Neuroactive steroids substituted in position 10 with a cyclic group for use in the treatment of CNS disorders

Abstract

Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n, R19, R5, R3a, R6a, R6b, R1, R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b, R17b, R15a, R15b, R16a, and R16b are as defined herein. Also provided herein are pharmaceutical compositions comprising compounds of Formula (I), and methods of using the compounds, for example, in the treatment of CNS-related disorders.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511082220.8 (22) Application Date 2019.10.11 (30) Priority Data 62 / 745,109 2018.10.12 US (62) Divisional Application Data 201980079330.5 2019.10.11 (71) Applicant Sachs Therapeutics Inc. Address Massachusetts, USA (72) Inventors M.J. Blanco-Pirado F.G. Salituro M.L. Monista (74) Patent Agency Beijing Liu Shen Law Firm 11105 Patent Attorney Liu Xiangyi (51) Int.Cl. C07J 7 / 00 (2006.01) C07J 43 / 00 (2006.01) (54) Invention Title: Neuroactive Steroid with Cyclic Group Substituted at Position 10 for the Treatment of CNS Disorders (57) Abstract: This document provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n, R19, R5, R3a, R6a, R6b, R1, R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b, R17b, R15a, R15b, R16a, and R16b are as defined herein. This document also provides pharmaceutical compositions comprising a compound of formula (I), and methods of using said compound, for example, in the treatment of CNS-related disorders. Claims 4 pages, Description 71 pages, CN 121045302 A 2025.12.02 CN 1 21 04 53 02 A 1. A compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein: represents a single bond or a double bond, provided that if a double bond is present, then one of R6a or R6b is absent; R1 is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -ORA1, -N(RA1)2, -SR A1, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -OC(=O)RA1, -OC(= O)ORA1,‑OC(=O)N(RA1)2,‑OC(=O)SR A1,‑OS(=O)2R A1,‑OS(=O)2OR A1,‑OS(=O)2N(R A1)2,‑N(R A1)C(=O)RA1,‑N(RA1)C(=NRA1)RA1,‑N(RA1)C(=O)ORA1,‑N(RA1)C(=O)N(RA1)2,‑N(R A1)C(=NRA1) N (RA1)2,‑N(R A1)S(=O)2R A1,‑N(RA1)S(=O)2OR A1,‑N(RA1)S(=O)2N(R A1)2,‑SC(=O)R A1,‑SC(=O) ORA1,‑SC(=O)SRA1,‑SC(=O)N(RA1)2,‑S(=O)2R A1,‑S(=O)2OR A1 or‑S(=O)2N(R A1)2, wherein RA1, each time it appears, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxyprotective group when attached to oxygen, nitrogen-protective group when attached to nitrogen, sulfur-protective group when attached to sulfur, or two RA1 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle; each of R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b or R17b is independently hydrogen, halogen, -CN, - NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA1, -N(RA1)2, -SRA1, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, -OC(=O)N(RA1)2, -OC(=O)SRA1, -OS(=O)2RA1, -OS(=O)2ORA1, -OS(=O)2N(RA1)2, -N(RA1)C(=O) RA1,‑N(RA1)C(=NRA1)RA1,‑N(RA1)C(=O)ORA1,‑N(RA1)C(=O)N(RA1)2,‑N(R A1)C(=NRA1) N(RA1)2,‑N(RA1)S(=O)2R A1,‑N(RA1)S(=O)2OR A1, ‑N(RA1)S(=O)2N(R A1)2, ‑SC(=O)R A1, ‑SC(=O)ORA1, ‑SC(= O)SRA1, ‑SC(=O)N(RA1)2, ‑S(=O)2R A1, ‑S(=O)2OR A1 or ‑S(=O)2N(R A1)2, where RA1 is unique in each occurrenceThe R3a is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxyprotective group when attached to oxygen, nitrogen-protective group when attached to nitrogen, sulfur-protective group when attached to sulfur, or two RA1 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle; R3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5 is hydrogen or methyl; R5 is absent when it is a double bond; each of R6a and R6b is hydrogen, halogen, -CN, -NO2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted claims 1 / 4 page 2 CN 121045302 A. Alkenyl, or substituted or unsubstituted alkynyl; or R6a and R6b conjugated to form an oxo group (=O); each of R15a, R15b, R16a, and R16b is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORC3, -N(RC3)2, -SR C3, -C(=O)RC3, -C(=O)ORC3, -C(=O)SRC3, -C(=O)N(RC3)2, -OC(=O)R C3, -OC(=O)ORC3, -OC(=O)N(RC3)2, -OC(=O)SR C3, -OS(=O)2R C3,‑OS(=O)2OR C3,‑OS(=O)2N(R C3)2,‑N(R C3)C(=O)RC3,‑N(RC3)C(=NRC3)RC3,‑N(RC3)C (=O)ORC3,‑N(RC3)C(=O)N(RC3)2,‑N(R C3)C(=NRC3) C3 C3,‑S(=O)2OR C3 or‑S(=O)2N(R C3)2, wherein RC3, each time it appears, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted...The compound is a heteroaryl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, a sulfur-protecting group when attached to sulfur, or two RC3 groups together with an intercalation atom to form a substituted or unsubstituted heterocycle; R19 is a substituted or unsubstituted C3-C6 carbocyclic group, or a substituted or unsubstituted aryl group; and n is 0, 1, or 2. 2. The compound of claim 1, wherein R1 is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. 3. The compound of claim 1, wherein R1 is hydrogen, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. 4. The compound of claim 1, wherein R1 is a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group, wherein each is further substituted by a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group. 5. The compound of claim 1, wherein R1 is selected from the group consisting of: , ... D4)C(=O) ORD4, -S(=O)2R D4, -S(=O)2OR D4, -OS(=O)2R D4, -S(=O)2N(R D4)2 or -N(RD4)S(=O)2R D4, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl; RD4 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstitutedThe compound is a substituted C5-10 aryl group, a substituted or unsubstituted 5- to 10-membered heteroaryl group, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RD4 groups forming a substituted or unsubstituted heterocycle with an intercalation atom; and p is an integer selected from 0 to 11. 6. The compound of claim 1, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , and; wherein Ra and p are as defined in claim 5. 7. The compound according to any one of claims 1-6, wherein R2a and R2b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5, each time it appears, is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the two RE5 groups together with intercalation atoms form a substituted or unsubstituted heterocycle. 8. The compound of any one of claims 1-6, wherein R2a and R2b are each independently hydrogen, halogen, -CN, -NO2, -OR F6, -OC(=O)RF6, -N(RF6)2 or -N(RF6)C(=O)RF6; wherein RF6, in each occurrence, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or the two RF6 groups together with intercalation atoms form a substituted or unsubstituted heterocycle. 9. The compound of any one of claims 1-6, wherein R2a and R2b are independently hydrogen, -OH or a substituted or unsubstituted C1-6 alkyl. 10. The compound according to any one of claims 1-6, wherein each of R2a and R2b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo. Claims 4 / 4 page 5 CN 121045302 A Neuroactive steroid substituted with a cyclic group at position 10 for the treatment of CNS conditions

[0001] This application is based on application number 201980079330.5 filed on October 11, 2019 (PCT / This is a divisional application of US2019 / 055926, entitled "A neuroactive steroid with a cyclic group substituted at position 10 for the treatment of CNS disorders".

[0002] Cross-Reference to Related Applications

[0003] This application claims priority to USSN 62 / 745,109, filed October 12, 2018, the contents of which are incorporated herein by reference in their entirety. Background Art

[0004] Brain excitability is defined as the level of arousal in an animal (a continuum ranging from coma to seizures) and is regulated by various neurotransmitters. Generally, neurotransmitters are responsible for regulating the conduction of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70 mV, which is negative inside the cell relative to outside. Potential (voltage) is the result of the balance of ions (K+, Na+, Cl-, organic anions) across the semipermeable membrane of the neuron. Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, the potential changes from -70 mV to -50 mV. This effect is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase membrane permeability to Na+ ions. The decreased membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0005] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by γ-aminobutyric acid (GABA), a neurotransmitter. GABA has a profound effect on overall brain excitability because up to 40% of neurons in the brain utilize GABA as a neurotransmitter. GABA modulates the excitability of individual neurons by regulating the conduction of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to promote the flow of chloride ions down the electrochemical gradient of the GRC into the cell. This increase in intracellular anion levels leads to hyperpolarization of the transmembrane potential, making neurons less susceptible to excitatory input, i.e., reducing neuronal excitability. In other words, the higher the chloride ion concentration in neurons, the lower the brain excitability and arousal level.

[0006] The literature provides ample evidence that the GRC is responsible for mediating anxiety, seizures, and sedation. Therefore, GABA and drugs that act like or promote GABA (e.g., therapeutically available barbiturates and benzodiazepines (BZs), such as Valium®) exert their therapeutically available effects by interacting with specific regulatory sites on the GRC. Accumulated evidence now indicates that, in addition to benzodiazepine and barbiturate binding sites, the GRC contains unique sites for neuroactive steroids. See, for example, Lan, NC et al., Neurochem. Res. (1991) 16:347–356.

[0007] Neuroactive steroids can be produced endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reductodrine-20-one and 3α-21-dihydroxy-5-reductodrine-20-one, which are metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

[0008] There is a need for novel and improved neuroactive steroids, which can be used as modulators of brain excitability and as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions, and methods described herein are intended for this purpose. Specification 1 / 71 pages 6 CN 121045302 A Summary of the Invention

[0009] This document provides compounds designed to function, for example, as GABA modulators. In some embodiments, such compounds are envisioned as therapeutic agents for treating CNS-related conditions.

[0010] In one aspect, this document provides a compound of formula (I):

[0011] (I)

[0012] or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound of formula (I) is a compound of formula (I-a):

[0014] (I-a)

[0015] or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound of formula (I) is a compound of formula (I-b):

[0017] (I-b)

[0018] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of formula (I) is a compound of formula (I-c):

[0020] (I-c)

[0021] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound of formula (I) is a compound of formula (I-d):

[0023] (I-d)

[0024] or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of formula (I) is a compound of formula (I-e):

[0026] (I-e)

[0027] or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the compound of formula (I) is a compound of formula (I-f):

[0029] (I-f)

[0030] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of formula (I) is a compound of formula (I-g): Specification 3 / 71 page 8 CN 121045302 A

[0032] (I-g)

[0033] Or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound of formula (I) is the compound of formula (I-h):

[0035] (I-h)

[0036] or a pharmaceutically acceptable salt thereof.

[0037] In one aspect, a pharmaceutical composition is provided herein comprising the compound described herein (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compound of the invention is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound of the invention is provided in a therapeutically effective amount. In some embodiments, the compound of the invention is provided in a preventatively effective amount.

[0038] In one aspect, a pharmaceutically acceptable salt of the compound described herein (e.g., the compound of formula (I)) is provided herein.

[0039] In some embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In some embodiments, the compound is administered orally. In some embodiments, the compound is administered for a prolonged period. In some embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0040] The compounds of the present invention as described herein are used in some embodiments as GABA modulators, for example, affecting GABAA receptors in a positive or negative manner. As modulators of the excitability of the central nervous system (CNS), such compounds are expected to have CNS activity, mediated by their ability to modulate GABAA receptors.

[0041] In one aspect, a method for treating a subject with a CNS-related disorder is described herein, the method comprising administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

[0043] In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, major depressive disorder is moderate major depressive disorder. In some embodiments, major depressive disorder is severe major depressive disorder. Specification 4 / 71 pages 9 CN 121045302 A

[0044] In some embodiments, the compound is selected from the group consisting of compounds identified in Table 1 herein. Detailed Description

[0045] As generally described herein, the present invention provides compounds designed, for example, to act as GABAA receptor modulators.In some embodiments, such compounds are envisioned as therapeutic agents for treating CNS-related conditions (e.g., conditions described herein, such as depression, such as postpartum depression or major depressive disorder).

[0046] Definitions

[0047] Chemical Definitions

[0048] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in the following: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, Marches Advanced Organic Chemistry, 5th 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, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0049] Isomers, such as stereoisomers, can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and OpticalResolutions, page 268 (EL Eliel, editor, Univ. of Notre Dame Press, Notre Dame, IN 1972). This invention further covers the compounds described herein in individual isomers substantially free of other isomers and alternatively in mixtures of various isomers.

[0050] "Stereoisomer": It should also be understood that compounds having the same molecular formula but differing in properties or in their atomic bonding sequence or in their atomic spatial arrangement are called "isomers." Isomers differing in atomic spatial arrangement are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and isomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described according to the R and S sequencing rules of Cahn and Prelog, or by the rotation of the molecule around a polarized plane and designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds may exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a “racemic mixture.”

[0051] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., an enantiomer excess). In other words, the “S” form of the compound is substantially free of the “R” form of the compound, and therefore an enantiomer in the “R” form is in excess. The term "enantiomerically pure" or "pure enantiomer" means that a 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 99.9% by weight. In some embodiments, weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0052] In the compositions provided herein, enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-site / center / carbon compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In some embodiments, such compositions are enantiomerically pure R-compounds.The compound may, for example, comprise at least about 95% by weight of R compound and at most about 5% by weight of S compound based on the total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S compound may comprise, for example, about 90% of excipient and about 10% of enantiomerically pure S compound. In some embodiments, such compositions may, for example, comprise at least about 95% by weight of S compound and at most about 5% by weight of R compound based on the total weight of the compound. In some embodiments, the active ingredient may be formulated with virtually no excipient or carrier.

[0053] As used herein, the term “diasteremeric purity” refers to the amount of compound having the absolute stereochemistry described, expressed as a percentage of the total amount of the described compound and its diastereomers. The term “diasteremeric purity” means 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. Methods for determining diastereomeric purity and enantiomeric purity are known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing a compound and its diastereomers (such as high performance liquid chromatography (HPLC)).

[0054] The article “a” may be used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an analogue” means one or more analogues.

[0055] When listing a range of values, it is intended to encompass the values ​​and subranges within the range. For example, “C1-6 alkyl” is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0056] The following terms are intended to have the meanings provided below and are suitable for understanding the description and intended scope of the invention.

[0057] “alkyl” refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms (“C1–20 alkyl”). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C1–12 alkyl”). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments...In the embodiments, the alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C1–6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, the alkyl group is optionally substituted independently each time it appears, i.e., unsubstituted (“unsubstituted alkyl”) or substituted by one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkyl”). In some embodiments, the alkyl group is an unsubstituted C1-10 alkyl group (e.g., -CH3). In some embodiments, the alkyl group is a substituted C1-10 alkyl group. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3) or i-Bu (-CH2CH(CH3)2).

[0058] "alkylene" refers to an alkyl group with two hydrogens removed to provide a divalent group and it may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2-), etc. Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted methylene (-CH) groups.(CH3)-, (-C(CH3)2-), substituted ethylenes (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. When a range or number of carbons is provided for a particular alkylene group, it should be understood that the range or number refers to the range or number of carbons in the straight-chain divalent carbon chain. Alkylenes may be substituted or unsubstituted by one or more substituents as described herein.

[0059] "Alkenyl" refers to a straight-chain or branched hydrocarbon group ("C2-20 alkenyl") having 2 to 20 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). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C2-7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, the alkenyl group has 2 carbon atoms (“C2 alkenyl”). One or more carbon-carbon double bonds may be located internally (e.g., 2-butenyl) or terminally (e.g., 1-butenyl). Examples of C2-4 alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octtrienyl (C8), etc. Unless otherwise stated, the alkenyl group is independently and optionally substituted each time it appears, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkenyl”).In some embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl group. In some embodiments, the alkenyl group is a substituted C2-10 alkenyl group.

[0060] "Alynyl" refers to a straight-chain or branched hydrocarbon group ("C2-20 ynyl") having 2 to 20 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). In some embodiments, the ynyl group does not contain any double bonds. In some embodiments, the ynyl group has 2 to 10 carbon atoms. The alkynyl group has 2 to 9 carbon atoms (“C2-10 alkynyl”). In some embodiments, the alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, the alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, the alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, the alkynyl group has 2 carbon atoms (“C2 alkynyl”). One or more carbon-carbon triple bonds may be located internally (e.g., 2-butynyl) or terminally (e.g., 1-butynyl). Examples of C2-4 alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), and 2-propynyl (C3). 1-Butynyl (C4), 2-Butynyl (C4), etc. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups, as well as pentyynyl (C5), hexynyl (C6), etc. Other examples of alkenyl groups include heptyynyl (C7), octyynyl (C8), etc. Unless otherwise stated, the alkenyl group is currently independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl group. In some embodiments, the alkenyl group is a substituted C2-10 alkenyl group.

[0061] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in a parent chain, wherein 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 connection points. In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroalkyl").In some embodiments, the heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“hetero-C1-9 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“hetero-C1-8 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“hetero-C1-7 alkyl”). In some embodiments, the heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“hetero-C1-6 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“hetero-C1-5 alkyl”). In some embodiments, the heteroalkyl group is a group having 1 to 4 carbon atoms and 1... Or a saturated group with 2 heteroatoms (“hetero-C1-4 alkyl”). In some embodiments, the heteroalkyl is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“hetero-C1-3 alkyl”). In some embodiments, the heteroalkyl is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“hetero-C1-2 alkyl”). In some embodiments, the heteroalkyl is a saturated group having 1 carbon atom and 1 heteroatom (“hetero-C1 alkyl”). In some embodiments, the heteroalkyl is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“hetero-C2-6 alkyl”). Unless otherwise stated, the heteroalkyl is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”) each time it appears. In some embodiments, the heteroalkyl is an unsubstituted hetero-C1-10 alkyl. In some embodiments, the heteroalkyl is a substituted hetero-C1-10 alkyl.

[0062] “Aryl” refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring. 4n+2 aromatic ring systems (e.g., those with 6, 10, or 14 rings shared in a ring array) An aryl group (with π electrons) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C10 aryl”; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14 aryl”; for example, anthracene). “Aryl” also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from: acepanthene, acenaphthene, phenanthrene, anthracene, azulene, benzene, benzoxene, fluorene, fluorene, and benzoxene.Benzene, hexalene, hexalene, asymmetric indole, symmetric indole, dihydroindene, indene, naphthalene, octabenzobenzene, octabenzone, aldrin, oleophane, pentadiene, pentabenzone, pentabenzone, dinaphthalene, phenaene, phenanthrene, dinaphthalene, heptabenzone, pyrene, pyroxane, rubigin, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthyl. Unless otherwise specified, the aryl group is optionally substituted independently each time it appears, i.e., unsubstituted (“unsubstituted aryl”) or substituted by one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C6-14 aryl group. In some embodiments, the aryl group is a substituted C6-14 aryl group.

[0063] In some embodiments, the aryl group is substituted with one or more of the following groups: halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxyl, C1-C8 alkoxy and amino.

[0064] Representative examples of substituted aryl groups include the following specification, page 8 / 71, CN 121045302 A

[0065]

[0066] wherein one of R56 and R57 may be hydrogen, and at least one of R56 and R57 is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclic, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59, NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56 and R57 may be from 5 to 8 The atoms are bonded to form a cyclic ring (saturated or unsaturated), which optionally contains one or more heteroatoms selected from the group consisting of N, O, or S. R60 and R61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclic group, C6-C10 aryl, substituted C6-C10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0067] "Fused aryl" refers to an aryl group whose two ring carbons are the same as the second aryl or heteroaryl ring or the same as the carbocyclic or heterocyclic ring.

[0068] "Heteroaryl" refers to a 5-10 member monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electrons shared in a cyclic array), wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings.The term "heteroaryl" includes ring systems fused with one or more carbocyclic or heterocyclic groups as defined above, wherein the connection point is located on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems fused with one or more aryl groups as defined above, wherein the connection point is located on the aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) whose ring does not contain a heteroatom can have a connection point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0069] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1 to 3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 to 2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, the heteroaryl is optionally substituted independently each time it appears, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl.

[0070] Exemplary 5-membered heteroaryl containing one heteroatom includes, but is not limited to, pyrroleyl, furanyl, and thiopheneyl. Exemplary 5-membered heteroaryl containing two heteroatoms includes, but is not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms includes, but is not limited to, triazolyl, oxadiazolyl, and thiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms includes, but is not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom (see page 9 / 71, CN 121045302 A). These heteroaryl groups include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl.Pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indoleyl, isoindoleyl, indazoleyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indoleazinyl, and purineyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxolinyl, phthalazinyl, and quinazolinyl.

[0071] Examples of representative heteroaryl groups include the following:

[0072]

[0073] wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65 is independently hydrogen, C1-C8 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclic group, C6-C10 aryl, and 5-10 membered heteroaryl.

