Neurostimulant steroids and compositions thereof

Abstract

As used herein, the term "compound of formula (I): TIFF2022534424000110.tif4777[where, R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 6a , R 6b , R 7a , R 7a , R 11a , R 11b , R 12a , R 12b , R 16a , R 16b , R 19 , R 11a , R 22 , R X , R Y and n is as defined herein, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions comprising compounds of formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders, are also provided herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 855,435, filed May 31, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Brain excitability is defined as the level of alertness of an animal, a continuum from coma to seizures, and is regulated by various neurotransmitters. In general, neurotransmitters serve to regulate the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane potential) of approximately -70 mV, making the cell interior negative compared to the cell exterior. The electrical potential (voltage) is determined by the flow of ions (K + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine causes membrane depolarization (a change in potential from -70 mV to -50 mV occurs). This effect is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, resulting in the release of Na + It increases membrane permeability to ions. The reduction in membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Because up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on overall brain excitability. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to promote the influx of chloride ions into the cell down the electrochemical gradient of the GRC. Increased levels of this anion in the cell cause hyperpolarization of the transmembrane potential, making the neuron less sensitive to excitatory inputs, i.e., reducing neuronal excitability. In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability and arousal levels.

[0004] The GRC is well-documented to be involved in mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or potentiate the action of GABA, such as therapeutically useful barbiturates and benzodiazepines (BZ) (e.g., Valium®), exert their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now suggests that the GRC contains unique sites for neuroactive steroids in addition to benzodiazepine and barbiturate binding sites. See, e.g., Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0005] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one (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)). There is a need for new and improved compounds that act as regulators of brain excitability and as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions, and methods described herein are directed to this end. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-Patent Document 2] Majewska, MDet al., Science 232:1004-1007(1986) [Non-Patent Document 3] Harrison,NLet al.,J Pharmacol.Exp.Ther.241:346-353(1987) Summary of the Invention [Means for solving the problem]

[0007] For example, compounds designed to act as GABA modulators are provided herein. In some embodiments, such compounds are expected to be useful as therapeutic agents for treating CNS-related disorders.

[0008] In one embodiment, the compound of formula (I): [ka] [In formula: [ka] represents a single or double bond, and when a double bond is present, R 6a or R 6b does not exist and R 5 does not exist; R X is halo, -CN, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo or substituted or unsubstituted alkyl; Or, R Y and R X may, together with the intervening atoms, form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each occurrence of is independently a halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA, -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R GA Each occurrence of is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group (for oxygen binding), and nitrogen protecting group (for nitrogen binding), or two R GA the groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12bEach of these independently represents hydrogen, halogen, cyano, -NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 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) 2 R A1 , -OS(=O) 2 OR A1 , -OS(=O) 2 N(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) 2 R A1 , -N(R A1 )S(=O) 2 OR A1 , -N(R A1 )S(=O) 2 N(R A1 ) 2 , -SC(=O)R A1 , -SC(=O)ORA1 , -SC(=O)SR A1 , -SC(=O)N(R A1 ) 2 , -S(=O) 2 R A1 , -S(=O) 2 OR A1 , or -S(=O) 2 N(R A1 ) 2 R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group (when oxygen is bonded), a nitrogen protecting group (when nitrogen is bonded), and a sulfur protecting group (when sulfur is bonded), or two R A1 the radicals together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b Each of the groups is independently hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b are linked to form an oxo (=O) group; R 15a , R 15b , R 16a , and R 16b Each of the groups is independently hydrogen, halogen, -CN, -NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 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) 2 R C3 , -OS(=O) 2 OR C3 , -OS(=O) 2 N(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) 2 R C3 , -N(R C3 )S(=O) 2 OR C3 , -N(R C3 )S(=O) 2 N(R C3 ) 2 , -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 ) 2 , -S(=O) 2 R C3 , -S(=O) 2 OR C3 , or -S(=O) 2 N(R C3 ) 2 selected from the group consisting of, RC3 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, oxygen protecting groups (when oxygen is bonded), nitrogen protecting groups (when nitrogen is bonded), and sulfur protecting groups (when sulfur is bonded), or two R C3 the radicals together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen or substituted or unsubstituted alkyl; n is selected from the group consisting of 0, 1, 2, and 3. or a pharma- ceutically acceptable salt thereof.

[0009] In some embodiments, the compound has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined above.

[0010] In some embodiments, the compound has formula I-b1: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined above.

[0011] In some embodiments, the compound has formula I-c3 or formula I-c4: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined above.

[0012] In some embodiments, the compound has formula I-d3 or formula I-d4: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined above.

[0013] In some embodiments, the compound has formula I-e5, formula I-e6, formula I-e7, or formula I-e8: [ka] or a pharma- ceutically acceptable salt thereof, in which the variables are as defined above.

[0014] In certain embodiments, the compound has formula I-Ib1: [ka] [In the formula, R 22 is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0015] In one embodiment, the compound has formula I-Ic1 or formula I-Ic2: [ka] [In the formula, R 22 is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0016] In one embodiment, the compound has formula I-Id1 or formula I-Id2: [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0017] In one embodiment, the compound has formula I-Ie1, formula I-Ie2, formula I-Ie3, or formula I-Ie4: [ka] [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0018] In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0019] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I)) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0020] In some embodiments, a method of treating a CNS-related disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I)) or a pharma- ceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. 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, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0021] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein.

[0022] The compounds of the invention described herein may, in certain embodiments, be used to treat, for example, GABA A These compounds act as GABA modulators, affecting the GABA receptors in either a positive or negative way. A They are predicted to have central nervous system (CNS) activity as modulators of CNS excitability as mediated by their ability to modulate receptors.

[0023] Therefore, in another aspect, a method for treating a CNS-related disorder in a subject is provided, comprising administering to the subject in need thereof an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example by continuous intravenous infusion. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description of Certain Embodiments of the Invention As generally described herein, the present invention provides compounds designed to act as, for example, GABA A receptor modulators.In certain embodiments, it is assumed that such compounds are useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, for example, depression, such as postpartum depression or major depressive disorder).

[0025] definition chemical definition The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are listed in the Periodic Table (CAS system, Handbook of Chemistry and Physics, 75 thEd., inside cover), and specific functional groups are generally defined as described therein. Further, general rules of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in the following references: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0026] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization, 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 Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0027] "Stereoisomers": It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonds of their atoms or in the spatial arrangement of their atoms are referred to as "isomers". Isomers that differ in the spatial arrangement of their atoms are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and those that are non-superimposable mirror images of each other are referred to as "enantiomers". For example, if a compound has an asymmetric center and is bonded to four different groups, a set of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, referred to as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal ratios of enantiomers is referred to as a "racemic mixture".

[0028] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of a compound (i.e., enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" refers to a compound that contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0029] In the compositions provided herein, the enantiomerically pure compounds can be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R position / center / carbon compound can contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition can contain, for example, at least about 95% by weight of the R compound and up to about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound can contain, for example, about 90% excipients and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can contain, for example, at least about 95% by weight of the S compound and up to about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

[0030] The term "diastereomerically pure" refers to a compound that 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 of a single diastereomer. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing a compound and its diastereomer, such as high performance liquid chromatography (HPLC).

[0031] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or multiple analogues.

[0032] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0033] The following terms are intended to have the meanings provided below with respect thereto and are helpful in understanding the specification and the intended scope of the invention.

[0034] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has one carbon atom ("C 1 In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 "Alkyl"). C 1-6 An example of an alkyl group is methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 Further examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (e.g., -CH 3 In certain embodiments, the alkyl group is a substituted C 1-10 It is an alkyl group. A common abbreviation for alkyl is Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ), or i-Bu(-CH 2 CH(CH 3 ) 2 ) are mentioned.

[0035] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 Examples of substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2-), and the like. When a range or number of carbons is given for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a divalent linear carbon chain. The alkylene group may be unsubstituted or substituted with one or more substituents described herein.

[0036] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group 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) ("C 2-20 In certain embodiments, an alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C 2 The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). 2-4 An example of an alkenyl group is ethenyl (C 2), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Further examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0037] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group 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) ("C 2-20 In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C 2 The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). 2-4 Examples of alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) and the like, but are not limited to these. C 2-6 Examples of alkynyl groups include the above-mentioned C 2-4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 Further examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0038] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group is a saturated group having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC 1 In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each occurrence of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted ("substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is an alkyl.

[0039] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) aromatic ring system radical having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of the aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0040] In certain embodiments, the aryl group is halo, C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, cyano, hydroxy, C 1 ~C 8 It is substituted with one or more groups selected from alkoxy and amino.

[0041] Representative examples of substituted aryl include the following: [ka] The following are some of the reasons: In the formula, R 56 and R 57 can be hydrogen, and R 56 and R 57 At least one of each independently represents C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 ~C 8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 58 SO 2 R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , S.O. 2 NR 58 R 59 , S-alkyl, SO alkyl, SO 2 Alkyl, S aryl, SO aryl, SO 2 aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O, or S). 60 and R 61 are independently hydrogen, C 1 ~C 8 Alkyl, C 1 ~C 4 Haloalkyl, C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 Aryl, Substituted C 6 ~C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0042] "Fused aryl" refers to an aryl having two of its ring carbons shared with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0043] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) aromatic ring system in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, with each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, as far as valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, in which case the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, in which case the point of attachment can be on either the aryl ring or the heteroaryl ring, and in such cases the ring member count refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0044] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, each heteroatom being 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 in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, each heteroatom being 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 in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0045] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0046] Representative examples of heteroaryl include the following: [ka] The following are some of the reasons: where each Z is carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C 1 ~C 8 Alkyl, C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 aryl, and 5- to 10-membered heteroaryl.

[0047] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Exemplary C 3-6 As a carbocyclyl group, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like. Exemplary C 3-8 The carbocyclyl group is the above-mentioned C 3-6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and the like, but are not limited to these. 3-10 As the carbocyclyl group, the above-mentioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. When the foregoing examples are illustrated, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or includes fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic carbocyclyl")), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, in which case the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to represent the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 It is a carbocyclyl.

[0048] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 "Cycloalkyl"). C 5-6 An example of a cycloalkyl group is cyclopentyl (C 5 ) and cyclohexyl (C 5 ) are listed. C 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 Cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ) are listed. C 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 Cycloalkyl groups, as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 It is cycloalkyl.

[0049] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon atom or at a nitrogen atom, as far as valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or may be fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, with the point of attachment being on the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of a heterocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0050] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. C 6Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0052] A "nitrogen-containing heterocyclyl" group refers to a 4-7 membered non-aromatic ring 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), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (e.g., N-methylpiperazine). Particular examples include azetidine, piperidone, and piperazone.

[0053] "Hetero", when used to describe a compound or a group present on a compound, means that one or more carbon atoms of the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, and especially 1 to 3, heteroatoms, such as alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkenyl, cycloheteroalkenyl, etc.

[0054] "Acyl" means -C(O)R 20 R refers to the radical 20is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to any group represented by R 20 is an acyl group, which is a group other than hydrogen. Representative acyl groups are formyl (-CHO), acetyl (-C(=O)CH 3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH 2 Ph), -C(O)-C 1 ~C 8 Alkyl, -C(O)-(CH 2 ) t (C 6 ~C 10 Aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 )t(C 3 ~C 10 cycloalkyl), and -C(O)-(CH 2 ) t (4-10 membered heterocyclyl) (t is an integer from 0 to 4). 21 is a halo or hydroxy substituted C 1 ~C 8 Alkyl; or C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 Aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 Alkoxy, unsubstituted C 1 ~C 4 Haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C1 ~C 4 substituted with haloalkoxy or hydroxy.

[0055] "Alkoxy" means -OR 29 R refers to the group 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0056] In certain embodiments, R 29 is amino, substituted amino, C 6 ~C 10 Aryl, aryloxy, carboxyl, cyano, C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent selected from the group consisting of. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH 2 ) t (C 6 ~C 10 Aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 ~C 10cycloalkyl), and -O-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present is itself an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 Alkoxy, unsubstituted C 1 ~C 4 Haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl, or unsubstituted C 1 ~C 4 Optionally, the group may be substituted with haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups include -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -Cyclopropyl, -OCH 2 CH 2 OH and -OCH 2 CH 2 NMe 2 It is.

[0057] "Amino" means -NH 2 Refers to radicals.

[0058] An "oxo group" refers to -C(=O)-.

[0059] "Substituted amino" refers to a group of the formula -N(R 38 ) 2 R refers to the amino group of 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C 1 ~C8 Alkyl, C 3 ~C 8 Alkenyl, C 3 ~C 8 Alkynyl, C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 3 ~C 10 Cycloalkyl; or halo or hydroxy substituted C 1 ~C 8 Alkyl; halo or hydroxy substituted C 3 ~C 8 Alkenyl; C substituted with halo or hydroxy 3 ~C 8 Alkynyl, or -(CH 2 ) t (C 6 ~C 10 Aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 ~C 10 cycloalkyl), or -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is selected from unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 Alkoxy, unsubstituted C 1 ~C 4 Haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 or both R are substituted with haloalkoxy, or hydroxy. 38 The groups are linked to form an alkylene group.

[0060] Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C 1 ~C 8 Alkyl, -NR39 -(CH 2 ) t (C 6 ~C 10 Aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C 3 ~C 10 cycloalkyl), and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 are independently H or C 1 ~C 8 any alkyl group present may itself be substituted with halo, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 Alkoxy, unsubstituted C 1 ~C 4 Haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl, or unsubstituted C 1 ~C 4 It may be substituted with haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0061] "Carboxy" refers to the -C(O)OH radical.

[0062] "Cyano" refers to the -CN radical.

[0063] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0064] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Exemplary haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0065] "Hydroxy" refers to the -OH radical.

[0066] "Nitro" means -NO 2 Refers to radicals.

[0067] "Thioketo" refers to the group ═S.

[0068] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, when substituted, gives rise to a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise stated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, i.e., any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates all combinations that arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0069] Exemplary carbon atom substituents include halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )Rbb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb ) 2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R aa 、-NR bb C(=O)N(R bb ) 2 、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb ) 2 、-OC(=NR bb )N(R bb ) 2 、-NR bb C(=NR bb )N(R bb ) 2 、-C(=O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(=O)R aa、-OS(=O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 -C(=S)N(R bb ) 2 、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O) 2 R aa 、-OP(=O) 2 R aa 、-P(=O)(R aa ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb ) 2 、-OP(=O) 2 N(R bb ) 2 、-P(=O)(NR bb ) 2 、-OP(=O)(NR bb ) 2 、-NR bb P(=O)(OR cc ) 2 、-NR bb P(=O)(NR bb ) 2 、-P(R cc ) 2 、-P(R cc ) 3 、-OP(R cc ) 2 、-OP(R cc ) 3 、-B(R aa ) 2 、-B(OR cc ) 2 、-BR aa (OR cc )、C 1-10 アルキル、C1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group or the two geminal hydrogens on the carbon atom are replaced by =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb , or =NOR cc substituted with a group; R aa Each occurrence of is independently 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; or two R aa groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 Raa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; or two R bb groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc Each occurrence of is independently hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14aryl, and 5- to 14-membered heteroaryl; or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N(R ff ) 2 , -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 ,-NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 ,-OP(=O)(OR ee ) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd the substituents can be linked to form =O or =S; R ee Each occurrence of is independently1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each occurrence of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl) 2 , -N(C 1-6 Alkyl) 2 , -N(C 1-6 Alkyl) 3 + X - , -NH(C 1-6 Alkyl) 2 + X - , -NH 2 (C 1-6 Alkyl) + X -, -NH 3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 Alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1-6 Alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl) 2 , -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 Alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 Alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C1-6 Alkyl), -SO 2 N(C 1-6 Alkyl) 2 , -SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 ,-SO 2 C 1-6 Alkyl, -SO 2 O.C. 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl) 3 , -OSi(C 1-6 Alkyl) 3 -C(=S)N(C 1-6 Alkyl) 2 , C(=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 Alkyl) 2 , -OP(=O)(C 1-6 Alkyl) 2 , -OP(=O)(OC 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S; X - is the counter ion.

[0070] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , HSO 4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0071] These and other exemplary substituents are described in detail in the detailed description and claims, and the invention is not intended to be limited in any manner by the exemplary substituents listed above.

[0072] Other definitions As used herein, the term "modulation" refers to the A The term "modulator" (e.g., a modulator compound) refers to, for example, the inhibition or enhancement of GABA receptor function. A It can be an agonist, partial agonist, antagonist, or partial antagonist of the receptor.

[0073] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of a federal or state government, or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, more specifically, humans.

[0074] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and inorganic or organic base addition salts. Specifically, such salts include: (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, or (2) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, where the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmacologically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0075] The term "prodrug" is intended to encompass therapeutically inactive compounds that are converted to the therapeutically active agents of the present invention under physiological conditions. One method for making prodrugs is to design selected moieties that are hydrolyzed or cleaved at the target in vivo site of action under physiological conditions to expose the molecule of interest and subsequently produce a therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

[0076] In an alternative embodiment, the present invention provides prodrugs of compounds of formula (I), which include a cleavable moiety at the C3 hydroxy, as shown in formula (I).

[0077] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, with changes in the movement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium with the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomers can be relevant to obtaining optimal chemical reactivity and biological activity of a compound of interest.

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

[0079] In certain 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, -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3、 -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd Edition, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0080] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0081] In certain 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, -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R aa , -C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb ) 2 , -S(=O)R aa , -SO 2 R aa , -Si(R aa ) 3、 -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 , and -P(=O)(NR bb ) 2 R aa , R bb , and R ccis as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd Edition, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0082] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc ) 2 , -S(=O) 2 R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 Rdd is substituted with a R aa , R bb , R cc , and R dd is as defined herein. Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Huts, 3rd Edition, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0083] Exemplary amino protecting groups include, but are not limited to, amide groups (e.g., -C(=O)R aa ) (including, but not limited to, formamide and acetamide); carbamate groups (e.g., -C(=O)OR aa ) (including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., -S(=O) 2 R aa ) (including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

[0084] Disease, disorder, and condition are used interchangeably herein.

[0085] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions taken before a subject is afflicted with a particular disease, disorder, or condition.

[0086] In general, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, for example, to treat a CNS-related disorder, and is sufficient to induce anesthesia or sedation.As will be understood by those skilled in the art, the "effective amount" of the compound of the present invention can vary depending on factors such as the biological endpoint of interest, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health status, and pathology of the subject.

[0087] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, an amount that alleviates or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0088] In an alternative embodiment, the present invention contemplates administering the compound of the present invention or a pharma- ceutically acceptable salt or pharma- ceutically acceptable composition thereof as a prophylactic agent before a subject is afflicted with a particular disease, disorder, or condition. As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of therapeutic agent alone or in combination with other agents that provide a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0089] As used herein, an "episodic dosing regimen" is a dosing regimen in which a compound of formula (I) or a composition comprising a compound of formula (I) is administered to a subject for a finite period of time in response to a diagnosis of a disorder or a symptom thereof, e.g., a diagnosis or symptom of depression, an episode of major depressive disorder, bipolar depression, anxiety, or postpartum depression. In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the compound is formulated as separate dosage units, each unit comprising a compound of formula (I) and one or more suitable pharmaceutical excipients. In some embodiments, the duration of the episodic dosing regimen is multiple weeks, e.g., about 8 weeks. In contrast to chronic administration as defined herein, episodic administration of a compound is administered for a finite period of time, e.g., about 2 weeks to about 8 weeks, in response to a diagnosis of a disorder, e.g., depression, or a symptom thereof. In some embodiments, the episodic administration is administered once a day for multiple weeks, e.g., about 2 weeks to about 6 weeks. In one embodiment, the duration of the episodic administration is 2 weeks. In some embodiments, a multiple episodic administration regimen is administered to a subject, for example, two or more episodic regimens throughout the subject's lifetime.

[0090] compound It is to be understood that the formulas set forth herein may refer to specific carbon atoms, for example, C17, C3, C19, etc. These references are as follows: [ka] Based on the carbon atom position according to the known steroid nomenclature used in the industry, as shown in For example, C17 refers to the 17th carbon and C3 refers to the 3rd carbon.

[0091] In one aspect, the present specification provides a compound of formula (I): [ka] [In the formula, [ka] represents a single or double bond, and when a double bond is present, R 6a or R 6b does not exist and R 5 does not exist; R X is halo, -CN, -OH, -OR Q1 and substituted or unsubstituted alkyl; R Q1 is substituted or unsubstituted alkyl; R Y is halo or substituted or unsubstituted alkyl; or R Y and R X may, together with the intervening atoms, form a substituted or unsubstituted carbocyclyl or a substituted or unsubstituted heterocyclyl; R 3 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 22 Each occurrence of is independently a halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 , -SRGA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R GA Each occurrence of is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group (for oxygen binding), and nitrogen protecting group (for nitrogen binding), or two R GA the groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b Each of these independently represents hydrogen, halogen, cyano, -NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -ORA1 、-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) 2 R A1 、-OS(=O) 2 OR A1 、-OS(=O) 2 N(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) 2 R A1 、-N(R A1 )S(=O) 2 OR A1 、-N(R A1 )S(=O) 2 N(R A1 ) 2 、-SC(=O)R A1 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 ) 2 、-S(=O) 2 R A1 、-S(=O) 2 OR A1 、または-S(=O)2 N(R A1 ) 2 R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen protecting group (when oxygen is bonded), a nitrogen protecting group (when nitrogen is bonded), and a sulfur protecting group (when sulfur is bonded), or two R A1 the radicals together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; R 6a and R 6b Each of the groups is independently hydrogen, halogen, cyano, -NO 2 , —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl, or R 6a and R 6b are linked to form an oxo (=O) group; R 15a , R 15b , R 16a , and R 16b Each of the groups is independently hydrogen, halogen, -CN, -NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 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(RC3 ) 2 , -OC(=O)SR C3 , -OS(=O) 2 R C3 , -OS(=O) 2 OR C3 , -OS(=O) 2 N(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) 2 R C3 , -N(R C3 )S(=O) 2 OR C3 , -N(R C3 )S(=O) 2 N(R C3 ) 2 , -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 ) 2 , -S(=O) 2 R C3 , -S(=O) 2 OR C3 , or -S(=O) 2 N(R C3 ) 2 R C3 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, oxygen protecting groups (when oxygen is bonded), nitrogen protecting groups (when nitrogen is bonded), and sulfur protecting groups (when sulfur is bonded), or two R C3 the radicals together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; R 19 is hydrogen or substituted or unsubstituted alkyl; n is selected from the group consisting of 0, 1, 2, and 3. or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (I-c1), formula (I-c2), formula (I-d1), formula (I-d2), formula (I-e1), formula (I-e2), formula (I-e3), formula (I-e4), formula (I-b1), formula (I-c3), formula (I-c4), formula (I-d3), formula (I-d4), formula (I-e5), formula (I-e6), formula (I-e7), or formula (I-e8).

[0093] In some embodiments, the compound of formula I has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, the compound is a compound of formula (I), wherein R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 6a , R 6b , R 15a , R 15b , R16a , and R 16b are hydrogen.

[0095] In some embodiments, the compound is a compound of Formula (I), n is 1, and R 22 is -CN and R 5 is hydrogen and R 19 is selected from the group consisting of hydrogen, methyl, and ethyl.

[0096] In some embodiments, the compound is a compound of Formula (I), n is 1, and R 22 is -CN and R 5 is hydrogen and R 19 is hydrogen.

