 20-53, Huvelle et al., Org. Biomol. Chem. 2017, 15(16), 3435-3443, and Alouane et al., Angewandte Chemie International Edition 2015, 54(26), 7492-7509, and Levine et al., Chem. Sci. 2012 3(8), 2412-2420, each of which is incorporated in whole by reference in this disclosure.

[0099] The term "acid instability" refers to a state of being sensitive to acid and its structure when exposed to acidic conditions. This refers to molecules or compounds whose structure or properties can be cleaved or significantly altered.

[0100] Generally as described herein, this disclosure provides compounds useful for the prevention and / or treatment of a wide range of disorders, including but not limited to NMDA-mediated disorders. These compounds are expected to exhibit, in particular, improved in vivo efficacy, pharmacokinetic (PK) properties, oral bioavailability, formulation properties, stability, and / or safety.

[0101] compound In one embodiment, the present disclosure relates to a compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, W is [ka] or -C(O)N(R 3 )2, and Q is -C 1-8 Alkilen- is; R 1 and R 2 Each of these can independently be hydrogen, an acid-unstable group, a lipid, or -C(O)R 3 and; Each R 3 C is independently and can be optionally substituted. 1-40 It is aliphatic; X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, -NR(C 1-6 aliphatic)-S-, -NR(C 1-6 Aliphatic)-NR-, or -(C 1-6 (Aliphatic) - and in the formula, C 1-6 The 0-2 methylene units of the aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, C 1-6 Each aliphatic example is independently and optionally substituted with 1 to 3 deuterium atoms or halogens; Each R is independently either hydrogen or C 1-6 Aliphatic, 3-8 membered carbon ring, C 6-10An optionally substituted group selected from the group consisting of a 4-8 member heterocycle containing 1-2 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and a 5-10 member heteroaryl group containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S; Y either does not exist, or is -C(O)-, -C(NR)-, or -C(S)-; Z is a bivalent C that does not exist or can be optionally substituted. 1-30 It is aliphatic, and the 0-8 methylene units of Z are independent of -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -OS(O)2-, -S(O)2O-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or substituted by an amino acid, in which one methylene unit of Z is optionally substituted with -M-; or Z is selected from the following group: C(R 4a )(R 4b )C(O)-M-, C(R 4a )(R 4b )-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH2) n C(O)-M-, -C(R) 4a )(R 4b )C(R 5a )(R 5b )(CH2) n -M-, -(CH2) m C(R 4a )(R 4b )(CH2) n C(R 5a )(R 5b )(CH2) m C(O)-M-, and -(CH2) m C(R 4a )(R 4b )(CH2) n C(R 5a )(R 5b )(CH2) m-M-; In the formula, both sides of Z may be bonded to the active substance; Each-R 8 - is independent of C 3-6 carbocycle, C 6-10 An optionally substituted divalent group selected from the group consisting of 3-6 member heterocycles containing 1-4 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and 5-10 member heteroaryls containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S; Each R 4a , R 4b , R 5b , and R 5b These are independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, -R 9 , and -R 10 Selected from the group consisting of; or R 4a and R 4b or R 5a and R 5b Together with the carbon atoms to which they are bonded, they contain one or two heteroatoms independently selected from the group consisting of N, O, and S. 3-6 Forming a carbon ring or a 3- to 6-membered heterocycle; Each R 9 This is a 3- to 8-membered carbon ring containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S, C 6-10 Selected from the group consisting of aryls, 4- to 8-membered heterocycles, and 5- to 10-membered heteroaryls containing 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; Each R 10 These can be used independently for 1 to 6 -CN, -OR, -NR2, -SR, -R 9 , selected from the group consisting of C1-6 aliphatic elements optionally substituted with deuterium or halogens; -M- is a detachable part. Each n is independent and ranges from 0 to 18. Each m is independent and ranges from 0 to 6. p is either 1 or 2. The active substance is, [ka] [ka] A selection is made from the group consisting of the active substance and its deuterated variant, and the bond site of the active substance to Z is such that one or more hydrogen atoms on the active substance are substituted.

[0102] In some embodiments, the present disclosure relates to a compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof, in the formula, W is [ka] or -C(O)N(R 3 )2, R 1 and R 2 Each of these can independently be hydrogen, an acid-unstable group, a lipid, or -C(O)R 3 and; Each R 3 C is independently and can be optionally substituted. 1-40 It is aliphatic; X is -O-, -NR-, -S-, -O(C 1-6 aliphatic)-O-, -O(C 1-6 aliphatic)-S-, -O(C 1-6 aliphatic)-NR-, -S(C1-6 aliphatic)-O-, -S(C 1-6 aliphatic)-S-, -S(C 1-6 aliphatic)-NR-, -NR(C 1-6 aliphatic)-O-, -NR(C 1-6 aliphatic)-S-, -NR(C 1-6 Aliphatic)-NR-, or -(C 1-6 (Aliphatic) - and in the formula, C 1-6 The 0-2 methylene units of the aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, C 1-6 Each aliphatic example is independently and optionally substituted with 1 to 3 deuterium atoms or halogens; Each R is independently either hydrogen or C 1-6 Aliphatic, 3-8 membered carbon ring, C 6-10 An optionally substituted group selected from the group consisting of a 4-8 member heterocycle containing 1-2 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and a 5-10 member heteroaryl group containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S; Y either does not exist, or is -C(O)-, -C(NR)-, or -C(S)-; Z is a bivalent C that does not exist or can be optionally substituted. 1-30 It is aliphatic, and in the formula, the 0-8 methylene units of Z are independent of -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -OS(O)2-, -S(O)2O-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, or amino acids, in which one methylene unit of Z is optionally substituted with -M-, or Z is selected from the following group: C(R 4a )(R 4b )C(O)-M-, C(R 4a )(R 4b )-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH2) n C(O)-M-, -C(R) 4a )(R 4b )C(R 5a )(R 5b )(CH2) n -M-, -(CH2) m C(R 4a )(R 4b )(CH2) n C(R 5a )(R 5b )(CH2) m C(O)-M-, and -(CH2) m C(R 4a )(R 4b)(CH2) n C(R 5a )(R 5b )(CH2) m -M-; In the formula, both sides of Z may be bonded to the active substance; Each-R 8 - is independent of C 3-6 carbocycle, C 6-10 A 3-6 member heterocycle containing 1-4 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and a 5-member heterocycle containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S. An optionally substituted divalent group selected from the group consisting of 10-membered heteroaryls; Each R 4a , R 4b , R 5b , and R 5b These are independently hydrogen, deuterium, halogen, -CN, -OR, -NR2, -SR, -R 9 , and -R 10 Selected from the group consisting of; or R 4a and R 4b or R 5a and R 5b Together with the carbon atoms to which they are bonded, they contain one or two heteroatoms independently selected from the group consisting of N, O, and S. 3-6 Forming a carbon ring or a 3- to 6-membered heterocycle; Each R 9 This is a 3- to 8-membered carbon ring containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S, C 6-10 Selected from the group consisting of aryls, 4- to 8-membered heterocycles, and 5- to 10-membered heteroaryls containing 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; Each R 10 These can be used independently for 1 to 6 -CN, -OR, -NR2, -SR, -R 9 , selected from the group consisting of C1-6 aliphatic elements optionally substituted with deuterium or halogens; -M- is a detachable part. Each n is independent and ranges from 0 to 18. Each m is independent and ranges from 0 to 6. p is either 1 or 2. The active substance is selected from the following group: [ka] [ka] A compound or its deuterated variant is selected from the group consisting of the compound and its deuterated variant, wherein the point of bonding of the active substance to Z substitutes one or more hydrogen atoms on the active substance.

[0103] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is -C(O)N-(R 3 )2.

[0104] In some embodiments, Q is -C 1-8 It is alkylene-. In some embodiments, Q is -C 1-6It is alkylene-. In some embodiments, Q is C1 alkylene-. In some embodiments, Q is C2 alkylene-. In some embodiments, Q is C3 alkylene-. In some embodiments, Q is C4 alkylene-. In some embodiments, Q is C5 alkylene-. In some embodiments, Q is C6 alkylene-. In some embodiments, Q is C7 alkylene-. In some embodiments, Q is C8 alkylene-.

[0105] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 R is an acid-unstable group. In some embodiments, 1 It is a lipid. In some embodiments, R 1 is a fatty acid. In some embodiments, R 1 is -C(O)R 3 That is the case.

[0106] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 R is an acid-unstable group. In some embodiments, 2 It is a lipid. In some embodiments, R 2 is a fatty acid. In some embodiments, R 2 is -C(O)R 3 That is the case.

[0107] In some embodiments, R 1 It is a lipid. In some embodiments, R 2 It is a lipid. Examples of lipids include fatty acids. Exemplary fatty acids may be saturated or unsaturated medium-chain or long-chain fatty acids. In some embodiments, fatty acids are C 2-40Contains an aliphatic group. In some embodiments, the fatty acid contains a C2 aliphatic group. In some embodiments, the fatty acid contains a C3 aliphatic group. In some embodiments, the fatty acid contains a C4 aliphatic group. In some embodiments, the fatty acid contains a C5 aliphatic group. In some embodiments, the fatty acid contains a C6 aliphatic group. In some embodiments, the fatty acid contains a C7 aliphatic group. In some embodiments, the fatty acid contains a C8 aliphatic group. In some embodiments, the fatty acid contains a C9 aliphatic group. It includes. In some embodiments, the fatty acid is C 10 Contains an aliphatic group. In some embodiments, the fatty acid is C 11 Contains an aliphatic group. In some embodiments, the fatty acid is C 12 Contains an aliphatic group. In some embodiments, the fatty acid is C 13 Contains an aliphatic group. In some embodiments, the fatty acid is C 14 Contains an aliphatic group. In some embodiments, the fatty acid is C 15 Contains an aliphatic group. In some embodiments, the fatty acid is C 16 Contains an aliphatic group. In some embodiments, the fatty acid is C 17 Contains an aliphatic group. In some embodiments, the fatty acid is C 18 Contains an aliphatic group. In some embodiments, the fatty acid is C 19 Contains an aliphatic group. In some embodiments, the fatty acid is C 20 Contains an aliphatic group. In some embodiments, the fatty acid is C 21 Contains an aliphatic group. In some embodiments, the fatty acid is C 22 Contains an aliphatic group. In some embodiments, the fatty acid is C 23 Contains an aliphatic group. In some embodiments, the fatty acid is C 24 Contains an aliphatic group. In some embodiments, the fatty acid is C 25 Contains an aliphatic group. In some embodiments, the fatty acid is C 26 Contains an aliphatic group. In some embodiments, the fatty acid is C 27 Contains an aliphatic group. In some embodiments, the fatty acid is C 28 Contains an aliphatic group. In some embodiments, the fatty acid is C 29 Contains an aliphatic group. In some embodiments, the fatty acid is C 30Contains an aliphatic group. In some embodiments, the fatty acid is C 31 Contains an aliphatic group. In some embodiments, the fatty acid is C 32 Contains an aliphatic group. In some embodiments, the fatty acid is C 33 Contains an aliphatic group. In some embodiments, the fatty acid is C 34 Contains an aliphatic group. In some embodiments, the fatty acid is C 35 Contains an aliphatic group. In some embodiments, the fatty acid is C 36 Contains an aliphatic group. In some embodiments, the fatty acid is C 37 Contains an aliphatic group. In some embodiments, the fatty acid is C 38 Contains an aliphatic group. In some embodiments, the fatty acid is C 39 Contains an aliphatic group. In some embodiments, the fatty acid is C 40 Contains aliphatic groups.

[0108] In some embodiments, R 1 R is an acid-unstable group. In some embodiments, 2 It is an acid-unstable group. An example of an acid-unstable group is -C(O)OR. -C(O)NR 2 Examples include, but are not limited to, -CH2OR, -C(NR)R, -P(O)2OR, amino acids, or PEG groups.

[0109] In some embodiments, R 1 and R 2 They are the same. In some embodiments, R 1 and R 2 They are different.

[0110] Some implementation methods, each R 3 These are independently, substitution C 1-40 It is aliphatic. In some embodiments, each R 3 These are independently substituted C1 aliphatic. In some embodiments, each R 3 These are independently substituted C2 aliphatic. In some embodiments, each R 3 These are independently substituted C3 aliphatic. In some embodiments, each R 3These are independently substituted C4 aliphatic. In some embodiments, each R 3 These are independently substituted C5 aliphatic. In some embodiments, each R 3 These are independently substituted C6 aliphatic. In some embodiments, each R 3 These are independently substituted C7 aliphatic. In some embodiments, each R 3 These are independently substituted C8 aliphatic. In some embodiments, each R 3 These are independently substituted C9 aliphatic. In some embodiments, each R 3 These are independently, substitution C 10 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 11 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 12 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 13 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 14 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 15 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 16 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 17 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 18 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 19 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 20 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 21 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 22 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 23 It is aliphatic. In some embodiments, each R3 These are independently, substitution C 24 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 25 It is an aliphatic. Some implementation methods, each R 3 These are independently, substitution C 26 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 27 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 28 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 29 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 30 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 31 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 32 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 33 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 34 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 35 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 36 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 37 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 38 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 39 It is aliphatic. In some embodiments, each R 3 These are independently, substitution C 40 It is an aliphatic.

[0111] Some implementation methods, each R 3 C is independently and can be optionally substituted.1-40 It is aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C1 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C2 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C3 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C4 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C5 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C6 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C7 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C8 aliphatic. In some embodiments, each R 3 R is an independently and optionally substituted C9 aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 10 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 11 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 12 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 13 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 14 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 15 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 16 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 17 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 18It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 19 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 20 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 21 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 22 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 23 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 24 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 25 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 26 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 27 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 28 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 29 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 30 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 31 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 32 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 33 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 34 It is aliphatic. In some embodiments, each R 3C is independently and can be optionally substituted. 35 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 36 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 37 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 38 It is aliphatic. In some embodiments, each R 3 C is independently and can be optionally substituted. 39 It is aliphatic. Some implementations In this state, each R 3 C is independently and can be optionally substituted. 40 It is an aliphatic.

[0112] Some implementation methods, each R 3 C 1-40 It is aliphatic. In some embodiments, each R 3 Independently, each R is C1 aliphatic. In some embodiments, each R 3 Independently, each R is C2 aliphatic. In some embodiments, each R 3 Independently, each R is a C3 aliphatic. In some embodiments, each R 3 Independently, each R is a C4 aliphatic. In some embodiments, each R 3 Independently, each R is a C5 aliphatic. In some embodiments, each R 3 Independently, each R is a C6 aliphatic. In some embodiments, each R 3 Independently, each R is a C7 aliphatic. In some embodiments, each R 3 Independently, each R is a C8 aliphatic. In some embodiments, each R 3 Independently, each R is a C9 aliphatic. In some embodiments, each R 3 C 10 It is aliphatic. In some embodiments, each R 3 C 11 It is aliphatic. In some embodiments, each R 3 C 12 It is aliphatic. In some embodiments, each R 3 C 13It is aliphatic. In some embodiments, each R 3 is independently C 14 It is aliphatic. In some embodiments, each R 3 is independently C 15 It is aliphatic. In some embodiments, each R 3 is independently C 16 It is aliphatic. In some embodiments, each R 3 is independently C 17 It is aliphatic. In some embodiments, each R 3 is independently C 18 It is aliphatic. In some embodiments, each R 3 is independently C 19 It is aliphatic. In some embodiments, each R 3 is independently C 20 It is aliphatic. In some embodiments, each R 3 is independently C 21 It is aliphatic. In some embodiments, each R 3 is independently C 22 It is aliphatic. In some embodiments, each R 3 is independently C 23 It is aliphatic. In some embodiments, each R 3 is independently C 24 It is aliphatic. In some embodiments, each R 3 is independently C 25 It is aliphatic. In some embodiments, each R 3 is independently C 26 It is aliphatic. In some embodiments, each R 3 is independently C 27 It is aliphatic. In some embodiments, each R 3 is independently C 28 It is aliphatic. In some embodiments, each R 3 is independently C 29 It is aliphatic. In some embodiments, each R 3 is independently C 30 It is aliphatic. In some embodiments, each R 3 is independently C 31 It is aliphatic. In some embodiments, each R 3 is independently C 32It is aliphatic. In some embodiments, each R 3 C 33 It is aliphatic. In some embodiments, each R 3 C 34 It is aliphatic. In some embodiments, each R 3 C 35 It is aliphatic. In some embodiments, each R 3 C 36 It is aliphatic. In some embodiments, each R 3 C 37 It is aliphatic. In some embodiments, each R 3 C 38 It is aliphatic. In some embodiments, each R 3 C 39 It is aliphatic. In some embodiments, each R 3 C 40 It is an aliphatic.