[0074] “Carbocyclic group” or “carbocyclic” refers to a non-aromatic hydrocarbon group having 3 to 10 cyclic carbon atoms (“C3-10 carbocyclic group”) and zero heteroatoms in a non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C3-8 carbocyclic group”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C3-6 carbocyclic group”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C3-6 carbocyclic group”). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C5-10 carbocyclic group”). Exemplary C3-6 carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C3-8 carbocyclic groups include, but are not limited to, the aforementioned C3-6 carbocyclic groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Exemplary C3-10 carbocyclic groups include, but are not limited to, the aforementioned C3-8 carbocyclic groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthyl (C10), spiro[4.5]decyl (C10), etc. As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or contains condensed...The system may be a cyclocyclic, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes cyclic systems fused with one or more aryl or heteroaryl groups as defined above, wherein the connection point is on the carbocyclic ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the carbocyclic system. Unless otherwise specified, the carbocyclic group is optionally substituted independently each time it appears, i.e., unsubstituted (“unsubstituted carbocyclic”) or substituted by one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C3-10 carbocyclic group. In some embodiments, the carbocyclic group is a substituted C3-10 carbocyclic group. Specification 10 / 71 pages 15 CN 121045302 A

[0075] In some embodiments, “carbocyclic” is a monocyclic saturated carbocyclic group (“C3-10 cycloalkyl”) having 3 to 10 ring carbon atoms. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3–8 cycloalkyl groups include the aforementioned C3–6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, the cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”) each time it appears. In some embodiments, the cycloalkyl group is an unsubstituted C3–10 cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted C3-10 cycloalkyl group.

[0076] "Heterocyclic group" or "heterocycle" refers to a group having a 3-10 membered nonaromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, where the valence allows. The heterocyclic group may be a monocyclic ("monocyclic heterocyclic group") or a fused, bridged, or spirocyclic system, such as a bicyclic system ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. A heterocyclic bicyclic system may include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems fused with one or more carbocyclic groups as defined above, wherein the connection point is located on the carbocyclic or heterocyclic ring, or ring systems fused with one or more aryl or heteroaryl groups as defined above, wherein...The connection point is located on the heterocyclic ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. Unless otherwise specified, the heterocyclic group is independently and optionally substituted each time it appears, i.e., unsubstituted (“unsubstituted heterocyclic group”) or substituted by one or more substituents (“substituted heterocyclic group”). In some embodiments, the heterocyclic group is an unsubstituted 3-10 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-10 membered heterocyclic group.

[0077] In some embodiments, the heterocyclic group is a 5-10 membered nonaromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered nonaromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0078] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolylyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiaalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxalyl.Triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with an aromatic ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0079] “Nitrogen-containing heterocyclic group” means a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azacyclic butane, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine, such as N-methylpiperazine. Specific examples include azacyclic butane, piperidinone, and piperazineone.

[0080] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur heteroatoms. The term "hetero" can be applied to any of the aforementioned hydrocarbon groups, such as alkyl groups (e.g., heteroalkyl, cycloalkyl), heterocyclic groups (e.g., heteroaryl), cycloalkenyl groups (e.g., cycloheterenyl), etc., having 1 to 5, and more specifically 1 to 3, heteroatoms.

[0081] "Acyl" refers to the group -C(O)R20, wherein R20 is, as defined herein, hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. "Alkyl" is an acyl group in which R20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1-C8 alkyl, -C(O)-(CH2)t (C6-C10 aryl), -C(O)-(CH2)t (5-10 heteroaryl), -C(O)-(CH2)t (C3-C10 cycloalkyl), and -C(O)-(CH2)t(4-10 membered heterocyclic group), where t is an integer from 0 to 4. In some embodiments, R21 is a C1-C8 alkyl group substituted with a halogen or hydroxyl group; or a C3-C10 cycloalkyl group, a 4-10 membered heterocyclic group, a C6-C10 aryl group, an arylalkyl group, a 5-10 membered heteroaryl group, or a heteroarylalkyl group, each of which is substituted with: an unsubstituted C1-C4 alkyl group, a halogen group, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, or an unsubstituted C1-C4 haloalkoxy group or hydroxyl group.

[0082] "Alkoxy" refers to the group -OR29, wherein R29 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0083] In some embodiments, R29 is a group having one or more substituents, for example, 1 to 5 substituents, and specifically 1 to 3 substituents, specifically 1 substituent, said substituent being selected from the group consisting of: amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3-C10 cycloalkyl, 4-10 heterocyclic, halogen, 5-10 heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary “substituted alkoxy groups” include, but are not limited to, -O-(CH2)t (C6-C10 aryl), -O-(CH2)t (5-10 heteroaryl), -O-(CH2)t (C3-C10 cycloalkyl), and -O-(CH2)t (4-10 heterocyclic), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may be substituted by: unsubstituted C1-C4 alkyl, halogroup, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. Specific exemplary “substituted alkoxy groups” are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2. Instruction manual, page 12 / 71, document number 17, CN 121045302 A

[0084] "Amino" refers to the group -NH2.

[0085] "Oxy group" refers to -C(=O)-.

[0086] "Substituted amino" refers to an amino group of formula -N(R38)2, wherein R38 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, or an amino protecting group, wherein at least one of R38 is not hydrogen. In some embodiments, each R38 is independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C10 aryl, 5-10-membered heteroaryl, 4-10-membered heterocyclic, or C3-C10 cycloalkyl, or a C1-C8 alkyl substituted with a halogen or hydroxyl group, or a C3-C8 alkenyl substituted with a halogen or hydroxyl group, a C3-C8 alkynyl substituted with a halogen or hydroxyl group, or -(CH2)t(C6-C10 aryl), -(CH2)t(5-10 (4-10 membered heterocyclic group), -(CH2)t (C3-C10 cycloalkyl group), or -(CH2)t (4-10 membered heterocyclic group), where t is an integer from 0 to 8, and each of the groups is substituted by: an unsubstituted C1-C4 alkyl group, a halogroup, an unsubstituted C1-C4 alkoxy group, an unsubstituted C1-C4 haloalkyl group, an unsubstituted C1-C4 hydroxyalkyl group, or an unsubstituted C1-C4 haloalkoxy group or a hydroxy group; or two R38 groups are joined to form an alkylene group.

[0087] Exemplary “substituted amino” includes, but is not limited to, -NR39-C1-C8 alkyl, -NR39-(CH2)t (C6-C10 aryl), -NR39-(CH2)t (5-10 heteroaryl), -NR39-(CH2)t (C3-C10 cycloalkyl), and -NR39-(CH2)t (4-10 heterocyclic), where t is an integer from 0 to 4, for example, 1 or 2, each R39 independently represents H or C1-C8 alkyl; and any alkyl present may itself be substituted with a halogen, substituted or unsubstituted amino, or hydroxyl; and any aryl, heteroaryl, cycloalkyl, or heterocyclic present may itself be substituted with: unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino encompasses both monosubstituted and disubstituted amino groups.

[0088] "Carboxyl" refers to the group -C(O)OH.

[0089] "Cyano" refers to the group -CN.

[0090] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is fluorine or chlorine.

[0091] “Halogenated alkyl” means an alkyl group in which one or more halogens are substituted. Typical halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, etc.

[0092] “Hydroxy” means the group -OH.

[0093] “Nitro” means the group -NO2.

[0094] “Thionyl” means the group =S.

[0095] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups as defined herein are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclic, “substituted” or “unsubstituted” heterocyclic, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl). Generally, regardless of whether the term "optionally" is preceding it, the term "substitution" means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, such as a compound that cannot spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, the group "substituted" has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position may be the same or different. The term "substitution" is contemplated to include substitution by all permissible substituents of an organic compound, and any substituent described herein that contributes to the formation of a stable compound. This invention covers any and all such combinations to obtain a stable compound. For the purposes of this invention, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the heteroatom valence and causes the formation of a stable moiety.

[0096] Exemplary carbon atom substituents include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa, -ON(Rbb)2, -N(R bb)2, -N(R bb)3 +X-, -N(ORcc)Rbb, -SH, -SRaa, -SSRcc, -C(=O)Raa, -CO2H, -CHO, -C(ORcc)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NR bbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NR bb)Raa,‑C(=NRbb)ORaa,‑OC(=NRbb)Raa,‑OC(=NRbb)ORaa,‑C(=NRbb)N(Rbb)2,‑OC(=NR bb)N(Rbb)2,‑NR bbC(=NRbb)N(Rbb)2,‑C(=O)NR bbSO2R aa,‑NRbbSO2R aa,‑SO2N(R bb)2,‑SO2R aa,‑SO2OR aa,‑OSO2R aa, ‑S(=O)Raa, ‑OS(=O)Raa, ‑Si(Raa)3, ‑OSi(R aa)3 ‑C(=S) N(Rbb)2, ‑C(=O)SR aa, ‑C(=S)SRaa, ‑SC(=S)SRaa, ‑SC(=O)SRaa, ‑OC(=O)SRaa, ‑SC(=O)ORaa, ‑SC (=O)Raa,‑P(=O)2R aa,‑OP(=O)2R aa,‑P(=O)(Raa)2,‑OP(=O)(R aa)2,‑OP(=O)(OR cc)2,‑P(=O)2N (Rbb)2,‑OP(=O)2N(R bb)2,‑P(=O)(NR bb)2,‑OP(=O)(NR bb)2,‑NR bbP(=O)(ORcc)2,‑NR bbP(=O) (NRbb)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(ORcc), C1‑10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 ynyl, C3-10 carbocyclic, 3-14 heterocyclic, C6-14 aryl, and 5-14 heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups; or two homocyclic hydrogens on a carbon atom are substituted by the groups =O, =S, =NN(Rbb)2, =NNR bbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raaa, =NRbb, or =NORcc;

[0097] Raa is independently selected each time it appears from C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 ynyl, C3-10 carbocyclic, 3-14 heterocyclic, C6-14 aryl and 5-14 heteroaryl rings, or two Raa groups are joined to form a 3-14 heterocyclic or 5-14 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 Rdd groups;

[0098] Rbb is independently selected each time it appears from hydrogen, -OH, -ORaa, -N(Rcc)2, -CN, -C(=O)Raaa, -C(=O)N(Rcc)2, -CO2Raa, -SO2R aa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(R cc)2, -SO2R cc, -SO2OR cc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SR cc, -C(=S)SRcc, -P(=O)2R aa, -P(=O)(Raa)2, -P(=O)2N(R cc)2, -P (=O)(NRcc)2, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 ynyl, C3-10 carbocyclic, 3-14 membered heterocyclic, C6-14 Aryl and 5-14-membered heteroaryl, or two Rbb groups conjoined to form a 3-14-membered heterocyclic or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups;

[0099] Rcc is independently selected each time it appears from hydrogen, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 ynyl, C3-10 carbocyclic, 3-14-membered heterocyclic, C6-14 aryl, and 5-14-membered heteroaryl ring, or two Rcc groups conjoined to form a 3-14-membered heterocyclic or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups;

[0100] Rdd is independently selected from halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3 +X-, -N(ORee)Rff, -SH, -SRee, -SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, -OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N (Rff)2,‑NR ffC(=NRff)N(Rff)2,‑NR ffSO2R ee,‑SO2N(R ff)2,‑SO2R ee,‑SO2OR ee,‑OSO2R ee,‑S(=O) Ree,‑Si(Ree)3,‑OSi(R ee)3,‑C(=S)N(R ff)2,‑C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O) 2R ee, -P(=O)(Ree)2, -OP(=O)(R ee)2, -OP(=O)(OR ee)2, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 carbocyclic, 3-10 heterocyclic, C6-10 aryl, 5-10 heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 Rgg groups, or two homocyclic Rdd substituents may be joined to form =O or =S;

[0101] Ree, in each occurrence, is independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 carbocyclic, C6-10 aryl, 3-10 heterocyclic, and 3-10 heteroaryl, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rgg groups;

[0102] Rff is independently selected each time it appears from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 carbocyclic, 3-10 heterocyclic, C6-10 aryl, and 5-10 heteroaryl, or two Rff groups are joined to form a 3-14 heterocyclic or 5-14 heteroaryl ring, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently substituted by 0, 1, 2, 3, 4, or 5 Rgg groups; and

[0103] Rgg is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON (C1-6 alkyl)2, -N (C1-6 alkyl)2, -N (C1-6 alkyl)3 +X-, -NH (C1-6 alkyl)2 +X-、-NH2(C1-6 alkyl)+X-、-NH3 + X-、-N(OC1-6 alkyl)(C1-6 alkyl),-N(OH)(C1-6 alkyl),-NH(OH),-SH、-SC1-6 alkyl、-SS(C1-6 alkyl),-C(=O)(C1-6 alkyl),-CO2H、-CO2(C1-6 alkyl),-OC(=O)(C1-6 alkyl),-OCO2(C1-6 alkyl),-C(=O)NH2、-C(=O)N(C1-6 alkyl)2、-OC(=O)NH(C1-6 alkyl),-NHC(=O)(C1-6 alkyl),-N(C1-6 alkyl)C(=O)(C1-6 alkyl)-NHCO2 (C1-6 alkyl), -NHC(=O)N (C1-6 alkyl)2, -NHC(=O)NH (C1-6 alkyl), -NHC(=O)NH2, -C(=NH)O (C1-6 alkyl), -OC(=NH)(C1-6 alkyl), -OC(=NH)OC1-6 alkyl, -C(=NH)N (C1-6 alkyl)2, -C(=NH)NH (C1-6 alkyl), -C(=NH)NH2, -OC(=NH)N (C1-6 alkyl)2, -OC(NH)NH (C1-6 alkyl), -OC(NH)NH2, -NHC (NH)N (C1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2 (C1-6 alkyl), -SO2N (C1-6 alkyl)2, -SO2NH (C1-6 alkyl), - SO2NH2, -SO2C1-6alkyl, -SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3-C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)2(C1-6alkyl), -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, -OP(= O)(OC1-6alkyl)2, C1-6alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-10 carbocyclic, C6-10 aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two homocyclic Rgg substituents may be joined to form =O or =S; wherein X- is a relative ion.

[0104] "Relative ion" or "anionic relative ion" is a negatively charged group that associates with a cationic quaternary amino group in order to maintain electron neutrality. Exemplary relative ions include halide ions (e.g., F-, Cl-, Br-, I-), NO3-, ClO4-, OH-, H2PO4-, HSO4-, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, acetyl-1-sulfonate-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0105] These and other exemplary substituents are described in more detail in the detailed embodiments and claims. The present invention is not intended to be limited in any way by the above list of exemplary substituents.

[0106] Other definitions

[0107] As used herein, the term “modulation” refers to the inhibition or enhancement of GABAA receptor function. A “modulator” (e.g., a modulator compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABAA receptor.

[0108] “Pharmaceutical acceptable” means approved or permitted by a federal or state regulatory agency or the corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more specifically for use in humans.

[0109] “Pharmaceutical acceptable salt” means a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic 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, etc. Benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthenic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) when the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth metal ions or aluminum ions); or when coordinated with organic bases (e.g. ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc.) to form salts. Salts also include (by example only) sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, etc.; and when the compound contains a basic functional group, it further includes salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. The term “pharmaceuticalally acceptable cation” refers to an acceptable cationic relative ion of an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc. See, for example, Berge, et al., J. Pharm. Sci. (1977) 66(1): 1–79.

[0110] The term “prodrug” is intended to cover compounds that are non-therapeutic and convert to the therapeutically active agents of the present invention under physiological conditions. One method for manufacturing a prodrug is to design hydrolysis or cleavage at the target site of action under physiological conditions.The selected portion of the desired molecule and subsequently produces its therapeutic effect. In some embodiments, the prodrug is converted via the enzymatic activity of the subject. In an alternative embodiment, the present invention provides a prodrug of a compound of formula (I), wherein the prodrug comprises a cleavable portion at a C3 hydroxyl group, as depicted in formula (I).

[0111] In some embodiments, the compound of formula (I) is a prodrug, wherein the prodrug comprises a cleavable portion at a C3 hydroxyl group, as depicted in formula (I). Exemplary prodrugs containing hydroxyl groups include, for example, esters.

[0112] A “tautomer” is a compound that is an interchangeable form of a particular compound structure and has variations in the displacement of hydrogen atoms and electrons. Thus, the two structures can be balanced via the movement of π electrons and atoms (typically H). For example, enols and ketones are tautomers because they can be rapidly interconverted by treatment with an acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are also formed by treatment with an acid or base. Tautomerism can be associated with the realization of optimal chemical reactivity and biological activity of the target compound.

[0113] The term "subject" encompasses, but is not limited to, humans (i.e., males or females of any age, such as child subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0114] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SR aa, -C(=O)Raa, -CO2R aa, -C(=O)N(Rbb)2, -C(= NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)R aa, -SO2R aa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3, -P(=O)2R aa, -P(=O)(Raa)2, -P(=O)(ORcc)2, -P(=O)2N(Rbb)2 and -P(=O)(NRbb)2, wherein Raa, Rbb and Rcc are as defined herein. Oxygen protecting groups are well-known in the field and include Protecting Groups in Organic Synthesis, TW Greene, and PGM Wuts, 3rd Edition, John Wiley & Sons.Those described in detail in 1999 are incorporated herein by reference.

[0115] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butylmethoxyphenyl silyl (TBMPS), methanesulfonate (methanesulfonate), and toluenesulfonate (Ts).

[0116] In some embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=O)SR aa, -C(=O)Raa, -CO2R aa, -C(=O)N(Rbb)2, -C(= NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=O)R aa, -SO2R aa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3, -P(=O)2R aa, -P(=O)(Raa)2, -P(=O)(ORcc)2, -P(=O)2N(Rbb)2 and -P(=O)(NRbb)2, wherein Raa, Rbb and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0117] In some embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -ORaa, -N(Rcc)2, -C(=O)Raa, -C(=O)ORaa, -C(=O)N(Rcc)2, -S(=O)2Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SRcc, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclic, 3-14 heterocyclic, C6-14 aryl, and 5-14 heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclicThe aryl, aryl, and heteroaryl groups are independently substituted by 0, 1, 2, 3, 4, or 5 Rdd groups, wherein Raa, Rbb, Rcc, and Rdd are as defined herein. The amino protecting groups are well-known in the art and include those described in detail in *Protecting Groups in Organic Synthesis*, TW Greene, and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0118] Exemplary amino protecting groups include, but are not limited to, amide groups (e.g., -C(=O)Raa), which include, but are not limited to, formamide and acetamide; urethane groups (e.g., -C(=O)ORaa), which include, but are not limited to, 9-fluorenyl methyl carbamate (Fmoc), tert-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., -S(=O)2Raaa), which include, but are not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

[0119] Disease, symptom, and ailment are used interchangeably herein.

[0120] As used herein, and unless otherwise specified, the terms “treat,” “treating,” and “treatment” encompass the effect of reducing the severity of a specified disease, condition, or ailment, or delaying or slowing its progression, when a subject has developed such disease, condition, or ailment. In an alternative embodiment, the invention covers the administration of the compound of the invention as a preventative measure before a subject begins to develop a specified disease, condition, or ailment.

[0121] Generally, an “effective amount” of a compound means an amount sufficient to induce anesthesia or sedation, for example, to produce a desired biological response. As will be appreciated by those skilled in the art, the effective amount of the compound of the invention can vary depending on factors such as desired biological endpoints, pharmacokinetics of the compound, the disease being treated, mode of administration, and the subject’s age, weight, health, and condition. Effective amounts encompass both therapeutic and preventative treatment.

[0122] As used herein, and unless otherwise specified, a “therapeuticly effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in treating a disease, condition, or disorder, or to delay or minimize one or more symptoms associated with the disease, condition, or disorder. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating a disease, condition, or disorder. The term “therapeuticly effective amount” may cover an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0123] As used herein, and unless otherwise specified, a “preventive effective amount” of a compound is an amount sufficient to prevent a disease, condition, or disorder, or one or more symptoms associated with a disease, condition, or disorder, or to prevent its recurrence. A preventive effective amount of a compound means the amount of a therapeutic agent, alone or in combination with other agents, which provides therapeutic benefit in preventing a disease, condition, or disorder. The term “preventive effective amount” may cover an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0124] Compound

[0125] It should be understood that the formulas described herein may refer to specific carbon atoms, such as C17, C3, C19, etc. These carbon atoms are based on the position of the carbon atom according to the steroid nomenclature known and used in industry, as shown below:

[0126] .

[0127] For example, C17 refers to the carbon at position 17, and C3 refers to the carbon at position 3.

[0128] In one aspect, this document provides a compound of formula (I)

[0129] (I)

[0130] or a pharmaceutically acceptable salt thereof;

[0131] wherein:

[0132] represents a single bond or a double bond, provided that if a double bond is present, then one of R6a or R6b is absent;

[0133] R1 is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -ORA1, -N(RA1)2, -SR A1, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -OC(=O)RA1, - OC(=O)ORA1,‑OC(=O)N(RA1)2,‑OC(=O)SR A1,‑OS(=O)2R A1,‑OS(=O)2OR A1,‑OS(=O)2N(R A1)2,‑N (RA1)C(=O)RA1,‑N(RA1)C(=NRA1)RA1,‑N(RA1)C(=O)ORA1,‑N(RA1)C(=O)N(RA1)2,‑N(R A1)C(=NRA1) N(RA1)2,‑N(R A1)S(=O)2R A1,‑N(RA1)S(=O)2OR A1,‑N(RA1)S(=O)2N(R A1)2,‑SC(=O)R A1,‑SC(=O) ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, -S(=O)2RA1, -S(=O)2ORA1, or -S(=O)2N(RA1)2, wherein RA1 is independently selected each time it appears from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyne.The following groups are substituted or unsubstituted carbocyclic groups, or substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, oxygen-protecting groups when attached to oxygen, nitrogen-protecting groups when attached to nitrogen, sulfur-protecting groups when attached to sulfur, or two RA1 groups together with intercalation atoms to form substituted or unsubstituted heterocycles;

[0134] Each of R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b or R17b is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA1, -N Specification 18 / 71 pages 23 CN 121045302 A (RA1)2,‑SR A1,‑C(=O)RA1,‑C(=O)ORA1,‑C(=O)SRA1,‑C(=O)N(RA1)2,‑OC(=O)R A1,‑OC(=O)ORA1,‑OC(=O)N(RA1)2,‑OC(=O)SR A1,‑OS(=O)2R A1,‑OS(=O)2OR A1,‑OS(=O)2N(R A1)2,‑N(R A1)C(=O) RA1,‑N(RA1)C(=NRA1)RA1,‑N(RA1)C(=O)ORA1,‑N(RA1)C(=O)N(RA1)2,‑N(R A1)C(=NRA1) N(RA1)2,‑N(RA1)S(=O)2R A1, -N(RA1)S(=O)2OR A1, -N(RA1)S(=O)2N(RA1)2, -SC(=O)RA1, -SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, -S(=O)2RA1, -S(=O)2OR A1 or -S(=O)2N(RA1)2, wherein RA1 is independently selected each time from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, sulfur protecting group when attached to sulfur, or two RA1 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle;

[0135] R3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0136] R5 is hydrogen or methyl; when it is a double bond, R5 is not present.

