Neuroactive steroids, compositions and uses thereof

Abstract

Described herein are neuroactive steroids of formula (I): or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 , R 5 , A and L are as defined herein. In certain embodiments, these compounds are contemplated to act as GABA modulators. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and methods of use and treatment, for example, for inducing sedation and / or anesthesia.

Description

[0001] This application is a divisional application based on a patent application with application date of August 22, 2014, application number 201480052272.4 (PCT / US2014 / 052417), and invention name: "Neurologically active steroids, compositions and uses thereof".

[0002] Related Applications

[0003] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application USSN 61 / 869,440 filed on August 23, 2013, U.S. Provisional Patent Application USSN 61 / 869,446 filed on August 23, 2013, and U.S. Provisional Patent Application USSN 62 / 014,018 filed on June 18, 2014, each of which is incorporated herein by reference. Background Art

[0004] Brain excitability is defined as the animal's level of arousal, a continuum ranging from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conduction of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of about -70 mV, with the interior of the cell being negative relative to the exterior of the cell. The potential (voltage) is the sum of the ions (K) across the semipermeable membrane of the neuron. + 、Na + , Cl – , organic anions) balance. Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine will cause membrane depolarization, for example, the potential changes from -70mV to -50mV. This effect is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase Na + Membrane permeability to ions. Reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

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

[0006] It has been well documented that the GRC is responsible for the mediation of anxiety, seizures, and sedation. Thus, GABA and drugs that act like GABA or enhance the actions of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZ), e.g. ) produces its therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulated evidence now suggests that, in addition to the benzodiazepine and barbiturate binding sites, the GRC contains different sites for neuroactive steroids. See, e.g., Lan, NC et al., Neurochem. Res. (1991) 16: 347-356.

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

[0008] The ovarian hormone progesterone and its metabolites have been shown to have a profound effect on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130: 19-24 (1985); Pfaff, DW and McEwen, BS, Science 219: 808-814 (1983); Gyermek et al., J Med Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 8: 224-227 (1987)). The levels of progesterone and its metabolites vary with the phase of the menstrual cycle. It has been well documented that the levels of progesterone and its metabolites decrease before the onset of menstruation. In addition, the monthly recurrence of certain physical symptoms before the onset of menstruation has been well documented. These symptoms, which have become associated with premenstrual syndrome (PMS), include tension, anxiety, and migraines (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)). Subjects with PMS have monthly recurrences of symptoms that are present before menstruation and absent after menstruation.

[0009] In a similar manner, progesterone reduction is also temporally associated with increased frequency of seizures in female epilepsy (i.e., catamenial epilepsy) (Laidlaw, J., Lancet, 1235-1237 (1956)). A more direct correlation has been observed with respect to reductions in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). In addition, for subjects with primary generalized petit mal epilepsy, the temporal incidence of seizures has been correlated with the incidence of symptoms of premenstrual syndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating subjects with petit mal epilepsy associated with their menstrual cycle (Aird, RB and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)).

[0010] In addition, the symptom associated with low progesterone levels is postpartum depression (PND). Shortly after childbirth, progesterone levels decrease sharply, causing PND to break out. The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe anxiety and irritability. PND-related depression is not suitable for treatment by classical antidepressants, and women experiencing PND show an increased incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).

[0011] Collectively, these observations implicate a key role for progesterone and deoxycorticosterone and more specifically their metabolites in the homeostatic regulation of brain excitability, which manifests as an increase in seizures or symptoms associated with catamenial epilepsy, PMS, and PND. The correlation between decreased progesterone levels and symptoms associated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8-20 (1983); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy," Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279-282; and Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd ed., Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in treating the aforementioned syndromes. For example, there is no dose-response relationship for progesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).

[0012] There is a need for new and improved neuroactive steroids that act as modulators of brain excitability, as well as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are directed to this goal. Summary of the invention

[0013] Provided herein is a C21-substituted neuroactive steroid designed, for example, to act as a GABA modulator. In certain embodiments, these compounds are envisioned to be used as therapeutic agents for inducing anesthesia and / or sedation in a subject. In some embodiments, these compounds are envisioned to be used as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders, schizophrenia spectrum disorders, spasticity, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes or tinnitus) in subjects in need (e.g., subjects with Rett syndrome, fragile X syndrome or Angelman syndrome).

[0014] In one aspect, there is provided a compound of formula (I):

[0015]

[0016] A pharmaceutically acceptable salt thereof, wherein: A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group; L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -; R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic or heterocyclic; R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy; each R 3 are independently hydrogen or C1-C6 alkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 Does not exist.

[0017] The invention also provides pharmaceutical compositions comprising the compounds of the invention as well as methods of use and treatment, for example, for inducing sedation and / or anesthesia, for treating CNS-related disorders.

[0018] The steroids of formula (I), subgenuses thereof and pharmaceutically acceptable salts thereof are collectively referred to herein as "compounds of the present invention".

[0019] In another aspect, a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient is provided. In certain embodiments, the compound of the invention is provided in an effective amount in a pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the invention is provided in a preventive effective amount.

[0020] In certain embodiments, the compounds of the invention as described herein act as GABA modulators, e.g., affecting GABA in a positive or negative manner. A receptors. As regulated by GABA A These compounds are modulators of central nervous system (CNS) excitability mediated by receptors and are expected to have CNS activity.

[0021] Therefore, in another aspect, there is provided a method for treating a CNS-related disorder in a subject in need thereof, comprising administering an effective amount of the compounds of the present invention to the subject. In certain embodiments, the CNS-related disorder is selected from sleep disorders, mood disorders, schizophrenia spectrum disorders, spasticity, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, drug abuse disorders and / or withdrawal syndrome and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously or intramuscularly. In certain embodiments, the compound is administered for a long time. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0022] Other objects and advantages will become apparent to those skilled in the art from consideration of the ensuing detailed description, examples, and claims.

[0023] definition

[0024] Chemical Definition

[0025] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside front cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0026] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers (including racemic mixtures and mixtures enriched in one or more stereoisomers). Isomers may be separated from a mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein in the form of individual isomers substantially free of other isomers and, optionally, in the form of mixtures of various isomers.

[0027] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of the 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" means that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0028] In the compositions provided herein, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in these compositions may, for example, comprise at least about 95% by weight R-compound and up to about 5% by weight S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in these compositions may, for example, comprise at least about 95% by weight S-compound and up to about 5% by weight R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated in small amounts or without excipients or carriers.

[0029] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O in any isotopic form, including 16 O and 18 O; etc.

[0030] The articles "a" and "an" may be used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article. For example, "an analogue" refers to one analogue or more than one analogue.

[0031] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0032] The following terms are intended to have the meanings presented therewith below and can be used to understand the description and intended scope of the present invention.

[0033] "Alkyl" refers to a straight-chain 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 8 carbon atoms (“C 1-8 In some embodiments, an alkyl group has 1 to 6 carbon atoms (“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 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5) and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each instance of alkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, the alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0034] "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C2-20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 In some embodiments, the alkenyl group is an unsubstituted C 1-4-alkenyl, an octenyl group, an octenyl group, an octatrienyl group, and the like. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of alkenyl is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkenyl”). In certain embodiments, the alkenyl group is an unsubstituted C 1-4-alkenyl, an octenyl group, an octatrienyl group, an octatrienyl group, and the like. 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 Alkenyl.

[0035] "Alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2-20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 In some embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 Alkynyl and pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each instance of alkynyl is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkynyl”). In certain embodiments, the alkynyl is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0036] "Aryl" refers to a group that provides 6-14 ring carbon atoms and 0 heteroatoms in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10 or 14 π electrons shared in the cyclic array) ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms (a "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (a "C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyls or heterocyclyls, wherein the radical or point of attachment is on the aryl ring, and in these cases, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. Aryl includes, but is not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise indicated, each instance of aryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, the aryl is unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl.

[0037] In certain embodiments, the aryl group substituted with one or more groups is selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0038] Representative examples of substituted aryl groups include the following

[0039]

[0040] Where R 56 and R 57 One of them may be hydrogen and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 S02R 59 、COO alkyl、COO aryl、CONR 58 R 59 ,CONR 58 OR 59 NR 58 R 59 、SO2NR 58 R 59 , S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R 56 and R 57 may be joined 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, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, substituted C6-C 10 aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl.

[0041] Other representative aryl groups having fused heterocyclic groups include the following:

[0042]

[0043] Where each W is selected from C(R 66 )2. NR 66 , O and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C10 Aryl and 5-10 membered heteroaryl.

[0044] Unless otherwise stated, "halo" or "halogen" by itself or as part of another substituent refers to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide" by itself or as part of another substituent refers to a fluoride, chloride, bromide, or iodide atom. In certain embodiments, halo is fluorine or chlorine.

[0045] "Haloalkyl" and "haloalkoxy" may include alkyl and alkoxy structures substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein the halo group is fluorine.

[0046] "Heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., sharing 6 or 10 π electrons in the cyclic array) providing ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as allowed by valence. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in these cases, the number of ring members continues to specify 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 to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in these cases, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryls, one of the rings contains no heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0047] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system providing ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system providing ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system providing ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl 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 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl.

[0048] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. 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, azobenzene, oxadiazolyl, and thiazolyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0049] Examples of representative heteroaryl groups include the following:

[0050]

[0051] wherein each Y is selected from carbonyl, N, NR 65 , O and S; and R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl.

[0052] "Carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the 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 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclic groups include (but are not limited to) the aforementioned C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include (but are not limited to) the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) and the like. As the aforementioned examples illustrate, in certain embodiments, the carbocyclyl is a monocyclic ring ("monocyclic carbocyclyl") or contains a fused, bridged or spirocyclic ring system such as a bicyclic ring system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in these cases, the carbon number continues to specify the carbon number in the carbocyclic ring system. Unless otherwise specified, each case of the carbocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, the carbocyclyl is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl is a substituted C 3-10 Carbocyclic group.

[0053] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-10 In 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 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the cycloalkyl group include the aforementioned C 5-6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the cycloalkyl group include the aforementioned C 3-6 Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl is unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 Cycloalkyl.

[0054] "Heterocyclyl" or "heterocycle" refers to a radical of a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. A heterocyclyl may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyls, wherein the point of attachment is on a carbocyclyl or heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryls or heteroaryls, wherein the point of attachment is on a heterocyclyl ring, and in these cases, the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each case of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl is a substituted 3-10 membered heterocyclyl.

[0055] In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0056] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxocanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. 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, and the like.

[0057] Specific examples of heterocyclic groups are shown in the following illustrative examples:

[0058]

[0059] where each W is selected from CR 67 , C(R 67 )2. NR 67 , O and S; and each Y is selected from NR 67 , O and S; and R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10aryl and 5-10 membered heteroaryl. These heterocyclic rings may be optionally substituted with one or more groups selected from acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amide), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxyl, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl and -S(O)2-aryl. Substituents include carbonyl or thiocarbonyl groups that provide, for example, lactam and urea derivatives.

[0060] "Acyl" refers to the group -C(O)R 20 , where R 20 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, or substituted or unsubstituted heteroaryl as defined herein. "Alkanoyl" is an acyl radical in which R 20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 Aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R 21 is a C1-C8 alkyl group substituted by a halogen or hydroxyl group; or a C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0061] "Acylamino" refers to the group -NR 22 C(O)R 23 , where R 22 and R 23each instance of is independently 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, or R 22 is an amino protecting group. Exemplary "acylamino" include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. A specific exemplary "acylamino" is -NR 24 C(O)-C1-C8 alkyl, -NR 24 C(O)-(CH2) t (C6-C 10 Aryl), -NR 24 C(O)-(CH2) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -NR 24 C(O)-(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and each R 24 In certain embodiments, R 25 is H, C1-C8 alkyl substituted by halogen or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; and R 26 is H, C1-C8 alkyl substituted by halogen or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that R 25 and R 26 At least one of them is not H.

[0062] "Acyloxy" refers to the group -OC(O)R 27 , where R27 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, or substituted or unsubstituted heteroaryl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 is a C1-C8 alkyl group substituted by a halogen or hydroxyl group; 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0063] "Alkoxy" refers to the group -OR 29 , where R 29 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0064] In certain embodiments, R 29 is a group having 1 or more substituents, for example 1 to 5 substituents, and particularly 1 to 3 substituents, particularly 1 substituent, selected from amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary "substituted alkoxy" include, but are not limited to, -O-(CH2) t (C6-C 10 Aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3-C 10Cycloalkyl) and -O-(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary 'substituted alkoxy' are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

[0065] "Amino" refers to the group -NH2.

[0066] "Substituted amino" refers to a group of the formula -N(R 38 )2 amino group, wherein R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or an amino protecting group, wherein R 38 In certain embodiments, at least one of R 38 independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted by halogen or hydroxy; C3-C8 alkenyl substituted by halogen or hydroxy; C3-C8 alkynyl substituted by halogen or hydroxy, or -(CH2) t (C6-C 10 Aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3-C 10 Cycloalkyl) or -(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 8, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; or two R 38 The groups are joined to form an alkylene group.

[0067] Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C1-C8 alkyl, -NR 39 -(CH2)t (C6-C 10 Aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 Cycloalkyl) and -NR 39 -(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, such as 1 or 2, and each R 39 independently represents hydrogen or C1-C8 alkyl; and any alkyl present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocyclyl present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term 'substituted amino' includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below. Substituted amino encompasses monosubstituted amino and disubstituted amino groups.

[0068] "Azide" refers to the group -N3.

[0069] "Carbamyl" or "amido" refers to the group -C(O)NH2.

[0070] "Substituted carbamyl" or "substituted amide" refers to the group -C(O)N(R 62 )2, where each R 62 are independently 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, wherein R 62 In certain embodiments, at least one of R 62 Selected from H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl; or C1-C8 alkyl substituted by halogen or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10aryl or 5-10 membered heteroaryl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R 62 Not H.

[0071] "Carboxy" refers to the group -C(O)OH.

[0072] "Cyano" refers to the radical -CN.

[0073] "Hydroxy" refers to the radical -OH.

[0074] "Nitro" refers to the radical -NO2.

[0075] "Vinyl" refers to substituted or unsubstituted -(C=C)-. "Ethylene" refers to substituted or unsubstituted -(CC)-. "Ethynyl" refers to -(C≡C)-.

[0076] "Nitrogen-containing heterocyclic group" refers to a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone and piperazinone.

[0077] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted (e.g., "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). In general, the term "substituted", whether preceded by the term "optionally" or not, 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, upon substitution, results in a stable compound (e.g., a compound that does not spontaneously undergo a transformation such as a 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 substituent at each position is the same or different. The term "substituted" is intended to include organic compounds substituted with all permissible substituents, any of which described herein results in the formation of stable compounds. The present invention encompasses any and all of these combinations to obtain stable compounds. For purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the heteroatom valence and result in the formation of a stable moiety.

[0078] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb , -SH, -SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc 2. -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2, -OC(=O)N(R bb )2.-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(Rbb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bbP(=O)(NR bb )2. -P(R cc )2. -P(R cc )3.-OP(R cc )2.-OP(R cc )3. -B(R aa )2、-B(OR cc )2. -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0079] R aa Each occurrence of is independently selected from C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0080] R bb Each instance of is independently selected from hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc)2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa ,-P(=O)(R aa )2、-P(=O)2N(R cc )2, -P(=O)(NR cc 2. C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0081] R cc Each instance of is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0082] R dd Each instance of is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2、-N(R ff )3 + X - 、-N(OR ee )R ff , -SH, -SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee、-C(=O)N(R ff )2, -OC(=O)N(R ff )2.-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2.-NR ff C(=NR ff )N(R ff )2.-NR ff S02R ee 、-SO2N(R ff 2. -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3.-OSi(R ee )3. -C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2R ee 、-P(=O)(R ee )2.-OP(=O)(R ee )2.-OP(=O)(OR ee 2. C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0083] R eeEach occurrence of is independently selected from C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0084] R ff Each instance of is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg group substitution; and

[0085] R gg Each instance of is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl; wherein X - It is a counter ion.

[0086] "Counter ions" or "anionic counter ions" are negatively charged groups associated with cationic quaternary amino groups to maintain electronic neutrality. Exemplary counter ions include halides (e.g., F - , Cl - Br - ,I - )、NO3 - 、ClO4 - OH - 、H2PO4 - 、HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0087] The nitrogen atoms may be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc 2. -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa ,-P(=O)(R aa)2、-P(=O)2N(R cc )2, -P(=O)(NR cc 2. C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R attached to a nitrogen atom cc The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc and R dd As defined above.

[0088] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -OR aa 、-N(R cc )2, -C(=O)R aa 、-C(=O)OR aa 、-C(=O)N(R cc )2, -S(=O)2R aa 、-C(=NR cc )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc 2. -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc , C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein Raa , R bb , R cc and R dd As defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, incorporated herein by reference.

[0089] 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), tert-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., -S(=O)2R aa ), including but not limited to toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

[0090] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxy protecting group). Oxygen protecting groups include, but are not limited to, -R aa 、-N(R bb )2, -C(=O)SR aa 、-C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2, -C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2, -S(=O)R aa 、-SO2R aa 、-Si(R aa )3. -P(R cc )2. -P(R cc )3, -P(=O)2R aa ,-P(=O)(R aa )2.-P(=O)(OR cc )2、-P(=O)2N(R bb )2 and -P(=O)(NR bb )2, where R aa , Rbb and R cc As defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0091] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0092] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known 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 、-CO2R aa 、-C(=O)N(R bb )2, -C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2, -S(=O)R aa 、-SO2R aa 、-Si(R aa ) 3、 -P(R cc )2. -P(R cc )3, -P(=O)2R aa 、-P(=O)(R aa )2.-P(=O)(OR cc )2、-P(=O)2N(R bb )2 and -P(=O)(NR bb )2, where R aa , R bb and R ccAs defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0093] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims.The present invention is not intended to be limited in any way by the foregoing exemplary list of substituents.

[0094] Other definitions

[0095] As used herein, the term "modulate" refers to the inhibition or enhancement of GABA receptor function. A "modulator" (eg, a modulator compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of a GABA receptor.

[0096] "Pharmaceutically acceptable" means approved or may be approved by a regulatory agency of the Federal or a state government, or corresponding agencies in countries outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0097] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, these salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, these salts include: (1) acid addition salts, which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or 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. or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth ions or aluminum ions; or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. By way of example only, salts also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, it is a salt of a non-toxic organic or non-polar acid, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, for example, Berge et al., J. Pharm. Sci. (1977) 66 (1): 1-79.

[0098] "Solvate" refers to a form of a compound that is associated with a solvent or water, usually by a solvolysis reaction (also referred to as a "hydrate"). This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the invention can be prepared, for example, in a crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include stoichiometric solvates and non-stoichiometric solvates. In certain cases, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to separate. "Solvate" encompasses both solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0099] As used herein, the term "isotopic variant" refers to a compound in which one or more atoms constituting such a compound contain isotopes in an unnatural proportion. For example, an "isotopic variant" of a compound may contain one or more non-radioactive isotopes, such as deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 It will be appreciated that in compounds subject to such isotopic substitution, the following atoms, when present, may be altered so that, for example, any hydrogen may be 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and placement of these atoms can be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants having radioactive isotopes, for example, where the resulting compounds are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose in view of their ease of incorporation and readily available detection means. In addition, it is possible to prepare 11 C. 18 F. 15 O and 13 N substituted and will be useful in compounds used in positron emission tomography (PET) studies to study substrate receptor occupancy. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0100] "Stereoisomers": It is further understood that compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers whose atoms are arranged differently in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequential rules of Cahn and Prelog, or by the following description: wherein the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0101] "Tautomers" refer to compounds that are interconvertible forms of a particular compound structure and that have altered displacements of hydrogen atoms and electrons. Thus, through the movement of π electrons and atoms (usually H), the two structures can be in equilibrium. For example, enols and ketones are tautomers because they can be rapidly interconverted by treatment with an acid or base. Another example of tautomerism is the acid- and nitro-forms of phenylnitromethane, which are also formed by treatment with an acid or base. Tautomeric forms may be relevant to the achievement of optimal chemical reactivity and biological activity of the compound of interest.

[0102] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0103] Disease, disorder and condition are used interchangeably herein.

[0104] As used herein, and unless otherwise indicated, the term "treatment" encompasses actions that occur while a subject is suffering from a specified disease, disorder or condition, that reduce the severity of the disease, disorder or condition, or that delay or slow the progression of the disease, disorder or condition ("therapeutic treatment"), as well as actions that occur before a subject begins to suffer from a specified disease, disorder or condition ("prophylactic treatment").

[0105] In general, an "effective amount" of a compound refers to an amount sufficient to cause a desired biological response, such as to treat a CNS-related disorder, to induce anesthesia or sedation. As will be appreciated by one of ordinary skill in the art, the effective amount of a compound of the invention may vary according to factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health and condition of the subject. An effective amount encompasses both therapeutic and prophylactic treatments.

[0106] As used herein, and unless otherwise indicated, 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 the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0107] As used herein, and unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the treatment of a disease, disorder or condition. The term "prophylactically effective amount" may encompass an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent. DETAILED DESCRIPTION

[0108] As generally described herein, the present invention provides C21 substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, these compounds are envisioned to be useful as therapeutic agents for inducing anesthesia and / or sedation in a subject. In certain embodiments, these compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders.

[0109] Compound

[0110] In one aspect, there is provided a compound of formula (I):

[0111]

[0112] A pharmaceutically acceptable salt thereof, wherein: A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group; L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -; R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic or heterocyclic; R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy; each R 3 are independently hydrogen or C1-C6 alkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 Does not exist.

[0113] In one aspect, a compound of formula (Ia) is provided:

[0114]

[0115] A pharmaceutically acceptable salt thereof, wherein: A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group; L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -; R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic or heterocyclic; each R 3 are independently hydrogen or C1-C6 alkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 Does not exist.

[0116] In some embodiments, the compound has formula (Ia-1):

[0117]

[0118] In some embodiments, the compound has formula (Ia-2):

[0119]

[0120] In some embodiments, A is monocyclic or bicyclic.

[0121] In some embodiments, A is monocyclic. In some aspects of these embodiments, A is attached through nitrogen. In some embodiments, A is heteroaryl. In some aspects of these embodiments, the heteroaryl contains up to five nitrogen atoms. In some embodiments, A is a 5-membered heteroaryl or heterocyclyl. In some embodiments, A is a 5-membered heteroaryl or heterocyclyl containing up to four nitrogen atoms. In some embodiments, A is a 5-membered heteroaryl or heterocyclyl containing 2, 3 or 4 nitrogen atoms. In some embodiments, A is pyrazole, triazole or tetrazole. In some embodiments, A is unsubstituted pyrazole, triazole or tetrazole. In some embodiments, A is In some embodiments, A is unsubstituted triazole. In some embodiments, A is

[0122] In some embodiments, A is bicyclic. In some aspects of these embodiments, A is connected by nitrogen. In some embodiments, A is heteroaryl. In some aspects of these embodiments, the heteroaryl comprises up to five nitrogen atoms. In some embodiments, the heteroaryl comprises at least two nitrogen atoms. In some embodiments, A is a heteroaryl comprising up to four nitrogen atoms. In some embodiments, A is a heteroaryl comprising up to three nitrogen atoms. In some embodiments, A is a heteroaryl comprising 2, 3 or 4 nitrogen atoms. In some embodiments, the heteroaryl is benzotriazole, azabenzotriazole, diazabenzotriazole, benzopyrazole, azabenzopyrazole or diazabenzopyrazole.

[0123] In some embodiments, the compound has formula (Ia-3):

[0124]

[0125] Where R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(R c )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a 、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c ); each R a is hydrogen or C1-C6 alkyl; each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or R b and R c Together with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and n is 0, 1, 2 or 3.

[0126] In some embodiments, the compound has formula (Ia-4):

[0127]

[0128] Where R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(R c )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a 、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c ); each R a is hydrogen or C1-C6 alkyl; each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or R b and R c Together with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and n is 0, 1, 2 or 3.

[0129] In some embodiments, n is 0.

[0130] In some embodiments, n is 1. In some aspects of these embodiments, R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)OR a or -S(O) 0-2 R a In some embodiments, n is 1 and R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)OR a or -S(O) 0-2 R a In some aspects of these embodiments, R 4 is halo (eg, F, Cl, Br). 4is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is C1-C6 alkoxy (e.g., -OCH3, -OCH2CH3). 4 In some embodiments, R 4 Yes-C(O)R a or-C(O)OR a In some aspects of these embodiments, R a is C1-C6 alkyl (e.g., -CH3, -CH2CH3). 4 Yes-S(O) 0-2 R a In some embodiments, R 4 Yes-S(O)2R a , and R a is C1-C6 alkyl. In some aspects of these embodiments, R a is -CH3. In some embodiments, R 4 is -S(O)2CH3. In some embodiments, R 4 It is a C1-C6 alkyl group (e.g., -CH3, -CH2CH3).

[0131] In some embodiments, n is 2. In some aspects of these embodiments, R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)OR a or -S(O) 0-2 R a In some embodiments, n is 2 and R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)OR a or -S(O) 0-2 R a In some aspects of these embodiments, R 4 is halo (eg, F, Cl, Br). 4 is F. In some embodiments, R 4 is Cl. In some embodiments, R 4 is Br. In some embodiments, R 4 is C1-C6 alkoxy (e.g., -OCH3, -OCH2CH3). 4In some embodiments, R 4 Yes-C(O)R a or-C(O)OR a In some aspects of these embodiments, R a is C1-C6 alkyl (e.g., -CH3, -CH2CH3). 4 Yes-S(O) 0-2 R a In some embodiments, R 4 Yes-S(O)2R a , and R a is C1-C6 alkyl. In some aspects of these embodiments, R a is -CH3. In some embodiments, R 4 It is a C1-C6 alkyl group (e.g., -CH3, -CH2CH3).

[0132] In some embodiments, n is 1 or 2, and R 4 is C1-C6 alkyl or C(O)OR a In some embodiments, the compound R 4 In some embodiments, the compound R a is C1-C6 alkyl. a It is ethyl.

[0133] In some embodiments, R 1 is hydrogen or C1-C6 alkyl, and R 4 Yes - C(O)OR a .

[0134] In some embodiments, R 1 is a C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic group or heterocyclic group. 1 is a C1-C6 alkyl group. 1 It is methyl, ethyl or isopropyl.

[0135] In some embodiments, R 1 is methyl and R 4 It is -C(O)OEt.

[0136] In some embodiments, the compound is selected from:

[0137]

[0138]

[0139] In one aspect, a compound of formula (Ib) is provided:

[0140]

[0141] A pharmaceutically acceptable salt thereof, wherein: A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group; L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -; R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic or heterocyclic; R 2 is C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy; each R 3 are independently hydrogen or C1-C6 alkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 Does not exist.

[0142] In some embodiments, the compound has formula (Ib-1):

[0143]

[0144] In some embodiments, the compound has formula (Ib-2):

[0145]

[0146] In some embodiments, the compound has formula (Ib-3)

[0147]

[0148] Where R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(R c )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c ); each R a is hydrogen or C1-C6 alkyl; each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or R b and R c Together with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and n is 0, 1, 2 or 3.

[0149] In some embodiments, the compound has formula (Ib-4)

[0150]

[0151] Where R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(R c )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a 、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c ); each R a is hydrogen or C1-C6 alkyl; each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or R b and R c Together with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and n is 0, 1, 2 or 3.

[0152] In some embodiments, A is monocyclic.

[0153] In some embodiments, A is bicyclic.

[0154] In some embodiments, A is linked through the nitrogen.

[0155] In some embodiments, A is a 5- or 6-membered heteroaryl or heterocyclyl. In some embodiments, A is a 5- or 6-membered heteroaryl or heterocyclyl containing up to four nitrogen atoms. In some embodiments, A is a 5- or 6-membered heteroaryl or heterocyclyl containing 1, 2, 3, or 4 nitrogen atoms.

[0156] In some embodiments, A is heterocyclyl. In some embodiments, A is morpholine or piperazine. In some embodiments, A is

[0157] In some embodiments, A is heteroaryl. In some aspects of these embodiments, the heteroaryl contains up to five nitrogen atoms. In some embodiments, the heteroaryl is benzotriazole, azabenzotriazole, diazabenzotriazole, benzopyrazole, azabenzopyrazole, or diazabenzopyrazole. In some embodiments, A is

[0158] In some embodiments, the heteroaryl is 5-membered.

[0159] In some embodiments, A comprises up to four nitrogen atoms. In some embodiments, A comprises 2, 3, or 4 nitrogen atoms. In some embodiments, A is pyrazole, triazole, or tetrazole. In some embodiments, A is unsubstituted pyrazole, triazole, or tetrazole. In some embodiments, A is In some embodiments, A is unsubstituted triazole. In some embodiments, A is

[0160] In some embodiments, R 1 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclyl or heterocyclyl. 1 is C1-C6 alkyl. 1 is methyl, ethyl or isopropyl. In some embodiments, R 1 In some embodiments, R 1 It is ethyl.

[0161] In some embodiments, R 2 It is C 1- C6 alkyl. In some embodiments, R 2 In some embodiments, R 2 It is C1- C6 haloalkyl. In some embodiments, R 2 It is -CF3.

[0162] In some embodiments, n is 0.

[0163] In some embodiments, n is 1 or 2, and R 4 is cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a or -S(O) 0-2 R a .

[0164] In some embodiments, R 4 is Br, Cl or F. In some embodiments, R 4 is F. In some embodiments, R 4 In some embodiments, R 4 is Br. In some embodiments, R 4 is -OCH3. In some embodiments, R 4 is -OCF3. In some embodiments, R 4 In some embodiments, R 4 is C1-C6 alkyl. 4 In some embodiments, R 4 Yes-C(O)R a In some embodiments, R a is C1-C6 alkyl. a In some embodiments, R 4 is -CF3. In some embodiments, R 4 Yes-S(O)2R a In some embodiments, R a It's methyl.

[0165] In some embodiments, R 1 is a C1-C6 alkyl group and R 4 Yes-C(O)R a In some embodiments, R 1 is methyl and R 4 It’s -C(O)Me.

[0166] In some embodiments, n is 2, and R 4 is cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a or -S(O) 0-2 R a In some embodiments, n is 2, one R4 is F and one R 4 is F. In some embodiments, n is 2, one R 4 is F and one R 4 In some embodiments, n is 2, one R 4 is -OCH3 and one R 4 It is -OCH3.

[0167] In some embodiments, n is 0 or 1; R 1 is hydrogen or C1-C6 alkyl; and R 2 It's methyl.