[0113] In some embodiments, X is -O-. In some embodiments, X is -NR-. In some embodiments, X is -S-. In some embodiments, X is -O(C 1-6 It is an aliphatic (-O-) group, where the 0-2 methylene units of the C1-6 aliphatic group are independent and optional: -O-, -NR-, or -S- are substituted, and in the formula, each C1-6 aliphatic example is independently and optionally substituted with 1 to 3 deuterium or halogen atoms. In some embodiments, X is -O(C 1-6 It is aliphatic)-S-, and in the formula, C 1-6 The 0 to 2 methylene units of the aliphatic group are independently and optionally substituted with -O-, -NR-, or -S- in the formula, C 1-6 Each aliphatic example is independently and optionally substituted with 1 to 3 deuterium or halogen atoms. In some embodiments, X is -O(C 1-6 Aliphatic)-NR-, where the 0-2 methylene units of the C1-6 aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, C 1-6Each aliphatic example is independently and optionally substituted with 1 to 3 deuterium or halogen atoms. In some embodiments, X is -S(C 1-6 It is aliphatic (-O-), and in the formula, The 0 to 2 methylene units of the C1-6 aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, and each example of the C1-6 aliphatic group is independently and optionally substituted with 1 to 3 deuterium or halogen units. In some embodiments, X is -S(C 1-6 fat (Fat group)-S-, in the formula C 1-6 The 0-2 methylene units of the aliphatic group can be independently and optionally replaced with the following: -O-, -NR-, or -S- are substituted, and in the formula, each C1-6 aliphatic example is independently and optionally substituted with 1 to 3 deuterium or halogen atoms. In some embodiments, X is -S(C 1-6 Aliphatic)-NR-, where 0 to 2 methylene units of the C1-6 aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, and each example of the C1-6 aliphatic group is independently and optionally substituted with 1 to 3 deuterium or halogens. In some embodiments, X is -NR(C 1-6 It is aliphatic (-O-), and in the formula, The 0 to 2 methylene units of the C1-6 aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, and each example of the C1-6 aliphatic group is independently and optionally substituted with 1 to 3 deuterium or halogen units. In some embodiments, X is -NR(C 1-6 It is an aliphatic (-S-) group, where the 0 to 2 methylene units of the C1-6 aliphatic group can be independently and optionally replaced with the following: -O-, -NR-, or -S- are substituted, and in the formula, each C1-6 aliphatic example is independently and optionally substituted with 1 to 3 deuterium or halogen atoms. In some embodiments, X is -NR(C 1-6 Aliphatic)-NR-, and the C 1-6Zero to two methylene units of the aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, C 1-6 Each example of the aliphatic group is independently and optionally substituted with one to three deuteriums or halogens, C 1-6 aliphatic group. In some embodiments, X is -(C 1-6 aliphatic)-. In some embodiments, X is -O(C 1-6 aliphatic)-O-. In some embodiments, X is -O(C 1-6 aliphatic)-S-. In some embodiments, X is -O(C 1-6 aliphatic)-NR-. In some embodiments, X is -S(C 1-6 aliphatic)-O-. In some embodiments, X is -S(C 1-6 aliphatic)-S-. In some embodiments, X is -S(C 1-6 aliphatic)-NR-. In some embodiments, X is -NR(C 1-6 aliphatic)-O-. In some embodiments, X is -NR(C 1-6 aliphatic)-S-. In some embodiments, X is -NR(C 1-6 aliphatic)-NR-. In some embodiments, X is -(C 1-6 aliphatic)-.

[0114] In some embodiments, R is hydrogen.

[0115] In some embodiments, R is an optionally substituted -6 aliphatic. In some embodiments, R is an optionally substituted 3- to 8-membered carbocyclic ring. In some embodiments, R is an optionally substituted C 6-10 aryl. In some embodiments, R is an optionally substituted 4- to 8-membered heterocyclic ring containing one to two heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, R is an optionally substituted 5- to 10-membered heteroaryl containing one to four heteroatoms independently selected from the group consisting of N, O, and S.

[0116] In some embodiments, R is hydrogen. C 1-6 Aliphatic, 3-8 membered carbon ring, C 6-10 The group is selected from the group consisting of 4-8 membered heterocycles containing 1-2 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and 5-10 membered heteroaryls containing 1-4 heteroatoms. In some embodiments, R is C 1-6 It is aliphatic. In some embodiments, R is a 3- to 8-membered carbon ring. In some embodiments, R is a 4- to 8-membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, R is a 5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S.

[0117] In some embodiments, R is replaced -6 It is aliphatic. In some embodiments, R is a substituted 3- to 8-membered carbon ring. In some embodiments, R is a substituted C 6-10 It is an aryl compound. In some embodiments, R is a substituted 4- to 8-membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, R is a substituted 5- to 10-membered heteroaryl compound containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S.

[0118] In some embodiments, Y does not exist. In some embodiments, Y is -C(O)-. In some embodiments, Y is -C(NR)-. In some embodiments, Y is -C(S)-.

[0119] In some embodiments, Z is absent. In some embodiments, Z is a divalent C which is optionally substituted. 1-30 It is aliphatic, and in the formula, the 0 to 8 methylene units of Z are independent of -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or an amino acid, and one methylene unit of Z is optionally substituted with -M-. In some embodiments, Z is optionally substituted with C 1-30 Alkylenes (i.e., C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, C6 alkylene, C7 alkylene, C8 alkylene, C9 alkylene, C 10 Alkilen, C 11 Alkilen, C 12 Alkilen, C 13 Alkilen, C 14 Alkilen, C 15 Alkilen, C 16 Alkilen, C 17 Alkilen, C 18 Alkilen, C 19 Alkilen, C 20 Alkilen, C 21 Alkilen, C 22 Alkilen, C 23 Alkilen, C 24 Alkilen, C 25 Alkilen, C 26 Alkilen, C 27 Alkilen, C 28 Alkilen, C 29 Alkylene or C 30 It is an alkylene, and in the formula, the methylene units 0 to 8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8)Z are independently -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or an amino acid is used to replace one methylene unit of Z, which is optionally replaced by -M-.

[0120] In some embodiments, Z is optionally replaced by C. 2-30Alkenylenes (i.e., C2 alkenylenes, C3 alkenylenes, C4 alkenylenes, C5 alkenylenes, C6 alkenylenes, C7 alkenylenes, C8 alkenylenes, C9 alkenylenes, C 10 Alkenylene, C 11 Alkenylene, C 12 Alkenylene, C 13 Alkenylene, C 14 Alkenylene, C 15 Alkenylene, C 16 Alkenylene, C 17 Alkenylene, C 18 Alkenylene, C 19 Alkenylene, C 20 Alkenylene, C 21 Alkenylene, C 22 Alkenylene, C 23 Alkenylene, C 24 Alkenylene, C 25 Alkenylene, C 26 Alkenylene, C 27 Alkenylene, C 28 Alkenylene, C 29 Alkenylene or C 30 (Alkenylene), and in the formula, 0 to 8 methylene units of Z are independent, -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or substitution with an amino acid, and one methylene unit of Z is optionally substituted with -M-.

[0121] In some embodiments, Z is optionally replaced by C. 2-30 Alkynylenes (i.e., C2 alkynylenes, C3 alkynylenes, C4 alkynylenes, C5 alkynylenes, C6 alkynylenes) Nirene, C7 alkynirene, C8 alkynirene, C9 alkynirene, C 10 Alkinylene, C 11 Alkinylene, C 12 Alkinylene, C 13 Alkinylene, C14 Alkinylene, C 15 Alkinylene, C 16 Alkinylene, C 17 Alkinylene, C 18 Alkinylene, C 19 Alkinylene, C 20 Alkinylene, C 21 Alkinylene, C 22 Alkinylene, C 23 Alkinylene, C 24 Alkinylene, C 25 Alkinylene, C 26 Alkinylene, C 27 Alkinylene, C 28 Alkinylene, C 29 Alkynylene or C 30 Alkynylene) is such that in the formula, 0 to 8 methylene units of Z are independent, -R 8 Substitutions include -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or amino acids, where one methylene unit of Z is optionally substituted with -M-.

[0122] In some embodiments, Z is divalent C 1-30 It is aliphatic, and in the formula, the 0 to 8 methylene units of Z are independent of -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O- or an amino acid is substituted, and in the formula, one methylene unit of Z is optionally substituted with -M-. In some embodiments, Z is C 1-30 Alkylenes (i.e., C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, C6 alkylene, C7 alkylene, C8 alkylene, C9 alkylene, C 10Alkilen, C 11 Alkilen, C 12 Alkilen, C 13 Alkilen, C 14 Alkilen, C 15 Alkilen, C 16 Alkilen, C 17 Alkilen, C 18 Alkilen, C 19 Alkilen, C 20 Alkilen, C 21 Alkilen, C 22 Alkilen, C 23 Alkilen, C 24 Alkilen, C 25 Alkilen, C 26 Alkilen, C 27 Alkilen, C 28 Alkilen, C 29 Alkylene or C 30 Alkylene), in the formula, 0 to 8 methylene units of Z are independent, -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or amino acids are used to replace one methylene unit of Z, which is optionally replaced by -M-.

[0123] In some embodiments, Z is C 2-30 Alkenylenes (i.e., C2 alkenylenes, C3 alkenylenes, C4 alkenylenes, C5 alkenylenes, C6 alkenylenes, C7 alkenylenes, C8 alkenylenes, C9 alkenylenes, C 10 Alkenylene, C 11 Alkenylene, C 12 Alkenylene, C 13 Alkenylene, C 14 Alkenylene, C 15 Alkenylene, C 16 Alkenylene, C 17 Alkenylene, C 18 Alkenylene, C 19Alkenylene, C 20 Alkenylene, C 21 Alkenylene, C 22 Alkenylene, C 23 Alkenylene, C 24 Alkenylene, C 25 Alkenylene, C 26 Alkenylene, C 27 Alkenylene, C 28 Alkenylene, C 29 Alkenylene or C 30 (Alkenylene), and in the formula, the 0 to 8 methylene units of Z are independent of -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or an amino acid is used to replace one methylene unit of Z, and one methylene unit of Z is optionally replaced with -M-.

[0124] In some embodiments, Z is C 2-30 Alkynylene (i.e., C2 alkynylene, C3 alkynylene, C4 alkynylene, C5 alkynylene, C6 alkynylene, C7 alkynylene, C8 alkynylene, C9 alkynylene, C 10 Alkinylene, C 11 Alkini Ren, C 12 Alkinylene, C 13 Alkinylene, C 14 Alkinylene, C 15 Alkinylene, C 16 Alkinylene, C 17 Alkinylene, C 18 Alkinylene, C 19 Alkinylene, C 20 Alkinylene, C 21 Alkinylene, C 22 Alkinylene, C 23 Alkinylene, C 24 Alkinylene, C 25 Alkinylene, C 26 Alkinylene, C 27Alkinylene, C 28 Alkinylene, C 29 Alkynylene or C 30 Alkynylene) is the methylene unit in the formula, where the 0 to 8 methylene units of Z are independent of -R 8 -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -C(S)-, -N(R)S(O)2-, -S(O)2NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or replaced with an amino acid, and one methylene unit of Z is optionally replaced with -M-.

[0125] In some embodiments, Z is -C(R 4a )(R 4b )C(O)-M-, -C(R 4a )(R 4b )-M-, -C(R 4a )(R 4b )C(R 5a )(R 5b )(CH2) n C(O)-M-, -C(R) 4a )(R 4b )C(R 5a )(R 5b )(CH2) n -M-, -(CH2) m C(R 4a )(R 4b )(CH2) n C(R 5a )(R 5b )(CH2) m C(O)-M-, and -(CH2) m C(R 4a )(R 4b )(CH2) n C(R 5a )(R 5b )(CH2) m A selection is made from the group consisting of -M-, and in the formula, either side of Z may be bound to the active substance.

[0126] In some embodiments, Z is -CH(R 4a )C(O)-M-,-CH(R4a )-M-, -CH(R 4a )CH(R 5a )C(O)-M-,-CH(R 4a )CH(R 5a )(CH2) n C(O)-M-, -CH(R) 4a )CH(R 5a )(CH2) n -M-, and -C(R 4a )(R 4b )(CH2) n C(R 5a )(R 5b A compound selected from the group consisting of C(O)-M-, where either side of Z may be bonded to the active substance.

[0127] In some embodiments, the 0-8 methylene units of Z are independently -R 8- is replaced by -. In some embodiments, the 0-8 methylene units of Z are independently replaced by -O-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -NR-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -S-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -OC(O)-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -C(O)O-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -C(O)-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -S(O)-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -S(O)2-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -C(S)-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -OS(O)2-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -S(O)2O-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -N(R)S(O)2-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -S(O)2NR-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -N(R)C(O)-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -C(O)NR-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -OC(O)NR-. In some embodiments, the 0-8 methylene units of Z are independently replaced by -N(R)C(O)O-. In some embodiments, 0 to 8 methylene units of Z are independently replaced by amino acids.

[0128] In some embodiments, the amino acid may be natural or unnatural. In some embodiments, the amino acid is an L-amino acid. In some embodiments, The amino acid is a D-amino acid. Examples of amino acids include, but are not limited to, glycine, alanine, leucine, isoleucine, valine, tyrosine, lysine, serine, threonine, methionine, proline, phenylalanine, tryptophan, asparagine, glutamine, aspartic acid, glutamic acid, arginine, histidine, cysteine, and selenocysteine. In some embodiments, the amino acid is, [ka] It is selected from the group consisting of the following.

[0129] In some embodiments, Z is deuterium, halogen, -CN, a 3- to 8-membered carbon ring, C 6-10 A 4-8 membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of aryl, N, O, and S; a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S; or C optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium or halogen atoms. 1-6 Divalent carbon is optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of aliphatic groups, where the 0 to 4 methylene units of Z are independently -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of Z is optionally substituted with -M-. 1-25 , C 5-25 , C 7-25 , or C 1-20 It is an aliphatic.

[0130] In some embodiments, each -R 8 - is independently a divalent C which is arbitrarily substituted. 3-6 It is a carbon ring. In some embodiments, -R 8 - represents each of the arbitrarily substituted divalent C's independently. 6-10 It is an arrow. In some embodiments, -R 8 - is a substituted, possibly divalent, 3-6 membered heterocycle containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, -R 8-Each is independent of N, O, and oyo It is a substituted, divalent 5-10 membered heteroaryl compound containing 1-4 heteroatoms independently selected from the group consisting of bi and sulfur.

[0131] In some embodiments, -R 8 -Each is independent of C 3-6 carbocycle, C 6-10 A divalent group selected from the group consisting of a 3-6 membered heterocycle containing 1-4 heteroatoms independently selected from the group consisting of aryl, nitrogen, oxygen, and sulfur, and a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, -R 8 -Each is independently divalent C 3-6 It is a carbon ring. In some embodiments, -R 8 -Each is independently divalent C 6-10 It is an arrow. In some embodiments, -R 8 - is a divalent substituted 3-6 membered heterocycle containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, -R 8 Each of these is a divalent substituted 5-10 member heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S.

[0132] In some embodiments, R 4a These are hydrogen, deuterium, halogens, -CN, -OR, -NR2, -SR, -R 9 , and -R 10 Selected from the group consisting of R 4a is hydrogen. In some embodiments, R 4a is deuterium. In some embodiments, R 4a is a halogen. In some embodiments, R 4a is -CN. In some embodiments, R 4a is -OR. In some embodiments, R 4a is -NR2. In some embodiments, R 4a is -SR. In some embodiments, R4a is, -R 9 In some embodiments, R 4a is, -R 10 That is the case.

[0133] In some embodiments, R 4b These are hydrogen, deuterium, halogens, -CN, -OR, -NR2, -SR, -R 9 , and -R 10 It is independently selected from the group consisting of. In some embodiments, R 4b is hydrogen. In some embodiments, R 4b is deuterium. In some embodiments, R 4b is a halogen. In some embodiments, R 4b is -CN. In some embodiments, R 4b is -OR. In some embodiments, R 4b is -NR2. In some embodiments, R 4b is -SR. In some embodiments, R 4b teeth, -R 9 In some embodiments, R 4b is, -R 10 That is the case.