[0097] R 1a Groups and R 1b basis In some embodiments, R 1a and R 1b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 ) 2 R A1 Each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0098] In some embodiments, R 1aand R 1b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0099] In some embodiments, R 1a and R 1b each independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen or unsubstituted C 1-6 It is an alkyl.

[0100] In some embodiments, R 1a and R 1b each independently represents hydrogen or a substituted or unsubstituted C 1-6 It is an alkyl.

[0101] In some embodiments, R 1a and R 1b are both hydrogen.

[0102] R 2a Groups and R 2b basis In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1, and -C(=O)N(R A1 ) 2 R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0103] In some embodiments, R 2a and R 2b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0104] In some embodiments, R 2a and R 2b each independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen or unsubstituted C 1-6 It is an alkyl.

[0105] In some embodiments, R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy.

[0106] In some embodiments, R 2a and R 2b are both hydrogen.

[0107] R 4a Groups and R 4b basis In some embodiments, R 4a and R 4b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 ) 2 R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0108] In some embodiments, R 4a and R 4b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0109] In some embodiments, R 4a and R 4beach independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen or unsubstituted C 1-6 It is an alkyl.

[0110] In some embodiments, R 4a and R 4b are each independently hydrogen or a substituted or unsubstituted C 1-6 It is an alkyl.

[0111] In some embodiments, R 4a and R 4b are both hydrogen.

[0112] R 7a Groups and R 7b basis In some embodiments, R 7a and R 7b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 ) 2 R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0113] In some embodiments, R7a and R 7b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0114] In some embodiments, R 7a and R 7b each independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen or unsubstituted C 1-6 It is an alkyl.

[0115] In some embodiments, R 7a and R 7b are each independently hydrogen or a substituted or unsubstituted C 1-6 It is an alkyl.

[0116] In some embodiments, R 7a and R 7b are both hydrogen.

[0117] R 11a Groups and R 11b basis In some embodiments, R 11a and R 11b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1, -C(=O)OR A1 , and -C(=O)N(R A1 ) 2 R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0118] In some embodiments, R 11a and R 11b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0119] In some embodiments, R 11a and R 11b each independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen or unsubstituted C 1-6 It is an alkyl.

[0120] In some embodiments, R 11a and R 11b are each independently hydrogen or a substituted or unsubstituted C 1-6 It is an alkyl.

[0121] In some embodiments, R 11a and R11b are both hydrogen.

[0122] R 12a Groups and R 12b basis In some embodiments, R 12a and R 12b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 ) 2 , -C(=O)R A1 , -C(=O)OR A1 , and -C(=O)N(R A1 ) 2 R A1 each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0123] In some embodiments, R 12a and R 12b each independently represents hydrogen, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 are independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0124] In some embodiments, R12a and R 12b each independently represents hydrogen, substituted or unsubstituted C 1-6 Alkyl and -OR A1 R A1 is hydrogen or unsubstituted C 1-6 It is an alkyl.

[0125] In some embodiments, R 12a and R 12b are each independently hydrogen or a substituted or unsubstituted C 1-6 It is an alkyl.

[0126] In some embodiments, R 12a and R 12b are both hydrogen.

[0127] R 6a Groups and R 6b basis In some embodiments, R 6a and R 6b each independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, and substituted or unsubstituted C 2-6 alkynyl.

[0128] In some embodiments, R 6a and R 6b are each independently hydrogen or a substituted or unsubstituted C 1-6 It is an alkyl.

[0129] In some embodiments, R 6a and R 6b each independently represents hydrogen or unsubstituted C 1-6 It is an alkyl.

[0130] In some embodiments, R 6a and R 6b are both hydrogen.

[0131] R 15aGroups and R 15b basis In some embodiments, R 15a and R 15b each independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, and substituted or unsubstituted heteroaryl.

[0132] In some embodiments, R 15a and R 15b are each independently hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 carbocyclyl.

[0133] In some embodiments, R 15a and R 15b are each independently selected from the group consisting of hydrogen, methyl, and cyclopropyl.

[0134] In some embodiments, R 15a and R 15b are both hydrogen.

[0135] R 16a Groups and R 16b basis In some embodiments, R 16a and R 16b each independently represents hydrogen, halogen, or substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, and substituted or unsubstituted heteroaryl.

[0136] In some embodiments, R 16a and R 16b are each independently hydrogen or a substituted or unsubstituted C 1-6 It is an alkyl.

[0137] In some embodiments, R 16a and R 16bare each independently hydrogen or unsubstituted C 1-6 It is an alkyl.

[0138] In some embodiments, R 16a and R 16b are both hydrogen.

[0139] R 3 basis In some embodiments, R 3 is a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, and substituted or unsubstituted C 2-6 alkynyl.

[0140] In some embodiments, R 3 is a substituted or unsubstituted C 1 ~C 6 It is an alkyl.

[0141] In some embodiments, R 3 is C 1-3 C optionally substituted with alkoxy 1-3 It is an alkyl.

[0142] In some embodiments, R 3 is methyl, ethyl, n-propyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 is selected from the group consisting of:

[0143] In some embodiments, R 3 is methyl.

[0144] R 19 basis In some embodiments, R 19 is hydrogen or substituted or unsubstituted C 1-6 It is an alkyl.

[0145] In some embodiments, R19 is hydrogen or unsubstituted C 1-3 It is an alkyl.

[0146] In some embodiments, R 19 is selected from the group consisting of hydrogen, methyl, and ethyl.

[0147] In some embodiments, R 19 is hydrogen.

[0148] In some embodiments, R 19 is unsubstituted C 1 ~C 3 It is an alkyl.

[0149] In some embodiments, R 19 is methyl or ethyl.

[0150] In some embodiments, R 19 is methyl.

[0151] In some embodiments, R 19 is ethyl.

[0152] R X Group and / or R Y basis In some embodiments, R X is halo, -CN, -OH, -OR Q1 , and substituted or unsubstituted C 1-3 alkyl.

[0153] In some embodiments, R X is halo, -CN, -OH, -OR Q1 , and unsubstituted C 1-3 alkyl.

[0154] In some embodiments, R X Fluoro, -CN, -OH, -OCH 3 and methyl.

[0155] In some embodiments, R X is -OH.

[0156] In some embodiments, R X is fluoro.

[0157] In some embodiments, R X is unsubstituted C 1 ~C 3 Alkylene-OR Q1 It is.

[0158] In some embodiments, R Y is halo or unsubstituted C 1-6 It is an alkyl.

[0159] In some embodiments, R Y is halo or unsubstituted C 1-3 It is an alkyl.

[0160] In some embodiments, R Y is selected from the group consisting of methyl, ethyl, and n-propyl.

[0161] In some embodiments, R Y is methyl.

[0162] In some embodiments, R Y is fluoro.

[0163] In some embodiments, R Y and R X together with the intervening atoms, substituted or unsubstituted C 3-6 It forms a carbocyclyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl.

[0164] In some embodiments, R Y and R X together with the intervening atom, represents an unsubstituted C 3-6 It forms a carbocyclyl or an unsubstituted 3- to 6-membered heterocyclyl.

[0165] In some embodiments, R Y and R X together with the intervening atoms form a substituted or unsubstituted 4-membered carbocyclyl.

[0166] In some embodiments, R Y and R X together with the intervening atoms form a substituted or unsubstituted 4-membered heterocyclyl.

[0167] In some embodiments, the 4-membered heterocycle contains a heteroatom selected from N, O, and S.

[0168] In some embodiments, R Y and R X together form an oxetane.

[0169] R Q1 basis In some embodiments, R Q1 is unsubstituted C 1-6 It is an alkyl.

[0170] In some embodiments, R Q1 is unsubstituted C 1-3 It is an alkyl.

[0171] In some embodiments, R Q1 is selected from the group consisting of methyl, ethyl, and n-propyl.

[0172] In some embodiments, R Q1 is methyl.

[0173] R 22 basis In some embodiments, R 22 are each independently halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)ORGA , -N(R GA )C(=O)R GA , -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 carbocyclyl, and substituted or unsubstituted 3- to 6-membered heterocyclyl; R GA Each occurrence is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 It is selected from the group consisting of carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0174] In some embodiments, each R 22 are independently halogen, -CN, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, and -OR GA R GA is hydrogen or substituted or unsubstituted C 1-3 It is an alkyl.

[0175] In some embodiments, R 22 is C optionally substituted by -CN or oxo 1-3 It is an alkyl.

[0176] In some embodiments, R 22 is located at the 4-position of the pyrazolyl. 22 is located at the 3-position of the pyrazolyl. 22 is located at the 5-position of the pyrazolyl.

[0177] In some embodiments, R 22 is -CN.

[0178] In another embodiment, R 22 is -CN located at the 4-position of the pyrazolyl.

[0179] integer n In some embodiments, n is 1, 2, or 3.

[0180] In some embodiments, n is 1 or 2.

[0181] In some embodiments, n is 0 or 1.

[0182] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0183] R 5 basis In some embodiments, R 5 is hydrogen.

[0184] In some embodiments, R 5 is hydrogen in the alpha or beta configuration.

[0185] In some embodiments, R 5 is a hydrogen in the alpha configuration.

[0186] In some embodiments, R 5 is a hydrogen in the beta configuration.

[0187] In some embodiments, the compound of formula I has formula I-b1: [ka] or a pharma- ceutically acceptable salt thereof.

[0188] In some embodiments, the compound of formula I has formula I-c3 or formula I-c4: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0189] In some embodiments, the compound of formula I has formula I-d3 or formula I-d4: [ka] or a pharma- ceutically acceptable salt thereof.

[0190] In some embodiments, the compound of formula I has formula I-e5, formula I-e6, formula I-e7, or formula I-e8: [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0191] In one embodiment, the compound of formula I has formula I-Ib1: [ka] [In the formula, R 22 is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0192] In one embodiment, the compound has formula I-Ic1 or formula I-Ic2: [ka] [In the formula, R 22 is CN; n is 1; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0193] In one embodiment, the compound has formula I-Id1 or formula I-Id2: [ka] [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0194] In one embodiment, the compound has formula I-Ie1, formula I-Ie2, formula I-Ie3, or formula I-Ie4: [ka] [ka] [In the formula, R 22 is CN; R 19 is selected from the group consisting of hydrogen, ethyl, and methyl; R 15a and R 15b is independently selected from the group consisting of hydrogen, methyl, and cyclopropyl; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxymethyl, and methoxy; R 3 is the unsubstituted C 1-3 Alkyl, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 selected from the group consisting of; R X and R Y are as defined herein. or a pharma- ceutically acceptable salt thereof.

[0195] In some embodiments, the pharmaceutical composition comprises a compound described herein or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0196] In some embodiments, the method of treating a CNS-related disorder in a subject in need of treatment comprises administering to the subject an effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. 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, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0197] In some embodiments, the compound is selected from the group consisting of the compounds shown in Table 1 below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] The compound is selected from the group consisting of the compounds specified in

[0198] In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0199] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I)) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0200] The compounds of the invention described herein may, in certain embodiments, be used to treat, for example, GABA A GAB affects receptors in either a positive or negative way A Such compounds act as GABA modulators. AThey are predicted to have central nervous system (CNS) activity as modulators of CNS excitability as mediated by their ability to modulate receptors.

[0201] Therefore, in another aspect, a method for treating a CNS-related disorder in a subject is provided, comprising administering to the subject in need thereof an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example by continuous intravenous infusion.

[0202] Exemplary compounds of the invention can be synthesized from the following known starting materials using methods known to those skilled in the art or methods of specific references: In one aspect, provided herein are pharma- ceutically acceptable salts of the compounds described herein (e.g., compounds of Formula (I)).

[0203] Alternative Embodiments In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen can be replaced by 2 H (D or deuterium) or 3 H (T or tritium). Carbon can be, for example, 13 C or 14 C. The oxygen can be, for example, 18O. The nitrogen can be, for example, 15 In other embodiments, a particular isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) may occur in 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 an element occupying a particular site in a compound.

[0204] Pharmaceutical Compositions In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I)) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0205] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.

[0206] The pharmaceutical compositions provided herein can be administered by 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.

[0207] In general, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by the physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0208] When used to prevent the development of CNS disorders, the compounds provided herein will typically be administered to subjects at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects who have a family history of the condition, or subjects who have been identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0209] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, for example, for the remaining life of a subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, within the therapeutic range, for an extended period of time.

[0210] The pharmaceutical composition of the present invention can also be delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, for the purpose of raising the blood concentration of the compound to an effective level. The location of the bolus administration will vary depending on the systemic level of the active ingredient desired throughout the body, for example, an intramuscular or subcutaneous bolus administration allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV infusion) allows for a much faster delivery and quickly raises the blood concentration of the active ingredient to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide for the maintenance of a steady state concentration of the active ingredient in the subject's body. Furthermore, in still further embodiments, the pharmaceutical composition can be administered as a bolus administration first, followed by continuous infusion.

[0211] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to obtain a desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled ampoules or syringes with premeasured amounts of liquid compositions, or pills, tablets, capsules, and the like, in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0212] For oral administration, a typical regimen is 1 to 5 times, particularly 2 to 4 times, typically 3 times per day. When using such a dosing pattern, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0213] A transdermal dose is generally selected to produce blood levels that are comparable to or lower than those achieved using an injected dose, and generally ranges from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0214] Injection dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is expected to not exceed about 5 g / day for a 40-80 kg human patient.

[0215] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: binders (such as microcrystalline cellulose, gum tragacanth, or gelatin); excipients (such as starch or lactose); disintegrating agents (such as alginic acid, Primogel, or corn starch); lubricants (such as magnesium stearate); glidants (such as colloidal silicon dioxide); sweetening agents (such as sucrose or saccharin); or flavoring agents (such as peppermint, methyl salicylate, or orange flavoring).

[0216] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As mentioned above, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0217] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s). When formulated as ointments, active ingredients are typically mixed with a paraffinic ointment base or a water-miscible ointment base. Alternatively, active ingredients may be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art, and generally include additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0218] The compounds provided herein can also be administered by a transdermal device.Thus, transdermal administration can be accomplished using a patch of the reservoir or porous membrane type, or of a solid matrix variety.

[0219] The ingredients described above for the compositions for oral administration, injection, or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which are incorporated herein by reference.

[0220] The compounds of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0221] The present invention also relates to pharma- ceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharma- ceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0222] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharma- ceutically acceptable excipient, e.g., a composition suitable for injection, such as intravenous (IV) administration.

[0223] Pharmaceutically acceptable excipients include any diluent or other liquid vehicle suitable for the particular dosage form desired, e.g., injection, dispersing or suspending aids, surfactants, isotonicity agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005).

[0224] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0225] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, consisting of 6, 7, and 8 α-1,4 linked glucose units, respectively, optionally containing one or more substituents (including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution) on the attached sugar moiety. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% aqueous solution).

[0226] Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium prior to use.

[0227] In general, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by the physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0228] The composition is provided in a unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to obtain a desired therapeutic effect together with a suitable pharmaceutical excipient. A typical unit dosage form includes a pre-filled ampoule or syringe containing a pre-measured amount of liquid composition. In such compositions, the compound is usually a minor component (about 0.1% to about 50% by weight or preferably about 1% to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0229] The compounds provided herein can be administered as a single active agent or in combination with other active agents.In one aspect, the present invention provides a combination of the compounds of the present invention with another pharmacologically active agent.The administration of the combination can be carried out by any technique that is clear to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0230] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make compositions suitable for administration to a variety of animals are well understood, and veterinary pharmacologists of skill in the art can design and / or perform such modifications using routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.

[0231] In one aspect, a kit is provided that includes a composition (eg, a solid composition) that includes a compound of formula (I).

[0232] Combination therapy The compounds or compositions described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) can be administered in combination with an additional drug or therapy. The subject to whom the compounds disclosed herein are administered can have a disease, disorder, or condition, or symptoms thereof, that would benefit from treatment with another drug or therapy. Combination therapy can be performed by administering two or more drugs, each of which is formulated and administered separately, or by administering two or more drugs that are in a single formulation form. In some embodiments, two or more drugs in combination therapy can be administered simultaneously. In other embodiments, two or more drugs in combination therapy are administered separately. For example, administration of a first drug (or combination of drugs) can occur minutes, hours, days, or weeks before administration of a second drug (or combination of drugs). Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. In many cases, it is desirable for two or more drugs used in combination therapy to be present in the patient's body at the same time, but this does not have to be the case.

[0233] Combination therapy may also include more than one administration of one or more drugs used in combination, using different sequences of component drugs. For example, when drug X and drug Y are used in combination, they can be administered one or more times in any combination in sequence, for example, in the sequence XYX, XXY, YXY, YYX, XXYY, etc. Exemplary additional drugs are described below.

[0234] Selective serotonin reuptake inhibitors (SSRIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered in combination with SSRI(s). SSRIs include antidepressants that increase the level of serotonin in the brain. Exemplary SSRIs include, but are not limited to, citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

[0235] Norepinephrine reuptake inhibitors (NERIs) In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered in combination with a NERI(s). Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Bestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramin), amidaline (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), and viloxazine (Vivaran).

[0236] Antipsychotics In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered in combination with an antipsychotic agent(s). Antipsychotic agents include D2 antagonists, which reduce dopaminergic neurotransmission in the dopamine pathway. Exemplary antipsychotics include, but are not limited to, asenapine (Safris), aripiprazole (Abilify), cariprazine (Brailer), clozapine (Clozaril), droperidol, fluperlapine, mesoridazine, quetiapine hemifumarate, raclopride, spiperone, sulpiride, trimethobenzamide hydrochloride, trifluoperazine dihydrochloride, lurasidone (Latuda), olanzapine (Zyprexa), quetiapine (Seroquel), zotepine, risperidone (Risperidal), ziprasidone (Geodon), mesoridazine, chlorpromazine hydrochloride, and haloperidol (Haldol).

[0237] Cannabinoids In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered in combination with a cannabinoid(s). Exemplary cannabinoids include, but are not limited to, cannabidiol (Epidiolex), tetrahydrocannabinolic acid, tetrahydrocannabinol, cannabidolic acid, cannabinol, cannabigerol, cannabichromene, tetrahydrocannabivarin, and cannabidivarin.

[0238] NMDA receptor antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered in combination with an NMDA receptor antagonist(s). An NMDA receptor antagonist is a type of drug that inhibits the action of N-methyl-d-aspartate receptors. Exemplary NMDA antagonists include, but are not limited to, ketamine, esketamine, ketobemidone, ifendopril, 5,7-dichlorokynurenic acid, lycostinel, memantine, gavestinel, phencyclidine, dextromethorphan, remacemide, selfotel, tiletamine, dextropropoxyphene, aptiganel, dexanabinol, and amantadine. NMDA receptor antagonists also include opioids such as methadone, dextropropoxyphene, pethidine, levorphanol, tramadol, neramexane, and ketobemidone.

[0239] GABA receptor antagonists In some embodiments, a compound or composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered in combination with a GABA receptor antagonist(s). A GABA receptor antagonist is a type of drug that is an antagonist of one or more GABA receptors. Exemplary GABA receptor antagonists include clobazam, topiramate, muscimol, progabide, riluzole, baclofen, gabapentin, vigabatrin, valproic acid, tiagabine, lamotrigine, pregabalin, phenyloin, carbamazepine, thiopental, thiamylal, pentobarbital, secobarbital, hexobarbital, butobarbital, amobarbital, barbital, mephobarbital, phenobarbital, primidone, midazolam, triazolam, lormetazepam, flutazolam, nitrazepam, fluritrazepam, nimetazepam, diazepam, medazepam, oxazolam, prazeam, tofisopam, rilmazafone, lorazepam, temazepam, oxazepam, fludiazepam, Chlordiazepoxide, Cloxazolam, Flutoprazepam, Alprazolam, Estazolam, Bromazepam, Flurazepam, Clorazepate potassium, Haloxazolam, Ethyl loflazepate, Quazepam, Clonazepam, Mexazolam, Etizolam, Brotizolam, Clotiazepam, Propofol, Fospropofol, Zolpidem, Zopiclone, Eszopiclone, Muscimol, TFQP / Gaboxadol, Isoguvacine, Kodiamine, GABA, Homotaurine, Homohypotaurine, Trans-Aminocyclopentane-3-Carboxylic Acid, Trans-Amino-4-Crotonic Acid, β-Guanidinopropionic Acid, Homo-β-Proline, Isonipecotic Acid, 3-((Aminoiminomethyl)thio)-2-Propenoic Acid (ZAP A), imidazole acetic acid, and piperidine-4-sulfonic acid (P4S).

[0240] Cholinesterase inhibitors In some embodiments, the compounds or compositions described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) are administered in combination with a cholinesterase inhibitor(s). In general, cholinergic agents are compounds that mimic the action of acetylcholine and / or butyrylcholine. Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine. Exemplary cholinesterase inhibitors include, but are not limited to, donepezil (Aricept), tacrine (Cognex), rivastigmine (Exelon, Exelon Patch), galantamine (Razadyne, Reminyl), memantine / donepezil (Namzalic), ambenonium (Mytelase), neostigmine (Broxivert), pyridostigmine (Mestinon Timespan, Regonol), and galantamine (Razadyne).

[0241] The present disclosure also contemplates administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject who has previously been administered an agent selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, oxygen, an antibody, and an antibacterial agent, among others. In some embodiments, an additional agent is administered to the subject prior to administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma-ceutically acceptable salt thereof), and the additional agent is selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, oxygen, an antibody, and an antibacterial agent. In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma-ceutically acceptable salt thereof) is co-administered to the subject with an agent selected from the group consisting of a bronchial muscle / airway relaxant, an antiviral agent, oxygen, and an antibacterial agent.

[0242] Methods of Use and Treatment In one aspect, the compounds described herein, e.g., compounds of Formula (I), are contemplated to be useful as therapeutic agents for treating a CNS-related disorder (e.g., a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a seizure disorder, an epileptic seizure, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in a subject in need thereof (e.g., a subject having Rett Syndrome, Fragile X Syndrome, or Angelman Syndrome). Exemplary CNS conditions associated with GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., minor depression), bipolar disorder (e.g., types I and / or 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, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognition disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD))], dementia (e.g., , Alzheimer's disease, dementia with Lewy bodies, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monogenetic cases of autism such as synaptic degeneration, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), cerebrovascular disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0243] In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.In certain embodiments, the CNS-related disorder is depression.In certain embodiments, the CNS-related disorder is postpartum depression.In certain embodiments, the CNS-related disorder is major depressive disorder.In certain embodiments, the major depressive disorder is moderate major depressive disorder.In certain embodiments, the major depressive disorder is severe major depressive disorder.

[0244] In one aspect, a method of reducing or preventing seizure activity in a subject is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi some embodiments, the method reduces or prevents epileptic seizures.

[0245] In yet another aspect, the present invention provides a combination of the compound of the present invention with another pharmacologically active agent.The compound provided herein can be administered as a single active agent or in combination with other agents.The administration of the combination can be performed by any technique that is clear to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0246] In another aspect, there is provided a method for treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention.

[0247] In yet another aspect, there is provided a method for treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, or a composition thereof.

[0248] In yet another aspect, there is provided a method for reducing or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, or a composition thereof.

[0249] In yet another aspect, there is provided a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, comprising administering an effective amount of a compound of the invention.

[0250] In yet another aspect, there is provided a method of alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.

[0251] In yet another aspect, there is provided a method of treating or preventing a mood disorder in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi certain embodiments, the mood disorder is depression.