[0168] In some embodiments, R 1 is methyl, ethyl or isopropyl. In some embodiments, R 1 It's methyl.

[0169] In some embodiments, R 4 is C1-C6 alkyl, -C(O)R a or -S(O) 0-2 R a In some embodiments, R 4 In some embodiments, R 4 is -C(O)Me. In some embodiments, R 4 is -S(O)2Me. In some embodiments, R 4 It's cyano.

[0170] In some embodiments, the compound is selected from:

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183] In one aspect, there is provided a pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable excipient.

[0184] In one aspect, a method of inducing sedation and / or anesthesia in a subject is provided, comprising administering to the subject an effective amount of a compound of formula (I):

[0185]

[0186] A pharmaceutically acceptable salt thereof, wherein: A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group; L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -; R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic or heterocyclic; R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy; each R 3 are independently hydrogen or C1-C6 alkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 Does not exist.

[0187] In one aspect, a method is provided for administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound as described herein (e.g., a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib), (Ib-1), (Ib-2), (Ib-3), or (Ib-4)) to a subject in need thereof, wherein the subject experiences sedation and / or anesthesia within two hours of administration.

[0188] In some embodiments, the subject experiences sedation and / or anesthesia within one hour of administration.

[0189] In some embodiments, the subject is immediately subjected to sedation and / or anesthesia.

[0190] In some embodiments, the compound is administered by intravenous administration.

[0191] In some embodiments, the compound is administered chronically.

[0192] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0193] In some embodiments, the compound is administered in combination with another therapeutic agent.

[0194] In another aspect, a method for treating convulsions in a subject is provided, comprising administering to the subject an effective amount of a compound of formula (I):

[0195]

[0196] A pharmaceutically acceptable salt thereof, wherein: A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group; L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -; R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic or heterocyclic; R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy; each R 3 are independently hydrogen or C1-C6 alkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 Does not exist.

[0197] In one aspect, a method for treating epilepsy or status epilepticus in a subject is provided, the method comprising administering to the subject an effective amount of a compound of formula (I):

[0198]

[0199] A pharmaceutically acceptable salt thereof, wherein: A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group; L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -; R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic or heterocyclic; R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy; each R 3are independently hydrogen or C1-C6 alkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 Does not exist.

[0200] In one aspect, a method for treating a disorder related to GABA function in a subject in need thereof is provided, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of the compounds described herein (e.g., a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib), (Ib-1), (Ib-2), (Ib-3), or (Ib-4)).

[0201] In one aspect, a method for treating a CNS-related disorder in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound as described herein, e.g., a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib), (Ib-1), (Ib-2), (Ib-3) or (Ib-4), or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a spasticity 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, or tinnitus. In some embodiments, the subject is a subject with Rett syndrome, fragile X syndrome, or Angelman syndrome.

[0202] In one aspect, a kit is provided comprising a solid composition comprising a compound as described herein, e.g., a compound of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ib), (Ib-1), (Ib-2), (Ib-3), or (Ib-4), and a sterile diluent.

[0203] Pharmaceutical composition

[0204] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. 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. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0205] 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.

[0206] In general, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0207] When used to prevent the onset of CNS disorders, the compounds provided herein will generally be administered to subjects at risk of developing the condition at the above dosage levels, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include those with a family history of the condition, or those who have been identified by genetic testing or screening as being particularly susceptible to the condition.

[0208] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, e.g., for the remainder of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window over an extended period of time.

[0209] The pharmaceutical composition of the present invention can be delivered using a variety of administration methods in addition. For example, in certain embodiments, the pharmaceutical composition can be provided in a push form, for example, to increase the concentration of the compound in the blood to an effective level. The placement of the push dose depends on the systemic level of the required active ingredient in the whole body, for example, intramuscular or subcutaneous push doses allow the slow release of the active ingredient, and the push directly delivered to the vein (for example, by IV drip) allows for faster delivery, which rapidly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be applied in a continuous infusion form (for example, by IV drip), to provide the maintenance of the steady-state concentration of the active ingredient in the subject. In addition, in other embodiments, the pharmaceutical composition can be first applied with a push dose, followed by continuous infusion.

[0210] Compositions for oral administration can be in the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, the composition is presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect, and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules, etc. in the case of solid compositions. In these compositions, the compound is usually a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), and the rest are various vehicles or excipients and processing aids that help form the desired dosage form.

[0211] Under oral administration, one to five and particularly two to four and usually three oral doses per day are representative schemes. Using these modes of administration, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, wherein preferred doses each provide about 0.1 to about 10 mg / kg and particularly about 1 to about 5 mg / kg.

[0212] Transdermal doses are generally selected to provide similar or lower blood levels than achieved using injectable doses, typically ranging from about 0.01 to about 20 weight percent, preferably about 0.1 to about 20 weight percent, preferably about 0.1 to about 10 weight percent, and more preferably about 0.5 to about 15 weight percent.

[0213] The injection dosage level ranges from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours and particularly for 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For a 40 to 80 kg human patient, the maximum total dose is not expected to exceed about 5 grams / day.

[0214] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0215] Injectable compositions are usually based on injectable sterile saline or phosphate buffered saline or other injectable excipients known in the art. As before, the active compound in these compositions is usually a minor component, usually about 0.05 to 10% by weight, and the rest is injectable excipients and the like.

[0216] Transdermal compositions are usually formulated into topical ointments or creams containing active ingredients. When formulated into an ointment, the active ingredient will usually be combined with a paraffin or water miscible ointment base. Alternatively, the active ingredient can be formulated into an ointment with, for example, an oil-in-water cream base. These transdermal preparations are well known in the art and usually include additional ingredients to enhance the skin penetration of the stability of the active ingredient or preparation. All of these known transdermal preparations and ingredients are included in the scope provided herein.

[0217] The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be achieved using a patch of either the reservoir or porous membrane type or the solid matrix variety.

[0218] The above components for orally administrable, injectable or topically administrable compositions are representative only. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8, which is incorporated herein by reference.

[0219] The compounds of the invention may also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0220] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochlorides, hydroiodides, hydrobromides, nitrates, sulfates, bisulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, p-toluenesulfonates, and the like.

[0221] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, eg, a composition suitable for injection, such as for intravenous (IV) administration.

[0222] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles suitable for the particular dosage form desired (e.g., injection), dispersion or suspension aids, surfactants, isotonic agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions and medicaments can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980); and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0223] 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.

[0224] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins composed of 6, 7 and 8 α-1,4-linked glucose units, respectively, which optionally contain one or more substituents on the linked sugar portion, including (but not limited to) substituted or unsubstituted methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as See, for example, US 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0225] The injectable compositions can be sterilized, for example, by filtration through a bacteria-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.

[0226] In general, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will generally be determined by a physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, etc.

[0227] The composition is presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions. In these compositions, the compound is usually a minor component (about 0.1% by weight to about 50% by weight or preferably about 1% by weight to about 40% by weight), and the rest are various vehicles or carriers and processing aids that help form the desired dosage form.

[0228] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. The combined administration can be performed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0229] Although the description of the pharmaceutical composition provided herein is mainly directed to a pharmaceutical composition suitable for administration to humans, it will be appreciated by those skilled in the art that these compositions are generally suitable for administration to animals of all kinds. The modification of a pharmaceutical composition suitable for administration to humans is fully understood so that the composition is suitable for administration to various animals, and a veterinary pharmacologist with ordinary skills can design and / or perform such modifications using ordinary experiments. General considerations in the preparation and / or manufacture of pharmaceutical compositions can be found in, for example, Remington: The Science and Practice of Pharmacy 21st edition, Lippincott Williams & Wilkins, 2005.

[0230] Use and treatment methods

[0231] As generally described herein, the present invention is directed to C21 substituted neuroactive steroids designed, for example, to act as GABA modulators. In certain embodiments, these compounds are envisioned to be useful as therapeutic agents for inducing anesthesia and / or sedation in a subject. In some embodiments, these compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders, schizophrenia spectrum disorders, spasticity, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, or tinnitus) in subjects in need (e.g., subjects with Rett syndrome, fragile X syndrome, or Angelman syndrome).

[0232] Thus, in one aspect, the present invention provides a method of inducing sedation and / or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention or a composition thereof. In certain embodiments, the compound is administered by intravenous administration.

[0233] Earlier studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) demonstrated that certain 3α-hydroxylated steroids are several orders of magnitude more effective as GABA receptor complex (GRC) modulators than others reported (see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. and Harrison et al. teach that 3α-hydroxylated-5-reduced steroids can only have a much lower level of effectiveness. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids makes them therapeutically effective for modulating brain excitability via the GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0234] Various synthetic steroids have also been made into neuroactive steroids. See, for example, U.S. Pat. No. 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, tic disorders and mood disorders in a therapeutically beneficial manner, which is suitable for GRC active agents, such as depression. Furthermore, it has been previously demonstrated that these steroids interact at a unique site on the GRC that is distinct from other known interaction sites (e.g., barbiturates, benzodiazepines, and GABA) where therapeutic benefits have previously been elicited for stress, anxiety, sleep, mood disorders, and tic disorders (see, e.g., Gee, KW and Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders," Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG and Morselli, PL, "Psychopharmacology of GABAergic Drugs," Psychopharmacology: The Third Generation of Progress, HY Meltzer, ed., Raven Press, NY (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable because of their duration, potency, and oral activity (along with other forms of administration).

[0235] The compounds of the present invention as described herein are generally designed to regulate GABA function, and therefore act as neuroactive steroids for treating and preventing CNS-related pathologies in subjects. Regulation as used herein refers to the inhibition or enhancement of GABA receptor function. Therefore, the compounds and pharmaceutical compositions provided herein can be used as therapeutic agents for preventing and / or treating CNS pathologies in mammals (including humans and non-human mammals). Therefore, and as previously described, the present invention includes and extends to the treatment methods within its scope, as well as compounds for these methods, and the use of these compounds for preparing drugs that can be used for these methods.

[0236] Exemplary CNS conditions associated with GABA modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., minor depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), tension, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], spastic disorders [e.g., epilepsy (e.g., status epilepticus (SE)), convulsions], memory and / or cognitive disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)) , dementia (e.g., Alzheimer's disease, Lewy body dementia, 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, autism of monogenic etiology such as synaptopathy, 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), vascular disease [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and / or withdrawal syndromes [e.g., opiate, cocaine, and / or alcohol addiction], and tinnitus.

[0237] In another aspect, a combination of a compound of the invention and another pharmacologically active agent is provided. The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. The combined administration can be performed by any technique apparent to those skilled in the art, including, for example, single, sequential, simultaneous, and alternating administration.

[0238] In another aspect, provided is a method of 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.

[0239] In another aspect, a method of treating or preventing stress or anxiety in a subject is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0240] In another aspect, a method of reducing or preventing convulsive 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.

[0241] In another aspect, provided is a method of alleviating or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0242] In another aspect, there is provided a method of inducing sleep and substantially maintaining the levels of REM sleep present in normal sleep without inducing substantial rebound insomnia, the method comprising administering an effective amount of a compound of the present invention.

[0243] In another aspect, a method of alleviating or preventing PMS or PND in a subject is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

[0244] In another aspect, a method of treating or preventing a mood disorder in a subject is provided, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In certain embodiments, the mood disorder is depression.

[0245] In another aspect, a method of inducing anesthesia in a subject is provided, comprising administering to the subject an effective amount of a compound of the invention.

[0246] In another aspect, a method of cognitive enhancement or treatment of memory disorders is provided, which is achieved by administering to the subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0247] In another aspect, a method of treating an attention disorder is provided by administering to the subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0248] In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

[0249] Anesthesia / sedation

[0250] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, hyporesponsiveness, skeletal muscle areflexia, reduced stress response, or all of these simultaneously. These effects can be obtained from a single drug that alone provides an appropriate combination of effects, or occasionally with a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the pain and suffering they would otherwise experience.

[0251] Sedation is the reduction of restlessness or agitation by the administration of pharmacological agents, usually to facilitate a medical procedure or diagnostic procedure.

[0252] Sedation and analgesia encompass a continuum of conscious states ranging from minimal sedation (anxiolysis) to general anesthesia.

[0253] Minimal sedation is also called anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are usually unaffected.

[0254] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness during which the patient intentionally responds to verbal naming, either alone or accompanied by mild tactile stimulation. Intervention is usually not required to maintain a patent airway. Spontaneous respiration is usually adequate. Cardiovascular function is usually maintained.

[0255] Deep sedation / analgesia is a drug-induced decrease in consciousness during which the patient cannot be easily aroused but responds intentionally to repeated or painful stimulation (not a reflexive withdrawal from painful stimulation). Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous breathing may be inadequate. Cardiovascular function is usually maintained.

[0256] General anesthesia is a drug-induced loss of consciousness during which the patient cannot be aroused, even to painful stimuli. The ability to maintain independent ventilatory function is often impaired and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required because of decreased spontaneous breathing or drug-induced decreases in neuromuscular function. Cardiovascular function may be impaired.

[0257] Sedation in the intensive care unit (ICU) reduces the patient's environmental awareness and their response to external stimuli. It can play a role in the care of critically ill patients and covers a wide variety of symptom control, which will vary between patients and in different individuals throughout their illness. Heavy sedation in intensive care has been used to facilitate endotracheal intubation tolerance and ventilator synchronization, often using neuromuscular blocking agents.

[0258] 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.

[0259] Procedural sedation and analgesia (also known as conscious sedation) is a technique in which a sedative or dissociative agent is administered with or without analgesics to induce a state that enables the subject to tolerate an unpleasant procedure while maintaining cardiopulmonary function.

[0260] Anxiety disorders

[0261] Anxiety disorders are an umbrella term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0262] Generalized anxiety disorder is a common chronic condition characterized by persistent anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety disorder experience nonspecific, persistent fears and worries and become overly concerned with everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0263] In panic disorder, a person suffers from brief episodes of intense fear and apprehension, often marked by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as fear or discomfort that comes on suddenly and peaks in less than ten minutes) can last for hours and can be triggered by stress, fear, or even exercise; but the specific cause is not always obvious. In addition to repeated, unexpected panic attacks, a diagnosis of panic disorder requires that the attack have long-term consequences: worry about the potential impact of the attack, persistent fear of future attacks, or significant changes in behavior associated with the attack. Therefore, those who suffer from panic disorder experience symptoms even outside of specific panic attacks. Typically, panic patients notice normal changes in heartbeat, leading them to feel that there is something wrong with their heart or that they are going to have another panic attack. In some cases, there is a heightened awareness of bodily functions (hypervigilance) during a panic attack, in which any perceived physiological changes are interpreted as potentially life-threatening illnesses (i.e., extreme hypochondriasis).

[0264] Obsessive-compulsive disorder is a group of anxiety disorders primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (compulsions to perform specific actions or rituals). The OCD thought pattern can be likened to a superstition in that it involves beliefs in cause-and-effect relationships that do not exist in reality. Often the process is completely illogical; for example, a compulsion to walk in a particular pattern may be used to mitigate a preoccupation with impending harm. And in many cases, the compulsions are completely inexplicable, simply a compulsion to complete a ritual triggered by nervous tension. In a few cases, an OCD patient may experience only obsessions, without overt compulsions; a much smaller number of patients experience only compulsions.

[0265] The single largest category of anxiety disorders is phobias, which include all cases in which fear and anxiety are triggered by specific stimuli or situations. Sufferers typically anticipate terrible consequences from encountering the object of their fear, which could be anything from an animal to a place to a bodily fluid.

[0266] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can result from extreme situations, such as war, rape, hostage situations, or even serious accidents. It can also result from long-term (chronic) exposure to severe stressors, such as a soldier who endures personal combat but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0267] Neurodegenerative diseases and conditions

[0268] The term "neurodegenerative disease" includes diseases and disorders associated with the progressive loss of neuronal structure or function, or neuronal death. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including symptoms associated with mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and spasticity (including for the treatment and prevention of seizures caused by schizoaffective disorder or caused by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injury (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; confusion; Down syndrome; drug-induced or medication-induced Parkinson's disease (e.g., neuroleptic-induced acute akathisia, acute dystonia, parkinsonism or tardive dyskinesia, neuroleptic malignant syndrome or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders, including akinesia and akinetic (rigid) syndromes (including calcification of the basal ganglia, corticobasal degeneration, multiple system atrophy, Parkinson's disease-ALS dementia complex, Parkinson's disease, postencephalitic Parkinson's disease, and progressive supranuclear palsy); muscle spasms and conditions associated with muscle spasms or weakness, including chorea (e.g., benign hereditary chorea, drug-induced chorea, hemitremors, Huntington's disease, neuroacanthocytosis, Sydenham chorea, and symptomatic chorea), movement disorders (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal myoclonus), The invention relates to a variety of neurological disorders, including focal myoclonus, tremor (e.g., rest tremor, postural tremor, and intention tremor), and dystonia (including longitudinal dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal damage, including eye damage, retinopathy of the eye, or macular degeneration; neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest; Parkinson's disease; convulsions; status epilepticus; stroke; tinnitus; tuberous sclerosis, and neurodegenerative diseases caused by viral infections (e.g., caused by acquired immune deficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include (but are not limited to) neurotoxic injury following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest.Methods of treating or preventing a neurodegenerative disease also include treating or preventing the loss of neuronal function characteristic of a neurodegenerative disorder.

[0269] epilepsy

[0270] Epilepsy is a brain disorder characterized by recurrent convulsions over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as absence epilepsy in children, myoclonic epilepsy in juveniles, epilepsy with grand mal convulsions upon awakening, West syndrome, Lennox-Gastaut syndrome; partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

[0271] Status epilepticus (SE)

[0272] Status epilepticus (SE) may include, for example, convulsive status epilepticus, for example, early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, for example, generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic convulsions, and may include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epileptic convulsions that persist despite treatment with first-line therapy, and second-line therapy is administered. Refractory status epilepticus is characterized by status epileptic convulsions that persist despite treatment with first-line and second-line therapy, and general anesthesia is usually administered. Super-refractory status epilepticus is characterized by status epileptic convulsions that persist despite treatment with first-line therapy, second-line therapy, and general anesthesia for 24 hours or more.

[0273] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as tardive absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0274] The compositions described herein can also be administered as a prophylactic agent prior to a seizure to a subject having: 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.

[0275] twitch

[0276] A convulsion is a physical consequence or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "convulsion" is often used interchangeably with "fit." A convulsion occurs when a person's body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0277] Seizures are divided into two categories based on the type of behavior and brain activity: generalized and partial (also called localized or focal). Categorizing seizure types helps doctors diagnose whether a patient has epilepsy.

[0278] Generalized convulsions are produced by electrical impulses from the entire brain, whereas partial convulsions are produced by electrical impulses in a relatively small part of the brain (at least initially). The part of the brain that produces the convulsion is sometimes called the focus.

[0279] There are six types of generalized convulsions. The most common and violent and therefore the most well-known are generalized spasms, also known as grand mal convulsions. In this type of convulsion, the patient loses consciousness and usually collapses. The loss of consciousness is followed by generalized body stiffness (called the "tonic" phase of the convulsion), which lasts for 30 to 60 seconds, followed by violent shaking (the "clonic" phase), which lasts for 30 to 60 seconds, after which the patient enters a deep sleep (the "postictal" or post-convulsive phase). During a grand mal convulsion, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0280] Absence convulsions cause a brief loss of consciousness (only a few seconds) with few or no symptoms. The patient (most often a child) usually stops moving and stares blankly. These convulsions start and end suddenly and may occur several times a day. Patients usually do not know they have a convulsion, but they may be aware of the "lost time".

[0281] Myoclonic jerks consist of sporadic twitching, usually on both sides of the body. Patients sometimes describe the twitches as brief electric shocks. When severe, these twitches may cause falling or involuntary throwing of objects.

[0282] Clonic seizures are repetitive, rhythmic spasms that involve both sides of the body at the same time.

[0283] Tonic convulsions are characterized by stiffening of the muscles.

[0284] Atonic seizures consist of a sudden and generalized loss of muscle tone, especially in the arms and legs, which often results in a fall.

[0285] Seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; uninterrupted seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory spasmodic status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic area seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized paroxysmal seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; micro-seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

[0286] Equivalents and scope

[0287] In the claims, unless indicated to the contrary or otherwise obvious from the context, articles such as "a", "an" and "the" may refer to one or more than one. Unless indicated to the contrary or otherwise obvious from the context, a claim or description that includes "or" between one or more group members is considered satisfied if one, more than one, or all of the group members are present, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one group member is present, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all of the group members are present, used in, or otherwise relevant to a given product or process.

[0288] In addition, the present invention encompasses all variations, combinations and arrangements in which one or more limitations, elements, clauses and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations present in any other claim that depends on the same basic claim. When an element is presented in a list form (e.g., in a Markush group format), each subgroup of the element is also disclosed, and any element can be removed from the group. It should be understood that, in general, when the present invention or aspects of the present invention are referred to as including specific elements and / or features, certain embodiments of the present invention or aspects of the present invention are composed of or substantially composed of these elements and / or features. For the purpose of simplification, those embodiments are not explicitly described in these words herein. It is further noted that the terms "comprising" and "containing" are intended to be open and allow the inclusion of additional elements or steps. When a range is given, the endpoints are included. In addition, unless otherwise stated or otherwise apparent from the context and understood by a person of ordinary skill in the art, the value represented by the range in different embodiments of the present invention may take any specific value or subrange within the range, to one tenth of the unit of the lower limit of the range, unless otherwise clearly stated in the context.

[0289] This application mentions various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any incorporated reference and this specification, the present specification shall prevail. In addition, any specific embodiment of the present invention that falls within the scope of the prior art may be explicitly excluded from any one or more claims. Because these embodiments are considered to be known to those of ordinary skill in the art, they may be excluded, even if the exclusion is not explicitly set forth herein. Any specific embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of the prior art.

[0290] Those skilled in the art will recognize or be able to determine using only routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above description, but is set forth in the appended claims. It will be appreciated by those of ordinary skill in the art that various changes and modifications may be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

[0291] Example

[0292] 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 should not be construed as limiting the scope thereof in any way.

[0293] Materials and methods

[0294] Compounds provided herein can be prepared from readily available raw materials using the following general methods and procedures. It should be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary with the specific reactants or solvents used, but those skilled in the art may determine these conditions by conventional optimization.

[0295] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from experiencing undesirable reactions. The selection of protecting groups suitable for specific functional groups and conditions suitable for protection and deprotection is well known in the art. For example, numerous protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, Protecting groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and the references cited therein.

[0296] The compounds provided herein can be isolated and purified by known standard procedures. These procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail to prepare the representative heteroaryl and heterocyclic groups listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from known or commercially available raw materials and reagents. Exemplary chiral columns that can be used in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to: AD-10, OB, OB-H, OD, OD-H, OF OG, OJ and OK.

[0297] This article reports 1 H-NMR (e.g., for an intermediate) can be a partial display of a complete NMR spectrum of a compound (e.g., a compound described herein). For example, the reported 1 H NMR can exclude the region between δ (ppm) of about 1 to about 2.5 ppm.

[0298] Exemplary general method for preparative HPLC: Column: Waters RBridge Preparative 10 μm C18, 19×250 mm. Mobile phase: acetonitrile, water (NH 4 HCO 3 ) (30 L water, 24 g NH 4 HCO 3 , 30 mL NH 3 .H 2 O). Flow rate: 25 mL / min.

[0299] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 minutes. Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6×50 mm, 3.5 μm at 45°C.

[0300] Synthesis method

[0301] Example 1. General Procedure A: Preparation of A / B-trans Framework

[0302]

[0303] Step 1. Preparation of compound A2. Finely ground potassium hydroxide (28.0 g, 165 mmol) was added to a solution of commercially available 19-hydroxyandrost-4-ene-3,17-dione (A1, 50.0 g, 165 mmol) in anhydrous 1,2-dimethoxyethane (500 mL) at 0 ° C under nitrogen, after which methyl sulfate (43.7 g, 208 mmol) was added portionwise. The mixture was slowly warmed to room temperature and stirred for a total of 18 hours, at which time TLC analysis of the mixture (7:3 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with heptane / ethyl acetate (2:1) to give A2 (26.8 g, 50%) as a yellow solid.

[0304] Step 2. Preparation of compound A3. Triethyl orthoformate (6.2mL, 37mmol) and p-toluenesulfonic acid (400mg, 9.3mmol) were added to a solution of compound A2 (9.9g, 31.0mmol) in anhydrous 1,4-dioxane (40mL) and anhydrous ethanol (30mL) at room temperature under nitrogen, and the mixture was stirred for 1.5 hours, when the TLC analysis of the mixture (7:3 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was diluted with saturated sodium bicarbonate aqueous solution (100mL), poured into water (300mL) and extracted with ethyl acetate (3×100mL). The combined organic extraction solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with heptane / ethyl acetate (2:1) to obtain compound A3 (7.0g, 66%) as a white solid.

[0305] Preparation of step 3. Compound A4. A mixture of compound A3 (7.0 g, 20.3) and palladium / carbon (3.0 g, 10% by weight) in anhydrous ethyl acetate (200 mL) was shaken at room temperature under a hydrogen atmosphere (1 atmosphere) for 1 hour, when the TLC analysis of the mixture (2: 1 hexane / ethyl acetate) indicated that the reaction was complete. The atmosphere was exchanged for nitrogen and the mixture was filtered through a Celite pad under reduced pressure, and the filter cake was washed with ethyl acetate (50 mL). The filtrate solvent was treated with 10% aqueous hydrochloric acid solution (100 mL) and the biphasic mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate (2 × 100 mL) and the combined organic extracts were washed sequentially with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution (50 mL each), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with heptane / ethyl acetate (4: 1) to obtain compound A4 (3.9 g, 60%) as a colorless oil.

[0306] Preparation of step 4. Compound A5. Sodium hydride (1.7 g, 45 mmol, 60% in mineral oil) was added portionwise to a solution of trimethyl sulfoxide iodide (9.1 g, 45 mmol) in anhydrous dimethyl sulfoxide (100 mL) at room temperature under nitrogen, and the mixture was stirred for 1 hour, after which a solution of compound A4 (9.5 g, 29.8 mmol) in anhydrous dimethyl sulfoxide (100 mL) was added. The resulting mixture was stirred at room temperature for 12 hours, at which point TLC analysis of the mixture (7:3 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was diluted with water (500 mL) and extracted with methyl tert-butyl ether (2 × 300 mL). The combined organic extracts were washed with water (2 × 300 mL), dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to obtain compound A5 as a colorless oil, which was used in the next step without further purification (7.5 g, 76%).

[0307] Step 5. Preparation of Compound A6. Lithium aluminum hydride (67 mL, 67 mmol, 1 M tetrahydrofuran solution) was added to a solution of crude Compound A5 (7.5 g, 22.2 mmol) in anhydrous tetrahydrofuran (5 mL) at 0 ° C under nitrogen, after which the mixture was slowly warmed to room temperature and stirred for a total of 2 hours, at which time TLC analysis of the mixture (7:3 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was carefully treated with water (10 mL) and saturated aqueous sodium chloride solution (30 mL) in turn and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to give Compound A6 as a colorless oil, which was used in the next step without further purification (5.5 g, 74%): LCMS m / z 319 [M+H-H2O] + .

[0308] Step 6. Preparation of compound A7. Pyridinium chlorochromate (4.0 g, 19 mmol) was added in one portion to a solution of crude compound A6 (4.2 g, 12.5 mmol) in anhydrous dichloromethane (100 mL) at 0 ° C under nitrogen. The mixture was slowly warmed to room temperature and stirred for a total of 3 hours, at which time TLC analysis of the mixture (7: 3 hexane / ethyl acetate) indicated that the reaction was complete. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluted with heptane / ethyl acetate (7: 3) to give compound A7 (2.1 g, 50%) as a light yellow solid: LCMS m / z 317 [M+H-H2O] + .

[0309] Step 7. Preparation of compound A8. Potassium tert-butoxide (4.3 g, 38 mmol) was added to a mixture of ethyltriphenylphosphonium bromide (14.2 g, 38 mmol) in anhydrous tetrahydrofuran (30 mL) at room temperature under nitrogen, after which the mixture was heated to 80 ° C and stirred for 1 hour. A solution of compound A7 (3.1 g, 9.3 mmol) in anhydrous tetrahydrofuran (10 mL) was added, followed by continuous stirring at 80 ° C for 2 hours, when TLC analysis of the mixture (7: 3 hexane / ethyl acetate) indicated that the reaction was complete. The cooled mixture was diluted with water (30 mL) and saturated aqueous sodium chloride solution (20 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extraction solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with heptane / ethyl acetate (7:3) to give compound A8 (2.0 g, 66%) as an off-white solid: LCMS m / z 329 [M+H-H2O] + .

[0310] Preparation of step 8. Compound A9. Borane-tetrahydrofuran complex (20.0mL, 20mmol, 1M tetrahydrofuran solution) was added to a solution of compound A8 (2.0g, 5.8mmol) in anhydrous tetrahydrofuran (15mL) at 0°C under nitrogen, after which the mixture was slowly warmed to room temperature and stirred for a total of 1 hour. The mixture was cooled in an ice bath and 10% aqueous sodium hydroxide solution (12mL) was slowly added, followed by 30% aqueous hydrogen peroxide solution (12mL). The resulting mixture was warmed to room temperature and stirred for 1 hour, when TLC analysis of the mixture (7:3 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was extracted with dichloromethane (2×100mL) and the combined organic extracts were washed with saturated sodium chloride aqueous solution (25mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to obtain crude compound A9 as a white solid, which was used in the next step without further purification (2.5g,>99%).

[0311] Step 9. Preparation of compound A10. Pyridinium chlorochromate (2.4 g, 11 mmol) was added in bulk to a solution of crude compound A9 (2.5 g, 6.9 mmol) in anhydrous dichloromethane (30 mL) at 0 ° C under nitrogen. The mixture was slowly warmed to room temperature and stirred for a total of 2 hours, when TLC analysis of the mixture (7: 3 hexane / ethyl acetate) indicated that the reaction was complete. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluted with heptane / ethyl acetate (7: 3) to obtain A10 (1.5 g, 61%) as an off-white solid.

[0312] Step 10. Preparation of compound A11. Hydrogen bromide (3 drops, 48% in water) was added to a solution of A10 (1.4 g, 3.9 mmol) in anhydrous methanol (150 mL) at room temperature in the dark under nitrogen, after which bromine (0.4 mL, 7.7 mmol) was added. The mixture was stirred for 1 hour, at which time TLC analysis of the mixture (7:3 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was poured into ice water (100 mL), treated with saturated aqueous sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (2 × 60 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (4 × 100 mL) and saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with heptane / ethyl acetate (1: 1) to give compound A11 (1.2 g, 71%) as a colorless semi-solid: LCMS m / z 441 [M+H] + .