[0134] In some embodiments, R 4a and R 4b Each of them independently is hydrogen, deuterium, halogen, -CN, or a C1-4 aliphatic atom optionally substituted with 1 to 6 deuterium or halogen atoms, or R 4a and R 4b Together with the carbon atoms to which they are bonded, these contain one or two heteroatoms independently selected from the group consisting of N, O, and S. 3-6 They form a carbon ring or a 3- to 6-membered heterocycle.

[0135] In some embodiments, R 5a These are hydrogen, deuterium, halogens, -CN, -OR, -NR2, -SR, -R 9 , and -R 10 Selected from the group consisting of R 5ais hydrogen. In some embodiments, R 5a is deuterium. In some embodiments, R 5a is a halogen. In some embodiments, R 5a is -CN. In some embodiments, R 5a is -OR. In some embodiments, R 5a is -NR2. In some embodiments, R 5a is -SR. In some embodiments, R 5a is, -R 9 In some embodiments, R 5a is, -R 10 That is the case.

[0136] In some embodiments, R 5b These are hydrogen, deuterium, halogens, -CN, -OR, -NR2, -SR, -R 9 , and -R 10 It is independently selected from the group consisting of. In some embodiments, R 5b is hydrogen. In some embodiments, R 5b is deuterium. In some embodiments, R 5b is a halogen. In some embodiments, R 5b is -CN. In some embodiments, R 5b is -OR. In some embodiments, R 5b is, -N R2 is R 5b is -SR. In some embodiments, R 5b teeth, -R 9 In some embodiments, R 5b is, -R 10 That is the case.

[0137] In some embodiments, R 5a and R 5b Each of these is independently hydrogen, deuterium, halogen, -CN, or C optionally substituted with 1 to 6 deuterium or halogen atoms. 1-4 It is aliphatic, or R 5a and R 5bTogether with the carbon atoms to which they are bonded, these contain one or two heteroatoms independently selected from the group consisting of N, O, and S. 3-6 They form a carbon ring or a 3- to 6-membered heterocycle.

[0138] In some embodiments, R 4a , R 4b , R 5a , and R 5b Each of these is independently a C atom optionally substituted with hydrogen or 1 to 6 deuterium or halogen atoms. 1-4 It is selected from alkyl groups.

[0139] In some embodiments, R 4a and R 4b At least one example is not hydrogen.

[0140] In some embodiments, R 5a and R 5b At least one example is not hydrogen.

[0141] In some embodiments, R 4a and R 4b Together with the carbon atoms to which they bond, C 3-6 It forms a carbon ring, or a 3-6 membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, R 4a and R 4b Together with the carbon atoms to which they bond, C 3-6 It forms a carbon ring. In some embodiments, R 4a and R 4b These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S.

[0142] In some embodiments, R 5a and R 5b Together with the carbon atoms to which they bond, C 3-6It forms a carbon ring, or a 3-6 membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, R 5a and R 5b Together with the carbon atoms to which they bond, C 3-6 It forms a carbon ring. In some embodiments, R 5a and R 5b These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S.

[0143] In some embodiments, R 9 is a 3- to 8-membered carbon ring. In some embodiments, R 9 C 6-10 It is an arrow. In some embodiments, R 9 R is a 4- to 8-membered heterocycle containing 1-2 heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, R 9 It is a 5- to 10-membered heterocycle containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S.

[0144] In some embodiments, R 10 Each of these can be used independently as -CN, -OR, -NR2, -SR, or -R 9 C which is optionally replaced by 1-6 Selected from the group consisting of aliphatic organisms, the C 1-6 The aliphatic may optionally and additionally be substituted with 1 to 6 deuterium or halogen atoms. In some embodiments, R 10 is unsubstituted C 1-6 It is aliphatic. In some embodiments, R 10 C is replaced by 1 to 6 -CNs. 1-6 It is aliphatic. In some embodiments, R 10 is a C1-6 aliphatic that is substituted with 1 to 6 -ORs. In some embodiments, R 10 C is replaced by 1 to 6 -NR2s. 1-6 It is aliphatic. In some embodiments, R 10C is replaced by 1 to 6 -SRs. 1-6 It is aliphatic. In some embodiments, R 10 This includes 1 to 6 -R 9 C is replaced by 1-6 It is aliphatic. In some embodiments, R 10 C is a carbon atom substituted with 1 to 6 deuterium atoms. 1-6 aliphatic In some embodiments, R 10 C is replaced by 1 to 6 halogens. 1-6 It is an aliphatic.

[0145] In some embodiments, -M- is a detachable portion. In some embodiments, the detachable portion is a self-destructing portion.

[0146] In some embodiments, -M- is selected from the group consisting of acetals, o-benzyl alcohols, p-benzyl alcohols, styryl groups, coumarins, and groups that self-destruct via cyclization reactions. In some embodiments, -M- is selected from the group consisting of disulfides, hydrazones, acetal self-destructing groups, carboxyacetal self-destructing moieties, carboxy(methylacetal) self-destructing moieties, para-hydroxybenzylcarbonyl self-destructing moieties, inverted ester self-destructing moieties, trimethyl locks, or 2-hydroxyphenylcarbamate (2-HPC) self-destructing moieties.

[0147] In some embodiments, -M- is [ka] [ka] [ka] [ka] A selection is made from the group consisting of the following, and in the formula, either side of M may be bound to the active substance. In the formula, each R 6a and R 6bThey are independently hydrogen, deuterium, and C 1-10 Selected from the group consisting of aliphatic, halogen, or -CN, Each R 7 These are independently hydrogen, deuterium, halogen, -CN, -OR, and -NR. 2 -NO2, -SR, -R 9 , or -R 10 Selected from the group consisting of, each Z 1 These are independently selected from the group consisting of -O-, -NR-, or -S-, each Z 2 These are independently selected from the group consisting of -O-, -NR-, -S-, -OC(O)-, -N(R)C(O)O-, or -OC(O)NR-, each Z 3 These are independently -O-, -NR-, -S-, and -C(R 6a )(R 6b )-, or selected from covalent bonds.

[0148] In some embodiments, R 6a is hydrogen. In some embodiments, R 6a is deuterium. In some embodiments, R 6a C 1-6 It is aliphatic. In some embodiments, R 6a C 1-6 It is alkyl. In some embodiments, R 6a is methyl, ethyl, propyl, or isopropyl. In some embodiments, R 6a is methyl. In some embodiments, R 6a is ethyl. In some embodiments, R 6a is propyl. In some embodiments, R 6a is isopropyl. In some embodiments, R 6a is a halogen. In some embodiments, R 6a It is -CN.

[0149] In some embodiments, R 6b is hydrogen. In some embodiments, R 6b is deuterium. In some embodiments, R6b C 1-6 It is aliphatic. In some embodiments, R 6b C 1-6 It is alkyl. In some embodiments, R 6b is methyl, ethyl, propyl, or isopropyl. In some embodiments, R 6b is methyl. In some embodiments, R 6b is ethyl. In some embodiments, R 6b is propyl. In some embodiments, R 6b is isopropyl. In some embodiments, R 6b is a halogen. In some embodiments, R 6b It is -CN.

[0150] In some embodiments, R 6a Each example is the same. In some embodiments, R 6b Each example is identical. In some embodiments, R 6a and R 6b Each example is identical. In some embodiments, R 6a Each example is different. In some embodiments, R 6b Each example is different. In some embodiments, R 6a and R 6b Each example is different.

[0151] Some implementation methods, each R 7 is hydrogen. In some embodiments, each R 7 is deuterium. In some embodiments, each R 7 is a halogen. In some embodiments, each R 7 is -CN. In some embodiments, each R 7 is -OR. In some embodiments, each R 7 is -NR2. In some embodiments, each R 7 is -NO2. In some embodiments, each R 7 is -SR. In some embodiments, each R 7 is, -R 9 In some embodiments, each R7 is, -R 10 That is the case.

[0152] In some embodiments, Z 1 is -O-. In some embodiments, Z 1 is -NR-. In some embodiments, Z 1 is -S-. In some embodiments, Z 1 It is -NH- or -NMe-.

[0153] In some embodiments, Z 2 is -O-. In some embodiments, Z 2 is -NR-. In some embodiments, Z 2 is -S-. In some embodiments, Z 2 is -OC(O)-. In some embodiments, Z 2 teeth, It is -N(R)C(O)O-. In some embodiments, Z 2 is -OC(O)NR-. In some embodiments, Z 2 is -NH-. In some embodiments, Z 2 is -NMe-. In some embodiments, Z 2 is -NHC(O)O-. In some embodiments, Z 2 is -NMeC(O)O-. In some embodiments, Z 2 is -OC(O)NH-. In some embodiments, Z 2 is -OC(O)NMe-. In some embodiments, Z 2 It is covalently bonded to A.

[0154] In some embodiments, each Z 3 These are independently -O-, -NR-, -S-, and -C(R 6a )(R 6b )-, or selected from covalent bonding. In some embodiments, Z 4 is -O- Yes. In some embodiments, Z 3 is -NR-. In some embodiments, Z 3is -S-. In some embodiments, Z 3 -C(R 6a )(R 6b )-. In some embodiments, Z 3 This is a covalent bond.

[0155] In some embodiments, -M- is [ka] [ka] A selection is made from the group consisting of the following, and in the formula, either side of M may be bound to the active substance.

[0156] In some embodiments, -M- is [ka] [ka] A selection is made from the group consisting of the following, and in the formula, either side of M may be bound to the active substance.

[0157] In some embodiments, -M- is [ka] A selection is made from the group consisting of the following, and in the formula, either side of M may be bound to the active substance.

[0158] In some embodiments, -M- is [ka] Selected from the group consisting of, in the formula, either side of M may be bound to the active substance.

[0159] In some embodiments, -M- is [ka] A selection is made from the group consisting of the following, and in the formula, either side of M may be bound to the active substance.

[0160] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18.

[0161] In some embodiments, m is 0. In some embodiments, m is 1. 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, m is 6. In some embodiments, each m is independently 0, 1, or 2. In some embodiments, each m is independently 1, 2, 3, or 4.

[0162] In some embodiments, p is 1. In some embodiments, p is 2.

[0163] In some embodiments, the active substance is one of the following: active substance numbers 1-14, their deuterated variants, their pharmaceutically acceptable salts, or a combination thereof. In some embodiments, the active substance is one of the following: active substance numbers 15-20 or 23-27, their deuterated variants, their pharmaceutically acceptable salts, or a combination thereof. In some embodiments, the active substance is one of the following: active substance number 21 or 22, its deuterated variant, its pharmaceutically acceptable salt, or a combination thereof.

[0164] In some embodiments, [ka] This refers to the structures listed in Table 1, their deuterated variants, their pharmaceutically acceptable salts, or combinations thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0165] For clarity, the parentheses and the representation of the integer p are shown in equation (I). [ka] It is 1 or 2, one or two [ka] This means that any part of it can be covalently bonded to the active substance. [ka] The bond to may be any available modifiable nitrogen, oxygen, or sulfur atom in the active material. Each wave bond in the structure shown in this disclosure ( [ka] ) This defines the connection point.

[0166] In some embodiments, the present disclosure relates to a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof is provided, where Z, p, and the active substance are each as defined herein.

[0167] In some embodiments, the present disclosure relates to a compound of formula (III): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 Each of X, Z, p, and the active substance is as defined herein.

[0168] In some embodiments, the present disclosure relates to a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof is provided, where each of X, Z, p, and the active substance is as defined herein.

[0169] In some embodiments, this disclosure relates to a compound of formula (V): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 3 Each of X, Z, p, and the active substance is as defined herein.

[0170] In some embodiments, this disclosure relates to compounds of formula (VI): [ka] or a pharmaceutically acceptable salt thereof is provided, where each of X, Z, p, and the active substance is as defined herein.

[0171] In some embodiments, this disclosure relates to compounds of formula (VII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 Each of X, p, and the active substance is as defined herein.

[0172] In some embodiments, this disclosure relates to compounds of formula (VIII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 3 Each of the active substances, p, and active substances are as defined herein.

[0173] In some embodiments, the present disclosure relates to a compound of formula (IX), [ka] or having a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a Each of X, M, p, and the active substance is as defined herein.

[0174] In some embodiments, this disclosure relates to compounds of formula (X): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 5a Each of M, X, p, and the active substance is as defined herein.

[0175] In some embodiments, this disclosure relates to compounds of formula (XI): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 5a Each of X, n, p, and the active substance is as defined herein.

[0176] In some embodiments, this disclosure relates to a compound of formula (XII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 Each of X, M, p, and the active substance is as defined herein.

[0177] In some embodiments, this disclosure relates to a compound of formula (XIII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b Each of M, p, and the active substance is as defined herein.

[0178] In some embodiments, this disclosure relates to compounds of formula (XIV): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of M, p, and the active substance is as defined herein.

[0179] In some embodiments, this disclosure relates to compounds of formula (XV): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 5a Each of M, p, and the active substance is as defined herein.

[0180] In some embodiments, this disclosure relates to compounds of formula (XVI): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 5a Each of M, p, and the active substance is as defined herein.

[0181] In some embodiments, this disclosure relates to compounds of formula (XVII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of M, p, and the active substance is as defined herein.

[0182] In some embodiments, this disclosure relates to compounds of formula (XVIII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of M, p, and the active substance is as defined herein.

[0183] In some embodiments, this disclosure relates to compounds of formula (XIX): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of the active substances, p, and active ingredients are as defined herein.

[0184] In some embodiments, this disclosure relates to compounds of formula (XX): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of the active substances, p, and active substances are as defined herein.

[0185] In some embodiments, this disclosure relates to compounds of formula (XXI): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5bEach of M, p, and the active substance is as defined herein.

[0186] In some embodiments, this disclosure relates to compounds of formula (XXII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 5a , R 5b Each of M, p, and the active substance is as defined herein.

[0187] In some embodiments, this disclosure relates to compounds of formula (XXIII): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of M, p, and the active substance is as defined herein.

[0188] In some embodiments, this disclosure relates to compounds of formula (XXIV): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of the active substances, p, and active substances are as defined herein.

[0189] In some embodiments, this disclosure relates to compounds of formula (XXV): [ka] or provides a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 4a , R 4b , R 5a , R 5b Each of M, p, and the active substance is as defined herein.

[0190] In some embodiments, this disclosure relates to compounds of formula (XXVI): [ka] or a pharmaceutically acceptable salt thereof is provided, where p and the active substance are as defined herein.

[0191] In some embodiments, this disclosure relates to compounds of formula (XXVII): [ka] or a pharmaceutically acceptable salt thereof is provided, where p and the active substance are as defined herein.

[0192] Where any of the formulas disclosed in this disclosure discloses a range of numbers such as 0–1, 0–4, or 1–18, the individual integers within that range are also specifically disclosed. Thus, the range 0–1 includes 0 and 1. The range 0–4 includes 0, 1, 2, 3, and 4. The range 1–18 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18. Where two or more ranges are disclosed in a formula, each range is selected independently and optionally from the disclosed range.

[0193] In one embodiment, the present disclosure relates to compounds 1 to 2201 shown in any one of Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32. The present invention provides one of these compounds, a pharmaceutically acceptable salt thereof, a deuterated variant thereof, or a combination thereof. In some embodiments, the compound is selected from one of compounds 1 to 2201 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from one of compounds 1 to 2201. In some embodiments, the compound is selected from a pharmaceutically acceptable salt of one of compounds 1 to 2201. In some embodiments, the compound is selected from a deuterated variant of one of compounds 1 to 2201. In some embodiments, the compound is selected from a deuterated variant of a pharmaceutically acceptable salt of one of compounds 1 to 2201.