[0137] Each of R6a and R6b is hydrogen, halogen, -CN, -NO2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R6a and R6b are conjugated to form an oxo group (=O);

[0138] Each of R15a, R15b, R16a and R16b is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORC3, -N(RC3)2, -SR C3, -C(=O)RC3, -C(=O)ORC3, -C(=O)SRC3, -C(=O)N(RC3)2, -OC(=O)R C3,‑OC(=O)ORC3,‑OC(=O)N(RC3)2,‑OC (=O)SRC3,‑OS(=O)2R C3,‑OS(=O)2OR C3,‑OS(=O)2N(R C3)2,‑N(R C3)C(=O)RC3,‑N(RC3)C(=NRC3) RC3,‑N(RC3)C(=O)ORC3,‑N(RC3)C(=O)N(RC3)2,‑N(R C3)C(=NRC3) N(RC3)2,‑N(R C3)S(=O)2R C3,‑N (RC3)S(=O)2OR C3,‑N(RC3)S(=O)2N(R C3)2,‑SC(=O)R C3, -SC(=O)ORC3, -SC(=O)SRC3, -SC(=O)N(RC3)2, -S(=O)2R C3, -S(=O)2OR C3 or -S(=O)2N(R C3)2, wherein RC3 is independently selected each time it appears from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, oxygen-protecting group when attached to oxygen, nitrogen-protecting group when attached to nitrogen, sulfur-protecting group when attached to sulfur, or two RC3 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle;

[0139] R19 is a substituted or unsubstituted C3-C6 carbocyclic, or a substituted or unsubstituted aryl; and

[0140] n is 0, 1 or 2.

[0141] Group R1

[0142] In some embodiments, R1 is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0143] In some embodiments, R1 is hydrogen, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0144] In some embodiments, R1 is a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group, wherein each is further substituted by a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group.

[0145] In some embodiments, R1 is hydrogen. In some embodiments, R1 is a substituted or unsubstituted alkyl group. In some embodiments, R1 is methyl. In some embodiments, R1 is...

[0146] In some embodiments, R1 is selected from the group consisting of:

[0147] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and;

[0148] wherein:

[0149] Ra is independently hydrogen, halogen, -NO2, -CN, -ORD4, -N(RD4)2, -C(=O)RD4, -C(=O)ORD4, -C(=O)N(RD4)2, -OC(=O)RD4, -OC(=O)ORD4, -N(RD4)C(=O)RD4, -OC(=O)N(RD4)2, -N(R D4)C(=O)ORD4, -S(=O)2R D4, -S(=O)2OR D4, -OS(=O)2R D4, -S(=O)2N(RD4)2 or -N(RD4)S(=O)2R D4, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0150] RD4 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, specification 20 / 71 pages 25 CN 121045302 A The heterocycle may be substituted or unsubstituted C2-6 ynyl group, substituted or unsubstituted C3-6 carbocyclic group, substituted or unsubstituted 3- to 6-membered heterocyclic group, substituted or unsubstituted C5-10 aryl group, substituted or unsubstituted 5- to 10-membered heteroaryl group, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RD4 groups together with an intercalation atom to form a substituted or unsubstituted heterocycle; and

[0151] p is an integer selected from 0 to 11.

[0152] In some implementations, R1 is selected from the group consisting of:

[0153] , , , , , , , , , , , , , , , , , and;

[0154] wherein:

[0155] Ra is independently hydrogen, halogen, -NO2, -CN, -ORD4, -N(RD4)2, -C(=O)RD4, -C(=O)ORD4, -C(=O)N(RD4)2, -OC(=O)RD4, -OC(=O)ORD4, -N(RD4)C(=O)RD4, -OC(=O)N(RD4)2, -N(RD4)C(=O)ORD4, -S(=O)2RD4, -S(=O)2ORD4, -OS(=O)2RD4, -S(=O)2N(R D4)2 or -N(RD4)S(=O)2R D4, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0156] RD4 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, ... The substituted or unsubstituted C2-6 alkynyl group, the substituted or unsubstituted C3-6 carbocyclic group, the substituted or unsubstituted 3- to 6-membered heterocyclic group, the substituted or unsubstituted C5-10 aryl group, the substituted or unsubstituted 5- to 10-membered heteroaryl group, the oxygen protecting group when attached to oxygen, the nitrogen protecting group when attached to nitrogen, or two RD4 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle; and

[0157] p is an integer selected from 0 to 11.

[0158] Groups R2a and R2b

[0159] In some embodiments, R2a and R2b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5, each time it appears, is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the two RE5 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0160] In some embodiments, R2a and R2b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2 or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or, as per specification page 21 / 71, page 26, CN 121045302 A, the two RF6 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle.

[0161] In some embodiments, R2a and R2b are independently hydrogen, -OH, or a substituted or unsubstituted C1-6 alkyl.

[0162] In some embodiments, each of R2a and R2b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0163] In some embodiments, R2a and R2b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0164] In some embodiments, both R2a and R2b are hydrogen.

[0165] In some embodiments, R2a and R2b are conjugated to form an oxo group (=O).

[0166] Group R3a

[0167] In some embodiments, R3a is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group.

[0168] In some embodiments, R3a is a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0169] In some embodiments, R3a is a substituted or unsubstituted C1-6 alkyl group.

[0170] In some embodiments, R3 is a substituted alkyl group. In some embodiments, R3a is an unsubstituted alkyl group.

[0171] In some embodiments, R3a is a methyl group. In some embodiments, R3a is hydrogen.

[0172] In some embodiments, R3a is […].

[0173] In some embodiments, R3a is […].

[0174] Groups R4a and R4b

[0175] In some embodiments, R4a and R4b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5, each time it appears, is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or both.The RE5 group, together with the intercalation atom, forms a substituted or unsubstituted heterocycle.

[0176] In some embodiments, R4a and R4b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2, or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or both RF6 groups together with the intercalation atom form a substituted or unsubstituted heterocycle.

[0177] In some embodiments, R4a and R4b are independently hydrogen, -OH, or a substituted or unsubstituted C1-6 alkyl.

[0178] In some embodiments, each of R4a and R4b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0179] In some embodiments, R4a and R4b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0180] In some embodiments, both R4a and R4b are hydrogen.

[0181] In some embodiments, R4a and R4b are conjugated to form an oxo group (=O).

[0182] Group R5

[0183] In some embodiments, R5 is hydrogen in the cis position relative to R19. In some embodiments, R5 is hydrogen in the trans position relative to R19. In some embodiments, R5 is methyl in the cis position relative to R19. In some embodiments, R5 is methyl in the trans position relative to R19. Specification 22 / 71 pages 27 CN 121045302 A

[0184] Groups R6a and R6b

[0185] In some embodiments, R6a and R6b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0186] In some embodiments, R6a and R6b are independently hydrogen or substituted alkyl.

[0187] In some embodiments, R6a and R6b are independently hydrogen or unsubstituted alkyl.

[0188] In some embodiments, both R6a and R6b are hydrogen.

[0189] In some embodiments, R6a is a halogroup or alkyl and R6b is hydrogen.

[0190] In some embodiments, both R6a and R6b are halogroups.

[0191] In some embodiments, both R6a and R6b are alkyl.

[0192] Groups R7a and R7b

[0193] In some embodiments, R7a and R7b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkane.RE5 is an alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a -ORE5 group, a -OC(=O)RE5 group, a -OS(=O)2OR E5 group, a -N(RE5)2 group or a -N(RE5)C(=O)RE5 group, a -N(RE5)S(=O)2R E5 group, a -N(RE5)S(=O)2OR E5 group; wherein RE5 is independently hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or two RE5 groups together with intercalated atoms to form a substituted or unsubstituted heterocycle.

[0194] In some embodiments, R7a and R7b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2, or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or the two RF6 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0195] In some embodiments, R7a and R7b are independently hydrogen, -OH, or a substituted or unsubstituted C1-6 alkyl.

[0196] In some embodiments, each of R7a and R7b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0197] In some embodiments, R7a and R7b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0198] In some embodiments, both R7a and R7b are hydrogen.

[0199] In some embodiments, R7a and R7b are combined to form an oxo group (=O).

[0200] Groups R11a and R11b

[0201] In some embodiments, R11a and R11b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the two RE5 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0202] In some embodiments, R11a and R11b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2, or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or the two RF6 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0203] In some embodiments, R11a and R11b are independently hydrogen, -OH, or a substituted or unsubstituted C1-6 alkyl.

[0204] In some embodiments, each of R11a and R11b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkane, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0205] In some embodiments, R11a and R11b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0206] In some embodiments, both R11a and R11b are hydrogen.

[0207] In some embodiments, R11a and R11b are conjugated to form an oxo group (=O).

[0208] Groups R12a and R12b

[0209] In some embodiments, R12a and R12b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5, each time it appears, is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the two RE5 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0210] In some embodiments, R12a and R12b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2, or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or two RF6 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle.

[0211] In some embodiments, R12a and R12b are independently hydrogen, -OH, or substituted or unsubstituted C1-6 alkyl.

[0212] In some embodiments, each of R12a and R12b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0213] In some embodiments, R12a and R12b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0214] In some embodiments, both R12a and R12b are hydrogen.

[0215] In some embodiments, R12a and R12b are conjugated to form an oxo group (=O).

[0216] Group R17b

[0217] In some embodiments, R17b is fluorine, hydroxyl, methyl, or hydrogen; wherein the hydrogen may optionally be replaced by deuterium. In some embodiments, R17b is hydrogen.

[0218] Group R19

[0219] In some aspects, R19 is a substituted or unsubstituted C3-6 carbocyclic group, or a substituted or unsubstituted C6-10 aryl group. In some embodiments, R19 is a substituted or unsubstituted C3-6 carbocyclic group. In some embodiments, R19 is cyclopropyl.

[0220] In some embodiments, R19 is a substituted or unsubstituted C3-6 carbocyclic group.

[0221] In some embodiments, R19 is a substituted or unsubstituted C6-10 aryl group.

[0222] In some embodiments, R19 is selected from the group consisting of:

[0223] , , , , and;

[0224] wherein:

[0225] Rb is independently hydrogen, halogen, -NO2, -CN, -OR G7, -N(RG7)2, -C(=O)RG7, -C(=O)ORG7, -C(=O)N(RG7)2, -OC(=O)RG7, -OC(=O)ORG7, -N(RG7)C(=O)RG7, -OC(=O)N(RG7)2, -N(RG7)C(=O)ORG7, -S(=O)2RG7, -S(=O)2OR G7, -OS(=O)2RG7, -S(=O)2N(RG7)2 or -N(RG7)S(=O)2R G7, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0226] RG7 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, ...The substituted or unsubstituted C2-6 alkynyl group, the substituted or unsubstituted C3-6 carbocyclic group, the substituted or unsubstituted 3- to 6-membered heterocyclic group, the substituted or unsubstituted C5-10 aryl group, the substituted or unsubstituted 5- to 10-membered heteroaryl group, the oxygen protecting group when attached to oxygen, the nitrogen protecting group when attached to nitrogen, or two RG7 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle; and

[0227] q is an integer selected from 0 to 11.

[0228] Groups R15a and R15b

[0229] In some embodiments, each of R15a and R15b is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORC3, -N(RC3)2, -SRC3, -C(=O)RC3, -C(=O)ORC3, -C(=O)SRC3, -C(=O)N(RC3)2, -OC(=O)RC3, -OC(=O)ORC3, -OC(=O)N(RC3)2, -OC(=O)SRC3, -OS(=O)2RC3, -OS(=O)2OR C3,‑OS(=O)2N(R C3)2,‑N(R C3)C(=O)RC3,‑N(RC3)C (=NRC3)RC3,‑N(RC3)C(=O)ORC3,‑N(RC3)C(=O)N(RC3)2,‑N(R C3)C(=NRC3) N(RC3)2,‑N(R C3)S(=O) 2R C3,‑N(RC3)S(=O)2OR C3,‑N(RC3)S(=O)2N(R C3)2,‑SC(=O)R C3,‑SC(=O)ORC3,‑SC(=O)SRC3,‑SC(= O)N(RC3)2,‑S(=O)2R C3,‑S(=O)2OR C3 or‑S(=O)2N(R C3)2, wherein RC3, each time it appears, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, oxygen-protecting group when attached to oxygen, nitrogen-protecting group when attached to nitrogen, sulfur-protecting group when attached to sulfur, or two RC3 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle.

[0230] In some embodiments, R15a and R15b are both hydrogen.

[0231] Groups R16a and R16b

[0232] In some embodiments, each of R16a and R16b is independently hydrogen, halogen, -CN, -NO2, substitutedOr unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORC3, -N(RC3)2, -SRC3, -C(=O)RC3, -C(=O)ORC3, -C(=O)SRC3, -C(=O)N(RC3)2, -OC(=O)R C3, -OC(=O)ORC3, -OC(=O)N(RC3)2, -OC(=O)SR C3, -OS(=O)2R C3, -OS(=O)2OR C3, -OS(=O)2N(R C3)2, -N(R C3)C(=O)RC3, -N(RC3)C =NRC3)RC3, -N(RC3)C(=O)ORC3, -N(RC3)C(=O)N(RC3)2, -N(RC3)C(=NRC3)N(RC3)2, -N(RC3)S(=O)2RC3, -N(RC3)S(=O)2ORC3, -N(RC3)S(=O)2N(RC3)2, -SC(=O)RC3, -SC(=O)ORC3, -SC(=O)SRC3, -SC(=O)N(RC3)2, -S(=O)2RC3, -S(=O)2ORC3 or -S(=O)2N(RC3)2, wherein RC3 is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, each time it appears. Substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, sulfur protecting group when attached to sulfur, or two RC3 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle.

[0233] In some embodiments, R16a and R16b are both hydrogen.

[0234] n

[0235] In some embodiments, n is 0. In some embodiments, n is 1. In some other embodiments, n is 2.

[0236] In some embodiments, the compound of formula (I) is the compound of formula (I-a): Specification 25 / 71 pages 30 CN 121045302 A

[0237] (I-a),

[0238] or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the compound of formula (I) is a compound of formula (I-b):

[0240] (I-b),

[0241] or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the compound of formula (I) is a compound of formula (I-c):

[0243] (I-c),

[0244] or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the compound of formula (I) is a compound of formula (I-d):

[0246] (I-d),

[0247] or a pharmaceutically acceptable salt thereof; wherein: Ra is independently a halogen, cyano, hydroxyl or substituted or unsubstituted alkyl group each time it appears; and p is 0, 1, 2 or 3.

[0248] In some embodiments, the compound of formula (I) is a compound of formula (I-e): Specification 26 / 71 pages 31 CN 121045302 A

[0249] (I-e),

[0250] or a pharmaceutically acceptable salt thereof; wherein:

[0251] each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N- or N(RN)-, wherein RN is independently hydrogen, substituted or unsubstituted C1-6 alkyl, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA or -S(=O)2N(RGA)2; RGA Each time it appears independently, it is hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 ynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0252] In some embodiments, the compound of formula (I) is a compound of formula (I-f):

[0253] (I-f),

[0254] or a pharmaceutically acceptable salt thereof; wherein:

[0255] each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N- or N(RN)-, wherein RN is independently hydrogen, a substituted or unsubstituted C1-6 alkyl, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA or -S(=O)2N(RGA)2; RGA Each time it appears independently, it is hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 ynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0256] In some embodiments, the compound of formula (I) is the compound of formula (I-g): Specification 27 / 71 pages 32 CN 121045302 A

[0257] (I-g),

[0258] Or a pharmaceutically acceptable salt thereof; wherein:

[0259] Ra is independently a halogen, alkyl, hydroxyl, or cyano group each time it appears; and

[0260] p is an integer selected from 0 to 11.

[0261] In some embodiments, the compound of formula (I) is a compound of formula (I-h):

[0262] (I-h),

[0263] or a pharmaceutically acceptable salt thereof; wherein:

[0264] each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N-, or N(RN)-, wherein RN is independently hydrogen, a substituted or unsubstituted C1-6 alkyl group, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA, or -S(=O)2N(RGA)2; RGA Each occurrence is independently hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0265] In one aspect, this document provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compounds of the present invention are provided in an effective amount in the pharmaceutical composition. In some embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In some embodiments, the compounds of the present invention are provided in a preventatively effective amount.

[0266] In one aspect, this document provides a pharmaceutically acceptable salt of a compound described herein (e.g., a compound of formula (I)).

[0267] In some embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In some embodiments, the compound is administered orally. In some embodiments, the compound is administered for a prolonged period. In some embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0268] The compounds of the invention described herein are used in some embodiments as GABA modulators, for example, affecting GABAA receptors in a positive or negative manner. As modulators of the excitability of the central nervous system (CNS), such compounds are expected to have CNS activity as mediated by their ability to modulate GABAA receptors. Specification 28 / 71 pages 33 CN 121045302 A

[0269] In one aspect, a method for treating a subject with CNS-related conditions is described herein, the method comprising administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, CNS-related disorders are sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus.

[0271] In some embodiments, CNS-related disorders are depression. In some embodiments, CNS-related disorders are postpartum depression. In some embodiments, CNS-related disorders are major depressive disorder. In some embodiments, major depressive disorder is moderate major depressive disorder. In some embodiments, major depressive disorder is severe major depressive disorder.

[0272] In some embodiments, the compounds are selected from the group consisting of compounds identified in Table 1 below:

[0273] Table 1.

[0274] Specification 29 / 71 pages 34 CN 121045302 A

[0275]

[0276] Exemplary compounds of the present invention can be synthesized from the following known starting materials using methods known to those skilled in the art or certain references. In one aspect, this document provides pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I)).

[0277] Alternative Embodiments

[0278] In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be 2H (D or deuterium) or 3H (T or tritium); carbon may be, for example, 13C or 14C; oxygen may be, for example, 18O; nitrogen may be, for example, 15N, and so on. In other embodiments, a particular isotope (e.g., 3H, 13C, 14C, 18O, or 15N) may represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular position in the compound.

[0279] Pharmaceutical Compositions

[0280] In one aspect, a pharmaceutical composition is provided herein comprising a compound described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound of the present invention is provided in a therapeutically effective amount. In some embodiments, the compound of the present invention is provided in a preventatively effective amount.

[0281] In some embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient.The composition contains a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition contains a preventatively effective amount of the active ingredient.

[0282] The pharmaceutical compositions provided herein can be administered via a variety of routes, including but not limited to oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0283] Generally, the compounds provided herein are administered in an effective amount. The actual amount of active agent administered will be determined by a physician based on relevant circumstances, including the disease to be treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0284] When used for the prevention of CNS symptoms, the compounds provided herein should generally be administered to subjects at risk of developing the disease at the dosage levels described above, as advised by and under the supervision of a physician. Subjects at risk of developing a specific disease generally include those with a family history of the disease, or those identified through genetic testing or screening as particularly susceptible to the disease.

[0285] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof for a period of time longer than that specified on page 30 / 71 of the specification, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, such as until the end of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood, for example, through a longer period of time within the therapeutic window.

[0286] The pharmaceutical compositions of the present invention can be further delivered using a variety of methods of administration. For example, in some embodiments, the pharmaceutical composition may be given in a pill form, for example, to increase the concentration of the compound in the blood to an effective level. The placement of a single dose depends on the systemic level of the desired active ingredient throughout the body. For example, an intramuscular or subcutaneous single dose allows for a slow release of the active ingredient, while delivering a large pill directly into the vein (e.g., via IV infusion) allows for a much faster delivery, which rapidly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered via continuous infusion (e.g., via IV infusion) to maintain a stable concentration of the active ingredient in the subject. Furthermore, in other embodiments, the pharmaceutical composition may be administered first as a single dose, followed by continuous infusion.

[0287] Compositions for oral administration may be in the form of a bulk liquid solution or suspension or a bulk powder. However, compositions are more commonly presented in unit dosage forms to facilitate precise dosing. The term "unit dosage form" refers to a form suitable for use in unit doses.Physically discontinuous units for use in human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, combined with suitable pharmaceutical excipients. Typical unit dosage forms include ampoules or syringes pre-filled with the predicted amount of liquid composition, or pills, tablets, capsules, etc. (for solid compositions). In such compositions, the compound is typically a minor component (about 0.1% to about 50% by weight, or preferably about 1% to about 40% by weight), with the remainder being various mediators or excipients and processing aids that contribute to the formation of the desired form of administration.

