NEUROACTIVE STEROID COMPOUNDS AND COMPOSITIONS UNDERSTANDING THE SAME

专利摘要:
neuroactive steroids, compositions comprising and use thereof neuroactive steroids of formula (i) are described herein: (formula (i)) or a pharmaceutically acceptable salt thereof; wherein r1a and r1b are as defined herein. such compounds behave, in certain modalities, as gaba modulators. the present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, for example, as for inducing sedation and / or anesthesia
公开号:BR112016000975B1
申请号:R112016000975-4
申请日:2014-07-18
公开日:2020-10-06
发明作者:Boyd L. Harrison；Gabriel MARTINEZ BOTELLA；Albert Jean Robichaud；Francesco Gerald Salituro
申请人:Sage Therapeutics, Inc.；
IPC主号:

专利说明:

Related requests
[001] The present application claims priority under 35 U.S.C. § 119 (e) for U.S. provisional patent application, U.S.S.N. 61 / 856,592, filed on July 19, 2013, which is incorporated herein by reference. Background of the invention
[002] Cerebral excitability is defined as the level of excitement of an animal, a continuum that varies from coma to seizures, and is regulated by several neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70 mV, the inside of the cell being negative in relation to the outside of the cell. The potential (voltage) is the result of ionic balance (K +, Na +, Cl “, organic anions) across the semipermeable neuronal membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, a chemical excitatory transmitter, such as acetylcholine, will cause the membrane to depolarize (change in potential from -70 mV to -50 mV). This effect is mediated by post-synaptic nicotinic receptors that are stimulated by acetylcholine to increase the membrane's permeability to Na + ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.
[003] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by GABA, a neurotransmitter. GABA has a profound influence on general brain excitability because up to 40% of neurons in the brain use GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its GRC recognition site to facilitate the flow of chloride ions to an electrochemical GRC gradient in the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, making the neuron less susceptible to excitatory stimuli (that is, reduced neuron excitability). In other words, the higher the concentration of the chloride ion in the neuron, the lower the cerebral excitability (the level of excitation).
[004] It is well documented that the GRC is responsible for mediating anxiety, seizure activity, and sedation. Therefore, GABA e that act like GABA or facilitate the effects of GABA (for example, therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium®) produce their therapeutically useful effects by interacting with specific regulatory sites in the GRC. Accumulated evidence has now indicated that in addition to the benzodiazepine and barbiturate binding site, the GRC contains a distinct site for neuroactive steroids (Lan, N. C. et al, Neurochem. Res. 16: 347-356 (1991)).
[005] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are pregnan-20-one 3-hydroxy-5-reduced and pregnan-20-one 3α-2l-dihydroxy-5-reduced, hormone steroid metabolites, progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232: 1,004-1,007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241: 346- 353 (1987)).
[006] Ovarian hormone progesterone and its metabolites have been shown to have profound effects 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)). Progesterone levels and their metabolites vary with the phases of the menstrual cycle. It has been well documented that levels of progesterone and its metabolites decrease before the onset of menstruation. The monthly recurrence of certain physical symptoms before menstruation has also been well documented. These symptoms, which were associated with premenstrual syndrome (PMS), include stress, anxiety, and migraine (Dalton, K., "Premenstrual Syndrome and Progesterone Therapy", 2nd edition, Chicago Yearbook, Chicago (1984)). Individuals with PMS have a monthly recurrence of symptoms that are present before menstruation and absent after menstruation. In a similar way, a reduction in progesterone has also been temporarily correlated with an increase in the frequency of seizures in women with epilepsy, ie catamenial epilepsy (Laidlaw, J., Lancet, 1.235-1.237 (1956)). A more direct correlation has been observed with a reduction in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49: 47-51 (1986)). In addition, for individuals with small generalized primary evil type epilepsy, the temporal incidence of seizures was 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 women with epileptic outbreaks correlated with their menstrual cycles (Aird, R.B. and Gordan, G., J. Arner. Med. Soc. 145: 715-719 (1951)).
[007] A syndrome also related to low progesterone levels is postpartum depression (PND). Immediately after delivery, progesterone levels decrease dramatically leading to the onset of PND. PND symptoms range from mild depression to psychosis that requires hospitalization. PND is also associated with severe anxiety and irritability. PND-associated depression is not amenable to treatment with classic antidepressants, and women experiencing PND show an increased incidence of PMS (Dalton, K., "Premenstrual Syndrome and Progesterone Therapy", 2nd edition, Chicago Yearbook, Chicago (1984)) .