[0313] Example 2. General Procedure A: Preparation of A / B-trans Framework

[0314]

[0315]

[0316] Step 1. Preparation of Compound A12. Prepared according to General Procedure A, Step 1 from A1 (10.0 g, 33 mmol) and ethyl sulfate (17.3 mL, 132 mmol) and purified by silica gel column chromatography to give Compound A12 (4.6 g, 42%) as a yellow oil.

[0317] Step 2. Preparation of Compound A13. Prepared according to General Procedure A, Step 2 from Compound A12 (4.6 g, 14 mmol) to give crude Compound A13 as a yellow oil, which was used in the next step without further purification.

[0318] Step 3. Preparation of Compound A14. Prepared according to General Procedure A, Step 3 from crude Compound A13, purified by silica gel column chromatography to give Compound A14 (1.5 g, 31%) as a yellow oil.

[0319] Step 4. Preparation of Compound A15. Prepared according to General Procedure A, Step 4 from Compound A14 (1.7 g, 5.1 mmol) to give crude Compound A15 as a yellow oil, which was used in the next step without further purification.

[0320] Step 5. Preparation of Compound A16. Prepared according to General Procedure A, Step 5 from crude Compound A15 to give crude Compound A16 as a yellow oil, which was used in the next step without further purification.

[0321] Step 6. Preparation of Compound A17. Prepared according to General Procedure A, Step 6 from crude Compound A16 and purified by silica gel column chromatography to give Compound A17 (751 mg, 40%) as an off-white solid.

[0322] Step 7. Preparation of Compound A18. Prepared according to General Procedure A, Step 7 from Compound A17 (750 mg, 2.2 mmol) and purified by silica gel column chromatography to give Compound A18 (757 mg, 97%) as a colorless oil.

[0323] Step 8. Preparation of Compound A19. Prepared according to General Procedure A, Step 8 from Compound A18 (757 mg, 2.1 mmol) to give crude Compound A19 as a yellow oil, which was used in the next step without further purification.

[0324] Step 9. Preparation of A20. Prepared according to general procedure A, step 9 from crude compound A19, purified by silica gel column chromatography to give A20 (515 mg, 65%) as a white solid: mp 106-107 °C; 1 HNMR(500MHz, CDCl3)δ3.51(d,J=16.5Hz,1H),3.43-3.36(m,3H),2.53(t,J=5.0Hz, 1H),2.18-1.96(m,6H),1.74-0.92(m,25H),0.84-0.82(m,1H),0.62(s,3H)ppm; ESI MS m / z 359[M+H-H2O] + .

[0325] Preparation of step 10.A21. Hydrogen bromide (10 drops, 48% in water) was added to a solution of A20 (490 mg, 1.30 mmol) in anhydrous methanol (40 mL) at room temperature in the dark under nitrogen, and bromine (235 mg, 13.0 mmol) was added thereto. The mixture was stirred for 1 hour, and the TLC analysis of the mixture (7:3 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was poured into ice water (100 mL), treated with saturated sodium bicarbonate aqueous solution (30 mL) and extracted with ethyl acetate (2 × 60 mL). The combined organic extracts were washed with saturated sodium bicarbonate aqueous solution (4 × 100 mL) and saturated sodium chloride aqueous solution (50 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with heptane / ethyl acetate (1: 1) to obtain compound A21 (468 mg, 79%) as a white solid. LCMS m / z 437[M+H-H2O] + .

[0326] Example 3. General Procedure B: Preparation of A / B-trans Framework C-21 Analogs

[0327]

[0328] 5-Chloro-1H-benzo[d][1,2,3]triazole (470 mg, 3.06 mmol) and potassium carbonate (704 mg, 5.1 mmol) were added to a solution of compound A11 (225 mg, 0.51 mmol) in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen, and the mixture was stirred for 16 hours, at which time TLC analysis of the mixture (2:1 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was diluted with water (120 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (60 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was semi-purified by silica gel column chromatography eluted with hexane / ethyl acetate (3:1) to give a mixture of three regioisomers. The residue was further purified by reverse phase preparative HPLC to give 35 (150 mg, 29%) as an off-white solid: mp 205-207° C.; 1 H NMR (300MHz, CDCl3) δ7.87(dd,J=1.8,0.6Hz,1H),7.81(dd,J=9.0,0.6Hz,1H),7.34(dd,J=9.0,1.8Hz,1H),5.55(d,J AB =17.1Hz,1H),5.46(d,J AB =17.1Hz,1H),3.48(d,J=9.9Hz,1H),3.38(d,J=10.2Hz,1H),3.30(s,3H),2.66(t,J=8.7Hz,1H),2.30-2.18(m,1H),2.18-2.09 (m,1H),2.09-2.00(m,1H),1.82-1.38(m,11H),1.38-1.06(m,10H),1.06-0.92(m,1H),0.92-0.80(m,1H),0.76(s,3H)ppm; ESI MS m / z 514[M+H] + .

[0329] Further elution afforded 36 (86 mg, 17%) as an off-white solid: mp 97-101 °C; 1 H NMR (300MHz, CDCl3) δ8.03-7.97(m,1H),7.36-7.31(m,2H),5.42(d,J AB =18.3Hz,1H),5.34(d,J AB=18.0Hz,1H),3.49(d,J=9.9Hz,1H),3.38(d,J=9.9Hz,1H),3.31(s,3H),2.72(t,J=8.7Hz,1H),2 .30-2.10(m,2H),2.10-2.00(m,1H),1.85-1.40(m,11H),1.39-0.80(m,12H),0.75(s,3H)ppm; ESI MS m / z 5140[M+H] + .

[0330] Further elution afforded 37 (112 mg, 21%) as an off-white solid: mp 106-110°C; 1 H NMR (300MHz, CDCl3) δ8.06(d,J=1.2Hz,1H),7.45(dd,J=9.0,1.5Hz,1H),7.27(d,J=8.7Hz,1H),5.41(s,2H),3.49(d,J=9.9Hz,1H),3.38 ESIMS m / z 514[M+H] + .

[0331] Example 4. Preparation of Compound 8.

[0332]

[0333] Prepared according to general procedure B from compound A11 (50 mg, 0.114 mmol) and N-methylpiperazine (227 mg, 2.27 mmol) and purified by reverse phase preparative HPLC to give compound 8 (36.6 mg, 70%) as a white solid: mp 136-137 °C; 1HNMR(500MHz, CDCl3)δ3.46(d,J=10.0Hz,1H),3.36(d,J=10.0Hz,1H),3.28( s,3H),3.17(s,2H),2.60-2.51(m,8H),2.30(s,3H),2.18-2.14(m,1H),2.02 (dt,J=13.0,3.5Hz,1H),1.88(dt,J=12.0,3.5Hz,1H),1.71-1.46(m,10H),1 .34-1.72(m,11H),0.98-0.84(m,1H),0.84-0.80(m,1H),0.64(s,3H)ppm; ESI MS m / z 461[M+H] + .

[0334] Example 5. Preparation of compounds 3 and 1.

[0335]

[0336] Prepared according to general procedure B from compound A11 (300 mg, 0.67 mmol) and 1H-1,2,3-triazole (188 mg, 2.71 mmol) and purified by reverse phase preparative HPLC to give compound 3 (36.6 mg, 70%) as a white solid: mp 72-74 °C; 1 HNMR (300MHz, CDCl3) δ7.75(d,J=1.2Hz,1H),7.63(d,J=1.2Hz,1H),5.20(q,J=18.0Hz,2H),3.46(d,J=9.9Hz,1H),3.37(d,J=10.2Hz,1H), 2.65(t,J=9.0Hz,1H),2.09-2.01(m,1H),1.78-1.68(m,4H),1.60-1.49(m,13H),1.46-1.26(m,9H),1.23-0.87(m,2H),0.63(s,3H)ppm; ESI MS m / z 430[M+H] + .

[0337] Further elution afforded compound 1 (110 mg, 38%) as an off-white solid: mp 157-150°C; 1HNMRδ7.67(s,2H),5.23(q,J=17.0Hz,2H),3.47(d,J=10.0Hz,1H),3.37(d, J=10.0Hz,1H),3.28(s,3H),2.57(t,J=9.5Hz,1H),2.24-2.17(m,1H),2.09 -2.01(m,2H),1.75-1.67(m,4H),1.62-1.47(m,10H),1.38-1.23(m,3H),1. 23-1.08(m,4H),1.02-0.92(m,1H),0.86-0.81(m,1H),0.73(s,3H)ppm; ESI MS m / z 430[M+H] + .

[0338] Example 6. Preparation of Compound 13.

[0339]

[0340] Prepared according to general procedure B from compound A11 (25 mg, 0.057 mmol) and 5-chlorotriazole (106 mg, 1.14 mmol) and purified by reverse phase preparative HPLC to give compound 13 (16.8 mg, 65%) as a white solid: mp 141-142 °C; 1 HNMR(500MHz, CDCl3)δ7.85(s,1H),7.80(s,1H),4.95(dd,J=62.5,17.5Hz,2H), 3.47(dd,J=10.0Hz,1H),3.37(dd,J=10.0Hz,1H),3.28(s,3H),2.60(t,J=9.0Hz ,1H),2.23-2.20(m,1H),2.05-2.01(m,2H),1.76-1.69(m,4H),1.63-1.49(m,7H ),1.47-1.10(m,10H),0.99-0.97(m,1H),0.87-0.85(m,1H),0.69(s,3H)ppm; ESI m / z 436[M+H-H2O] + .

[0341] Example 7. Preparation of Compounds 14 and 15.

[0342]

[0343] Prepared according to general procedure B from compound A11 (60 mg, 0.14 mmol) and tetrazole (57 mg, 0.81 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC sequentially to give compound 15 (6 mg, 10%) as an off-white solid: mp 88-91 °C; 1 H NMR (500MHz, CDCl3) δ8.73 (s, 1H), 5.30 (d, J AB =18.5Hz,1H),5.17(d,J AB =18.5Hz,1H),3.47(d,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.29(s,3H),2.66(t,J=9.0Hz,1H),2.28-2.20(m,1H),2.07-2.0 0(m,2H),1.82-1.69(m,4H),1.65-1.40(m,7H),1.35-1.09(m,10H),1.04-0.95(m,1H),0.92-0.83(m,1H),0.69(s,3H)ppm; ESI MS m / z431[M+H] + .

[0344] Further elution gave compound 14 (7 mg, 12%) as an off-white solid: mp 72-75°C; 1 H NMR (500MHz, CDCl3) δ8.56 (s, 1H), 5.47 (d, J AB =17.0Hz,1H),5.42(d,J AB =17.5Hz,1H),3.47(d,J=10.5Hz,1H),3.38(d,J=10.0Hz,1H),3.29(s,3H),2.64(t,J=9.0Hz,1H),2.27-2.19(m,1H),2.18-2.00(m,2H), 1.80-1.68(m,4H),1.66-1.46(m,6H),1.44-1.37(m,1H),1.35-1.08(m,10H),1.04-0.94(m,1H),0.90-0.83(m,1H),0.74(s,3H)ppm; ESI MS m / z 431[M+H] + .

[0345] Example 8. Preparation of Compounds 16 and 17.

[0346]

[0347] Prepared according to general procedure B from compound A11 (215 mg, 0.49 mmol) and 5-methyl-1H-tetrazole (253 mg, 2.92 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 16 (56 mg, 26%) as an off-white solid: mp 88-91 °C; 1 H NMR (300 MHz, CDCl3) δ 5.13 (d, J AB =18.0Hz,1H),5.06(d,J AB =18.0Hz,1H),3.48(d,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.29(s,3H),2.66(t,J=9.0Hz,1H),2.47(s,3H),2.2 7-2.15(m,1H),2.08-1.98(m,2H),1.85-1.38(m,11H),1.37-0.95(m,11H),0.91-0.83(m,1H),0.70(s,3H)ppm; ESI MS m / z 445[M+H] + .

[0348] Further elution afforded 17 (95 mg, 44%) as an off-white solid: mp 71-74 °C; 1 H NMR (500 MHz, CDCl3) δ 5.37 (d, J AB =17.0Hz,1H),5.32(d,J AB =17.5Hz,1H),3.47(d,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.29(s,3H),2.62(t,J=9.0Hz,1H),2.56(s,3H),2.26-2.18(m,1H),2. 09-2.00(m,2H),1.80-1.68(m,4H),1.65-1.46(m,6H),1.43-1.08(m,11H),1.04-0.94(m,1H),0.90-0.82(m,1H),0.73(s,3H)ppm; ESI MS m / z 445[M+H] + .

[0349] Example 9. Preparation of Compound 18.

[0350]

[0351] Prepared according to general procedure B from compound A11 (21 mg, 0.047 mmol) and 4-chloro-1H-pyrazole (29 mg, 0.28 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 18 (10 mg, 46%) as an off-white solid: mp 100-104 °C; 1 H NMR(500MHz, CDCl3)δ7.45(s,1H),7.40(s,1H),4.90(d,J AB =17.5Hz,1H),4.80(d,J AB =17.5Hz,1H),3.46(d,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.28(s,3H),3.13(s,3H),2.57(t,J=9.0Hz,1H),2.26-2.16(m,1H),2. 07-1.98(m,2H),1.76-1.67(m,4H),1.63-1.46(m,6H),1.41-1.07(m,11H),1.03-0.92(m,1H),0.91-0.80(m,1H),0.69(s,3H)ppm; ESI MS m / z 463[M+H] + .

[0352] Example 10. Preparation of Compound 19.

[0353]

[0354] Prepared according to general procedure B from compound A11 (30 mg, 0.06 mmol) and 1H-pyrazole-3-carbonitrile (25 mg, 0.03 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 19 (17 mg, 56%) as an off-white solid: mp 115-120 °C; 1 HNMR (300MHz, CDCl3) δ7.47(d,J=2.4Hz,1H),6.72(d,J=2.4Hz,1H),5.00(q,J=18.0Hz,2H),3.49(d,J=9.9Hz,1H),3.39(d,J=10.2Hz,1H),3.29(s ,3H),2.65(t,J=9.0Hz,1H),2.09-2.01(m,1H),1.78-1.68(m,4H),1.60- 1.49(m,10H),1.46-1.26(m,9H),1.23-0.87(m,2H),0.63(s,3H)ppm; ESI MS m / z436[M+H-H2O] + .

[0355] Example 11. Preparation of Compound 20.

[0356]

[0357] Prepared according to general procedure B from compound A11 (130 mg, 0.29 mmol) and 4-methyl-1H-pyrazole (247 mg, 3.01 mmol) with substitution of cesium carbonate (480 mg, 1.5 mmol) in anhydrous acetonitrile (8 mL), semi-purified by silica gel column chromatography followed by reverse phase preparative HPLC to give 20 (15 mg, 11%) as an off-white solid: mp 67-71 °C; 1 H NMR(500MHz, CDCl3)δ7.33(s,1H),7.16(s,1H),4.87(d,J AB =18.0Hz,1H),4.79(d,J AB =17.5Hz,1H),3.46(d,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.28(s,3H),3.13(s,3H),2.56(t,J=8.5Hz,1H),2.23-2.15(m,1H),2.09(s,3 ESI MS m / z 443[M+H] + .

[0358] Example 12. Preparation of Compound 21.

[0359]

[0360] Prepared according to general procedure B from compound A11 (50 mg, 0.13 mmol) and 2-fluoroimidazole hydrochloride (75 mg, 0.61 mmol), with substitution of cesium carbonate (200 mg, 0.62 mmol) in anhydrous acetonitrile (4 mL), semi-purified by silica gel column chromatography followed by reverse phase preparative HPLC to give 21 (35 mg, 69%) as a yellow solid: mp 78-81 °C; 1 H NMR (300MHz, CDCl3) δ6.91(d,J=1.5Hz,1H),6.64(s,J=1.5Hz,1H),5.54(d,J AB =18.3Hz,1H),4.41(d,JAB =18.0Hz,1H),3.48(d,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.30(s,3H),2.54(t,J=9.0Hz,1H),2.28-2.1 4(m,1H),2.09-1.98(m,2H),1.80-1.64(m,4H),1.64-1.46(m,6H),1.44-0.80(m,13H),0.69(s,3H)ppm; ESI MS m / z 470[M+H] + .

[0361] Example 13. Preparation of Compound 23.

[0362]

[0363] Prepared according to general procedure B from compound A11 (75 mg, 0.17 mmol) and 4-methylimidazole (279 mg, 3.4 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 23 (18 mg, 24%) as a white solid: mp 87-89 °C; 1 H NMR (500MHz, CDCl3) δ7.40 (s, 1H), 6.56 (s, 1H), 4.63 (dd, J = 18.0, 10.8Hz, 2H), 3.47 (d ,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.29(s,3H),2.60-2.54(m,1H),2.24-2.17(m, 3H),2.08(s,1H),2.04-2.01(m,1H),1.96-1.93(m,1H),1.76-1.68(m,4H),1.63-1.46( m,6H),1.42-1.09(m,11H),1.02-0.93(m,1H),0.87-0.82(m,1H),0.68(s,3H)ppm; APCI MS m / z 443[M+H] + .

[0364] Example 14. Preparation of Compound 24.

[0365]

[0366] Prepared according to general procedure B from compound A11 (100 mg, 0.23 mmol) and 4-(methylsulfonyl)-1H-pyrazole (99 mg, 0.68 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 24 (6 mg, 5%) as a white solid: mp 90-92 °C;1 H NMR(500MHz, CDCl3)δ7.91(s,1H),7.86(s,1H),5.02(d,J AB =18.0Hz,1H),4.90(d,J AB =17.5Hz,1H),3.47(d,J=10.0Hz,1H),3.37(d,J=10.0Hz,1H),3.28(s,3 H),3.13(s,3H),2.61(t,J=9.0Hz,1H),2.26-2.16(m,1H),2.07-2.00(m ,2H),1.78-1.68(m,4H),1.64-1.46(m,6H),1.44-1.36(m,1H),1.35-1. 08(m,10H),1.04-0.94(m,1H),0.89-0.82(m,1H),0.69(s,3H)ppm; APCI MS m / z 507[M+H] + .

[0367] Example 15. Preparation of Compounds 25 and 26.

[0368]

[0369] Prepared according to general procedure B from compound A21 (150 mg, 0.33 mmol) and 5-methyltetrazolyl (554 mg, 6.6 mmol) and purified by reverse phase preparative HPLC to give 25 (43.6 mg, 28%) as a white solid: mp 71-72 °C; 1 HNMR (500MHz, CDCl3) δ5.34(dd,J=26.5,17.5Hz,2H),3.52(d,J=10.0Hz,1H),3.42-3.38(m,3H),2.62(t,J=9.0Hz,1H),2.56(s,3H),2. 24-2.22(m,1H),2.08-2.03(m,2H),1.75-1.48(m,11H),1.39-1.08(m,13H),0.99-0.98(m,1H),0.86-0.85(m,1H),0.72(s,3H)ppm; ESI MSm / z 459[M+H] + .

[0370] Further elution afforded 26 (14.9 mg, 7%) as a white solid: mp 82-83 °C; 1HNMR(500MHz, CDCl3)δ5.09(dd,J=37.0,18.0Hz,2H),3.52(d,J=10.0Hz,1H),3.43-3.37(m,3H),2.65(t,J=9.0Hz,1H),2.47(s,3H),2. 24-2.22(m,1H),2.06-2.03(m,2H),1.75-1.41(m,11H),1.33-1.09(m,13H),0.99-0.98(m,1H),0.87-0.86(m,1H),0.69(s,3H)ppm; ESI MS m / z 459[M+H] + .

[0371] Example 16. General Procedure C: Preparation of A / B-cis Backbone

[0372]

[0373] Step 1. Preparation of compound C2. A mixture of commercially available 19-hydroxyandrost-4-ene-3,17-dione (A1, 13.6 g, 45 mmol) and palladium / carbon (3.2 g, 10 wt%) in anhydrous tetrahydrofuran (150 mL) was shaken at room temperature under a hydrogen (50 psi) atmosphere for 12 hours, at which time TLC analysis of the mixture (2:1 hexane / ethyl acetate) indicated that the reaction was complete. The atmosphere was exchanged for nitrogen and the mixture was filtered through a Celite pad under reduced pressure, and the filter cake was washed with ethanol. The filtrate solvent was removed under reduced pressure to give C2 as a white solid, which was used in the next step without further purification (13.0 g, 95%): LCMS m / z 305 [M+H] + .

[0374] Step 2. Preparation of compound C3. Pyridine hydrochloride (750 mg, 6.5 mmol) was added to a solution of crude compound C2 (15.0 g, 49 mmol) in ethylene glycol (65 mL) and anhydrous toluene (180 mL) at room temperature under nitrogen. The mixture was heated at reflux for 12 hours, and water was removed by a Dean-Stark apparatus, at which point TLC analysis of the mixture (2: 1 hexane / ethyl acetate) indicated that the reaction was complete. The solvent was removed from the cooled mixture under reduced pressure and the residue was treated with a saturated aqueous sodium chloride solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (3 × 10 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to obtain compound C3 as a colorless oil, which was used in the next step without further purification (20.3 g, > 99%): 1H NMR (300MHz, CDCl3) δ4.11-3.81(m,8H),3.60-3.54(m,1H),2.05-1.92(m,3H) ,1.81-163(m,4H),1.59-1.35(m,12H),1.28-1.12(m,5H),0.8(s,3H)ppm; LCMS m / z 393[M+H] + .

[0375] Step 3. Preparation of compound C4. A solution of crude compound C3 (20.3 g, 49 mmol) in anhydrous tetrahydrofuran (120 mL) was added dropwise to a suspension of sodium hydride (7.9 g, 197 mmol, 60% in mineral oil) in anhydrous tetrahydrofuran (120 mL) at 0 ° C under nitrogen, after which the mixture was stirred at 0 ° C for 30 minutes. Iodomethane (15.3 mL, 246 mmol) was added dropwise, after which the mixture was heated to 35 ° C and stirred for 3 hours, at which time TLC analysis of the mixture (3: 1 hexane / ethyl acetate) indicated that the reaction was complete. The cooled mixture was treated with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with saturated sodium chloride aqueous solution (2 × 20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to give crude compound C4 as a yellow oil, which was used in the next step without further purification (25.6 g, >99%): LCMS m / z 407 [M+H] + .

[0376] Step 4. Preparation of compound C5. A mixture of crude compound C4 (25.5 g, 49 mmol) in tetrahydrofuran (150 mL) and acetone (90 mL) was treated with 2N HCl (123 mL) at room temperature and the mixture was stirred for 16 hours, at which time TLC analysis of the mixture (2: 1 hexane / ethyl acetate) indicated that the reaction was complete. The reaction mixture was adjusted to pH 8 by slowly adding saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (3 × 125 mL). The combined organic extracts were washed with saturated sodium chloride aqueous solution (2 × 20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluted with hexane / ethyl acetate (2: 1) to obtain compound C5 (10.6 g, 67%) as a white solid: 1H NMR (300MHz, CDCl3) δ3.62-3.59(m,1H),3.36-3.33(m,4H),2.67-2.63(m,1H),2.58-2.4 5(m,1H),2.42-2.27(m,3H),2.25-1.84(m,6H),1.71-1.23(m,11H),0.89(s,3H)ppm; LCMS m / z 319[M+H] + .

[0377] Step 5. Preparation of compound C6. Iodine (84 mg, 0.3 mmol) was added to a solution of compound C5 (10.6 g, 33 mmol) in anhydrous methanol (200 mL) at room temperature under nitrogen, after which the mixture was heated to 60 ° C and stirred for 90 minutes, at which time TLC analysis of the mixture (2: 1 hexane / ethyl acetate) indicated that the reaction was complete. The cooled mixture was treated with 1N sodium hydroxide solution (200 mL) and extracted with hexane / ethyl acetate (3: 1, 3 × 100 mL). The combined organic extracts were washed with saturated sodium chloride aqueous solution (2 × 25 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to obtain compound C6 as a colorless oil, which was used in the next step without further purification (13.8 g, > 99%); LCMS m / z 365 [M + H] + .

[0378] Step 6. Preparation of compound C7. Potassium tert-butoxide (11.2 g, 100 mmol) was added to a mixture of ethyltriphenylphosphonium bromide (36.9 g, 100 mmol) in anhydrous tetrahydrofuran (150 mL) at room temperature under nitrogen, after which the mixture was heated to 60 ° C and stirred for 4 hours. A solution of compound C6 (13.8 g, 33 mmol) in anhydrous tetrahydrofuran (100 mL) was added, after which stirring was continued at 60 ° C for 18 hours. The cooled mixture was diluted with water (200 mL) and hexane (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2×25 mL), treated with 2N HCl (100 mL) and stirred at room temperature for 3 hours. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with hexane / ethyl acetate (9:1) to give compound C7 (9.2 g, 84%) as a colorless oil: LCMS m / z 331 [M+H] + .

[0379] Step 7. Preparation of Compound C8. Bis(2,6-di-tert-butyl-4-methylphenoxide)methylaluminum (40.6 mL, 16 mmol, 0.4 M in toluene) was added in one portion to a solution of Compound C7 (1.8 g, 5.4 mmol) in anhydrous toluene (20 mL) at -78°C under nitrogen, after which the mixture was stirred for 10 minutes. Methylmagnesium bromide (11.6 mL, 16 mmol, 1.4 M in tetrahydrofuran / toluene) was added dropwise, after which the mixture was stirred at -78°C for 1 hour. The mixture was warmed to ice bath temperature and slowly treated with 2N HCl (60 mL), warmed to room temperature and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2×20 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with hexane / ethyl acetate (2:1) to give crude compound C8 (1.5 g, 91%) as a white semisolid; LCMS m / z 347 [M+H] + .

[0380] Step 8. Preparation of compound C9. Borane-tetrahydrofuran complex (27.6 mL, 27.6 mmol, 1.0 M tetrahydrofuran solution) was added to a solution of compound C8 (2.4 g, 6.9 mmol) in anhydrous tetrahydrofuran (24 mL) at 0 ° C under nitrogen, after which the mixture was slowly warmed to room temperature and stirred for a total of 4 hours. The mixture was cooled in an ice bath and 10% aqueous sodium hydroxide solution (20 mL) was slowly added, followed by 30% aqueous hydrogen peroxide solution (20 mL). The resulting mixture was warmed to room temperature and stirred for 1 hour, then treated with saturated sodium chloride aqueous solution (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with saturated sodium chloride aqueous solution (25 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give crude compound C9 as a white solid, which was used in the next step without further purification (2.7 g, >99%); LCMS m / z 365 [M+H] + .

[0381] Step 9. Preparation of C10. Pyridinium chlorochromate (6.0 g, 28 mmol) was added in one portion to a solution of compound C9 (2.7 g, 6.9 mmol) in dichloromethane (100 mL) at 0°C under nitrogen, after which the mixture was slowly warmed to room temperature and stirred for a total of 16 hours. The solids were removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was semi-purified by silica gel column chromatography eluting with hexane / ethyl acetate (1:1), followed by further purification by reverse phase preparative HPLC to give C10 (2.15 g, 86%) as a white solid: mp 142-144°C; 1HNMR (300MHz, CDCl3) δ3.55(d,J=9.0Hz,1H),3.33(s,3H),3.19(d,J=9.0Hz,1H),2.53(t,J=9.0Hz,1H),2.21-2.11(m ,4H),2.08-1.87(m,3H),2.14-1.91(m,7H),1.77-1.36(m,16H),1.28(s,3H),1.26-1.07(m,2H),0.60(s,3H)ppm; LCMS m / z 345[M+H-H2O] + .

[0382] Step 10. Preparation of compound C11. Hydrogen bromide (5 drops, 48% in water) was added to a solution of C10 (2.15 g, 5.9 mmol) in anhydrous methanol (150 mL) at room temperature in the dark under nitrogen, after which bromine (0.6 mL, 12 mmol) was added and the mixture was stirred for 90 minutes. The mixture was poured into ice water (250 mL) and treated successively with 2N sodium hydroxide solution (20 mL) and saturated sodium bicarbonate aqueous solution (100 mL). Solids were collected under reduced pressure and purified by silica gel column chromatography eluted with hexane / ethyl acetate (1: 1) to give compound C11 (1.4 g, 53%) as a white solid: LCMS m / z442[M+H] + .

[0383] Example 17. Alternative preparation of intermediate C9.

[0384]

[0385] Step 1. Preparation of compound C2. A solution of A1 (10 g, 33.07 mmol) in anhydrous THF (140 mL) was added to a solution of Pd / C (1 g, 10% wet) in THF (10 mL) and added to the mixture. After TLC showed complete consumption of the starting material, the mixture was filtered with CH2Cl2 (300 mL) and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 8: 1-4: 1-2: 1-1: 1-EA) to give C2 (8.3 g, 82.43%) as a white solid. 1 H NMR (400MHz, CDCl3) δ (ppm) = 3.96 (d, J = 8.0Hz, 1H), 3.69 (d, J = 8.0Hz, 1H), 2.69-2 .65(m,1H),2.45-2.29(m,4H),2.12-1.69(m,8H),1.63-1.23(m,7H),0.88(s,3H).

[0386] Step 2. Preparation of compound C20. KOH (8.4 g, 149.7 mmol) and Me2SO4 (12.9 g, 100.67 mol) were added to a solution of compound C2 (15 g, 49.3 mmol) in THF (150 mL) at 0 ° C. The mixture was then warmed to 25 ° C and stirred for 3 hours at the same temperature. TLC (PE: EA = 1: 4) showed that the raw material was almost consumed. The mixture was quenched by adding 300 mL of water. The resulting solution was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with saturated NaCl aqueous solution (50 mL), dried over anhydrous Na2SO4 and evaporated in vacuo to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound C20 (9.5 g, 60.5%) as a white solid.

[0387] Step 3. Preparation of compound C21. AlMe3 (4.7 mL, 9.42 mmol, 2 M in toluene) was added dropwise to a solution of compound 2,6-di-tert-butyl-4-methylphenol (4.15 g, 18.84 mmol) in toluene (8 mL) at less than 25 ° C. The solution was stirred at room temperature for 1 hour. Then a solution of compound C20 (1 g, 3.14 mmol) in toluene (3 mL) was added dropwise at -78 ° C. After stirring for 1 hour at the same temperature, MeMgBr (5.23 mL, 15.7 mmol, 3 M in ether) was added dropwise at -78 ° C. The resulting solution was stirred at -78 ° C to -50 ° C for 3 hours. TLC (PE / EtOAc=1 / 1) showed that the reaction was complete. The reactant was quenched by saturated NH4Cl aqueous solution (200 mL) at -78 ° C. The resulting mixture was filtered through a celite pad and the pad was washed with EtOAc (100 mL). The combined organic layers were separated, washed with brine (100 mL x 2) and concentrated in vacuo. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound C21 (1 g, 95%) as a light yellow oil.