[0288] In oral administration, one to five, and especially two to four, and typically three oral doses per day are representative therapies. Using these administration modalities, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, wherein preferred doses each provide about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg.

[0289] The transdermal dose is generally selected to provide blood levels similar to or lower than those achieved using the injectable dose, in an amount generally ranging from about 0.01% to about 20% by weight, preferably from about 0.1% to about 20% by weight, more preferably from about 0.1% to about 10% by weight, and more preferably from about 0.5% to about 15% by weight.

[0290] The injectable dose level ranges from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, and is sustained for about 1 to about 120 hours, and especially 24 to 96 hours. Preloaded pellets of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve a sufficiently stable level. For human patients weighing 40 to 80 kg, the maximum total dose is expected not to exceed about 5 g / day.

[0291] Suitable liquid forms for oral administration may include suitable aqueous or non-aqueous media and buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components or compounds having similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, sodium hydroxyacetate (Primogel), or corn starch; lubricants, such as magnesium stearate; slip agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavorings, such as peppermint, methyl salicylate, or orange flavorings.

[0292] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As previously mentioned, the active compound in such compositions is typically a minor component, often ranging from about 0.05% to 10% by weight, with the remainder being injectable excipients, etc.

[0293] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients. When formulated asIn ointments, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated into an ointment using, for example, an oil-in-water emulsion base. Transdermal formulations are well known in the art and generally include additional ingredients to enhance the dermal penetration stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein on page 31 / 71 of the specification, CN 121045302 A.

[0294] The compounds provided herein can also be administered via transdermal devices. Thus, transdermal administration can be achieved using reservoir-type or porous membrane-type or solid matrix patches.

[0295] The components described above for oral, injectable, or topical compositions are representative only. Other substances and processing techniques, etc., are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0296] The compounds of the present invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. A description of representative sustained-release substances can be found in Remington's Pharmaceutical Sciences.

[0297] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., acids containing a pharmaceutically acceptable anion, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, hydrogen sulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.

[0298] In another aspect, the present invention provides a pharmaceutical composition comprising the compounds of the present invention and a pharmaceutically acceptable excipient, for example, a composition suitable for injection, such as for intravenous (IV) administration.

[0299] Pharmaceutically acceptable excipients include any and all diluents or other liquid media, dispersants or suspending agents, surfactants, isotonic agents, preservatives, lubricants, etc., as suitable for the desired specific dosage form, such as an injection. General considerations in the formulation and / or manufacturing of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy.21st edition (Lippincott Williams & Wilkins, 2005).

[0300] For example, injectable formulations (such as sterile injectable aqueous suspensions) can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Exemplary excipients that may be used include, but are not limited to, water, sterile saline or phosphate-buffered saline or Ringer's solution.

[0301] In some embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively, consisting of 6, 7, and 8 α-1,4-linked glucose units, optionally containing one or more substituents on the linked sugar moieties, including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfonyl alkyl ether substitution. In some embodiments, the cyclodextrin is a sulfonyl alkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, for example, US 5,376,645. In some embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10%–50% in water).

[0302] The injectable composition may be sterilized, for example, by filtering through a bacterial retention filter or by incorporating a sterilizing agent in the form of a sterile solid composition that is soluble or dispersed in sterile water or other sterile injectable media prior to use.

[0303] Generally, the compounds provided herein are administered in an effective amount. The actual amount of active agent administered will be determined by the physician based on relevant circumstances, including the disease to be treated, the route of administration chosen, the actual compound administered, the individual patient's age, weight, response, and the severity of the patient's symptoms.

[0304] The composition is presented in unit dosage form to facilitate precise dosing. The term "unit dosage form" refers to a physically discontinuous unit suitable for administration to human subjects and other mammals in unit doses, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, combined with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled liquid compositions, ampoules of predicted amounts, or syringes. In such compositions, the compound is typically a minor component (about 0.1% by weight to about 50% by weight, or preferably about 1% by weight to about 40% by weight), with the remainder being various media or carriers and processing aids that contribute to the formation of the desired administration form.

[0305] The compounds provided herein may be administered as the sole active agent, or may be administered in combination with other active agents. In one aspect, the present invention provides a combination of the compounds of the invention with another pharmacologically active agent. Combination administration can be performed using techniques in the art.Any technique known to a practitioner, including, for example, administration alone, sequentially, simultaneously, and alternately.

[0306] Although the description of the pharmaceutical compositions provided herein relates primarily to pharmaceutical compositions suitable for human administration, those skilled in the art should understand that such compositions are generally suitable for administration to all types of animals. It should be fully understood that modifications to pharmaceutical compositions suitable for human administration are made to make the compositions suitable for administration to a variety of animals, and such modifications can generally be designed and / or made by a veterinary pharmacologist with only general experiments. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005.

[0307] In one aspect, a cassette comprising a composition (e.g., a solid composition) is provided, said composition comprising a compound of formula (I).

[0308] Use and Treatment Methods

[0309] In one aspect, it is envisioned that the compounds described herein, such as compounds of formula (I), may be used as therapeutic agents for treating CNS-related conditions (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, seizure disorders, epilepsy, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes or tinnitus) in subjects in need (e.g., subjects with Rett syndrome, Fragile X syndrome or Angelman syndrome). Exemplary CNS disorders associated with GABA regulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), mild depression (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizophrenic affective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive disorders [e.g., attention deficit disorder (e.g., attention deficit hyperactivity disorder (ADHD))], dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular dementia)], and movement disorders [e.g., Huntington's disease]. Parkinson's disease[Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenic autism, such as synaptic disorders, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuralgia, injury-related pain syndrome, acute pain, chronic pain], traumatic brain injury (TBI), vascular disease [e.g., stroke, ischemia, vascular malformation], substance abuse disorders and / or withdrawal syndromes [e.g., opiate, cocaine and / or alcohol addiction], and tinnitus.

[0310] In some embodiments, CNS-related conditions are sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In some embodiments, CNS-related conditions are depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, major depressive disorder is moderate major depressive disorder. In some embodiments, major depressive disorder is severe major depressive disorder.

[0311] In one aspect, a method for alleviating or preventing epileptic seizures in a subject is provided, the method comprising administering an effective amount of the compound of the invention to a subject in need of such treatment. In some embodiments, the method alleviates or prevents the occurrence of epilepsy.

[0312] In another aspect, a combination of the compound of the invention with another pharmacologically active agent is provided. The compound provided herein may be administered as the sole active agent, or may be administered in combination with other agents. Combination administration may be performed by any technique known to those skilled in the art, including, for example, administration alone, sequentially, simultaneously, and alternately.

[0313] In another aspect, a method for treating or preventing brain excitability in a subject susceptible to or suffering from a disorder related to brain excitability is provided, the method comprising administering an effective amount of the compound of the invention to the subject.

[0314] In another aspect, a method for treating or preventing stress or anxiety in a subject is provided, the method comprising administering an effective amount of a compound of the present invention or a composition thereof to a subject requiring such treatment.

[0315] In another aspect, a method for relieving or preventing insomnia in a subject is provided, the method comprising administering an effective amount of a compound of the present invention or a composition thereof to a subject requiring such treatment.

[0316] In another aspect, a method for inducing sleep and substantially maintaining REM sleep levels found in normal sleep is provided, wherein substantial rebound insomnia is not induced, the method comprising administering an effective amount of a compound of the present invention.

[0317] In another aspect, a method is provided to alleviate or prevent premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, the method comprising administering an effective amount of the compound of the present invention to a subject requiring such treatment.

[0318] In another aspect, a method is provided to treat or prevent a mood disorder in a subject, the method comprising administering an effective amount of the compound of the present invention to a subject requiring such treatment. In some embodiments, the mood disorder is depression.

[0319] In another aspect, a method is provided to enhance cognition or treat memory disorders by administering a therapeutically effective amount of the compound of the present invention to a subject. In some embodiments, the disorder is Alzheimer's disease. In some embodiments, the disorder is Rett syndrome.

[0320] In another aspect, a method is provided to treat attention disorders by administering a therapeutically effective amount of the compound of the present invention to a subject. In other embodiments, the attention disorder is ADHD.

[0321] In some embodiments, the compound is administered to the subject over a long period of time. In some embodiments, the compound is administered to the subject orally, subcutaneously, intravenously, or intramuscularly.

[0322] Neuroendocrine Disorders and Dysfunctions

[0323] Methods for treating neuroendocrine disorders and dysfunctions are provided herein. As used herein, “neuroendocrine disorders” or “neuroendocrine dysfunction” refer to a variety of disorders caused by imbalances in the production of hormones directly related to the brain. Neuroendocrine disorders involve the interaction between the nervous and endocrine systems. Because the hypothalamus and pituitary gland are two brain regions that regulate hormone production, damage to the hypothalamus or pituitary gland, such as from traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, neuroendocrine disorders or dysfunctions are associated with women’s health conditions or disorders (e.g., the women’s health conditions or disorders described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women’s health condition or disorder is polycystic ovary syndrome (PCOS).

[0324] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, mood and sleep-related symptoms, reproductive function-related symptoms and somatic symptoms; including but not limited to fatigue, poor memory, anxiety, depression, weight gain or loss, mood instability, poor concentration, difficulty paying attention, loss of libido, infertility, amenorrhea, muscle loss, increased abdominal body fat, low blood pressure, decreased heart rate, hair loss, anemia, constipation, poor cold tolerance and dry skin. Specification 34 / 71 pages 39 CN 121045302 A

[0325] Neurodegenerative diseases and conditions

[0326] The methods described herein can be used to treat neurodegenerative diseases and conditions. The term "neurodegenerative disease" includes diseases and conditions associated with progressive loss of neuronal structure or function or neuronal death. Neurodegenerative diseases and conditionsSymptoms include, but are not limited to, Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); hypoxic and ischemic injuries; ataxia and seizures (including seizures induced by medications used to treat and prevent schizophrenia or schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusionary injuries (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and Alzheimer's disease; confusion; Down syndrome; drug-induced or drug-induced Parkinson's disease (e.g., acute akathisia induced by tranquilizers); Acute dystonia, Parkinson's disease or tardive dyskinesia, tranquilizer-induced malignant syndrome or drug-induced postural tremor; epilepsy; Fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced motor difficulties; intellectual disability; motor disorders, including akinesia and akinesia (rigid) syndromes (including basal ganglia calcification, corticobasal ganglia degeneration, multiple systemic atrophy, Parkinson's-ALS dementia complex, Parkinson's disease, post-encephalitis Parkinson's disease, and progressive supranuclear palsy); muscle spasms and conditions associated with muscle spasms or weakness, including chorea (such as benign hereditary chorea, drug-induced chorea, hemiparesis, Huntington's disease, neuroacanthosis, Sydenham's chorea). Chorea and symptomatic chorea), motor difficulties (including convulsions, such as complex convulsions, simple convulsions, and symptomatic convulsions), myoclonus (including generalized myoclonus and focal mania), tremors (such as resting tremor, postural tremor, and intention tremor) and dystonia (including axial dystonia, dystonic finger spasticity, hemiplegic dystonia, sudden dystonia, and focal dystonia, such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage, including eye damage, retinopathy, or macular degeneration; stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, hypoxia, neurotoxic damage following perinatal asphyxia and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tubular sclerosis and viral infection-induced neurodegeneration (e.g., by acquired immunodeficiency syndrome (AIDS) and(Caused by encephalopathy). Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, hypoxia, neurotoxic damage following perinatal asphyxia and cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function specific to neurodegenerative diseases.

[0327] Mood Disorders

[0328] This article also provides methods for treating mood disorders such as clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder, mild depression, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, treatment-resistant depression, suicidal tendencies, suicidal ideation or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect on a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with the diseases or conditions described herein (e.g., neuroendocrine disorders and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health conditions or disorders).

[0329] Clinical depression is also known as major depressive disorder, major depressive disorder (MDD), severe depression, unipolar depression, unipolar mental disorder, and recurrent depression, and is a mental disorder characterized by a generalized and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normal recreational activities. Some people with clinical depression have difficulty falling asleep, lose weight, and generally feel anxious and irritable. Clinical depression affects an individual's feelings, thoughts, and behaviors and can cause a number of emotional and physical problems. Individuals with clinical depression may experience difficulty with daily activities and may feel that life is not worth living.

[0330] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, feeling anxious, difficulty falling asleep, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, a sense of disconnection from the baby and / or fetus, and loss of interest in previously pleasurable activities.

[0331] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0332] In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0333] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, the subject experiencing perinatal depression has an increased risk of experiencing PND.

[0333] Atypical depression (AD) is characterized by mood responsiveness (e.g., anomalous anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also have excessive sleep or somnolence (hypersomnia), a feeling of heaviness in the limbs, and significant social impairment due to hypersensitivity to perceived interpersonal rejection.

[0334] Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, inability to respond to pleasurable stimuli, more pronounced melancholic mood than sadness or loss, excessive weight loss, or excessive guilt.

[0335] Major psychotic depression (PMD) or psychotic depression refers to a major depressive episode, specifically of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0336] Catatonic depression refers to major depression involving motor behavioral disturbances and other symptoms. An individual may become silent and apathetic, and be unable to move or exhibit aimless or bizarre movements.

[0337] Seasonal affective disorder (SAD) refers to a type of seasonal affective disorder in which an individual experiences depressive episodes that occur seasonally in the fall or winter.

[0338] Mild depression refers to a disorder associated with unipolar depression in which the same physical and cognitive problems are evident. It is not very severe and tends to last for a long time (e.g., at least 2 years).

[0339] Dual depression refers to an extremely depressed mood (mild depression) lasting at least 2 years, interspersed with periods of major depression.

[0340] Depressive personality disorder (DPD) refers to a personality disorder characterized by depression.

[0341] Recurrent transient depression (RBD) is a condition in which an individual experiences approximately one episode of depression per month, each episode lasting two weeks or less and typically less than two to three days.

[0342] Mild depressive disorder or mild depression is a condition in which at least two symptoms are present for two weeks.

[0343] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including elevated mood (mania or hypomania) and depressed mood (depression). During mania, an individual may feel or exhibit abnormal happiness, energy, or irritability. They often make hasty decisions with little regard for consequences. Sleep needs are usually reduced. During depression, they may cry out, lack eye contact with others, and have a negative outlook on life. The risk of suicide is higher in patients with these conditions, exceeding 6% over 20 years, while the incidence of self-harm is 30%–40%. Other mental health conditions such as anxiety disorders and substance use disorders are also mentioned.Page 36 / 71 41 CN 121045302 A Health problems are often associated with bipolar disorder.

[0344] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, etc.

[0345] Treatment-resistant depression refers to a condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or psychotherapy (psychotherapy) have not reduced the depressive symptoms of a subject with treatment-resistant depression. In some cases, the symptoms of an individual with treatment-resistant depression improve but then relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatment, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple reuptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0346] Postoperative depression refers to depressive mood that occurs after a surgical procedure (e.g., having to face the outcome of death). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in normally enjoyed hobbies and activities, or persistent feelings of worthlessness or despair.

[0347] Mood disorder associated with a woman’s health condition or illness refers to a mood disorder (e.g., caused by) a woman’s health condition or illness (e.g., as described herein).

[0348] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual’s tendency to commit suicide. Suicidal ideation involves thoughts about suicide or an unusual focus on suicide. The range of suicidal ideation varies greatly, from fleeting thoughts to deep thoughts, detailed planning, role-playing, and attempted suicide. Symptoms include discussing suicide, acquiring ways to commit suicide, social withdrawal, preoccupation with death, feeling trapped or hopeless about something, increased alcohol or drug use, doing risky or self-destructive things, and saying goodbye to people as if they will never see them again.

[0349] Symptoms of depression include persistent anxiety or sadness, feelings of helplessness, hopelessness, pessimism, worthlessness, lethargy, restlessness, difficulty falling asleep, insomnia, irritability, fatigue, aggression, lack of interest in recreational activities or hobbies, lack of attention, lack of energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary depending on the circumstances. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., through a mental status examination).

[0350] In some embodiments, the method includes using known depression scales, such as the Hamilton Depression Rating Scale (HAM-D) and the Clinical Global Impression Improvement Scale (CGA).Subjects were monitored using the Impression-Improvement Scale (CGI) and the Montgomery-Asperger Depression Rating Scale (MADRS). In some implementations, treatment effectiveness was determined by a decrease in the subject's total Hamilton Depression Rating Scale (HAM-D) score. The decrease in the total HAM-D score occurred within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours, or less. Treatment effectiveness could be assessed throughout the entire designated treatment period. For example, therapeutic effect can be determined by a decrease in the total HAM-D score compared to baseline after administration of a compound described herein, such as a compound of formula (I) (e.g., 12 hours, 24 hours, or 48 hours after administration; or 24 hours, 48 ​​hours, 72 hours, or 96 hours or longer; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or a lifetime).

[0351] In some embodiments, the subject has a mild depressive disorder, such as mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, such as moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, such as severe major depressive disorder. In some embodiments, the subject has an extremely severe depressive disorder, such as extremely severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., prior to treatment with the compounds described herein, such as compound (I)) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18 (inclusive). In some embodiments, the subject's baseline HAM-D total score is between 19 and 22 (inclusive). In some embodiments, the subject's HAM-D total score prior to treatment with the compounds described herein, such as compound (I) is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, after treatment with the compounds described herein, such as compound (I), the subject's HAM-D total score is about 0 to 10 (e.g., less than 10; 0 to 10; 0 to 6; 0 to 4; 0 to 3; 0 to 2, or 1.8). In some implementation schemes, in the use of thisThe total HAM-D score is less than 10, 7, 5, or 3 after treatment with the compounds described herein, such as compounds of formula (I). In some embodiments, the total HAM-D score decreases from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a total HAM-D score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with the compounds described herein, such as compounds of formula (I). In some embodiments, the reduction in the total HAM-D score from baseline to total HAM-D score after treatment with the compounds described herein, such as compounds of formula (I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 times. In some embodiments, the percentage reduction in the baseline HAM-D total score to the baseline HAM-D total score after treatment with a compound described herein, such as a compound of formula (I), is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score after treatment with a compound described herein, such as a compound of formula (I), relative to the baseline HAM-D total score (e.g., at 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or longer; or 1, 2, or 14 days or longer).

[0352] In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a reduction in the Hamilton Depression Rating Scale (HAM-D)). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect within the first or second day of treatment with a compound described herein, such as a compound of formula (I) (e.g., as measured by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect within 14 days of the start of treatment with a compound described herein, such as a compound of formula (I) (e.g., as measured by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 21 days of initiation of treatment with a compound described herein, such as a compound of formula (I).The therapeutic effect is provided within 28 days or more (e.g., as determined by a statistically significant reduction in the total HAM-D score). In some embodiments, the therapeutic effect is a reduction in the total HAM-D score from baseline following treatment with a compound described herein, such as compound (I) (e.g., treatment with a compound described herein, such as compound (I), once daily for 14 days). In some embodiments, the subject's total HAM-D score was at least 24 prior to treatment with a compound described herein, such as compound (I). In some embodiments, the subject's total HAM-D score was at least 18 prior to treatment with a compound described herein, such as compound (I). In some embodiments, the subject's total HAM-D score was between 14 and 18 (inclusive) prior to treatment with a compound described herein, such as compound (I). In some embodiments, the subject's total HAM-D score decreased by at least 10 relative to baseline after treatment with a compound described herein, such as compound (I). In some embodiments, the total HAM-D score decreases by at least 15 (e.g., at least 17) relative to a baseline total HAM-D score after treatment with the compound described herein, such as compound (I). In some embodiments, the total HAM-D score associated with treatment with the compound described herein, such as compound (I), on page 38 / 71 of this specification, is no more than a value in the range of 6 to 8. In some embodiments, the total HAM-D score associated with treatment with the compound described herein, such as compound (I), is no more than 7.

[0353] In some embodiments, the method provides a therapeutic effect within a timeframe of 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a reduction in the Clinical Global Impression Improvement Scale (CGI)). In some embodiments, the CNS condition is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating depressive disorders (e.g., major depressive disorder) provides therapeutic effect on the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0354] In some embodiments, the method provides therapeutic effect within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a decrease in the Montgomery-Asperger Depression Rating Scale (MADRS)). In some embodiments, the CNS condition is a depressive disorder, e.g.For example, major depressive disorder. In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect on the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0355] The therapeutic effect of major depressive disorder can be measured by a decrease in the Montgomery-Asperger's Depression Rating Scale (MADRS) score exhibited by the subject. For example, the MADRS score may decrease within 4 days, 3 days, 2 days, or 1 day; or within 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less. The Montgomery-Asperger's Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (about facial sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, feelings of weakness, pessimistic thoughts, and suicidal thoughts) that psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.

[0356] In some embodiments, the method provides therapeutic effects over 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)). In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0357] In some embodiments, the method provides therapeutic effects over a period of 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours or less (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-Item Scale (GAD-7)).

[0358] Anxiety Disorders

[0359] This document provides methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorders are a broad term encompassing several different forms of abnormal and pathological fear and anxiety. Current diagnostic criteria for mental illness identify various anxiety disorders.