[0252] In yet another aspect, the present invention provides a method for enhancing cognition or treating memory disorder by administering to a subject a therapeutically effective amount of the compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease.In certain embodiments, the disorder is Rett syndrome.

[0253] In yet another aspect, there is provided a method for treating attention disorders by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0254] Inflammation of the central nervous system (CNS) (neuroinflammation) is recognized as a hallmark of all neurological disorders. Major inflammatory neurological disorders include multiple sclerosis (characterized by immune-mediated reactions against myelin proteins) and meningoencephalitis (where an infectious agent initiates an inflammatory response). In addition, scientific evidence suggests a potential role for inflammatory mechanisms in other neurological pathologies, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury. In one embodiment, the compounds of the present invention are useful for treating neuroinflammation. In another embodiment, the compounds of the present invention are useful for treating inflammation in neurological pathologies, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury.

[0255] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0256] Neuroendocrine Disorders and Dysfunctions Methods are provided herein that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various pathologies caused by an imbalance in the body's hormone production that is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. The hypothalamus and pituitary gland are two areas of the brain that control the production of hormones, so damage to the hypothalamus or pituitary gland, for example, from traumatic brain injury, can affect the production of hormones and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., a women's health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women's health disorder or condition is polycystic ovarian syndrome.

[0257] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms, including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, difficulty paying attention, decreased libido, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0258] Neurodegenerative Diseases and Disorders The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" encompasses diseases and disorders associated with progressive loss of neuronal structure or function, or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and seizures (including for treatment and prevention, and for prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusion injury (e.g. spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; impaired consciousness; Down's syndrome; drug-induced or medication-induced Parkinson's disease (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; Fragile X syndrome; Gilles de la Tourette syndrome; head trauma; deafness and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced Dyskinesias; mental retardation; movement disorders including akinesia and akinetic (rigid) syndromes (including brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasms or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesias (complex chyloarthritis, tics, including tics such as tics, simple tics, and asymptomatic tics), myoclonus, including generalized myoclonus and focal siroclonus, tremors, such as rest tremor, postural tremor, and intention tremor, and dystonias, including truncal dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonias, such as blepharospasm, temporomandibular dystonia, and spasmodic dysphonia and spasmodic torticollis); neuronal damage, including eye damage, retinopathy, or macular degeneration of the eye;Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tuberous sclerosis, and viral infection-induced neurodegeneration (e.g., caused by acquired immune deficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest. Methods of treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0259] Mood disorders Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar or manic-depressive disorder, depression due to chronic medical conditions, treatment-resistant depression, refractory depression, suicidal, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0260] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and loss of interest or pleasure in activities that are usually enjoyed. Some people with clinical depression experience sleep problems, weight loss, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and acts, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0261] Perinatal depression refers to depression during pregnancy. Symptoms may include irritability, cryability, restlessness, sleep problems, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of detachment from the baby and / or fetus, and loss of interest in previously enjoyed activities.

[0262] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that women suffer from after giving birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, loss of libido, tearful episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0263] 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 who experiences perinatal depression has a high risk of experiencing PND.

[0264] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, marked weight gain or increased appetite. Patients with AD may also have significant social impairments as a result of excessive sleepiness or drowsiness (hypersomnia), heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0265] Melancholic depression is characterized by loss of pleasure from most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, a depressed mood that is more pronounced than feelings of sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0266] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly one of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0267] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit purposeless or bizarre movements.

[0268] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0269] Dysthymia refers to a condition related to unipolar depression that causes the same physical and cognitive problems, but tends to be less severe and last for a longer period of time (e.g., at least 2 years).

[0270] Dual depression refers to at least two years of significant depressed mood (dysthymia) interspersed with periods of major depression.

[0271] Depressive personality disorder (DPD) refers to a personality disorder that has depressive traits.

[0272] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes approximately once per month, with each episode lasting for a short period of time (less than two weeks), typically less than two to three days.

[0273] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0274] Bipolar or manic-depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During manic periods, an individual may experience unusual euphoria, energy, or irritability in their emotions or behavior. Such individuals often make ill-considered decisions with little regard for the consequences. There is usually a decreased need for sleep. During depressive periods, individuals may be tearful, make little eye contact with others, and be pessimistic about life. The risk of suicide for people with the disorder is high at over 6% over a 20-year period, and 30-40% will self-harm. Other mental health problems, such as anxiety disorders and substance abuse disorders, often co-occur with bipolar disorder.

[0275] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0276] Treatment-resistant depression refers to a state in which an individual is treated for depression but does not improve symptoms. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve symptoms but relapse. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple doses of inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0277] Postoperative depression refers to depressed feelings that continue after a surgical procedure (e.g., as a result of facing death.) For example, patients may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0278] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a women's health condition or disorder (eg, as described herein).

[0279] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to attempt suicide. Suicidal ideation involves thoughts about suicide or an abnormal obsession with suicide. The spectrum of suicidal ideation varies significantly, for example, from passing thoughts to widespread thoughts, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to attempt suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never see each other again.

[0280] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty exercising, loss of interest in enjoyable activities or hobbies, poor concentration, low energy, low self-esteem, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Depression symptoms and their relief can be confirmed by a doctor or psychologist (e.g., by mental status examination).

[0281] In some embodiments, the method includes monitoring the subject with known depression rating scales, such as the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression Improvement Scale (CGI), and Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by the subject's reduction in the Hamilton Depression Rating Scale (HAM-D) total score. The reduction in the HAM-D total score can occur within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours. The therapeutic effect can be evaluated over a specific treatment period. For example, therapeutic efficacy can be determined by a reduction from baseline in HAM-D total score following administration of a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; 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 lifetime).

[0282] In some embodiments, the subject has a mild depressive disorder, e.g., a mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., a moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., a severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., a very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a compound described herein, e.g., a compound of Formula (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 14 to 18, inclusive. In some embodiments, the subject's baseline HAM-D total score is 19 to 22, inclusive. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is less than 10, i.e., 7, 5, or 3. In some embodiments, after treatment with a compound described herein, e.g., a compound of Formula (I), the HAM-D total score is reduced from a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a HAM-D total score of about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), from baseline HAM-D total score is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100-fold.In some embodiments, the percentage reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), from baseline HAM-D total score is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured by a reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, 48 hours; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days or more after administration) compared to the baseline HAM-D total score, which is at least 10, 15, or 20 points.

[0283] In some embodiments, the method of treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as measured by a reduction in the Hamilton Rating Scale for Depression (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the method of treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the HAM-D total score) by the first or second day of treatment with a compound described herein, e.g., a compound of formula (I). In some embodiments, the method of treating a depressive disorder, e.g., a major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 14 days of initiating treatment with a compound described herein, e.g., a compound of formula (I). In some embodiments, the method of treating a depressive disorder, e.g., a 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 initiating treatment with a compound described herein, e.g., a compound of formula (I). In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 28 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the therapeutic benefit is a reduction from baseline in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., treatment with a compound described herein, e.g., a compound of Formula (I) once daily for 14 days). In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula (I), is at least 24. In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula (I), is at least 18. In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula (I), is between 14 and 18, inclusive.In some embodiments, the reduction in HAM-D total score following treatment of a subject with a compound described herein, e.g., a compound of Formula (I), compared to a baseline HAM-D total score is at least 10. In some embodiments, the reduction in HAM-D total score following treatment of a subject with a compound described herein, e.g., a compound of Formula (I), compared to a baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score following treatment of a subject with a compound described herein, e.g., a compound of Formula (I), is no greater than a number in the range of 6-8. In some embodiments, the HAM-D total score following treatment of a subject with a compound described herein, e.g., a compound of Formula (I), is no greater than 7.

[0284] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in the Clinical Global Impression (CGI) score) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit by the second day of the treatment period. In some embodiments, the therapeutic benefit is a reduction in CGI score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0285] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit by the second day of the treatment period. In some embodiments, the therapeutic benefit is a reduction in MADRS score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0286] The effectiveness of treatment of major depressive disorder can be determined by a reduction in the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score can be reduced within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (related to outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, lack of emotion, pessimistic thoughts, and suicidal thoughts) that psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.

[0287] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0288] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in Generalized Anxiety Disorder 7-item Scale (GAD-7)) within 4, 3, 2, 1 day; or within 24, 20, 16, 12, 10, 8 hours.

[0289] Anxiety disorders Provided herein is a method for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorder is an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria distinguish a wide variety of anxiety disorders.

[0290] Generalized anxiety disorder is a common chronic disorder characterized by long periods of anxiety that are not focused on any one object or situation. People suffering from generalized anxiety experience non-specific persistent fear and worry, and become excessively worried about minor everyday occurrences. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0291] In panic disorder, patients suffer from brief attacks of intense fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. Defined by the APA as fear or discomfort that occurs suddenly and peaks in less than 10 minutes, such panic attacks can last for hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always evident. In addition to recurrent and unexpected panic attacks, a diagnosis of panic disorder also requires that the attacks have chronic consequences (either worry about the potential impact of the attack, persistent fear of future attacks, or significant behavioral changes associated with the attack). Thus, those suffering from panic disorder also experience symptoms outside of a particular panic episode. Often, when panic sufferers notice normal heart rate changes, they think there is something wrong with their heart or that another panic attack is coming. In some cases, heightened perceptions of bodily functions (hyperarousal) occur during a panic attack, leading to the interpretation of the perceived physiological changes as a potentially life-threatening disorder (i.e., extreme hypochondria).

[0292] Obsessive-compulsive disorder is a type of anxiety disorder that is primarily characterized by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform certain movements or habitual acts). OCD thought patterns can be likened to superstitions because they involve belief in causal relationships that do not actually exist. The process is often entirely illogical, for example, a person may adopt a compulsive behavior, such as walking in a certain pattern, to alleviate an obsession that they are about to be harmed. In many more cases, the compulsions are entirely inexplicable and are simply urges to complete habitual acts triggered by nervousness. In a minority of cases, OCD patients may only experience obsessions without overt compulsions, and even fewer experience only compulsions.

[0293] The largest single category of anxiety disorder is that of the phobias, which includes all cases in which fear and anxiety are provoked by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering their feared object (which could be anything from an animal to a place to a bodily fluid).

[0294] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to significant stressors (e.g., soldiers who can tolerate individual combat but are unable to cope with sustained combat). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0295] Women's Health Disorders Provided herein is a method for treating a condition or disorder related to women's health.The condition or disorder related to women's health includes, but is not limited to, gynecological health conditions and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovarian syndrome (PCOS)), other disorders and conditions, and problems related to women's overall health and wellness (e.g., menopause).

[0296] Gynecological health conditions and disorders affecting women include menstruation and menstrual irregularities; urinary tract health conditions, including urinary incontinence and pelvic floor disorders; and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0297] Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's period. Symptoms vary but can include bleeding, mood swings, breast tenderness, overeating, fatigue, irritability, acne, and depression.

[0298] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to PMS but are more severe and may interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, noticeable anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, appetite changes, uncontrollable or irresistible feelings, sleep problems, and physical problems (e.g., swelling, breast tenderness, edema, headaches, joint or muscle pain).

[0299] Pregnancy issues include pre-conception and pre-natal care, pregnancy loss (miscarriage and stillbirth), preterm labor and delivery, sudden infant death syndrome (SIDS), breastfeeding, and congenital anomalies.

[0300] A miscarriage is a pregnancy that ends naturally within the first 20 weeks of pregnancy.

[0301] Abortion refers to the intentional interruption of a pregnancy which can be performed during the first 28 weeks of pregnancy.

[0302] Infertility and related disorders include uterine fibroids, polycystic ovarian syndrome, endometriosis, and primary ovarian failure.

[0303] Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a set of symptoms resulting from elevated levels of male hormones in women. Most women with PCOS have many small cysts growing on their ovaries. Symptoms of PCOS include irregular menstrual periods, amenorrhea, menorrhagia, excessive body and facial hair growth, acne, pelvic pain, difficulty conceiving, and thickened, dark, velvety patches of skin. PCOS can be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0304] Other disorders and conditions that only affect women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0305] Issues relating to women's overall health and wellness include violence against women, women with disabilities and their particular challenges, osteoporosis and bone health, and menopause.

[0306] Menopause refers to the 12 months following a woman's last menstrual period and is characterized by the end of the menstrual cycle. Menopause usually occurs in women in their 40s or 50s. The physical (such as hot flushes) and emotional symptoms of menopause can disrupt sleep, reduce energy, induce anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of menopause induced by events such as surgery (e.g., hysterectomy, oophorectomy, cancer). It is induced when the ovaries are severely damaged, such as by radiation, chemotherapy, or other medications.

[0307] Epilepsy The compounds of formula (I) or pharma- ceutically acceptable salts, or pharma- ceutically acceptable compositions can be used in the methods described herein, e.g., for the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizures.

[0308] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal childhood epilepsy.

[0309] Epileptic seizures The compounds and methods described herein can be used to treat or prevent epileptic seizures. Epileptic seizures are a sequential process in which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptic seizures result from neuronal damage that is suddenly caused by an initial injury (e.g., status epilepticus).

[0310] Status epilepticus (SE) Status epilepticus (SE) may include, for example, convulsive status epilepticus, e.g., early status epilepticus, confirmed status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and may include early status epilepticus, confirmed status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Confirmed status epilepticus is characterized by status epilepticus that persists despite treatment with first-line therapy and for which second-line therapy is implemented. Refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line and second-line therapies and for which a general anesthetic is administered systemically. Super-refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line, second-line, and general anesthetic for more than 24 hours.

[0311] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, latent non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0312] The compounds of formula (I) or pharma- ceutically acceptable salts, or pharma- ceutically acceptable compositions thereof, may also be administered as a prophylactic before the onset of a seizure to subjects with a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges.

[0313] Seizures A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used synonymously with "convulsion." A convulsion is when the human body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0314] Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized and partial (also called focal or focal). Classifying the type of seizures helps doctors diagnose whether a patient has epilepsy.

[0315] Generalized seizures are caused by electrical excitation from the entire brain, whereas partial seizures (at least initially) are caused by electrical excitation in a smaller part of the brain. The part of the brain that produces the seizure is sometimes called the focal point.

[0316] There are six types of generalized seizures. The most common, most severe, and therefore the best known is the generalized convulsion, also called grand mal. In this type of seizure, the patient loses consciousness, usually passing out. Loss of consciousness is followed by 30-60 seconds of generalized stiffening (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent convulsive seizures (the "clonic" phase), after which the patient enters a deep sleep state (the "postictal" or postictal phase). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence can occur.

[0317] Absence seizures cause a brief (only a few seconds) loss of consciousness with little or no symptoms. Typically, the patient (mostly a child) stops moving and stares blankly. Such seizures begin and end abruptly and may occur several times a day. Patients are usually unaware that they are having a seizure, except for the perception of "time passing."

[0318] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body, which patients may describe as brief electric shocks. Such seizures, when severe, may cause the patient to drop or throw objects involuntarily.

[0319] Clonic seizures are recurrent rhythmic convulsions that involve both sides of the body simultaneously.

[0320] Tonic seizures are characterized by muscle stiffness.

[0321] Cataplexy consists of a sudden generalized loss of muscle tone, especially in the arms and legs, often causing a fall.

[0322] The seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; persistent seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile convulsions; affective seizures; focal seizures; galvanic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; widespread bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; latent seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0323] Movement disorders Also described herein is a method for treating movement disorders.As used herein, "movement disorder" refers to various diseases and disorders associated with hyperkinetic movement disorders and related to abnormalities in muscle control.Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle reflex, tic disorder and Tourette's syndrome, restless legs syndrome, stiff person syndrome, and gait disorder.

[0324] Tremor The methods described herein can be used to treat tremor, for example, the compounds of formula (I) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor, or red tremor. Tremors include genetic, degenerative, and idiopathic disorders (such as Wilson's disease, Parkinson's disease, and essential tremor, respectively); metabolic disorders (e.g., thyroid disease, parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy syndrome, diabetes mellitus, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (sleep inducers, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified as physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task-specific and position-specific tremor), dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0325] Tremor is an involuntary, intermittent rhythmic movement, muscle contraction, and relaxation that may involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0326] Cerebellar tremor or intention tremor is a slow, widespread limb tremor that occurs after intentional movement. Cerebellar tremor is caused by lesions or damage to the cerebellum, for example, caused by tumor, stroke, disease (e.g., multiple sclerosis, hereditary degenerative disease).

[0327] Dystonic tremor occurs in individuals with dystonia and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful, abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is often relieved by complete rest.

[0328] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor may be mild and non-progressive or may progress slowly, starting on one side of the body but affecting both sides within three years. It most often affects the hands, but may also affect the head, vocal cords, tongue, legs, and trunk. Tremor may become less frequent but more severe with age. Emotional excitement, stress, fever, physical fatigue, or hypoglycemia may induce tremor and / or increase its severity. Symptoms generally evolve over time and may be visible and persistent after onset.

[0329] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Patients may experience painful muscle spasms in the thighs and legs and may shake uncontrollably when asked to stand in one place. Patients with essential tremor may experience orthostatic tremor.

[0330] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill-rolling" movement of the hands, and may also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremor usually begins after age 60. Movements may begin in one limb or side of the body and progress to involve the other side.

[0331] Physiologic tremor can occur in normal individuals and has no clinical significance. Physiologic tremor can be found in all voluntary muscle groups. Physiologic tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. Classical tremor has a frequency of approximately 10 Hz.

[0332] Psychogenic or hysterical tremor can occur at rest or during postural or motor movements. Patients with psychogenic tremor may suffer from conversion disorder or another psychiatric illness.

[0333] Red tremor is characterized by a slow, coarse tremor that can occur at rest, postural, and intention. Tremor is associated with conditions affecting the red nucleus of the midbrain, classic abnormal stroke.

[0334] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms with Parkinson's disease, but is not a progressive neurodegenerative disease, but a complex of symptoms.

[0335] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal, often repetitive, movements or postures. Dystonic movements can be stereotyped, torsional, and may be tremulous. Dystonia is often initiated by or exacerbated by voluntary movements and is associated with an overflow of muscle activation.

[0336] Chorea is a neurological disorder characterized by intermittent involuntary movements that typically affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that causes loss of nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and problems with balance. Huntington's disease can interfere with walking, talking, and swallowing.

[0337] Ataxia refers to the complete loss of control of bodily movements and can affect fingers, hands, arms, legs, trunk, speech, and eye movements.

[0338] Myoclonus and the startle reflex are responses to a sudden, unexpected stimulus, which may be auditory, tactile, visual, or vestibular.

[0339] Tics are involuntary movements that are usually sudden, brief, repetitive, but non-rhythmic, typically mimicking normal behavior and often occurring as a remote cause of normal behavior. Tics can be classified as motor or vocal tics, with motor tics being associated with movement, while vocal tics are associated with vocalization. Tics can be simple or complex in nature. For example, simple motor tics involve only a few muscles that are confined to a particular body part. Tourette's syndrome is a childhood-onset, inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0340] Restless legs syndrome is a neurosensory-motor disorder characterized by a strong desire to move the legs while at rest.

[0341] Stiff person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, usually involving the lower back and legs. A stiff gait, usually with lumbar hyperlordosis, occurs. Characteristic abnormalities in EMG recordings with sequential motor unit activity of the paraspinal axial muscles are commonly observed. Variants include "stiff limb syndrome" causing focal stiffness, usually affecting the distal legs and feet.

[0342] Gait disorders refer to abnormalities in the way or style of walking due to neuromuscular, arthritic, or other physical changes. Gait is classified according to the system involved in the abnormal gait and includes hemiplegic, diplegic, neuropathic, myopathic, parkinsonian, choreiform, ataxic, and sensory gait.

[0343] Anesthesia / Sedation Anesthesia is a pharmacologically induced reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. Such effects can be obtained from a single drug that provides a reasonable combination of effects alone, or in some cases by combinations of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) that achieve extremely specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the discomfort and pain that they would otherwise experience.

[0344] Sedation is the reduction of irritability or excitement by the administration of pharmacological agents, generally to facilitate a medical or diagnostic procedure.

[0345] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0346] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are generally not affected.

[0347] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness during which the patient responds purposefully to verbal commands alone or with mild tactile stimulation. No intervention is usually required to maintain a patent airway. Spontaneous ventilation is usually adequate. Cardiovascular function is usually preserved.

[0348] Deep sedation / analgesia is a drug-induced decrease in consciousness during which the patient cannot be easily aroused but responds purposefully following repetitive or painful stimuli (not reflex withdrawal from painful stimuli). Independent ventilation may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0349] General anesthesia is a drug-induced loss of consciousness during which the patient cannot be aroused by painful stimuli. The ability to maintain independent ventilation is often impaired, and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to decreased spontaneous ventilation or drug-induced neuromuscular depression. Cardiovascular function may be impaired.

[0350] Sedation in the intensive care unit (ICU) allows for a reduction in the patient's awareness of the environment and a decrease in the patient's response to external stimuli. It can take care of critically ill patients and encompasses the management of a wide range of symptoms that vary between patients and individuals over the course of the disease. Heavy sedation has been used in critical care to facilitate tolerance to endotracheal intubation and ventilator synchrony, often with neuromuscular blockade.

[0351] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives can have a long duration of action. Sedatives in the ICU can have a short elimination half-life.

[0352] Procedural sedation and analgesia, also called conscious sedation, is a technique in which a sedative or dissociative agent is administered with or without analgesics to induce a state that allows the subject to tolerate an unpleasant procedure while preserving cardiopulmonary function.

[0353] Also described herein are methods for ameliorating one or more symptoms of a respiratory condition in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof).

[0354] In one aspect, provided herein is a method of treating a subject exhibiting one or more symptoms of a respiratory condition and / or diagnosed with a respiratory condition, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof).

[0355] In some embodiments, the present disclosure contemplates a method of treating a subject when the subject has a respiratory condition, comprising administering to the subject a compound or pharmaceutical composition described herein (e.g., a compound of formula I or a pharmaceutical salt thereof, or a composition comprising a compound of formula I or a pharma- ceutical acceptable salt thereof).

[0356] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition may result in a reduction in the severity of one or more symptoms of the respiratory condition, or a delay or slowing of the progression of one or more symptoms of the respiratory condition.

[0357] In some embodiments, the subject with a respiratory condition has been or is being treated with mechanical ventilation or oxygen. In some embodiments, the subject with a respiratory condition has been or is being treated with mechanical ventilation.

[0358] In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered to a subject undergoing or having been treated with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is continued throughout the treatment of the subject with mechanical ventilation. In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is continued after the subject has completed treatment with mechanical ventilation.

[0359] In some embodiments, a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) is administered to a subject undergoing or having been treated with a sedative agent. In some embodiments, the sedative agent is propofol or a benzodiazepine.

[0360] In some embodiments, the disclosure includes administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject in need thereof in an amount sufficient to increase blood oxygen saturation. In some embodiments, blood oxygen saturation is measured using a pulse oximeter.

[0361] In some embodiments, the present disclosure contemplates a method for treating a cytokine storm in a patient. In some embodiments, the method comprises administering to a patient a compound or pharmaceutical composition described herein (e.g., a compound of formula I or a pharmaceutical salt thereof, or a composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof). In some embodiments, the symptom of the cytokine storm is pulmonary inflammation. In some embodiments, the patient experiencing a cytokine storm has acute respiratory distress syndrome (ARDS).

[0362] respiratory pathology In some embodiments, the subject with a respiratory condition suffers from dyspnea, hi some embodiments, the dyspnea comprises acute respiratory distress.