[0194] In some embodiments, the compound is selected from any of the compounds shown in Table 2, their pharmaceutically acceptable salts, their deuterated variants, or combinations thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0195] In some embodiments, the compounds are those listed in Table 3, which are pharmaceutically acceptable. Selected from salts, their deuterated variants, or combinations thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

[0196] In some embodiments, the compound is one of the compounds shown in Table 4, which is pharmaceutically acceptable. Selected from the salts, their deuterated variants, or combinations thereof. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5]

[0197] In some embodiments, the compound is one of the compounds shown in Table 5, which is pharmaceutically acceptable. Selected from the salts, their deuterated variants, or combinations thereof. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0198] In some embodiments, the compounds are those listed in Table 6, which are pharmaceutically acceptable. Selected from salts, their deuterated variants, or combinations thereof. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5]

[0199] In some embodiments, the compound is any of the compounds shown in Table 7, which are pharmaceutically acceptable. Selected from the salts, their deuterated variants, or combinations thereof. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0200] In some embodiments, the compound is selected from any of the compounds shown in Table 8, their pharmaceutically acceptable salts, their deuterated variants, or combinations thereof. . [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

[0201] In some embodiments, the compound is selected from any of the compounds shown in Table 9, their pharmaceutically acceptable salts, their deuterated variants, or combinations thereof. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5]

[0202] In some embodiments, the compound is one of the compounds shown in Table 10, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5]

[0203] In some embodiments, the compound is one of the compounds shown in Table 11, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5]

[0204] In some embodiments, the compound is one of the compounds shown in Table 12, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5]

[0205] In some embodiments, the compound is one of the compounds shown in Table 13, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 13-1] [Table 13-2] [Table 13-3] [Table 13-4] [Table 13-5]

[0206] In some embodiments, the compound is one of the compounds shown in Table 14, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5]

[0207] In some embodiments, the compound is one of the compounds shown in Table 15, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5]

[0208] In some embodiments, the compound is one of the compounds shown in Table 16, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5]

[0209] In some embodiments, the compound is one of the compounds shown in Table 17, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 17-1] [Table 17-2] [Table 17-3] [Table 17-4] [Table 17-5]

[0210] In some embodiments, the compound is one of the compounds shown in Table 18, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5]

[0211] In some embodiments, the compound is one of the compounds shown in Table 19, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] [Table 19-5]

[0212] In some embodiments, the compound is one of the compounds shown in Table 20, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5]

[0213] In some embodiments, the compound is one of the compounds shown in Table 21, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5]

[0214] In some embodiments, the compound is one of the compounds shown in Table 22, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5]

[0215] In some embodiments, the compound is one of the compounds shown in Table 23, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5]

[0216] In some embodiments, the compound is selected from any of the compounds shown in Table 24, their pharmaceutically acceptable salts, their deuterated variants, or combinations thereof. [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5]

[0217] In some embodiments, the compound is selected from any of the compounds shown in Table 25, their pharmaceutically acceptable salts, their deuterated variants, or combinations thereof. [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] [Table 25-5]

[0218] In some embodiments, the compound is one of the compounds shown in Table 26, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 26-1] [Table 26-2] [Table 26-3] [Table 26-4] [Table 26-5]

[0219] In some embodiments, the compound is one of the compounds shown in Table 27, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 27-1] [Table 27-2] [Table 27-3] [Table 27-4] [Table 27-5]

[0220] In some embodiments, the compound is one of the compounds shown in Table 28, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4] [Table 28-5]

[0221] In some embodiments, the compound is selected from any of the compounds shown in Table 29, their pharmaceutically acceptable salts, their deuterated variants, or combinations thereof. [Table 29-1] [Table 29-2] [Table 29-3] [Table 29-4] [Table 29-5]

[0222] In some embodiments, the compound is one of the compounds shown in Table 30, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 30-1] [Table 30-2] [Table 30-3] [Table 30-4] [Table 30-5]

[0223] In some embodiments, the compound is one of the compounds shown in Table 31, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 31-1] [Table 31-2] [Table 31-3] [Table 31-4] [Table 31-5]

[0224] In some embodiments, the compound is one of the compounds shown in Table 32, which is pharmaceutically acceptable. Selected from the acceptable salts, their deuterated variants, or combinations thereof. [Table 32-1] [Table 32-2] [Table 32-3] [Table 32-4] [Table 32-5]

[0225] Pharmaceutical composition In one aspect, the Disclosure relates to compounds (for example, compounds of the formulas disclosed herein or their (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), The present invention provides a pharmaceutical composition comprising (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), (XLVI), (XLVII), (XLVIII), (XLIX), (L), (LI), (LII), (LIII), (LIV), (LV), (LVI), (LVII), (LVIII), a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0226] In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are provided in an effective amount in a pharmaceutical composition. In some embodiments, the compounds of the Disclosure or pharmaceutically acceptable salts thereof are provided in a therapeutically effective amount. In some embodiments, the pharmaceutical composition is provided in an effective amount of The compound or a pharmaceutically acceptable salt thereof is included. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

[0227] The pharmaceutical compositions provided in this disclosure can be administered by various routes, including oral, parenteral, rectal, percutaneous, intradermal, subarachnoid, subcutaneous, intravenous, intramuscular, and intranasal.

[0228] The amount of compound administered to a patient is typically determined by a physician, taking into account relevant circumstances, including the condition being treated, the route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

[0229] When used to prevent the development of a disease, condition, or disorder, the compounds provided in this disclosure are typically administered to subjects at risk of developing the disease, condition, or disorder, under the advice and supervision of a physician, and in the dosages described in this disclosure. Subjects at risk of developing a particular condition include, but are not limited to, subjects with a family history of the condition, or subjects identified as being particularly likely to develop the condition by screening or assessment methods.

[0230] The pharmaceutical compositions provided in this disclosure may also be administered chronically ("chronic administration"). Chronic administration means administration of the compound or pharmaceutical composition over a long period of time, for example, over three months, six months, one year, two years, three years, five years, or indefinitely (for example, over the rest of the subject's life).

[0231] In some embodiments, the pharmaceutical compositions of this disclosure are formulated for oral administration to a subject. Compositions for oral administration may take the form of a bulk liquid solution or suspension, or a bulk powder. However, more generally, compositions are presented in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically distinct unit suitable as a single dose to a human subject and other mammals, each unit containing a predetermined amount of the active substance calculated to produce a desired therapeutic effect in conjunction with a suitable pharmaceutically acceptable excipient. Typical unit dosage forms include liquid compositions in the case of solid compositions, or pre-filled, pre-measured ampoules or syringes such as pills, tablets, capsules, etc. In such compositions, the compound is usually a small component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers, and processing aids useful in forming the desired dosage form.

[0232] For oral administration, typical regimens involve doses of 1 to 5 times per day (e.g., 1, 2, 3, 4, or 5 doses). Using these dosing patterns, each dose provides the compound provided in this disclosure in amounts ranging from approximately 0.01 to approximately 20 mg / kg.

[0233] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle containing buffers, suspensions and dispensers, colorants, flavorings, etc. Solid forms may include, for example, a binder such as microcrystalline cellulose, an excipient such as tragacanth gum or gelatin, an excipient such as starch or lactose, a disintegrant such as alginic acid, a lubricant such as Primogel, or corn starch or magnesium stearate, a flow enhancer such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or a flavoring such as peppermint, methyl salicylate, or orange flavoring, or any of these components or compounds of similar properties.

[0234] In some embodiments, the pharmaceutical compositions of this disclosure are formulated as lipid-based formulations for oral administration to a subject. Lipid formulations for oral administration are known in the art and typically contain one or more lipid components that can be classified according to the Lipid Formulation Classification System (LFCS). Including. Examples of lipid formulations that may be used in the lipid formulations disclosed herein include type I, type II, type III, and type IV formulations according to the LFCS classification system. (Pouton, Eur.J.Pharm.Sci.11(Supp 2), S93-S98, 2000; Pouton, Eur.J.Pharm.Sci.29 278-287, 2006). Lipid-based pharmaceutical compositions may contain one or more of the following: oil or lipid, surfactant, co-surfactant, co-emulsifier, co-solvent, antioxidant, and / or solidifying agent.

[0235] Lipid-based pharmaceutical compositions may be formulated and selected to provide sustained release of activity in the gastrointestinal tract in order to control the absorption rate. These methodologies and formulations are known in the art. See, for example, Mishra, Handbook of Encapsulation and Controlled Release, CRC Press, Boca Raton, (2016); Wilson and Crowley, Controlled Release in Oral Drug Delivery, Springer, NY (2011); and Wise, Handbook of Pharmaceutical Controlled Release Technology, Marcel Dekker, NY (2000).

[0236] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable carriers known in the art. As previously mentioned, the active compounds in such compositions are typically trace components, often amounting to about 0.05–10% by weight, with the remainder being the injectable carrier, etc. Injectable compositions can be sterilized, for example, by filtration, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0237] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injectable doses.

[0238] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with either paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream containing, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to enhance the dermal penetration of the active ingredient or formulation for stability. All such known transdermal formulations and ingredients are included within the scope provided in this disclosure.

[0239] The compounds provided in this disclosure can also be administered by transdermal devices. Therefore, transdermal administration can be achieved using either a reservoir or a porous membrane type, or a patch of a solid matrix variety.

[0240] This disclosure also relates to pharmaceutically acceptable acid addition salts of compounds or active substances disclosed herein. Acids that may be used to prepare pharmaceutically acceptable salts form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, sulfate, sulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, and p-toluenesulfonate.

[0241] This disclosure also relates to pharmaceutical compositions comprising the compound of the present invention and a pharmaceutically acceptable carrier, e.g. For example, the present invention provides compositions suitable for injection, such as intravenous (IV) or oral administration.

[0242] Pharmaceutically acceptable carriers include any and all diluents or other liquid vehicles, dispersants or suspension aids, surfactants, isotonic agents, preservatives, lubricants, etc., suitable for the desired specific dosage form, e.g., injection, oral administration. For general considerations in the formulation and / or manufacture of pharmaceutical compositions, see, for example, Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0243] This disclosure also relates to pharmaceutical compositions comprising cyclodextrin derivatives. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, each consisting of 6, 7, and 8 α-1,4-linked glucose units, and optionally comprising one or more substituents on the linked sugar moiety, including but not limited to methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0244] The compounds provided in this disclosure may be administered as sole activators or in combination with other activators. In one embodiment, the present invention provides combinations of the compounds of the present invention with other pharmacological activators. Combination administration may be carried out by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0245] The above-mentioned components for orally administered, injectable, or topically administered compositions are merely representative. Other materials and processing techniques are described in Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott. This is presented in Part 8 of Williams & Wilkins, which is incorporated herein by reference.

[0246] The compounds disclosed herein can also be administered in sustained-release form or via sustained-release active ingredient delivery systems. For a description of typical sustained-release materials, see Remington's Pharmaceutical Sciences.

[0247] Treatment methods and usage methods In one embodiment, the present disclosure relates to compounds that are lymphoid target compounds (for example, compounds of the formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XX V), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XX XVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII), (XLIII), (XLIV), (XLV), (XLVI), (XLVII), (XLVIII), (XL The present invention provides compounds of formula (I) to (LVIII) disclosed herein, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. In some embodiments, the compounds of formula (I) to (LVIII) disclosed herein, their pharmaceutically acceptable salts, and pharmaceutical compositions are useful for delivering the active substances of the present disclosure to the lymphatic system and releasing the active substances at target sites (e.g., any target tissue). In some embodiments, the compounds of formula (I) to (LVIII) disclosed herein, their pharmaceutically acceptable salts, and pharmaceutical compositions are useful for delivering the active substances of the present disclosure to the enterolymphatic system and releasing the active substances at target sites (e.g., lymph, lymphocytes, lymphoid tissue, tissues with high lipase activity, liver, systemic circulation, brain). The compounds of formulas (I) to (LVIII) disclosed herein, their pharmaceutically acceptable salts, and their pharmaceutical compositions are useful for transporting and releasing the active substances disclosed herein in target tissues by avoiding primary metabolic pathways. The compounds of formulas (I) to (LVIII) disclosed herein, their pharmaceutically acceptable salts, and their pharmaceutical compositions are useful for improving the bioavailability and other pharmacokinetic properties of the active substances disclosed herein.

[0248] In some embodiments, the compounds of formulas (I) to (LVIII) disclosed herein or pharmaceutically acceptable salts thereof are delivered to the central nervous system (CNS). In some embodiments, the compounds of formulas (I) to (LVIII) disclosed herein or pharmaceutically acceptable salts thereof cross the blood-brain barrier (BBB) ​​via the lymphatic system.

[0249] In some embodiments, the compounds of formulas (I) to (LVIII) disclosed herein or pharmaceutically acceptable salts thereof are cleaved to release the active substances disclosed herein after the compounds of formulas (I) to (LVIII) disclosed herein or pharmaceutically acceptable salts thereof have reached a target tissue. The active substances are released when the cleavable linker is cleaved.

[0250] Compounds described in this disclosure (e.g., formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXI II) (XXIV) Compounds of (XLIII), (XLIV), (XLV), (XLVI), (XLVII), (XLVIII), (XLIX), (L), (LI), (LII), (LIII), (LIV), (LV), (LVI), (LVII), (LVIII), or pharmaceutically acceptable salts thereof) and the active agents of this disclosure (e.g., active agents 1-27, their deuterated variants, pharmaceutically acceptable salts of the active agents, or pharmaceutically acceptable salts of the deuterated variants of the active agents) are generally designed to be positive allosteric modulators of NMDA receptor function and are therefore useful, for example, in the treatment and prevention of CNS-related conditions in subjects.

[0251] In some embodiments, the compounds, active ingredients, pharmaceutically acceptable salts, deuterated variants, or combinations thereof described herein are generally designed to penetrate the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier).

[0252] In certain embodiments, the compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof of the disclosed herein are positive allosteric modulators (PAMs) of the NMDA receptor and activate NMDA receptor function. In certain embodiments, the compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof of the disclosed herein The combination is a negative allosteric modulator (NAM) of the NMDA receptor and inhibits NMDA receptor function. In certain embodiments, the compound, active agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof is a neutral allosteric ligand (NAL) of the NMDA receptor, which binds at the allosteric site and blocks the effects of PAM and / or NAM on the NMDA receptor.

[0253] In one embodiment, the present disclosure provides a method for inducing allosteric modulation of the NMDA receptor in a subject, the method comprising administering an effective amount of the compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, to the subject. In some embodiments, the method is for inducing positive allosteric modulation of the NMDA receptor in the subject. In some embodiments, the method is for inducing negative allosteric modulation of the NMDA receptor in the subject. In some embodiments, the method comprises binding the NMDA receptor at an allosteric site with the compounds disclosed herein and blocking the effects of allosteric NMDA modulogenators (i.e., PAM and / or NAM) in the subject.

[0254] In one embodiment, the present disclosure provides a method for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject, the method comprising administering an effective amount of a compound, active agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or a pharmaceutical composition thereof, to a subject. In some embodiments, treating the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in the subject. In some embodiments, treating the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in the subject.

[0255] In one embodiment, the disclosure provides a method for treating a CNS-related condition in a subject, the method comprising administering an effective amount of a compound, active substance, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or a pharmaceutical composition thereof, to the subject.

[0256] In one embodiment, the Disclosure provides a method for preventing a disease, disorder, or condition requiring allosteric NMDA receptor modulation in a subject, the method comprising administering an effective amount of a compound, active agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or a pharmaceutical composition thereof, to the subject. In some embodiments, the prevention of the disease, disorder, or condition requires positive allosteric NMDA receptor modulation in the subject. In some embodiments, the prevention of the disease, disorder, or condition requires negative allosteric NMDA receptor modulation in the subject.

[0257] In one embodiment, the Disclosure provides a method for preventing a CNS-related condition in a subject, the method comprising administering an effective amount of a compound, active substance, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or a pharmaceutical composition thereof, to the subject.

[0258] In one embodiment, the present disclosure provides a method for inducing sedation or anesthesia in a subject, comprising administering to the subject an effective amount of a compound, active substance, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or pharmaceutical composition thereof, disclosed herein.

[0259] In one embodiment, the present disclosure provides compounds, activators, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions thereof, for use in inducing allosteric modulation of the NMDA receptor in a subject. In some embodiments, the compound, active substance, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or pharmaceutical composition is intended for use in inducing positive allosteric modulation of the NMDA receptor in a subject. In some embodiments, the compound, active substance, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or pharmaceutical composition is intended for use in inducing negative allosteric modulation of the NMDA receptor in a subject.

[0260] In one embodiment, the Disclosure provides compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for use in the treatment of diseases, disorders, or conditions requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the treatment of a disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, the treatment of a disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject.

[0261] In one embodiment, the disclosure provides compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein for use in the treatment of CNS-related conditions in subjects.