[0360] Generalized anxiety disorder is a common chronic condition characterized by persistent anxiety and an inability to focus on any one goal or situation. Individuals with generalized anxiety disorder experience nonspecific, persistent fear and worry and become excessively concerned about daily events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0361] In panic disorder, an individual experiences brief episodes of intense fear and anxiety, typically characterized by trembling, shaking,Confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as sudden onset of fear or discomfort that peaks in less than ten minutes, can last for several hours, and can be triggered by stress, fear, or even movement; however, the specific cause remains unclear. In addition to recurrent accidental panic attacks, the diagnosis of panic disorder requires that the attacks have chronic consequences: worry about the potential effects of the attack, persistent fear of future attacks, or significant behavioral changes associated with the attack. Thus, individuals with panic disorder experience symptoms even outside of specific panic attacks. Typically, panic sufferers notice normal changes in their heart rate, leading them to believe that there is something wrong with their heart or that they are about to have another panic attack. In some cases, heightened perception of bodily functions (hypervigilance) occurs during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

[0362] Obsessive-compulsive disorder is a type of anxiety disorder characterized by repetitive troubling (distressing, persistent, and intrusive thoughts or images) and compulsions (intense urges to perform specific actions or rituals). OCD thought patterns can be likened to superstition to the point that they link beliefs to causal relationships that do not actually exist. Often this process is completely illogical; for example, compulsive walking in a certain pattern can be used to alleviate distress over impending harm. And in many cases, the compulsion is completely inexplicable, merely an impulse to complete a ritual triggered by tension. In rare cases, OCD patients may only experience distress without obvious compulsive behavior; very few patients experience only compulsive behavior.

[0363] The single largest category of anxiety disorders is phobias, which include all situations in which fear and anxiety are triggered by specific stimuli or circumstances. Patients typically anticipate terrifying consequences from encountering the object they fear, which can be anything from animals to bodily fluid locations.

[0364] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can be caused by extreme situations such as fighting, rape, hostage situations, or even serious accidents. It can also be caused by prolonged (chronic) exposure to severe stressors, such as soldiers who have endured individual combat but are unable to cope with continuous fighting. Common symptoms include momentary re-experiencing, avoidance behavior, and depression.

[0365] Women's Health Disorders

[0366] This article provides methods for treating disorders or conditions related to women's health. Disorders or conditions related to women's health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual anxiety disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related conditions (e.g., polycystic ovary syndrome (PCOS)), other conditions and disorders, and problems related to women's overall health and wellness (e.g., amenorrhea).

[0367] Women’s gynecological health and conditions include menstruation and irregular menstruation; urinary tract health, including urinary incontinence and pelvic floor disorders; and conditions such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvar pain.

[0368] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks before a woman’s menstrual period. Symptoms can vary but may include bleeding, mood swings, breast tenderness, food cravings, fatigue, irritability, acne, and depression.

[0369] Premenstrual anxiety disorder (PMDD) is a severe form of PMS. PMDD symptoms are similar to PMS but more severe and can interfere with work, social activities, and relationships. PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in common activities, difficulty concentrating, fatigue, changes in appetite, feeling out of control or overwhelmed, sleep problems, and physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

[0370] Pregnancy problems include preconception and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm and premature birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0371] Miscarriage is the spontaneous termination of pregnancy within 20 weeks prior to conception.

[0372] Abortion is the intentional termination of pregnancy, which may be performed during the first 28 weeks of pregnancy.

[0373] Infertility and related conditions include uterine fibroids, polycystic ovary syndrome (PCOS), endometriosis, and primary ovarian insufficiency.

[0374] Polycystic ovary syndrome (PCOS) is an endocrine disorder in women of reproductive age. PCOS is a group of symptoms caused by elevated levels of androgens in the female body. Most women with PCOS have numerous small follicles growing on their ovaries. Symptoms of PCOS include irregular or absent menstruation, menorrhagia, excessive body and facial hair, acne, pelvic pain, difficulty conceiving, and spots on rough, dark, smooth, and soft skin. PCOS can be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0375] Other conditions and disorders that affect women only include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0376] Women’s general health and wellness-related issues include violence against women, women with disabilities and their specific challenges, osteoporosis and bone health, and menopause.

[0377] Menopause refers to the period 12 months after a woman’s last menstrual period and marks the end of the menstrual cycle. Menopause typically occurs in women in their 40s or 50s. Physical symptoms of menopause (such as hot flashes) and emotional symptoms can disrupt sleep, reduce energy, or cause discomfort.Anxiety or feelings of sadness or loss. Amenorrhea includes natural amenorrhea and surgical amenorrhea, which is a class of amenorrhea induced by events such as surgery (e.g., hysterectomy, oophorectomy; cancer). Amenorrhea can be induced when the ovaries are severely damaged, for example, by radiation, chemotherapy or other drug treatments.

[0378] Epilepsy

[0379] A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, may be used in the methods described herein, for example for the treatment of the conditions described herein, such as epilepsy, status epilepticus or seizures.

[0380] Epilepsy is a brain condition characterized by recurrent seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, awakening-onset grand mal epilepsy, West syndrome, Lennox-Gastaut syndrome; partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy.

[0381] Epilepsy Occurrence

[0382] The compounds and methods described herein can be used to treat or prevent epilepsy. Epilepsy is a progressive process by which the normal brain produces epilepsy (a chronic disorder of epileptic seizures). Epilepsy is caused by neuronal damage resulting from initial injury (e.g., status epilepticus).

[0383] Status Epilepticus (SE)

[0384] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus; nonconvulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epileptic seizures that persist despite treatment with first-line therapy and the administration of second-line therapy. Refractory status epilepticus is characterized by status epileptic seizures that persist despite treatment with first-line and second-line therapy and is usually treated with general anesthetics. Extremely refractory status epilepticus is characterized by status epileptic seizures that persist despite treatment with first-line, second-line, and general anesthetics for 24 hours or longer.

[0385] Nonconvulsive status epilepticus may include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, and subtle nonconvulsive status epilepticus.State; generalized nonconvulsive status epilepticus, such as late-onset absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus. Instructions for use 41 / 71 pages 46 CN 121045302 A

[0386] The compound of formula (I) or a pharmaceutically acceptable salt, or a pharmaceutically acceptable combination thereof, may also be administered as a prophylactic agent to a subject with a CNS condition (e.g., traumatic brain injury; status epilepticus, such as convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; nonconvulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateral epileptiform discharges) before a seizure.

[0387] Seizure

[0388] A seizure is a physiological finding or change in behavior that occurs following an event of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” A convulsion is a rapid and uncontrollable shaking of the body. During a convulsion, the body’s muscles repeatedly contract and relax.

[0389] Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized and partial (also known as focal or localized). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0390] Generalized seizures are produced by electrical impulses throughout the entire brain, while partial seizures (at least initially) are produced by electrical impulses in a relatively small part of the brain. The part of the brain that produces the seizure is sometimes called a lesion.

[0391] There are six types of generalized seizures. The most common and severe, and therefore the most well-known, is the generalized seizure, also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and is usually in a state of collapse. After loss of consciousness, there is generalized body rigidity (known as the "tonic" phase of a seizure) for 30 to 60 seconds, followed by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient enters a deep sleep (the "postictal" or post-ictal phase). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence may occur.

[0392] Absence seizures cause brief loss of consciousness (only a few seconds) and are almost asymptomatic. Patients (most often children) usually stop their activity and stare blankly. These seizures start and end abruptly and may occur several times a day. Patients are usually unaware of their seizure, but they may be aware of "the passage of time."

[0393] Myoclonic seizures consist of occasional muscle twitches, usually on both sides of the body. Patients sometimes describe the muscle twitches as brief electric shocks. In severe cases, these seizures may cause objects to fall or be unintentionally thrown.

[0394] Clonic seizures are repetitive, rhythmic muscle jerks that involve both sides of the body simultaneously.

[0395] Tonic seizures are characterized by muscle rigidity.

[0396] Atonic seizures consist of a sudden and generalized loss of muscle tone, particularly in the arms and legs, and usually result in a fall.

[0397] The epileptic seizures described herein may include: epileptic seizures; acute repetitive seizures; dense seizures; continuous seizures; uninterrupted seizures; long-term seizures; recurrent seizures; status epilepticus, such as refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized seizures; infantile spasms; Jacksonian seizures. Seizures; massive bilateral myoclonic seizures; multifocal seizures; neonatal paroxysmal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet Syndrome, Leigh-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 epilepsy in female infants. Specification 42 / 71 pages 47 CN 121045302 A

[0398] Movement Disorders

[0399] Methods for treating movement disorders are also described herein. As used herein, “movement disorder” refers to a variety of diseases and conditions associated with hyperkinetic movement disorders and abnormalities related to muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and Parkinson's syndrome (specifically defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle reflex, tics and Tourette syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0400] Tremor

[0401] The methods described herein can be used to treat tremor, for example, compounds of formula (I) can be used to treat cerebellar tremor or intention tremor, dystonia-related tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor, or red nucleus tremor. Tremors include: hereditary, degenerative, and idiopathic conditions, such as Wilson's disease.Diseases such as Parkinson's disease and spontaneous tremor; metabolic disorders (e.g., thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Roussy-Levy disease, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (narcolepsy, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremors can be classified into physiological tremors, enhanced physiological tremors, essential tremor syndromes (including classic essential tremor, primary orthostatic tremor, and task-specific and position-specific tremors), dystonia tremors, Parkinsonian tremors, cerebellar tremors, Hodgkin's tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxin- or drug-induced tremors, and psychogenic tremors.

[0402] A tremor is an involuntary, sometimes rhythmic, muscle contraction and relaxation that may involve oscillations or twitches of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cord folds, trunk, legs).

[0403] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the extremities that occurs after purposeful movement. Cerebellar tremor is caused by cerebellar lesions or damage resulting from, for example, tumors, stroke, or diseases (e.g., multiple sclerosis, a hereditary degenerative disease).

[0404] Dystonic tremor occurs in individuals affected by dystonia (a movement disorder in which persistent involuntary muscle contractions cause twisting and repetitive movements and / or pain and abnormal posture or position). Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and often can be relieved by complete rest.

[0405] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and in some cases does not progress, and can progress slowly, starting on one side of the body but affecting both sides within 3 years. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremor may decrease with age, but the severity may increase. Elevated emotions, stress, fever, exhaustion, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms generally develop over time, are visible after an attack, and persist.

[0406] Orthostatic tremor is characterized by rapid (e.g., over 12 Hz) rhythmic muscle contractions that occur quickly in the legs and trunk after standing. Cramps may be felt in the thighs and legs, and the patient may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0407] Parkinson's tremor is caused by damage to structures in the brain that control movement. Parkinson's tremor is often associated with Parkinson's disease.Parkinson's disease is a precursor to and typically manifests as a "pill-rolling" motion of the hands, which can also affect the jaw, lips, legs, and trunk. Onset of Parkinson's tremor usually begins after age 60. The movement begins in one limb or one side of the body and can progress to include the other side.

[0408] Physiological tremor can occur in normal individuals and is not clinically significant. It is present in all voluntary muscle groups. (Instructions 43 / 71, page 48, CN 121045302 A) Physiological tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including overactive thyroid and hypoglycemia. The tremor typically has a frequency of about 10 Hz.

[0409] Psychogenic tremor or hysterical tremor can occur at rest or during postural or dynamic movements. Patients with psychogenic tremor may have conversion disorder or another mental illness.

[0410] Red nucleus tremor is characterized by a coarse, slow tremor that can be present at rest, during posture, and intentionally. Tremor is associated with disorders affecting the red nucleus in the midbrain, a classic aberrant stroke.

[0411] Parkinson's disease affects dopamine-producing nerve cells in the brain. Symptoms include muscle rigidity, tremor, and changes in speech and gait. Parkinson's disease is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinson's disease shares the symptoms found in Parkinson's disease, but it is a complex rather than a progressive neurodegenerative disease.

[0412] Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that cause abnormal (often repetitive) movements or postures. Dystonian movements can be patterned, twisting, and may be tremor-like. Dystonia often begins or worsens with voluntary actions and is associated with spillover muscle activation.

[0413] Chorea is a neurological disorder characterized by twitching involuntary movements of the muscles, typically affecting the shoulders, hips, and face. Huntington's disease is a genetic disorder that causes progressive weakness of nerve cells in the brain. Symptoms include uncontrolled movement, clumsiness, and balance problems. Huntington's disease can impair walking, speaking, and swallowing.

[0414] Ataxia is the loss of complete control over the movement of limbs and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0415] Myoclonus and startle reflexes are responses to sudden and unexpected stimuli, which can be auditory, tactile, visual, or vestibular.

[0416] Tics are involuntary movements that usually have a sudden onset, are brief, repetitive, but non-rhythmic, usually mimic normal behavior, and usually occur in a background of normal activity. Tics can be classified as motor tics or vocal tics; motor tics are associated with movement, while vocal tics are associated with sound. Tics can be simple or complex. For example, a simple motor tic involves only some muscles limited to a specific part of the body. Tourette syndrome is a hereditary neuropsychiatric disorder that occurs in children and is characterized by multiple motor tics and at least one vocal tic.

[0417] Restless legs syndrome is a neurosensory-motor disorder characterized by an uncontrollable urge to move the legs at rest.

[0418] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle rigidity, typically involving the lower back and legs. It usually produces a stiff-legged gait with increased lumbar hyperbola. Characteristic abnormalities are usually observed on EMG recordings of continuous motor unit activity involving the paravertebral muscles. Variants include “stiff limb syndrome” which produces focal rigidity that typically affects the distal legs and feet.

[0419] Gait disorders refer to abnormalities in the manner or style of walking caused by neuromuscular, arthritis, or other bodily changes. Gait is classified according to the system responsible for abnormal movement and includes hemiplegic gait, bilateral paraplegic gait, neuropathic gait, myopathic gait, Parkinsonian gait, choreiform gait, ataxia gait, and sensory gait.

[0420] Anesthesia / Sedation

[0421] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of musculoskeletal reflexes, reduced stress response, or all of these simultaneously. These effects can be achieved by a single drug alone providing the correct combination of effects, or by combination of drugs (e.g., hypnotics, sedatives, anesthetics, analgesics) to achieve very specific combinations of results. Anesthesia allows a patient to undergo surgery and other procedures without the pain and discomfort that would otherwise be experienced.

[0422] Sedation is the reduction of irritability or agitation through the administration of pharmacological agents, generally facilitating medical or diagnostic procedures.

[0423] Sedation and analgesia encompass a continuum of states of consciousness ranging from mild sedation (sedatives) to general anesthesia.

[0424] Mild sedation is also referred to as sedation. Mild sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are generally unaffected.

[0425] Moderate sedation / analgesia (awake sedation) is drug-induced inhibition of consciousness during which the patient purposefully responds to verbal commands, alone or with light-tactile stimulation. No intervention is usually required to maintain airway patency. Spontaneous ventilation is usually sufficient. Cardiovascular function is generally maintained.

[0426] Deep sedation / analgesia is drug-induced inhibition of consciousness during which the patient is not easily awakened but will purposefully respond to repeated or painful stimuli (reflex withdrawal of non-painful stimuli). Independent ventilation may be impaired and the patient may require assistance to maintain airway patency. Spontaneous ventilation may be insufficient. Cardiovascular function is generally maintained.

[0427] General anesthesia is drug-induced loss of consciousness during which the patient is unawakenable, even with painful stimuli. The ability to maintain independent ventilation is usually impaired and assistance is usually required to maintain airway patency. Due to lower spontaneous ventilation...Gas or drug-induced neuromuscular inhibition may require positive pressure ventilation. Cardiovascular function may be impaired.

[0428] Sedation in the intensive care unit (ICU) allows suppression of the patient's environmental awareness and reduction of their response to external stimuli. It can be effective in caring for critically ill patients and covers a wider range of symptom control that will vary with the individual patient and the course of their disease. In critical care, deep sedation has been used to promote endotracheal tube tolerance and ventilator synchronization, typically using neuromuscular blocking agents.

[0429] In some embodiments, sedation is induced and maintained in the ICU for a longer period of time (e.g., long-term sedation, continuous sedation) (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives may have a long duration of action. Sedatives in the ICU may have a shorter elimination half-life.

[0430] Programmed sedation and analgesia, also known as conscious sedation, is a technique that administers a sedative or dissociative agent, with or without an analgesic, to induce a procedure that allows the subject to undergo an unbearable procedure while maintaining cardiopulmonary function.

[0431] Examples

[0432] The following examples are set forth in order to provide a more complete understanding of the invention described 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 in any way.

[0433] Substances and Methods

[0434] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0435] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing unwanted reactions. The selection of protecting groups suitable for specific functional groups and suitable conditions for protection and deprotection is well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0436] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC or supercritical fluid chromatography (SFC). Details of the preparation of the representative oxidized sterols listed herein are presented below. The compounds provided herein can be described by those skilled in the art of organic synthesis from known or commercially available sources.Pages 45 / 71, CN 121045302 A. Preparation of starting materials and reagents. Exemplary chiral columns that can be used to separate / purify the enantiomers / diastereomers provided herein include, but are not limited to, ChiralPak® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0437] The 1H-NMR reported herein (e.g., for the region between about 0.5 and about 4 ppm δ (ppm)) should be understood as an exemplary interpretation of the NMR spectrum of the compound (e.g., exemplary peak integration). 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.

[0438] Exemplary general method of analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile Gradient: 5%–95% B over 1.6 or 2 min; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 °C.

[0439] Exemplary general method for preparative HPLC: Column: Waters Xbridge 150*25, 5u conditional water (10mM NH4HCO3)-ACN, start B 85, ​​end B 100, gradient time (min) 6.5, 100% B hold time (min) 1, flow rate (ml / min) 25, injection 4).

[0440] Exemplary general method for SFC: Column: DAICL CHIRALPAK AD (250 mm*50 mm, 10 μm; condition: 0.1% NH3H2O ​​ETOH; start B: 25%, end B: 25%; flow rate (ml / min): 200).

[0441] Exemplary general method for LCMS / LC: ELSD: 30-90AB_2 min. Lcm. (Mobile phase: 1.5 mL / 4L TFA / water (solvent A) and 0.75 mL / 4L TFA / acetonitrile (solvent B), eluted at 1.2 mL / min for 0.9 min using an elution gradient of 30%–90% (solvent B) and maintained at 90% for 0.6 min; Column: Xtimate C18 2.1*30 mm, 3 µm;Wavelength: UV 220 nm; Column temperature: 50℃; MS ionization: ESI; Detector: PDA & ELSD)

[0442] Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin-layer chromatography; PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-boron bicyclo[3.3.1]nonane; Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium(O); AcCl: acetyl chloride; i-PrMgCl: isopropyl magnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: tetraisopropyl... Titanium propoxide; BHT: 2,6-di-tert-butyl-4-methylbenzene oxide; Me: methyl; i-Pr: isopropyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; DMP: Dess-Martin periodinane; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: tert-butoxycarbonyl. Py: Pyridine; TBAF: Tetra-n-Butylammonium Fluoride; THF: Tetrahydrofuran; TBS: Tert-Butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-Toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium Aluminum Hydrate; LDA: Lithium Diisopropylamino; LiOH.H2O: Lithium Hydroxide Hydrate; MAD: Bis(2,6-Di-tert-Butyl-4-methylphenyloxide)methylaluminum; MeCN: Acetonitrile; NBS: N-Bromosuccinimide; Na2SO4: Sodium Sulfate; Na2S2O3: Sodium Thiosulfate; MeCN: Acetonitrile; MeOH: Methanol; Boc: Tert-Butoxycarbonyl; MTBE: Methyl Tert-Butyl Ether; K-Selectride: Potassium Tris(Sec-Butyl)Borohydride; 9-BBN Dimer: 9-Boron bicyclo(3.3.1)nonane (dimer).

[0443] Example 1: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3,13-dimethylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl-1-one (A9) Specification 46 / 71 pages 51 CN 121045302 A

[0444]

[0445] Synthesis of A2

[0446]

[0447] MePPh3Br (145 g, 408 mmol) was added to THF (300) at 15°C.t-BuOK (45.7 g, 408 mmol) was added to the suspension in 200 mL of THF. After stirring at 45 °C for 0.5 h, a solution of A1 (CAS# 5696-44-6) (80 g, 204 mmol) in 200 mL of THF was added at 45 °C and the reaction mixture was stirred at 45 °C for 1 h. The mixture was diluted with PE (300 mL) and then filtered. The filtrate was concentrated to give an oil (200 g). After stirring the product with PE (1 L) for 16 h, the solid was filtered and the filtrate was concentrated to give product A2 as an oil, which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δH 6.30 (dd , J = 11.2, 17.6 Hz, 1H) , 5.15‑4.96 (m, 2H) , 3.94‑3.81 (m, 8H) , 2.02‑1.73 (m, 7H) , 1.58‑1.35 (m, 13H) , 1.22‑1.14 (m, 2H) , 0.81 (s, 3H).

[0448] Synthesis of A3

[0449]

[0450] Under a N2 atmosphere, CF3COOH (3.47 g, 30.4 mmol) (in 5 mL of DCM) was added dropwise to a solution of Et2Zn (30.5 mL, 1 M in hexane) in DCM (50 mL) over a 1 h time period. Then, CH2I2 (8.16 g, 30.5 mmol) (in 5 mL of DCM) was added dropwise to the mixture over a 15 min time period at 0 °C. After the addition, A2 (4 g, 10.2 mmol) (in 5 mL of DCM) was added to the reaction mixture and stirred at 0 °C for 3 h, followed by stirring at 25 °C for 16 h. The reactants were quenched by adding saturated NH4Cl aqueous solution (80 mL), and the aqueous phase was extracted with DCM (3 x 60 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give A3 (4.5 g) as an oil. (Based on H-NMR, approximately 40% of the starting material remained.)