[0363] In some embodiments, a subject with a respiratory condition may exhibit one or more symptoms selected from the group consisting of airway hyperresponsiveness, inflammation of lung tissue, pulmonary hyperresponsiveness, and inflammation-associated lung pain.

[0364] In some embodiments, the subject with a respiratory condition may exhibit inflammation of lung tissue. In some embodiments, the inflammation of lung tissue is bronchitis or bronchiectasis. In some embodiments, the inflammation of lung tissue is pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia or hospital-acquired pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia.

[0365] In some embodiments, administration of a compound or pharmaceutical composition described herein to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of dyspnea in a subject with a respiratory condition, or a delay or slowing of the progression of dyspnea in a subject with a respiratory condition.

[0366] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of airway hyperresponsiveness in a subject with a coronavirus-related disease, or a delay or slowing of the progression of airway hyperresponsiveness in a subject with a respiratory condition.

[0367] In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of inflammation of lung tissue in the subject with the respiratory condition, or a delay or slowing of the progression of inflammation of lung tissue in the subject with the respiratory condition. In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of pneumonia in the subject with the respiratory condition, or a delay or slowing of the progression of pneumonia in the subject with the respiratory condition.

[0368] In some embodiments, administration of a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of pulmonary hypersensitivity in a subject with a respiratory condition, or a delay or slowing of the progression of pulmonary hypersensitivity in a subject with a respiratory condition.

[0369] In some embodiments, administering a compound or pharmaceutical composition described herein (e.g., a compound of Formula I or a pharmaceutical salt thereof, or a composition comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof) to a subject exhibiting symptoms of a respiratory condition results in a reduction in the severity of inflammation-associated lung pain in the subject with the respiratory condition, or a delay or slowing of the progression of inflammation-associated lung pain in the subject with the respiratory condition.

[0370] In some embodiments, the subject with a respiratory disease is receiving or has received treatment for an infection, fibrosis, fibrotic disease, chronic obstructive pulmonary disease, sarcoidosis (or pulmonary sarcoidosis), or asthma / asthma-related inflammation.

[0371] In some embodiments, the subject is exhibiting symptoms of and / or has been diagnosed with asthma, hi some embodiments, the subject is experiencing or has experienced an asthma attack.

[0372] In some embodiments, the subject is undergoing or has undergone treatment for fibrosis or a fibrotic condition, hi some embodiments, the fibrosis is cystic fibrosis.

[0373] In some embodiments, the respiratory condition is cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility due to congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation fibrinolysis deficiency such as protein C deficiency. type 1 hereditary angioedema, lipid processing deficiencies such as familial hypercholesterolemia, type 1 chylomicroemia, abetalipoproteinemia, lysosomal storage disorders such as I-cell disease / pseudo-Hurler disease, mucopolysaccharidoses, Sandhoff disease / Tay-Sachs disease, Crigler-Najjar type II, polyendocrinopathy / hyperinsulinemia, diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary parathyroid insufficiency, melanoma, glycosylation abnormalities or is the result of and / or associated with a disease or condition selected from the group consisting of: chronic kidney disease type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurogenic DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Pelizaeus-Merzbacher disease, neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, several polyglutamine neuropathies such as progressive supranuclear palsy, Pick's disease, Huntington's disease, spinocerebellar ataxia type I, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease (due to defects in prion protein processing), Fabry disease, Streussler-Scheinker syndrome, COPD, dry eye disease, or Sjogren's syndrome.

[0374] infectious disease The present disclosure contemplates, inter alia, the treatment of a subject having an infectious disease. The present disclosure contemplates, inter alia, the treatment of a subject having a disease associated with an infectious disease. In some embodiments, the infectious disease is a viral infection or a bacterial infection. In some embodiments, the infectious disease is a viral infection. In some embodiments, the infectious disease is a bacterial infection.

[0375] In some embodiments, the viral infection is an infection with a virus selected from the group consisting of a coronavirus, influenza virus, human rhinovirus, human parainfluenza virus, human metapneumovirus, and hantavirus. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV, SARS-CoV-2, and MERS-CoV.

[0376] The present disclosure contemplates, inter alia, the treatment of a subject having a disease associated with a coronavirus. In some embodiments, the disease associated with a coronavirus is selected from the group consisting of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). In some embodiments, the disease associated with a coronavirus is selected from the group consisting of COVID-19. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV-1, SARS-CoV-2, and 2012-nCoV. In some embodiments, the coronavirus is SARS-CoV-2.

[0377] In some embodiments, the bacterial infection is an infection with a bacteria selected from the group consisting of Streptococcus pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Haemophilus influenzae, hi some embodiments, the Staphylococcus aureus is Methicillin-resistant Staphylococcus aureus. EXAMPLES

[0378] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0379] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0380] Furthermore, as will be appreciated by those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in TW Greene and PG M Huts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

[0381] 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). The following schemes are presented with details regarding the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns that can be used for the separation / purification of 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.

[0382] As reported herein 1 H-NMR (e.g., in the region of about 0.5 to about 4 ppm δ (ppm)) is understood to be an exemplary interpretation of the NMR spectrum of a compound (e.g., exemplary peak integrals).

[0383] 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-borabicyclo[3.3.1]nonane; Pd(t-Bu 3 P) 2 : Bis(tri-tert-butylphosphine)palladium(0);AcCl: Acetyl chloride;i-PrMgCl: Isopropylmagnesium chloride;TBSCl: tert-butyl(chloro)dimethylsilane;(i-PrO) 4Ti: titanium tetraisopropoxide;BHT: 2,6-di-t-butyl-4-methylphenoxide;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;DMAP: 4-dimethylaminopyridine;DMP: Dess-Martin periodinane;EtMgBr: ethyl magnesium bromide;EtOAc: ethyl acetate;TEA: triethylamine;AlaOH: alanine;Boc: t-butoxycarbonyl;Py: pyridine;TBAF: tetra-n-butylammonium fluoride;THF: tetrahydrofuran;TBS: t-butyldimethylsilyl;TMS: trimethylsilyl;TMSCF 3 : (Trifluoromethyl)trimethylsilane; Ts: p-Toluenesulfonyl; Bu: Butyl; Ti(OiPr) 4 : tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH.H 2 O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: Acetonitrile; NBS: N-bromosuccinimide; Na 2 SO 4 : Sodium sulfate; Na 2 S 2 O 3 : sodium thiosulfate; MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: potassium tri(s-butyl)borohydride; 9-BBN dimer: 9-borabicyclo(3.3.1)nonane (dimer); DIPEA: diisopropylethylamine; DMF: dimethylformamide; FA: formic acid; SM: starting material.

[0384] Examples 1 and 2: Synthesis of 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (1) and 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (2) [ka] Synthesis of 1-1 Ph 3 To a suspension of PMeBr (10 g, 28.2 mmol) in anhydrous THF (40 mL), t-BuOK (3.16 g, 28.2 mmol) was added 2 After stirring at 50°C for 30 min, a solution of 1-0 (3 g, 9.4 mmol) in anhydrous THF (10 mL) was added dropwise. After stirring at 60°C for 1 h, the mixture was diluted with 10% NH 4 Cl (50 mL) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic solutions were washed with saturated brine (2×50 mL), filtered and concentrated. The residue was dissolved in MeOH (50 mL) and water (50 mL). The resulting compound was collected by filtration and dried to give the desired 1-1 (2.97 g, 100%). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.84 (s, 1H), 4.70 (s, 1H), 2.08-1.99 (m, 1H), 1.90-1.78 (m, 4H), 1.75 (s, 3H), 1.74-1.56 (m, 5H), 1.49-1.28 (m, 8H), 1.26 (s, 3H), 1.23-1.13 (m, 3H), 1.11-0.97 (m, 3H), 0.57 (s, 3H)

[0385] Synthesis of 1-2 To a solution of 1-1 (500 mg, 1.57 mmol) in DCM (10 mL) was added mCPBA (541 mg, 3.14 mmol) at 25 °C. After stirring at 40 °C for 1 h, the mixture was cooled to room temperature and cooled to room temperature. 3 The mixture was quenched with aqueous solution (100 mL). The DCM phase was separated and washed with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 2×100 mL), brine (100 mL), and anhydrous Na 2 SO 4 The mixture was dried over rt, filtered and concentrated in vacuo to give a residue which was purified by flash column (10-20% EtOAc in PE) to give 1-2 (685 mg).

[0386] Synthesis of 1 and 2 A solution of 1-2 (685 mg, 2.05 mmol) in DMF (10 mL) was added with 1H-pyrazole-4-carbonitrile (285 mg, 3.07 mmol) and Cs 2 CO 3 (3.32g, 10.2mmol) was added at 20°C. After stirring at 120°C for 2h, the mixture was diluted with water (100mL) and extracted with EtOAc (2x50mL). The combined organic solution was separated, concentrated and purified by flash column (30-65% EtOAc in PE) to give a mixture of epimers (600mg, 69%). The epimers were separated by HPLC (Column: XtimateC18 150*25mm*5μm; Conditioning solvent: Water (0.225% FA)-ACN; Start B: 74%; End B: 74%) to give 1 (133mg) and 2 (259.2mg).

[0387] 1: 1 H NMR (400 MHz, CDCl 3) δ 7.93 (s, 1H), 7.82 (s, 1H), 4.35 (d, J = 14.0 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 2.51 (s, 1H), 2.05 - 1.98 (m, 1H), 1.83 - 1.71 (m, 5H), 1.70 - 1.62 (m, 3H), 1.51 - 1.41 (m, 3H), 1.40 (br s, 2H), 1.37 - 1.27 (m, 3H), 1.26 (s, 3H), 1.23 - 1.20 (m, 1H), 1.19 - 1.10 (m, 2H), 1.10 - 1.02 (m, 4H), 0.97 (s, 3H), 0.92 (s, 3H); LC - ELSD / MS purity 99%, de 100% based on H - NMR; MSESIC 26 H 36 N 3 [M - 2H 2 O + H] + Calculated value for

[0388] 2: 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.80 (s, 1H), 4.22 - 4.13 (m, 1H), 4.06 - 3.94 (m, 1H), 2.31 (br s, 1H), 2.10 - 2.02 (m, 1H), 1.96 - 1.82 (m, 2H), 1.80 (br d, J = 6.8 Hz, 2H), 1.70 - 1.61 (m, 4H), 1.40 (br s, 8H), 1.26 (s, 3H), 1.25 - 1.09 (m, 5H), 1.09 (s, 3H), 1.07 - 1.00 (m, 2H), 0.87 (s, 3H); LC - ELSD / MS purity 99%, de 100% based on H - NMR; MSESIC 26 H 36 N 3 [M - 2H 2 O + H] + Calculated value for

[0389] Examples 3 and 4: Synthesis of 1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (3) and 1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (4) [ka] Synthesis of 3-1 To a solution of 3-0 (10 g, 25.4 mmol, reported in patent WO2016 / 134301, 2016, A2) in DCM (100 mL) was added silica gel (10 g) and PCC (8.17 g, 38 mmol) at 0° C. After stirring at 25° C. for 1 h, the suspension was filtered and the filter cake was washed with DCM (2×100 mL). The combined filtrate was concentrated to give 3-1 (10 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 9.56 (s, 1 H), 4.00-3.80 (m, 8 H), 2.24-1.88 (m, 5 H), 1.87-1.70 (m, 5 H), 1.46-1.35 (m, 5 H), 1.33-0.99 (m, 5 H), 0.92 (s, 3 H), 0.89-0.69 (m, 2 H).

[0390] Synthesis of 3-2 MePPh in THF (100 mL) 3 To a mixture of Br (27.1 g, 76.1 mmol), t-BuOK (8.53 g, 76.1 mmol) was added 2 After stirring at 50°C for 30 min, 3-1 (9.91 g, 25.4 mmol) was added in portions at less than 50°C. After stirring at 50°C for 1 h, the mixture was diluted with 10% NH4 The reaction mixture was quenched with aqueous Cl (200 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (300 mL). The combined organic phase was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EtOAc=20 / 1 to 5 / 1) to give 3-2 (5 g, 50.7%). 1 H NMR (400 MHz, CDCl 3 ) δ H 6.32-6.25 (m, 1 H), 5.15-4.94 (m, 2 H), 3.95-3.80 (m, 8 H) 2.02-1.72 (m, 6 H), 1.69-1.61 (m, 1 H), 1.59-1.31 (m, 12 H), 1.21-1.04 (m, 3 H), 0.80 (s, 3 H).

[0391] Synthesis of 3-3 A solution of 3-2 (15 g, 12.8 mmol) in THF (30 mL) was diluted with aqueous HCl (38.6 mL, 2 M, 77.2 mmol) and N 2 After stirring at 25°C for 5 hours, saturated NaHCO 3 The mixture was quenched with (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (30 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 3-3 (9.3 g, 80.8%). 1 H NMR (400 MHz, CDCl 3 ) δ H 6.35-6.25 (m, 1 H), 5.19 (d, J=11.2 Hz, 1 H), 5.09 (d, J=18.0 Hz, 1 H), 2.79-2.64 (m, 1 H), 2.54-2.13 (m, 5 H), 2.13-2.05 (m, 3 H), 2.02-1.79 (m, 3 H), 1.69-1.50 (m, 6 H), 1.37-1.23 (m, 4 H), 0.87 (s, 3 H).

[0392] Synthesis of 3-4 A solution of 3-3 (11 g, 36.6 mmol) in THF (200 mL) was diluted with Pd / C (wet, 50%, 2 g) and N 2 The suspension was degassed under vacuum and H 2 The tank was purged three times with H 2 After stirring at 25° C. under (30 psi) for 16 h, the reaction mixture was filtered through a pad of Celite and washed with THF (2×100 mL). The residue was triturated from PE (300 mL) to give 3-4 (12 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.67 (t, J=13.60 Hz, 1 H), 2.52-2.06 (m, 5 H), 2.00-1.91 (m, 1 H), 1.89-1.48 (m, 12 H), 1.39-1.19 (m, 5 H), 0.87 (s, 3 H), 0.80 (t, J=7.53 Hz, 3 H).

[0393] Synthesis of 3-5 A solution of BHT (26 g, 118 mmol) in toluene (60 mL) was added to AlMe at 0° C. under nitrogen. 3 (2M solution in toluene, 29.7 mL, 59.4 mmol) was added dropwise. After stirring at 15° C. for 1 h, a solution of 3-4 (6.0 g, 19.8 mmol) in DCM (10 mL) was added dropwise at −70° C. 2 After stirring at −70° C. for 1 h under reduced pressure, MeMgBr (19.8 mL, 59.4 mmol, 3 M in ethyl ether) was added dropwise at −70° C. After stirring at −70° C. for 4 h, the reaction mixture was poured into saturated 20% citric acid (300 mL) at less than 10° C. The reaction mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with Na 2 SO 4 The residue was purified by silica gel column (PE / EtOAc=0-20%) to give 3-5 (5.6 g, 88.8%). 1 H NMR (400 MHz, CDCl 3 ) δ H2.50-2.37 (m, 1 H), 2.13-2.04 (m, 1 H), 2.04-1.81 (m, 3 H), 1.81-1.62 (m, 5 H), 1.62-1.47 (m, 5 H), 1.46-1.28 (m, 6 H), 1.25 (s, 3 H), 1.24-1.11 (m, 4 H), 0.84 (s, 3 H), 0.80 (t, J=7.60 Hz, 3 H).

[0394] Synthesis of 3-6 EtPPh in THF (50 mL) 3 To a mixture of Br (9.72 g, 26.2 mmol), t-BuOK (2.93 g, 26.2 mmol) was added 2 After stirring at 50°C for 30 min, 3-5 (5.6 g, 17.5 mmol) was added in portions at less than 40°C. After stirring at 40°C for 1 h, the mixture was diluted with 10% NH 4 The reaction mixture was quenched with aqueous Cl (200 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (300 mL). The combined organic phase was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EtOAc=20 / 1 to 5 / 1) to give 3-6 (4.9 g, 84.7%). 1 H NMR (400 MHz, CDCl 3 ) δ H 5.15-5.05 (m, 1 H), 2.41-2.09 (m, 3 H), 2.03-1.89 (m, 1 H), 1.85-1.71 (m, 1 H), 1.70-1.59 (m, 6 H), 1.59-1.37 (m, 9 H), 1.37-1.27 (m, 3 H), 1.25 (s, 3 H), 1.22-1.04 (m, 5 H), 0.85 (s, 3 H), 0.79 (t, J=7.6 Hz, 3 H).

[0395] Synthesis of 3-7 To a solution of 3-6 (4.9 g, 14.8 mmol) in THF (50 mL) was added 9-BBN dimer (10.8 g, 44.4 mmol) at 15 °C. After stirring at 40 °C for 1 h, the mixture was added with ethanol (6.8 g, 148 mmol), followed by aqueous NaOH (29.5 mL, 5 M, 148 mmol), and then H 2 O 2 (14.7 mL, 10 M, 148 mmol) was added dropwise at -10 °C. After stirring at 80 °C for 1 h, the reaction mixture was added with saturated Na 2 S 2 O 3 (50 mL) was added. After stirring for 30 min, the mixture was extracted with EtOAc (2×100 mL). The combined organic phase was washed with saturated brine (2×100 mL) and anhydrous Na 2 SO 4 The mixture was dried over rt and concentrated in vacuo to give 3-7 (11 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.77-3.62 (m, 1 H), 2.03-1.91 (m, 3 H), 1.83-1.71 (m, 5 H), 1.57-1.45 (m, 12 H), 1.24 (s, 3 H), 1.21 (d, J=6.40 Hz, 3 H), 1.18-0.94 (m, 7 H), 0.81-0.76 (m, 3 H), 0.64 (s, 3 H).

[0396] Synthesis of 3-8 To a solution of 3-7 (5.15 g, 14.8 mmol) in DCM (100 mL) was added silica gel (10 g) and PCC (6.36 g, 29.6 mmol) at 0° C. After stirring at 15° C. for 3 h, the suspension was filtered and the filter cake was washed with DCM (2×100 mL). The combined filtrate was concentrated under vacuum to give a residue, which was purified by flash column (PE / EtOAc=20 / 1 to 4 / 1) to give 3-8 (2.8 g, 54.6%). 1 H NMR (400 MHz, CDCl 3 ) δ H2.60-2.45 (m, 1 H) 2.28-2.12 (m, 1 H), 2.11 (s, 3 H), 2.03-1.91 (m, 2 H), 1.82-1.59 (m, 6 H), 1.54-1.28 (m, 10 H), 1.25 (s, 3 H), 1.24-1.03 (m, 6 H), 0.79 (t, J=7.60 Hz, 3 H), 0.59 (s, 3 H).

[0397] Synthesis of 3-9 MePPh in THF (20 mL) 3 To a mixture of Br (4.5 g, 12.6 mmol), t-BuOK (1.41 g, 12.6 mmol) was added 2 After stirring at 50°C for 30 min, 3-8 (2.2 g, 6.34 mmol) was added in small portions at less than 50°C. After stirring at 50°C for 1 h, the mixture was diluted with 10% NH 4 The reaction mixture was quenched with aqueous Cl (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (100 mL). The combined organic phase was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EtOAc=20 / 1 to 5 / 1) to give 3-9 (1.6 g, 73.3%). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.84 (s, 1 H), 4.69 (s, 1 H), 2.04-1.90 (m, 2 H), 1.87-1.76 (m, 2 H), 1.75 (s, 3 H), 1.73-1.57 (m, 5 H), 1.53-1.26 (m, 9 H), 1.25 (s, 3 H), 1.23-0.82 (m, 8 H), 0.79 (t, J=7.60 Hz, 3 H), 0.54 (s, 3 H).

[0398] Synthesis of 3-10 3-9 (600 mg, 1.74 mmol) and NaHCO 3To a solution of mCPBA (146 mg, 1.74 mmol) in DCM (30 mL) was added mCPBA (352 mg, 1.74 mmol) at 20 °C. After stirring for 2 h at 20 °C, the mixture was cooled to room temperature and cooled to room temperature. 3 The mixture was quenched with aqueous solution (50 mL). The DCM phase was separated and washed with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 2×100 mL), brine (100 mL), and Na 2 SO 4 The mixture was dried over rt, filtered and concentrated in vacuo to give 3-10 (600 mg). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.88-2.30 (m, 2H), 2.08-1.60 (m, 9 H), 1.54-1.37 (m, 8 H), 1.36-1.32 (m, 3 H), 1.31-1.27 (m, 1 H), 1.25 (s, 3 H), 1.23-0.97 (m, 8 H), 0.83-0.74 (m, 4 H), 0.66 (s, 2 H).

[0399] Synthesis of 3 and 4 A solution of 3-10 (600 mg, 1.66 mmol) in DMF (20 mL) was added to Cs 2 CO 3 (1.08 g, 3.32 mmol) and 1H-pyrazole-4-carbonitrile (230 mg, 2.48 mmol) were added. After stirring at 120° C. for 16 h, the mixture was diluted with saturated NH 4 Cl (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with LiCl (100 mL, 5% aq.), saturated brine (2×100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give a mixture of 3 and 4 (800 mg).

[0400] SFC (Column: DAICEL CHIRALPAK AS (250mm*30mm, 10um), Adjustment solvent: 0.1%NH 3 H2 The epimers (500 mg, 1.1 mmol) were separated by O EtOH, start B: 30%, end B: 30%, flow rate (ml / min): 80) to give 3 (200 mg, 40%) and 4 (150 mg, 30%).

[0401] 3: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1 H), 7.82 (s, 1 H), 4.34 (d, J=13.60 Hz, 1 H), 4.07 (d, J=13.60 Hz, 1 H), 2.52 (s, 1 H), 2.08-1.88 (m, 2 H), 1.83-1.59 (m, 6 H), 1.55-1.45 (m, 3 H), 1.44-1.27 (m, 8 H), 1.25 (s, 3 H), 1.23-1.02 (m, 7 H), 0.97 (s, 3 H), 0.89 (s, 3 H), 0.79 (t, J=7.60 Hz, 3 H).LC-ELSD / MS: >99% purity; Analysis SFC: 100% de; MSESIC 28 H 40 N 3 [M-2H 2 O+H] + Calculated value: 418.3, measured value: 418.3.

[0402] 4: 1 H NMR (400 MHz, CDCl 3 ) δ H7.89 (s, 1 H), 7.80 (s, 1 H), 4.15 (d, J=14.0 Hz, 1 H), 4.00 (d, J=14.0 Hz, 1 H), 2.31 (s, 1 H), 2.10-1.84 (m, 3 H), 1.83-1.60 (m, 5 H), 1.55-1.47 (m, 3 H), 1.46-1.26 (m, 8 H), 1.25 (s, 3 H), 1.24-1.09 (m, 7 H), 1.08 (s, 3 H), 0.85 (s, 3 H), 0.79 (t, J=7.60 Hz, 3 H).LC-ELSD / MS: >99% purity; Analysis SFC: 99.18% de; MSESIC 28 H 40 N 3 [M-2H 2 O+H] + Calculated value: 418.3, measured value: 418.3.