[0388] Step 4. Preparation of compound C22. To a solution of PPh3EtBr (42.17 g, 113.6 mmol) in THF (40 mL) at 0°C, a solution of t-BuOK (12.75 g, 113.6 mmol) in THF (40 mL) was added. After stirring at 60°C for 1 hour, a solution of compound C21 (7.6 g, 22.72 mmol) in THF (40 mL) was added dropwise at 60°C. The reaction mixture was then stirred at 60°C for 8 hours. TLC (PE / EtOAc=3 / 1) showed that there was still raw material remaining. To a solution of PPh3EtBr (42.17 g, 113.6 mmol) in THF (40 mL) at 0°C, a solution of t-BuOK (12.75 g, 113.6 mmol) in THF (40 mL) was added. After stirring at 60°C for 1 hour, the solution was added to the reaction mixture. The reaction mixture was then stirred at 60 ° C for 8 hours. TLC (PE / EA = 3 / 1) shows that there is still raw material remaining and the reaction is almost unchanged. The reaction mixture is filtered and the filtrate is concentrated in vacuo to remove most of the solvent. The residue is distributed between EtOAc (300mL) and water (100mL × 3). The organic layer is washed with brine (100mL), dried over Na2SO4 and concentrated in vacuo. The crude product is purified by a silica column (PE: EA = 5: 1) to obtain compound C22 (4.0g, 50.8%) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ5.15-5.09(m,1H),3.58(d,J=9.2Hz,1H),3.49(s,1H),3.33(s,3H),3.20(d,J=8.8Hz,1H),2.40-1.10(m,28H),0.85(s,3H).

[0389] Preparation of step 5. Compound C9. BH3-Me2S solution (7.21mL, 32.88mmol) was added dropwise to a solution of compound C22 (2.5g, 7.21mmol) in THF (30mL) at 0°C. The solution was stirred for 3 hours at 25°C. TLC (PE / EtOAc=1 / 1) showed that the reaction was complete. After cooling to 0°C, NaOH solution (27.5mL, 3M) was added very slowly. After the addition was complete, H2O2 (15mL, 30%) was added slowly and the internal temperature was maintained below 10°C. The resulting solution was stirred at room temperature for 2 hours. The resulting solution was extracted with EtOAc (100mL×3). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (100mL), brine (100mL), dried over Na2SO4 and concentrated in vacuo to obtain a crude product compound C23 (2.5g, 95.15%) as a white solid. The crude product was used in the next step without further purification.

[0390] Example 18. General Procedure E: Preparation of A / B-cis Framework C-21 Analogs

[0391]

[0392] Preparation of compounds 73, 74 and 75. 5-Fluoro-1H-benzo[d][1,2,3]triazole (112 mg, 0.82 mmol) and potassium carbonate (373 mg, 2.7 mmol) were added to a solution of compound C11 (120 mg, 0.27 mmol) in anhydrous tetrahydrofuran (12 mL) at room temperature under nitrogen and the mixture was stirred for 16 hours, at which time TLC analysis of the mixture (2:1 hexane / ethyl acetate) indicated that the reaction was complete. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (3×80 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (2×25 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was semi-purified by silica gel column chromatography eluted with hexane / ethyl acetate (3:1) to give a mixture of three regioisomers. The residue was further purified by reverse phase preparative HPLC to give 73 (44 mg, 33%) as a white solid: mp 82-84 °C; 1H NMR (500 MHz, CDCl3) δ 7.86 (dd, J = 9.0, 4.5 Hz, 1H), 7.46 (dd, J = 9.0, 2.5 Hz, 1H), 7.20 (ddd, J = 9.0, 9.0, 2.0 Hz, 1H), 5.50 (d, J = 9.0, 9.0, 2.0 Hz, 1H), 5.78 (d, J = 9.0, 9.0, 2.0 Hz, 1H). AB =17.5Hz,1H),5.46(d,J AB=17.0Hz,1H),3.54(d,J=9.5Hz,1H),3.34(s,3H),3.21(d,J=9.0Hz,1H),2.64(t,J=9.0Hz,1H),2.27-2.18 (m,1H),2.18-2.11(m,1H),1.96-1.88(m,2H),1.83-1.40(m,12H),1.39-1.10(m,10H),0.73(s,3H)ppm; ESI MS m / z 496[MH] - .

[0393] Further elution afforded 75 (25 mg, 18%) as a white solid: mp 205-207°C; 1 H NMR (500MHz, CDCl3) δ7.72-7.68(m,1H),7.31-7.27(m,2H),5.43(d,J AB =18.0Hz,1H),5.36(d,J AB =18.0Hz,1H),3.54(d,J=9.0Hz,1H),3.34(s,3H),3.23(d,J=9.0Hz,1H),2.70(t,J=9.0Hz,1H),2.27-2.18(m,1H),2.18-2.12 (m,1H),1.97-1.88(m,2H),1.84-1.72(m,3H),1.70-1.58(m,3H),1.57-1.43(m,6H),1.40-1.12(m,10H),0.71(s,3H)ppm; ESI MS m / z 498[M+H] + .

[0394] Further elution afforded 74 (30 mg, 22%) as an off-white solid: mp 195-197°C; 1 H NMR (500MHz, CDCl3) δ8.04(dd,J=9.0,4.5Hz,1H),7.15(dt,J=9.0,2.5Hz,1H),6.97(dd,J=7.5,2.0Hz,1H),5.40(d,J AB =18.0Hz,1H),5.33(d,J AB=18.0Hz,1H),3.54(d,J=9.0Hz,1H),3.34(s,3H),3.22(d,J=9.0Hz,1H),2.70(t,J=9.0Hz,1H),2.27-2.18(m,1H),2.18-2.12 (m,1H),1.97-1.89(m,2H),1.84-1.72(m,3H),1.71-1.57(m,3H),1.57-1.42(m,6H),1.40-1.12(m,10H),0.72(s,3H)ppm; ESI MS m / z 498[M+H] + .

[0395] Example 19. Preparation of Compound 27.

[0396]

[0397] Prepared according to General Procedure E Step 2 from compound C11 (60 mg, 0.14 mmol) and 1H-pyrazole-4-carbonitrile (63 mg, 0.67 mmol) and purified by silica gel column chromatography to give compound 27 (27.3 mg, 44%) as an off-white solid: mp 176-178 °C; 1 HNMR (300MHz, CDCl3) δ7.83 (d, J = 12.3Hz, 2H), 4.95 (q, J = 18.3Hz, 2H), 3.53 (d, J = 9.0Hz, 1H), 3.33 (s, 3H) ,3.22(d,J=9.0Hz,1H),2.59(t,J=9.3Hz,1H),2.26-1.35(m,17H),1.31-1.08(m,9H),0.66(s,3H)ppm; ESI MS m / z 437[M+H-H2O] + .

[0398] Example 20. Preparation of Compound 28.

[0399]

[0400] Prepared according to General Procedure E, Step 2 from compound C11 (80 mg, 0.18 mmol) and 4-methyl-1H-pyrazole (45 mg, 0.54 mmol) with replacement by cesium carbonate (177 mg, 0.54 mmol) in anhydrous acetonitrile (6 mL) at 65 °C, purified by silica gel column chromatography to give compound 28 (58 mg, 73%) as a white solid: mp 158-160 °C; 1H NMR (500MHz, CDCl3) δ7.34(s,1H),7.16(s,1H),4.86(d,J AB =17.5Hz,1H),4.78(d,J AB =18.0Hz,1H),3.54(d,J=9.0Hz,1H),3.32(s,3H),3.19(d,J=9.0Hz,1H),2.54(t,J=9.5Hz,1H),2.23-2.13(m,1H) ,2.09(s,3H),2.07-2.02(m,1H),1.97-1.87(m,2H),1.80-1.35(m,12H),1.33-1.10(m,10H),0.66(s,3H)ppm; ESI MS m / z 443[M+H] + .

[0401] Example 21. Preparation of Compounds 29 and 30.

[0402]

[0403] Prepared according to General Procedure E, Step 2 from compound C11 (100 mg, 0.23 mmol) and 5-methyltetrazolyl (95 mg, 1.13 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 29 (12.2 mg, 12%) as an off-white solid: mp 90-92 °C; 1 HNMR(300MHz, CDCl3)δ5.09(q,J=18.0Hz,2H),3.53(d,J=9.0Hz,1H),3.33(s,3H),3.22(d,J=9.0Hz, 1H), 2.65 (t, J = 9.0Hz, 1H), 2.47 (s, 3H), 2.25-1.58 (m, 9H), 1.55-1.14 (m, 17H), 0.67 (s, 3H)ppm; ESI MS m / z 428[M+H-H2O] + .

[0404] Further elution afforded 30 (13.4 mg, 13%) as an off-white solid: mp 70-72 °C; 1 HNMR (300MHz, CDCl3) δ5.34(s,2H),3.54(d,J=9.0Hz,1H),3.33(s,3H),3.20(d,J=9.0 Hz,1H),2.64-2.57(m,4H),2.43-1.91(m,6H),1.81-1.10(m,20H),0.70(s,3H)ppm; ESI MS m / z 428[M+H-H2O]+ .

[0405] Example 22. Preparation of compounds 31 and 32.

[0406]

[0407] Prepared according to General Procedure E, Step 2 from compound C11 (82 mg, 0.18 mmol) and 1H-1,2,3-triazole (75 mg, 1.08 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 32 (17 mg, 22%) as an off-white solid: mp 80-83 °C; 1 H NMR(500MHz, CDCl3)δ7.79(s,1H),7.66(s,1H),5.26(d,J AB =18.0Hz,1H),5.13(d,J AB =18.0Hz,1H),3.53(d,J=9.0Hz,1H),3.33(s,3H),3.20(d,J=9.0Hz,1H),2.64(t,J=9.0Hz,1H),2.26-2.16(m,1H),2 .12-2.06(m,1H),1.96-1.70(m,6H),1.66-1.42(m,6H),1.35-1.10(m,11H),0.90-0.83(m,1H),0.66(s,3H)ppm; ESI MS m / z430[M+H] + .

[0408] Further elution afforded 31 (12 mg, 16%) as an off-white solid: mp 71-74 °C; 1 H NMR (500MHz, CDCl3) δ7.68 (s, 2H), 5.24 (d, J AB =17.5Hz,1H),5.21(d,J AB =17.5Hz,1H),3.54(d,J=9.0Hz,1H),3.33(s,3H),3.19(d,J=9.0Hz,1H),2.56(t,J=9.0Hz,1H),2.24-2.15(m,1H),2.11-2.05 (m,1H),1.96-1.88(m,2H),1.82-1.68(m,3H),1.66-1.40(m,6H),1.40-1.09(m,11H),0.90-0.83(m,1H),0.70(s,3H)ppm; ESI MS m / z 430[M+H] + .

[0409] Example 23. Preparation of Compound 33.

[0410]

[0411] Prepared according to General Procedure E, Step 2 from compound C11 (80 mg, 0.18 mmol) and 4-(methylsulfonyl)-1H-pyrazole (79 mg, 0.54 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 33 (62 mg, 69%) as a white solid: mp 110-112 °C; 1 H NMR(500MHz, CDCl3)δ7.92(s,1H),7.86(s,1H),5.00(d,J AB =18.0Hz,1H),4.90(d,J AB =17.5Hz,1H),3.53(d,J=9.0Hz,1H),3.33(s,3H),3.21(d,J=9.0Hz,1H),3.13(s,3H),2.60(t,J=9.0Hz,1H),2.25-2.15(m,1H),2.0 8-2.02(m,1H),1.96-1.88(m,2H),1.82-1.71(m,3H),1.67-1.56(m,3H),1.54-1.41(m,6H),1.39-1.13(m,10H),0.67(s,3H)ppm; ESI MS m / z 505[MH] - .

[0412] Example 24. Preparation of Compound 34.

[0413]

[0414] Prepared according to general procedure E, step 2 from compound C11 (80 mg, 0.18 mmol) and 4-chloro-1H-pyrazole (45 mg, 0.54 mmol), purified by silica gel column chromatography to give compound 34 (58 mg, 70%) as a white solid: mp 163-165 °C; 1 H NMR (500MHz, CDCl3) δ7.45(s,1H),7.41(s,1H),4.99(d,J AB =17.5Hz,1H),4.80(d,J AB=17.5Hz,1H),3.53(d,J=9.0Hz,1H),3.33(s,3H),3.21(d,J=9.0Hz,1H),2.56(t,J=9.0Hz,1H),2.24-2.14(m,1H),2 .07-2.01(m,1H),1.96-1.88(m,2H),1.80-1.69(m,3H),1.66-1.35(m,9H),1.34-1.10(m,10H),0.66(s,3H)ppm; ESI MS m / z 463[M+H] + .

[0415] Example 25. Preparation of Compound 38.

[0416]

[0417] Prepared according to general procedure B from compound A11 (31 mg, 0.071 mmol) and 2H-pyrazolo[4,3-b]pyridine (168 mg, 1.41 mmol) and purified by reverse phase preparative HPLC to give 38 (8.7 mg, 25%) as a white solid: mp 153-154 °C; 1 HNMR(500MHz, CDCl3)δ8.60(d,J=3.5Hz,1H),8.28(s,1H),7.59(d,J=8.5Hz,1H),7.29(dd,J=8 .5,4.5Hz,1H),5.16(dd,J=29.0,18.0Hz,2H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3 .30(s,3H),2.66(t,J=9.0Hz,1H),2.22-2.00(m,1H),2.13-2.11(m,1H),2.10-2.08(m,1H),1.7 9-1.40(m,11H),1.33-1.11(m,10H),0.99-0.97(m,1H),0.88-0.86(m,1H),0.73(s,3H)ppm; ESI MS m / z 480[M+H] + .

[0418] Example 26. Preparation of Compounds 39 and 40.

[0419]

[0420] Prepared according to general procedure B from compound A11 (21 mg, 0.047 mmol) and 1H-benzotriazole (33 mg, 0.28 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 39 (13 mg, 58%) as an off-white solid: mp 78-80 °C; 1 H NMR (500MHz, CDCl3) δ8.11-8.07(m,1H),7.51-7.46(m,1H),7.40-7.36(m,1H),7.33(d,J=7. 5,1H),5.41(s,2H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.71(t,J=9 .0Hz,1H),2.27-2.18(m,1H),2.17-2.10(m,1H),2.08-2.02(m,1H),1.82-1.68(m,4H),1.67 -1.42(m,7H),1.35-1.09(m,10H),1.05-0.95(m,1H),0.91-0.83(m,1H),0.76(s,3H)ppm; ESI MS m / z 480[M+H] + .

[0421] Further elution afforded 40 (7 mg, 30%) as an off-white solid: mp 70-72 °C; 1 H NMR (500MHz, CDCl3) δ7.90-7.85(m,2H),7.41-7.36(m,2H),5.54(d,J AB =17.0Hz,1H),5.48(d,J AB =17.0Hz,1H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.290(s,3 H),2.63(t,J=9.0Hz,1H),2.28-2.20(m,1H),2.17-2.12(m,1H),2.07-2. 01(m,1H),1.80-1.68(m,4H),1.67-1.46(m,6H),1.45-1.36(m,1H),1.35 -1.08(m,10H),1.04-0.94(m,1H),0.90-0.82(m,1H),0.77(s,3H)ppm; ESI MS m / z 480[M+H] + .

[0422] Example 27. Preparation of Compounds 41, 42 and 43.

[0423]

[0424] Prepared according to general procedure B from compound A11 (100 mg, 0.23 mmol) and 5-fluorobenzotriazole (124 mg, 0.91 mmol) and purified by reverse phase preparative HPLC to give 43 (39.2 mg, 40%) as an off-white solid: mp 55-60 °C; 1 HNMR (300MHz, CDCl3) δ7.86(dd,J=4.8,4.5Hz,1H),7.46(dd,J=9.0,2.1Hz,1H),7.23-7.16(m,1H),5.49(q,J=18.0Hz,2H),3.48(d,J=9.9Hz,1H),3.38 (d,J=9.9Hz,1H),3.37(s,3H),2.66(t,J=8.7Hz,1H),2.29-2.01(m,3H),1. 79-1.50(m,15H),1.45-1.05(m,6H),1.01-0.82(m,2H),0.76(s,3H)ppm; ESI MS m / z 498[M+H] + .

[0425] Further elution afforded 41 (21.2 mg, 34%) as an off-white solid: mp 65-70 °C; 1 HNMR(300MHz, CDCl3)δ8.03(dd,J=9.0,4.5Hz,1H),7.18-7.12(m,1H),6.99-6.58(m,1H),5.37(q,J=18.3Hz,2H),3.47(d,J=10.2Hz,1H),3 .38(d,J=10.2Hz,1H),3.31(s,3H),2.72(t,J=9.0Hz,1H),2.28-2.02(m,3H),1.79-1.33(m,13H),1.29-0.84(m,10H),0.75(s,3H)ppm; ESI MS m / z 498[M+H] + .

[0426] Further elution afforded 42 (21.2 mg, 34%) as an off-white solid: mp 60-65 °C; 1HNMR (300MHz, CDCl3) δ7.73(d,J=9.9Hz,1H),7.35-7.21(m,2H),5.40(q,J=18.3Hz,2H),3.49(d,J=9.9Hz,1H),3.37(d,J=10.2Hz,1H) ,3.30(s,3H),2.72(t,J=9.0Hz,1H),2.28-2.03(m,3H),1.82-1.46(m,9H),1.37-1.16(m,12H),1.06-0.84(m,2H),0.74(s,3H)ppm; ESI MSm / z 498[M+H] + .

[0427] Example 28. Preparation of Compounds 44 and 45.

[0428]

[0429] Prepared according to general procedure B from compound A11 (50 mg, 0.11 mmol) and 1H-pyrazolo[3,4-c]pyridine (67 mg, 0.57 mmol) and purified by reverse phase preparative HPLC to give 44 (7.5 mg, 14%) as an off-white solid: mp 160-162 °C; 1 HNMR (300MHz, CDCl3) δ9.26 (s, 1H), 8.17 (d, J = 6.0Hz, 1H), 7.97 (d, J = 0.9Hz, 1H), 7. 53(dd,J=6.0,1.2Hz,1H),5.27(q,J=18.0Hz,2H),3.46(d,J=9.9Hz,2H),3.37(d,J=1 0.2Hz,2H),2.68(t,J=9.3Hz,1H),2.30-2.19(m,1H),1.18-2.01(m,3H),1.79-1.64( m,5H),1.61-1.45(m,7H),1.39-1.08(m,8H),1.05-0.84(m,3H),0.74(s,3H)ppm; ESI MSm / z 480[M+H] + .

[0430] Further elution afforded 45 (14.2 mg, 26%) as an off-white solid: mp 92-94 °C; 1H NMR (300MHz, CDCl3) δ8.80 (s, 1H), 8.34 (d, J = 5.4Hz, 1H), 8.09 (d, J = 0.6Hz, 1H ),7.64(dd,J=5.7,1.2Hz,1H),5.25(q,J=18.0Hz,2H),3.48(d,J=9.9Hz,2H), 3.38(d,J=9.9Hz,2H),3.31(s,3H),2.70(t,J=8.7Hz,1H),2.27-1.98(m,3H), 1.81-1.44(m,10H),1.34-1.12(m,9H),1.10-0.81(m,2H),0.74(s,3H)ppm; ESI MS m / z 480[M+H] + .

[0431] Example 29. Preparation of Compound 46.

[0432]

[0433] Prepared according to general procedure B from compound A11 (50 mg, 0.114 mmol) and benzimidazole (268 mg, 2.3 mmol) and purified by reverse phase preparative HPLC to give 46 (36.5 mg, 67%) as a white solid: mp 104-105 °C; 1 HNMR(500MHz, CDCl3)δ7.99(s,1H),7.86-7.82(m,1H),7.33-7.29(m,2H),7.20-7.18( m,1H),4.93(dd,J=24.0,18.5Hz,2H),3.49(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H), 3.30(s,3H),2.66(t,J=9.0Hz,1H),2.24-2.22(m,1H),2.07-2.05(m,1H),1.80-1.42( m,11H),1.34-1.11(m,11H),0.99-0.98(m,1H),0.88-0.86(m,1H),0.73(s,3H)ppm; ESI MS m / z 479[M+H] + .

[0434] Example 30. Preparation of Compounds 47, 48 and 49.

[0435]

[0436] Prepared according to general procedure B from compound A11 (100 mg, 0.227 mmol) and 4-fluorobenzotriazole (311 mg, 2.27 mmol) and purified by reverse phase preparative HPLC to give 49 (22.5 mg, 20%) as a white solid: mp 125-126 °C; 1 HNMR(500MHz, CDCl3)δ7.67(d,J=8.5Hz,1H),7.32-7.30(m,1H),7.03(dd,J=10.5,7.5Hz,1H),5 .54(dd,J=28.0,17.0Hz,2H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.67 (t,J=9.0Hz,1H),2.24-2.22(m,1H),2.15-2.13(m,1H),2.05-2.03(m,1H),1.78-1.50(m,9H),1 .42-1.40(m,1H),1.34-1.12(m,11H),0.99-0.98(m,1H),0.87-0.86(m,1H),0.77(s,3H)ppm; ESI MS m / z 498[M+H] + .

[0437] Further elution afforded 47 (7.3 mg, 6%) as a white solid: mp 83-84 °C; 1 HNMR(500MHz, CDCl3)δ7.86(d,J=8.0Hz,1H),7.29-7.27(m,1H),7.13(dd,J=10.5,7.5Hz,1 H),5.54(s,2H),3.49(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.70(t,J=9.0 Hz,1H),2.24-2.22(m,1H),2.15-2.13(m,1H),2.06-2.04(m,1H),1.79-1.73(m,4H),1.63- 1.43(m,7H),1.34-1.13(m,10H),1.02-1.00(m,1H),0.89-0.87(m,1H),0.75(s,3H)ppm; ESI MS m / z498[M+H] + .

[0438] Further elution afforded 48 (26.3 mg, 23%) as a white solid: mp 129-130 °C; 1HNMR(500MHz, CDCl3)δ7.42(td,J=8.0,4.5Hz,1H),7.10(d,J=8.5Hz,1H),7.04(dd,J=10 .0,7.5Hz,1H),5.42(s,2H),3.49(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H), 2.70(t,J=9.0Hz,1H),2.23-2.21(m,1H),2.15-2.13(m,1H),2.06-2.04(m,1H),1.78-1.4 6(m,10H),1.34-1.12(m,11H),1.01-0.99(m,1H),0.89-0.88(m,1H),0.74(s,3H)ppm; ESI MSm / z 498[M+H] + .

[0439] Example 31. Preparation of Compounds 50 and 51.

[0440]

[0441] Prepared according to general procedure B from compound A11 (140 mg, 0.32 mmol) and 5-methoxybenzotriazole (132 mg, 0.89 mmol) and purified by reverse phase preparative HPLC to give 50 (12.9 mg, 8%) as a white solid: mp 165-166 °C; 1 HNMR (500MHz, CDCl3) δ7.72 (d, J = 10.0 Hz, 1H), 7.07-7.05 (m, 2H), 5.43 (dd, J = 29.5, 17. 0Hz,2H),3.87(s,3H),3.47(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.29(s,3H),2.63 (t,J=9.0Hz,1H),2.24-2.22(m,1H),2.14-2.12(m,1H),2.05-2.04(m,1H),1.77-1.69( m,4H),1.62-1.10(m,17H),0.99-0.98(m,1H),0.86-0.84(m,1H),0.76(s,3H)ppm; ESIMS m / z 510[M+H] + .

[0442] Further elution afforded 51 (11.8 mg, 7%) as a white solid: mp 106-107 °C; 1HNMR(500MHz, CDCl3) δ7.93(d,J=9.0Hz,1H),7.02(dd,J=9.0,2.0Hz,1H),6.61(d,J=2.0Hz,1H),5. 33(d,J=3.5Hz,2H),3.88-3.86(m,3H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H) ,2.70(t,J=9.0Hz,1H),2.23-2.21(m,1H),2.15-2.13(m,1H),2.06-2.04(m,1H),1.76-1.70(m,4H) ,1.64-1.44(m,6H),1.34-1.13(m,11H),0.99-0.98(m,1H),0.89-0.87(m,1H),0.75(s,3H)ppm; ESI MS m / z 510[M+H] + .

[0443] Example 32. Preparation of Compounds 52, 53 and 54.

[0444]

[0445] Prepared according to general procedure B from compound A11 (100 mg, 0.23 mmol) and 4,5-difluorobenzotriazole (352 mg, 2.3 mmol) and purified by reverse phase preparative HPLC to give 54 (46.0 mg, 32%) as a white solid: mp 86-87 °C; 1 HNMR (500MHz, CDCl3) δ7.63 (ddd, J=9.0, 3.5, 1.0Hz, 1H), 7.30-7.28 (m, 1H), 5.53 (dd, J=31 .5,17.0Hz,2H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.65(t,J=9.0 Hz,1H),2.24-2.22(m,1H),2.14-2.12(m,1H),2.06-2.04(m,1H),1.78-1.73(m,4H),1.63- 1.41(m,7H),1.34-1.12(m,10H),1.03-1.00(m,1H),0.88-0.86(m,1H),0.77(s,3H)ppm; ESI MS m / z 498[M+H-H2O] + .

[0446] Further elution afforded 52 (19.3 mg, 13%) as a white solid: mp 82-83 °C;1 HNMR(500MHz, CDCl3)δ7.80(ddd,J=9.0,3.5,1.0Hz,1H),7.23-7.21(m,1H),5.52(s,2 H),3.49(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.70(t,J=9.0Hz,1H), 2.23-2.21(m,1H),2.14-2.12(m,1H),2.07-2.05(m,1H),1.79-1.72(m,4H),1.64-1.44 (m,7H),1.35-1.13(m,10H),1.02-1.01(m,1H),0.89-0.88(m,1H),0.75(s,3H)ppm; ESI MS m / z 516[M+H] + .

[0447] Further elution afforded 53 (34.3 mg, 24%) as a white solid: mp 144-145 °C; 1 HNMR (500MHz, CDCl3) δ7.38-7.37(m,1H),7.04(ddd,J=9.0,3.0,1.0Hz,1H),5.41(dd,J=22. 5,18.0Hz,2H),3.49(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.71(t,J=9.0H z,1H),2.24-7.22(m,1H),2.12.14-2.12(m,1H),2.07-2.05(m,1H),1.78-1.71(m,4H),1.64 -1.47(m,7H),1.34-1.13(m,10H),1.02-1.01(m,1H),0.89-0.88(m,1H),0.74(s,3H)ppm; ESI MS m / z 516[M+H] + .

[0448] Example 33. Preparation of Compounds 55 and 56.

[0449]

[0450] Prepared according to general procedure B from compound A11 (125 mg, 0.28 mmol) and 4,6-difluoro-1H-benzo[d][1,2,3]triazole (219 mg, 1.60 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 55 (28 mg, 19%) as an off-white solid: mp 182-186 °C;1 H NMR (300MHz, CDCl3) δ7.30 (dd, J=8.1, 1.5Hz, 1H), 6.90 (ddd, J=9.9, 9.9, 2.1Hz, 1H), 5.55 (d, J AB =17.1Hz,1H),5.47(d,J AB =17.1Hz,1H),3.48(d,J=9.9Hz,1H),3.37(d,J=10.2Hz,1H),3.30(s,3H),2.67(t,J=8.7Hz,1H),2.30-2.17(m,1H), 2.17-2.09(m,1H),2.09-1.99(m,1H),1.83-1.66(m,4H),1.66-1.40(m,7H),1.40-0.81(m,12H),0.76(s,3H)ppm; ESI MS m / z 516[M+H] + .

[0451] Further elution afforded 56 (19 mg, 13%) as an off-white solid: mp 96-100 °C; 1 H NMR (300MHz, CDCl3) δ6.87(ddd,J=9.6,9.6,1.8Hz,1H),6.79(ddd,J=7.5,2.1,0.6Hz,1H),5.41(d,J AB =18.0Hz,1H),5.34(d,J AB =18.3Hz,1H),3.49(d,J=9.9Hz,1H),3.38(d,J=9.9Hz,1H),3.31(s,3H),2.72(t,J=8.7 Hz,1H),2.30-2.00(m,3H),1.85-1.41(m,11H),1.38-0.82(m,12H),0.74(s,3H)ppm;SI MS m / z 516[M+H] + .

[0452] Example 34. Preparation of Compounds 57 and 58.

[0453]

[0454] Prepared according to general procedure B from compound A11 (100 mg, 0.23 mmol) and 4-methoxybenzotriazole (675 mg, 4.5 mmol) and purified by reverse phase preparative HPLC to give 58 (27 mg, 23%) as a light brown solid: mp 78-80 °C; 1H NMR (500MHz, CDCl3) δ7.39(t,J=8.0Hz,1H),6.86(d,J=8.1Hz,1H),6.70(d,J=7.8Hz,1H),5.37(dd,J=18.0, 2.7Hz,2H),4.12(s,3H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.1Hz,1H),3.30(s,3H),2.68(t,J=9.0Hz,1H) ,2.24-2.18(m,1H),2.14-2.09(m,1H),2.06-2.02(m,1H),1.76-1.69(m,4H),1.64-1.55(m,3H),1.54-1.37 (m,4H),1.36-1.19(m,10H),1.18-1.08(m,2H),1.04-0.93(m,1H),0.90-0.84(m,2H),0.75(s,3H)ppm; APCI MS m / z 510[M+H] + .

[0455] Further elution afforded 57 (33 mg, 29%) as an off-white solid: mp 200-202°C; 1 H NMR (500MHz, CDCl3) δ7.63(d,J=8.4Hz,1H),7.24(d,J=8.3Hz,1H),6.76(d,J=7.7Hz,1H),5.58(dd ,J=17.9,9.3Hz,2H),3.89(s,3H),3.49(d,J=10.0Hz,1H),3.39(d,J=10.0Hz,1H),3.30(s,3H),2. 67(t,J=8.9Hz,1H),2.25-2.18(m,1H),2.15-2.11(m,1H),2.06-2.02(m,1H),1.73-1.67(m,3H),1 .65-1.47(m,7H),1.42-1.11(m,12H),1.04-0.95(m,1H),0.89-10.84(m,1H),0.75(s,3H)ppm; APCI MS m / z 510[M+H] + .