[008] Collectively, these observations indicate a crucial role for progesterone and deoxycorticosterone and more specifically their metabolites in the homeostatic regulation of cerebral excitability, which is manifested as an increase in seizure activity or symptoms associated with catamenial epilepsy, PMS, and PND. The correlation between reduced 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 edition, Chicago Yearbook, Chicago (1984)) have led to the use of progesterone in its treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy," in Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279-282, and Dalton, K., "Premenstrual syndrome and Progesterone Therapy", 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in treating the aforementioned syndromes. For example, no dose-response relationship exists 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 )).
[009] New and improved neuroactive steroids are needed to act as modulating agents for brain excitability, as well as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions, and methods described herein are intended for this purpose. Summary of the invention
[010] Here 17-cyano-substituted neuroactive steroids are provided which comprise at least one substituent in one or more positions 2, 4, and / or 11 in the steroid skeleton, and designed, for example, to act as GABA modulators. In certain embodiments, such compounds are seen to be useful as therapeutic agents for inducing anesthesia and / or sedation in an individual. In some embodiments, such compounds are seen as useful with therapeutic agents for the treatment of a CNS disorder (for example, sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory disorder and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in an individual in need (for example, an individual with Rett's syndrome, fragile X's syndrome, or Angelman's syndrome).
[011] In one aspect, the present invention provides compounds of Formula (I):
where Rb «is hydrogen, halo, alkyl, alkoxy, -C (O) R», C (O) N (Rb) (Rc), -C (O) ORa, -N (Rb) (Rc), ~ OC (O) N (Rb) (Rc), OC (O) OR «, -S (O) n.2R- ', -s (0) 0-: OR«, or "S (O) 0_2N (Rb ) (Rc). Rlb is H, halo, hydroxy, alkyl, alkoxy, -C (O) R ", -C (0) N (Rb) (Rc), - C (O) OR., -N (Rd ) (Re), -OC (O) N (Rb) (Rc), - OC (O) ORa, -OC (O) R>, - S (O) 0-, Ra, -S (O) A- 2OR «, OU -S (O)„ - 2N (Rb) (Rc); where one of Rla θ R'b is hydrogen; each R- is hydrogen or C1-C6 alkyl; each Rb and RC is independently hydrogen or C1 -C6 alkyl or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered); and each Rd and Re is hydrogen, substituted methyl or C2-C6 alkyl, or Rd and Re, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) ).
[012] The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, for example, for inducing sedation and / or anesthesia. Definitions Chemical definitions
[013] Definitions of specific functional groups and specific chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and physics, 75th Ed., Inner cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry, as well as 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).
[014] The compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, for example, enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an enantiomer, diastereomer or individual geometric isomer, or they can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures 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 the preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33: 2,725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, mixtures of various isomers.
[015] As used herein, a pure enantiomeric compound is substantially free of enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises 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, weights are based on the total weight of all enantiomers or stereoisomers of the compound.
[016] In the compositions provided here, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure compound R in such compositions may comprise, for example, at least about 95% by weight of compound R and at most about 5% by weight of compound S, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S. In certain embodiments, the enantiomerically pure compound S in such compositions, for example, can comprise at least about 95% by weight of compound S and at most about 5% by weight of compound R, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
[017] The compounds described herein can also comprise one or more isotopic substitutions. For example, H can be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C can be in any isotopic form, including 12C, 13C, and 14C; O can be in any isotopic form, including 16O and 18O; and the like.
[018] When a range of values is listed, it must encompass each value and sub-range within the range. For example, "Ci-e alkyl" should encompass, Ci, C , Cs, C4, Cs, Ce, Cl-6, Cl-5, Cl-4, Cl-3, Cl- ', C2-6, C2 -5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5 and C5-6 alkyl.
[019] The following terms are intended to have the meanings presented below and are useful in understanding the description and scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein, any of the portions defined below can be substituted with several substituents, and that the respective definitions must include such substituted portions in their scope presented below. Unless otherwise stated, the term "replaced" should be defined as shown below. It should also be understood that the terms "groups" and "radicals" can be considered interchangeable when used here. The articles "one" and "one" can be used here to refer to one or more of one (that is, at least one) of the grammatical objects of the article. As an example "an analogue" means an analogue or more than one analogue.