[0262] In one embodiment, the Disclosure provides compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for use in preventing diseases, disorders, or conditions requiring allosteric NMDA receptor modulation in a subject. In some embodiments, preventing a disease, disorder, or condition requires positive allosteric NMDA receptor modulation in the subject. In some embodiments, preventing a disease, disorder, or condition requires negative allosteric NMDA receptor modulation in the subject.

[0263] In one embodiment, the disclosure provides compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for use in the prevention of CNS-related conditions in a subject.

[0264] In one embodiment, the disclosure provides compounds, active substances, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for use in inducing sedation or anesthesia in a subject.

[0265] In one embodiment, the present disclosure provides the use of compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for the manufacture of a pharmaceutical product for inducing allosteric modulation of the NMDA receptor in a subject. In some embodiments, the pharmaceutical product is for inducing positive allosteric modulation of the NMDA receptor in a subject. In some embodiments, the pharmaceutical product is for inducing negative allosteric modulation of the NMDA receptor in a subject.

[0266] In one embodiment, the Disclosure provides the use of compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for the manufacture of agents for treating diseases, disorders, or conditions requiring allosteric NMDA receptor modulation in a subject. In some embodiments, treating a disease, disorder, or condition requires positive allosteric NMDA receptor modulation in a subject. In some embodiments, treating a disease, disorder, or condition requires negative allosteric NMDA receptor modulation in a subject.

[0267] In one embodiment, the disclosure provides the use of compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for the manufacture of agents for treating CNS-related conditions in a subject.

[0268] In one embodiment, the Disclosure provides the use of compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for the manufacture of agents for preventing diseases, disorders, or conditions requiring allosteric NMDA receptor modulation in a subject. In some embodiments, the agent is for preventing diseases, disorders, or conditions requiring positive allosteric NMDA receptor modulation in a subject. In some embodiments, the agent is for preventing diseases, disorders, or conditions requiring negative allosteric NMDA receptor modulation in a subject.

[0269] In one embodiment, the disclosure provides a compound used, active agent, pharmaceutically acceptable salt, deuterated variant, or combination thereof, or pharmaceutical composition disclosed herein, for the manufacture of a drug for preventing a CNS-related condition in a subject.

[0270] In one embodiment, the disclosure provides the use of compounds, active agents, pharmaceutically acceptable salts, deuterated variants, or combinations thereof, or pharmaceutical compositions disclosed herein, for the manufacture of agents for inducing sedation or anesthesia in a subject.

[0271] In some embodiments, a method for treating a disease, disorder, or condition involves administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition of the Disclosure in combination with one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are administered simultaneously with the compound, pharmaceutically acceptable salt, or pharmaceutical composition of the Disclosure. In some embodiments, one or more additional therapeutic agents and the compound, pharmaceutically acceptable salt, or pharmaceutical composition of the Disclosure are administered sequentially. In some embodiments, one or more additional therapeutic agents are administered before the compound, pharmaceutically acceptable salt, or pharmaceutical composition of the Disclosure. In some embodiments, one or more additional therapeutic agents are administered after the compound, pharmaceutically acceptable salt, or pharmaceutical composition of the Disclosure.

[0272] Examples of CNS conditions associated with positive allosteric regulation of NMDA receptors include, but are not limited to, dysregulation, anxiety disorders (such as obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairment (such as Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (such as depression, bipolar disorder, and dysthymia), schizophrenia or other psychotic disorders (such as schizoaffective disorder and postpartum psychosis), sleep disorders (such as insomnia), substance-related disorders, personality disorders (such as obsessive-compulsive personality disorder), and autism. These include spectrum disorders (such as those involving mutations in scaffold proteins), multiple sclerosis, neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (such as acute and chronic pain), metabolic encephalopathy (such as phenylketonuria), encephalopathy secondary to medical conditions (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (such as status epilepticus and monogenotypes of epilepsy like Dravet disease), stroke, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), and tinnitus.

[0273] Examples of CNS conditions associated with negative allosteric regulation of NMDA receptors include, but are not limited to, dysregulation, stress or stress disorders (such as post-traumatic stress disorder (PTSD)), anxiety disorders (such as obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, social anxiety disorder, and generalized anxiety disorder), cognitive impairments (such as Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactivity disorder (ADHD), eating disorders, mood disorders (e.g., depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidal tendencies, etc.), and schizophrenia spectrum disorders (e.g., schizoaffective disorder). Harm, schizophrenic disorders, etc.), psychotic disorders, sleep disorders (insomnia, etc.), substance abuse-related disorders and / or withdrawal syndromes (e.g., addiction to opioids, cocaine, and / or alcohol), personality disorders (e.g., obsessive-compulsive personality disorder (OCD)), autism spectrum disorders (including those with mutations in scaffolding proteins (e.g., Shank3), Rett syndrome, fragile X syndrome, Anselmann syndrome, etc.), addictive disorders, neurodevelopmental disorders (e.g., Rett syndrome), pain (neuropathic These include pain, injury-related pain syndromes, acute and chronic pain, headaches (e.g., migraines), seizures (grand mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and asymptomatic seizures, etc.) and seizure disorders (e.g., status epilepticus and monogenotype epilepsy such as Dravet disease, and tuberous sclerosis complex (TSC)), vascular diseases (e.g., stroke, ischemia, vascular deformities, etc.), traumatic brain injury, motor disorders (e.g., Huntington's disease, Parkinson's disease, tremors, etc.), neuropsychiatric lupus, and tinnitus.

[0274] Examples of CNS conditions associated with positive allosteric regulation of NMDA receptors include, but are not limited to, dysregulation, anxiety disorders (such as obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairment (such as Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (such as depression, bipolar disorder, and dysthymia), schizophrenia or other psychotic disorders (such as schizoaffective disorder and postpartum psychosis), sleep disorders (such as insomnia), substance-related disorders, personality disorders (such as obsessive-compulsive personality disorder), and autism. These include spectrum disorders (such as those involving mutations in scaffold proteins), multiple sclerosis, neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), attention deficit disorder, attention deficit hyperactivity disorder, pain (such as acute and chronic pain), metabolic encephalopathy (such as phenylketonuria), encephalopathy secondary to medical conditions (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (such as status epilepticus and monogenotypes of epilepsy like Dravet disease), stroke, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), and tinnitus.

[0275] Examples of CNS conditions associated with negative allosteric regulation of NMDA receptors include, but are not limited to, dysregulation, stress or stress disorders (such as post-traumatic stress disorder (PTSD)), anxiety disorders (such as obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, social anxiety disorder, and generalized anxiety disorder), cognitive impairments (such as Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia), as well as attention disorders such as attention deficit hyperactivity disorder (ADHD), eating disorders, mood disorders (e.g., depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidal tendencies), schizophrenia spectrum disorders (e.g., schizoaffective disorder, schizotypal disorder), psychotic disorders, sleep disorders (such as insomnia), substance abuse-related disorders and / or withdrawal syndromes (e.g., opioid, cocaine, and / or alcohol). These include addiction, personality disorders (such as obsessive-compulsive personality disorder (OCD)), autism spectrum disorders (including those with mutations in scaffold proteins (e.g., Shank3), Rett syndrome, fragility X syndrome, Anselmann syndrome), addictive disorders, neurodevelopmental disorders (such as Rett syndrome), pain (neuropathic pain, injury-related pain syndrome, acute pain, and chronic pain, headaches, such as migraines), seizures (grand mal seizures, absence seizures, myoclonic seizures, clonic seizures, tonic seizures, and asymptomatic seizures), seizure disorders (such as status epilepticus and monogenotype epilepsy like Dravet disease), and tuberous sclerosis complex (TSC), vascular diseases (e.g., stroke, ischemia, vascular deformities), traumatic brain injury, motor disorders (such as Huntington's disease, Parkinson's disease, and tremors), neuropsychiatric lupus, and tinnitus.

[0276] Administration regimen In one embodiment, the present disclosure provides lymphatic uptake, metabolism, and release of an active substance in an administration regimen. For example, if a given dose of the compound of the present disclosure is absorbed more efficiently than an equivalent dose of the active substance alone, the dose of the compound provides a desired plasma or lymphatic system concentration of the active substance. They may be adjusted to provide. In some embodiments, the dose of the compound or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt of the compound is selected to provide a desired, effective concentration or dose of the active substance for treating the disease, disorder, or condition disclosed herein, when the compound or a pharmaceutically acceptable salt of the compound is administered to a subject, during lymphatic uptake, metabolism, and release of the active substance.

[0277] In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608- (1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a dose of active substance number 18 of approximately 0.3 mg to 2.1 mg, 0.3 mg to 1.8 mg, 0.3 mg to 1.5 mg, 0.3 mg to 1.2 mg, 0.6 mg to 1.2 mg, 0.6 mg to 1.8 mg, 0.9 mg to 1.2 mg, or 0.9 mg to 1.5 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-2176-2178 of the Disclosure) or 48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-111 Subjects 3, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, and 2105-2107 are administered to subjects in amounts sufficient to provide a dose of approximately 0.3 mg of active substance number 18.In some embodiments, the compounds of the disclosed herein or pharmaceutically acceptable salts thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1 (253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a dose of approximately 0.6 mg of active ingredient number 18. In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1) (253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a dose of approximately 0.9 mg of active ingredient number 18. In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326). (1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a dose of approximately 1.2 mg of active substance number 18. In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1) (253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a dose of approximately 1.5 mg of active ingredient number 18. In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 4648, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 12 (53-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a dose of approximately 1.8 mg of active ingredient number 18.In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1) (253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a dose of approximately 2.1 mg of active ingredient number 18.

[0278] In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-16) (10, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a total daily dose of active substance number 18 of approximately 0.3 mg to 2.1 mg, 0.3 mg to 1.8 mg, 0.3 mg to 1.5 mg, 0.3 mg to 1.2 mg, 0.6 mg to 1.2 mg, 0.6 mg to 1.8 mg, 0.9 mg to 1.2 mg, or 0.9 mg to 1.5 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 4648, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-1255, 1324-1326, 1395-1) (397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a total daily dose of approximately 0.3 mg of active substance number 18. In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 125) (3-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a total daily dose of approximately 0.6 mg of active substance number 18. In some embodiments, the compounds of the disclosed herein or pharmaceutically acceptable salts thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 125 (3-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a total daily dose of approximately 0.9 mg of active substance number 18.In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 125) (3-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a total daily dose of approximately 1.2 mg of active substance number 18. In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 125) (3-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a total daily dose of approximately 1.5 mg of active substance number 18.In some embodiments, the compound or a pharmaceutically acceptable salt thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 125) (3-1255, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to the subject in an amount sufficient to provide a total daily dose of approximately 1.8 mg of active substance number 18. In some embodiments, Compounds or pharmaceutically acceptable salts thereof (e.g., compounds 46-48, 117-119, 188-190, 259-261, 330-332, 401-403, 472-474, 543-545, 614-616, 685-687, 756-768, 827-829, 898-900, 969-971, 1040-1042, 1111-1113, 1182-1184, 1253-125) 5, 1324-1326, 1395-1397, 1466-1468, 1537-1539, 1608-1610, 1679-1681, 1750-1752, 1821-1823, 1892-1894, 1963-1965, 2034-2036, 2105-2107 or 2176-2178) are administered to subjects in an amount sufficient to provide a total daily dose of approximately 2.1 mg of active substance number 18. [Examples]

[0279] The following examples are provided to allow for a more complete understanding of the disclosures contained herein. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope.

[0280] The absolute configuration of an asymmetric center can be elucidated using methods known to those skilled in the art. In some embodiments, the absolute configuration of a chiral center in a compound can be elucidated from the X-ray single crystal structure of the compound. In some embodiments, the absolute configuration of a chiral center elucidated by the X-ray crystal structure of a compound can be used to estimate the absolute configuration of the corresponding chiral center in another compound obtained from the same or similar synthetic methodology. In some embodiments, the absolute configuration of a chiral center elucidated by the X-ray crystal structure of a compound can be used to estimate the absolute configuration of a chiral center in spectroscopic techniques, such as NMR spectroscopy, for example. 1 1H NMR spectroscopy or 19 1F NMR spectroscopy can be used to estimate the absolute configuration of the corresponding chiral center in another compound.

[0281] Abbreviation CSA: Camphor sulfonic acid; DMAP: 4-dimethylaminopyridine; DCM: Dichloromethane; DCC: Dicyclohexylcarbodiimide; TBS: t-Butyldimethylsilyl; MeOH: Methanol; Â: Ethyl acetate; ACN: Acetonitrile; AgOTf: Silver trifluoromethanesulfonate; DCE: 1,2-Dichloroethane; THF: Tetrahydrofuran; TBAF: Tetra-n-butylammonium fluoride; DMP: Des-Martinperiodinane.

[0282] material and method The compounds provided in this disclosure can be prepared from readily available starting materials using the following general methods and procedures. Naturally, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), 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 routine optimization.

[0283] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as 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.

[0284] The compounds provided in this disclosure may be isolated and purified by known standard procedures. These procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details of the preparation of representative compounds disclosed herein. The compounds provided herein may be prepared from starting materials and reagents known or commercially available to those skilled in the art of organic synthesis. Examples of chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK(R) AD-10, CHIRALCEL(R) OB, CHIRALCEL(R) OB-H, CHIRALCEL(R) OD, CHIRALCEL(R) OD-H, CHIRALCEL(R) OF, CHIRALCEL(R) OG, CHIRALCEL(R) OJ, and CHIRALCEL(R) OK.

[0285] The 1H-NMR reported in this disclosure (e.g., for the region between approximately 0.5 and 4 ppm of δ(ppm)) should be understood as exemplary interpretations of the NMR spectrum of the compound (e.g., exemplary peak integrals). Exemplary general method of preparative HPLC: Column: Waters RBridge preparative 10 μm C18, 19 × 250 mm. Mobile phase: Acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min.

[0286] A typical general method for analytical HPLC: Mobile phase: A: Water (10 mM NH4HCO3), B: Acetonitrile, Gradient: 5% to 95% B over 1.6 or 2 mins, Flow rate: 1.8 or 2 mL / min, Column: XBridge C18, 4.6 × 50 mm, 3.5 μm at 45°C.

[0287] Exemplary general method for SFC: Column: CHIRALPAK® AD CSP (250mm × 30mm, 10μm), gradient: 45% B, A=NH3H2O, B=MeOH, flow rate: 60mL / min. For example, AD_3_EtOH_DEA_5_40_25ML would show the following: Column: Chiralpak AD-3 150×4.6mm inner diameter, 3um mobile phase: A:CO2 B:ethanol (0.05% DEA) gradient: 5%~40% B over 5 mins, 40% for 2.5 mins, then hold 5% B for 2.5 mins, flow rate: 2.5mL / min, column temperature: 35℃.

[0288] Example 1: Exemplary general method for the synthesis of the compounds of the present disclosure: PG=protecting group.

[0289] A carboxylic acid of formula (i), which can be prepared according to a procedure known in the art, is dissolved in dichloromethane, treated with dimethylaminopyridine, and then the active substance is added. If the active substance contains two hydroxyl groups, one of the hydroxyl groups is protected, and only the free hydroxyl group reacts with the carboxylic acid of formula (ii) to form the compound of formula (iii). See Panel A. If neither of the hydroxyl groups of the active substance is protected, both can react with two equivalents of the carboxylic acid of formula (i) to form the compound of formula (iv). See Panel B. [ka] During the ceremony, [ka] = One of the active substances 1-27. [ka] During the ceremony, [ka] = One of the active substances 1-27.

[0290] Example 2: Synthesis of Compound 9 [ka]

[0291] Step 1: Synthesis of B [ka]

[0292] To a solution of A (1.00 g, 1.93 mmol) in DCM (10.0 mL), DMAP (236 mg, 1.93 mmol), DCC (798 mg, 3.87 mmol), and 5-((1,3-bis(palmitoyloxy)propan-2-yl)oxy)-5-oxopentanoic acid (1.98 g, 2.90 mmol) were added, N 2(g) The mixture was added at 0°C. After stirring at 20°C for 16 hours, the mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and purified by column chromatography (0-6% dimethyl in petroleum ether) to obtain B (1.5 g, yield 66%). 1 1H NMR (400MHz, CDCl3)δ H 5.31-5.24(m,2H),4.72-4.19(m,1H),4.32-4.28(m,2H),4.15-4.09(m,3H),3.50-3.45(m,1H),2.42-2.29(m,10H),2.04-1.94(m,7H),1. 83-1.76(m,4H),1.62-1.57(m,10H),1.48-1.42(m,2H),1.27-1.25(m,50H),0.99(s,5H),0.92-0.86(m,26H),0.66(s,3H),0.053(s,6H).