[0456] Example 35. Preparation of Compounds 59, 60 and 61.

[0457]

[0458] Prepared according to general procedure B from compound A11 (150 mg, 0.34 mmol) and 4-chlorobenzotriazole (156 mg, 1.02 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 61 (64 mg, 37%) as a light brown solid: mp 170-172 °C; 1 H NMR (500MHz, CDCl3) δ7.79(dd,J=8.5,0.5Hz,1H),7.40(dd,J=7.0,0.5Hz,1H),7.32(dd,J=8.5,7.5Hz,1H),5.57(d,J AB =17.0Hz,1H),5.53(d,J AB =17.0Hz,1H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H ),2.66(t,J=9.0Hz,1H),2.28-2.18(m,1H),2.17-2.10(m,1H),2.07-2.0 1(m,1H),1.81-1.68(m,4H),1.66-1.46(m,6H),1.44-1.36(m,1H),1.35- 1.08(m,10H),1.04-0.94(m,1H),0.90-0.83(m,1H),0.77(s,3H)ppm; ESI MS m / z 514[M+H] + .

[0459] Further elution afforded 59 (8 mg, 4%) as a light brown solid: mp 162-164 °C; 1 H NMR (500MHz, CDCl3) δ7.99(d,J=8.5Hz,1H),7.43(d,J=7.5,1H),7.29(t,J=7.5, 1H),5.71(s,2H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2 .72(t,J=9.0Hz,1H),2.27-2.10(m,2H),2.08-2.02(m,1H),1.85-1.37(m,11H), 1.35-1.09(m,10H),1.05-0.95(m,1H),0.91-0.83(m,1H),0.76(s,3H)ppm; APCI m / z 514[M+H] + .

[0460] Further elution afforded 60 (32 mg, 18%) as a light brown solid: mp 105-107 °C;1 H NMR (500MHz, CDCl3) δ7.43-7.36 (m, 2H), 7.23 (dd, J = 7.5, 1.5Hz, 1H), 5.42 (s, 2H), 3. 49(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.71(t,J=9.0Hz,1H),2.2 7-2.18(m,1H),2.18-2.10(m,1H),2.08-2.01(m,1H),1.82-1.68(m,4H),1.67-1.42( m,7H),1.35-1.09(m,10H),1.05-0.95(m,1H),0.91-0.84(m,1H),0.75(s,3H)ppm; ESI MS m / z 514[M+H] + .

[0461] Example 36. Preparation of Compounds 62, 63 and 64.

[0462]

[0463] Prepared according to general procedure B from compound A11 (100 mg, 0.23 mmol) and 4,5-dimethoxy-1H-benzo[d][1,2,3]triazole (101 mg, 0.57 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 64 (32 mg, 26%) as a light yellow solid: mp 188-190 °C; 1 H NMR (500MHz, CDCl3) δ7.50(d,J=9.0Hz,1H),7.22(d,J=9.5Hz,1H),5.49(d,J AB =17.0Hz,1H),5.43(d,J AB =17.0Hz,1H),4.27(s,3H),3.95(s,3H),3.48(d,J=10.0Hz,1H),3.38(d,J =10.0Hz,1H),3.29(s,3H),2.63(t,J=8.5Hz,1H),2.27-2.17(m,1H),2.16- 2.10(m,1H),2.07-2.01(m,1H),1.79-1.68(m,4H),1.65-1.46(m,7H),1.42 -1.08(m,10H),1.03-0.93(m,1H),0.89-0.81(m,1H),0.76(s,3H)ppm; APCI MS m / z 540[M+H] + .

[0464] Further elution afforded 63 (19 mg, 15%) as a white solid: mp 88-90°C; 1 H NMR (500MHz, CDCl3) δ7.24(d,J=9.0Hz,1H),6.82(d,J=9.0Hz,1H),5.36(d,J AB =18.0Hz,1H),5.32(d,J AB =18.0Hz,1H),4.57(s,3H),3.93(s,3H),3.49(d,J=10.0Hz,1H),3.38(d,J =10.0Hz,1H),3.30(s,3H),2.69(t,J=9.0Hz,1H),2.26-2.17(m,1H),2.16- 2.10(m,1H),2.08-2.01(m,1H),1.80-1.68(m,4H),1.66-1.41(m,7H),1.36 -1.09(m,10H),1.04-0.94(m,1H),0.90-0.83(m,1H),0.74(s,3H)ppm; APCI MS m / z 540[M+H] + .

[0465] Further elution afforded 62 (13 mg, 11%) as a white solid: mp 110-112 °C; 1 H NMR (500MHz, CDCl3) δ7.75 (br s, 1H), 7.11 (d, J = 7.5Hz, 1H), 5.54 (d, J AB =18.0Hz,1H),5.50(d,J AB =18.0Hz,1H),3.96(s,3H),3.90(s,3H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.69(t,J=8.5Hz,1H),2.28-2.01(m,3 H),1.83-1.68(m,4H),1.65-1.47(m,6H),1.44-1.37(m,1H),1.36-1.08(m,10H),1.04-0.94(m,1H),0.90-0.83(m,1H),0.76(s,3H)ppm; APCI MS m / z 540[M+H] + .

[0466] Example 37. Preparation of Compounds 65 and 66.

[0467]

[0468] Prepared according to general procedure B from compound A11 (125 mg, 0.28 mmol) and 4,6-dimethoxy-1H-benzo[d][1,2,3]triazole (127 mg, 0.71 mmol) and purified by silica gel column chromatography to give 65 (42 mg, 28%) as a light yellow solid: mp 106-108 °C; 1 H NMR (500MHz, CDCl3) δ6.67(d,J=2.0Hz,1H),6.33(d,J=2.0Hz,1H),5.43(d,J AB =17.0Hz,1H),5.38(d,J AB =17.0Hz,1H),3.98(s,3H),3.96(s,3H),3.47(d,J=10.0Hz,1H),3.38(d,J =10.0Hz,1H),3.29(s,3H),2.61(t,J=9.0Hz,1H),2.26-2.16(m,1H),2.13- 2.07(m,1H),2.07-2.00(m,1H),1.77-1.67(m,4H),1.63-1.46(m,7H),1.39 -1.08(m,10H),1.02-0.93(m,1H),0.88-0.80(m,1H),0.75(s,3H)ppm; APCI MS m / z 540[M+H] + .

[0469] Further elution afforded 66 (52 mg, 34%) as an off-white solid: mp 110-112 °C; 1 H NMR (500MHz, CDCl3) δ6.34(d,J=2.0Hz,1H),6.16(d,J=2.0Hz,1H),5.28(s,2H),4.06(s,3H),3. 84(s,3H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.29(s,3H),2.66(t,J=9.0Hz,1H),2. 25-2.16(m,1H),2.13-2.08(m,1H),2.07-2.01(m,1H),1.79-1.67(m,4H),1.64-1.46(m,6H),1. 45-1.37(m,1H),1.35-1.08(m,10H),1.03-0.93(m,1H),0.89-0.82(m,1H),0.74(s,3H)ppm; APCI MS m / z 540[M+H] + .

[0470] Example 38. Preparation of Compound 67.

[0471]

[0472] Prepared according to general procedure B from compound A11 (200 mg, 0.45 mmol) and 6-bromo-1H-pyrazolo[4,3-b]pyridine (450 mg, 2.27 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 67 (43 mg, 17%) as an off-white solid: mp 102-105 °C; 1 H NMR (300MHz, CDCl3) δ8.60(d,J=1.5Hz,1H),8.23(s,1H),7.75(s,1H),5.16(d,J AB =18.0Hz,1H),5.06(d,J AB =18.0Hz,1H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.68(t,J=9. 3Hz,1H),2.30-1.93(m,3H),1.92-1.38(m,11H),1.37-0.80(m,12H),0.73(s,3H)ppm; ESI MS m / z 558[M+H] + .

[0473] Example 39. Preparation of Compounds 68 and 69.

[0474]

[0475] Prepared according to general procedure B from compound A11 (86 mg, 0.19 mmol) and 6-chloro-1H-pyrazolo[4,3-b]pyridine (570 mg, 3.7 mmol) and purified by reverse phase preparative HPLC to give 68 (12 mg, 12%) as a white solid: mp 88-90 °C; 1H NMR(500MHz, CDCl3)δ8.59(s,1H),8.51(s,1H),8.34(s,1H),5.40-5.22(m, 2H),3.48(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.67(t,J =8.6Hz,1H),2.27-2.21(m,1H),2.11-1.86(m,2H),1.85-1.41(m,11H),1.3 4-1.09(m,11H),1.04-0.93(m,1H),0.91-0.81(m,1H),0.73(s,3H)ppm; APCI MS m / z 514[M+H] + .

[0476] Further elution afforded 69 (40 mg, 40%) as a white solid: mp 115-117 °C; 1 H NMR(500MHz, CDCl3)δ8.58(s,1H),8.40(s,1H),7.77(s,1H),5.18(dd,J=18.0,32.1Hz,2H), 3.49(d,J=10.0Hz,1H),3.38(d,J=10.0Hz,1H),3.30(s,3H),2.69(t,J=8.9Hz,1H),2.24-2.1 8(m,1H),2.14-2.10(m,1H),2.07-2.03(m,1H),1.80-1.68(m,4H),1.67-1.56(m,3H),1.55- 1.42(m,4H),1.39-1.11(m,10H),1.05-0.98(m,1H),0.91-0.85(m,1H),0.73(s,3H)ppm; APCI MSm / z 514[M+H] + .

[0477] Example 40. Preparation of Compounds 70, 71 and 72.

[0478]

[0479] Prepared according to general procedure B from compound A21 (200 mg, 0.44 mmol) and 5-chlorobenzotriazole (1.35 g, 8.8 mmol) and purified by reverse phase preparative HPLC to give 72 (12.6 mg, 5%) as a white solid: mp 76-77 °C; 1HNMR(500MHz, CDCl3)δ7.87(d,J=1.5Hz,1H),7.81(d,J=9.0Hz,1H),7.34(dd,J=9.0,1.5Hz, 1H),5.50(dd,J=32.5,17.0Hz,2H),3.52(d,J=9.5Hz,1H),3.43-3.38(m,3H),2.65(t,J=9.0 Hz,1H),2.25-2.23(m,1H),2.14-2.13(m,1H),2.06-2.04(m,1H),1.77-1.48(m,10H),1.41- 1.38(m,1H),1.33-1.11(m,13H),1.02-1.00(m,1H),0.88-0.86(m,1H),0.75(s,3H)ppm; ESI MS m / z 528[M+H] + .

[0480] Further elution afforded 70 (17.1 mg, 7%) as a white solid: mp 69-70°C; 1 HNMR (500MHz, CDCl3) δ8.00 (d, J = 9.0 Hz, 1H), 7.35-7.33 (m, 2H), 5.37 (dd, J = 40. 5,18.0Hz,2H),3.53(d,J=9.5Hz,1H),3.43-3.40(m,3H),2.72(t,J=9.0Hz,1H), 2.24-2.23(m,1H),2.16-2.14(m,1H),2.08-2.06(m,1H),1.79-1.42(m,11H),1. 37-1.13(m,11H),1.01-0.99(m,1H),0.88(t,J=7.0Hz,3H),0.74(s,3H)ppm; ESI m / z 528[M+H] + .

[0481] Further elution afforded 71 (23.6 mg, 10%) as a white solid: mp 82-83 °C; 1HNMR(500MHz, CDCl3) δ8.06(d,J=1.5Hz,1H),7.45(dd,J=9.0,1.5Hz,1H),7.28(d,J=9.0 Hz,1H),5.40(dd,J=29.5,18.0Hz,2H),3.53(d,J=10.0Hz,1H),3.42-3.39(m,3H),2.71( t,J=9.0Hz,1H),2.24-2.23(m,1H),2.16-2.14(m,1H),2.08-2.05(m,1H),1.77-1.48(m, 11H),1.33-1.13(m,11H),1.02-0.99(m,1H),0.88(t,J=7.0Hz,3H),0.74(s,3H)ppm; ESI MS m / z 528[M+H] + .

[0482] Example 41. Preparation of Compound 76.

[0483]

[0484] Prepared according to General Procedure E, Step 2 from compound C11 (120 mg, 0.27 mmol) and 5-chlorobenzimidazole (125 mg, 0.82 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 76 (19 mg, 14%) as a white solid: mp 85-87 °C; 1 H NMR (300MHz, CDCl3) δ7.88-7.80(m,2H),7.35(d,J=9.1Hz,1H),5.49(s,2H),3.55(d,J=9.0Hz,1H),3.34(s,3H),3.22(d,J=9.0Hz ,1H),2.64(t,J=8.5Hz,1H),2.27-2.12(m,2H),1.94-1.85(m,2H),1.84-1.36(m,15H),1.35-1.14(m,10H),0.73(s,3H)ppm; APCI MS m / z 514[M+H] + .

[0485] Example 42. Preparation of Compounds 77, 78 and 79.

[0486]

[0487] Prepared according to General Procedure E, Step 2 from compound C11 (120 mg, 0.27 mmol) and 4,5-difluoro-1H-benzo[d][1,2,3]triazole (126 mg, 0.82 mmol), semi-purified by silica gel column chromatography and reverse phase preparative HPLC to give 79 (62 mg, 44%) as a white solid: mp 103-105 °C; 1 H NMR (500MHz, CDCl3) δ7.64 (ddd, J = 9.0, 3.5, 1.0Hz, 1H), 7.32-7.26 (m, 1H), 5.54 (d, J AB =17.0Hz,1H),5.49(d,J AB =17.0Hz,1H),3.54(d,J=9.0Hz,1H),3.34(s,3H),3.22(d,J=9.0Hz,1H),2.65(t,J=9.0Hz,1H),2.27-2.18(m,1H),2 .17-2.11(m,1H),1.97-1.88(m,2H),1.84-1.73(m,3H),1.68-1.40(m,9H),1.40-1.11(m,10H),0.74(s,3H)ppm; ESI MS m / z 514[MH] - .

[0488] Further elution afforded 77 (20 mg, 14%) as a white solid: mp 98-100 °C; 1 H NMR(500MHz, CDCl3)δ7.81(ddd,J=9.0,4.0,1.0Hz,1H),7.24-7.19(m,1H),5.54(d,J AB =18.5Hz,1H),5.50(d,J AB =18.5Hz,1H),3.55(d,J=9.0Hz,1H),3.34(s,3H),3.22(d,J=9.0Hz,1H),2.71(t,J=9.0Hz,1H),2.27-2.17(m,1H),2 .17-2.10(m,1H),1.98-1.89(m,2H),1.88-1.72(m,3H),1.70-1.42(m,9H),1.40-1.10(m,10H),0.72(s,3H)ppm; ESI MS m / z 514[MH] - .

[0489] Further elution afforded 78 (39 mg, 28%) as an off-white solid: mp 100-102°C; 1H NMR (500MHz, CDCl3) δ7.41-7.34(m,1H),7.05(ddd,J=9.0,3.0,1.0Hz,1H),5.44(d,J AB =18.0Hz,1H),5.36(d,J AB =18.0Hz,1H),3.53(d,J=9.0Hz,1H),3.34(s,3H),3.23(d,J=9.0Hz,1H),2.70(t,J=9.0Hz,1H),2.26-2.17(m,1H),2 .17-2.11(m,1H),1.98-1.88(m,2H),1.84-1.73(m,3H),1.69-1.42(m,9H),1.41-1.12(m,10H),0.71(s,3H)ppm; ESI MS m / z514[MH] - .

[0490] Example 43. Preparation of Compound 80.

[0491]

[0492] Prepared according to General Procedure E, Step 2 from compound C11 (100 mg, 0.23 mmol) and benzimidazole (80 mg, 0.68 mmol) and purified by reverse phase preparative HPLC to give 80 (68 mg, 63%) as a white solid: mp 130-132 °C; 1 H NMR (300MHz, CDCl3) δ8.74(bs,1H),7.91-7.87(m,1H),7.41-7.38(m,2H),7.25-7.22(m,1H),5.16(dd,J=18.3,5.8Hz,2H),3.54(d,J =9.1Hz,1H),3.34(s,3H),3.23(d,J=9.1Hz,1H),2.71(t,J=8.9Hz,1H),2.29-2.08(m,2H),1.94-1.09(m,26H),0.72(s,3H)ppm; APCI MS m / z 479[M+H] + .

[0493] Example 44. Preparation of Compounds 81, 82 and 83.

[0494]

[0495] Prepared according to General Procedure E, Step 2 from compound C11 (120 mg, 0.27 mmol) and 4-fluoro-1H-benzo[d][1,2,3]triazole (112 mg, 0.82 mmol) and purified by reverse phase preparative HPLC to give 82 (40 mg, 30%) as an off-white solid: mp 199-201 °C; 1 H NMR(500MHz, CDCl3)δ7.45-7.40(m,1H),7.11(d,J=8.3Hz,1H),7.06-7.02(m, 1H),5.41(dd,J=18.0,9.2Hz,2H),3.54(d,J=9.0Hz,1H),3.34(s,3H),3.23(d ,J=9.0Hz,1H),2.70(t,J=8.9Hz,1H),2.27-2.13(m,2H),1.97-1.89(m,2H),1 .83-1.68(m,5H),1.67-1.43(m,9H),1.41-1.12(m,9H),0.72(s,3H)ppm; APCI MS m / z 498[M+H] + .

[0496] Further elution afforded 81 (20 mg, 15%) as a white solid: mp 98-100 °C; 1 H NMR (500MHz, CDCl3) δ7.86(d,J=8.4Hz,1H),7.31-7.26(m,1H),7.15-7.11(m,1H),5.43(dd,J=18.2,0.95Hz,2H),3.55(d,J=9.0Hz,1H),3.34(s,3H ),3.22(d,J=9.0Hz,1H),2.70(t,J=9.0Hz,1H),2.25-2.12(m,2H),1.97- 1.75(m,6H),1.70-1.44(m,9H),1.39-1.13(m,10H),0.72(s,3H)ppm; APCI MS m / z 498[M+H] + .

[0497] Further elution afforded 83 (48 mg, 36%) as an off-white solid: mp 172-174 °C; 1H NMR(500MHz, CDCl3)δ7.67(d,J=8.6Hz,1H),7.35-7.30(m,1H),7.06-7.02(m, 1H),5.53(dd,J=17.0,2.6Hz,2H),3.55(d,J=9.0Hz,1H),3.34(s,3H),3.21(d ,J=9.0Hz,1H),2.65(t,J=9.0Hz,1H),2.26-2.13(m,3H),1.96-1.89(m,2H),1 .83-1.71(m,3H),1.67-1.40(m,9H),1.37-1.11(m,9H),0.74(s,3H)ppm; APCI MS m / z 498[M+H] + .

[0498] Example 45. Preparation of Compound 4.

[0499]

[0500] To a solution of compound A11 (40 mg, 0.09 mmol) in THF (2 mL) was added morpholine (390 mg, 4.5 mmol) and K2CO3 (120 mg, 0.9 mmol). The resulting solution was stirred at room temperature overnight. Then LCMS showed that the reaction was complete. The reactant was diluted with EtOAc (40 mL) and washed with brine (15 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to give compound 4 (18 mg, 45%) as a white solid. Compound 4: 1 H NMR: (500MHz, CDCl3), δ (ppm), 3.79-3.77 (m, 4H), 3.48 (AB, 1H, J = 10Hz), 3.38 (AB, 1H, J = 10 Hz), 3.30 (s, 3H), 3.22 (s, 2H), 2.58 (t, 1H, J = 9.3Hz), 2.5 (s, 4H), 1.25 (s, 3H), 0.66 (s, 3H).

[0501] Example 46. Preparation of Compound 2.

[0502]

[0503] 1H-pyrazole (300 mg, 4.5 mmol) and K2CO3 (120 mg, 0.9 mmol) were added to a solution of compound A11 (40 mg, 0.09 mmol) in THF (2 mL). The resulting solution was stirred at room temperature overnight. Then LCMS showed that the reaction was complete. The reactant was diluted with EtOAc (40 mL) and washed with brine (15 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to give 2 (16 mg, 40%) as a white solid. Compound 2: 1 H NMR: (500MHz, CDCl3), δ (ppm), 7.57 (d, 1H, J = 1Hz), 7.43 (d, 1H, J = 1.5Hz), 6.35 (s, 1H), 4.98 (AB, 1H, J = 17.5Hz), 4.90 (AB, 1 H, J = 18Hz), 3.48 (AB, 1H, J = 10.5Hz), 3.39 (AB, 1H, J = 9.5Hz), 3.31 (s, 3H), 2.60 (t, 1H, J = 8.8Hz), 1.25 (s, 3H), 0.72 (s, 3H).

[0504] Example 47. Preparation of Compound 5.

[0505]

[0506] Compound A11 (30 mg, 0.07 mmol), K2CO3 (50 mg) and 1-(piperazin-1-yl)ethanone (200 mg) were dissolved in THF (3 mL) and stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give Compound 5 (6 mg, 20%) as a white solid. Compound 5: 1 H NMR: (400MHz, CDCl3), δ (ppm), 3.68-3.66 (m, 2H), 3.51 (t, 2H, J = 5Hz), 3.45 (AB, 1H, J = 10Hz), 3.37 (A B,1H,J=10Hz),3.28(s,3H),3.21(s,2H),2.52-2.44(m,5H),2.08(s,3H),1.23(s,3H),0.64(s,3H).

[0507] Example 48. Preparation of Compound B11.

[0508]

[0509] Step 1. Preparation of compound B2. Compound B1 (10.0 g, 33 mmol) was dissolved in 100 mL THF. Dihydropyran (25 ml, 270 mmol) and PPTS (4.16, 16 mmol) were added and the resulting reaction mixture was vigorously stirred at room temperature for 15 hours. After concentration under reduced pressure, the reaction mixture was dissolved in EtOAc (500 mL), washed with water (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc=10 / 1~3 / 1) to obtain 12.52 g of compound B2 (97.65%). Compound B2: LC-MS: m / z=409.0 [M+Na] +

[0510] Preparation of step 2. Compound B3. Lithium metal (3.0 g, 0.4 mmol) was added to concentrated ammonia (500 ml) in a three-necked flask at -70 °C. A solution of compound B2 (5.0 g, 13 mmol) and tert-BuOH (0.95 g, 13 mmol) in anhydrous tetrahydrofuran (100 mL) was then added dropwise and stirred for 0.8 hours. Ammonium chloride (30.0 g) was added to quench the reaction and ammonia was evaporated overnight. The residue was extracted with EtOAc (300 mL). The organic layer was washed with saturated NaCl solution (2 × 200 mL), dried over Na2SO4 and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether / EtOAc=10 / 1~2 / 1) to give 2.0 g of compound 3 (39.60%). Compound B3: LC-MS: m / z=413.3 [M+Na] +

[0511] Preparation of step 3. compound B4. Me3SOI (16.9 g, 76.80 mmol) was dissolved in 80 mL DMSO and NaH (1.84 g, 76.80 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then compound B3 (6.0 g, 15.36 mmol) dissolved in 60 mL DMSO was added. The solution was stirred at room temperature overnight. Water (10 mL) was then added to the reaction mixture. The aqueous reaction mixture was extracted with EtOAc (300 mL × 3). The extract was dried over Na2SO4, filtered, and concentrated. Crude compound B4 was used directly in the next step without further purification.

[0512] Step 4. Preparation of compound B5. Crude compound B4 was slowly added to a suspension of LiAlH4 (1.75 g, 51 mmol) in 100 ml of anhydrous THF at 0 ° C. The mixture was stirred at room temperature for 2 hours, and then 2.1 g of 15% NaOH aqueous solution was slowly added to quench the reaction. The reaction mixture was extracted with EtOAc (200 mL × 3). The organic layer was dried over MgSO4, filtered and concentrated. Crude compound B5 was used directly in the next step without further purification.

[0513] Step 5. Preparation of compound B6. Crude compound B5 was dissolved in 100 ml of anhydrous CH2Cl2 and 4.0 g of PCC was added at 0°C. The mixture was then stirred at room temperature for 6 hours. The reaction mixture was then filtered, concentrated and purified by flash chromatography on silica gel using 10 / 1-3 / 1 petroleum ether: ethyl acetate = 10 / 1-3 / 1 wash-out to give compound B6, 3.10 g (50.89%, three-step yield).

[0514] Step 6. Preparation of compound B7. KOtBu (4.30 g, 38.3 mmol) was added to a suspension of ethyltriphenylphosphonium bromide (14.20 g, 38.3 mmol) in anhydrous THF (40 mL) under N2 atmosphere. The mixture was heated at reflux for 1 hour, at which time the mixture turned bright orange. Compound B6 (3.1 g, 7.66 mmol) in anhydrous THF (25 mL) was then added to the above reflux solution and stirred overnight at reflux. After cooling to room temperature, the solution was poured into brine (100 mL). The aqueous solution was extracted with ethyl acetate (100 mL × 3). The extract was washed with brine (30 mL × 2), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (petroleum ether / EtOAC: 10 / 1 to 4 / 1) to give 2.2 g (68.97%) of compound B7 as a white solid. In addition, C-3 isomer (0.30 g, 9.63%) was also obtained.

[0515] Preparation of step 7. Compound B8. Add borane-tetrahydrofuran complex (29mL of 1.0M THF solution) to a solution of compound B7 (3g, 7.2mmol) in anhydrous THF (20mL) and stir the reaction mixture at ambient temperature for 1 hour. Slowly add 10% NaOH aqueous solution (20mL). Cool the mixture in ice and slowly add 30% H2O2 aqueous solution (20mL). Stir the mixture at ambient temperature for 1 hour, then extract with CH2Cl2 (3×100mL). Wash the combined CH2Cl2 extracts with 10% Na2S2O3 aqueous solution (50mL), which is directly used in the next step without further purification.

[0516] Step 8. Preparation of compound B9. The combined CH2Cl2 extracts of compound B8 of the last step were used without further purification. 3.5 g PCC was added at 0°C. The mixture was then stirred at room temperature for 6 hours. The mixture was filtered, concentrated and purified by flash chromatography on silica gel eluted with 12 / 1 to 7 / 1 (petroleum ether: ethyl acetate) to give 1.28 g of compound B9 (41.23%, two steps). Compound B9: LC-MS: m / z=455.3 [M+Na] + . 1 H NMR (500 MHz, CDCl3) δ (ppm): 4.57 and 4.53 (1H, t, J = 3.5 Hz), 3.96 and 3.87 (1H, AB, J = 11.0 Hz,), 3.82 (1H, t, J = 9.5 Hz), 3.56-3.53 (1H, m), 3.44 and 3.27 (1H, AB, J = 10.5 Hz), 2.53 (1H, t, J = 9.0 Hz), 2.12 and 2.11 (3H, s), 1.22 and 1.21 (3H, s), 0.64 and 0.61 (1H, s).

[0517] Step 9. Preparation of Compound B10. Compound B9 (1.28 g, 2.96 mmol) was dissolved in 50 mL of anhydrous MeOH and 100 mg of PTSA was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. This product mixture was separated by silica gel flash chromatography eluted with 8 / 1 to 2 / 1 (petroleum ether: EtOAc) to give 674 mg of Compound B10 (65.32%). Compound B10: LC-MS: m / z=331.3 [M-H2O+H] + ,m / z=349.2[M+H] +1 H NMR (500MHz, CDCl3) δ (ppm): 3.89 (1H, AB, J = 12.0Hz), 3.72 (1H, AB, J = 12.0Hz), 2.53 (1H, t, J = 9.0Hz), 2.11 (3H, s), 1.22 (3H, s), 0.64 (3H, s). 13 C NMR(125.77MHz, CDCl3)δ(ppm):209.78,69.68,63.80,60.12,57.07,54.39,44.36,42.04,41.1 8,39.62,39.31,36.05,35.39,31.85,31.68,31.54,28.04,27.91,24.39,22.86,22.75,13.72.

[0518] Step 10. Preparation of Compound B11. Compound B10 (50 mg, 0.14 mmol) was dissolved in 5 mL of anhydrous MeOH and 3 drops of Br2 and 2 drops of aqueous HBr were added. The reaction mixture was stirred at room temperature for 3 hours, then the reaction mixture was treated with triethylamine at 0°C, concentrated under reduced pressure and used directly in the next step without further purification. Compound B11: LC-MS: m / z=410.1 & 411.2 [M-H2O+H] + .

[0519] Example 49. Preparation of Compound 9.

[0520]

[0521] Crude compound B11 was directly used, 8mL THF and 100mg K2CO3, 0.5ml morpholine were added. The reaction mixture was stirred at room temperature overnight. The solution was diluted with ethyl acetate (100mL). The resulting solution was washed with brine (100mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to obtain 25mg (41.18%, two steps, from 50mg compound B10) of product 9 as a white solid. Compound 9: 1 H NMR (500MHz, CDCl3) δ (ppm): 3.89 (1H, dd, J = 4.0Hz, J = 11.5Hz), 3.76 (4H, t, J = 4.5Hz), 3.72 (1H, dd, J = 3.0Hz, J = 11.0Hz), 3.19 (2H ,s),2.58(1H,t,J=9.5Hz),2.45-2.55(4H,m),2.20~2.15(1H,m),2.07~2.04(1H,m),1.92~1.89(1H,m),1.23(3H,s),0.67(3H,s).

[0522] Example 50. Preparation of compounds 12 and 10.

[0523]

[0524] Crude compound B11 was used directly, and 8 mL of anhydrous THF and 100 mg of K2CO3, 0.5 ml of 1H-1, 2, 3-triazole were added. The reaction mixture was stirred at room temperature overnight. The solution was diluted with EtOAc (100 mL). The resulting solution was washed with saline (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to obtain 10 mg of compound 12 and 19 mg of compound 10 as a white solid.

[0525] Compound 12:1 H NMR (500MHz, CDCl3) δ (ppm): 7.76 (1H, s), 7.64 (1H, s), 5.24 (1H, AB, J = 17.5Hz), 5.16 (1H, AB, J = 18.0Hz), 3.89 (1H, AB, J = 11.5Hz), 3.73 (1H, AB, J = 11.5Hz), 2.65 (1H, t, J = 9.0Hz), 2.25 ~ 2.19 (1H, m), 2.10 ~ 2.05 (2H, m), 1.23 (3H, s), 0.71 (3H, s).