[0403] Example 5: Synthesis of 1-((S)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile [ka] To a solution of 3 (200 mg, 0.4408 mmol) in THF (5 mL) was added NaH (52.6 mg, 1.32 mmol, 60% in oil) at 0° C. After stirring for 20 min, MeI (93.8 mg, 0.6612 mmol) was added. After stirring at 25° C. for 16 h, the reaction mixture was diluted with H 2 The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-50% EtOAc in PE) to give product 5 (68.8 mg, 33.3%). 1 H NMR (400 MHz, CDCl3 ) δ H 7.91 (s, 1 H), 7.75 (s, 1 H), 4.30-4.15 (m, 2 H), 3.18 (s, 3 H), 2.00-1.88 (m, 2 H), 1.81-1.71 (m, 2 H), 1.66-1.60 (m, 3 H), 1.54-1.47 (m, 3 H), 1.47-1.26 (m, 8 H), 1.24 (s, 3 H), 1.23-1.07 (m, 7 H), 1.06 (s, 3 H), 1.05-1.00 (m, 1 H), 0.86-0.75 (m, 6 H).LC-ELSD / MS: >99% purity; Analysis SFC: 100% de; MSESIC 28 H 43 N 3 [M-2H 2 O-CH 3 +2H] + Calculated value: 418.3, measured value: 418.3.

[0404] Example 6: Synthesis of 1-((R)-2-((3R,5R,8S,9S,10S,13S,14S,17S)-10-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile [ka] To a solution of 4 (150 mg, 0.3306 mmol) in THF (5 mL) was added NaH (39.6 mg, 0.9918 mmol, 60% in oil) at 0 °C. After stirring for 20 min, MeI (70.3 mg, 0.4959 mmol) was added. After stirring at 25 °C for 16 h, the reaction mixture was diluted with H 2 The mixture was diluted with 2×O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-50% EtOAc in PE) to give product 6 (23.4 mg). 1H NMR (400 MHz, CDCl 3 ) δ H 7.90 (s, 1 H), 7.75 (s, 1 H), 4.23 (s, 2 H), 3.14 (s, 3 H), 2.12-1.91(m, 2 H), 1.80-1.61 (m, 7 H), 1.53-1.27 (m, 10 H), 1.25 (s, 3 MSESI C 28 H 43 N 3 [M-2H 2 O-CH 3 +2H] + Calculated value: 418.3, measured value: 418.3.

[0405] Examples 7 and 8: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (7) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (8) [ka] Synthesis of 7-1 A solution of 2,6-di-tert-butyl-4-methylphenol (13.1 g, 59.6 mmol) in toluene (20 mL) was added to the 3 (14.9 mL, 29.8 mmol, 2 M toluene solution) was added dropwise at 0° C. After stirring at 25° C. for 30 min, a solution of 7-0 (3 g, 9.91 mmol) in anhydrous toluene (40 mL) was added dropwise at −70° C. 2After stirring at −70° C. for 1 h under reduced pressure, n-PrMgCl (14.8 mL, 29.7 mmol, 2 M in diethyl ether) was added dropwise at −70° C. After stirring at −70° C. for an additional 2 h, the reaction mixture was poured into saturated aqueous citric acid (100 mL) at less than 10° C. and extracted with EtOAc (2×100 mL). The combined organic layers were washed with Na 2 SO 4 The residue was purified by flash column (0-10% EtOAc in PE) to give 7-1 (1.7 g, 49%). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.53 (t, J = 8 Hz, 1H), 2.16-2.11 (m, 4H), 2.04-1.98 (m, 1H), 1.83-1.52 (m, 3H), 1.50-1.30 (m, 5H), 1.27-1.02 (m, 10H), 0.97-0.77 (m, 11H), 0.61 (s, 3H).

[0406] Synthesis of 7-2 Ph 3 To a suspension of PMeBr (3.50 g, 9.80 mmol) in THF (20 mL) was added t-BuOK (1.09 g, 9.80 mmol). 2 After stirring at 16 °C for 30 min under reduced pressure, 7-1 (1.7 g, 4.90 mmol) was added. After stirring at 35 °C for 16 h, the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (150 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by flash column (0-5% EtOAc in PE) to give 7-2 (1.3 g). 1 H NMR (400 MHz, CDCl 3 ) δ H4.84 (s, 1H), 4.70 (s, 1H), 2.06-2.01 (m, 1H), 1.85-1.58 (m, 9H), 1.56-1.25 (m, 12H), 1.19-0.96 (m, 7H), 0.95-0.91 (m, 3H), 0.9-0.83 (m, 3H), 0.57 (s, 3H).

[0407] Synthesis of 7-3 To a solution of 7-2 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA (1.17 g, 85%, 5.80 mmol) at 15 °C. After stirring at 15 °C for 1 h, the mixture was dissolved in saturated NaHCO 3 The mixture was quenched with aqueous solution (200 mL). The organic phase was separated and washed with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 3×100 mL), brine (100 mL), and Na 2 SO 4 The mixture was dried over rt, filtered and concentrated in vacuo to give 7-3 (1 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.89 (d, J = 4 Hz, 0.7H), 2.56-2.49 (m, 1H), 2.32 (d, J = 4 Hz, 0.3H), 2.04-1.51 (m, 10H), 1.48-1.23 (m, 15H), 1.21-0.99 (m, 6H), 0.95-0.91 (m, 3H), 0.81-0.76 (m, 1H), 0.68 (s, 3H).

[0408] Synthesis of 7 and 8 A solution of 7-3 (680 mg, 1.88 mmol) in DMF (10 mL) was added with 1H-pyrazole-4-carbonitrile (349 mg, 3.76 mmol) and Cs 2 CO 3(3.06g, 9.40mmol) was added. After stirring at 125°C for 12h, the reaction mixture was diluted with water (100mL) and extracted with EtOAc (2x100mL). The combined organic layers were separated, concentrated and purified by flash column (0-20% EtOAc in PE) to give a mixture of epimers. SFC (Column: DAICEL CHIRALPAK AS (250mm*50mm, 10um); Conditioning solvent: 0.1%NH 3 .H 2 The epimers were separated by elution with O EtOH; start B: 30; end B: 30; flow rate (mL / min): 200) to give 7 (250 mg) and 8 (104 mg).

[0409] 7: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.93 (s, 1H), 7.81 (s, 1H), 4.36-4.33 (m, 1H), 4.09-4.06 (m, 1H), 2.52 (s, 1H), 2.02-1.99 (m, 1H), 1.80-1.60 (m, 8H), 1.56-1.41 (m, 5H), 1.40-1.03 (m, 15H), 0.97-0.91 (m, 9H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N 3 [M-2H 2 O+H] + Calculated value 418.3, measured value 418.3. SFC 99.9% de

[0410] 8: 1 H NMR (400 MHz, CDCl 3 ) δ H7.89 (s, 1H), 7.80 (s, 1H), 4.17-4.14 (m, 1H), 4.03-3.99 (m, 1H), 2.31 (s, 1H), 2.08-2.03 (m, 1H), 1.95-1.50 (m, 10H), 1.47-1.18 (m, 13H), 1.16-1.00 (m, 8H), 0.95-0.87 (m, 6H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N 3 [M-2H 2 O+H] + Calculated value 418.3, measured value 418.3. SFC 98.22% de

[0411] Examples 9 and 10: Synthesis of 1-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (9) and 1-((R)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (10) [ka] Synthesis of 9-1 To a solution of 9-0 (15 g, 54.6 mmol) in THF (200 mL) was added n-PrMgCl (81.5 mL, 163 mmol, 2 M THF solution) dropwise at -60 °C. After stirring at -60 °C for 2 h, the reaction mixture was diluted with saturated NH 4 Cl (100 mL) and extracted with EtOAc (2×200 mL). 2 SO 4 The residue was triturated from MeCN (50 mL) at 80° C. to give 9-1 (7 g, 40.4%). 1H NMR (400 MHz, CDCl 3 ) δ H 2.44 (dd, J = 8.4, 19.2 Hz, 1H), 2.14-2.00 (m, 1H), 1.99-1.84 (m, 2H), 1.83-1.71 (m, 3H), 1.70-1.44 (m, 5H), 1.43-1.12 (m, 10H), 1.11-0.99 (m, 4H), 0.97-0.90 (m, 3H), 0.88 (s, 3H), 0.81-0.66 (m, 2H).

[0412] Synthesis of 9-2 EtPPh in THF (80 mL) 3 To a mixture of Br (24.3 g, 65.6 mmol), t-BuOK (7.36 g, 65.6 mmol) was added 2 After stirring at 15° C. for 30 min, 9-1 (7 g, 21.9 mmol) in THF (20 mL) was added. After stirring at 40° C. for 1 h, the mixture was diluted with NH 4 Cl (50 mL) and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (100 mL) and anhydrous Na 2 SO 4 The residue was heated in MeOH (50 mL) at 70° C. for 30 min, cooled to room temperature, poured into water (50 mL), and the resulting residue was filtered to give 9-2 (11 g).

[0413] 1 H NMR (400 MHz, CDCl 3 ) δ H 5.24-4.98 (m, 1H), 2.45-2.30 (m, 1H), 2.28-2.11 (m, 2H), 1.88-1.74 (m, 2H), 1.73-1.57 (m, 7H), 1.55-1.48 (m, 2H), 1.44-1.25 (m, 6H), 1.24-0.96 (m, 9H), 0.95-0.90 (m, 3H), 0.88 (s, 3H), 0.78-0.62 (m, 2H).

[0414] Synthesis of 9-3 To a solution of 9-2 (6 g, 18.1 mmol) in anhydrous THF (60 mL), 9-BBN dimer (13.2 g, 54.3 mmol) was added. 2 After stirring at 60° C. for 2 h, the mixture was cooled and quenched with EtOH (15 mL). NaOH (15 mL, 5 M, 75.5 mmol) was added very slowly. After the addition, H 2 O 2 (22.6 mL, 226 mmol, 10 M) was added slowly below 30° C. After stirring at 60° C. for 2 h, the mixture was cooled, poured into water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried over 1000 ml, filtered and concentrated in vacuo, and the residue was purified by column chromatography (20-25% EtOAc in PE) to give 9-3 (6.1 g, 52.8%). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.86-3.57 (m, 1H), 1.98-1.81 (m, 2H), 1.81-1.70 (m, 2H), 1.70-1.60 (m, 3H), 1.57-1.48 (m, 3H), 1.42-1.25 (m, 7H), 1.23 (d, J = 6.0 Hz, 3H), 1.17-0.96 (m, 9H), 0.95-0.89 (m, 3H), 0.67 (s, 5H).

[0415] Synthesis of 9-4 To a solution of 9-3 (6.1 g, 17.5 mmol) in DCM (50 mL) was added PCC (11.2 g, 52.5 mmol) and silica gel (15 g) at 25 °C. After stirring at 25 °C for 1 h, the reaction mixture was filtered and the residue was washed with anhydrous DCM (2 × 20 mL). The combined filtrate was concentrated in vacuum and then purified by column (15-20% EtOAc in PE) to give 9-4 (3 g, 49.5%). 1 H NMR (400 MHz, CDCl 3 ) δ H2.55 (t, J = 8.8 Hz, 1H), 2.12 (s, 4H), 2.00 (td, J = 3.2, 12.0 Hz, 1H), 1.89-1.73 (m, 2H), 1.59 (br d, J = 2.8 Hz, 1H), 1.55-1.50 (m, 1H), 1.49-1.16 (m, 10H), 1.15-0.97 (m, 6H), 0.96-0.90 (m, 3H), 0.81-0.65 (m, 2H), 0.62 (s, 3H).

[0416] Synthesis of 9-5 MePPh in THF (40 mL) 3 To a mixture of Br (9.25 g, 25.9 mmol), t-BuOK (2.9 g, 25.9 mmol) was added 2 After stirring at 15° C. for 30 min, 9-4 (3 g, 8.65 mmol) in THF (10 mL) was added. After stirring at 40° C. for 2 h, the mixture was diluted with NH 4 Cl (150 mL) and the aqueous phase was extracted with EtOAc (2×200 mL). The combined organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The residue was heated in MeOH (500 mL) at 70° C. for 30 min, cooled to room temperature, added water (300 mL), filtered and dried to give 9-5 (3 g, 100%). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.85 (s, 1H), 4.71 (s, 1H), 2.11-1.98 (m, 1H), 1.76 (s, 7H), 1.71-1.64 (m, 3H), 1.64-1.53 ​​(m, 3H), 1.39 (d, J = 3.6 Hz, 4H), 1.14 (br s, 12H), 0.95-0.88 (m, 3H), 0.77-0.62 (m, 2H), 0.58 (s, 3H).

[0417] Synthesis of 9-6 To a solution of 9-5 (1 g, 2.90 mmol) in DCM (10 mL) was added m-CPBA (750 mg, 4.35 mmol) at 20 °C. After stirring at 20 °C for 2 h, the mixture was diluted with saturated NaHCO 3 aqueous solution (20 mL) and extracted with EtOAc (2×50 mL). The combined organic solutions were diluted with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 2×20 mL), brine (20 mL), and Na 2 SO 4 The mixture was dried over rt, filtered and concentrated to give 9-6 (1.5 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.89 (d, J = 4.4 Hz, 1H), 2.58-2.54 (m, 1H), 2.04-1.86 (m, 2H), 1.81-1.72 (m, 3H), 1.66-1.50 (m, 8H), 1.39-1.37 (m, 6H), 1.35 (s, 3H), 1.31-1.16 (m, 5H), 1.15-1.05 (m, 7H), 1.04-0.94 (m, 5H), 0.93-0.89 (m, 5H), 0.68 (s, 3H).

[0418] Synthesis of 9 and 10 A solution of 9-6 (750 mg, 2.07 mmol) in DMF (10 mL) was added with 1H-pyrazole-4-carbonitrile (481 mg, 5.17 mmol) and Cs 2 CO 3 (3.35 g, 10.3 mmol) was added. After stirring at 130° C. for 16 h, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give a mixture of epimers (600 mg, 63.8%), which was purified by SFC (column: DAICEL CHIRALPAK AS 250 mm × 30 mm, 10 um; conditioning solvent: 0.1% NH3 H 2 This was separated using 30 mL of ethyl acetate (OEtOH; gradient: 25% to 25% B; flow rate: 70 mL / min; column temperature: 40 °C) to give 9 (230 mg) and 10 (86.9 mg). 9 (230 mg) was triturated from MeCN (5 mL) at 20 °C to give 9 (193.3 mg).

[0419] 9: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.81 (s, 1H), 4.36 (d, J = 14.0 Hz, 1H), 4.08 (d, J = 14.0 Hz, 1H), 2.49 (s, 1H), 2.04-1.96 (m, 1H), 1.78-1.57 (m, 8H), 1.54-1.49 (m, 1H), 1.45-1.41 (m, 1H), 1.38 (br d, J = 3.2 Hz, 4H), 1.34-1.12 (m, 5H), 1.12-1.02 (m, 5H), 1.01-0.94 (m, 5H), 0.92 (s, 6H), 0.71-0.62 (m, 2H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N 3 [M-2H 2 Calculated value for O+H]+ 418.3 Found value 418.3. SFC 99%de.

[0420] 10: 1 H NMR (400 MHz, CDCl 3 ) δ H7.89 (s, 1H), 7.80 (s, 1H), 4.19-4.12 (m, 1H), 4.04-3.98 (m, 1H), 2.27 (s, 1H), 2.07-2.01 (m, 1H), 1.91 (q, J = 10.4 Hz, 1H), 1.75 (br d, J = 13.2 Hz, 2H), 1.70-1.57 (m, 5H), 1.52-1.45 (m, 2H), 1.38 (br d, J = 3.2 Hz, 4H), 1.35-1.12 (m, 6H), 1.11-1.08 (m, 5H), 1.05-0.90 (m, 7H), 0.88 (s, 3H), 0.72-0.63 (m, 2H).LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N 3 [M-2H 2 Calculated value for O+H]+ 418.3 Found value 418.3. SFC 99%de.

[0421] Examples 11 and 12: Synthesis of 1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (11) and 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (12) [ka] Synthesis of 11-1 Trimethylaluminum (2M in toluene, 14 mL, 28 mmol) was added dropwise to a solution of BHT (12 g, 54.4 mmol) in toluene (120 mL) at 0° C. under nitrogen. After stirring at 25° C. for 1 h, a solution of 7-0 (6 g, 19.8 mmol) in DCM (60 mL) was added dropwise to the MAD solution at −70° C. 2After stirring at −70° C. for 1 h, EtMgBr (20 mL, 60 mmol, 3 M in ethyl ether) was added dropwise at −70° C. After stirring at −70° C. for 1 h, the reaction mixture was poured into saturated aqueous citric acid (600 mL) at less than 10° C. and extracted with DCM (2×800 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was triturated with PE to give 11-1 (3.83 g, 58%). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.56-2.50 (m, 1H), 2.24-2.10 (m, 4H), 2.07-1.99 (m, 1H), 1.89-1.51 (m, 9H), 1.50-1.20 (m, 12H), 1.19-1.00 (m, 3H), 0.98-0.80 (m, 3H), 0.61 (s, 3H).

[0422] Synthesis of 11-2 MePh 3 To a suspension of PBr (6.4 g, 18.0 mmol) in THF (50 mL) was added t-BuOK (2.01 g, 18.0 mmol). After stirring at 40 °C for 10 min, the mixture was slowly added dropwise to a solution of 11-1 (3 g, 9.02 mmol) in THF (30 mL). After stirring at 20 °C for 18 h, the mixture was diluted with saturated NH 4 The mixture was quenched with Cl (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phase was washed with saturated NH 4 Cl (100 mL) and washed with Na 2 SO 4 The residue was purified by Combiflash (0-25% EtOAc in PE) to give 11-2 (2.445 g, 82%). 1 H NMR (400 MHz, CDCl 3 ) δ H4.84 (s, 1H), 4.69 (s, 1H), 2.02-1.53 ​​(m, 13H), 1.50-1.33 (m, 4H), 1.32-1.11 (m, 11H), 1.10-0.99 (m, 2H), 0.85-0.80 (m, 3H), 0.56 (s, 3H).

[0423] Synthesis of 11-3 To a solution of 11-2 (1.8 g, 5.44 mmol) in DCM (20 mL) was added m-CPBA (2.18 g, 85%, 10.8 mmol). After stirring at 15 °C for 1 h, the mixture was diluted with NaHCO 3 (50mL, saturated aqueous solution) and Na 2 S 2 O 3 (20 mL, saturated aqueous solution). The organic layer was separated and 2 SO 4 The mixture was dried at rt, filtered and concentrated in vacuo to give 11-3 (1.7 g), which was used as is.

[0424] Synthesis of 11 and 12 A solution of 11-3 (850 mg, 2.45 mmol) in DMF (10 mL) was added with 1H-pyrazole-4-carbonitrile (341 mg, 3.67 mmol) and Cs 2 CO 3 (3.97g, 12.2mmol) was added at 20°C. After stirring at 120°C for 2 h, the reaction mixture was diluted with water (100mL) and extracted with EtOAc (2x50mL). The combined organic layers were separated, concentrated and purified by flash column (30-65% EtOAc in PE) to give a mixture of epimers. SFC (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um), conditioning solvent: 0.1%NH 3 H 2 The epimers were separated using O EtOH, start B: 25%, end B: 25%, gradient time (min), hold time 100% B (min), flow rate (ml / min) 70) to give 11 (395.8 mg, 49.6%) and 12 (155.4 mg, 19.4%).

[0425] 11: 11H NMR (400 MHz, CDCl 3 ) δ H 7.93 (s, 1H), 7.82 (s, 1H), 4.45 - 3.99 (m, 2H), 2.50 (br s, 1H), 2.08 - 1.94 (m, 1H), 1.84 - 1.57 (m, 10H), 1.47 - 1.02 (m, 16H), 0.97 (s, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.5 Hz, 3H). LC-ELSD / MS purity 99%, MS ESI C 27 H 38 N 3 [M - 2H 2 O + H] + Calculated value for [M - 2H + H] is 404.3, measured value is 404.3. SFC 100% de

[0426] 12: 1 1H NMR (400 MHz, CDCl 3 ) δ H 7.90 (br s, 1H), 7.81 (s, 1H), 4.24 - 3.90 (m, 2H), 2.29 (br s, 1H), 2.06 (br d, J = 12.3 Hz, 1H), 1.96 - 1.86 (m, 1H), 1.84 - 1.56 (m, 9H), 1.53 - 1.19 (m, 12H), 1.19 - 1.09 (m, 7H), 0.92 - 0.85 (m, 6H). LC-ELSD / MS purity 99%, MS ESI C 27 H 38 N 3 [M - 2H 2 O + H] + Calculated value for [M - 2H + H] is 404.3, measured value is 404.3. SFC 99% de.

[0427] Examples 13 and 14: Synthesis of 1-((S)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (13) and 1-((R)-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (14) [ka] Synthesis of 13-1 Lithium (7.27 g, 915 mmol) was added portionwise to freshly prepared liquid ammonia (500 mL) at -70 °C. After stirring for 1 h at -70 °C, a solution of 13-0 (50 g, 183 mmol) in dry THF (500 mL) and t-butanol (27 g, 366 mmol) was added. After stirring for 1 h at -70 °C, ammonium chloride (500 g) was added and allowed to warm to room temperature. After stirring for 16 h, the reaction mixture was diluted with H 2 The combined organic solutions were diluted with HCl (1M, 2×500 mL), saturated NaHCO 3 Wash with aqueous solution (500 mL), brine (1 L), and add Na 2 SO 4 The mixture was dried over rt and concentrated in vacuo to give 13-1 (97 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.75-3.55 (m, 1H), 2.50-2.00 (m, 10H), 2.00-1.25 (m, 8H), 1.25-0.60 (m, 9H).

[0428] Synthesis of 13-2 To a solution of 13-1 (100 g, 361 mmol) in DCM (1000 mL) at 0° C., silica gel (116 g) and PCC (116 g, 541 mmol) were added. After stirring at 25° C. for 2 h, the reaction mixture was diluted with PE (1000 mL) and filtered through a pad of silica gel. The filter cake was washed with DCM (2000 mL). The combined filtrates were concentrated to give 13-2 (90 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.55-2.02 (m, 8H), 2.02-1.39 (m, 8H), 1.39-0.69 (m, 10H).

[0429] Synthesis of 13-3 To a solution of 13-2 (51.5 g, 187 mmol) in MeOH (600 mL) was added 4-methylbenzenesulfonic acid (6.44 g, 37.4 mmol) at 25 °C. After stirring at 55 °C for 16 h, Et 3 N (20 mL) was added and the mixture was filtered to give 13-3 (57 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.49 (d, J = 5.6 Hz, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.48-2.38 (m, 1H), 2.12-2.01 (m, 2H), 1.96-1.90 (m, 2H), 1.88-1.74 (m, 4H), 1.68-1.62 (m, 1H), 1.56-1.44 (m, 1H), 1.35-1.20 (m, 5H), 1.13-0.95 (m, 5H), 0.87 (s, 1H), 0.80-0.68 (m, 2H).

[0430] Synthesis of 13-4 EtPPh in THF (250 mL) 3 To a mixture of Br (98.7 g, 266 mmol), t-BuOK (29.8 g, 266 mmol) was added 2After stirring at 15° C. for 30 min, 13-3 (28.5 g, 88.9 mmol) in THF (50 mL) was added. After stirring at 40° C. for 2 h, the mixture was diluted with NH 4 Cl (150 mL) and extracted with EtOAc (2×200 mL). The combined organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The residue was heated in MeOH (500 mL) at 70° C. for 30 min, cooled to room temperature, diluted with water (300 mL), filtered and concentrated to give 13-4 (25.5 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 5.15-5.07 (m, 1H), 3.20 (s, 3H), 3.14 (s, 3H), 2.41-2.31 (m, 1H), 2.27-2.12 (m, 2H), 2.10-2.02 (m, 1H), 1.91 (td, J = 3.2, 13.2 Hz, 1H), 1.85-1.76 (m, , 2H), 1.71-1.58 (m, 6H), 1.57-1.48 (m, 3H), 1.30-1.13 (,m, 6H), 1.11-0.93 (m, 5H), 0.87 (s, 3H), 0.75-0.67 (m, 2H).