[0293] Step 2: Synthesis of Compound 9 [ka]

[0294] To a solution of B (1.20 g, 1.02 mmol) in DCM (10 mL) and MeOH (10 mL), add camphor sulfonic acid (70.8 mg, 0.305 mmol) to N 2(g)The compound was added at 0°C below. After stirring for 1 hour, the mixture was quenched with water (5 mL) and extracted with DCM (2 × 5 mL). The combined organic layer was washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and purified by SFC (column: Chiralpak IK-3 50 × 4.6 mm ID, 3 μm, mobile phase: CO₂ phase A and MeOH phase B (0.05% DEA), isocratic elution: 40% B in A, flow rate: 3 mL / min, detector: PDA, column temperature: 35°C, back pressure: 100 Bar) to obtain compound 9 (505.6 mg, yield 42%). 1 1H NMR (400MHz, CDCl3)δ H 5.34-5.33(m,1H),5.27-2.25(m,1H),4.70-4.69(m,1H),4.32-4.28(m,2H),3.52-3.49(m,1H),2.42-2.29(m,10H),1 .97-1.79(m,9H),1.59-1.48(m,14H),1.25(s,50H),1.15-1.07(m,5H)1.00(s,4H),0.92-0.88(m,17H),0.67(s,3H). 13 ¹³C NMR (10¹ MHz, CDCl3) δ c 173.28,172.64,172.03,140.77,121.65,79.18,77.34,77.03,76.70,71.77,69.16,62.03,56.73,50.09,42.32,36.49 ,34.02,31.93,31.66,29.71,29.49,29.37,29.13,24.85,22.69,20.25,19.39,18.79,17.30,14.12,11.85.LC-ELSD / MS 50-100AB_6min_ELSD_2000, purity>99%;C 67 H 118 O9Na[M+Na] + The MS ESI calculated value was 1089.9, and the measured value was 1089.7.

[0295] Example 3: Synthesis of Compound 19 [ka]

[0296] Step 1: Synthesis of Compound C-2

[0297] To a solution of compound C-1 (8.50 g, 13.5 mmol) in MeOH (80.0 mL), add K2CO3 (3.72 g, 26.9 mmol) and KOH (1.51 g, 26.9 mmol) in N2. 2(g) The mixture was added at 20°C below. After stirring at 60°C for 16 hours, the mixture was diluted with dimethyl (100 mL), washed with H2O (2 × 80 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by recrystallization from ACN (100 mL) to obtain compound C-2 (4.10 g, yield 58.9%). 1 1H NMR (400MHz, CDCl3)δ H 5.33-5.29(m,1H),3.54-3.36(m,3H),2.32-1.92(m,5H),1.85-1.69(m,3H),1.65-1.50(m,6H),1.49-1 .17(m,10H),1.16-0.97(m,10H),0.93-0.90(m,5H),0.89-0.87(m,8H),0.79-0.64(m,3H),0.06(s,6H).

[0298] Step 2: Synthesis of Compound C-4

[0299] In a solution of compound C-3 (3.17 g, 4.64 mmol) in DCE (20 mL), CC (1.20g, 5.80 mmol) and DMAP (473mg, 3.87 mmol) were added to N 2(g)下で50℃で添加した。 After stirring at 20°C for 30 minutes, compound C-2 (2.00 g, 3.87 mmol) was added to the mixture. After stirring at 50°C for 16 hours, the mixture was filtered, concentrated, and purified by silica gel chromatography (0-4% siRNA in petroleum ether) to obtain compound C-4 (1.03 g, yield 22.5%). 1 1H NMR (400MHz, CDCl3)δ H5.36-5.15(m,2H),4.37-4.25(m,2H),4.19-4.07(m,2H),4.03-3.78(m,2H),3.52-3.43(m,1H),2.45-2.25(m,9H),2.08-1.90(m,6H) ,1.84-1.68(m,7H),1.66-1.56(m,9H),1.51-1.44(m,3H),1.30-1.23(m,54H),1.06-0.95(m,7H),0.92-0.85(m,19H),0.79-0.59(m,3 H),0.05(s,6H).

[0300] Step 3: Synthesis of Compound 19

[0301] To a solution of compound C-4 (2.00 g, 1.69 mmol) in a mixture of DCM (10 mL) and MeOH (10 mL), camphor sulfonic acid (118 mg, 0.508 mmol) was added. 2(g) The compound was added at 0°C. After stirring at 0°C for 1 hour, the mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography (0%-10% ethyl acetate in petroleum ether). Further purification by SFC (instrument: CAS-CD-Prep-SFC-F, column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), conditions: CO₂-i-PrOH, start B: 35, end B: 35, gradient time (8.8 min), 100% B retention time (0 min), flow rate (70 mL / min), injection: 266, Rt = 1.622 min) yielded compound 19 (520.0 mg, yield 44.1%). 1 1H NMR (400MHz, CDCl3)δ H5.38-5.32(m,1H),5.30-5.18(m,1H),4.34-4.26(m,2H),4.19-4.09(m,2H),4. 02-3.91(m,1H),3.91-3.79(m,1H),3.59-3.45(m,1H),2.44-2.35(m,4H),2.34 -2.20(m,6H),2.06-1.91(m,4H),1.89-1.76(m,4H),1.63-1.57(m,5H),1.50-1 .42(m,5H),1.25(s,54H),1.13-0.98(s,12H),0.93-0.85(m,12H),0.68(s,3H). 13 C NMR (101MHz, CDCl3)δ c 173.28,173.28,172.91,172.02,140.77,122.10,121.69,102.48,71.81,69.60,69.20,68.81,62.02,58.77,56.11,50.14,42.34,42.32,39.79,37.26,36.51,36.17,36.06,35.77,35.72,34.20,34.03,33.79,33.23,33.18,33.04,32.58,31.93,31.93,3 1.80, 31.66, 29.70, 29.70, 29.70, 29.67, 29.67, 29.67, 29.63, 29.46, 29.36, 29.27, 29.12, 28.95, 28.25, 24.89, 24.85, 24.85, 24.29, 23.28, 22.69, 22.69, 22.60, 21.09, 20.08, 19.39, 19.34, 16.67, 16.83, 14.11, 14.11, 11.88, 1.10. LC-ELSD / MS purity > 99%, C 27 H 45 [M+HC 40 H 74 O9] + The calculated value of MS ESI is 369.3, and the measured value is 369.3.

[0302] Example 4: Synthesis of Compound 194

change

[0303] Step 1: Synthesis of Compound D-2

[0304] (R)-6-((3S,5S,8R,9S,10S,13R,14S,17R)-3-(benzyloxy)-3-ethyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-methylheptan-2-ol (I, 836 mg, 1.60 mmol) was dissolved in DCE (18.0 mL), to which AgOTf (123 mg, 4.82 mmol) and 2,6-di-tert-butylpyridine (1.07 mg, 5.62 mmol) were added at 20°C. The reaction mixture was cooled to 0°C, and compound D-1 (1.8 g, 2.41 mmol) was added. After stirring at 40°C for 16 hours, the mixture was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine (2 × 300 mL), dried over anhydrous Na₂SO₄, filtered, and purified by flash column (0-3% siRNA in petroleum ether) to obtain compound D-2 (1.03 g, yield 52%). 1 1H NMR (400MHz, CDCl3)δ H 7.38-7.27(m,4H),7.24-7.16(m,1H),5.42-5.36(m,2H),5.28-5.20(m,1H), 4.41(s,2H),4.25-4.32(m,2H),4.18-4.07(m,2H),2.50-2.35(m,3H),2.32- 2.25(m,4H),1.99-1.92(m,1H),1.78-1.58(m,13H),1.55-1.45(m,10H),1.2 5(s,48H),1.21(s,7H),1.10-1.02(m,8H),0.94-0.82(m,22H),0.65(s,4H).

[0305] Step 2: Synthesis of Compound 194

[0306] In a solution of compound D-2 (1.5 g, 1.21 mmol) in THF (15 mL), H 2(g)Pd / C (800 mg, 10% palladium-carbon, 1% water-moistened) was added below. After stirring at 40°C for 16 hours, the mixture was filtered through a Celite pad, washed with THF (100 mL), filtered, concentrated, and purified by flash column (0-7% toluene in petroleum ether) to obtain compound 194 (716.1 mg, yield 17%). 1 1H NMR (400MHz, CDCl3)δ H 5.38-5.32(m,2H),5.30-5.25(m,1H),4.32-4.26(m,2H),4.17-4.10(m,2H),2.49-2.3 4(m,3H),2.33-2.21(m,6H),1.99-1.92(m,1H),1.83-1.75(m,1H),1.65-1.51(m,13H), 1.48-1.34(m,9H),1.31-1.23(m,51H),1.21(s,6H),1.19-0.96(m,11H),0.92-0.85(m ,13H),0.83(s,3H),0.65(s,4H).QNMR(1,2,4,5-tetrachloro-3-nitrobenzene,99.8% as IS)95.68% wt found. 13 ¹³C NMR (10¹ MHz, CDCl3) δ C 173.26, 171.66, 171.31, 84.17, 78.13, 72.80, 69.06, 62.04, 56.50, 56.25, 54.54, 43.66, 42.61, 40.01, 35.90, 35.76, 35.49, 33.98, 31.90, 29.68, 29.46, 29.34, 29.24, 29.10, 26.12, 24.81, 22.66, 19.59, 14.10, 12.06, 7.08.

[0307] Example 5: Synthesis of Compound 121 [ka]

[0308] Step 1: Synthesis of Compound E-3

[0309] Two batches were prepared as follows: To a solution of compound E-2 (1.00 g, 1.91 mmol) in DCE (10 mL), AgOTf (1.46 g, 5.72 mmol) and 2,6-di-tert-butylpyridine (1.27 g, 6.68 mmol) were added at 20°C. Compound E-1 (2.79 g, 3.82 mmol) was added to the reaction mixture at 0°C. After stirring at 40°C for 16 hours, the reaction product was quenched with H2O (20 mL) and extracted with DCM (2 × 50 mL). The combined organic phases were washed with saturated brine (2 × 40 mL). The organic layers from both batches were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The compound E-3 (3.0 g, 65% yield) was obtained by purification using a flash column (0-5% alkyl group in petroleum ether). 1 1H NMR (400MHz, CDCl3)δ H 7.39-7.27(m,4H),7.26-7.19(m,1H),5.40-5.33(m,2H),5.29-5.22(m,1H),4 .48-4.34(m,2H),4.34-4.27(m,2H),4.17-4.09(m,2H),2.43-2.25(m,4H),2. 33-2.28(m,4H),2.00-1.91(m,3H),1.75-1.59(m,10H),1.57-1.41(m,10H),1 .36-1.23(m,58H),1.23-1.16(m,8H),0.98-0.80(m,17H),0.70-0.58(m,4H).

[0310] Step 2: Synthesis of Compound 121

[0311] A mixture of compound E-3 (3.0 g, 2.46 mmol) and Pd / C (1.1 g, 10% palladium-carbon) in THF (150 mL) was hydrogenated at 25°C for 16 hours under 25 psi of hydrogen. The reaction mixture was filtered through Celite, washed with THF (100 mL), concentrated, and purified by flash column (0-3% butyl in petroleum ether) to obtain compound 121 (953.7 mg, yield 31%). 1 1H NMR (400MHz, CDCl3)δ H5.45-5.30(m,2H),5.29-5.22(m,1H),4.34-4.24(m,2H),4.19-4.07(m,2H),2.44-2.34(m,4H),2.34-2.27(m,4H),2.02-1.90(m,3H),1 .58-1.53(m,12H),1.46-1.33(m,9H),1.31-1.23(m,50H),1.22-1.19(m,8H),1.12-0.94(m,8H),0.92-0.79(m,17H),0.67-0.61(m,4H). 13 C NMR(101MHz,CDCl3)δC=173.28,171.96,84.25,78.15,77.35,72.80,69.20,62.00,56.53,54.57,43. 70,40.05,35.53,34.01,33.13,31.93,29.70,29.12,24.84,24.19,22.69,19.81,14.11,12.10,7.10.

[0312] Example 6: Synthesis of Compound 80 [ka]

[0313] Step 1: Synthesis of Compound F-2

[0314] Two batches were prepared as follows: To a solution of compound F-1 (2.50 g, 4.84 mmol) in DCM (25.0 mL), AgOTf (3.73 g, 14.5 mmol) and 2,6-di-tert-butylpyridine (3.24 g, 3.79 mL, 16.9 mmol) were added under N2 conditions at 25°C. Benzyl(chloromethyl)glutarate (3.93 g, 14.5 mmol) was added at 0°C, and the reaction mixture was stirred at 25°C for 30 minutes. Both batches were combined and NH4Cl (水溶液) The mixture was quenched with (100 mL) and extracted with toluene (2 × 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium 2SO4, filtered, concentrated, and purified by column chromatography (0-3% toluene in petroleum ether) to obtain compound F-2 (4.30 g, 50% yield).1 1H NMR (400MHz, CDCl3)δ H 7.38-7.31(m.5H),5.37-5.26(m,3H),5.11(s,1H),3.52-3.43(m,1H),3.32-3.25(m,1H),2.45-2.35(m,3H),2.30-2.11(m,2H) ),2.02-1.94(m,4H),1.84-1.64(m.6H),1.25-0.98(m,14H),0.95-0.85(m,25H),0.70-0.64(m,4H),0.06(s,6H).

[0315] Step 2: Synthesis of Compound F-3

[0316] In a solution of compound F-2 (5.00 g, 6.66 mmol) in THF (50.0 mL), Ar (g) Below, 10% Pd / C (500 mg, 4.7 mmol) was added in a wet state. The suspension was degassed under vacuum and H 2(g) The mixture was purged three times. 2(g) The mixture was stirred at 25°C for 2 hours under (15 psi) pressure to obtain a black suspension. The reaction mixture was filtered through a Celite pad and washed with THF (100 mL). The filtrate was concentrated to obtain compound F-3 (4.30 g, 80%).

[0317] Step 3: Synthesis of Compound F-4

[0318] To a solution of 2-hydroxypropane-1,3-diyldipalmitinate (4.54 g, 7.99 mmol) in DCE (45.0 mL), add DCC (2.06 g, 9.98 mmol) and DMAP (813 mg, 6.66 mmol) and heat at 25°C. 2(g)Compound F-3 (4.30 g, 6.66 mmol) was added as described below, and the reaction mixture was stirred at 50°C for 16 hours. The mixture was quenched with water (200 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were washed with water (200 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by silica gel chromatography (0% to 3% ethyl acetate in petroleum ether) to obtain compound F-4 (2.70 g, 33.5%). 1 1H NMR (400MHz, CDCl3)δ H 5.33-5.25(m,4H),4.33-4.48(m,2H),4.15-4.11(m,2H),3.53-3.42(m,1H),3.30-3.25(m,1H),2.43-2.38(m,5H),2.33-2.28 (m,5H),2.05-1.92(m,5H),1.83-1.63(m,5H),1.32-1.23(m,65H),0.99(s,5H),0.90-0.85(m,25H),0.67(s,3H),0.06(s,6H).

[0319] Step 4: Synthesis of Compound 80

[0320] To a solution of compound F-4 (2.7 g, 2.2 mmol) in THF (20.0 mL), add TBAF (4.5 mL, 1.00 M in THF, 4.5 mmol). N2(g) The mixture was added at 25°C and the reaction was stirred at 25°C for 16 hours. The mixture was then mixed with NH4Cl (水溶液) The mixture was quenched with (50 mL) and extracted with toluene (2 × 50 mL). The combined organic layer was washed with water (50 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 13% toluene in petroleum ether) to obtain compound 80 (766.7 mg, 0.6985 mmol, yield 31%). 1 1H NMR (400MHz, CDCl3)δ H5.37-5.22(m,4H),4.34-4.26(m,2H),4.16-4.10(m,2H),3.58-3.47(m,1H ),3.31-3.24(m,1H),2.42-2.38(m,4H),2.32-2.22(m,6H),2.03-1.93(m, 4H),1.86-1.73(m,4H),1.62-1.58(m,5H),1.50-1.43(m,4H),1.34-1.21( m,54H),1.18-1.05(m,5H),1.01(s,4H),0.94-0.84(m,17H),0.68(s,3H). 13 ¹³C NMR (10¹ MHz, CDCl3) δ C 173.275, 172.407, 171.942, 140.745, 121.653, 88.803, 86.026, 71.775, 69.189, 61.982, 56.729, 55.880, 50.088, 42.323, 39.756, 36.486, 34.010, 33.115, 31.918, 29.689, 29.653, 29. 479,29.351,29.260,29.114,24.838,22.682,19.375,18.745,18.416,14.114,11.857.LC-ELSD / MS LIPID_50-100AB_6 min_ELSD_2000.M(purity 100.0%), MS ESI C 68 H 120 O 10 Na[M+Na] + The calculated value 1119.88 for C could not be found. 35 H 67 O4[MC 35 H 67 O4] + The detected fragment with a calculated value of 551.5 corresponds to an actual measured value of 551.5.