[0526] Compound 10: 1 H NMR (500MHz, CDCl3) δ (ppm): 7.68 (2H, s), 5.25 (1H, AB, J = 17.5Hz), 5.22 (1H, AB, J = 17.5Hz) 3.89 (1H, AB, J = 11.5Hz) ,3.73(1H,AB,J=11.5Hz),2.58(1H,t,J=8.5Hz),2.24~2.20(1H,m),2.11~2.04(21H,m),1.23(3H,s),0.75(3H,s).

[0527] Example 51. Preparation of Compound 11.

[0528]

[0529] The crude compound B11 was used directly, and 8 mL of anhydrous THF and 100 mg of K2CO3, 0.5 ml of pyrazole were added. The reaction mixture was stirred at room temperature overnight. The solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to obtain 30 mg of compound 11 as a white solid. Compound 11: 1 H NMR (500MHz, CDCl3) δ (ppm): 7.54 (1H, d, J = 1.0Hz), 7.40 (1H, dt, J = 2.0Hz), 6.33 (1H, t, J = 1.5Hz), 4.94 (1H, AB, J = 17.5Hz), 4.90 (1H, AB, J = 17. 0Hz), 3.88 (1H, AB, J = 11.5Hz), 3.73 (1H, AB, J = 12.0Hz), 2.58 (1H, t, J = 8.5Hz) 2.23 ~ 2.17 (1H, m), 2.07 ~ 2.05 (2H, m), 1.23 (3H, s), 0.72 (3H, s).

[0530] Example 52. Preparation of Compound 6.

[0531]

[0532] Crude compound B11 was used directly, 8mL of anhydrous THF and 100mg of K2CO3, 0.5ml of 1-(piperazine-1-yl) ethyl ketone were added. The reaction mixture was stirred at room temperature overnight. The solution was then diluted with ethyl acetate (100mL). The resulting solution was washed with brine (100mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to obtain 29mg (43.64%, two steps, from 50mg of compound B10) of compound 6 as a white solid. Compound 6: 1 H NMR (500MHz, CDCl3) δ (ppm): 3.89 (1H, AB, J = 11.5Hz), 3.72 (1H, AB, J = 11.5Hz), 3.68 ~ 3.65 (2H, m), 3.5 1(2H,t,J=5.0Hz)3.21(3H,s),2.55(1H,t,J=9.5Hz),2.45(3H,t,J=5.0Hz),1.23(3H,s),0.67(3H,s)

[0533] Example 53. Preparation of Compound 7.

[0534]

[0535] 59 mg (0.12 mmol) of crude compound B11 was dissolved in 8 mL of THF and 100 mg (0.77 mmol) of K2CO3, 100 mg (0.61 mmol) of 1-(methylsulfonyl)piperazine were added. The reaction mixture was stirred at room temperature overnight. The solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to obtain 8 mg (0.02 mmol, 10.9%) of product 7 as a white solid. Compound 7: 1 HNMR (500MHz, CDCl3) δ (ppm): 3.89 (1H, AB, J = 11.5Hz), 3.72 (1H, AB, J = 12Hz), 3.30 (4H, t, J = 5.0Hz), 3.25 (2 H,s),2.78(3H,s)2.61(4H,t,J=5.0Hz),2.52(1H,t,J=8.5Hz),2.13~2.01(1H,m),1.23(3H,s),0.67(3H,s).

[0536] Example 54. Preparation of Compound E15.

[0537]

[0538] Preparation of step 1.E2. Ac2O (168.8 g, 1.65 mol) was added dropwise to a solution of E1 (250.0 g, 0.83 mol) in pyridine (1 L) at 19 ° C. After the addition was completed, the reaction mixture was stirred overnight at 19 ° C. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. The reaction mixture was then concentrated in vacuo, the residue was poured into water and extracted with dichloromethane (3 × 500 mL), the organic layer was washed with 2N HCl (200 mL), saturated NaHCO3 (300 mL), brine and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude target product E2 (283.7 g, 99.7%) as a brown oil. 1 H NMR(E2): (400MHz, CDCl3)δ5.95-5.90(m,1H),4.70-4.64(m,1H),4.20-4.13(m,1H),2.68-2.55(m,1H),2. 54-2.30(m,5H),2.15-1.90(m,6H),1.90-1.75(m,4H),1.63-1.38(m,2H),1.33-1.07(m,4H),0.90(s,3H).

[0539] Preparation of step 2.E3. CH(OEt)3(227.2g, 1.53mol) and p-TsOH(2.8g, 14.60mmol) were added to a solution of E2(250.0g, 0.73mol) in 1,4-dioxane(700mL) and EtOH(467mL) at 29°C. After the addition was complete, the reaction mixture was stirred at 29°C for 1 hour. TLC (petroleum ether:ethyl acetate=3:1) showed that the reaction was complete. The reaction mixture was then quenched with saturated NaHCO3(300mL) and poured into water, extracted with EtOAc(3×500mL), the organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from petroleum ether:ethyl acetate=10:1 to obtain the target product E3(155.8g, 57.6%) as a white solid. 1H NMR(E3): (400MHz, CDCl3)δ5.42-5.38(m,1H),5.15-5.10(m,1H),4.46-4.50(m,1H),4.32-4.25(m,1H),4..05-3.98(m,1H),3.85-3.70(m,2H),2 .53-2.42(m,1H),2.37-2.20(m,3H),2.18-1.91(m,7H),1.90-1.72(m,3H ),1.62-1.48(m,2H),1.40-1.20(m,6H),1.20-1.12(m,1H),0.90(s,3H).

[0540] Preparation of step 3.E4. Pd / C (1.5 g, 50% water) was added to a solution of E3 (30.0 g, 80.54 mmol) in EtOAc (400 mL) under N2. The reaction mixture was degassed under vacuum and purified with H2 several times. The reaction mixture was then stirred at 15 ° C under H2 atmosphere for 1 hour. It was then filtered and the filtrate was stirred at 15 ° C, 10% HCl (100 mL) was added and the reaction mixture was stirred at 15 ° C for 1 hour. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. The reaction mixture was poured into water and extracted with EtOAc (3 × 200 mL), the organic layer was washed with saturated NaHCO3, brine and dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column (petroleum ether: ethyl acetate = 10: 1-3: 1) to obtain the product E4 (33.0 g, yield: 59.1%) as a colorless oil. 1 H NMR(E4): (400MHz, CDCl3)δ4.75-4.50(m,1H),4.45-4.38(m,1H),2.55-2.35(m,5H),2.31-2.20(m, 1H),2.15-2.05(m,4H),2.05-1.65(m,6H),1.60-1.15(m,7H),1.15-1.00(m,1H),0.95-0.85(m,4H).

[0541] Preparation of step 4.E5. A catalytic amount of pyridine.HCl (0.3 g, 2.60 mmol) was added to a solution of E4 (31.0 g, 89.48 mmol) and ethane-1,2-diol (50 mL) in toluene (200 mL) at 16 ° C. After the addition was completed, the reaction mixture was heated to reflux and water was removed by a Dean-Stark collector for 18 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. The reaction mixture was then cooled to 16 ° C, poured into water, and extracted with EtOAc (3 × 100 mL), the organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product E5 (36.9 g, yield: 94.8%) as a white solid, which was used in the next step. 1 H NMR(E5): (400MHz, CDCl3)δ4.40-4.30(m,2H),4.20-4.10(m,2H),4.00-3.80(m,8H),2.20-1.90(m,5H),1.85-1.05(m,20H),1.05-0.75(m,5H).

[0542] Preparation of step 5.E6. 4N LiOH (94.9 mL, 379.69 mmol) was added to a solution of E5 (55.0 g, 126.56 mmol) in THF (200 mL) and MeOH (50 mL) at 20 ° C. After the addition was completed, the reaction mixture was stirred at 20 ° C for 18 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. The reaction mixture was then poured into water and extracted with EtOAc (3 × 200 mL), the organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product E6 (46.3 g, yield: 93.1%) as a white solid. 1 H NMR(E6): (400MHz, CDCl3)δ4.00-3.75(m,10H),2.25-2.15(m,1H),2.05-1.90(m, 1H),1.85-1.60(m,8H),1.60-1.40(m,7H),1.35-1.00(m,5H),1.00-0.75(m,5H).

[0543] Preparation of step 6.E7. At 25 ° C under N2, a suspension of 60% NaH (9.6 g, 0.24 mol) in anhydrous THF (100 mL) was added dropwise to a solution of compound E6 (46.3 g, 0.12 mol) in anhydrous THF (200 mL). The mixture was stirred for 30 minutes, and then MeI (51.1 g, 0.36 mol) was added dropwise at 25 ° C. After the addition was completed, the reaction mixture was stirred at 45 ° C for 4 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. The reactant was cooled to room temperature, quenched with saturated NH4Cl (200 mL), poured into water, extracted with EtOAc (3 × 200 mL), the organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product E7 (50.0 g, thick) as a yellow solid. 1 H NMR(E7): (400MHz, CDCl3) δ3.95-3.80(m,8H),3.55-3.40(m,2H),3.28(s,3H),2.18-2.10(m,1H) ,2.01-1.95(m,1H),1.81-1.57(m,8H),1.46-1.37(m,8H),1.29-1.18(m,4H),1.02-0.85(m,7H).

[0544] Preparation of step 7.E8. 2N HCl aqueous solution (40mL) was added to a solution of compound E7 (50.0g, 0.12mol) in THF (200mL) and acetone (40mL). After the addition was completed, the reaction mixture was stirred at 25°C for 18 hours. TLC (petroleum ether: ethyl acetate = 3: 1) indicated that the reaction was complete. The reaction mixture was then poured into water, extracted with EtOAc (3 × 200mL), the organic layer was washed with saturated NaHCO3, brine and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product E8 (41.0g, thick) as a yellow solid, which was used directly in the next step. 1 H NMR(E8): (400MHz, CDCl3) δ3.73-3.58(m,2H),3.34(s,3H),2.55-2.40(m,3H) ,2.42-2.30(m,1H),2.20-1.65(m,8H),1.60-1.20(m,10H),1.10-0.75(m,7H).

[0545] Preparation of step 8.E9. K-selectride (151 mL, 150.8 mmol, 1 M in THF) was added dropwise to a solution of E8 (40.0 g, 125.7 mmol) in anhydrous THF (500 mL) at -78 ° C under N2. After the addition was complete, the reaction mixture was stirred at -78 ° C for 3 hours. TLC (petroleum ether: ethyl acetate = 3: 1) indicated that the reaction was complete. The reaction mixture was slowly quenched with 30% H2O2 (17.1 g, 150.5 mmol) at -78 ° C, and then the reaction mixture was poured into saturated NH4Cl and extracted with EtOAc (3 × 100 mL). The organic phase was washed with saturated Na2S2O3, brine, dried over sodium sulfate and evaporated to give a crude product. The crude product was purified by washing with PE: EtOAc = 10: 1 to give the target product E9 (23.5 g, 58%) as a white solid. 1 H NMR(E9): (400MHz, CDCl3) δ4.10(m,1H),3.52(d,1H),3.42(d,1H),3.30(s,3H),2.50-2.40(m,1H),2.16-2.03(m,1H) ,1.98-1.90(m,2H),1.86-1.64(m,10H),1.55-1.47(m,3H),1.32-1.17(m,6H),1.12-0.95(m,1H),0.88-0.81(m,4H).

[0546] Preparation of step 9.E10. To a suspension of Ph3PEtBr (25.97 g, 70 mmol) in anhydrous THF (100 mL) at 0 ° C under N2, a solution of t-BuOK (7.70 g, 70 mmol) in anhydrous THF (50 mL) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. Then a solution of E9 (2.8 g, 8.75 mmol) in THF (30 mL) was added dropwise and the resulting mixture was stirred at 60 ° C for 12 hours. TLC (petroleum ether: ethyl acetate = 3: 1) indicated that the raw material was completely consumed. The reactant was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 40: 1) to obtain E10 (1.8 g, 62%) as a white powder. 1H NMR(E10): (400MHz, CDCl3) δ5.15-5.05(m,1H),4.13-4.05(m,1H),3.55-3.35(m,2H),3.30(s, 3H),2.45-1.90(m,4H),1.80-1.35(m,13H),1.30-0.95(m,8H),0.90(s,3H),0.85-0.70(m,1H).

[0547] Preparation of step 10.E11. Imidazole (737 mg, 10.82 mmol) and TBSCl (1.22 g, 8.12 mmol) were added to a solution of E10 (1.8 g, 5.41 mmol) in DMF (20 mL). The mixture was stirred at room temperature overnight. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the raw material was completely consumed. The reactant was diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified on silica gel by silica gel chromatography eluted with petroleum ether to obtain E11 (2.33 g, 96%) as a white solid. 1 H NMR(E11): (400MHz, CDCl3) δ5.11-5.09(m,1H),4.01-4.00(m,1H),3.50-3.39(m,2H),3.29(s,3H),2.40-2.30(m,1H),2.25-2 .10(m,2H),1.90-1.82(m,1H),1.53-1.40(m,5H),1.30-0.95(m,8H),0.89-0.88(m,9H),0.86-0.75(m,2H),0.02-0.01(m,6H).

[0548] Preparation of step 11.E12. THF (20 mL) containing E11 (2.33 g, 5.06 mmol) was added to 9-BBN solution (81 mL, 40.84 mmol). The mixture was stirred at 60 ° C for 16 hours. The mixture was then cooled to room temperature and 10% NaOH aqueous solution (40 mL) and H2O2 (20 mL) were added dropwise. After stirring for 1 hour, the mixture was quenched with Na2S2O3 aqueous solution and extracted with EtOAc (100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 40: 1) to obtain E12 (2.3 g, 90%) as a white solid. 1H NMR(E12): (400MHz, CDCl3) δ4.00-3.99(m,1H),3.71-3.65(m,1H),3.49-3.38(m,2H),3.28(s,3H),2.42-2.3 9(m,1H),1.89-1.82(m,5H),1.75-1.46(m,17H),1.38-1.00(m,14H),0.89(s,9H),0.68(s,3H),0.00(m,6H).

[0549] Step 12. Preparation of E13. Dess-Martin (3.8 g, 9.04 mmol) was added to a solution of E12 (2.1 g, 4.52 mmol) in CH2Cl2 (20 mL). The mixture was stirred at 12 ° C for 5 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the raw material was completely consumed. The mixture was quenched with a mixture solution of Na2S2O3 / NaHCO3 (3: 1, 12 g) in water (50 mL). The mixture was extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum to obtain E13 (2.3 g, thick) as a white solid. 1 H NMR(E13): (400MHz, CDCl3)4.00-3.99(m,1H),3.49-3.38(m,2H),3.27(s,3H),2.41-2.39(m,2H),2.20-2.12(m,1H),2.11(s,3H),2.0 0-1.95(m,1H),1.89-1.84(m,3H),1.75-1.45(m,14H),1.42-0.92(m,11H),0.89(s,9H),0.87-0.82(m,1H),0.62(s,3H),0.00(m,6H).

[0550] Preparation of step 13.E14. TFA (1 mL) was added to a solution of E13 (230 mg, 0.48 mmol) in CH2Cl2 (6 mL). The mixture was stirred at 15 ° C for 30 minutes. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the raw material was completely consumed. The reactant was quenched with NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (30 mL × 2). The organic layer was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1) to obtain E14 (166 mg, 95%) as a white solid. 1H NMR(E14): (400MHz, CDCl3)4.12-4.11(m,1H),3.52-3.42(m,2H),3.30(s,3H),2.58-2.53(m,1H),2.20-2.16(m,1H),2. 13(s,3H),2.06-1.97(m,2H),1.75-1.60(m,8H),1.59-1.10(m,11H),1.03-0.92(m,1H),0.90-0.82(m,1H),0.63(s,3H).

[0551] Preparation of step 14.E15. To a solution of E14 (2 g, 5.21 mmol) in MeOH (25 mL) was added HBr (5 drops) and Br2 (8 mL). The mixture was stirred at room temperature for 4 hours. LC-MS showed that the starting material was consumed. The reactant was diluted with H2O (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10: 1) to give E15 (1 g, 41%) as a white solid. 1 H-NMR showed the presence of 70% E15 and 30% E14. 1 H NMR(E15): (400MHz, CDCl3)4.11-4.10(m,1H),3.94-3.88(m,2H),3.49-3.39(m,2H),3.28(s,3H),2.84-2.79(m,1 H),2.20-2.15(m,1H),2.04-1.87(m,2H),1.74-1.60(m,8H),1.57-1.16(m,12H),1.03-0.76(m,2H),0.64(s,3H).

[0552] Example 55. Preparation of Compounds 90 and 91.

[0553]

[0554] 2H-1,2,3-triazole (969 mg, 13.8 mmol) was added to a solution of K2CO3 (952 mg, 6.9 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 30 minutes, and then a solution of E15 (1 g, 2.3 mmol) in DMF (20 mL) was added. The mixture was stirred at room temperature overnight. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the raw material was completely consumed. The reactant was diluted with EtOAc (50 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5: 1) to give 90 (204 mg, 21%) and 91 (437 mg, 45%) as a white powder. 1 H NMR(90): (400MHz, CDCl3)7.70(s,2H),5.31-5.20(m,2H),4.13-4.12(m,1H),3.52-3.43(m,2H),3.31(s,3H),2.63-2.58(m,1H), 2.24-2.22(m,1H),2.12-1.97(m,2H),1.78-1.62(m,9H),1.54-1.10(m,10H),1.09-0.96(m,1H),0.91-0.84(m,1H),0.75(s,3H). 1 H NMR(91): (400MHz, CDCl3)7.75(s,1H),7.63(s,1H),5.27-5.11(m,2H),4.13-4.10(m,1H),3.50-3.40(m,2H),3.28( s,3H),2.67-2.64(m,1H),2.26-2.18(m,1H),2.08-1.92(m,2H),1.74-1.25(m,15H),1.19-0.87(m,8H),0.69(s,3H).

[0555] Example 56. Preparation of Compound 92.

[0556]

[0557] A mixture of E15 (200 mg, 0.45 mmol), K2CO3 (188 mg, 1.36 mmol), 1H-pyrazole-3-carboxylic acid ethyl ester (317 mg, 2.27 mmol) and DMF (2 mL) was stirred at 25 ° C for 12 hours. TLC showed that the reaction was complete. The mixture was diluted with EtOAc (20 mL), washed with brine (30 mL × 3), and the organic layer was dried over anhydrous Na2SO4 and then concentrated to give a crude product. Purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to give 92 (96 mg, 44.4%) as a white solid. 1 H NMR(92): (400MHz, CDCl3) δ7.42(d,J=2.4Hz,1H),6.86(d,J=2.4Hz,1H),5.05-4.95(m,2H),4.39(q,J=7.2Hz,2H),4.20-4.10(m,1H),3.49-3.39(m ,2H),3.28(s,3H),2.60-2.55(m,1H),2.22-1.91(m,3H),1.75-1.50(m,6H ),1.45-1.10(m,15H),1.05-0.92(m,1H),0.90-0.84(m,1H),0.70(s,3H).

[0558] Example 57. Preparation of Compound 93.

[0559]

[0560] A solution of E15 (200 mg, 0.47 mmol) in CH3CN (15 mL) at 29 ° C was then added K2CO3 (194.01 g, 1.4 mmol) and 4-methyl-1H-pyrazole (192.09 mg, 2.34 mmol) in the mixture at 29 ° C. The solution was stirred at 60 ° C for 10 hours. After TLC showed that the raw material was completely consumed, the mixture was then concentrated. The mixture was extracted with CH2Cl2 (30 mL) and NaCl (aqueous solution) (20 mL × 2). The combined organic layer was dried over Na2SO4 and concentrated to give a crude product. The product was purified by silica gel column chromatography eluted with (petroleum ether / ethyl acetate=10:1 to 6:1) to give 93 (94.4 mg, yield: 46.81%). 1H NMR (93): (400MHz, CDCl3) δ7.36 (s, 1H), 7.18 (s, 1H), 4.85 (dd, J = 34Hz, J = 17.6Hz, 2H), 4.15-4.10 (m, 1H), 3.47 (dd, J = 28.8Hz, J = 10Hz, 2H), 3 .31(s,3H),2.62-2.55(m,1H),2.28-2.18(m,1H),2.13-1.97(m,5H),1 .78-1.64(m,8H),1.48-1.13(m,10H),1.04-0.84(m,2H),0.71(s,3H).

[0561] Example 58. Preparation of Compounds 94, 95 and 96.

[0562]

[0563] Cs2CO3 (343 mg, 1.05 mmol) and 4-methyl-1,2,3-triazole (145 mg, 1.75 mmol) were added to a solution of E15 (150 mg, 0.35 mmol) in DMF (6 mL) at 28 ° C. The reaction mixture was stirred at the same temperature for 6 hours. TLC showed that the starting material was completely consumed. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL×2). The combined organic layer was dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative HPLC to give pure 94 (35.8 mg) and a mixture of 95 and 96 (20 mg). The mixture was then purified by SFC to give 95 (3.9 mg) and 96 (5.6 mg). Total yield: 23.7%. The structures of the three targets were confirmed by NOE.

[0564] 1 H NMR(94): (400MHz, CDCl3) δ7.42(s,1H),5.19-5.08(m,2H),4.13-4.09(m,1H),3.53-3.38(m,2H),3.29(s,3H),2.61-2.54(m, 1H),2.33(s,3H),2.26-2.15(m,1H),2.11-1.95(m,2H),1.78-1.61(m,9H),1.52-1.06(m,9H),1.04-0.81(m,2H),0.72(s,3H).

[0565] 1H NMR(95): (400MHz, CDCl3) δ7.50(s,1H),5.23-5.05(m,2H),4.15-4.06(m,1H),3.58-3.42(m,2H),3.31(s,3H) ,2.71-2.61(m,1H),2.33-2.14(m,6H),2.12-1.96(m,4H),1.34-1.18(m,10H),1.06-0.83(m,6H),0.70(s,3H).

[0566] 1 H NMR(96): (400MHz, CDCl3) δ7.35(s,1H),5.22-5.02(m,2H),4.15-4.10(m,1H),3.56-3.39(m,2H),3.31(s,3H),2.67- 2.61(m,1H),2.39(s,3H),2.29-1.88(m,10H),1.33-1.22(m,10H),1.02-0.97(m,1H),0.92-0.84(m,2H),0.70(s,3H).

[0567] Example 59. Preparation of 97 and 98.

[0568]

[0569] To a solution of A11 (360 mg, 0.82 mmol) in acetone (2.5 mL) was added 5,6-difluoro-2H-benzo[d][1,2,3]triazole (BB-1) (190 mg, 1.23 mmol) and K2CO3 (230 mg, 1.64 mmol). The mixture was stirred at 30 ° C for 3 hours. TLC showed that the reaction was complete. Water (2 mL) was added to the mixture and extracted with EtOAc (5 mL×2). The combined organic layers were concentrated in vacuo and purified by preparative HPLC to give 97 (25 mg, 6%) and 98 (141 mg, 33%) as white solids.

[0570] 1 H NMR (97): (400MHz, CDCl3) δ7.59 (t, J = 8.4Hz, 2H), 5.53-5.42 (m, 2H), 3.48-3.36 (m, 2H), 3.29(s,3H),2.65(t,J=8.4Hz,1H),2.27-2.02(m,3H),1.80-0.85(m,23H),0.75(s,3H). LCMS(97):t R= 1.366 min, 10-80AB, 96.3% purity in 2 min chromatography, MS ESI: about C 29 H 40 Calculated for F2N3O3 [M+H] + 516, found 498 ([M+H-18] + ).

[0571] 1 H NMR(98): (400MHz, CDCl3) δ7.83(t,J=8.0Hz,1H),7.12(t,J=7.6Hz,1H),5.43-5.32(m,2H),3.50- 3.37(m,2H),3.30(s,3H),2.80-2.68(m,1H),2.30-2.02(m,3H),1.80-0.85(m,23H),0.75(s,3H). LCMS(98):t R = 1.317 min, 10-80AB, 99.6% purity in 2 min chromatography, MS ESI: about C 29 Calculated value of H40F2N3O3 [M+H] + 516, measured value 516.

[0572] Scheme A. General procedure for the preparation of compounds 99-146.

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582] Example 76. Preparation of Compounds 154 and 155.

[0583]

[0584] To a solution of compound D6 (300 mg, 0.679 mmol) in acetone (5 mL) was added K2CO3 (186 mg, 1.35 mmol) and 2H-pyrazolo [3,4-b] pyrazine (120 mg, 1.01 mmol). After stirring at 25 ° C for 3 hours, LCMS showed that the reaction was complete, one product (27%) and one product (21%). The reaction mixture was concentrated in vacuo to remove most of the solvent to obtain a residue. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL). The reaction mixture was extracted with EtOAc (50 mL × 3). The organic layers were combined and concentrated in vacuo to obtain a crude product. The crude product was purified by preparative HPLC (FA) to obtain compound 154 (4 mg, 1.22%) as a white solid and compound 155 (4 mg, 1.22%) as a white solid.

[0585] 1 H NMR (154) (yield 1.2%): (400MHz, CDCl3) δ8.64 (d, J = 2.0Hz, 1H), 8.56 (d, J = 2.0Hz, 1H), 8.26 (s, 1H), 5.40-5.19 (m, 2H), 3.54 (d,J=8.4Hz,1H),3.33(s,3H),3.20(d,J=9.2Hz,1H),2.68(t,J=8.8Hz,1H),2.30-1.20(m,26H),0.72(d,J=13.2Hz,3H). LCMSt R = 1.155 min, 10-80AB, 96.2% purity in 2 min chromatography, MS ESI: about C 28 H 41 Calculated value of N4O3 [M+H] + 481, measured value 481.

[0586] 1 H NMR (155) (yield 1.2%): (400 MHz, CDCl3) δ 8.59 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 5.36-5.24 (m, 2H), 3.55 (d, J = 9.2 Hz, 1H), 3.34 (s, 3H), 3.22 (d, J = 9.2 Hz, 1H), 2.68 (t, J = 8.8 Hz, 1H), 2.30-1.20 (m, 26H), 0.71 (s, 3H). LCMS t R = 0.854 min, 10-80AB, 96.8% purity in 1.5 min chromatography, MS ESI: about C 28 H41 Calculated value of N4O3 [M+H] + 481, found 463 [M+H-18] + .

[0587] Example 77. Preparation of Compound 156.

[0588]

[0589] 1 H NMR (156) (yield 41%): (400MHz, CDCl3) δ7.88 (s, 1H), 7.83 (s, 1H), 5.07-4.87 (m, 2H), 3.55 (d, J = 9.0Hz, 1H), 3.35 (s, 3H), 3.22 (d, J = 9.0Hz ,1H),2.65-2.58(m,1H),2.28-2.15(m,1H),2.10-2.01(m,1H),1.97-1.91(m,2H),1.82-1.40(m,14H),1.35-1.09(m,8H),0.68(s,3H). LCMSt R = 2.744 min, in 4 min chromatography, 10-80AB, purity 100.0%, MS ESI: about C 27 H 39 Calculated value of N3O3Na[M+Na] + 477, measured value 477.

[0590] Example 78. Preparation of Compound 147.

[0591]

[0592] 1 H NMR (147) (yield 4%): (400MHz, CDCl3) δ8.03 (s, 1H), 7.68 (d, J = 8.5Hz, 1H), 7.22 (s, 1H), 7.15 (d, J = 8.5Hz, 1H), 5.20-5.03 (m, 2H), 3.57 (d, J = 9.0Hz, 1H), 3.36(s,3H),3.23(d,J=9.0Hz,1H),2.65(t,J=8.7Hz,1H),2.30-2.09(m,2 H),1.99-1.91(m,2H),1.77-1.45(m,14H),1.34-1.14(m,8H),0.73(s,3H). LCMSt R = 3.185 min, in 4 min chromatography, 10-80AB, purity 100.0%, MS ESI: about C 30 H42 Calculated value of ClN2O3 [M+H] + 513, measured value 513.

[0593] Example 79. Preparation of Compound 157.

[0594]

[0595] 1 H NMR (157) (yield 3.5%): (400 MHz, CDCl3) δ 7.47-7.43 (m, 1H), 7.14-7.06 (m, 2H), 5.49-5.38 (m, 2H), 3.55 (t, J = 9.2 Hz, 1H), 3.36 (d, J = 4.0 Hz, 3H), 3.25 (d, J = 8.8 Hz, 1H), 2.73 (s, 1H), 2.30-1.20 (m, 26H), 0.74 (s, 3H). LCMS t R = 0.931 min, 5-95AB, 96.8% purity in 1.5 min chromatography, MS ESI: about C 29 H 41 Calculated value of FN3O3 [M+H] + 498, found 520 [M+Na] + .

[0596] Example 80. Preparation of Compound 158.

[0597]

[0598] 1 H NMR (158) (yield 18%): (400MHz, CDCl3) δ7.50 (d, J = 2.5Hz, 1H), 6.75 (d, J = 2.5Hz, 1H), 5.08-4.90 (m, 2H), 3.55 (d, J = 9.0Hz, 1H), 3.37-3.31 ( m,3H),3.22(d,J=9.0Hz,1H),2.64-2.57(m,1H),2.28-01(m,2H),1.99-1.91(m,2H),1.84-1.40(m,14H),1.39-1.08(m,8H),0.67(s,3H). LCMSt R = 2.821 min, in 4 min chromatography, 10-80AB, purity 100.0%, MS ESI: about C 27 H 39 Calculated value of N3O3Na[M+Na] + 476, measured value 476.

[0599] Example 81. Preparation of Compound 159.

[0600]

[0601] 1 H NMR (159) (yield: 13%): (400MHz, CDCl3) δ7.48 (s, 1H), 6.60 (d, J = 2.0Hz, 1H), 5.07-4.88 (m, 2H), 3.56 (d, J = 9.0Hz, 1H), 3.35 (s, 3H), 3.22 (d, J = 9.0Hz,1H),2.65-2.54(m,1H),2.28-2.15(m,1H),2.10-2.02(m,1H),1 .99-1.90(m,2H),1.84-1.37(m,14H),1.36-1.07(m,8H),0.68(s,3H). LCMSt R = 3.049 min, in 4 min chromatography, 10-80AB, purity 100.0%, MS ESI: about C 27 H 40 Calculated for F3N2O3 [M+H] + 497, found 479 [M+H-H2O] + .

[0602] Example 82. Preparation of Compound 160.

[0603]

[0604] 1 H NMR (160) (yield 11%): (400MHz, CDCl3) δ8.59 (s, 1H), 5.47 (s, 2H), 3.56 (d, J = 9.0Hz, 1H), 3.35 (s, 3H), 3.23 (d, J = 9.0Hz, 1H), 2.66 (t,J=8.8Hz,1H),2.30-2.16(m,1H),2.15-2.05(m,1H),1.98-1.89(m,2H),1.84-1.41(m,14H),1.40-1.11(m,9H),0.72(s,3H). LCMSt R = 2.667 min, in 4 min chromatography, 10-80AB, purity 100.0%, MS ESI: about C 24 H 39 Calculated value of N4O3 [M+H] + 431, found 413 [M+H-18] + .