[0431] Synthesis of 13-5 To a solution of 13-4 (51 g, 153 mmol) in THF (500 mL) was added 1 M HCl (153 mL, 153 mmol). After stirring at 15 °C for 2 h, the mixture was diluted with NaHCO 3 The combined organic phase was washed with brine (200 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 13-5 (42 g, 95.8%). 1 H NMR (400 MHz, CDCl 3 ) δ H5.16-5.08 (m, 1H), 2.42-2.17 (m, 7H), 2.09 (t, J = 13.2 Hz, 1H), 1.88-1.79 (m, 2H), 1.76-1.63 (m, 6H), 1.59 (s, 1H), 1.56-1.40 (m, 2H), 1.28-1.16 (m, 8H), 1.04-0.94 (m, 1H), 0.90 (s, 1H), 0.78-0.69 (m, 1H).

[0432] Synthesis of 13-6 Me 3 To a stirred solution of SIO (47.9 g, 218 mmol) in DMSO (300 mL) and THF (300 mL) was added NaH (5.23 g, 218 mmol) at 0° C. 2 After stirring for 1 h under reduced pressure, 13-5 (42 g, 146 mmol) in THF (200 mL) was added. After stirring for 3 h at 25° C., the reaction mixture was poured into water (1000 mL). After stirring for 3 h at 25° C., the mixture was filtered to give 13-6 (48 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 5.15-5.07 (m, 1H), 2.64-2.61 (m, 5H), 2.41-2.30 (m, 1H), 2.27-2.11 (m, 2H), 2.00-1.92 (m, 1H), 1.91-1.80 (m, 2H), 1.67-1.60 (m, 5H), 1.56-1.50 (m, 1H), 1.45-1.35 (m, 1H), 1.30-1.10 (m, 8H), 1.07-0.95 (m, 2H), 0.89 (s, 3H), 0.84-0.72 (m, 2H).

[0433] Synthesis of 13-7 To a suspension of CuCN (3.92 g, 43.8 mmol) in THF (40 mL) at -70 °C was added MeLi (54.7 mL, 87.6 mmol, 1.6 M). After stirring at -70 °C for 1 h, 13-6 (4.4 g, 14.6 mmol) in THF (10 mL) was added at -70 °C. After slowly warming to room temperature and stirring for 2 h, the reaction was diluted with 10% NH 4 Cl (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 Hz, filtered, and concentrated to give 13-7 (4.4 g). 1H NMR (400 MHz, CDCl 3 ) δ H 5.14-5.08 (m, 1H), 2.39-2.10 (m, 3H), 1.85-1.39 (m, 10H), 1.39-0.94 (m, 13H), 0.94-0.60 (m, 9H).

[0434] Synthesis of 13-8 To a solution of 13-7 (4.4 g, 13.3 mmol) in anhydrous THF (50 mL), 9-BBN dimer (8.03 g, 33.2 mmol) was added 2 After stirring at 60° C. for 16 h, the mixture was cooled and diluted with EtOH (20 mL) at 0° C. NaOH (2.66 g, 13.3 mL, 5 M, 66.5 mmol) was added very slowly, followed by H 2 O 2 (13.3 mL, 133 mmol, 10 M aqueous solution) was added very slowly until the internal temperature no longer rose. The internal temperature was maintained below 30° C. After stirring at 60° C. for 2 h, the mixture was cooled and Na 2 S 2 O 3 (100 mL, saturated aqueous solution) and extracted with EtOAc (3×100 mL). The combined organic layers were 2 SO 4 The mixture was dried over 1000 Hz, filtered, and concentrated in vacuo. The residue was purified by column chromatography (5% to 30% EtOAc in PE) to give 13-8 (10 g). 1H NMR (400 MHz, CDCl 3 ) δH 3.74-3.66 (m, 1H), 1.96-1.39 (m, 13H), 1.39-1.00 (m, 14H), 1.00-0.85 (m, 5H), 0.75-0.57 (m, 5H).

[0435] Synthesis of 13-9 To a solution of 13-8 (1.3 g, 3.88 mmol) in DCM (20 mL) was added DMP (3.29 g, 7.76 mmol). After stirring at 25 °C for 1 h, the mixture was diluted with NaHCO 3 (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with Na 2 S 2 O 3 (3 × 30 mL, saturated), washed with brine (50 mL), and then with Na 2 SO 4 The residue was purified by column chromatography (5% to 30% EtOAc in PE) to give 13-9 (1.16 g, 90%). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.53 (t, J = 8.8 Hz, 1H), 2.21-1.53 ​​(m, 9 H), 1.53-1.10 (m, 10H), 1.10-0.63 (m, 13H), 0.61 (s, 3H).

[0436] Synthesis of 13-10 MePPh in THF (40 mL) 3 To a mixture of Br (2.48 g, 6.96 mmol), t-BuOK (779 mg, 6.96 mmol) was added 2 After stirring at 50° C. for 30 min, 13-9 (1.16 g, 3.48 mmol) in THF (10 mL) was added at 25° C. After stirring at 50° C. for 18 h, the reaction mixture was quenched with water (40 mL) at 25° C. and extracted with EtOAc (2×50 mL). The combined organic phase was washed with water (3×10 mL), brine (30 mL), and diluted with anhydrous Na 2 SO 4The mixture was dried at 400 rpm, filtered and concentrated in vacuum. The residue was purified by column (2% EtOAc in PE) to give 13-10 (620 mg, 54%). 1H NMR (400 MHz, CDCl3) δ H 4.84(s, 1H), 4.70(s, 1H), 2.08-1.57 (m, 10H), 1.57-1.06 (m, 13H), 1.06-0.52 (m, 13H).

[0437] Synthesis of 13-11 To a solution of 13-10 (620 mg, 1.87 mmol) in DCM (10 mL) was added m-CPBA (601 mg, 2.8 mmol, 80%) at 15 °C. After stirring at 15 °C for 1 h, the mixture was diluted with saturated NaHCO 3 and Na 2 S 2 O 3 (40 mL, v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phase was washed with saturated NaHCO 3 and Na 2 S 2 O 3 (50mL, v:v=1:1), and washed with Na 2 SO 4 The mixture was dried over rt, filtered and concentrated to give 13-11 (820 mg). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.89 (d, J = 4.8 Hz, 0.6H), 2.55-2.48 (m, 1H), 2.32 (d, J = 5.2 Hz, 0.4H), 2.02-1.45 (m, 10H), 1.45-1.11 (m, 11H), 1.11-0.74 (m, 10H), 0.74-0.58 (m, 5H).

[0438] Synthesis of 13 and 14 A solution of 13-11 (800 mg, 2.3 mmol) in DMF (10 mL) was added to Cs 2 CO 3(2.24 g, 6.89 mmol) and 1H-pyrazole-4-carbonitrile (535 mg, 5.75 mmol) were added. After stirring at 120° C. for 48 h, the reaction mixture was diluted with saturated NH 4 The mixture was added to 100 mL of LiCl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (100 mL, 5% aqueous solution), saturated brine (2×100 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40°C, filtered and concentrated. The residue was purified by column (0-10% EtOAc in PE) to give a mixture of epimers (800 mg). SFC (column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5um), conditioning solvent: 0.1% NH 3 H 2 The epimers were separated with O EtOH, start B: 25%, end B: 25%) to give 13 (264 mg) and 14 (122 mg).

[0439] 13:1H NMR (400 MHz, CDCl3) δ H 7.92 (s, 1H), 7.81 (s, 1H), 4.37-4.33 (m, 1H), 4.10-4.06 (m, 1H), 2.48 (s, 1H), 2.02-1.96 (m, 1H), 1.79-1.37 (m, 12H), 1.37-0.94 (m, 15H), 0.94-0.87 (m, 6H), 0.75-0.61 (m, 2H).LC-ELSD / MS purity 99%, MS ESI C 27 H 38 N 3 [M-2H 2 O+H] + Calculated value 404 Measured value 404.SFC 99.522% de.

[0440] 14:1H NMR (400 MHz, CDCl3) δ H7.88 (s, 1H), 7.79 (s, 1H), 4.17-4.13 (m, 1H), 4.02-3.99 (m, 1H), 2.27 (s, 1H), 2.07-1.53 ​​(m, 1H), 1.53-1.12 (m, 12H), 1.12-0.94 (m, 15H), 0.94-0.84 (m, 6H), 0.73-0.61 (m, 2H).LC-ELSD / MS purity 99%, MS ESI C 27 H 38 N 3 [M-2H 2 O+H] + Calculated value 404 Actual value 404. SFC 100% de.

[0441] Examples 15 and 16: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(hydroxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (15) and 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (16) [ka] Synthesis of 15-1 MePPh 3 To a solution of Br (2.94 g, 8.25 mmol) in THF (20 mL), t-BuOK (925 mg, 8.25 mmol) was added with N 2 After stirring for 1 h, 15-0 (1 g, 2.75 mmol, WO2018013613) in THF (10 mL) was added. After stirring for 3 h at 40 °C, the reaction mixture was diluted with NH 4 Cl (50 mL) and extracted with EtOAc (2×80 mL). The combined organic phase was washed with saturated brine (50 mL) and anhydrous Na 2SO 4 The residue was purified by flash column (0-6% EtOAc in PE) to give 15-1 (750 mg, 76%). 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1H), 4.70 (s, 1H), 3.57-3.49 (m, 2H), 3.47-3.38 (m, 2H), 2.70 (s, 1H), 2.07-2.00 (m, 1H), 1.75 (s, 7H), 1.72-1.59 (m, 5H), 1.49-1.33 (m, 6H), 1.28-0.97 (m, 11H), 0.56 (s, 3H).

[0442] Synthesis of 15-2 To a solution of 15-1 (880 mg, 2.44 mmol) in DCM (20 mL) was added m-CPBA (990 mg, 85%, 4.88 mmol) at 15 °C. The reaction mixture was stirred at 15 °C for 1 h, and then saturated NaHCO 3 The reaction mixture was quenched with aqueous solution (200 mL). The organic phase was separated and washed with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 3×100 mL), brine (100 mL), and Na 2 SO 4 The mixture was dried over rt, filtered and concentrated in vacuo to give 15-2 (900 mg). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.54 (q, J = 8 Hz, 2H), 3.43 (q, J = 8 Hz, 2H), 2.88 (d, J = 4 Hz, 0.6H), 2.55 (d, J = 4 Hz, 0.7H), 2.49 (d, J = 4 Hz, 0.3H), 2.31 (d, J = 4 Hz, 0.4H), 2.03-1.57 (m, 10H), 1.48-1.32 (m, 9H), 1.28-0.93 (m, 12H), 0.79 (s, 1H), 0.67 (s, 2H).

[0443] Synthesis of 15 and 16 A solution of 15-2 (600 mg, 1.59 mmol) in DMF (5 mL) was added with 1H-pyrazole-4-carbonitrile (369 mg, 3.97 mmol) and Cs 2 CO 3 (2.59g, 7.95mmol) was added. After stirring at 125°C for 12h, the reaction mixture was diluted with water (100mL) and extracted with EtOAc (3x60mL). The combined organic layers were washed with LiCl (3x150mL, 5% aqueous solution) and then concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give a mixture of epimers (600mg). SFC (column: DAICEL CHIRALPAK AS (250mm*50mm, 10um); conditioning solvent: 0.1%NH 3 H 2 The epimers were separated by elution with O EtOH; start B: 60%; end B: 60%; flow rate (ml / min) 80) to give 15 (353.8 mg, 59%) and 16 (138.3 mg, 23%).

[0444] 15: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.37-4.34 (m, 1H), 4.10- 4.07 (m, 1H), 3.54 (q, J = 8 Hz, 2H), 3.41 (q, J = 8 Hz, 2H), 2.70 (s, 1H), 2.51 (s, 1H), 2.02-1.99 (m, 1H), 1.83-1.55 (m, 8H), 1.50-1.19 (m, 13H), 1.15-1.02 (m, 5H), 0.96-0.91 (m, 6H).LC-ELSD / MS Purity 99%, MS ESI C 28 H 42 N 3 O 2 [M+HH 2 O] + Calculated value 452, measured value 452. SFC 100% de.

[0445] 16:1 H NMR (400 MHz, CDCl 3 ) δ H 7.89 (s, 1H), 7.80 (s, 1H), 4.18-4.15 (m, 1H), 4.03- 3.99 (m, 1H), 3.54 (q, J = 8 Hz, 2H), 3.41 (q, J = 8 Hz, 2H), 2.71 (s, 1H), 2.33 (s, 1H), 2.07-2.04 (m, 1H), 1.95-1.56 (m, 9H), 1.50-1.19 (m, 13H), 1.16-1.00 (m, 8H), 0.87 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 28 H 42 N 3 O 2 [M+HH 2 O] + Calculated value 452, measured value 452. SFC 99.94% de.

[0446] Examples 17 and 18: Synthesis of 1-((S)-2-hydroxy-2-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (17) and 1-((R)-2-hydroxy-2-((3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (18) [ka] Synthesis of 17-1 Me 3To a stirred solution of SIO (3.12 g, 14.2 mmol) in DMSO (30 mL) and THF (30 mL) was added NaH (340 mg, 14.2 mmol) at 0 °C. After stirring for 1 h, the reaction mixture was added 17-0 (pregn-20-en-3-one, 20-methyl-, (5α)- as described in WO2018 / 75699) (3 g, 9.53 mmol) in DMSO (30 mL). After stirring for 3 h at 25 °C, the reaction mixture was poured into water (200 mL). After stirring for 3 h at 25 °C, the reaction mixture was filtered to give 17-1 (3.3 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.84 (s, 1H), 4.70 (s, 1H), 2.64-2.59 (m, 2H), 2.06-1.98 (m, 2H), 1.88-1.79 (m, 2H), 1.75 (s, 3H), 1.71-1.65 (m, 3H), 1.60-1.52 (m, 3H), 1.35-1.12 (m, 8H), 1.00-0.76 (m, 8H), 0.57 (s, 3H).

[0447] Synthesis of 17-2 To a solution of 17-1 (2.7 g, 8.21 mmol) in THF (20 mL) with CuI (234 mg, 1.23 mmol) at 0 °C was added EtMgBr (8.20 mL, 3 M, 24.6 mmol). After stirring at 0 °C for 1 h, the reaction was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (100 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by column chromatography (0-3% EtOAc in PE) to give 17-2 (1.8 g, 61%). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.83 (s, 1H), 4.69 (s, 1H), 2.01 (t, J = 9.2 Hz, 1H), 1.83-1.40 (m, 13H), 1.40-1.02 (m, 15H), 1.02-0.70 (m, 8H), 0.55 (s, 3H).

[0448] Synthesis of 17-3 To a solution of 17-2 (1.7 g, 4.74 mmol) in DCM (10 mL) was added m-CPBA (2.03 g, 9.48 mmol, 80%) at 15 °C. After stirring at 15 °C for 1 h, the mixture was diluted with saturated NaHCO 3 and Na 2 S 2 O 3 (40 mL, v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phase was washed with saturated NaHCO 3 and Na 2 S 2 O 3 (50mL, v:v=1:1), and washed with Na 2 SO 4 The mixture was dried over rt, filtered and concentrated to give 17-3 (2.35 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.88 (d, J = 4.4 Hz, 0.7H), 2.55-2.48 (m, 1H), 2.30 (d, J = 4.8 Hz, 0.3H), 2.04-1.55 (m, 10H), 1.55-1.37 (m, 10H), 1.37-1.23(m, 10H), 1.23-0.66 (m, 10H),

[0449] Synthesis of 17 and 18 A solution of 17-3 (600 mg, 1.6 mmol) in DMF (5 mL) was added to Cs 2 CO 3 (1.56 g, 4.8 mmol) and 1H-pyrazole-4-carbonitrile (372 mg, 4 mmol) were added. After stirring at 120° C. for 48 h, the reaction mixture was diluted with saturated NH 4 The mixture was added to 100 mL of LiCl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (100 mL, 5% aq.), brine (2×100 mL) and anhydrous Na 2 SO 4The mixture was dried at 40°C, filtered and concentrated. The residue was purified by column (5-20% EtOAc in PE) to give a mixture of epimers (750 mg). SFC (column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5um), conditioning solvent: 0.1% NH 3 H 2 The epimers were separated with O EtOH, start B: 30%, end B: 30%) to give 17 (272 mg) and 18 (123 mg).

[0450] 17: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.80 (s, 1H), 4.36-4.33 (m, 1H), 4.09-4.06 (m, 1H), 2.49 (s, 1H), 2.01-1.98 (m, 1H), 1.77-1.42 (m, 11H), 1.42-1.08 (m, 13H), 1.08-0.80 (m, 11H), 0.77-0.70 (m, 4H).LC-ELSD / MS purity 99%, MS ESI C 29 H 42 N 3 [M-2H 2 O+H] + Calculated value 432 Measured value 432.SFC 99.06% de.

[0451] 18: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.88 (s, 1H), 7.79 (s, 1H), 4.17-4.13 (m, 1H), 4.02-3.98 (m, 1H), 2.28 (s, 1H), 2.06-1.86 (m, 2H), 1.71-1.42 (m, 10H), 1.42-1.11 (m, 13H), 1.11-0.60 (m, 11H), 0.77-0.70 (m, 4H).LC-ELSD / MS purity 99%, MS ESI C 29 H 42 N 3 [M-2H 2 O+H]+ Calculated value 432 Measured value 432. SFC 100%de.

[0452] Examples 19 and 20: Synthesis of 1-((S)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (19) and 1-((R)-2-hydroxy-2-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (20) [ka] Synthesis of 19-1 MePPh in THF (15 mL) 3 A mixture of Br (4.28 g, 12.0 mmol) and t-BuOK (1.34 g, 12.0 mmol) was added to N 2 After stirring at 50°C for 30 min, 19-0 (1.4 g, 4.01 mmol) in THF (5 mL) was added. After stirring at 60°C for 3 h, the reaction mixture was cooled, poured into ice water, and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give 19-1 (1.1 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.94-4.61 (m, 2H), 3.45-3.32 (m, 3H), 3.25-3.12 (m, 2H), 2.11-1.97 (m, 2H), 1.87-1.53 ​​(m, 10H), 1.49-0.82 (m, 14H), 0.79-0.65 (m, 2H), 0.57 (s, 3H).

[0453] Synthesis of 19-2 To a solution of 19-1 (600 mg, 1.73 mmol) in DCM (20 mL) was added m-CPBA (556 mg, 2.59 mmol, 80%) at 15 °C. After stirring at 15 °C for 1 h, the reaction mixture was diluted with saturated NaHCO 3 and Na 2 S 2 O 3 (40 mL, v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phase was washed with saturated NaHCO 3 and Na 2 S 2 O 3 (50mL, v:v=1:1), and washed with Na 2 SO 4 The mixture was dried over rt, filtered and concentrated to give 19-2 (650 mg). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.38 (s, 3H), 3.24-3.14 (m, 2H), 2.88 (d, J = 4.4 Hz, 1H), 2.55 (d, J = 4.4 Hz, 1H), 2.49 (d, J = 4.8 Hz, 1H), 2.31 (d, J = 4.8 Hz, 1H), 2.09-1.52 (m, 10H), 1.47-0.87 (m, 14H), 0.80 (s, 1H), 0.74-0.64 (m, 4H).

[0454] Synthesis of 19 and 20 A solution of 19-2 (650 mg, 1.79 mmol) in DMF (10 mL) was added to Cs 2 CO 3 (1.75 g, 5.37 mmol) and 1H-pyrazole-4-carbonitrile (416 mg, 4.47 mmol) were added. After stirring at 130° C. for 12 h, the reaction mixture was diluted with saturated NH 4 The mixture was added to 100 mL of LiCl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (100 mL, 5% aq.), brine (2×100 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated. The residue was purified by column (0-50% EtOAc in PE) to give a mixture of epimers (750 mg). SFC (column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 um); conditioning solvent: 0.1% NH 3 H 2 The epimers were separated using O (EtOH) to give 20 (116.0 mg, 15.5%) and 19 (280.6 mg, 37.4%).

[0455] 19: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.81 (s, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 2.48 (s, 1H), 2.13-1.92 (m, 2H), 1.81-1.56 (m, 9H), 1.43 (br t, J = 9.6 Hz, 2H), 1.29-0.98 (m, 9H), 0.96 (s, 4H), 0.92 (s, 3H), 0.69 (br s, 2H).LC-ELSD / MS purity 99%, MS ESI C 26 H 35 N 3 [M-MeOH-2H 2 O+H] + Calculated value 388.2, measured value 388.2. SFC 96.66% de

[0456] 20: 1 H NMR (400 MHz, CDCl 3 ) δ H7.89 (s, 1H), 7.82-7.75 (m, 1H), 4.22-4.09 (m, 1H), 4.06-3.93 (m, 1H), 3.48-3.31 (m, 3H), 3.27-3.11 (m, 2H), 2.35-2.22 (m, 1H), 2.12-1.99 (m, 2H), 1.97-1.83 (m, 1H), 1.81-1.60 (m, 8H), 1.53-1.32 (m, 2H), 1.29-1.14 (m, 4H), 1.09 (s, 5H), 1.05-0.92 (m, 4H), 0.87 (s, 3H), 0.69 (br t, J = 7.2 Hz, 2H).LC-ELSD / MS purity 99%, MS ESI C 26 H 35 N 3 [M-MeOH-2H 2 O+H] + Calculated value 388.2, measured value 388.2. SFC 100% de

[0457] Example 21: Synthesis of 1-(2,2-difluoro-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1H-pyrazole-4-carbonitrile [ka] Synthesis of 21-1 To a solution of 21-0 (1 g, 2.44 mmol) in DCM (10 mL) was added DMAP (298 mg, 2.44 mmol) and acetyl acetate (622 mg, 6.10 mmol). After stirring at 25 °C for 16 h, the reaction mixture was poured into ice water (50 mL), stirred for 10 min, and extracted with DCM (2 x 30 mL). The combined organic phase was washed with saturated brine (2 x 50 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 21-1 (650 mg, 59%). 1H NMR (400 MHz, CDCl 3 ) δ H 7.86 (s, 1H), 7.81 (s, 1H), 5.05-4.87 (m, 2H), 2.64-2.57 (m, 1H), 2.34-2.06 (m, 2H), 1.99 (s, 3H), 1.87-1.58 (m, 10H), 1.54 (s, 3H), 1.51-1.30 (m, 7H), 1.15-0.82 (m, 4H), 0.67 (s, 3H).