[0451] Synthesis of A4 and A5

[0452]

[0453] Hydrochloric acid (12 mL, 2 M aqueous solution) was added to a solution of A3 (4.5 g) in THF (25 mL), and the reaction mixture was stirred at 25°C for 16 hours. Saturated NaHCO3 (50 mL) was added to the reaction mixture to pH approximately 8, and the mixture was extracted with EtOAc (2 x 80 mL). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered, and concentrated to give A3 (4.5 g) as an oil. (Based on H-NMR, approximately 40% of the starting material remained.)The sample was washed with a solution of 1 mL, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (0 to 10% EtOAc / PE) to give A₅ (1.1 g). Purification was performed by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm; conditions: 0.1% NH3H2O ​​ETOH; start B: 25%, end B: 25%; flow rate (ml / min): 200) to obtain oily substances A4 (550 mg, 29.1%) and A5 (420 mg).

[0454] A4: 1H NMR (400 MHz, CDCl3) δH 2.73–2.61 (m, 1H), 2.47 (dd, J=8.8, 19.2 Hz, 1H), 2.35–2.22 (m, 1H), 2.17–1.85 (m, 8H), 1.77–1.61 (m, 4H), 1.56–1.50 (m, 1H), 1.47–1.39 (m, 1H), 1.36–1.22 (m, 5H), 0.92 (s, 3H), 0.90–0.84 (m, 1H), 0.54–0.40 (m, 2H), 0.34–0.25 (m, 1H), 0.12–0.04 (m, 1H).

[0455] Synthesis of A6

[0456]

[0457] AlMe3 (2.6 mL, 2 M in toluene) was added dropwise to a solution of BHT (2.22 g, 10.08 mmol) in toluene (6 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at 25 °C for 1 minute. h. The reaction mixture was used directly as the MAD solution for the next step without monitoring or further purification. A4 (530 mg, 1.68 mmol) in DCM (5 mL) was added dropwise to the MAD (5.04 mmol) solution at -70 °C. After stirring at -70 °C for 1 h under N2, MeMgBr (1.7 mL, 5.1 mmol, 3 M in diethyl ether) was added dropwise at -70 °C. The resulting solution was stirred at -70 °C for another 3 h. The reaction mixture was poured into a 100 mL saturated aqueous solution of citric acid below 10 °C and extracted with EtOAc (2 x 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by a rapid column (0 to 20% EtOAc / PE) to give A6 (480 mg, 86.4%) as a solid.

[0458] 1H NMR (400 MHz, CDCl3) δH 2.44 (dd,J=8.2, 19.2 Hz, 1H), 2.14-1.88 (m, 4H), 1.87-1.76 (m, 2H), 1.64-1.60 (m, 1H), 1.58-1.49 (m, 5H), 1.48-1.33 (m, 4H) , 1.31-1.21 (m, 6H), 1.19 (s, 3H), 0.88 (s, 3H), 0.56-0.33 (m, 3H), 0.30-0.20 (m, 1H), 0.10-0.00 (m, 1H).

[0459] LCMS Rt = 0.980 min / 2 min Chromatography, 30-90AB_2 min. Lcm. (Mobile phase: 1.5 mL / 4L TFA / water (solvent A) and 0.75 mL / 4L TFA / acetonitrile (solvent B), at a flow rate of 1.2 mL / min for 0.9 min, using a gradient of 30%-90% (solvent B) and maintaining at 90% for 0.6 min; Column: Ultimate C18 2.1*30 mm, 3 µm; Wavelength: UV 220 nm; Column temperature: 50℃; MS ionization: ESI; Detector: PDA & ELSD), LC-ELSD purity 99%; MS ESI calculated value of C22H33O [M-H2O+H]+ 313.2, experimental value 313.2.

[0460] Synthesis of A7

[0461]

[0462] t-BuOK (461 mg, 4.11 mmol) was added to a suspension of EtPPh3Br (1.52 g, 4.11 mmol) in THF (10 mL) at 25 °C under N2. The mixture was stirred at 50 °C for 30 min. A6 (455 mg, 1.37 mmol) was added below 40 °C. The reaction mixture was stirred at 40 °C for 3 h to obtain a suspension. The reaction mixture was quenched with a saturated NH4Cl aqueous solution (150 mL) at 25 °C. The aqueous layer was extracted with EtOAc (2 x 80 mL). The combined organic phases were concentrated. The residue was purified by a rapid column (0 to 10% EtOAc / PE) to give A7 (320 mg, 68.2%) as an oil. 1H NMR (400 MHz, CDCl3) δH 5.16‑5.07 (m, 1H) , 2.42‑2.31 (m, 1H) , 2.29‑2.13 (m, 2H) , 2.07‑1.89 (m, 2H) , 1.68‑1.61 (m, 5H) ,1.54–1.40 (m, 6H), 1.38–1.14 (m, 12H), 0.93–0.79 (m, 4H), 0.53–0.33 (m, 3H), 0.29–0.16 (m, 1H), 0.09–0.04 (m, 1H).

[0463] Synthesis of A8

[0464]

[0465] 9-BBN dimer (427 mg, 1.75 mmol) was added to a solution of A7 (300 mg, 0.88 mmol) in THF (10 mL), and the mixture was stirred at 45 °C for 14 hours. Ethanol (2 mL) was added to the resulting mixture at 15 °C, followed by the addition of an aqueous solution of NaOH (1.75 mL, 5.0 M, 8.75 mmol) at 0 °C. Hydrogen peroxide (1 mL, 10 M, 10 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 78 °C for 1 hour. The mixture was cooled to 15 °C. The mixture was added to water (10 mL). A saturated aqueous solution of Na₂S₂O₃ (20 mL) was added, and the excess H₂O₂ was confirmed to be destroyed (not turning blue) by checking with potassium iodide starch paper. The aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (10 to 35% EtOAc / PE) to give isomer 1 (150 mg) and isomer 2 (80 mg) as solids.

[0466] Isomer 1: 1H NMR (400 MHz, CDCl3) δH 3.76-3.63 (m, 1H), 2.02-1.82 (m, 4H), 1.71-1.60 (m, 3H), 1.53-1.32 (m, 9H), 1.31-1.09 (m, 15H), 0.67 (s, 3H), 0.52-0.33 (m, 3H), 0.28-0.19 (m, 1H), 0.08-0.03 (m, 1H).

[0467] Isomer 2: 1H NMR (400 MHz, CDCl3) δH 3.79–3.66 (m, 1H), 2.07–1.81 (m, 5H), 1.71–1.59 (m, 4H), 1.50–1.33 (m, 6H), 1.32–1.10 (m, 16H), 0.77 (s, 3H), 0.51–0.33 (m, 3H), (See specification, pages 49 / 71, CN 121045302 A)0.27–0.19 (m, 1H), 0.07–0.02 (m, 1H).

[0468] Synthesis of A9

[0469]

[0470] DMP (188 mg, 0.44 mmol) was added to a solution of A8 (80 mg, 0.22 mmol) in DCM (2 mL), and the reaction mixture was stirred at 25 °C for 6 hours. The reaction mixture was quenched with saturated NaHCO3 (80 mL) and saturated Na2S2O3 (30 mL), and extracted with DCM (2 x 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (10% to 30% EtOAc / PE) to give A9 as a solid. ¹H NMR (400 MHz, CDCl₃) δH 2.54 (t, J = 8.8 Hz, 1H), 2.28–2.14 (m, 1H), 2.11 (s, 3H), 2.06–1.90 (m, 3H), 1.72–1.57 (m, 5H), 1.53–1.35 (m, 6H), 1.33–1.11 (m, 11H), 0.62 (s, 3H), 0.53–0.35 (m, 3H), 0.28–0.20 (m, 1H), 0.07–0.01 (m, 1H); LC-ELSD purity 99%; MS ESI calculated value of C24H37O [M- H2O+H] + 341.3, experimental value 341.3.

[0471] Example 2: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3,13-dimethylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-oxyethyl)-1H-pyrazole-4-carboxynitrile (A11)

[0472]

[0473] Synthesis of A10

[0474]

[0475] HBr (6.75 mg,0.03 mmol, 40% in water) and Br2 (32 mg,0.2 mmol) were added to a solution of A9 (60 mg, 0.17 mmol) in MeOH (2 ml) at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was quenched with saturated NaHCO3 aqueous solution (10 mL), treated with water (30 mL), and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain an oily substance, A10 (65 mg), which was directly used in the next step.

[0476] Synthesis of A11

[0477] Specification pages 50 / 7155 CN 121045302 A

[0478] K2CO3 (61.5 mg, 0.45 mmol) and 1H-pyrazole-4-carboxynitrile (20.7 mg, 0.22 mmol) were added to a solution of A10 (65 mg, 0.15 mmol) in acetone (2 mL), and the reaction mixture was stirred at 25 °C for 14 hours. Water (20 mL) was added to the mixture and extracted with EtOAc (2 x 30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by a rapid column (20% to 50% EtOAc / PE) to give A11 (15 mg, 22.4%) as a solid. 1H NMR (400 MHz, CDCl3) δH 7.85 (s, 1H), 7.81 (s, 1H), 5.06-4.85 (m, 2H), 2.61 (t, J=8.8 Hz, 1H), 2.27-2.15 (m, 1H), 2.09‑1.89 (m, 3H) , 1.81‑1.63 (m, 4H) , 1.54‑1.37 (m, 5H) , 1.32‑1.18 (m, 12H) , 0.92‑0.78 (m, 1H) , 0.68 (s, 3H) , 0.54‑0.35 (m, 3H) , 0.29–0.21 (m, 1H), 0.07–0.01 (m, 1H); LC-ELSD purity 99%; MS ESI calculated value of C28H39N3O2Na [M+Na]+ 472.3, experimental value 472.3.

[0479] Example 4: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one, 4.12

[0480]

[0481] Synthesis 4.2

[0482] Under N2, Pd-C (wet, 10%, 5 g) was added to a solution of 4.1 (50 g, 165 mmol) in THF (500 mL). The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred at 25°C under H2 (15 psi) for 16 hours to obtain a suspension. The reaction mixture was filtered through a diatomaceous earth pad and washed with THF (3 x 200 mL). The filtrate was concentrated to obtain 4.2 (40 g) as a solid. This solid was then mixed with five other batches (5 x 50 g 4.1) in acetone (150 mL) and stirred at 25°C for 1 hour.h. Filter the mixture to obtain 4.2 (180 g) in solid form.

[0483] 1H NMR (400 MHz, CDCl3) δH 3.94 (dd, J = 4.8, 10.8 Hz, 1H), 3.67 (dd, J = 5.6, 10.8 Hz, 1H), 2.64 (t, J = 14.4 Hz, 1H), 2.45 (dd, J = 8.8, 19.6 Hz, 1H), 2.39–2.23 (m, 3H), 2.12–1.80 (m, 8H), 1.69–1.19 (m, 10H), 0.86 (s, 3H)

[0484] Synthesis 4.3

[0485] To 4.2 (180 g, 591 13.5 g (118 mmol) of pyridine hydrochloride and ethane-1,2-diol (183 g, 2955 mmol) were added to a solution of toluene (1500 mL). The mixture was stirred at 140 °C for 48 hours. The mixture was cooled to 25 °C. Water (1000 mL) was then added to the mixture, followed by extraction with EtOAc (3 x 1000 mL). The combined organic phases were washed with brine (2 x 1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 4.3 g (180 g, 460 mmol) of an oil.

[0486] 1H NMR (400 MHz, CDCl3) δH 3.95–3.79 (m, 10H), 2.05–1.92 (m, 3H), 1.78–1.64 (m, 5H), 1.56–1.36 (m, 10H), 1.30–1.03 (m, 5H), 0.82 (s, 3H)

[0487] Synthesis 4.4

[0488] Silica gel (82 g) and PCC (81.9 g, 381 mmol) were added in portions to a solution of 4.3 (100 g, 254 mmol) in DCM (1000 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was filtered, and the filter cake was washed with DCM (3 x 200 mL). The combined filtrates were concentrated to give an oily substance of 4.4 g (100 g, 254 mmol).

[0489] ¹H NMR (400 MHz, CDCl₃) δH 9.57 (s, 1H), 3.96–3.84 (m, 8H), 2.26–2.07 (m, 2H), 1.84–1.46 (m, 2H).20H), 0.91 (s, 3H)

[0490] Synthesis of 4.5

[0491] PPh3MeBr (274 g, 768 mmol) was added to a solution of t-BuOK (86.1 g, 768 mmol) in THF (500 mL) at 25 °C. After stirring at 50 °C for 0.5 h, a solution of 4.4 (100 g, 256 mmol) in THF (300 mL) was added to the reaction mixture at 50 °C. After stirring at 50 °C for 12 h, the mixture was poured into water (1000 mL) and extracted with EtOAc (2 x 500 mL). The combined organic phases were washed with saturated brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum (100 g). The solid was ground from MTBE (500 mL) at 25 °C to obtain 4.5 (90 g) as an oil. The oil was ground again from MTBE (500 mL) at 25 °C to obtain 4.5 (80 g) as an oil, which was purified by rapid column chromatography (0 to 10% EtOAc / PE) to obtain 4.5 (30 g, 38%) as a solid.

[0492] 1H NMR (400 MHz, CDCl3) δH 6.30 (dd, J = 11.2, 17.6 Hz, 1H), 5.13–5.01 (m, 2H), 3.94–3.83 (m, 8H), 2.01–1.76 (m, 6H), 1.54–1.36 (m, 12H), 1.27–1.15 (m, 4H), 0.81 (s, 3H)

[0493] Synthesis 4.6

[0494] CF3COOH (4.38 g, 38.5 g) was added dropwise to a solution of Et2Zn (46.2 mL, 1M in hexane) in DCM (250 mL) over a period of 1 h at 0 °C under N2 atmosphere. mmol), then CH2I2 (12.3 g, 46.2 mmol) was added dropwise over a 15 min period, followed by the final addition of a DCM (50 mL) solution containing 4.5 (6 g, 15.4 mmol). The reaction mixture was stirred at 0 °C for 1 h, followed by stirring at 25 °C for 12 h. The reactants were quenched by adding saturated NH4Cl aqueous solution (150 mL). The aqueous phase was extracted with DCM (3 x 100 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 4.7 (6.0 g, 14.9 mmol) as an oil, which was used as is.

[0495] Synthesis of 4.7

[0496] To 4.6Hydrogen chloride (14.9 mL, 29.8 mmol, 2 M) was added to a solution of THF (50 mL). After stirring at 25 °C for 16 h, the reaction mixture was adjusted to pH 8 with saturated NaHCO3 (150 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated, and then purified by a rapid column (0 to 30% EtOAc / PE) to give 4.7 g (1.8 g, 52%) as a solid.

[0497] 1H NMR (400 MHz, CDCl3) δH 2.72–2.62 (m, 1H), 2.52–2.22 (m, 3H), 2.16–2.06 (m, 4H), 2.01–1.67 (m, 7H), 1.60–1.29 (m, 8H), 0.92 (s, 3H), 0.55–0.36 (m, 2H), 0.34–0.25 (m, 1H), 0.12–0.02 (m, 1H)

[0498] Synthesis 4.8 Specification 52 / 71 pages 57 CN 121045302 A

[0499] NaH (475 mg, 11.9 mmol, 60% in oil) was added to a stirred solution of trimethylsulfonium iodide (2.42 g, 11.9 mmol) in DMSO (10 mL) and THF (5 mL) at 0 °C under N2 for 1.0 h. A solution of 4.7 (2.5 g, 7.9 mmol) in DMSO (5 mL) was added to the mixture at 0 °C. After stirring at 25 °C for 6 h, the reactants were diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with water (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give an oily product of 4.8 (2.5 g, 7.6 mmol), which was used as is.

[0500] Synthesis of 4.9a and 4.9b

[0501] Na (874 mg, 38.0 mmol) was added in three portions to anhydrous EtOH (10 mL) at 25 °C. After stirring at 75 °C for 1 h, anhydrous EtOH (20 mL) containing 4.8 (2.5 g, 7.6 mmol) was added to the sodium ethoxylate solution at 75 °C. After stirring at 75 °C for 4 h, the reactants were diluted with water (50 mL) and then concentrated to remove most of the solvent. The solution was then treated with EtOAc (2 x 30 g / mL).Extract the mixture with 2 x 50 mL of saturated brine, dry with anhydrous Na2SO4, filter, and concentrate. The residue was purified by a rapid column (0 to 30% EtOAc / PE) to obtain 4.9a (950 mg, de% > 99 (via 1H NMR, Rf = 0.3, PE / EtOAc = 3 / 1) and 4.9b (750 mg, de% > 99 (via 1H NMR), Rf = 0.55, PE / EtOAc = 3 / 1), both of which were oily.

[0502] 4.9a (50 mg) was further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5μ, gradient: 50%–80% B (water (10 mM NH4HCO3)–ACN, flow rate: 25 mL / min) to obtain 4.9a (10 mg, 20%) in solid form.

[0503] 4.9b (50 mg) was purified by preparative HPLC (column: Waters Xbridge) (column: Waters Xbridge) Prep OBD C18 150*30 5μm, gradient: 60%-90% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min) was further purified to obtain 4.9b (12 mg, 24%) in solid form.

[0504] 4.9a: 1H NMR (400 MHz, CDCl3) δH 3.52 (q, J = 7.2 Hz, 2H), 3.34 (dd, J = 8.8, 24.0 Hz, 2H), 2.68 (s, 1H), 2.44 (dd, J = 8.4, 19.2 Hz, 1H), 2.14-1.59 (m, 9H), 1.55-1.24 (m, 12H) , 1.20 (t, J = 6.8 Hz, 3H), 0.88 (s, 3H), 0.47–0.36 (m, 3H), 0.29–0.21 (m, 1H), 0.06–0.03 (m, 1H)

[0505] LC-ELSD / MS purity 99%, MS ESI calculated value of C24H37O2 [M–H2O+H]+ 357.2, calculated value 357.2.

[0506] 4.9b: 1H NMR (400 MHz, CDCl3) δH 3.52 (q, J = 7.2 Hz, 2H), 3.22 (dd, J = 8.8, 12.8 Hz, 2H), 2 .45 (dd, J = 8.4), 19 .2 Hz , 1H) , 2 .13-1 .61 (m , 9H) , 1.56-1.08 (m, 16H) , 0.95-0.85 (m, 4H) , 0.47- 0.34 (m, 2H) , 0.29-0.17 (m, 2H)

[0507] LC-ELSD / MS purity 99%, MS ESI calculated value of C24H37O2 [M-H2O+H]+ 357.3, calculated value 357.3.

[0508] Synthesis of 4.10

[0509] Ethyltriphenylphosphine bromide (4.41 g, 11.9 mmol) was added to a solution of t-BuOK (1.33 g, 11.9 mmol) in THF (20 mL) at 25 °C. After stirring at 40 °C for 0.5 h, a solution of 4.9a (900 mg, 2.4 mmol) in THF (10 mL) was added to the reactants at 40 °C. After stirring at 40 °C for 16 h, the mixture was poured into water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturated brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified by a rapid column (0 to 30% EtOAc / PE) to give 4.10 (300 mg, 32%) as an oil.

[0510] ¹H NMR (400 MHz, CDCl₃) δH 5.14–5.09 (m, ¹H), 3.51 (q, J = 7.2 Hz, 2H), 3.34 (dd, J = 9.6, 15.2 Hz, 2H), 2.40–2.16 (m, 4H), 2.01–1.82 (m, 3H), 1.68–1.45 (m, 16H), 1.30–1.10 (m, 6H), 0.88 (s, 3H), 0.45–0.30 (m, 3H), 0.28– (See specification, pages 53 / 71, CN 121045302 A) 0.17 (m, 1H), 0.02–0.08 (m, 1H)

[0511] Synthesis of 4.11

[0512] 9-BBN dimer (2.01 g, 8.24 mmol) was added to a solution of 4.10 (800 mg, 2.1 mmol) in THF (10 mL) at 25 °C. The mixture was then stirred at 40 °C for 16 hours to obtain a solution. After cooling to 0 °C, the mixture was successively treated with ethanol (1.89 g, 41.2 mmol) and NaOH (8.24 mmol).The solution was diluted very slowly (41.2 mmol, 5 M). After the addition was complete, H2O2 (4 mL, 39.7 mmol, 30%) was slowly added while maintaining the internal temperature below 25°C. After stirring at 75°C for 1 h, saturated Na2S2O3 aqueous solution (50 mL) was added, and the mixture was stirred at 0°C for another 1 h. The reactants were examined with potassium iodide starch paper to confirm that the excess H2O2 had been destroyed. The mixture was cooled and poured into water (50 mL). The mixture was extracted with EtOAc (3 x 20 mL), washed with saturated brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue (800 mg) was purified by rapid column chromatography (0 to 30% EtOAc / PE) to give 4.11 (400 mg, 50%) as an oil. H NMR (400 MHz, CDC13) δH 3.72-3.65 (m, 1H), 3.51 (q, J=6.8 Hz, 2H), 3.34 (dd, J=9.6, 24.0 Hz, 2H), 2.00-1.83 (m, 7H) , 1.69‑1.32 (m, 15H) , 1.28‑1.11 (m, 9H) , 0.66 (s, 3H) , 0.44‑0.30 (m, 3H) , 0.27‑0.17 (m, 1H) , 0.02‑ 0.09 (m, 1H)

[0514] Synthesis 4.12

[0515] DMP (419 mg, 0.9884 mmol) was added in portions to a solution of 4.11 (200 mg, 0.5 mmol) in DCM (10 mL). After stirring at 25 °C for 0.5 h, the mixture was quenched with NaHCO3 (50 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with Na2S2O3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue (190 mg) was purified by rapid column chromatography (0 to 50% EtOAc / PE) to give 4.12 (180 mg, 95%) as a solid. 1H NMR (400 MHz, CDC13) δH 3.52 (q, J=6.8 Hz, 2H), 3.34 (dd, J=8.8, 23.2 Hz, 2H), 2.70 (s, 1H), 2.55 (t, J= 8.8 Hz, 1H), 2.11 (m, 4H), 2.03–1.86 (m, 3H), 1.74–1.59 (m, 5H), 1.54–1.36 (m, 7H), 1.29–1.13 (m, 9H), 0.62 (s, 3H), 0.47–0.31 (m, 3H), 0.28–0.18 (m, 1H), 0.04–0.07 (m, 1H); LC-ELSD / MS purity 98%, MS ESI calculated value of C26H41O2 [M–H2O+H]+ 385.3, experimental value 385.3.