[0321] Example 7: Synthesis of Compound 293 [ka]

[0322] Step 1: Synthesis of Compound G-3

[0323] To a solution of compound G-2 (1.00 g, 1.93 mmol) in DCM (10.0 mL), add AgOTf (1.49 g, 5.80 mmol) and 2,6-di-tert-butylpyridine (1.30 g, 1.52 mL, 6.77 mmol). N2(g) The mixture was then added at 25°C. The mixture was then cooled to 0°C, and compound G-1 (1.11 g, 1.93 mmol) was added. The reaction mixture was heated to 25°C and stirred for 16 hours, and then saturated NH4Cl was added. (水溶液) The mixture was quenched with (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by flash chromatography (0-10% siRNA in petroleum ether) to obtain compound G-3 (700 mg, yield 34.4%). 1 1H NMR (400MHz, CDCl3)δ H 5.35-5.21 (m, 2H), 3.55-3.41 (m, 1 H),3.32-3.24(m,3H),3.22-3.15(m,2H),2.47-2.33(m,4H),2.30-2.11(m,2H),2.06-1.94(m,4H),1.87-1.67(m,4H),1.54-1.39(m, 10H),1.34-1.26(m,50H),1.19-1.03(m,5H),1.00(s,3H),0.92(d,J=6.4Hz,3H),0.90-0.84(m,23H),0.68-0.63(m,3H),0.06(s,6H).

[0324] Step 2: Synthesis of Compound 293

[0325] To a solution of compound G-3 (700 mg, 665 μmol) in THL (30.0 mL), add TBAF (87.3 mg, 2.66 mL, 1.00 mol, 2.66 mmol) and N 2(g) The mixture was added at 25°C. The reaction mixture was stirred at 25°C for 4 hours, and then saturated NH4Cl (水溶液)The mixture was quenched with (5 mL) and extracted with ₹ (2 × 20 mL). The combined organic layers were washed with water, dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified twice by silica gel chromatography (0-15% ₹ in petroleum ether). The mixture was then purified by SFC (column: DAIEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), conditions: CO₂-EtOH (0.1% NH₃H₂O), start B: 35, end B: 35, gradient time (45 min), 100% B retention time (0 min), flow rate (80 mL / min), injection: 60) to obtain compound 293 (222 mg, yield 35.5%). 1 H NMR(400MHz,CDCl3)δ=5.36-5.32(m,1H),5.32-5.23(m,2H),3.58-3.47(m,1H),3.32-3. 24(m,3H),3.23-3.14(m,2H),2.49-2.34(m,4H),2.33-2.16(m,2H),2.07-1.91(m,4H),1 .89-1.74(m,4H),1.56-1.33(m,15H),1.31-1.21(m,46H),1.17-1.03(m,5H),1.01(s,3H) ),0.99-0.96(m,1H),0.92(d,J=6.4Hz,3H),0.90-0.84(m,12H),0.67(s,3H).LC-ELSD / MS ESI C 61 H 112 The calculated value of 938.8 for NO5[M+H]+ is the same as the measured value of 938.8.

[0326] Example 7: Synthesis of Compound 334 [ka]

[0327] Step 1: Synthesis of compound H-2

[0328] To a solution of dihydro-2H-pyran-2,6(3H)-dione (2.78 g, 24.4 mmol) in toluene (80 mL), compound H-1 (10.0 g, 24.4 mmol) was added. 2(g)The mixture was added as shown below. The mixture was heated to 85°C for 3 hours, and then concentrated to obtain compound H-2 (12 g, 94% yield). 1 1H NMR (400MHz, CDCl3)δ H 3.35-3.26(m,2H),3.24-3.13(m,2H),2.45(q,J=6.8Hz,4H),2.03-1.92(m,2H),1.59-1.46(m,4H),1.37-1.17(m,45H),0.88(t,J=6.8Hz,6H).

[0329] Step 2: Synthesis of compound H-3

[0330] A solution of compound H-2 (12.0 g, 22.9 mmol) and ammonium tetra(buta-1-yl) sulfate (778 mg, 2.29 mmol) in DCM (120 mL) is prepared by adding K2C. A solution of O3 (12.7g, 91.6 mmol) in H2O (120mL) is N 2(g) The mixture was added as shown below. The mixture was stirred at 25°C for 0.1 hours, and then a solution of chloromethylchlorosulfate (5.67 g, 34.4 mmol) in DCM (120 mL) was added dropwise. The mixture was stirred at 25°C for 16 hours, and then DCM (100 mL) and brine (100 mL) were added to the mixture. The organic layer was separated and concentrated, and the residue was purified by flash chromatography (0-20% dimethyl in petroleum ether) to obtain compound H-3 (6 g, yield 46%). 1 1H NMR (400MHz, CDCl3)δ H 5.70(s,2H),3.33-3.24(m,2H),3.22-3.10(m,2H),2.49(t,J=7.2Hz,2H),2.37(t,J=7.2 Hz,2H),2.11-1.91(m,2H),1.58-1.44(m,4H),1.29-1.21(m,44H),0.88(t,J=6.8Hz,6H).

[0331] Step 3: Synthesis of Compound H-5

[0332] To a solution of compound H-4 (2.00 g, 3.83 mmol) in DCM (20.0 mL), AgOTf (2.95 g, 11.5 mmol) and 2,6-di-tert-butylpyridine (2.56 g, 3.00 mL, 13.4 mmol) were added. 2(g) The mixture was added at 25°C. The mixture was cooled to 0°C, and compound H-3 (2.19 g, 3.83 mmol) was added. The mixture was heated to 25°C and stirred for 16 hours, then saturated NH4Cl was added. (水溶液) The mixture was quenched with (20 mL) and extracted with Ã(2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and the residue was purified by flash chromatography (0-10% Ã in petroleum ether) to obtain compound H-5 (1.50 g), which was ground with MeOH (50.0 mL) at 25°C for 1 hour. The mixture was filtered and concentrated to obtain compound H-5 (800 mg, yield 21.6%). 1 1H NMR (400MHz, CDCl3)δ H 7.39-7.27(m,5H),5.35(s,2H),4.41(s,2H),3.30-3.24(m,2H),3.22-3.15(m,2H),2.43-2.32( m,4H),2.02-1.87(m,4H),1.83-1.59(m,9H),1.54-1.43(m,9H),1.33-1.24(m,58H),1.13-1.04 m,4H),0.93-0.85(m,15H),0.83(s,3H),0.65(s,4H).

[0333] Step 4: Synthesis of Compound 334

[0334] To a solution of compound H-5 (700 mg, 661 μmol) in THF (15.0 mL), Pd / C (700 mg, 6.58 mmol) was added. 2(g) The mixture was then added at 25°C below. Next, the mixture was heated to 15 psi of H 2(g) The mixture was stirred at 25°C for 24 hours, then the reaction mixture was filtered and concentrated. The residue was purified twice by flash chromatography (0-15% siRNA in petroleum ether) to obtain compound 334 (221.7 mg, 30.2% yield). 11H NMR (400MHz, CDCl3)δ H 5.35(s,2H),3.32-3.24(m,2H),3.23-3.11(m,2H),2.46-2.28(m,4H),2.03-1.91(m,3H),1.86-1.74(m,1H),1.68-1.36 (m,22H),1.30-1.25(m,44H),1.20(s,8H),1.17-0.93(m,9H),0.92-0.85(m,13H),0.82(s,3H),0.64(s,4H).LC-ELSD / MS ESI C 63 H 118 The calculated value of 968.8 for NO5[M+H]+ is the same as the measured value of 968.8.

[0335] Example 7: Synthesis of Compound 222 [ka]

[0336] Step 1: Synthesis of Compound I-3

[0337] In a solution of compound I-2 (1.00 g, 1.93 mmol) in DCM (2.00), Silver(I) trifluoromethanesulfonate (1.49 g, 5.80 mmol) and 2,6-di-tert-butylpyridine (1.30 mmol) were added under N2 (g) at 25°C. g (6.77 mmol) was added, and the reaction mixture was then cooled to 0°C. 2-(3-(chloromethoxy)-3-oxopropyl)-1,3-dioxan-5-ylpalmitate I-1 (985 mg, 2.13 mmol) was added. The reaction mixture was heated to 25°C and stirred for 16 hours. The reaction mixture was directly purified by flash chromatography (0-6% ethyl ether in petroleum ether) to obtain compound I-3 (960 mg, yield 53%). 1H NMR(400MHz,CDCl3)5.29(s,2H),5.11-4.99(m,1H),4.34-4.22(m,1H),4.13-3.56(m,4H),3.53-3.43(m,1H),3.29-3.27(m,1H),2 .46(q,J=8.0Hz,2H),2.33(t,J=7.6Hz,2H),2.28-1.59(m,14H),1.47-1.22(m,33H),1.09-0.81(m,32H),0.67(s,3H),0.05(s,6H).

[0338] Step 2: Synthesis of Compound 222

[0339] Solution of compound I-3 (832 mg, 0.882 mmol) in THF (4.00 mL) TBAF (692 mg, 2.65 mmol) was added under N2 (g) at 25°C. After stirring at 25°C for 16 hours, the reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (2 × 50 mL), washed with brine (2 × 50 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by flash chromatography (0-12% ethyl acetate in petroleum ether) and SFC (column: DAIEL CHIRALCEL OD (250 mm × 30 mm, 10 μm), conditions: CO2-MeOH, start B: 50, end B: 50, gradient time (min): 7, flow rate (ml / min): 70, injection: 140) to obtain compound 222 (200.6 mg, yield 27%). 1 H NMR(400MHz,CDCl3)5.36-5.25(m,1H),5.29(s,2H),5.12-4.97(m,1H),4.27-3.53(m,5H),3.32-3.23(m,1H),2.46(q,J=8.0Hz,2H ),2.34(t,J=7.6Hz,2H),2.29-1.76(m,10H),1.67-1.46(m,12H),1.34-1.22(m,26H),1.18-0.84(m,23H),0.68(s,3H).LC-ELSD / MS MS ESI C 29 H 49 [M+HC 22 H 40 O8] +The calculated value is 397.4, and the measured value is 397.4.

[0340] Example 7: Synthesis of Compound 263 [ka]

[0341] Step 1: Synthesis of Compound J-2

[0342] To a solution of 1,3-bis(benzyloxy)propan-2-ol (6.00 g, 22.0 mmol) in DCM (150 mL), pyridine (8.71 g, 110 mmol), palmitic acid chloride compound J-1 (15.1 g, 55.1 mmol), and DMAP (135 mg, 1.10 mmol) were added. 2(g) It was added at 25°C below. 25 ℃ After stirring for 2 hours, the reaction mixture, saturated NaHCO3, 3(水溶液) Quench with (200 mL), The mixture was extracted using DCM (3 × 200 mL), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography (0-6% toluene in petroleum ether) to obtain compound J-2 (11.8 g, 98% yield). 1 H NMR(400MHz,CDCl3)7.36-7.26(m,10H),5.26-5.19(m,1H),4.59-4.48(m,4H),3.66-3. 55(m,4H),2.3-2.31(m,2H),1.64-1.60(m,2H),1.26-1.24(m,24H),0.90-0.86(m,3H).

[0343] Step 2: Synthesis of Compound J-3

[0344] To a solution of compound J-2 (10.0 g, 19.6 mmol) in SiO (150 mL), add wet Pd / C (1.04 g, 0.979 mmol) and N 2(g) It was added below. Then, the reaction mixture was heated to 30 psi of H 2(g) 45 ℃The mixture was stirred for 16 hours, then filtered and concentrated to obtain compound J-3 (8g), which was used directly without purification.

[0345] Step 3: Synthesis of Compound J-6

[0346] To a solution of benzyl 4-hydroxybutanoate compound J-5 (4.00 g, 20.6 mmol) in DCM (40.0), add DMP (17.5 g, 41.2 mmol) 2(g) The mixture was added at 25°C. After stirring at 25°C for 2 hours, the reaction mixture was quenched with 400 mL of a 1:1 mixture of saturated NaHCO3 aqueous solution and Na2S2O3 solution, extracted with DCM (2 × 100 mL), and the combined organic layer was concentrated to obtain compound J-6 (4 g), which was used directly without purification.

[0347] Step 4: Synthesis of Compound J-7

[0348] Compound J-3 (8.00 g, 24.2 mmol) in toluene (80.0 mL) is mixed with compound J-6 (3.88 g, 20.2 mmol) and p-toluenesulfonic acid monohydrate (76.7 mg, 0.403 mmol) in N 2(g) The compound was added at 25°C below. The reaction mixture was heated to 110°C, stirred for 2 hours, then quenched with water (20 mL), extracted with toluene (2 × 200 mL), and the combined organic layer was dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by flash chromatography (0-10% toluene in petroleum ether) to obtain compound J-7 (5.1 g, 50% yield over 3 steps). 1 H NMR(400MHz,CDCl3)7.39-7.26(m,5H),5.17-5.10(m,2H),5.09-4.98(m,1H),4.26-3.54(m,5H),2.49(q,J=8. 0Hz,2H),2.35-2.30(m,2H),2.10-2.00(m,2H),1.64-1.59(m,2H),1.28-1.23(m,24H),0.88(t,J=6.8Hz,3H).

[0349] Step 5: Synthesis of Compound J-8

[0350] To a solution of compound J-7 (5.10 g, 10.1 mmol) in SiO (5.00 mL), add wet Pd / C (1.08 g, 1.01 mmol). N2(g) The mixture was then added at 25°C below. Next, the mixture was heated to 30 psi of H 2(g) The mixture was stirred at 45°C for 16 hours, then filtered and concentrated to obtain compound J-8 (4.1 g), which was used directly without purification.

[0351] Step 6: Synthesis of Compound J-9

[0352] Compound J-8 (4.10 g, 9.9 g) in 1:1 DCM:H2O (4.00 mL) at 0°C. To a mixture of 89 mmol, sodium carbonate (4.19 g, 39.6 mmol) and chloromethyl chlorosulfonate (1.96 g, 11.9 mmol) are added. 2(g) The mixture was added as shown below. The reaction mixture was stirred at 0°C for 15 minutes, and then ammonium tetra(buta-1-yl)bisulfate (336 mg, 0.989 mmol) was added. The mixture was then stirred at 25°C for 1 hour, then quenched with water (40 mL), extracted with DCM (2 × 70 mL), and the combined organic layer was concentrated. The residue was purified by flash chromatography (0-7% toluene in petroleum ether) to obtain compound J-9 (3.21 g, 70% yield via 2 steps). 1 H NMR(400MHz,CDCl3)5.74-5.67(m,2H),5.13-4.99(m,1H),4.31-3.63(m,5H),2.56-2.49(m,2H),2 .36-2.31(m,2H),2.13-2.03(m,2H),1.66-1.59(m,2H),1.30-1.24(m,24H),0.88(t,J=6.8Hz,3H).

[0353] Step 7: Synthesis of compound J-11

[0354] A solution of compound J-10 (400 mg, 0.765 mmol) in DCM (5.00 mL) is dissolved in N2 (g Under these conditions, at 25°C, silver(I) trifluoromethanesulfonate (590 mg, 2.30 mmol) and 2,6-di-tert-butylpyridine (512 mg, 2.68 mmol) were added. The mixture was cooled to 0°C, and compound J-9 (425 mg, 0.918 mmol) was added. The reaction mixture was heated to 25°C and stirred for 16 hours, then saturated with NH4Cl (水溶液) The mixture was quenched with (20 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography (0-6% ethyl ether in petroleum ether) to obtain compound J-11 (430 mg, yield 52%). 1 H NMR(400MHz,CDCl3)7.36-7.26(m,5H),5.36(s,2H),5.12-4.98(m,1H),4.41(s,2H),4.34-3.58(m,7H),2.44(q,J=7.6Hz,2H),2.34(t,J=7. 6Hz,2H),2.07-1.82(m,4H),1.74-1.39(m,19H),1.20-1.29(m,33H),1 .14-0.99(m,6H),0.92-0.86(m,10H),0.83(s,3H),0.60-0.70(m,4H).