[0458] Synthesis of 21-2 To a solution of 21-1 (300 mg, 0.66 mmol) in chloroform (5 mL), DAST (0.79 ml, 5.97 mmol) was added under N 2 After stirring at 60 °C for 12 h, the reaction mixture was diluted with saturated NaHCO 3 (50 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was washed with saturated NaHCO 3 (50 mL), and then washed with Na 2 SO 4 The residue was purified by Combiflash (0-30% EtOAc in PE) to give 21-2 (65 mg, 20%). 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.59-4.30 (m, 2H), 1.97 (s, 3H), 1.85-1.58 (m, 12H), 1.53 (s, 3H), 1.49-1.28 (m, 7H), 1.14-1.03 (m, 5H), 0.88-0.86 (m, 3H)

[0459] Synthesis of 21 To a solution of 21-2 (35 mg, 0.074 mmol) in dioxane (0.5 mL) was added MeOH (1 mL) and NaOH (2.94 ml, 5 M, 14.7 mmol) at 15° C. After stirring at 35° C. for 16 h, the reaction mixture was poured into water (20 mL), stirred for 10 min, and extracted with EtOAc (3×40 mL). The combined organic phase was washed with saturated brine (2×50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-40% EtOAc in PE) and purified by SFC (Method: Column: DAICEL CHIRALPAK AD (250mm*50mm, 10um); Adjusted solvent: 0.1% NH 3 H 2 Purification with O EtOH; start B: 60%; end B: 60%) gave 21 (14.4 mg, 41%). 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.55-4.34 (m, 2H), 2.02-1.96 (m, 1H), 1.86-1.60 (m, 10H), 1.49-1.27 (m, 9H), 1.25 (s, 3H), 1.13-1.05 (m, 5H), 0.87 (d, J=3.2 Hz, 3H).LC-ELSD / MS: >99% purity; MSESIC 25 H 35 F 2 N 3 O[MH 2 O+H] + Calculated value: 414.2, measured value: 414.2.

[0460] Examples 22 and 23: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile (22) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile (23) [ka] A solution of 7-3 (300 mg, 0.831 mmol) in DMF (5 mL) was added with 1H-pyrazole-3-carbonitrile (154 mg, 1.66 mmol) and Cs 2 CO 3 (1.35g, 4.15mmol) was added. After stirring at 125°C for 12h, the mixture was diluted with water (100mL) and extracted with EtOAc (3x50mL). The combined organic layers were concentrated and purified by flash column (0-25% EtOAc in PE) to give a mixture of epimers (200mg, 53%). SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um; conditioning solvent: 0.1%NH 3 H 2 The epimers were separated by O IPA; start B: 55%; end B: 55%; flow rate (ml / min): 80) to give 22 (80.5 mg) and 23 (47.2 mg). The regiochemistry of the pyrazole was assigned by HMBC (H22 correlated with C5 of the pyrazole ring).

[0461] twenty two: 1 H NMR (400 MHz, CDCl 3 ) δ H7.58 (d, J = 4 Hz, 1H), 6.68 (d, J = 4 Hz, 1H), 4.38 - 4.35 (m, 1H), 4.13 - 4.09 (m, 1H), 2.35 (s, 1H), 2.02 - 1.99 (m, 1H), 1.81 - 1.60 (m, 10H), 1.55 - 1.31 (m, 7H), 1.28 - 1.03 (m, 11H), 0.96 - 0.91 (m, 9H). LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N 3 [M - 2H 2 Calculated value for [M - 2H + H]+ is 418.3, measured value is 418.3. SFC 100% de.

[0462] 23: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.53 (d, J = 4 Hz, 1H), 6.67 (d, J = 4 Hz, 1H), 4.19 - 4.16 (m, 1H), 4.05 - 4.02 (m, 1H), 2.21 (s, 1H), 2.07 - 2.04 (m, 1H), 1.94 - 1.58 (m, 10H), 1.55 - 1.25 (m, 11H), 1.22 - 1.02 (m, 10H), 0.95 - 0.87 (m, 6H). LC-ELSD / MS purity 99%, MS ESI C 28 H 40 N 3 [M - 2H 2 Calculated value for [M - 2H + H]+ is 418.3, measured value is 418.3. SFC 100% de.

[0463] Examples 24 and 25: Synthesis of 1-((S)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (24) and 1-((R)-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (25) [ka] Synthesis of 24-1 MePPh in THF (70 mL) 3 To a mixture of Br (5.67 g, 15.9 mmol), t-BuOK (1.78 mg, 15.9 mmol) was added 2 After stirring at 55° C. for 30 min, 24-0 (2.0 g, 5.31 mmol) in THF (30 mL) was added portionwise below 55° C. After stirring at 55° C. for 2 h, the reaction mixture was poured into water (300 mL) at 25° C. and extracted with EtOAc (2×300 mL). The combined organic layers were washed with water (300 mL), brine (200 mL), and diluted with Na 2 SO 4 The residue was purified by silica gel chromatography (0-5% EtOAc in PE) to give 24-1 (900 mg). 1 H NMR (400 MHz, CDCl 3 ) δ H4.84 (s, 1H), 4.69 (s, 1H), 3.55-3.51 (q, J=6.9 Hz, 2H), 3.47-3.33 (m, 2H), 2.73-2.65 (m, 1H), 2.06-1.97 (m, 2H), 1.96-1.81 (m, 3H), 1.77-1.72 (m, 4H), 1.58-1.54 (m, 2H), 1.45-1.38 (m, 4H), 1.25-1.18 (m, 8H), 0.90-0.82 (m, 9H), 0.54 (s, 3H).

[0464] Synthesis of 24-2 To a solution of 24-1 (900 mg, 2.40 mmol) in DCM (20 mL) was added m-CPBA (974 mg, 85%, 4.80 mmol) at 15 °C. After stirring at 15 °C for 1 h, the mixture was dissolved in saturated NaHCO 3 The mixture was quenched with aqueous solution (200 mL). The organic phase was separated and washed with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 3×100 mL), brine (100 mL), and Na 2 SO 4 The mixture was dried over rt, filtered and concentrated in vacuo to give 24-2 (1.0 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.55-3.51 (q, J=6.9 Hz, 2H), 3.47-3.35 (m, 2H), 1.98-1.77 (m, 4H), 1.76-1.66 (m, 2H), 1.64-1.44 (m, 6H), 1.43-1.31 (m, 7H), 1.27-1.17 (m, 7H), 1.16-0.99 (m, 4H), 0.95-0.90 (m, 3H), 0.81-0.74 (m, 1H), 0.71-0.61 (m, 2H).

[0465] Synthesis of 24 and 25 A solution of 24-2 (1.0 g, 2.56 mmol) in DMF (15 mL) was added with 1H-pyrazole-4-carbonitrile (595 mg, 6.40 mmol) and Cs 2 CO 3 (4.17 g, 12.8 mmol) was added. After stirring at 125 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with saturated LiCl (3 x 150 mL) and then concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give a mixture of epimers (700 mg). SFC (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 um, mobile phase: A:CO 2 The epimers were separated using 24 (284.9 mg, 40.8%) and 25 (88.4 mg, 12.7%) in 25 ml of ethanol (0.05% DEA), gradient: 5% to 40% B for 2 min, held at 40% for 1.2 min, then 5% B for 0.8 min, flow rate: 4 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0466] twenty four: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.36-4.32 (d, J=13.8 Hz, 1H), 4.09-4.05 (d, J=13.8 Hz, 1H), 3.53-3.50 (q, J=6.9 Hz, 2H), 3.47-3.36 (m, 2H), 2.72 (s, 1H), 2.54 (s, 1H), 2.01-1.99 (d, J=10.8 Hz, 1H), 1.96-1.79 (m, 2H), 1.77-1.64 (m, 4H), 1.62-1.46 (m, 5H), 1.45-1.35 (m, 6H), 1.26-1.18 (m, 6H), 1.13-1.08 (m, 1H), 0.96-0.93 (d, J=10.8 Hz, 7H), 0.89 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 27 H 36 N 3 [M-EtOH-2H2 Calculated value for O+H] 402.3 Measured value 402.3. SFC 100% de.

[0467] twenty five: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.89 (s, 1H), 7.81 (s, 1H), 4.17-4.14 (d, J=13.8 Hz, 1H), 4.02-3.99 (d, J=13.8 Hz, 1H), 3.55-3.50 (q, J=7.0 Hz, 2H), 3.46-3.35 (m, 2H), 2.72 (s, 1H), 2.34 (s, 1H), 2.06 (d, 1H), 1.97-1.79 (m, 3H), 1.73-1.64 (m, 3H), 1.62-1.53 ​​(m, 3H), 1.53-1.34 (m, 8H), 1.27-1.18 (m, 6H), 1.17-1.10 (m, 2H), 1.07 (s, 3H), 0.93 (s, 3H), 0.85 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 27 H 36 N 3 [M-EtOH-2H 2 Calculated value for O+H]+ 402.3 Measured value 402.3. SFC 100% de.

[0468] Examples 26 and 27: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (26) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9S,10S,13S,14S,17S)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (27) [ka] Synthesis of 26-1 MePPh in THF (30 mL) 3 To a mixture of Br (2.96 g, 8.30 mmol), t-BuOK (931 mg, 236 mmol) was added 2 After stirring at 50° C. for 30 min, 26-0 (1.0 g, 2.77 mmol) in THF (20 mL) was added portionwise below 50° C. After stirring at 50° C. for 2 h, the reaction mixture was poured into water (300 mL) at 25° C. and extracted with EtOAc (2×300 mL). The combined organic layers were washed with water (300 mL), brine (200 mL), and diluted with Na 2 SO 4 The residue was purified by silica gel chromatography (0-5% EtOAc in PE) to give 26-1 (880 mg, 88.6%). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.84 (s, 1H), 4.69 (s, 1H), 2.06-1.98 (m, 1H), 1.93-1.79 (m, 3H), 1.75 (s, 3H), 1.73-1.64 (m, 3H), 1.60-1.49 (m, 3H), 1.48-1.33 (m, 8H), 1.32-1.17 (m, 6H), 1.17-0.99 (m, 4H), 0.97-0.90 (m, 6H), 0.54 (s, 3H).

[0469] Synthesis of 26-2 To a solution of 26-1 (880 mg, 2.45 mmol) in DCM (20 mL) was added m-CPBA (994 mg, 85%, 4.90 mmol) at 15 °C. After stirring at 15 °C for 1 h, the mixture was added with saturated NaHCO 3 The mixture was quenched with aqueous solution (200 mL). The organic phase was separated and washed with saturated NaHCO 3 / Na 2 S 2 O 3 Wash with aqueous solution (1:1, 3×100 mL), brine (100 mL), and Na 2 SO 4The mixture was dried over rt, filtered and concentrated in vacuo to give 26-2 (900 mg). 1 H NMR (400 MHz, CDCl 3 ) δ H 2.89-2.86 (d, J=4.3 Hz, 1H), 2.57-2.53 (d, J=4.3 Hz, 1H), 2.51-2.29 (m, 1H), 1.95-1.80 (m, 5H), 1.73-1.64 (m, 2H), 1.63-1.54 (m, 4H), 1.39-1.32 (m, 9H), 1.27-1.20 (m, 5H), 0.97-0.88 (m, 10H), 0.77 (s, 1H), 0.65 (s, 3H).

[0470] Synthesis of 26 and 27 A solution of 26-2 (900 mg, 2.40 mmol) in DMF (5 mL) was added with 1H-pyrazole-4-carbonitrile (557 mg, 5.99 mmol) and Cs 2 CO 3 (3.87 g, 11.9 mmol) was added. After stirring at 125 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with saturated LiCl (3 x 150 mL) and then concentrated. The residue was purified by flash column (0-20% EtOAc in PE) to give a mixture of epimers (740 mg, 66.0%). SFC (column: Chiralpak AD-3 50 x 4.6 mm ID, 3 um, mobile phase: A:CO 2 The epimers were separated using a column chromatography (HPLC) of 200 sq. m. (B: ethanol (0.05% DEA), gradient: 5% to 40% B for 2 min, held at 40% for 1.2 min, then 5% B for 0.8 min, flow rate: 4 mL / min, column temperature: 35°C, ABPR: 1500 psi) to give 26 (318.7 mg) and 27 (154.0 mg).

[0471] 26: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.92 (s, 1H), 7.82 (s, 1H), 4.35 - 4.32 (d, J = 13.6 Hz, 1H), 4.09 - 4.05 (d, J = 13.8 Hz, 1H), 2.52 (s, 1H), 2.05 - 1.98 (m, 1H), 1.91 - 1.82 (m, 2H), 1.78 - 1.63 (m, 4H), 1.57 - 1.49 (m, 5H), 1.48 - 1.32 (m, 10H), 1.30 - 1.19 (m, 5H), 1.16 - 1.02 (m, 4H), 0.97 (s, 3H), 0.95 - 0.92 (m, 5H), 0.89 (s, 3H). LC-ELSD / MS purity 99%, MS ESI C 29 H 41 N 3 [M - 2H 2 O + H] + Calculated value for 432.3, measured value 432.3. SFC 100% de.

[0472] 27: 1 H NMR (400 MHz, CDCl 3 ) δ H 7.89 (s, 1H), 7.80 (s, 1H), 4.21 - 4.11 (m, 1H), 4.02 - 3.98 (d, J = 13.8 Hz, 1H), 2.30 (s, 1H), 2.06 (s, 1H), 1.97 - 1.78 (m, 3H), 1.73 - 1.63 (m, 3H), 1.55 (s, 3H), 1.52 - 1.33 (m, 12H), 1.32 - 1.18 (m, 6H), 1.08 (s, 3H), 0.97 - 0.91 (m, 6H), 0.85 (s, 3H). LC-ELSD / MS purity 99%, MS ESI C 29 H 41 N 3 [M - 2H 2 Calculated value for [M - 2H + O + H]+ is 432.3, measured value 432.3.

[0473] Example 28: Synthesis of 1-((3-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)oxetan-3-yl)methyl)-1H-pyrazole-4-carbonitrile [ka] Synthesis of 28-1 A suspension of NaH (2.75 g, 60%, 68.8 mmol) in THF (60 mL) was 2 P(O)CH 2 COOEt (15.4 g, 68.8 mmol) was added dropwise at 0° C. After stirring for 10 min at 20° C., a solution of 28-0 (10 g, 34.4 mmol, reported in patent WO2014 / 169833, 2014, A1) in THF (20 mL) was added dropwise at 20° C. After stirring for 16 h at 70° C., the reaction mixture was diluted with NH 4 Cl (200 mL, 10% aqueous solution) and extracted with EtOAc (200 mL). The organic layer was separated and 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 28-1 (12 g, 97%). 1 H NMR (400 MHz, CDCl 3 ) δ H 5.52 (t, J = 2.4 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.90-2.75 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

[0474] Synthesis of 28-2 A solution of 28-1 (12 g, 33.2 mmol) in THF (150 mL) was dissolved in Pd / C (2 g, dry, 10%) and N 2 H 2After stirring at 40 °C under (40 psi) for 24 h, the reaction mixture was filtered through a pad of Celite, which was then washed with THF (3 x 50 mL). The combined filtrate was concentrated to give 28-2 (11.7 g, 97.5%). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.11 (q, J = 6.8 Hz, 2H), 2.35 (dd, J = 5.2, 14.4 Hz, 1H), 2.10 (dd, J = 10.0, 14.8 Hz, 1H), 2.00-1.75 (m, 6H), 1.70-1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

[0475] Synthesis of 28-3 i-Pr 2 To a solution of NH (1.66 g, 16.5 mmol) in THF (30 mL) was added BuLi (6.6 mL, 2.5 M in hexane, 16.5 mmol) at -70 °C. After warming at 0 °C for 15 min, it was then cooled to -70 °C and a solution of 28-2 (2 g, 5.5 mmol) in THF (10 mL) was added. After stirring at -70 °C for 1 h, a solution of ClCOOEt (1.79 g, 16.5 mmol) in THF was added. After stirring at -70 °C for 1 h, the reaction mixture was diluted with NH 4 The mixture was quenched with 10% NaCl (20 mL, 10%) and extracted with EtOAc (2×20 mL). 2 SO 4 The mixture was dried over rt, filtered and concentrated in vacuo to give 28-3 (2.7 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.25-4.05 (m, 4H), 3.29 (d, J = 11.2 Hz, 1H), 2.25-2.15 (m, 1H), 2.00-1.75 (m, 4H), 1.70-1.35 (m, 12H), 1.35-1.20 (m, 10H), 1.20-0.95 (m, 7H), 0.70 (s, 3H).

[0476] Synthesis of 28-4 To a suspension of t-BuOK (4.85 g, 31.0 mmol) in THF (20 mL) was added a solution of 28-3 (2.25 g, 5.17 mmol) in THF (20 mL) at 0 °C. After stirring at 15 °C for 1 h, BOMCl (3.47 g, 31.0 mmol) was added at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was diluted with NH 4 Cl (100 mL, sat.) and extracted with EtOAc (100 mL). The organic layer was separated and 2 SO 4 The mixture was dried at 40° C. for 24 hours, filtered, and concentrated to give 28-4 (8.5 g), which contained some amount of 2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-((benzyloxy)methoxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((benzyloxy)methyl)diethyl malonate.

[0477] Synthesis of 28-5 LiAlH 4 To a suspension of 28-4 (1.96 g, 51.7 mmol) in THF (80 mL) was added dropwise a solution of 28-4 (5.17 mmol mixture) in THF (20 mL) at 0 °C. After stirring for 1 h at 0 °C, the reaction mixture was quenched with water / THF (2 mL / 100 mL), followed by NaOH (2 mL, 10%) and water (6 mL). The mixture was filtered and the residue was washed with THF (3 × 50 mL). The combined filtrate was concentrated to 100 mL and HCl (2 M, 10 mL) was added. After stirring for 1 h at 50 °C, the reaction mixture was quenched with NaHCO 3 (50 mL, saturated) and extracted with EtOAc (100 mL). The organic layer was separated and 2 SO 4 The residue was purified by flash column (30-80% EtOAc in PE) to give 28-5 (1 g, 41% for two steps). 1 H NMR (400 MHz, CDCl 3 ) δ H7.45-7.30 (m, 5H), 4.50 (s, 2H), 3.95-3.55 (m, 6H), 2.80-2.70 (br, 1H), 2.70-2.60 (br, 1H), 1.95-1.70 (m, 4H), 1.70-1.50 (m, 5H), 1.50-1.20 (m, 13H), 1.15-0.90 (m, 6H), 0.73 (s, 3H).

[0478] Synthesis of 28-6 To a solution of 28-5 (1 g, 2.12 mmol) in THF (20 mL) was added BuLi (1.01 mL, 2.5 M in hexane, 2.54 mmol) at 0 °C. After stirring for 10 min at 0 °C, a solution of TsCl (484 mg, 2.54 mmol) in THF (5 mL) was added. After stirring for 1 h at 0 °C, BuLi (1.01 mL, 2.5 M in hexane, 2.54 mmol) was added at 0 °C. After stirring for 2 h at 15 °C, the reaction mixture was diluted with NH 4 The mixture was quenched with Cl (20 mL, sat.) and extracted with EtOAc (2×30 mL). 2 SO 4 The residue was purified by flash column (0-15% EtOAc in PE) to give 28-6 (650 mg, 68%). 1 H NMR (400 MHz, CDCl 3 ) δ H 7.45-7.30 (m, 5H), 4.83 (d, J = 6.4 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.55-4.50 (m, 2H), 4.44 (d, J = 5.6 Hz, 1H), 4.23 (d, J = 6.4 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.66 (d, J = 9.2 Hz, 1H), 2.20-2.10 (m, 1H), 2.00-1.60 (m, 8H), 1.50-1.30 (m, 7H), 1.30-0.95 (m, 12H), 0.52 (s, 3H).

[0479] Synthesis of 28-7 A solution of 28-6 (650 mg, 1.43 mmol) in THF (20 mL) was diluted with Pd / C (0.5 g, 10%, wet) and N 2 H 2 After stirring at 20 °C under (20 psi) for 20 h, the reaction mixture was filtered and the residue was washed with THF (20 mL). The combined filtrate was concentrated and purified by flash column (40-70% EtOAc in PE) to give 28-7 (380 mg, 73%). 1 H NMR (400 MHz, CDCl 3 ) δ H 4.85 (d, J = 6.8 Hz, 1H), 4.54 (d, J = 5.6 Hz, 1H), 4.46 (d, J = 5.6 Hz, 1H), 4.24 (d, J = 6.4 Hz, 1H), 4.08 (dd, J = 4.0, 10.8 Hz, 1H), 3.82 (d, J = 10.0 Hz, 1H), 2.20-2.10 (m, 1H), 2.00-1.65 (m, 10H), 1.55-1.00 (m, 18H), 0.53 (s, 3H).LC-ELSD / MS: >99% purity, MS ESI C 23 H 37 O 2 [M+HH 2 O] + Calculated value: 345.3, measured value: 345.3.

[0480] Synthesis of 28-8 To a solution of 28-7 (185 mg, 0.51 mmol) in DCM (5 mL) was added N-Me-Im (41.8 mg, 0.51 mmol), TEA (258 mg, 2.55 mmol), and TsCl (194 mg, 1.02 mmol). After stirring at 15 °C for 16 h, the reaction mixture was washed with water (5 mL) and 2 SO 4 The residue was purified by flash column (0-25% EtOAc in PE / DCM (1:1)) to give 28-8 (200 mg, 76%). 1 H NMR (400 MHz, CDCl 3 ) δ H7.83 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.82 (d, J = 6.8 Hz, 1H), 4.50-4.40 (m, 2H), 4.22 (d, J = 9.6 Hz, 1H), 4.18 (d, J = 6.0 Hz, 1H), 4.11 (d, J = 6.8 Hz, 1H), 2.46 (s, 3H), 2.10-2.00 (m, 1H), 1.95-1.55 (m, 8H), 1.50-0.90 (m, 19H), 0.47 (s, 3H).

[0481] Synthesis of 28 A solution of 28-8 (200 mg, 0.39 mmol) in DMF (5 mL) was added with 4-cyano-pyrazole (72 mg, 0.77 mmol), KI (64.2 mg, 0.38 mmol), and K 2 CO 3 (108 mg, 0.77 mmol) was added. After stirring at 80 °C for 16 h, the reaction mixture was poured into water (30 mL) and filtered. The residue was purified by flash column (20-50% EtOAc in PE), dissolved in MeCN (30 mL) / water (30 mL) and lyophilized to give 28 (135.7 mg, 79%). 1 H NMR (400 MHz, CDCl 3 ) δ H 7.88 (s, 1H), 7.83 (s, 1H), 4.96 (d, J = 6.8 Hz, 1H), 4.70-4.60 (m, 2H), 4.53 (d, J = 6.4 Hz, 1H), 4.47 (d, J = 7.2 Hz, 1H), 4.35 (d, J = 14.0 Hz, 1H), 2.10-2.00 (m, 1H), 2.00-1.65 (m, 8H), 1.55-0.95 (m, 19H), 0.69 (s, 3H).LC-ELSD / MS >99% purity, MS ESI C 27 H 40 N 3 O 2 [M+H] + Calculated value: 438.3, measured value: 438.3.

[0482] Examples 29 and 30: Synthesis of 1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (29) and 1-((R)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (30) [ka] Synthesis of 29.2 MePPh 3 To a solution of Br (12.2 g, 34.0 mmol) in THF (20 mL) was added t-BuOK (2.88 g, 25.8 mmol) at 15 °C. After stirring at 15 °C for 1 h, 29.1 (3 g, 8.60 mmol) in THF (20 mL) was added. After stirring at 45 °C for 3 h, the mixture was washed with saturated NH 4 The combined organic solutions were washed with brine (100 mL) and anhydrous NaCl (2×30 mL). 2 SO 4 The residue was purified by flash column (0-40% EtOAc in PE) to give 29.2 (4.5 g). 1 H NMR (400MHz, CDCl 3 ) δ 4.83 (s, 1H), 4.45 (s, 1H), 3.47-3.31 (m, 5H), 2.61 (s, 1H), 2.05-2.02 (m, 1H), 1.91-1.77 (m, 4H), 1.74 (s, 3H), 1.68-1.52 (m, 5H), 1.49-1.31 (m, 7H), 1.28-1.04 (m, 7H), 0.59-0.50 (m, 3H).