[020] "Alkyl" refers to a radical of a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms ("C1-20 alkyl"). In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-12 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-6 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-6 alkyl" also referred to herein as "lower alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-6 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4) , iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (Cs), 3-methyl-2-butanyl (Cs), tertiary amyl (Cs), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and others. Unless otherwise specified, each case of an alkyl group is independently optionally substituted, that is, unsubstituted (an "unsubstituted alkyl") or substituted (an "substituted alkyl") in one or more substituents; for example, from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is C1-10 unsubstituted alkyl (for example, -CH1). In certain embodiments, the alkyl group is C1-10 alkyl substituted. Common alkyl abbreviations include Me (-CHs), Et (-CH2CH3), iPr (-CH (CH3) 2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH (CH3) ) 2) .
[021] As used herein, "alkylene", "alkenylene" and "alkynylene", refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is provided for a particular group "alkylene", "alkenylene" and "alkynylene", the range or number is understood to refer to the range or number of carbons in the divalent linear carbon chain. The "alkylene", "alkenylene" and "alkynylene" groups can be substituted or unsubstituted with one or more substituents as described herein.
[022] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, and which can be substituted or unsubstituted. Unsubstituted alkylene groups include, without limitation, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-) , and others. Examples of substituted alkylene groups, for example, substituted with one or more alkyl (methyl) groups, include, without limitation, substituted methylene (-CHICs) -, (-CICCHsA-), substituted ethylene (-CH (CH3) CH2-, -CH2CH (CH3) -, -C (CH3) 2CH2-, CH2C (CH3) 2-), substituted propylene (-CH (CH3) CH2CH2-, CH2CH (CH3) CH2-, -CH2CH2CH (CH3) -, -C (CH3) 2CH2CH2-, CH2C (CH,) 2CH2-, -CH2CH2C (CH3) 2-), and others.
[023] "Alkenyl" refers to a radical of a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds and no triple bond ("C2-2o alkenyl" ). In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C2-10 alkenyl"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-s alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-e alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-s alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and others. Examples of C2- and alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (Cs), pentadienyl (Cs), hexenyl (Ce), and others. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (C3), and others. Unless otherwise specified, each case of an alkenyl group is independently optionally substituted, that is, unsubstituted (an "unsubstituted alkenyl") or substituted (an "substituted alkenyl") with one or more substituents, for example, from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is C2-10 unsubstituted alkenyl. In certain embodiments, the alkenyl group is C2-10 substituted alkenyl.
[024] "Alkenylene" refers to an alkenyl group in which two hydrogens are removed to provide a divalent radical, and which can be substituted or unsubstituted. Examples of unsubstituted divalent alkenylene groups include, without limitation, ethylene (~ CH = CH-) and propenylene (for example, -CH = CHCH2-, -CH2-CH = CH-). Examples of substituted alkenylene groups, for example, substituted with one or more alkyl (methyl) groups, include, without limitation, substituted ethylene (-C (CH3) = CH-, -CH = C (CH3) -), substituted propylene ( for example, -C (CH3) = CHCH2-, -CH = C (CH3) CH2-, - CH = CHCH (CH3) -, -CH = CHC (CH3) 2-, -CH (CH3) ~ CH = CH -, -C (CH3) 2- CH = CH-, -CH2-C (CH3) = CH-, -CH2-CH = C (CH3) -), and others.
[025] "Alquinyl" refers to a radical of a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C2 -20 alkynyl "). In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butinyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and others. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (Cs), hexynyl (Ce), and others. Additional examples of alkynyl include heptinyl (C '), octinyl (Cs), and others. Unless otherwise specified, each case of an alkynyl group is independently optionally substituted, that is, unsubstituted (an "unsubstituted alkynyl") or substituted (an "substituted alkynyl") with one or more substituents; for example, from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is C2-10 unsubstituted alkynyl. In certain embodiments, the alkynyl group is C2-10 substituted alkynyl.
[026] "Alkylene" refers to a linear alkynyl group in which two hydrogens are removed to provide a divalent radical, and which can be substituted or unsubstituted. Examples of divalent alkynylene groups include, without limitation, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene and the like.
[027] The term "heteroalkyl", as used herein, refers to an alkyl group, as defined herein, which also comprises 1 or more (for example, 1, 2, 3, or 4) hetero atoms (for example, oxygen , sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where one or more hetero atoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more hetero atoms are inserted between a carbon atom and the molecule relative, that is, between the attachment point. In certain embodiments, a heteroalkyl group refers to a saturated group that has 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCyl alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCi-9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroCis-alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 to 7 carbon atoms and 1, 2, 3, or 4 hetero atoms ("heteroCi- Alkyl"). In some embodiments, a heteroalkyl group is a group that has 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroCi-s alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 to 4 carbon atoms and for 2 heteroatoms ("heteroCi-4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 to 3 carbon atoms and 1 heteroatom ("heteroCi-a alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 to 2 carbon atoms and 1 heteroatom ("heteroCi-2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 1 carbon atom and 1 heteroatom ("heteroCialalkyl"). In some embodiments, a heteroalkyl group is a saturated group that has 2 to 6 carbon atoms and 1 or 2 hetero atoms ("heteroC2-6 alkyl"). Unless otherwise specified, each case of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted alkyl heteroCyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.