[0355] Step 8: Synthesis of Compound 263

[0356] To a solution of compound J-11 (430 mg, 0.464 mmol) in THF (7.00 mL), add wet Pd / C (300 mg, 2.82 mmol). N2(g) The mixture was added at 25°C below. Then, the mixture was heated to 15 psi of H 2(g) The mixture was stirred at 25°C for 16 hours, and then the reaction mixture was filtered and concentrated. The residue was purified by flash chromatography (0-16% RINKAN in petroleum ether) and freeze-dried to obtain compound 263 (214.3 mg, 57%). 1H NMR(400MHz, CDCl3)5.35(s,2H),5.11-4.97(m,1H),4.30-3.60(m,5H),2.44(q,J=7.6Hz,2H),2.34(t,J=7.6Hz,2H),2.06-1.70(m ,5H),1.65-1.56(m,8H),1.50-1.30(m,16H),1.26-1.19(m,26H),1.11-0.85(m,20H),0.82(s,3H),0.62-0.67(m,4H);LC-ELSD / MS ESI C 53 H 94 O8Na[M+Na] + The calculated value of Hako is 881.9, and the measured value is 881.9.

Claims

1. Compound of formula (I), 【Chemistry 71】 or a pharmaceutically acceptable salt thereof, in the formula, W is 【Chemistry 72】 or -C(O)N(R ３ ) ２ And; Q is -C １－８ -Alkilen-; R １ and R ２ Each of these independently comprises hydrogen, an acid-unstable group, a lipid, or -C(O)R ３ And; Each R ３ C is independently and arbitrarily substituted. １－４０ It is aliphatic; X is -O-, -NR-, -S-, -O(aliphatic)-O-, -O(aliphatic)-S-, -O(aliphatic)-NR-, -S(aliphatic)-O-, -S(aliphatic)-S-, -S(aliphatic)-NR-, -NR(aliphatic)-O-, -NR(aliphatic)-S-, -NR(aliphatic)-NR-, or -(aliphatic)-, wherein 0 to 2 methylene units of the aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, and each instance of aliphatic is independently and optionally substituted with 1 to 3 deuteriums or halogens; １－６ (aliphatic)-O- １－６ (aliphatic)-S- １－６ (aliphatic)-NR- １ - ６ (aliphatic)-O- １－６ (aliphatic)-S- １－６ (aliphatic)-NR- １－６ (aliphatic)-O- １－６ (aliphatic)-S- １－６ (aliphatic)-NR- １－６ or -(aliphatic)-, wherein １ - ６ 0 to 2 methylene units of the aliphatic group are independently and optionally substituted with -O-, -NR-, or -S-, and １ - ６ each instance of aliphatic is independently and optionally substituted with 1 to 3 deuteriums or halogens; Each R is independently either hydrogen or C １－６ Aliphatic, 3-8 membered carbon ring, C ６－１０ An optionally substituted group selected from the group consisting of a 4-8 member heterocycle containing 1-2 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and a 5-10 member heteroaryl group containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S; Y does not exist, or is -C(O)-, -C(NR)-, or -C(S)-; Z is either nonexistent or a divalent C that can be optionally substituted. １－３０ It is aliphatic, and in the formula, the 0 to 8 methylene units of Z are independent of -R ８ -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -C(S)-, -OS(O) ２ -, -S(O) ２ O-, -N(R)S(O) ２ -, -S(O) ２ NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or an amino acid; one methylene unit of Z is optionally substituted with -M-; or Z is -C(R ４ａ ) (Caution ４ｂ )C(O)-M-,-C(R ４ａ ) (Caution ４ｂ )-M-,-C(R ４ａ ) (Caution ４ｂ ) C (R ５ａ ) (Caution ５ｂ ) (CH ２ ) ｎ C(O)-M-, -C(R ４ａ ) (Caution ４ｂ ) C (R ５ａ ) (Caution ５ｂ ) (CH ２ ) ｎ -M-, -(CH ２ ) ｍ C(R ４ａ ) (Caution ４ｂ ) (CH ２ ) ｎ C(R ５ａ ) (Caution ５ｂ ) (CH ２ ) ｍ C(O)-M-, and-(CH ２ ) ｍ C(R ４ａ ) (Caution ４ｂ ) (CH ２ ) ｎ C(R ５ａ ) (Caution ５ｂ ) (CH ２ ) ｍ Selected from the group consisting of -M-; In the formula, both sides of Z may be bonded to the active substance; Each -R ８ - became independent, C ３－６ carbocycle, C ６－１０ An optionally substituted divalent group selected from the group consisting of 3-6 membered heterocycles containing 1-4 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and 5-10 membered heteroaryl groups containing 1-4 heteroatoms independently selected from the group consisting of N, O, and S; Each R ４ａ , R ４ｂ , R ５ｂ , and R ５ｂ These independently produce hydrogen, deuterium, halogen, -CN, -OR, and -NR. ２ -SR, -R ９ , and -R １０ Selected from the group consisting of; or R ４ａ and R ４ｂ or R ５ａ and R ５ｂ However, together with the carbon atoms to which they are bonded, they form a carbon atom containing one or two heteroatoms independently selected from the group consisting of N, O, and S. ３－６ Forming a carbon ring or a 3- to 6-membered heterocycle; Each R ９ C ３－８ carbocycle, C ６－１０ Selected from the group consisting of 4-8 membered heterocycles containing 1-2 heteroatoms independently selected from the group consisting of aryl, N, O, and S, and 5-10 membered heteroaryls containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; Each R １０ These independently have 1 to 6 -CN, -OR, -NR ２ -SR, -R ９ , selected from the group consisting of C1-6 aliphatic elements optionally substituted with deuterium or halogens; -M- is the part that can be cut, Each n is independent and ranges from 0 to 18. Each m is independent and ranges from 0 to 6. p is 1 or 2, The active substance is, 【Chemistry 73-1】 【Chemistry 73-2】 A compound selected from the group consisting of and its deuterated variants, wherein the bond site of the active substance to Z substitutes one or more hydrogen atoms on the active substance.

2. W 【Chemistry 74】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. W 【Chemistry 75】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. W 【Transformation 76】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. W 【Chemical 77】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. W is -C(O)N-(R ３ ), ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein W is -C(O)N-(R).

7. Q is -C ５ The compound according to claim 1 or 2, which is alkylene-.

8. R1 and R ２ Each of them independently, -C(O)R ３ The compound according to claim 1, 3, 4, or 5, or a pharmaceutically acceptable salt thereof.

9. Each R ３ C １－４０ A compound according to any one of claims 1, 6, or 8, which is aliphatic, or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 9, wherein X is -O-, or a pharmaceutically acceptable salt thereof.

11. X is -(C １－６ aliphatic)-, the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

12. Each R independently produces hydrogen, C １－６ Aliphatic, 3-8 membered carbon ring, C ６－１０ Aryl, N, A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is a 4- to 8-membered heterocycle containing 1 to 2 heteroatoms independently selected from the group consisting of O and S, or a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S.

13. A compound according to any one of claims 1 to 12, wherein Y is -C(O)-, or a pharmaceutically acceptable salt thereof.

14. Z is a divalent C which can be optionally substituted. １－３０ It is aliphatic, and the 0-8 methylene units of Z are independent of -R ８ -, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ２ -, -C(S)-, -N(R)S(O) ２ -, -S(O) ２ A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, which is substituted with NR-, -N(R)C(O)-, -C(O)NR-, -OC(O)NR-, -N(R)C(O)O-, or an amino acid, wherein one methylene unit of Z is optionally substituted with -M-.

15. The aforementioned amino acid, 【Transformation 78】 A compound according to claim 14, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

16. Z is -CH(R ４ａ )C(O)-M-,-CH(R ４ａ ) -M-, -CH(R ４ａ )CH(R ５ａ )C(O)-M-,-CH(R ４ａ )CH(R ５ａ ) (CH ２ ) ｎ C(O)-M-, -CH(R ４ａ )CH(R ５ａ ) (CH ２ ) ｎ -M-, and -C(R ４ａ ) (Caution ４ｂ ) (CH ２ ) ｎ C(R ５ａ ) (Caution ５ｂ A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, selected from the group consisting of C(O)-M-, wherein either side of Z can be bound to the active substance.

17. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

18. Z is deuterium, halogen, -CN, 3-6 member carbon ring, C ６－１０ A 4-6 membered heterocycle containing 1-2 heteroatoms independently selected from aryl, N, O, and S; 5-6 heteroaryl rings containing 1-4 heteroatoms independently selected from N, O, and S; or C optionally substituted with 1-6 deuterium or halogen atoms. １－６ C is optionally substituted with 1 to 4 substituents selected from the group consisting of aliphatic molecules. １－２５ A compound according to any one of claims 1 to 13, wherein the compound is alkylene, and in the formula, 0 to 4 methylene units of Z are independently -O-, -OC(O)-, -C(O)O-, or -C(O)-, and one methylene unit of Z is optionally substituted with -M-, or a pharmaceutically acceptable salt thereof.

19. -M- 【Chemistry 79-1】 【Chemistry 79-2】 【Chemistry 79-3】 【Chemistry 79-4】 A selection is made from the group consisting of the following, and one side of M is bound to the active substance. During the ceremony, R ６ａ and R ６ｂ Each of them independently consists of hydrogen, deuterium, and C １－５ Selected from the group consisting of aliphatic, halogen, and -CN; Each R ７ These independently produce hydrogen, deuterium, halogen, -CN, -OR, and -NR. ２ , -NO ２ -SR, -R ９ , or -R １０ Selected from the group consisting of, Each Z １ These are independently selected from the group consisting of -O-, -NR-, and -S-, Each Z ２ These are independently selected from the group consisting of -O-, -NR-, -S-, -OC(O)-, -N(R)C(O)O-, and -OC(O)NR-, Each Z ３ Either they do not exist independently, or -O-, -NR-, -S-, and -C(R ６ａ ) (Caution ６ｂ A compound according to any one of claims 1 to 18, selected from ) - a pharmaceutically acceptable salt thereof.

20. -M- 【Chemistry 80】 A compound according to claim 19, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following, wherein either side of M may be bound to the active substance.

21. R ４ａ and R ４ｂ Each of these is independently substituted with hydrogen, deuterium, halogen, -CN, or C, which is arbitrarily substituted with 1 to 6 deuterium or halogen atoms. １－４ Aliphatic, or R ４ａ and R ４ｂ However, together with the carbon atoms to which they are bonded, they form a carbon atom containing one or two heteroatoms independently selected from the group consisting of N, O, and S. ３－６ A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, which forms a carbocyclic ring or a 3- to 6-membered heterocyclic ring.

22. R ５ａ and R ５ｂ Each of these is independently substituted with hydrogen, deuterium, halogen, -CN, or C, which is optionally substituted with 1 to 6 deuterium or halogen atoms. １－４ Aliphatic, or R ５ａ and R ５ｂ However, together with the carbon atoms to which they are bonded, C ３－６ A compound according to any one of claims 1 to 20, or its pharmaceutically acceptable form, which forms a carbon ring or a 3- to 6-membered heterocycle comprising one or two heteroatoms independently selected from the group consisting of N, O, and S. A salt that is acceptable for this purpose.

23. R ４ａ , R4b, R ５ａ , and R ５ｂ Each of these is independently substituted with hydrogen, or optionally with 1 to 6 deuterium atoms or halogen atoms. １－４ A compound according to any one of claims 1 to 22, which is alkyl, or a pharmaceutically acceptable salt thereof.

24. A compound according to any one of claims 1 to 22, wherein p is 1, or a pharmaceutically acceptable salt thereof.

25. A compound according to any one of claims 1 to 22, wherein p is 2, or a pharmaceutically acceptable salt thereof.

26. 【Chemistry 81】 The compound according to any one of claims 1 to 25, which is the structure described in Table 1, a pharmaceutically acceptable salt thereof, a deuterated variant thereof, or a combination thereof, or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of compounds 1 to 2201, a pharmaceutically acceptable salt thereof, a deuterated variant thereof, or a combination thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. The pharmaceutical composition according to claim 28, further comprising an additional therapeutic agent.

30. A method for treating a disease, disorder, or condition in which allosteric NMDA receptor modulation is required in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 28 or 29.

31. The method according to claim 30, wherein the disease, disorder, or condition requiring allosteric NMDA receptor modulation is a CNS-related condition.

32. The method according to claim 31, wherein the CNS-related condition is selected from the group consisting of dysregulation, anxiety disorders (such as obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairment (such as Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (such as depression, bipolar disorder, and dysthymia), schizophrenia or other mental disorders (such as schizophrenia), sleep disorders (such as insomnia), substance-related disorders, personality disorders (such as obsessive-compulsive personality disorder), autism spectrum disorders (such as those with mutations in scaffold proteins), neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), pain (such as acute and chronic pain), encephalopathy secondary to a medical condition (such as hepatic encephalopathy and anti-NMDA receptor encephalopathy), seizure disorders (such as status epilepticus and a single genotype of epilepsy such as Dravet disease), stroke, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), and tinnitus.

33. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition requiring allosteric NMDA receptor modulation.

34. The compound for use according to claim 33 or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition requiring allosteric NMDA receptor modulation is a CNS-associated condition.

35. A compound for use according to claim 34 or a pharmaceutically acceptable salt thereof, wherein the CNS-related condition is a dysregulation disorder, anxiety disorder (such as obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairment (such as Alzheimer's disease and other forms of dementia), dissociative disorder, eating disorder, mood disorder (such as depression, bipolar disorder, and dysthymia), schizophrenia or other mental disorder (such as schizoaffective disorder), sleep disorder (such as insomnia), substance-related disorder, personality disorder (such as obsessive-compulsive disorder). A method selected from the group consisting of sonality disorders, autism spectrum disorders (including those with mutations in scaffold proteins), neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), pain (such as acute and chronic pain), encephalopathy secondary to medical conditions (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (such as status epilepticus and a single genotype of epilepsy like Dravet disease), stroke, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), and tinnitus.

36. A composition comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition requiring allosteric NMDA receptor modulation.

37. The composition for use according to claim 36, wherein the disease, disorder, or condition requiring allosteric NMDA receptor modulation is a CNS-related condition.

38. A composition for use according to claim 37, wherein the CNS-related condition is selected from the group consisting of dysregulation anxiety disorders (such as obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairment (such as Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (such as depression, bipolar disorder, and dysthymia), schizophrenia or other mental disorders (such as schizoaffective disorder), sleep disorders (such as insomnia), substance-related disorders, personality disorders (such as obsessive-compulsive personality disorder), autism spectrum disorders (such as those with mutations in scaffold proteins), neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), pain (such as acute and chronic pain), encephalopathy secondary to a medical condition (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (such as status epilepticus and a single genotype of epilepsy such as Dravet disease), stroke, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), and tinnitus.

39. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27 for the manufacture of a pharmaceutical product for treating a disease, disorder, or condition requiring allosteric NMDA receptor modulation.

40. The use according to claim 39, wherein the disease, disorder, or condition requiring allosteric NMDA receptor modulation is a CNS-related condition.

41. The use according to claim 40, wherein the CNS-related condition is a dysregulation disorder, anxiety disorder (such as obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairment (such as Alzheimer's disease and other forms of dementia), dissociative disorder, eating disorder, mood disorder (such as depression, bipolar disorder, and dysthymia), schizophrenia or other mental disorder (such as schizoaffective disorder), Use is selected from the group consisting of sleep disorders (such as insomnia), substance-related disorders, personality disorders (such as obsessive-compulsive personality disorder), autism spectrum disorders (such as those involving mutations in scaffold proteins), neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), pain (such as acute and chronic pain), encephalopathy secondary to medical conditions (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (such as status epilepticus and a specific genotype of epilepsy, such as Dravet disease), stroke, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), and tinnitus.

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