[0483] Synthesis of 29.3 To a solution of 29.2 (500 mg, 1.44 mmol) in DCM (20 mL) was added m-CPBA (461 mg, 2.15 mmol, 85%) at 15 °C. After stirring for 1 h, the mixture was diluted with saturated NaHCO 3 and Na 2 S 2 O 3 (40 mL, v:v=1:1) and extracted with DCM (2×20 mL). The combined organic phase was washed with saturated NaHCO 3 and Na 2 S 2 O 3 (50mL, v:v=1:1), and washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 29.3 (520 mg). 1 H NMR (400 MHz, CDCl 3 ) δH = 3.46 - 3.32 (m, 8H), 2.88 (d, J = 4.4 Hz, 1H), 2.55 (d, J = 4.4 Hz, 1H), 2.51 - 2.47 (m, 1H), 2.31 (d, J = 5.2 Hz, 1H), 2.04 - 1.98 (m, 1H), 1.95 - 1.53 (m, 8H), 1.50 - 1.29 (m, 8H), 1.28 - 0.98 (m, 5H), 0.82 - 0.78 (m, 1H), 0.68 (s, 3H).

[0484] Synthesis of 29.4 A solution of 29.3 (520 mg, 1.43 mmol) in DMF (10 mL) was added to Cs 2 CO 3 (1.39 g, 4.29 mmol) and 1H-pyrazole-4-carbonitrile (332 mg, 3.57 mmol) were added to N 2 After stirring at 130 °C for 12 h, the mixture was added with saturated NH 4 The mixture was added to 100 mL of LiCl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with LiCl (100 mL, 5% aq.), brine (2×100 mL) and anhydrous Na 2 SO 4The mixture was dried over 1000 ml, filtered and concentrated. The residue was purified by column (0-50% EtOAc in PE) to give 29.4 (650 mg). LC-ELSD / MS Purity 99%, MS ESI C 26 H 35 N 3 [M-2H 2 O-CH 3 OH+H] + Calculated value: 388.3, ​​measured value: 388.3.

[0485] Separation of 29 and 30 SFC (column: Chiralcel OD-3 50iA 4.6 mm ID, 3 um; mobile phase: A:CO 2 Separation of 29.4 by HPLC using a 5% column chromatography (HPLC-HPLC) column (A: ethanol (0.05% DEA); gradient: 5% to 40% B for 2 min, hold at 40% for 1.2 min, then 5% B for 0.8 min; flow rate: 4 mL / min) gave 30 (73 mg, 18.2%) and 29 (189.9 mg, 47.3%).

[0486] 29: 1 H NMR (400 MHz, CDCl 3 ) δ H = 7.92 (s, 1H), 7.82 (s, 1H), 4.36 (d, J = 13.6 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 3.46 - 3.33 (m, 5H), 2.59 (s, 1H), 2.52 (s, 1H), 2.01 (br d, J = 12.0 Hz, 1H), 1.87 - 1.57 (m, 9H), 1.52 - 1.31 (m, 7H), 1.29 - 1.04 (m, 7H), 0.96 (s, 3H), 0.91 (s, 3H)LC-ELSD / MS Purity 99%, MS ESI C 26 H 35 N 3 [M-2H 2 O-CH 3 OH+H] + Calculated value: 388.3, ​​measured value: 388.3.

[0487] 30: 1H NMR (400 MHz, CDCl 3 ) δ H = 7.89 (s, 1H), 7.80 (s, 1H), 4.17 (d, J = 13.6 Hz, 1H), 4.01 (d, J = 13.6 Hz, 1H), 3.48 - 3.32 (m, 5H), 2.60 (s, 1H), 2.32 (s, 1H), 2.06 (br d, J = 13.6 Hz, 1H), 1.98 - 1.60 (m, 9H), 1.51 - 1.24 (m, 9H), 1.08 (s, 8H), 0.87 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 26 H 35 N 3 [M-2H 2 O-CH 3 OH+H] + Calculated value: 388.3, ​​measured value: 388.3.

[0488] Example 31: Synthesis of 1-(1-((S)-2-hydroxy-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazol-4-yl)ethanone (31) [ka] Synthesis of 31.1 To a solution of 21.0 (2 g, 4.88 mmol), 2,6-dimethylpyridine (1.30 g, 12.2 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (2.57 g, 9.76 mmol) dropwise at 0° C. After stirring at 15° C. for 5 h, the reaction mixture was quenched with water (60 mL) and extracted with DCM (2×50 mL). The combined organic phase was washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried over 1000 ml, filtered and concentrated in vacuo. The residue was purified by flash column (10-20% EtOAc in PE) to give 31.1 (2.5 g, 98.0%).1 H NMR (400 MHz, CDCl 3 ) δ H 7.87 (s, 1H), 7.82 (s, 1H), 5.10-4.97 (m, 1H), 4.96-4.84 (m, 1H), 2.72-2.60 (m, 1H), 2.28-2.17 (m, 1H), 2.09-2.02 (m, 1H), 1.87-1.67 (m, 7H), 1.46-1.40 (m, 4H), 1.29-1.26 (m, 3H), 1.24 (s, 4H), 1.16-1.07 (m, 3H), 0.88 (s, 11H), 0.68 (s, 3H), 0.09 (s, 6H).

[0489] Synthesis of 31.2 To a solution of 31.1 (200 mg, 0.381 mmol) in THF (5 mL) was added MeMgBr (1.27 mL, 3.81 mmol, 3.0 M) at -60 °C. After stirring at 25 °C for 2 h, the mixture was diluted with NH 4 Cl (20 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 31.2 (120 mg, 56.6%). 1 H NMR (400 MHz, CDCl3) δ H 7.94-7.93 (m, 1H), 7.92-7.90 (m, 1H), 4.41-4.30 (m, 1H), 4.08-4.00 (m, 1H), 2.68-2.62 (m, 1H), 2.45-2.44 (m, 3H), 2.28-2.17 (m, 1H), 2.11-2.02 (m, 2H), 1.81-1.74 (m, 8H), 1.44 (s, 3H), 1.24 (s, 6H), 1.15-1.06 (m, 6H), 1.01-0.93 (m, 4H), 0.88 (s, 9H), 0.70-0.68 (m, 3H), 0.09 (s, 6H), 0.10-0.09 (m, 1H).

[0490] Synthesis of 31 To a solution of 31.2 (120 mg, 0.215 mmol) in THF (2 mL), HF (21.4 mg, 1.07 mmol, 1.1 g / mL) was added 2 After stirring at 25° C. for 16 h, the mixture was diluted with NH 4 Cl (10 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated. HPLC (Welch Xtimate C18 150×25 mm, 5 um; adjusted solvent: water (0.04% NH 3 H 2 The residue was purified by 6)-ACN; gradient: 50% to 80% B in 8.5 min, hold 100% for 2 min; flow rate: 30 mL / min; injection: 6) to give 31 (3.8 mg, 3.99%). 1 H NMR (400 MHz, CDCl3) δ H 7.97-7.95 (m, 1H), 7.95-7.93 (m, 1H), 4.38-4.31 (m, 1H), 4.06-4.01 (m, 1H), 3.08-3.05 (m, 1H), 2.46 (s, 3H), 2.08-2.02 (m, 1H), 1.87-1.73 (m, 5H), 1.70-1.61 (m, 4H), 1.47-1.35 (m, 8H), 1.27 (s, 5H), 1.14-1.04 (m, 5H), 1.00 (s, 3H), 0.93 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 27 H 42 N 2 O 3 [M+H] + Calculated value 443.3 Measured value 443.3.

[0491] Examples 32 and 33: Synthesis of 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methoxypropyl)-1H-pyrazole-4-carbonitrile (32) and 1-[(2S)-2-[(1S,3aS,3bR,5aR,7R,9aS,9bR,11aS)-7-hydroxy-7-(methoxymethyl)-11a-methyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2-methoxypropyl]-1H-pyrazole-4-carbonitrile (33) [ka] Synthesis of 32.1 To a solution of 29.2 (4 g, 11.5 mmol) and 2,6-dimethylpyridine (6.14 g, 57.4 mmol) in DCM (150 mL) was added TBSOTf (12.1 g, 46.0 mmol) at 0° C. After stirring at 25° C. for 16 h, the mixture was diluted with DCM (150 mL) and washed with water (300 mL). The organic phase was separated and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 32.1 (6 g) which was used directly in the next step. 1 H NMR (400 MHz, CDCl 3 ) δ 4.85 (s, 1H), 4.70 (s, 1H), 3.42 - 3.29 (m, 5H), 2.11 - 2.05 (m, 1H), 1.89 - 1.79 (m, 5H), 1.72 - 1.56 (m, 8H), 1.49 - 0.99 (m, 16H), 0.95 - 0.88 (m, 6H), 0.57 (s, 3H), 0.08 - 0.05 (m, 6H).

[0492] Synthesis of 32.2 To a solution of 32.1 (3 g, 6.51 mmol) in DCM (150 mL) was added m-CPBA (1.96 g, 9.76 mmol, 85%). After stirring at 25 °C for 2 h, the reaction mixture was diluted with NaHCO3 (150 mL, sat.) and extracted with DCM (2×80 mL). The combined organic phase was washed with brine (150 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 32.2 (2.3 g).

[0493] Synthesis of 32.3 and 32.4 A solution of 32.2 (2.3 g, 4.82 mmol) in DMF (50 mL) was diluted with 1H-pyrazole-4-carbonitrile (1.34 g, 14.4 mmol) and Cs 2 CO 3 (4.69 g, 14.4 mmol) was added at 25° C. After stirring at 140° C. for 8 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (2×60 mL). The combined organic phase was washed with water (100 mL), brine (100 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by flash column (0% to 30% EtOAc in PE) to give 32.4 (1.3 g, 47.4%) and 32.3 (680 mg, 24.8%).

[0494] 32.3: 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.80 (s, 1H), 4.23-4.13 (m, 1H), 4.05-3.90 (m, 1H), 3.43-3.26 (m, 5H), 2.29 (s, 1H), 2.10-2.05 (m, 1H), 1.98-1.62 (m, 8H), 1.57-1.27 (m, 7H), 1.23-0.97 (m, 10H), 0.94-0.81 (m, 13H), 0.06 (s, 6H).

[0495] 32.4: 1 H NMR (400 MHz, CDCl 3) δ 7.93 (s, 1H), 7.82 (s, 1H), 4.36 (d, J = 14.0 Hz, 1H), 4.10-4.05 (m, 1H), 3.41-3.29 (m, 5H), 2.50 (s, 1H), 1.83-1.59 (m, 9H), 1.53-1.27 (m, 7H), 1.24-1.01 (m, 8H), 1.00-0.90 (m, 6H), 0.85 (s, 9H), 0.06 (s, 6H).

[0496] Synthesis of 32.5 To a solution of 32.3 (680 mg, 1.19 mmol) in THF (20 mL), add NaH (71.1 mg, 1.78 mmol, 60% in oil) 2 After stirring at 25° C. for 30 min, MeI (337 mg, 2.38 mmol) was added. After stirring at 25° C. for 16 h, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine (2×50 mL) and washed with anhydrous Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 32.5 (600 mg).

[0497] Synthesis of 32 To a solution of 32.5 (1.3 g, 2.22 mmol) in THF (20 mL) was added TBAF (22.2 mL, 22.2 mmol, 1 M in THF). After stirring at 80 °C for 16 h, the reaction mixture was diluted with NH 4 The mixture was quenched with Cl (50 mL, sat.) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (2×50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-50% EtOAc in PE) to give 32 (301.8 mg, 28.9%). 1 H NMR (400 MHz, CDCl 3) δ 7.91 (s, 1H), 7.75 (s, 1H), 4.33-4.12 (m, 2H), 3.45-3.32 (m, 5H), 3.18 (s, 3H), 2.57 (s, 1H), 1.98-1.91 (m, 1H), 1.85-1.59 (m, 9H), 1.50-1.22 (m, 8H), 1.18-1.00 (m, 9H), 0.85 (s, 3H).LCMS30~90AB_2min_E, purity 99% or more, MS ESI C 27 H 38 N 3 O [M+H-MeOH-H 2 O] + The calculated value was 420.3, and the measured value was 420.2.

[0498] Synthesis of 32.6 To a solution of 32.4 (1.3 g, 2.28 mmol) in THF (20 mL), add NaH (136 mg, 3.42 mmol, 60% in oil) 2 After stirring for 30 min, MeI (647 mg, 4.56 mmol) was added at 25° C. After stirring for 16 h at 25° C., the reaction mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (2×50 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by flash column (0-20% EtOAc in PE) to give 32.6 (1.2 g).

[0499] Synthesis of 33 To a solution of 32.6 (600 mg, 1.02 mmol) in THF (10 mL) was added TBAF (5.10 mL, 5.10 mmol, 1 M in THF). After stirring at 80 °C for 16 h, the reaction mixture was diluted with NH 4 The mixture was quenched with Cl (50 mL, sat.) and extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine (2×50 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-50% EtOAc in PE) to give 33 (144.7 mg, 30%).1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.75 (s, 1H), 4.24 (s, 2H), 3.45-3.34 (m, 5H), 3.13 (s, 3H), 2.59 (s, 1H), 2.09-1.99 (m, 1H), 1.86-1.59 (m, 9H), 1.49-1.19 (m, 9H), 1.13-0.98 (m, 8H), 0.81 (s, 3H).LCMS purity 99% or more, MS ESI C 27 H 38 N 3 O [M+H-MeOH-H 2 O] + The calculated value was 420.3, and the measured value was 420.2.

[0500] Examples 34 and 35: Synthesis of 1-((S)-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (34) and 1-((R)-2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-2-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile (35) [ka] Synthesis of 34.1 To a solution of 34.0 (100 g, 364 mmol) in DCM (1000 mL) was added imidazole (49.5 g, 728 mmol) and TBSCl (109 g, 728 mmol) at 25° C. After stirring for 2 h at 25° C., the mixture was poured into water (500 mL) and extracted with DCM (2×500 mL). The combined organic phase was washed with brine (500 mL) and diluted with anhydrous Na 2 SO 4The residue was dried at 40° C., filtered and concentrated. The residue was triturated from PE (200 mL) at 25° C. to give 34.1 (83 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 5.82 (s, 1H), 3.56 (t, J = 8.3 Hz, 1H), 2.50-2.36 (m, 2H), 2.32-2.19 (m, 3H), 2.14-2.04 (m, 1H), 1.94-1.74 (m, 3H), 1.59-1.21 (m, 6H), 1.07-0.90 (m, 4H), 0.88 (s, 9H), 0.84-0.78 (m, 1H), 0.76 (s, 3H), 0.00 (d, J = 2.8 Hz, 6H).

[0501] Synthesis of 34.2 To a solution of 34.1 (50 g, 128 mmol) in THF (300 mL), LiHMDS (128 mL, 1 M in THF, 128 mmol) was added with N 2 After stirring at -70°C for 30 min, HMPA (22.9 g, 22.4 mL, 128 mmol) was added under N 2 After stirring at -70 °C for 30 min, EtI (199 g, 102 mL, 128 mmol) was added under N 2 After stirring at 20 °C for 1 h, the mixture was cooled and concentrated under reduced pressure at 40 °C. The residue was diluted with NH 4 Cl (500 mL), stirred for 20 min, and extracted with EtOAc (3×400 mL). The combined organic phase was washed with brine (2×200 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column (0-1% EtOAc in PE) to give 34.2 (40 g). 1 H NMR (400 MHz, CDCl 3 ) δ H5.79 (s, 1H), 5.72 (s, 1H), 3.57 (t, J = 8.3 Hz, 1H), 2.48-2.39 (m, 1H), 2.34-2.06 (m, 4H), 1.96-1.61 (m, 3H), 1.26 (br d, J = 1.8 Hz, 9H), 1.07-0.98 (m, 2H), 0.93 (br t, J = 7.5 Hz, 4H), 0.88 (s, 10H), 0.76 (s, 3H), 0.01 (d, J = 2.8 Hz, 6H).

[0502] Synthesis of 34.3 To a mixture of 34.2 (20 g, 47.9 mmol) in THF (200 mL) was added Pd / C (2 g, 10%). The mixture was degassed under vacuum and washed with H 2 The tank was purged three times with H 2 After stirring at 25° C. under (15 psi) for 24 h, the reaction mixture was filtered through a pad of Celite and washed with THF (3×500 mL). The filtrate was concentrated to give 34.3 (18 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.61-3.52 (m, 1H), 2.67-2.55 (m, 1H), 2.34-2.05 (m, 4H), 1.94-1.62 (m, 4H), 1.58-0.92 (m, 14H), 0.92-0.85 (m, 13H), 0.73 (d, J = 3.8 Hz, 3H), 0.00 (dd, J = 3.0, 4.4 Hz, 6H).

[0503] Synthesis of 34.4 N 2 Trimethylaluminum (68 mL, 2 M in toluene, 136 mmol) was slowly added dropwise to a solution of BHT (60 g, 272 mmol) in toluene (200 mL) at 0° C. After stirring at 0° C. for 1 h, the MAD solution was used as is without further purification. A solution of MAD (64.8 g in toluene, 135 mmol) was added to a solution of 34.3 (19 g, 45.3 mmol) in DCM (200 mL) with N 2The mixture was added dropwise at -70°C under reduced pressure. 2 After stirring at −70° C. for 1 h, MeMgBr (30.2 mL, 3 M in ethyl ether, 90.6 mmol) was added dropwise at −70° C. After stirring for 2 h, the reaction mixture was slowly poured into aqueous citric acid (500 mL, saturated) at 10° C. and extracted with DCM (2×200 mL). The combined organic phase was washed with brine (300 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by flash column (0-5% EtOAc in PE) to give 34.4 (11 g). 1 H NMR (400 MHz, CDCl 3 ) δ H 3.54 (t, J = 8.3 Hz, 1H), 2.03-1.94 (m, 1H), 1.91-1.61 (m, 6H), 1.58-1.36 (m, 5H), 1.32-1.13 (m, 6H), 1.12-0.89 (m, 11H), 0.87 (s, 11H), 0.70 (d, J = 2.3 Hz, 3H), 0.00 (t, J = 2.6 Hz, 6H).

[0504] Synthesis of 34.5 and 34.5a To a solution of 34.4 (11 g, 25.3 mmol) in THF (20 mL), TBAF.3H 2 2H2O (126 ml, 1M, 126 mmol) was added at 15° C. After stirring at 55° C. for 12 h, the mixture was poured into water (200 mL) and extracted with EtOAc (2×200 mL). The o...

Claims

1. Formula (I-e6): 【Chemistry 86】 [In the formula, R ２ａ , R ２ｂ , R １５ａ , and R １５ｂ each of is hydrogen; R ３ is unsubstituted C １－３ Alkyl, -CH ２ OCH ３ , or -CH ２ OCH ２ CH ３ and R １９ is hydrogen, methyl, or ethyl; R Ｘ is -OH; R Ｙ is methyl; R ２２ is -CN. or a pharma- ceutically acceptable salt thereof.

2. R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is methyl, ethyl, or propyl.

3. R ３ 3. The compound or pharma- ceutically acceptable salt of claim 1 or claim 2, wherein is methyl.

4. R ３ 3. The compound or pharma- ceutically acceptable salt of claim 1 or claim 2, wherein is ethyl.

5. R ３ 3. The compound or pharma- ceutically acceptable salt of claim 1 or claim 2, wherein is propyl.

6. R ３ But -CH ２ OCH ３ 2. The compound of claim 1, wherein:

7. R ３ But -CH ２ OCH ２ CH ３ 2. The compound of claim 1, wherein:

8. R １９ The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 7, wherein is hydrogen.

9. R １９ The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 7, wherein is methyl.

10. R １９ The compound or pharma- ceutically acceptable salt according to any one of claims 1 to 7, wherein is ethyl. 【Request 11】 【Table 4-1】 【Table 4-2】 or a pharma- ceutically acceptable salt thereof.

12. 【Table 5】 or a pharma- ceutically acceptable salt thereof.

13. formula: 【Chemistry 87】 Compound.

14. formula: 【Chemistry 88】 Compound.

15. formula: 【Chemistry 89】 Compound.

16. formula: 【Chemistry 90】 Compound.

17. formula: 【Chemistry 91】 Compound.

18. formula: 【Chemistry 92】 Compound.

19. formula: 【Chemistry 93】 Compound.

20. formula: 【Chemistry 94】 Compound.

21. formula: 【Chemistry 95】 Compound.

22. formula: 【Chemistry 96】 Compound.

23. formula: 【Chemistry 97】 Compound.

24. formula: 【Chemistry 98】 Compound.

25. formula: 【Chemistry 99】 Compound.

26. formula: 【Chemistry 100】 Compound.

27. formula: 【Chemistry 101】 Compound.

28. formula: 【Chemistry 102】 Compound.

29. formula: 【Chemistry 103】 Compound.

30. formula: 【Chemistry 104】 Compound.

31. formula: 【Chemistry 105】 Compound.

32. formula: 【Chemistry 106】 Compound.

33. formula: 【Chemistry 107】 Compound.

34. formula: 【Chemistry 108】 Compound.

35. formula: 【Chemistry 109】 Compound.

36. formula: 【Chemistry 110】 Compound.

37. formula: 【Chemistry 111】 Compound.

38. formula: 【Chemistry 112】 Compound.

39. formula: 【Chemistry 113】 A pharma- ceutically acceptable salt of

40. formula: 【Chemistry 114】 A pharma- ceutically acceptable salt of

41. formula: 【Chemistry 115】 A pharma- ceutically acceptable salt of

42. formula: 【Chemistry 116】 A pharma- ceutically acceptable salt of

43. formula: 【Chemistry 117】 A pharma- ceutically acceptable salt of

44. formula: 【Chemistry 118】 A pharma- ceutically acceptable salt of

45. formula: 【Chemistry 119】 A pharma- ceutically acceptable salt of

46. formula: 【Chemistry 120】 A pharma- ceutically acceptable salt of

47. formula: 【Chemistry 121】 A pharma- ceutically acceptable salt of

48. formula: 【Chemistry 122】 A pharma- ceutically acceptable salt of

49. formula: 【Chemistry 123】 A pharma- ceutically acceptable salt of

50. formula: 【Chemistry 124】 A pharma- ceutically acceptable salt of

51. formula: 【Chemistry 125】 A pharma- ceutically acceptable salt of

52. formula: 【Chemistry 126】 A pharma- ceutically acceptable salt of

53. formula: 【Chemistry 127】 A pharma- ceutically acceptable salt of

54. formula: 【Chemistry 128】 A pharma- ceutically acceptable salt of

55. formula: 【Chemistry 129】 A pharma- ceutically acceptable salt of

56. formula: 【Chemistry 130】 A pharma- ceutically acceptable salt of

57. formula: 【Chemistry 131】 A pharma- ceutically acceptable salt of

58. formula: 【Chemistry 132】 A pharma- ceutically acceptable salt of

59. formula: 【Chemistry 133】 A pharma- ceutically acceptable salt of

60. formula: 【Chemistry 134】 A pharma- ceutically acceptable salt of

61. formula: 【Chemistry 135】 A pharma- ceutically acceptable salt of

62. formula: 【Chemistry 136】 A pharma- ceutically acceptable salt of

63. formula: 【Chemistry 137】 A pharma- ceutically acceptable salt of

64. formula: 【Chemistry 138】 A pharma- ceutically acceptable salt of

65. A pharmaceutical composition comprising a compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 12, a compound according to any one of claims 13 to 38, or a pharma- ceutically acceptable salt according to any one of claims 39 to 64, and a pharma- ceutically acceptable excipient.

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