[028] The term "heteroalkenyl", as used herein, refers to an alkenyl group, as defined herein, which also comprises one or more (for example, 1, 2, 3, or 4) heteroatoms (for example, oxygen , sulfur, nitrogen, boron, silicon, phosphorus) in which one or more hetero atoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more hetero atoms are inserted between a carbon atom and the parent molecule, ie , between the attachment point. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-alkenyl hetero"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-9 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("alkenyl heteroC2-s"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2- Alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC2-and alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("alkenyl heteroCc-s"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 2 heteroatoms ("heteroC2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("heteroC2-3 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC2-and alkenyl"). Unless otherwise specified, each case of the heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is a heteroC2-alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl.
[029] The term "heteroalkynyl", as used herein, refers to an alkynyl group, as defined herein, which also comprises one or more (for example, 1, 2, 3, or 4) heteroatoms (for example, oxygen , sulfur, nitrogen, boron, silicon, phosphorus) in which one or more hetero atoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more hetero atoms are inserted between a carbon atom and the parent molecule, ie , between the attachment point. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-io alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-9 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-s alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC2-7alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC2-6 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2-s alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroC2-a alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC2-o alkynyl"). Unless otherwise specified, each case of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl.
[030] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene", refer to a divalent radical of an alkyl, alkenyl, alkynyl, heteroalkyl group, heteroalkenyl, and heteroalkynyl respectively. When a range or number of carbons is provided for a particular group "alkylene", "alkenylene", "alkylene", "heteroalkylene", "heteroalkenylene", or "heteroalkynylene", it is understood that the range or number refers to the range or number of carbons in the carbon divalent linear chain. The groups "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" can be substituted or unsubstituted with one or more substituents as described herein.
[031] "Aril" refers to a radical of a 4n + 2 monocyclic or polycyclic aromatic ring system (for example, bicyclic or tricyclic) (for example, having 6, 10, or 14 π electrons shared in a cyclic arrangement ) having 6-14 carbon ring atoms and zero hetero atoms provided in the aromatic ring system ("Ce-i4 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("Ce aryl"; for example, phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("Cio aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("Cu aryl"; for example, anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups where the radical or point of attachment is in the aryl ring, and in such cases, the number of atoms carbon continues to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, without limitation, groups derived from aceanthylene, acenaphthene, acephenanthrene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexafene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene , octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinafthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each case of an aryl group is independently optionally substituted, that is, unsubstituted (an "unsubstituted aryl") or replaced (an "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is unsubstituted Ce-14 aryl. In certain embodiments, the aryl group is Ce-i4 substituted aryl.
[032] In certain embodiments, an aryl group substituted with one or more groups selected from halo, C1 -Cs alkyl, C1-Cg haloalkyl, cyano, hydroxy, C1-Cs alkoxy, and amino.
[033] Examples of representative substituted aryl groups include the following:
where one of R56 and R57 can be hydrogen and at least one of R55 θ R57 is independently selected from C1 -Cs alkyl, CI-CH haloalkyl, 4-10 membered heterocyclyl, alkanoyl, CI-CH alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59 NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saril, SOaryl, SO2aryl; or R56 and R57 can 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. R60 and R61 are independently hydrogen, C 1 -C 6 alkyl , C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Cβ-C10 aryl, substituted Ce-Cio aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted.
[034] Other representative aryl groups that have a fused heterocyclyl group include the following:
wherein each W is selected from C (R66) 2, NR66, O, and S; and each Y is selected from carbonyl, NR66, O and S; and R66 is independently hydrogen, C1 -Cn alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Cg-C10aryl, and 5-10 membered heteroaryl.
[035] "Fused aryl" refers to an aryl that has two of its ring carbons in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.
[036] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group, substituted by an optionally substituted aryl group.
[037] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n + 2 aromatic ring system (for example, having 6 or 10 π electrons shared in a cyclic arrangement) having carbon atoms of ring and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, as valence allows. Bicyclic heteroaryl ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups where the attachment point is at the heteroaryl ring, and in such cases, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring, as defined above, is fused with one or more aryl groups where the attachment point is at the aryl or heteroaryl ring, and in such cases, the number of ring members designates the number of ring members in the fused ring system (aryl / heteroaryl). Bicyclic heteroaryl groups in which a ring does not contain a heteroatom (for example, indolyl, quinolinyl, carbazolyl, and others) the attachment point can be on each ring, that is, the ring that supports a heteroatom (for example, 2-indolyl ) or the ring that does not contain a hetero atom (for example, 5-indolyl).