[0605] Example 83. Preparation of Compound F5.

[0606]

[0607] Step 1. Preparation of compound F1. CsF (953 mg, 6.28 mmol) was added to a solution of C2 (2 g, 6.28 mmol) in THF (30 mL) in a flask at 0 ° C, and then TMSCF3 (1.33 g, 9.42 mmol) was added dropwise. The reactant was warmed to 25 ° C and stirred for 2 hours. TLC (PE: EtOAc = 3: 1) showed that the raw material was completely consumed. The reaction mixture was then treated with 2M HCl aqueous solution (10 mL) and stirred for 6 hours. The reactant was then diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to give a crude product, which was purified by a silica gel column (PE: EtOAc = 50: 1 to 10: 1) to give product F1 (1.1 g, 45.0% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ3.49 (d, J = 8.0Hz, 1H), 3.32-3.22 (m, 4H), 2.46-2.39 (m, 1H), 2.10-1.71 (m, 8H), 1.68-1.10 (m, 14H), 0.85 (s, 3H).

[0608] Step 2. Preparation of compound F2. T-BuOK (1.57 g, 14.0 mmol) was added to a solution of ethyltriphenylphosphonium bromide (5.19 g, 14.0 mmol) in THF (30 mL). The reaction mixture was heated to 60 ° C for 1 hour and F1 (1.1 g, 2.83 mmol) was added to the mixture, which was stirred for another 8 hours at 60 ° C. TLC (PE: EtOAc = 3: 1) showed that the reaction was complete. The reaction mixture was cooled, then diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by a silica gel column (PE: EtOAc = 100: 1 to 15: 1) to obtain product F2 (1 g, 88.6% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ5.15-5.02(m,1H),3.56(d,J=8.0Hz,1H),2.46-2.39(m,1H),3. 34(s,3H),3.29(d,J=8.0Hz,1H),2.43-1.80(m,7H),1.58-1.10(m,19H),0.90(s,3H).

[0609] Step 3. Preparation of compound F3. At 0°C under N2 protection, BH3-Me2S solution (2.48mL, 10M) was added dropwise to a solution of F2 (1g, 2.49mmol) in THF (15mL). The solution was stirred at 25°C for 4 hours. TLC (PE / EtOAc=3 / 1) showed that the reaction was complete. After cooling to 0°C, NaOH solution (9.93mL, 3M) was added very slowly, releasing a large amount of gas. After the addition was complete, H2O2 (4.53mL, 33%) was added slowly and the internal temperature was maintained below 10°C. The resulting solution was stirred at 25°C for 1 hour. The resulting solution was extracted with EtOAc (20mL×3). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (20mL×3), brine (20mL), dried over Na2SO4 and concentrated in vacuo to obtain a crude product (1g) in the form of a yellow oil. The crude product was used in the next step without further purification.

[0610] Step 4. Preparation of compound F4. A mixture of F3 (1.0 g, 2.38 mmol), PCC (0.767 g, 3.56 mmol) and silica gel (0.843 g, w / w=1 / 1.1) in DCM (15 mL) was stirred at 25 ° C for 2 hours, and the reaction mixture color turned brown. TLC (PE / EtOAc=3 / 1) showed that the reaction was complete. The solution was filtered and the filter cake was washed with DCM (20 mL). The combined filtrate was concentrated in vacuo. The residue was purified by a silica gel column eluted with PE:EtOAc=15:1 to 8:1 to obtain F5 (800 mg, 80.6%) as a white solid. MS ESI: about C 24 H 41 Calculated value of O4 [M+H] + 417, found 399 ([M+H-18] + ). 1 H NMR (400MHz, CDCl3) δ3.52(d,J=8.0Hz,1H),3.33(s,3H),3.28(d,J=8.0Hz,1 H),2.58-2.52(m,1H),2.20-1.60(m,15H),1.53-1.10(m,11H),0.62(s,3H).

[0611] Step 5. Preparation of compound F5. Dibromo (230 mg, 1.44 mmol) was added dropwise to a solution of F4 (0.5 g, 1.20 mmol) and a catalytic amount of concentrated HBr (12.1 mg, 40% in water) in MeOH (15 mL) at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 hour. TLC (PE: EtOAc = 3: 1) showed that the reaction was complete. The reaction was quenched with saturated NaHCO3 aqueous solution and the pH was adjusted to 7-8. The reaction mixture was extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to give a crude product F5 (500 mg) as a yellow oil.

[0612] Example 84. Preparation of Compounds 161 and 162.

[0613]

[0614] To a solution of compound F5 (150 mg, 0.302 mmol) in acetone (5 mL) was added K2CO3 (62.6 mg, 0.453 mmol) and 4,5-difluoro-2H-benzo [d] [1,2,3] triazole (70.2 mg, 0.453 mmol). After stirring at 25 ° C for 3 hours, TLC (PE: EA = 3: 1) showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude product (150 mg). The crude product was purified by preparative HPLC (HCl) to give compound 162 (18 mg, 10.4%) and compound 161 (31 mg, 18%) as a white solid.

[0615] 1 H NMR (161) (yield 10.4%): (400 MHz, CDCl3) δ 7.42-7.36 (m, 1H), 7.09-7.06 (m, 1H), 5.53-5.35 (m, 2H), 3.50 (t, J = 9.2 Hz, 1H), 3.34-3.29 (m, 4H), 2.71 (d, J = 8.8 Hz, 1H), 2.20-1.00 (m, 23H), 0.74 (s, 3H). LCMS t R = 1.350 min, in 2 min chromatography, 10-80AB, purity 100%, MS ESI: about C 29 H 37 Calculated value of F5N3O3 [M+H] + 570, measured value 570.

[0616] 1H NMR (162) (yield 18%): (400MHz, CDCl3) δ7.68-7.64(m,1H),7.37-7.29(m,1H),5.59-5.49(m,2H),3 .51(t,J=7.6Hz,1H),3.34-3.29(m,4H),2.69(d,J=8.8Hz,1H),2.24-1.14(m,23H),0.77(s,3H). LCMSt R = 1.398 min, in 2 min chromatography, 10-80AB, purity 100%, MS ESI: about C 29 H 37 Calculated value of F5N3O3 [M+H] + 570, measured value 570.

[0617] Example 85. Preparation of Compounds 163, 164 and 165.

[0618]

[0619] 1 H NMR (163) (yield 11%): (400 MHz, CDCl3) δ 7.73 (t, J = 5.6 Hz, 1H), 7.09-7.06 (m, 2H), 5.48-5.38 (m, 2H), 3.88 (s, 3H), 3.50 (d, J = 8.8 Hz, 1H), 3.31 (s, 3H), 3.28 (d, J = 9.2 Hz, 1H), 2.62 (t, J = 8.8 Hz, 1H), 2.17-1.11 (m, 23H), 0.74 (s, 3H). LCMS t R = 1.354 min, in 2 min chromatography, 10-80AB, 100% purity, MS ESI: about C 30 H 41 Calculated value of F3N3O4 [M+H] + 564, measured value 564.

[0620] 1H NMR (164) (yield 11%): (400MHz, CDCl3) δ7.38 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.15 (dd, J1 = 7.2 Hz, J2 = 1.6 Hz, 1H), 5.34 (s, 2H ),3.89(s,3H),3.49(d,J=6.8Hz,1H),3.31(s,3H),3.28(d,J=6.8Hz,1H),2.66(t,J=7.2Hz,1H),2.35-1.10(m,23H),0.71(s,3H). LCMSt R = 0.964 min, in 1.5 min chromatography, 5-95AB, 95% purity, MS ESI: about C 30 H 41 Calculated value of F3N3O4 [M+H] + 564, measured value 564.

[0621] 1 H NMR (165) (yield 19%): (400MHz, CDCl3) δ7.91 (d, J = 9.2Hz, 1H), 7.01 (dd, J1 = 9.2Hz, J2 = 2.0Hz, 1H), 6.59 (d, J = 2.0Hz, 1H), 5.38-5.27 (m, 2H), 3. 85(s,3H),3.49(d,J=9.2Hz,1H),3.31(s,3H),3.28(d,J=9.2Hz,1H),2.67(t,J=8.4Hz,1H),2.43(brs,1H),2.30-1.05(m,23H),0.71(s,3H). LCMSt R = 1.354 min, in 2 min chromatography, 10-80AB, 100% purity, MS ESI: about C 30 H 41 Calculated value of F3N3O4 [M+H] + 564, measured value 564.

[0622] Example 86. Preparation of Compound 166.

[0623]

[0624] 1H NMR (166) (yield 10.5%): (400 MHz, CDCl3) δ 7.73 (t, J = 5.6 Hz, 1H), 7.09-7.06 (m, 2H), 5.48-5.38 (m, 2H), 3.88 (s, 3H), 3.50 (d, J = 8.8 Hz, 1H), 3.31 (s, 3H), 3.28 (d, J = 9.2 Hz, 1H), 2.62 (t, J = 8.8 Hz, 1H), 2.17-1.11 (m, 22H), 0.74 (s, 3H). LCMS t R = 1.354 min, in 2 min chromatography, 10-80AB, 100% purity, MS ESI: about C 30 H 41 Calculated value of F3N3O4 [M+H] + 564, measured value 564.

[0625] Example 87. Preparation of Compounds 167, 168 and 169.

[0626]

[0627] 1 H NMR (167) (yield 1%): (400 MHz, CDCl3) δ 7.89-7.83 (m, 2H), 7.38 (t, J = 7.2 Hz, 1H), 5.56-5.46 (m, 2H), 3.52 (d, J = 9.2 Hz, 1H), 3.34 (s, 1H), 3.30 (d, J = 9.2 Hz, 1H), 2.65 (t, J = 4.4 Hz, 1H), 2.26-1.07 (m, 25H), 0.76 (s, 3H). LCMS t R = 1.424 min, in 2 min chromatography, 10-80AB, purity 99%, MS ESI: about C 29 H 38 Calculated value of ClF3N3O3 [M+H] + 568, measured value 568.

[0628] 1 H NMR (168) (yield 6%): (400 MHz, CDCl3) δ 8.01-7.99 (m, 1H), 7.36-7.34 (m, 2H), 5.43-5.31 (m, 2H), 3.50 (d, J = 8.8 Hz, 1H), 3.28-3.35 (m, 4H), 2.70 (t, J = 8.8 Hz, 1H), 2.24-1.13 (m, 23H), 0.73 (s, 3H). LCMS t R= 1.009 min, 5-95AB, 97% purity in 1.5 min chromatography, MS ESI: about C 29 H 38 Calculated value of ClF3N3O3 [M+H] + 568, measured value 568.

[0629] 1 H NMR (169) (yield 8%): (400MHz, CDCl3) δ8.07 (s, 1H), 7.45 (t, J = 7.2Hz, 1H), 7.29 (s, 1H), 5.34-5.45 (m, 2 H), 3.49 (d, J = 8.8Hz, 1H), 3.28-3.32 (m, 4H), 2.70 (t, J = 9.2Hz, 1H), 2.20-0.88 (m, 23H), 0.71 (s, 3H). LCMSt R = 0.995 min, 5-95AB, 99% purity in 1.5 min chromatography, MS ESI: about C 29 H 38 Calculated value of ClF3N3O3 [M+H] + 568, measured value 568.

[0630] Example 88. Preparation of Compound C19.

[0631]

[0632] Step 1. Preparation of compound C12. To a solution of C2 (4 g, 13.14 mmol) in 15 mL of CH2Cl2 was added 1H-imidazole (2.68 g, 39.42 mmol) and tert-butylchlorodimethylsilane (2.97 g, 19.71 mmol) at 25 ° C, and the reactant was stirred at 25 ° C for 16 hours. The reaction mixture was filtered with 50 mL of CH2Cl2 and evaporated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 50: 1-30: 1-20: 1-15: 1-10: 1) to obtain C12 (5 g, 90.87% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ3.81(d,J=8.0Hz,1H),3.58(d,J=8.0Hz,1H),2.62-2.55(m,1H),2.48-2.43(m,1H),2.40-2.2 8(m,3H),2.26-2.07(m,2H),1.87-1.86(m,1H),1.84-1.75(m,4H),1.56-1.27(m,10H),0.87(s,12H),0.042(s,6H).

[0633] Step 2. Preparation of compound C13. To a solution of C12 (15.79 g, 71.64 mmol) in 30 mL of toluene was added AlMe3 solution (17.91 mL, 3 eq.) dropwise at 0°C. After 1 hour, a solution of (5R, 8R, 9S, 10R, 13S, 14S)-10-(((tert-butyldimethylsilyl)oxy)methyl)-13-methyldodecahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,4H)-dione (5 g, 11.94 mmol) in toluene (40 mL) was added dropwise at -78°C, the reaction mixture was stirred at -78°C for 1 hour, then MeMgBr solution (11.94 mL, 3 eq.) was added dropwise to the mixture at -78°C, which was stirred for another 2 hours at -78°C. After TLC (PE: EtOAc = 3: 1) showed that the raw material was completely consumed, the reaction mixture was quenched with NH4Cl aqueous solution (15 mL), filtered and washed with 500 mL EtOAc. The organic layer was extracted with 300 mL EtOAc, washed with brine and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 100-50: 1-20: 1-10: 1-4: 1) to obtain C13 (5 g, 96.3%) as a white solid. 1 H NMR (400MHz, CDCl3), δ3.76 (d, J=8.0Hz, 1H), 3.40 (d, J=8.0Hz, 1H), 2.44-2. 39(m,1H),2.09-1.70(m,6H),1.61-1.18(m,19H),0.89(s,12H),0.04(s,6H).

[0634] Step 3. Preparation of compound C14. To a solution of C13 (7 g, 16.1 mmol) in 70 mL of MeOH was added HBr solution (6.5 g, 32.2 mmol, 40% in water). The reaction mixture was stirred at 25 ° C for 0.7 hours. After TLC (PE: EtOAc = 3: 1) showed that the raw material was completely consumed, the reaction mixture was quenched with saturated NaHCO3 aqueous solution (200 mL) and extracted with 500 mL EtOAc, washed with brine (100 mL) and concentrated to give the product C14 (5.6 g, thick) as a white solid.

[0635] Step 4. Preparation of compound C15. To a solution of PPh3EtBr (51.8 g, 140 mmol) in THF (40 mL) was added a solution of t-BuOK (15.7 g, 140 mmol) in THF (40 mL) at 0 ° C. After stirring at 60 ° C for 1 hour, a solution of compound C14 (9 g, 28.0 mmol) in THF (40 mL) was added dropwise at 60 ° C. The reaction mixture was then stirred for 8 hours at the same temperature. TLC (PE / EtOAc=3 / 1) showed that the reaction was complete, and the main product with lower polarity was found. The reaction mixture was extracted three times with EtOAc (300 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by a silica gel column (PE:EA=5:1) to give compound C15 (5.0 g, 53.5%) as a light yellow oil. 1 H NMR (400MHz, CDCl3) δ5.15-5.05(m,1H),3.94(d,J=10.8Hz,1H),3.56(d,J=10.8 Hz,1H),2.40-2.12(m,3H),2.01-1.71(m,3H),1.69-1.12(m,24H),0.85(s,3H).

[0636] Step 5. Preparation of compound C16. NaH (171 mg, 4.5 mmol, 60% in oil) was added portionwise to a solution of C15 (500 mg, 1.50 mmol) in THF (15 mL) in a flask under N2 protection. The reaction mixture was stirred for 10 minutes. Then iodoethane (701 mg, 4.5 mmol) was added. The reaction mixture was heated and stirred for another 2 hours at 50 ° C. TLC (PE: EA = 3: 1) showed that the reaction was complete, and the main product with lower polarity was found. The reactant was quenched with NH4Cl aqueous solution (10 ml) and extracted with EtOAc (20 mL × 2). The combined organic layer was washed with NaCl aqueous solution (20 mL) and dried over Na2SO4, then concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 15: 1 to 8: 1) to obtain product C16 (500 mg, 91.9% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ5.12-5.09(m,1H),3.60(d,J=9.2Hz,1H),3.48-3.42(m,2H),3.23( d,J=9.2Hz,1H),2.38-2.12(m,3H),1.95-1.72(m,3H),1.65-1.10(m,26H),0.85(s,3H).

[0637] Step 6. Preparation of compound C17. BH3-Me2S solution (1.38mL, 10M) was added dropwise to a solution of C16 (500mg, 1.38mmol) in THF (15mL) at 0°C. The solution was stirred at 25°C for 4 hours. TLC (PE: EtOAc = 3: 1) showed that the reaction was almost complete, and the main product with higher polarity was found. After cooling to 0°C, NaOH solution (5.5mL, 3M) was added very slowly. After the addition was complete, H2O2 (2.51mL, 33%) was added slowly and the internal temperature was maintained below 10°C. The resulting solution was stirred at 25°C for 2 hours. The resulting solution was extracted with EtOAc (20mL × 3). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (30mL × 3), brine (30mL), dried over Na2SO4 and concentrated in vacuo to obtain a crude product (500mg) as a yellow oil. The crude product was used in the next step without further purification.

[0638] Step 7. Preparation of compound C18. A suspension of C17 (500 mg, 1.32 mmol), PCC (426 mg, 1.98 mmol) and silica gel (469 mg, w / w=1 / 1.1) in DCM (15 mL) was stirred at 30 ° C for 2 hours. The reaction mixture turned brown in color. TLC (PE / EtOAc=3 / 1) showed that the reaction was complete and a major product with lower polarity was found. The solution was filtered and the filter cake was washed with DCM (20 mL). The combined filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE / EtOAc=15 / 1 to 5 / 1 to give C18 (400 mg, 80.3%) as a white solid. MS ESI: About C 24 H 40 Calculated value of O3 [M+H] + 377, found 359 ([M+H-18] + ). 1 H NMR(400MHz, CDCl3)δ3.58(d,J=9.2Hz,1H),3.49-3.42(m,2H),3.24(d,J=9.2H z,1H),2.56-2.51(m,1H),2.18-1.65(m,12H),1.60-1.10(m,19H),0.61(s,3H).

[0639] Step 8. Preparation of compound C19. Dibromo (254 mg, 1.59 mmol) was added dropwise to a solution of C18 (400 mg, 1.06 mmol) and catalytic amount of concentrated HBr (10.7 mg, 40% in water) in MeOH (15 mL) at 0 ° C. The reaction mixture was stirred for 1 hour at 25 ° C. TLC (PE: EtOAc = 3: 1) showed that the reaction was complete, and the main product with lower polarity was found. The reaction was quenched by saturated NaHCO3 aqueous solution and the pH was adjusted to 7-8. The reaction mixture was extracted with DCM (20 mL × 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated to give the crude product C19 (400 mg, 82.8% yield) as a yellow oil.

[0640] Example 89. Preparation of Compound 170.

[0641]

[0642] To a solution of compound F5 (150 mg, 0.329 mmol) in acetone (5 mL) was added KCO (68.1 mg, 0.493 mmol) and 1H-pyrazole-4-carbonitrile (45.8 mg, 0.493 mmol). After stirring at 25 ° C for 3 hours, LCMS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a crude product (150 mg). The crude product was purified by preparative HPLC (HCl) to give the desired product 170 (13 mg, 8.41%) as a white solid.

[0643] 1 H NMR (170) (yield 8.4%): (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.03-4.87 (m, 2H), 3.54 (d, J = 9.2 Hz, 1H), 3.68-3.41 (m, 2H), 3.24 (d, J = 9.2 Hz, 1H), 2.59 (t, J = 9.2 Hz, 1H), 2.21-1.15 (m, 29H), 0.65 (s, 3H). LCMS t R = 0.949 min, 5-95AB, 98.6% purity in 1.5 min chromatography, MS ESI: about C 28 H 42 Calculated value of N3O3 [M+H] + 467, found 450 [M+H-18] + .

[0644] Example 90. Alternative preparation of compound A21.

[0645]

[0646] Step 1. Preparation of compound E16. To a solution of ((5S, 8R, 9S, 10R, 13S, 14S)-13-methyl-3,17-dioxohexadecahydro-1H-cyclopenta[a]phenanthrene-10-yl)methyl acetate (E4, 5 g, 14.4 mmol) in THF (50 mL) was added dropwise MeMgBr (15 mL, 3M in ether, 450 mmol) to control the internal temperature below -70 ° C. The mixture was then stirred at -78 ° C for 1 hour. TLC showed that the reaction was complete. A solution of NH4Cl (6 g) in water (30 mL) was added to the mixture and the internal temperature was raised to -20 ° C. The mixture was then warmed to 20 ° C. The organic layer was separated. The aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, concentrated under vacuum and purified by column chromatography (PE:EtOAc=6:1 to 3:1) to give ((3R,5S,8R,9S,10R,13S,14S)-3-hydroxy-3,13-dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-10-yl)methyl acetate (E16, 2.4 g, 46%) and ((3S,5S,8R,9S,10R,13S,14S)-3-hydroxy-3,13-dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-10-yl)methyl acetate (1 g, 19%) as white solids. 1 H NMR(400MHz, CDCl3) δ4.29(d,J=12.1Hz,1H),4.13(d,J=12.1Hz,1H),2.48-2.35(m ,1H),2.11-1.85(m,7H),1.85-1.59(m,6H),1.55-1.22(m,11H),1.09-0.74(m,7H).

[0647] Step 2. Preparation of compound E17. To a suspension of PPh3EtBr (4.61 g, 12.4 mmol) in THF (10 mL) at 20 ° C., a solution of t-BuOK (1.86 g, 16.6 mmol) in THF (20 mL) was added. The color of the suspension turned dark red. After stirring at 60 ° C. for 1 hour, a solution of acetic acid ((3R, 5S, 8R, 9S, 10R, 13S, 14S) -3-hydroxy-3, 13-dimethyl-17-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-10-yl) methyl ester (E16, 1.5 g, 4.14 mmol) in THF (20 mL) was added dropwise at 60 ° C. The reaction mixture was then stirred at 60 ° C. for 16 hours. TLC showed that the reaction was complete. NH4Cl (50 mL, saturated aqueous solution) was added to the reaction mixture. The color of the mixture turned light yellow. The organic layer was separated. The aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were concentrated under vacuum and purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 4: 1) to give (3R, 5S, 8S, 9S, 10R, 13S, 14S)-17-ethylidene-10-(hydroxymethyl)-3, 13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-ol (E17, 1.0 g, 72.6%) as a white solid. 1 H NMR (400MHz, CDCl3) δ5.19-5.08(m,1H),3.93(d,J=11.5Hz,1H),3.74(d,J=11.5Hz,1H),2.44-2.33(m,1H),2.3 2-2.13(m,2H),2.12-2.04(m,1H),1.87-1.71(m,2H),1.69-1.43(m,12H),1.38-1.08(m,11H),1.07-0.74(m,6H)

[0648] Step 3. Preparation of compound A18. To a solution of E17 (0.8 g, 2.4 mmol) in THF (10 mL) was added sodium hydride (475 mg, 11.9 mmol) and iodoethane (1.85 g, 11.9 mmol) in multiple portions. The mixture was stirred at 50 ° C for 12 hours. The reaction mixture was quenched with water and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 50: 1) to give A18 (0.5 g, 57.5%) as a colorless oil. 1H NMR (400MHz, CDCl3) δ5.13-5.08(m,1H),3.52(d,J=9.6Hz,1H),3.43-3.38(m,3H),2.38-2.32(m,1H),2.25-2.12(m,2H),2.06-2.01(m,1H),1.7 4-1.57(m,2H),1.56-1.39(m,6H),1.31-1.27(m,2H),1.24-1.16(m,11H ),1.14-1.07(m,2H),1.05-0.91(m,2H),0.88(s,3H),0.87-0.74(m,3H).

[0649] Step 4. Preparation of compound A19. BH3-Me2S (0.69 mL, 6.9 mmol) was added dropwise to a solution of A18 (0.5 g, 1.38 mmol) in THF (5 mL) at 0 ° C. The solution was stirred for 2 hours at 30 ° C. TLC (PE / EtOAc=5 / 1) showed that the reaction was complete. After cooling to 0 ° C, an aqueous NaOH solution (5.51 g, 10% in water) was added very slowly. After the addition was complete, H2O2 (1.56 g, 30%) was added slowly and the internal temperature was maintained below 10 ° C. The resulting solution was stirred at room temperature for 1 hour. A white solid was formed. EtOAc (5 mL) was added to the mixture and filtered. The filter cake was washed with EtOAc (5 mL). The combined organic layers were separated, washed with Na2S2O3 (5 mL, 20%, aqueous solution), dried over Na2SO4 and concentrated in vacuo to afford A19 (0.4 g, purity: 78%, yield: 59.7%) as a colorless oil, which was used directly without further purification. LCMS tR = 1.085 min, 30-90AB in 2 min chromatography, purity 77.6%, MS ESI: about C 24 H 42 Calculated value of O3 [M+H] + 379, found 361 ([M+H-18] + ).

[0650] Step 5. Preparation of compound A20. To a solution of A19 (0.4 g, 0.824 mmol, purity: 78%) in dichloromethane (5 mL) was added silica gel (1 g) and PCC (0.885 g, 4.11 mmol). The suspension was stirred at 30 ° C for 16 hours. TLC (PE: EA = 5: 1) showed that the reactant was completely consumed. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE: EA = 10: 1) to obtain A20 (0.2 g, 64.4%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.50 (d, J = 10.0 Hz, 1H), 3.42-3.37 (m, 3H), 2.53 (t, J = 8.8 Hz, 1H), 2.20-2.15 (m, 1H), 2.11 (s, 3H), 2.07-1.97 (m, 2H), 1.73-1.64 (m, 4H), 1.50-1.47 (m, 2H), 1.37-1.25 (m, 6H), 1.21-1.14 (m, 9H), 1.12-0.75 (m, 5H), 0.61 (s, 3H). LCMS tR = 1.124 min, in 2 min chromatography, 30-90AB, purity 100%, MS ESI: about C 24 H 40 Calculated value of O3 [M+H] + 377, found 359 ([M+H-18] + ).

[0651] Step 6. Preparation of compound A21. To a solution of A20 (0.2 g, 0.531 mmol) in methanol (2 mL) was added HBr (8.93 mg, 0.053 mmol, 48% in water) and Br2 (127 mg, 0.796 mmol). The mixture was stirred at 30 ° C for 2 hours. The reaction mixture was quenched with aqueous NaHCO3 to adjust the pH to about 8. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give A21 (0.2 g, 82.6%) as a light yellow solid, which was used without further purification. LCMS tR=1.184 min, 30-90AB in 2 min chromatography, purity 100%, MS ESI: about C 24 H 39 Calculated value of BrO3 [M+H] + 455, found 437 ([M+H-18] + ).

[0652] Example 91. Preparation of Compound 171.

[0653]

[0654] To a solution of A21 (90 mg, 0.197 mmol) in acetone (2 mL) was added potassium carbonate (67.9 mg, 0.492 mmol) and 1H-pyrazole-4-carbonitrile (27.4 mg, 0.295 mmol). The suspension was stirred at 40 ° C for 12 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 171 (22 mg, 23.8%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.81 (s, 1H), 5.02 (d, J = 18.0 Hz, 1H), 4.89 (m, J = 18.0 Hz, 1H), 3.51 (d, J = 9.2 Hz, 1H), 3.42-3.37 (m, 3H), 2.60 (t, J = 9.2 Hz, 1H), 2.25-2.17 (m, 1H), 2.06-1.99 (m, 2H), 1.75-1.69 (m, 4H), 1.54-1.50 (m, 3H), 1.46-0.81 (m, 19H), 0.67 (s, 3H). LCMS tR = 1.109 min, in 2 min chromatography, 30-90AB, purity 100%, MSESI: about C 28 H 41 Calculated value of N3O3 [M+H] + 468, found 490 ([M+Na] + ).

[0655] Example 92. Preparation of Compounds 172 and 173.

[0656]

[0657] To a solution of 2-bromo-1-((3R,5S,8S,9S,10R,13S,14S,17S)-10-(ethoxymethyl)-3-hydroxy-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethanone (90 mg, 0.197 mmol) in acetone (2 mL) was added potassium carbonate (67.9 mg, 0.492 mmol) and 4,5-difluoro-2H-benzo[d][1,2,3]triazole (45.7 mg, 0.295 mmol). The mixture was stirred at 50 °C for 16 hours. The mixture was cooled, filtered and concentrated. The residue was purified by preparative HPLC to give 2-(4,5-difluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((3R,5S,8S,9S,10R,13S,14S,17S)-10-(ethoxymethyl)-3-hydroxy-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethanone (172, 10 mg, 9.28%) as a light yellow solid , purity: 97%) and 2-(4,5-difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((3R,5S,8S,9S,10R,13S,14S,17S)-10-(ethoxymethyl)-3-hydroxy-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethanone (173, 15 mg, 14.0%, purity: 98%) as a light yellow solid.

[0658] 1 H NMR (172): (400MHz, CDCl3) δ7.63 (dd, J=3.2Hz, 8.8Hz, 1H), 7.31-7.24 (m, 2H), 5.57-5.46 (m, 2H), 3.53 (d, J=9.6Hz, 1H), 3.43-3.40 (m, 3H), 2.66 (t,J=8.8Hz,1H),2.27-2.03(m,3H),1.79-1.69(m,4H),1.65-1.57(m,4H ),1.32-1.26(m,6H),1.22-1.12(m,8H),1.09-0.82(m,4H),0.76(s,3H). LCMSt R = 1.066 min, 5-95AB, 97% purity in 1.5 min chromatography, MS ESI: about C 30 H 42 Calculated for F2N3O3 [M+H] + 530, measured value 512 ([M+H-18] + ).

[0659] 1H NMR(173): (400MHz, CDCl3) δ7.40-7.33(m,1H),7.05(d,J=7.2Hz,1H),5.46-5.35(m,2H),3.52(d,J=10.0Hz,1H),3.43-3.38(m,3H), 2.71(t,J=8.4Hz,1H),2.24-2.03(m,3H),1.75-1.69(m,4H),1.62-1.53(m,4H),1.32-1.16(m,14H),1.13-0.83(m,4H),0.72(s,3H). LCMSt R = 1.037 min, 5-95AB, 98% purity in 1.5 min chromatography, MS ESI: about C 30 H 42 Calculated for F2N3O3 [M+H] + 530, measured value 530 ([M+H] + ).