[0517] Example 5: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecylhydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-oxyethyl)-1H-pyrazole-4-carboxynitrile, 5.2

[0518]

[0519] HBr (6.5 mg, 0.03 mmol, 40% in water) and Br2 (26.1 mg, 0.16 mmol) were added to a solution of 4.12 (60 mg, 0.15 mmol) in MeOH (10 ml) at 25 °C. After stirring at 25 °C for 2 h, the mixture was quenched with saturated NaHCO3 (30 mL) and water (30 mL), followed by extraction with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain an oily substance, 5.1 (70 mg, 0.15 mmol), which was used directly in the next step without further purification.

[0520] Synthesis of 5.2

[0521] 1H-pyrazole-4-carboxynitrile (20.2 mg, 0.22 mmol) was added to a solution of 5.1 (70 mg, 0.15 mmol) in acetone (5 mL), followed by the addition of K2CO3 (40.1 mg, 0.29 mmol). After stirring at 50 °C for 2 h, the mixture was quenched with water (30 mL) and then extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5μm, gradient: 60%–90% B (water (10 mM NH4HCO3)–ACN, flow rate: 25 mL / min) to obtain a solid 5.2(17 mg, 24%).

[0522] 1H NMR (400 MHz, CDC13) δH 7.85 (s, 1H), 7.80 (s, 1H), 4.95 (dd, J = 18.0, 51.2 Hz, 2H), 3.52 (q, J = 6.8 Hz, 2H), 3.34 (dd, J = 9.2, 22.4 Hz, 2H), 2.72 (s, 1H), 2.61 (t, J = 8.4 Hz, 1H), 2.26-1.74 (m, 6H), 1.65-1.42 (m, 9H), 1.37‑1.17 (m, 10H) , 0.67 (s, 3H), 0.47–0.32 (m, 3H), 0.29–0.19 (m, 1H), 0.05–0.04 (m, 1H); LC-ELSD / MS purity 97%, MS ESI calculated value of C30H42N3O2 [M–H2O+H]+ 476.3, experimental value 476.3.

[0523] Example 6: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxyethyl)-1H-pyrazole-3-carboxynitrile, 6

[0524]

[0525] 1H-pyrazole-5-carboxynitrile (31.8 mg, 0.34 mmol) and K2CO3 (63.1 mg, 0.46 mmol) were added to a solution of 5.1 (110 mg, 0.23 mmol) in acetone (10 mL). After stirring at 50 °C for 2 h, saturated water (50 mL) was added to the mixture, followed by extraction with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Ultimate C18 150*25mm*5μm, gradient: 65%-95% B (water (10 mM NH4HCO3)-ACN, flow rate: 30 mL / min) to obtain 6 (28 mg, 25%) in solid form.

[0526] 1H NMR (400 MHz, CDCl3) δH 7.48 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 4.97 (dd, J = 18.0, 53).2 Hz, 2H), 3.52 (q, J = 7.2 Hz, 2H), 3.35 (dd, J = 9.2, 22.4 Hz, 2H), 2.72 (s, 1H), 2.61 (t, J = 8.8 Hz, 1H), 2.25-1.88 (m, 4H) , 1.79‑1.59 (m, 6H) , 1.52‑1.18 (m, 15H) , 0.68 (s, 3H) , 0.48‑0.34 (m, 3H) , 0.31‑0.20 (m, 1H) , 0.06‑‑0.07 (m, 1H); Structure confirmed by HMBC (H1 shows a clear signal with C4); LC-ELSD / MS purity 99%, MS ESI calculated value of C30H42N3O2 [M-H2O+H]+ 476.3, experimental value 476.3.

[0527] Example 7: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl-1-one, 7.4 Specification 55 / 71 pages 60 CN 121045302 A

[0528]

[0529] Synthesis of 7.1a and 7.1b

[0530] Na (979 mg, 42.6 mmol) was added to anhydrous MeOH (10 mL) in three portions at 25°C. The reaction mixture was stirred at 65°C for 1 h. Anhydrous MeOH (20 mL) containing 4.8 g (2.8 g, 8.5 mmol) was added to sodium methoxide solution at 65°C. After stirring at 65°C for 4 h, the reaction mixture was diluted with water (50 mL) and then concentrated to remove most of the solvent. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturated brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by a rapid column (0 to 10% EtOAc / PE) to give 7.1a (900 mg, Rf=0.2, PE / EtOAc=3 / 1, de%>99 (via 1H NMR)) and 7.1b (900 mg, Rf=0.35, PE / EtOAc=3 / 1), de%>99 (via 1H NMR)).

[0531] 7.1a (100 mg) was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5 μm, gradient: 58%–88% B (water (10 mM)).Purified by NH4HCO3-ACN at a flow rate of 25 mL / min, yielding 7.1a (24 mg, 24%) in solid form.

[0532] 7.1b (100 mg) was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5 μm, gradient: 58%–88% B (water (10 mM NH4HCO3)–ACN, flow rate: 25 mL / min) to obtain 7.1b (25 mg, 25%) in solid form.

[0533] 7.1a: 1H NMR (400 MHz, CDCl3) δH 3.38 (s, 3H), 3.32 (dd, J = 8.8, 23.2 Hz, 2H), 2.57 (s, 1H), 2.44 (dd, J = 8.8, 19.2 Hz, 1H), 2.15–1.57 (m, 9H), 1 0.54–1.16 (m, 12H), 0.88 (s, 3H), 0.49–0.34 (m, 3H), 0.31–0.21 (m, 1H), 0.07–0.03 (m, 1H); LC-ELSD / MS purity 98%, MS ESI calculated value of C23H35O2 [M–H2O+H]+ 343.3, experimental value 343.3.

[0534] 7.1b: 1H NMR (400 MHz, CDCl3) δH 3.38 (s, 3H), 3.19 (d, J = 2.4 Hz, 2H), 2.45 (dd, J = 8.4, 19.2 Hz, 1H), 2.13–1.60 (m, 9H), 1.55–1.10 (m, 13H), 0.89 (m, 4H), 0.48–0.32 (m, 2H), 0.29–0.16 (m, 2H); LC-ELSD / MS purity 98%, MS ESI calculated value of C23H35O2 [M–H2O+H]+ 343.3, experimental value 343.3.

[0535] Synthesis 7.2

[0536] Ethyltriphenylphosphine bromide (4.08 g, 11.0 mmol) was added to a solution of t-BuOK (1.23 g, 11.0 mmol) in THF (20 mL) at 25 °C. The mixture was stirred at 40 °C for 0.5 minutes. h later, 7.1a (800 mg, 2.2 mmol) was in THF (10) at 40 °C.The solution in 7.2 (500 mg, 1.3 mmol) in THF (10 mL) was added to the reactants. After stirring at 40 °C for 16 h, the mixture was poured into water (50 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturated brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was purified by a rapid column (0 to 20% EtOAc / PE) to give 7.2 (500 mg, 1.3 mmol) as an oil.

[0537] Synthesis of 7.3

[0538] 9-BBN dimer (1.30 g, 5.4 mmol) was added to a solution of 7.2 (500 mg, 1.3 mmol) in THF (10 mL) at 25 °C. The mixture was stirred at 40 °C for 16 h to obtain a solution. After cooling to 0°C, the mixture was diluted very slowly with ethanol (1.23 g, 26.8 mmol) and NaOH (5.36 mL, 26.8 mmol, 5 M). After the addition was complete, H₂O₂ (2.7 mL, 26.8 mmol, 30%) was slowly added while maintaining the internal temperature below 25°C. The resulting solution was stirred at 75°C for 1 hour. A saturated aqueous solution of Na₂S₂O₃ (50 mL) was added, and the mixture was stirred again at 0°C for 1 hour. The reactants were examined with potassium iodide starch paper to confirm that the excess H₂O₂ had been destroyed. The mixture was cooled and poured into water (50 mL). The mixture was extracted with EtOAc (3 x 20 mL), washed with saturated brine (2 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue (500 mg) was purified by rapid column chromatography (0 to 30% EtOAc / PE) to obtain 7.3 (250 mg, 50%) as an oil. 80 mg of 7.3 was purified by preparative HPLC (HT high-loaded C18 column 250*25 mm*5 μm, conditions: water (10 mM NH4HCO3)-ACN, start B 75, end B 95) to obtain 7.3 (23 mg) as a solid. 1H NMR (400 MHz, CDC13) δH 4.25-4.15 (m, 1H), 3.40-3.27 (m, 5H), 2.07-1.77 (m, 5H), 1.70-1.00 (m, 23H), 0.67 (m, 3H), 0.45-0.30 (m, 3H), 0.30-0.20 (m, 1H), 0.05-(-0.05) (m, 1H).

[0540] The LC-ELSD / MS purity was 98%, and the MS ESI calculated value for C25H41O [M-H2O+H]+ was 373.3, with an experimental value of 373.3.

[0541] Synthesis of 7.4

[0542] DMP (325 mg, 0.8 mmol) was added dropwise to a solution of 7.3 (150 mg, 0.4 mmol) in DCM (10 mL). After stirring at 25 °C for 0.5 h, the mixture was quenched with saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with Na2S2O3 (2 x 50 mL) and brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue (140 mg) was purified by rapid column chromatography (0 to 50% EtOAc / PE) to give 7.4 (120 mg, 86%) as a solid. H NMR (400 MHz, CDC13) δH 3.38 (s, 3H), 3.32 (dd, J = 9.2, 22.4 Hz, 2H), 2.60 (s, 1H), 2.54 (t, J = 9.2 Hz, 1H), 2.32-2.11 (m, 5H) , 2.04‑1.87 (m, 3H) , 1.70‑1.63 (m, 4H) , 1.51‑1.37 (m, 7H) , 1.28‑1.16 (m, 6H) , 0.62 (s, 3H) , 0.46‑0.32 (m, 3H) , 0.28‑0.19 (m, 1H) , 0.04--0.06 (m, 1H)

[0544] LC-ELSD / MS purity 98%, MS ESI calculated value of C25H39O2 [M-H2O+H]+ 371.3, calculated value 371.3.

[0545] Example 8: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3-(methoxymethyl)-13-methylhexadecylhydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxyethyl)-1H-pyrazole-4-carboxynitrile (8.2b)

[0546]

[0547] Synthesis 8.1

[0548] HBr (10.4 mg,0.05 mmol, 40% in water) and Br2 (45.2 mg,0.3 mmol) were added to a solution of 7.4 (100 mg, 0.3 mmol) in MeOH (10 mL) at 25 °C. After stirring at 25 °C for 2 h, the mixture was rinsed with a saturated NaHCO3 solution (30 mL).The mixture was quenched with water (30 mL) and then extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 8.1 (120 mg, 0.3 mmol) as an oil, which was used directly in the next step without further purification.

[0549] Synthesis 8.2b

[0550] 1H-pyrazole-4-carboxynitrile (35.8 mg, 0.4 mmol) was added to a solution of 8.1 (120 mg, 0.3 mmol) in acetone (10 mL), followed by K2CO3 (70.9 mg, 0.5 mmol). After stirring at 50 °C for 12 h, the mixture was quenched with water (30 mL) and then extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5μ, gradient: 60%-90% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min) to obtain 8.2b (35 mg, 28%) in solid form.

[0551] 8.2b: 1H NMR (400 MHz, CDCl3) δH 7.85 (s, 1H), 7.81 (s, 1H), 4.96 (dd, J = 18.0, 51.6 Hz, 2H), 3.39 (s, 3H), 3.32 (dd, J = 8.8, 22.0 Hz, 2H), 2.68-2.56 (m, 2H), 2.26-2.16 (m, 1H), 2.08–1.65 (m, 8H), 1.53–1.16 (m, 13H), 0.68 (s, 3H), 0.47–0.34 (m, 3H), 0.28–0.19 (m, 1H), 0.05–0.03 (m, 1H). The structure was confirmed by 2DNMR (H18 showed a clear signal with H2O, H18 showed a weak signal with H17); the purity of LC-ELSD / MS based on H-NMR was 99%, 100% de; the MS ESI calculated value of C29H42N3O3 [M+H]+ was 480.3, and the experimental value was 480.3.

[0552] Example 9:

[0553] Steroid inhibition by TBPS binding

[0554] It has been described that in the presence of 5 mM[35S]-tert-butyl bicyclic thiophosphate (TBPS) binding assays were performed using rat cerebral cortical membranes under GABA conditions (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985; Lewin, A.H. et al., Mol. Pharmacol. 1989, 35, 189-194).

[0555] Briefly, the cortex was rapidly removed after decapitation of Sprague-Dawley rats (200-250 g) under carbon dioxide anesthesia. The cortex was homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass / Teflon homogenizer and centrifuged at 1500 xg for 10 min at 4°C. The resulting supernatant was centrifuged at 10,000 xg for 20 min at 4 °C to obtain P2 aggregates. The P2 aggregates were resuspended in 200 mM NaCl / 50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000 xg for 10 min at 4 °C. This washing procedure was repeated twice, and the aggregates were resuspended in 10 volumes of buffer. In the presence of 5 mM GABA, aliquots (100 mL) of the membrane suspension were incubated with 5 mL aliquots of 3 nM [35S]-TBPS and the test drug dissolved in dimethyl sulfoxide (DMSO) (final 0.5%). Incubation was brought to a final volume of 1.0 mL with buffer. Nonspecific binding was determined in the presence of 2 mM unlabeled TBPS in the range of 15% to 25%. After incubation at room temperature for 90 min, the assay was terminated by filtration through a glass fiber filter (Schleicher and Schuell No. 32) using a cell collector (Brandel) and rinsing three times with ice-cold buffer. Filter-bound radioactivity was measured by liquid scintillation spectroscopy. Nonlinear curve fitting was performed on all data for each drug at each concentration average using Prism (GraphPad). If the sum of squares was significantly lower by the F-test, the data were fitted to a partial rather than complete inhibition model. Similarly, if the sum of squares was significantly lower by the F-test, the data were fitted to a two-component rather than a one-component inhibition model. With the same model used for all data, the concentrations of the test compound that produced 50% inhibition (IC50) and maximum inhibition (Imax) of a specific binding were determined for individual experiments, and then the mean + SEM of the individual experiments was calculated. Stephania tetrandra was used as a positive control in these studies, which has been shown to robustly inhibit TBPS binding.

[0556] Various compounds may be screened to determine their potential as modulators of in vitro [35S]-TBPS binding. These determinations may be performed according to or can be performed according to the above.

[0557] In Table 2 below, A indicates TBPS IC50 (μM) < 0.1 μM, B indicates TBPS IC50 (μM) from 0.1 μM to < 1.0 μM, C indicates TBPS IC50 (μM) from 1 μM to < 10.0 μM, and D indicates ≥ 10 μM. Specification 58 / 71 pages 63 CN 121045302 A

[0558] Table 2.

[0559] Specification 59 / 71 pages 64 CN 121045302 A

[0560]

[0561] Equivalents and Scope

[0562] Unless otherwise indicated or obvious from the context, in the claims, the articles such as “a,” “an,” and “described” may mean one or more. Unless otherwise indicated or obvious from the context, the claim or description of one or more members of a group is satisfied if one, more than one, or all of the members are present, employed, or otherwise involved in a given product or process. The invention includes embodiments in which a given product or process is present, employed, or otherwise involved in an exact one member of the group. The invention also includes embodiments in which a given product or process is present, employed, or otherwise involved in more than one or all of the members of the group.

[0563] Furthermore, the present invention covers all variations, combinations, and arrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations visible in any other claim dependent on the same basic claim. Where elements are presented in list form, for example in Markush group format, each subgroup of said elements is also disclosed, and any one or more elements may be removed from that group. It should be understood that, in general, when the invention or an aspect of the invention is referred to as comprising a particular element and / or feature, certain embodiments of the invention or the aspect of the specification of the invention (pages 60 / 71, 65 CN 121045302 A) consist of or are substantially composed of such elements and / or features. For simplicity, those embodiments are not specifically described herein in the same terms. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. When a scope is given, end values ​​are included. Furthermore, unless otherwise specified or apparent from the context and understanding of those skilled in the art, in different embodiments of the inventionIn this application, a value expressed as a range may be assumed to be any specific value or subrange within the range, accurate to one-tenth of the lower limit of the range, unless the context otherwise clearly specifies.

[0564] This application references various published patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. In addition, any particular embodiment of the invention that belongs to the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are considered to be known to those skilled in the art, they may be excluded even if the exclusion is not expressly stated herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of the prior art.

[0565] Those skilled in the art will recognize or be able to determine many equivalents of the particular embodiments described herein using only conventional experimentation. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications may be made to this specification without departing from the spirit or scope of the invention as defined in the claims.

[0566] The present invention relates to:

[0567] 1. A compound of formula I:

[0568] (I)

[0569] or a pharmaceutically acceptable salt thereof;

[0570] wherein:

[0571] represents a single bond or a double bond, provided that if a double bond is present, then one of R6a or R6b is absent;

[0572] R1 is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -ORA1, -N(RA1)2, -SR A1, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -OC(=O)RA1, - OC(=O)ORA1,‑OC(=O)N(RA1)2,‑OC(=O)SR A1,‑OS(=O)2R A1,‑OS(=O)2OR A1,‑OS(=O)2N(R A1)2,‑N (RA1)C(=O)RA1,‑N(RA1)C(=NRA1)RA1,‑N(RA1)C(=O)ORA1,‑N(RA1)C(=O)N(RA1)2,‑N(R A1)C(=NRA1) N(RA1)2,‑N(R A1)S(=O)2R A1,‑N(RA1)S(=O)2OR A1,‑N(RA1)S(=O)2N(R A1)2,‑SC(=O)R A1,‑SC(=O)ORA1, -SC(=O)SRA1, -SC(=O)N(RA1)2, -S(=O)2RA1, -S(=O)2ORA1 or -S(=O)2N(RA1)2, wherein RA1 is independently selected each time from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen-protecting group when attached to oxygen, nitrogen-protecting group when attached to nitrogen, sulfur-protecting group when attached to sulfur, or two RA1 groups together with intercalated atoms to form a substituted or unsubstituted heterocycle;

[0573] Each of R2a, R2b, R4a, R4b, R7a, R7b, R11a, R11b, R12a, R12b, or R17b is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA1, -N(RA1)2, -SRA1, -C(=O)RA1, -C(=O)ORA1, -C(=O)SRA1, -C(=O)N(RA1)2, -OC(=O)RA1, -OC(=O)ORA1, -OC(=O)N(RA1)2, -OC(=O)SRA1, -OS(=O)2R A1,‑OS(=O)2OR A1,‑OS(=O)2N(R A1)2,‑N(R A1)C(=O) RA1,‑N(RA1)C(=NRA1)RA1,‑N(RA1)C(=O)ORA1,‑N(RA1)C(=O)N(RA1)2,‑N(R A1)C(=NRA1) N(RA1)2,‑ N(RA1)S(=O)2R A1,‑N(RA1)S(=O)2OR A1,‑N(RA1)S(=O)2N(R A1)2,‑SC(=O)R A1,‑SC(=O)ORA1,‑SC(= O)SRA1,‑SC(=O)N(RA1)2,‑S(=O)2R A1,‑S(=O)2OR A1 or‑S(=O)2N(R A1)2, wherein RA1 is independently selected each time it appears from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, sulfur protecting group when attached to sulfur, or two RA1 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle;

[0574] R3a is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0575] R5 is hydrogen or methyl; R5 is absent when it is a double bond;

[0576] Each of R6a and R6b is hydrogen, halogen, -CN, -NO2, -OH, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group; or R6a and R6b are conjugated to form an oxo group (=O);

[0577] Each of R15a, R15b, R16a, and R16b is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORC3, -N(RC3)2, -SR C3, -C(=O) RC3, -C(=O)ORC3, -C(=O)SRC3, -C(=O)N(RC3)2, -OC(=O)R C3, -OC(=O)ORC3, -OC(=O)N(RC3)2, -OC(=O)SRC3, -OS(=O)2R C3, -OS(=O)2OR C3, -OS(=O)2N(R C3)2, -N(R C3)C(=O)RC3,‑N(RC3)C(=NRC3) RC3,‑N(RC3)C(=O)ORC3,‑N(RC3)C(=O)N(RC3)2,‑N(R C3)C(=NRC3) N(RC3)2,‑N(R C3)S(=O)2R C3,‑N (RC3)S(=O)2OR C3,‑N(RC3)S(=O)2N(R C3)2,‑SC(=O)R C3,‑SC(=O)ORC3,‑SC(=O)SRC3,‑SC(=O)N (RC3)2,‑S(=O)2R C3,‑S(=O)2OR C3 or‑S(=O)2N(R C3)2, wherein RC3, each time it appears, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, oxygen-protecting group when attached to oxygen, nitrogen-protecting group when attached to nitrogen, sulfur-protecting group when attached to sulfur, or two RC3 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle;

[0578] R19 is a substituted or unsubstituted C3-C6 carbocyclic, or a substituted or unsubstituted aryl; and

[0579] n is 0, 1, or 2.

[0580] 2.The compound of embodiment 1, wherein R1 is hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0581] 3. The compound of embodiment 1, wherein R1 is hydrogen, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted heteroaryl group.

[0582] 4. The compound of embodiment 1, wherein R1 is a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group, wherein each of them is further substituted by a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group.

[0583] 5. The compound as described in embodiment 1, wherein R1 is selected from the group consisting of:

[0584] , ... D4, -OC(=O)ORD4, -N(RD4)C(=O)RD4, -OC(=O)N(RD4)2, -N(RD4)C(=O)ORD4, -S(=O)2R D4, -S(=O)2OR D4, -OS(=O)2R D4, -S(=O)2N(RD4)2 or -N(RD4)S(=O)2R D4, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted C5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0587] RD4, each time it appears, is independently hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted C5- to 10-membered aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RD4 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle; and

[0588] p is an integer selected from 0 to 11.

[0589] 6.The compound as described in embodiment 1, wherein R1 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , and;

[0591] wherein Ra and p are as defined in embodiment 5.

[0592] 7. The compound of any one of embodiments 1-6, wherein R2a and R2b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2ORE5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2RE5, -N(RE5)S(=O)2ORE5; wherein RE5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the two RE5 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0593] 8. The compound of any one of embodiments 1-6, wherein R2a and R2b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2 or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or the two RF6 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0594] 9. The compound of any one of embodiments 1-6, wherein R2a and R2b are independently hydrogen, -OH or a substituted or unsubstituted C1-6 alkyl.

[0595] 10. The compound of any one of embodiments 1-6, wherein each of R2a and R2b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0596] 11. The compound of any one of embodiments 1-6, wherein R2a and R2b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0597] 12. The compound of any one of embodiments 1-6, wherein both R2a and R2b are hydrogen.

[0598] 13. The compound of any one of embodiments 1-6, wherein R2a and R2b are combined to form an oxo group (=O).

[0599] 14.The compound of any one of embodiments 1-13, wherein R3a is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl.

[0600] 15. The compound of any one of embodiments 1-13, wherein R3a is a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0601] 16. The compound of any one of embodiments 1-13, wherein R3a is a substituted or unsubstituted C1-6 alkyl.

[0602] 17. The compound of any one of embodiments 1-13, wherein R3a is a substituted alkyl.

[0603] 18. The compound of any one of embodiments 1-13, wherein R3a is an unsubstituted alkyl. Specification 64 / 71 pages 69 CN 121045302 A

[0604] 19. The compound of any one of embodiments 1-13, wherein R3a is methyl.

[0605] 20. The compound as described in any one of embodiments 1-13, wherein R3a is hydrogen.

[0606] 21. The compound as described in embodiments 1-20, wherein R4a and R4b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5, each time it appears, is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the two RE5 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0607] 22. The compound as described in embodiments 1-20, wherein R4a and R4b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2 or -N(RF6)C(=O)RF6; wherein RF6, in each occurrence, is independently hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or the two RF6 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0608] 23. The compound as described in any one of embodiments 1-20, wherein R4a and R4b are independently hydrogen, -OH or a substituted or unsubstituted C1-6 alkyl group.

[0609] 24.The compound of any one of embodiments 1-20, wherein each of R4a and R4b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0610] 25. The compound of any one of embodiments 1-20, wherein R4a and R4b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0611] 26. The compound of any one of embodiments 1-20, wherein both R4a and R4b are hydrogen.

[0612] 27. The compound of any one of embodiments 1-20, wherein R4a and R4b are combined to form an oxo group (=O).

[0613] 28. The compound of any one of embodiments 1-27, wherein R5 is hydrogen in the cis position relative to R19.

[0614] 29. The compound of any one of embodiments 1-27, wherein R5 is hydrogen in the trans position relative to R19.

[0615] 30. The compound of any one of embodiments 1-27, wherein R5 is methyl in the cis position relative to R19.

[0616] 31. The compound of any one of embodiments 1-27, wherein R5 is methyl in the trans position relative to R19.

[0617] 32. The compound of any one of embodiments 1-31, wherein R6a and R6b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0618] 33. The compound of any one of embodiments 1-31, wherein R6a and R6b are independently hydrogen or substituted alkyl.

[0619] 34. The compound of any one of embodiments 1-31, wherein R6a and R6b are independently hydrogen or unsubstituted alkyl.

[0620] 35. The compound of any one of embodiments 1-31, wherein R6a and R6b are both hydrogen.

[0621] 36. The compound of any one of embodiments 1-31, wherein R6a is a halogroup or alkyl group, and R6b is hydrogen.

[0622] 37. The compound of any one of embodiments 1-31, wherein R6a and R6b are both halogroups. Specification 65 / 71 pages 70 CN 121045302 A

[0623] 38. The compound of any one of embodiments 1-31, wherein R6a and R6b are both alkyl groups.

[0624] 39. The compound of embodiments 1-38, wherein R7a and R7b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5 is, in each occurrence, independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two RE5 groups together with intercalated atoms to form a substituted or unsubstituted heterocycle.

[0625] 40. The compound as described in embodiments 1-38, wherein R7a and R7b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2 or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or the two RF6 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0626] 41. The compound as described in any one of embodiments 1-38, wherein R7a and R7b are independently hydrogen, -OH or a substituted or unsubstituted C1-6 alkyl.

[0627] 42. The compound of any one of embodiments 1-38, wherein each of R7a and R7b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0628] 43. The compound of any one of embodiments 1-38, wherein R7a and R7b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0629] 44. The compound of any one of embodiments 1-38, wherein both R7a and R7b are hydrogen.

[0630] 45. The compound of any one of embodiments 1-38, wherein R7a and R7b are conjugated to form an oxo group (=O).

[0631] 46. The compound as described in embodiments 1-45, wherein R11a and R11b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2R E5, -N(RE5)S(=O)2OR E5; wherein RE5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, each time it appears.Substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group, or two RE5 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle.

[0632] 47. The compound as described in embodiments 1-45, wherein R11a and R11b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2 or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, or two RF6 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle.

[0633] 48. The compound of any one of embodiments 1-45, wherein R11a and R11b are independently hydrogen, -OH, or substituted or unsubstituted C1-6 alkyl.

[0634] 49. The compound of any one of embodiments 1-45, wherein each of R11a and R11b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0635] 50. The compound of any one of embodiments 1-45, wherein R11a and R11b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0636] 51. The compound of any one of embodiments 1-45, wherein both R11a and R11b are hydrogen.

[0637] 52. The compound of any one of embodiments 1-45, wherein R11a and R11b are conjugated to form an oxo group (=O). Specification 66 / 71 pages 71 CN 121045302 A

[0638] 53. The compound of embodiments 1-52, wherein R12a and R12b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -ORE5, -OC(=O)RE5, -OS(=O)2OR E5, -N(RE5)2 or -N(RE5)C(=O)RE5, -N(RE5)S(=O)2RE5, -N(RE5)S(=O)2OR E5; wherein RE5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, each time it appears. Substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group, or two RE5 groups together with intercalated atoms to form a substituted or unsubstituted heterocycle.

[0639] 54.The compounds of embodiments 1-52, wherein R12a and R12b are each independently hydrogen, halogen, -CN, -NO2, -ORF6, -OC(=O)RF6, -N(RF6)2 or -N(RF6)C(=O)RF6; wherein RF6, each time it appears, is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, or the two RF6 groups together with intercalation atoms form a substituted or unsubstituted heterocycle.

[0640] 55. The compounds of any one of embodiments 1-52, wherein R12a and R12b are independently hydrogen, -OH or a substituted or unsubstituted C1-6 alkyl.

[0641] 56. The compound of any one of embodiments 1-52, wherein each of R12a and R12b is independently hydrogen, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkoxyhalo.

[0642] 57. The compound of any one of embodiments 1-52, wherein R12a and R12b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0643] 58. The compound of any one of embodiments 1-52, wherein both R12a and R12b are hydrogen.

[0644] 59. The compound of any one of embodiments 1-52, wherein R12a and R12b are combined to form an oxo group (=O).

[0645] 60. The compound of any one of embodiments 1-59, wherein R17b is fluorine, hydroxyl, methyl, or hydrogen; wherein the hydrogen is optionally substituted with deuterium.

[0646] 61. The compound of any one of embodiments 1-60, wherein R19 is a substituted or unsubstituted C3-6 carbocyclic group, or a substituted or unsubstituted C6-10 aryl group.

[0647] 62. The compound of any one of embodiments 1-60, wherein R19 is a substituted or unsubstituted C3-6 carbocyclic group.

[0648] 63. The compound of any one of embodiments 1-60, wherein R19 is a substituted or unsubstituted C6-10 aryl group.

[0649] 64. The compound of any one of embodiments 1-60, wherein R19 is selected from the group consisting of:

[0650] , , , , and;

[0651] wherein:

[0652] Rb is independently hydrogen, halogen, -NO2, -CN, -OR G7, -N(RG7)2, -C(=O)R G7, -C(=O)ORG7, -C(=O)N(RG7)2, -OC(=O)RG7, -OC(=O)ORG7, -N(RG7)C(=O)RG7, -OC(=O)N(RG7)2, -N(RG7)C(=O)ORG7, -S(=O)2R G7, -S(=O)2OR G7, -OS(=O)2R G7, -S(=O)2N(RG7)2 or -N(RG7)S(=O)2R G7, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 ynyl, substituted or unsubstituted C3-6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted C5- to 10-membered aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0653] RG7, each time it appears, is independently hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted C5-10 aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RG7 groups together with intercalation atoms to form a substituted or unsubstituted heterocycle; and

[0654] q is an integer selected from 0 to 11.

[0655] 65. The compound of any one of embodiments 1-64, wherein n is 0.

[0656] 66. The compound of any one of embodiments 1-64, wherein n is 1.

[0657] 67. The compound of any one of embodiments 1-64, wherein n is 2.

[0658] 68. The compound of embodiment 1, wherein the compound of formula I is a compound of formula I-a:

[0659] (I-a)

[0660] or a pharmaceutically acceptable salt thereof.

[0661] 69. The compound of embodiment 1, wherein the compound of formula I is a compound of formula I-b:

[0662] (I-b)

[0663] or a pharmaceutically acceptable salt thereof.

[0664] 70. The compound of embodiment 1, wherein the compound of formula I is a compound of formula I-c:

[0665] (I-c)

[0666] or a pharmaceutically acceptable salt thereof.

[0667] 71. The compound of embodiment 1, wherein the compound of formula I is a compound of formula I-d: Specification 68 / 71 pages 73 CN 121045302 A

[0668] (I-d)

[0669] or a pharmaceutically acceptable salt thereof;

[0670] wherein:

[0671] Ra is independently a halogen, cyano, hydroxy or substituted or unsubstituted alkyl group each time it appears; and

[0672] p is 0, 1, 2 or 3.

[0673] 72. The compound of embodiment 1, wherein the compound of formula I is a compound of formula I-e:

[0674] (I-e)

[0675] or a pharmaceutically acceptable salt thereof;

[0676] wherein:

[0677] each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N- or N(RN)-, wherein RN is independently hydrogen, substituted or unsubstituted C1-6 alkyl, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA or -S(=O)2N(RGA)2; RGA Each time it appears independently, it is hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 ynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0678] 73. The compound of embodiment 1, wherein the compound of formula I is a compound of formula I-f: Specification 69 / 71 pages 74 CN 121045302 A

[0679] (I-f)

[0680] or a pharmaceutically acceptable salt thereof;

[0681] wherein:

[0682] each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N- or N(RN)-, wherein RN is independently hydrogen, substituted or unsubstituted C1-6 alkyl, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA or -S(=O)2N(RGA)2; RGA Each time it appears independently, it is hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0683] 74. The compound as described in Embodiment 1, wherein the compound of Formula I is a compound of Formula I-g:

[0684] (I-g)

[0685] or a pharmaceutically acceptable salt thereof;

[0686] wherein:

[0687] Ra is independently, each time it appears, a halogen, alkyl, hydroxyl, or cyano; and

[0688] p is an integer selected from 0 to 11.

[0689] 75.The compound as described in Embodiment 1, wherein the compound of Formula I is a compound of Formula I-h:

[0690] (I-h)

[0691] or a pharmaceutically acceptable salt thereof;

[0692] wherein:

[0693] each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N- or N(RN)-, wherein RN is independently hydrogen, a substituted or unsubstituted C1-6 alkyl, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA or -S(=O)2N(RGA)2; RGA Each time it appears independently, it is hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 alkynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0694] 76. A pharmaceutical composition comprising a compound as described in any one of embodiments 1-75 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0695] 77. A method of treating a subject with CNS-related conditions, the method comprising administering to the subject an effective amount of a compound as described in any one of embodiments 1-76 or a pharmaceutically acceptable salt thereof.

[0696] 78. The method of embodiment 77, wherein the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

[0697] 79. The method of embodiment 77, wherein the CNS-related disorder is depression.

[0698] 80. The method of embodiment 79, wherein the CNS-related disorder is postpartum depression.

[0699] 81. The method of embodiment 79, wherein the CNS-related disorder is major depressive disorder.

[0700] 82. The method of embodiment 81, wherein the major depressive disorder is moderate major depressive disorder.

[0701] 83. The method of embodiment 81, wherein the major depressive disorder is severe major depressive disorder. Instruction manual, 71 / 71 pages, 76 pages, CN 121045302, A. Abstract: Abdominal ultrasound examination.method, system and device Abstract Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein n, R 19 , R 5 , R 3a , R 6a , R 6b , R 1 , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 17b , R 15a , R 15b , R 16a and R 16b are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

Claims

1. A compound of formula I: (I) Or its pharmaceutically acceptable salt; in: R represents a single bond or a double bond, provided that a double bond exists. 6a or R 6b One of them does not exist; R 1 It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 -N(R) A1 )2、-SR A1 -C(=O)R A1 -C(=O)OR A1 -C(=O)SR A1 -C(=O)N(R) A1 )2、-OC(=O)R A1 -OC(=O)OR A1 -OC(=O)N(R) A1 )2、-OC(=O)SR A1 -OS(=O)2R A1 -OS(=O)2OR A1 -OS(=O)2N(R) A1 )2、-N(R A1 )C(=O)R A1 -N(R) A1 )C(=NR A1 )R A1 -N(R) A1 )C(=O)OR A1 -N(R) A1 )C(=O)N(R A1 )2、-N(R A1 )C(=NR A1 ) N(R A1 )2、-N(R A1 )S(=O)2R A1 -N(R) A1 )S(=O)2OR A1 -N(R) A1 )S(=O)2N(R A1 )2、-SC(=O)R A1 -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R) A1 )2、-S(=O)2R A1 -S(=O)2OR A1 or -S(=O)2N(R) A1 )2, where R A1 Each time it appears, it is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, sulfur protecting group when attached to sulfur, or two R groups. A1 Groups and intercalated atoms together form substituted or unsubstituted heterocycles; R 2a R 2b R 4a R 4b R 7a R 7b R 11a R 11b R 12a R 12b or R 17b Each of these elements independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 -N(R) A1 )2、-SR A1 -C(=O)R A1 -C(=O)OR A1 -C(=O)SR A1 -C(=O)N(R) A1 )2、-OC(=O)R A1 -OC(=O)OR A1 -OC(=O)N(R) A1 )2、-OC(=O)SR A1 -OS(=O)2R A1 -OS(=O)2OR A1 -OS(=O)2N(R) A1 )2、-N(R A1 )C(=O)R A1 -N(R) A1 )C(=NR A1 )R A1 -N(R) A1 )C(=O)OR A1 -N(R) A1 )C(=O)N(R A1 )2、-N(R A1 )C(=NR A1 ) N(R A1 )2、-N(R A1 )S(=O)2R A1 -N(R) A1 )S(=O)2OR A1 -N(R) A1 )S(=O)2N(R A1 )2、-SC(=O)R A1 -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R) A1 )2、-S(=O)2R A1 -S(=O)2OR A1 or -S(=O)2N(R) A1 )2, where R A1 Each time it appears, it is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, sulfur protecting group when attached to sulfur, or two R groups. A1 Groups and intercalated atoms together form substituted or unsubstituted heterocycles; R 3a It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 It is hydrogen or methyl; when When it is a double bond, R 5 It does not exist; R 6a and R 6b Each of these is hydrogen, halogen, -CN, -NO2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6b To combine and form an oxo group (=O); R 15a R 15b R 16a and R 16b Each of these elements independently represents hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -OR. C3 -N(R) C3 )2、-SR C3 -C(=O)R C3 -C(=O)OR C3 -C(=O)SR C3 -C(=O)N(R) C3 )2、-OC(=O)R C3 -OC(=O)OR C3 -OC(=O)N(R) C3 )2、-OC(=O)SR C3 -OS(=O)2R C3 -OS(=O)2OR C3 -OS(=O)2N(R) C3 )2、-N(R C3 )C(=O)R C3 -N(R) C3 )C(=NR C3 )R C3 -N(R) C3 )C(=O)OR C3 -N(R) C3 )C(=O)N(R C3 )2、-N(R C3 )C(=NR C3 ) N(R C3 )2、-N(R C3 )S(=O)2R C3 -N(R) C3 )S(=O)2OR C3 -N(R) C3 )S(=O)2N(R C3 )2、-SC(=O)R C3 -SC(=O)OR C3 -SC(=O)SR C3 -SC(=O)N(R) C3 )2、-S(=O)2R C3 -S(=O)2OR C3 or -S(=O)2N(R) C3 )2, where R C3 Each time it appears, it is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, oxygen-protecting group when attached to oxygen, nitrogen-protecting group when attached to nitrogen, sulfur-protecting group when attached to sulfur, or two R groups. C3 Groups and intercalated atoms together form substituted or unsubstituted heterocycles; R 19 It is a substituted or unsubstituted C3-C6 carbocyclic group, or a substituted or unsubstituted aryl group; and n is 0, 1, or 2.

2. The compound of claim 1, wherein R 1 It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

3. The compound of claim 1, wherein R 1 It is hydrogen, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group.

4. The compound of claim 1, wherein R 1 It is a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group, wherein each of them is further substituted by a substituted carbocyclic group, a substituted heterocyclic group, a substituted aryl group, or a substituted heteroaryl group.

5. The compound of claim 1, wherein R 1 Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; in: R a Each occurrence is independently of hydrogen, halogen, -NO2, -CN, or -OR. D4 -N(R) D4 )2、-C(=O)R D4 -C(=O)OR D4 -C(=O)N(R) D4 )2、-OC(=O)R D4 -OC(=O)OR D4 -N(R) D4 )C(=O)R D4 -OC(=O)N(R) D4 )2、-N(R D4 )C(=O)OR D4 -S(=O)2R D4 -S(=O)2OR D4 -OS(=O)2R D4 -S(=O)2N(R) D4 )2 or -N(R D4 )S(=O)2R D4 C, substituted or unsubstituted 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3- to 6-membered heterocyclic group, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted 5 to 10-membered heteroaryl; R D4 Each time it appears, it is independently hydrogen, substituted, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3- to 6-membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5 to 10-membered heteroaryl, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two R groups. D4 The group and the intercalated atom together form a substituted or unsubstituted heterocycle; and p is an integer selected from 0 to 11.

6. The compound of claim 1, wherein R 1 Choose from the following groups: , , , , , , , , , , , , , , , , and ; Where R a p as defined in claim 5.

7. The compound according to any one of claims 1-6, wherein R 2a and R 2b Each of these can be independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or -OR. E5 -OC(=O)R E5 -OS(=O)2OR E5 -N(R) E5 )2 or -N(R E5 )C(=O)R E5 -N(R) E5 )S(=O)2R E5 -N(R) E5 )S(=O)2OR E5 ;where R E5 Each time it appears, it is independently hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or two R groups. E5 Groups and intercalated atoms together form substituted or unsubstituted heterocycles.

8. The compound according to any one of claims 1-6, wherein R 2a and R 2b Each is independently hydrogen, halogen, -CN, -NO2, -OR F6 -OC(=O)R F6 -N(R) F6 )2 or -N(R F6 )C(=O)R F6 ;where R F6 Each time it appears, it is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, or two R groups. F6 Groups and intercalated atoms together form substituted or unsubstituted heterocycles.

9. The compound according to any one of claims 1-6, wherein R 2a and R 2b It is independently a hydrogen, -OH, or substituted or unsubstituted C. 1-6 alkyl.

10. The compound according to any one of claims 1-6, wherein R 2a and R 2b Each of these is independently hydrogen, -OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Alkyl halogen group.