[0660] Determination method

[0661] The compounds provided herein can be evaluated using a variety of assays; examples of which are described below.

[0662] Steroid inhibition of TBPS binding

[0663] A TBPS binding assay using rat brain cortical membranes in the presence of 5 μM GABA has been described (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985; Lewin, AH et al., Mol. Pharmacol. 1989, 35, 189-194).

[0664] Briefly, the cortex was removed rapidly after decapitation of carbon dioxide anesthetized Sprague-Dawley rats (200-250 g). The cortex was homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass / Teflon homogenizer and centrifuged at 1500×g for 10 minutes at 4°C. The supernatant was centrifuged at 10,000×g for 20 minutes at 4°C to obtain a P2 pellet. The P2 pellet was resuspended in 200 mM NaCl / 50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000×g for 10 minutes at 4°C. This washing procedure was repeated twice and the pellet was resuspended in 10 volumes of buffer. The cells were washed with 3 nM [ 35S]-TBPS and 5 μ L aliquots (final 0.5%) of the test drug dissolved in dimethyl sulfoxide (DMSO) were incubated with aliquots (100 μ L) of the membrane suspension. Buffer was used to make the incubation reach a final volume of 1.0 mL. Non-specific binding was determined in the presence of 2 μ M unlabeled TBPS and the range was 15% to 25%. After incubation for 90 minutes at room temperature, the assay was terminated by filtering through a glass fiber filter (Schleicher and Schuell No.32) using a cell collector (Brandel) and rinsed three times with ice-cold buffer. The filter was measured for radioactivity by liquid scintillation spectrometry. Prism (GraphPad) was used to perform nonlinear curve fitting of the total data of each drug averaged for each concentration. If the sum of squares tested according to F is significantly lower, the data are fitted with a partial rather than a complete inhibition model. Similarly, if the sum of squares tested according to F is significantly lower, the data are fitted with a two-component rather than a single-component inhibition model. For a single experimental determination, the test compound concentration (IC) that produces 50% inhibition of specific binding 50 ) and the maximum inhibition level (I max ), where the same model was used for the total data and the mean ± SEM of the individual experiments was then calculated. Picrotoxin served as a positive control for these studies, as it has been shown to potently inhibit TBPS binding.

[0665] Various compounds have been or can be screened to determine whether they are effective as in vitro [ 35 [S]-TBPS binding modulator potential. These assays are or can be performed according to the procedures discussed above.

[0666] Regarding Table 1, "A" indicates IC 50 <10nM, “B” indicates IC 50 10nM to 50nM, "C" indicates IC 50 >50nM to 100nM, "D" indicates IC 50 >100nM to 500nM, and "E" indicates IC 50 >500nM.

[0667] Table 1.

[0668]

[0669]

[0670]

[0671] Recombinant α1β2γ2 and α4β3δ GABA A Patch clamp electrophysiology of receptors

[0672] Using cellular electrophysiology to measure our GABA A Pharmacological properties of GABA receptor modulators in heterologous cell systems. Each compound was tested at a submaximal agonist dose (GABA EC 20 =2 μM) under the ability to affect GABA-mediated currents. LTK cells were stably transfected with the α1β2γ2 subunit of the GABA receptor via the Lipofecatamine method and CHO cells were transiently transfected with the α4β3δ subunit. The cells were passaged at about 50-80% confluence and then inoculated into a 35mm sterile culture dish containing 2ml complete medium without antibiotics or antimycotics. The confluent clusters of cells were electrically coupled (Pritchett et al., Science, 1988, 242, 1306-1308). Because the response in the distant cells was insufficiently voltage-clamped and due to uncertainty about the degree of coupling (Verdoorn et al., Neuron 1990, 4, 919-928), cells were cultured at a density that enabled recording of single cells (without visible connections to other cells).

[0673] Whole-cell currents were measured using a HEKA EPC-10 amplifier or by using a high-throughput QPatch platform (Sophion) using PatchMaster software. The bath solution for all experiments contained (in mM): NaCl 137mM, KCl 4mM, CaCl2 1.8mM, MgCl2 1mM, HEPES 10mM, D-glucose 10mM, pH (NaOH) 7.4. In some cases, 0.005% cremophor was also added. The intracellular (pipette) solution contained: KCl 130mM, MgCl2 1mM, Mg-ATP 5mM, HEPES10mM, EGTA 5mM, pH 7.2. During the experiment, cells and solutions were maintained at room temperature (19°C-30°C). For manual patch clamp recordings, the cell culture dish was placed on the dish rack of the microscope and the bath solution was continuously perfused (1ml / min). After forming a gigaohm seal between the patch electrode and the cell (electrode resistance range: 2.5 MΩ-6.0 MΩ; seal resistance range: >1 GΩ), the cell membrane across the electrode tip was ruptured to ensure electrical access to the cell interior (whole-cell patch configuration). For experiments using the QPatch system, cells were transferred to the QPatch system in suspension in bath solution and automated whole-cell recordings were performed.

[0674] The cell voltage is clamped at a holding potential of -80mV. For the analysis of the test article, after the sequential pre-incubation of the test article of increasing concentration, the GABA receptor is stimulated by 2 μM GABA. The pre-incubation duration is 30 seconds and the duration of GABA stimulation is 2 seconds. The test article is dissolved in DMSO to form a stock solution (10mM). The test article is diluted to 0.01, 0.1, 1 and 10 μM in the bath solution. The test article of all concentrations is tested on each cell. The relative percentage enhancement is defined as the response to GABA EC in the presence of the test article. 20 The peak amplitude of the response to GABA alone was divided by the EC 20 The peak amplitude of the oscillator, multiplied by 100.

[0675] Table 2. Exemplary compounds in GABA A -Electrophysiological assessment under R.

[0676]

[0677] About Table 2. GABAA receptor α1β2γ2 and α4β3δ efficacy %: “A” 10-100, “B” >100-500, “C” >500; D indicates data not available or not determined.

[0678] GABA receptor enhancement

[0679] The two-electrode voltage clamp (TEVC) technique was used to study the effects of compounds at a concentration of 10 μM on GABAergic proteins composed of either α1β2γ2 or α4β3δ subunits expressed in oocytes from the African clawed frog (Xenopus laevis). A Effects of GABA receptors. GABA-evoked currents are recorded from oocytes expressing GABA receptors and the modulation of these currents by the test items is investigated.

[0680] Ovaries were collected from female African clawed frogs that had been deeply anesthetized by cooling at 4°C and immersing in tricaine methanesulfonate (MS-222, concentration of 150 mg / L) in sodium bicarbonate (300 mg / L). Once anesthetized, the animals were decapitated and the spinal cord was destroyed in accordance with the animal rights regulations of the State of Geneva. A small piece of ovary was isolated for immediate preparation, while the rest was placed in sterile Barth's solution at 4°C containing (in mM) NaCl 88, KCl 1, NaHCO 2.4, HEPES 10, MgSO .7H O 0.82, Ca (NO ) .4H O 0.33, CaCl .6H O 0.41 (pH 7.4) and supplemented with 20 μg / ml kanamycin, 100 units / ml penicillin and 100 μg / ml streptomycin. All recordings were performed at 18°C ​​and cells were superfused with medium containing (in mM) NaCl 82.5, KCl 2.5, HEPES 5, CaCl2.2H2O, CaCl2.6H2O 1 (pH 7.4).

[0681] Plasmids containing RNA of human GABRA1 / GABRB2 / GABRG2 and GABRA4 / GABRB3 / GABRD genes were injected into oocytes using a proprietary automatic injection device (Hogg et al., J. Neurosci. Methods, (2008) 169:65-75). These genes encode α1β2γ2 and α4β3δ GABA A Subunits. Receptor expression was assessed using electrophysiology at least two days later. The ratio of RNA injection for α1β2γ2 was 1:1:1 and for α4β3δ was 5:1:5. Electrophysiological recordings were performed using an automated process equipped with a standard TEVC and data were captured and analyzed using proprietary data acquisition and analysis software running under Matlab (Mathworks Inc.). The membrane potential of the oocytes was maintained at -80 mV throughout the experiment. To explore the effects of proprietary compounds, currents were induced by applying 10 μM (α1β2γ2) or 3 μM (α4β3δ) GABA for 30 seconds. These concentrations approximate the EC of GABA at each receptor subtype. 50Concentration. Then make oocytes be exposed to GABA again for 30 seconds. After GABA is applied and started 15 seconds, test article is applied jointly with the concentration of 10 μM for 15 seconds. The enhancement of peak current is assessed. Data are filtered at 10 Hz, captured at 100 Hz and analyzed using the proprietary data acquisition and analysis software running under Matlab (Mathworks Inc.). For statistical analysis, Excel (Microsoft) or Matlab (mathworks Inc.) are used to calculate values. In order to obtain the mean value measurement with standard deviation, all experiments are carried out using at least three cells.

[0682] GABA was prepared as a concentrated stock solution in water (10 -1 Compounds were prepared as stock solutions in DMSO (10 M) and then diluted in recording medium to obtain the desired test concentration. -2 M) and then diluted in recording medium to obtain the desired test concentration. Residual DMSO did not exceed a concentration of 1%, which has been shown to have no effect on Xenopus oocyte function.

[0683] Table 3. Exemplary compounds in GABA A -Electrophysiological assessment under R.

[0684]

[0685]

[0686]

[0687] About Table 3. GABAA receptor α1β2γ2 and α4β3δ efficacy %: “A” 50-500, “B” >500-1000, “C” >1000-1500, “D” >1500-2000; “E” >2000.

[0688] The present invention includes the following contents:

[0689] 1. A compound of formula (I):

[0690]

[0691] Its pharmaceutically acceptable salt,

[0692] in:

[0693] A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group;

[0694] L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR3 -;

[0695] R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic group or heterocyclic group;

[0696] R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy;

[0697] Each R 3 are independently hydrogen or C1-C6 alkyl;

[0698] R 5 is absent or is hydrogen; and

[0699] represents a single bond or a double bond, where

[0700] when When one of the two is a double bond, the other is a single bond; and

[0701] When the When one of the two bonds is a double bond, R 5 Does not exist.

[0702] 2. A compound of formula (Ia):

[0703]

[0704] Its pharmaceutically acceptable salt,

[0705] in:

[0706] A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group;

[0707] L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -;

[0708] R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic group or heterocyclic group;

[0709] Each R 3 are independently hydrogen or C1-C6 alkyl;

[0710] R 5 is absent or is hydrogen; and

[0711] represents a single bond or a double bond, where

[0712] when When one of the two is a double bond, the other is a single bond; and

[0713] When the When one of the two bonds is a double bond, R 5 Does not exist.

[0714] 3. The compound according to embodiment 2, wherein the compound has formula (Ia-1):

[0715]

[0716] 4. The compound according to embodiment 2, wherein the compound has formula (Ia-2):

[0717]

[0718] 5. The compound as described in embodiment 2, wherein A is monocyclic.

[0719] 6. A compound as described in embodiment 5, wherein A is linked through nitrogen.

[0720] 7. The compound as described in embodiment 5, wherein A is heteroaryl.

[0721] 8. A compound as described in embodiment 7, wherein the heteroaryl group contains up to five nitrogen atoms.

[0722] 9. The compound of embodiment 7, wherein the heteroaryl group is benzotriazole, azabenzotriazole, diazabenzotriazole, benzopyrazole, azabenzopyrazole or diazabenzopyrazole.

[0723] 10. The compound as described in embodiment 5, wherein A is a 5-membered heteroaryl or heterocyclyl.

[0724] 11. The compound as described in embodiment 10, wherein A is a 5-membered heteroaryl or heterocyclyl containing up to four nitrogen atoms.

[0725] 12. The compound as described in embodiment 11, wherein A is a 5-membered heteroaryl or heterocyclyl containing 2, 3 or 4 nitrogen atoms.

[0726] 13. A compound as described in embodiment 12, wherein A is pyrazole, triazole or tetrazole.

[0727] 14. The compound according to embodiment 3, wherein the compound has formula (Ia-3):

[0728]

[0729] in

[0730] R4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(R c )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a 、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c );

[0731] Each R a is hydrogen or C1-C6 alkyl;

[0732] Each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or

[0733] R b and R c Together with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and

[0734] n is 0, 1, 2 or 3.

[0735] 15. The compound according to embodiment 3, wherein the compound has formula (Ia-4):

[0736]

[0737] in

[0738] R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(Rc )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a 、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c );

[0739] Each R a is hydrogen or C1-C6 alkyl;

[0740] Each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or

[0741] R b and R c Together with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and

[0742] n is 0, 1, 2 or 3.

[0743] 16. The compound of embodiment 3, wherein n is 0.

[0744] 17. The compound of embodiment 3, wherein n is 1 or 2, and R 4 is C1-C6 alkyl or C(O)OR a .

[0745] 18. The compound according to embodiment 17, wherein R 4 It's methyl.

[0746] 19. The compound according to embodiment 17, wherein R a It is a C1-C6 alkyl group.

[0747] 20. The compound according to embodiment 19, wherein R a It is ethyl.

[0748] 21. The compound as described in embodiment 3, wherein R 1 is hydrogen or C1-C6 alkyl, and R 4 Yes - C(O)OR a .

[0749] 22. The compound according to embodiment 21, wherein R 1It is a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, a carbocyclic group or a heterocyclic group.

[0750] 23. The compound as described in embodiment 22, wherein R 1 It is a C1-C6 alkyl group.

[0751] 24. The compound as described in embodiment 23, wherein R 1 It is methyl, ethyl or isopropyl.

[0752] 25. The compound according to embodiment 21, wherein R 1 is methyl and R 4 It is -C(O)OEt.

[0753] 26. The compound according to embodiment 14, wherein the compound is selected from:

[0754]

[0755] 27. A compound of formula (Ib):

[0756]

[0757] Its pharmaceutically acceptable salt,

[0758] in:

[0759] A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group;

[0760] L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -;

[0761] R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic group or heterocyclic group;

[0762] R 2 is a C1-C6 alkyl group (e.g., a C1-C6 haloalkyl group) or a C1-C6 alkoxy group;

[0763] Each R 3 are independently hydrogen or C1-C6 alkyl;

[0764] R 5 is absent or is hydrogen; and

[0765] represents a single bond or a double bond, where

[0766] when When one of the two is a double bond, the other is a single bond; and

[0767] When the When one of the two bonds is a double bond, R 5 Does not exist.

[0768] 28. The compound according to embodiment 27, wherein the compound has formula (Ib-1):

[0769]

[0770] 29. The compound of embodiment 27, wherein the compound has formula (Ib-2):

[0771]

[0772] 30. The compound according to embodiment 28, wherein the compound has formula (Ib-3)

[0773]

[0774] in

[0775] R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(R c )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a 、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c );

[0776] Each R a is hydrogen or C1-C6 alkyl;

[0777] Each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or

[0778] R b and R cTogether with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and

[0779] n is 0, 1, 2 or 3.

[0780] 31. The compound according to embodiment 29, wherein the compound has formula (Ib-4)

[0781]

[0782] in

[0783] R 4 is cyano, nitro, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a 、-C(O)N(R b )(R c )、-C(O)OR a 、-N(R b )(R c )、-OC(O)N(R b )(R c )、-OC(O)OR a 、-OC(O)R a 、-S(O) 0-2 R a 、-S(O) 0-2 OR a or -S(O) 0-2 N(R b )(R c );

[0784] Each R a is hydrogen or C1-C6 alkyl;

[0785] Each R b and R c are independently hydrogen, C 1- C6 alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, or

[0786] R b and R c Together with the nitrogen atom to which it is bound, it forms a ring (e.g., a 3-7 membered ring, e.g., a 5-7 membered ring; a ring containing at least one heteroatom such as a nitrogen, oxygen or sulfur atom); and

[0787] n is 0, 1, 2 or 3.

[0788] 32. A compound as described in embodiment 27, wherein A is monocyclic.

[0789] 33. A compound as described in embodiment 27, wherein A is bicyclic.

[0790] 34. A compound as described in embodiment 27, wherein A is linked through nitrogen.

[0791] 35. A compound as described in embodiment 34, wherein A is a 5-membered or 6-membered heteroaryl or heterocyclyl.

[0792] 36. A compound as described in embodiment 35, wherein A is a 5-membered or 6-membered heteroaryl or heterocyclyl containing up to four nitrogen atoms.

[0793] 37. A compound as described in embodiment 36, wherein A is a 5-membered or 6-membered heteroaryl or heterocyclyl group containing 1, 2, 3 or 4 nitrogen atoms.

[0794] 38. A compound as described in embodiment 27, wherein A is a heterocyclyl.

[0795] 39. A compound as described in embodiment 38, wherein A is morpholine or piperazine.

[0796] 40. The compound of embodiment 27, wherein A is heteroaryl.

[0797] 41. A compound as described in embodiment 40, wherein the heteroaryl group contains up to five nitrogen atoms.

[0798] 42. The compound of embodiment 40, wherein the heteroaryl is benzotriazole, azabenzotriazole, diazabenzotriazole, benzopyrazole, azabenzopyrazole or diazabenzopyrazole.

[0799] 43. A compound as described in embodiment 40, wherein the heteroaryl group is 5-membered.

[0800] 44. A compound as described in embodiment 43, wherein A contains up to four nitrogen atoms.

[0801] 45. A compound as described in embodiment 43, wherein A contains 2, 3 or 4 nitrogen atoms.

[0802] 46. ​​A compound as described in embodiment 40, wherein A is pyrazole, triazole or tetrazole.

[0803] 47. The compound as described in embodiment 27, wherein R 1 It is a C1-C6 alkyl group, a C1-C6 alkenyl group, a C1-C6 alkynyl group, a carbocyclic group or a heterocyclic group.

[0804] 48. The compound as described in embodiment 47, wherein R 1 It is a C1-C6 alkyl group.

[0805] 49. The compound as described in embodiment 48, wherein R 1 It is methyl, ethyl or isopropyl.

[0806] 50. The compound as described in embodiment 48, wherein R 1 It's methyl.

[0807] 51. The compound as described in embodiment 27, wherein R 2 It's methyl.

[0808] 52. The compound of embodiment 27, wherein n is 0.

[0809] 53. The compound of embodiment 27, wherein n is 1 or 2, and R 4 is cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a or -S(O) 0-2 R a .

[0810] 54. The compound as described in embodiment 53, wherein R 4 is Br, Cl or F.

[0811] 55. The compound as described in embodiment 53, wherein R 4 It is -OCH3.

[0812] 56. The compound as described in embodiment 53, wherein R 4 It's cyano.

[0813] 57. The compound as described in embodiment 53, wherein R 4 It is a C1-C6 alkyl group.

[0814] 58. The compound as described in embodiment 57, wherein R 4 It's methyl.

[0815] 59. The compound as described in embodiment 53, wherein R 4 Yes-C(O)R a .

[0816] 60. The compound as described in embodiment 59, wherein R a It is a C1-C6 alkyl group.

[0817] 61. The compound as described in embodiment 60, wherein R a It's methyl.

[0818] 62. The compound as described in embodiment 53, wherein R 4 Yes-S(O)2R a .

[0819] 63. The compound as described in embodiment 62, wherein R a It's methyl.

[0820] 64. The compound as described in embodiment 27, wherein R 1 is a C1-C6 alkyl group and R 4 Yes-C(O)R a .

[0821] 65. The compound as described in embodiment 64, wherein R 1 is methyl and R 4 It’s -C(O)Me.

[0822] 66. The compound of embodiment 27, wherein n is 0 or 1; R 1 is hydrogen or C1-C6 alkyl; and R 2 It's methyl.

[0823] 67. The compound as described in embodiment 27, wherein R 1 It is methyl, ethyl or isopropyl.

[0824] 68. The compound as described in embodiment 67, wherein R 1 It's methyl.

[0825] 69. The compound as described in embodiment 27, wherein R 4 is C1-C6 alkyl, -C(O)R a or -S(O) 0-2 R a .

[0826] 70. The compound as described in embodiment 69, wherein R 4 It's methyl.

[0827] 71. The compound as described in embodiment 69, wherein R 4 It’s -C(O)Me.

[0828] 72. The compound as described in embodiment 69, wherein R 4 It is -S(O)2Me.

[0829] 73. The compound according to embodiment 27, wherein the compound is selected from:

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841] 74. A pharmaceutical composition comprising a compound as described in any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[0842] 75. A method of inducing sedation and / or anesthesia in a subject, comprising administering to the subject an effective amount of a compound of formula (I):

[0843]

[0844] Its pharmaceutically acceptable salt,

[0845] in:

[0846] A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group;

[0847] L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -;

[0848] R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic group or heterocyclic group;

[0849] R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy;

[0850] Each R 3 are independently hydrogen or C1-C6 alkyl;

[0851] R 5 is absent or is hydrogen; and

[0852] represents a single bond or a double bond, where

[0853] when When one of the two is a double bond, the other is a single bond; and

[0854] When the When one of the two bonds is a double bond, R 5 Does not exist.

[0855] 76. A method of administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound as described in Embodiment 1 to a subject in need thereof, wherein the subject experiences sedation and / or anesthesia within two hours of administration.

[0856] 77. The method of embodiment 76, wherein the subject experiences sedation and / or anesthesia within one hour of administration.

[0857] 78. The method of embodiment 76, wherein the subject immediately undergoes sedation and / or anesthesia.

[0858] 79. The method of embodiment 76, wherein the compound is administered by intravenous administration.

[0859] 80. The method of embodiment 76, wherein the compound is administered chronically.

[0860] 81. The method of embodiment 76, wherein the subject is a mammal.

[0861] 82. The method of embodiment 81, wherein the subject is human.

[0862] 83. The method of embodiment 76, wherein the compound is administered in combination with another therapeutic agent.

[0863] 84. A method for treating convulsions in a subject, comprising administering to the subject an effective amount of a compound of formula (I):

[0864]

[0865] Its pharmaceutically acceptable salt,

[0866] in:

[0867] A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group;

[0868] L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -;

[0869] R 1is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic group or heterocyclic group;

[0870] R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy;

[0871] Each R 3 are independently hydrogen or C1-C6 alkyl;

[0872] R 5 is absent or is hydrogen; and

[0873] represents a single bond or a double bond, where

[0874] when When one of the two is a double bond, the other is a single bond; and

[0875] When the When one of the two bonds is a double bond, R 5 Does not exist.

[0876] 85. A method for treating epilepsy or status epilepticus in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I):

[0877]

[0878] Its pharmaceutically acceptable salt,

[0879] in:

[0880] A is an optionally substituted nitrogen-containing heteroaryl or heterocyclic group;

[0881] L is -C(R 3 )(R 3 )-, -O-, -S-, or -NR 3 -;

[0882] R 1 is hydrogen or C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, carbocyclic group or heterocyclic group;

[0883] R 2 is hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl) or C1-C6 alkoxy;

[0884] Each R 3 are independently hydrogen or C1-C6 alkyl;

[0885] R 5 is absent or is hydrogen; and

[0886] represents a single bond or a double bond, where

[0887] when When one of the two is a double bond, the other is a single bond; and

[0888] When the When one of the two bonds is a double bond, R 5 Does not exist.

[0889] 86. A method for treating a disorder related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of one of the compounds of Embodiment 1.

[0890] 87. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound as described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0891] 88. The method of embodiment 87, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a spasticity 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, or tinnitus.

[0892] 89. The method of embodiment 87, wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

[0893] 90. A kit comprising a solid composition comprising a compound of formula (I) as described in embodiment 1 and a sterile diluent.

Claims

1. Use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating depression in a subject, wherein the compound of formula (II) is: in: A is a nitrogen-containing monocyclic heteroaryl or heterocyclic group; R 1 is hydrogen or C1-C6 alkyl; R 2 is hydrogen or C1-C6 alkyl; R 5 Absent or hydrogen; represents a single bond or a double bond, where when When one of the two is a double bond, the other is a single bond; and When the When one of the two bonds is a double bond, R 5 does not exist; R 4 is hydrogen, cyano, hydroxyl, halogen, –CF3, C1-C6 alkyl, C1-C6 alkoxy, –C(O)R a or –S(O) 0-2 R a ; Each R a is hydrogen or C1-C6 alkyl; and n is 1 or 2.

2. Use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating depression in a subject, wherein the compound of formula (II) is: in: A is a nitrogen-containing monocyclic heteroaryl or heterocyclic group; R 1 is hydrogen or C1-C6 alkyl; R 2 is hydrogen or C1-C6 haloalkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where When one of the two is a double bond, the other is a single bond; and when the When one of the two bonds is a double bond, R 5 does not exist; R 4 is hydrogen, cyano, hydroxyl, halogen, –CF3, C1-C6 alkyl, C1-C6 alkoxy, –C(O)R a or –S(O) 0-2 R a ; Each R a is hydrogen or C1-C6 alkyl; and n is 1 or 2.

3. The method according to claim 1 or 2, wherein A is a substituted 5-membered or 6-membered nitrogen-containing heteroaryl or heterocyclic group.

4. The method of claim 3, wherein A is a substituted 5-membered or 6-membered nitrogen-containing heteroaryl or heterocyclic group containing up to four nitrogen atoms.

5. The method of claim 4, wherein A is a substituted 5- or 6-membered nitrogen-containing heteroaryl or heterocyclic group containing 2, 3 or 4 nitrogen atoms.

6. The method of claim 5, wherein A is a substituted pyrazole, triazole, tetrazole, morpholine or piperazine.

7. The use according to claim 1, wherein the compound of formula (II) is a compound of formula (IIa-1): or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein n is 1 and R 4 It's methyl.

9. The use as claimed in claim 7, wherein R 4 Yes-C(O)R a or -S(O) 0-2 R a , and R a It is a C1-C6 alkyl group.

10. The use according to claim 9, wherein R a It is ethyl.

11. The use as claimed in claim 7, wherein R 1 is hydrogen or C1-C6 alkyl, n is 1, and R 4 Yes -C(O)OR a .

12. The use according to claim 11, wherein R 1 It is a C1-C6 alkyl group.

13. The use as claimed in claim 12, wherein R 1 It is methyl, ethyl or isopropyl.

14. The use according to claim 12, wherein R 1 is methyl and R 4 It is -C(O)OEt.

15. The use according to claim 7, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

16. The use according to claim 1, wherein the compound of formula (II) is a compound of formula (IIa-2) or (IIa-3): or a pharmaceutically acceptable salt thereof.

17. The use according to claim 2, wherein the compound of formula (II) is a compound of formula (IIa-2) or (IIa-3): or a pharmaceutically acceptable salt thereof.

18. The use according to claim 16 or 17, wherein R 1 It is a C1-C6 alkyl group.

19. The use as claimed in claim 18, wherein R 1 It is methyl, ethyl or isopropyl.

20. The use according to claim 19, wherein R 1 It's methyl.

21. The use according to claim 16, wherein R 2 It's methyl.

22. The use of claim 16 or 17, wherein n is 1 or 2, and each R 4 are independently cyano, halo, C1-C6 alkyl, C1-C6 alkoxy, -C(O)R a or -S(O) 0-2 R a .

23. The use of claim 22, wherein n is 1 or 2, and each R 4 is independently -Br, -Cl or -F.

24. The use of claim 22, wherein n is 1 or 2, and each R 4 It is -OCH3.

25. The use of claim 22, wherein n is 1, and R 4 It's cyano.

26. The use of claim 22, wherein n is 1, and R 4 It is a C1-C6 alkyl group.

27. The use as claimed in claim 26, wherein R 4 It's methyl.

28. The use of claim 22, wherein n is 1, and each R 4 Yes-C(O)R a .

29. The use of claim 28, wherein each R a It is a C1-C6 alkyl group.

30. The use of claim 29, wherein each R a It's methyl.

31. The use of claim 22, wherein n is 1, and R 4 Yes-S(O)2R a .

32. The use of claim 31, wherein R a It's methyl.

33. The use of claim 16 or 17, wherein R 1 is a C1-C6 alkyl group, n is 1, and R 4 Yes-C(O)R a .

34. The use of claim 33, wherein R 1 is methyl and R 4 It’s -C(O)Me.

35. The use of claim 16 or 17, wherein n is 1, and R 4 It’s -C(O)Me.

36. The use of claim 16 or 17, wherein n is 1, and R 4 It is -S(O)2Me.

37. The use according to claim 16, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

38. Use of a compound of formula (III) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating depression in a subject, wherein the compound of formula (III) is: in: A is benzotriazole, azabenzotriazole, diazabenzotriazole, benzopyrazole, azabenzopyrazole or diazabenzopyrazole; R 1 is a C1-C6 alkyl group; R 2 is C1-C6 alkyl or C1-C6 haloalkyl; R 5 is absent or is hydrogen; and represents a single bond or a double bond, where when When one of the two is a double bond, the other is a single bond; and When the When one of the two bonds is a double bond, R 5 does not exist; R 4 is hydrogen, cyano, hydroxyl, halogen, –CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, –C(O)R a or –S(O) 0-2 R a ; Each R a is hydrogen or C1-C6 alkyl; and n is 1, 2, or 3.

39. The use of claim 38, wherein R 2 Yes – CF3.

40. The use of claim 38, wherein R 2 It's methyl.

41. The use according to claim 38, wherein the compound of formula (III) is a compound of formula (IIIa-1) or (IIIa-2): or a pharmaceutically acceptable salt thereof.

42. The use of any one of claims 38-41, wherein n is 1 or 2, and each R 4 are independently hydrogen, cyano, halogen, -CF3, C1-C6 alkyl or C1-C6 alkoxy.

43. The use of claim 42, wherein R 1 It is methyl, ethyl or isopropyl.

44. The use of any one of claims 38-41, wherein n is 1 or 2, and each R 4 is independently -Br, -Cl or -F.

45. The use of any one of claims 38-41, wherein n is 1 or 2, and each R 4 It is -OCH3 or -OCF3.

46. ​​The use as claimed in claim 38, wherein the compound of formula (III) is selected from: or a pharmaceutically acceptable salt thereof.

47. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating depression in a subject, wherein the compound is selected from:

48. The use of any one of claims 1, 38 or 47, wherein the medicament is administered to a subject orally, subcutaneously, intravenously or intramuscularly.

49. The use of claim 48, wherein the medicament is administered to the subject orally or intravenously.

50. The use of any one of claims 1, 38 or 47, wherein the depression is postpartum depression.

51. The use of any one of claims 1, 38 or 47, wherein the medicament is administered chronically.

52. The use of any one of claims 1, 38 or 47, wherein the subject is a mammal.

53. The use of claim 52, wherein the subject is a human.

54. The use of any one of claims 1, 38 or 47, wherein the medicament is administered in combination with another therapeutic agent.

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