[038] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen , oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system that has ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where 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 specified, each case of a heteroaryl group is independently optionally substituted, that is, unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is 5-14 membered unsubstituted heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
[039] Examples of 5-membered heteroaryl groups containing a heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Examples of 6-membered heteroaryl groups that contain a heteroatom include, without limitation, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups that contain a heteroatom include, without limitation, azepinyl, oxepinyl, and tiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benziazyl, benzyl, benzyl and Examples of 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl.
[040] Examples of representative heteroaryl groups include the following:
where each Y is selected from carbonyl, N, NR65, O, and S; and R65 is independently hydrogen, C1 -C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-C10aryl, and 5-10 membered heteroaryl.
[041] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group, substituted by an optionally substituted heteroaryl group.
[042] "Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C3-10 carbocyclyl") and zero hetero atoms in the non-aromatic ring system . In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl"). Examples of C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce ), cyclohexadienyl (Ce), and others. Examples of C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs ), bicycles [2.2.1] heptanyl (C7), bicycles [2.2.2] octanyl (Cs), and others. Examples of C3-10 carbocyclyl groups include, without limitation, the previously mentioned C3-8 carbocyclyl groups as well as cyclononyl (Cg), cyclononenyl (Cg), cyclodecyl (Cio), cyclodecenyl (Cio), octahydro-1H-indenyl (Cg) , decahidronaf talenil (Cio), spiro [4.5] decanil (Cio), and others. As the preceding examples illustrate, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged or spiro ring system as a bicyclic system ("bicyclic carbocyclyl") and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups where the point of attachment is in the carbocyclyl ring, and in such cases, the number of carbons continues to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each case of a carbocyclyl group is independently optionally substituted, that is, unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is C3-10 unsubstituted carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl.
[043] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring hetero atoms, where each hetero atom is independently selected nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the attachment point can be a carbon or nitrogen atom, as valence allows. A heterocyclyl group can be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system like a bicyclic system ("bicyclic heterocyclyl"), and can be saturated or may be partially unsaturated. Bicyclic heterocyclyl ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems where the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups where the point of attachment is on the carbocyclyl or heterocyclyl ring, or ring systems where the heterocyclyl ring, such as defined above, is fused to one or more aryl or heteroaryl groups, where the attachment point is on the heterocyclyl ring, and in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system . Unless otherwise specified, each case of heterocyclyl is independently optionally substituted, that is, unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is 3-10 membered unsubstituted heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
[044] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system that has ring carbon atoms and 1-4 ring hetero atoms, where each hetero atom is independently selected from nitrogen, oxygen, sulfur , boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system that has ring carbon atoms and 1-4 ring hetero atoms, where each hetero atom is independently selected from nitrogen, oxygen, and sulfur (" 5-8 membered heterocyclyl "). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system that has ring carbon atoms and 1-4 ring hetero atoms, where each hetero atom 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 a ring heteroatom selected from nitrogen, oxygen, and sulfur.
[045] Examples of 3-membered heterocyclyl groups that contain a heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Examples of 4-membered heterocyclyl groups that contain a heteroatom include, without limitation, azetidinyl, oxetanil and tietanyl. Examples of 5-membered heterocyclyl groups that contain a hetero atom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanil, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups that contain three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups that contain a heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanil. Examples of 6-membered heterocyclyl groups that contain two heteroatoms include, without limitation, triazinanil. Examples of 7-membered heterocyclyl groups that contain a heteroatom include, without limitation, azepanyl, oxepanyl and tiepanyl. Examples of 8-membered heterocyclyl groups that contain a heteroatom include, without limitation, azocanil, oxecanil and thiocanil. Examples of 5-membered heterocyclyl groups fused to a Cearyl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranil, dihydrobenzothienyl, benzoxazolinonyl, and others. Examples of 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and others.
[046] Particular examples of heterocyclyl groups are shown in the following illustrative examples:
wherein each W is selected from CR67, C (R67) 2, NR67, O, and S; and each Y is selected from NR67, O, and S; and R67 is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, Ce-C 10 aryl, 5-10 membered heteroaryl. These heterocyclyl rings can be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or starch), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S (O) -alkyl, -S (O) -aryl, -S (O ) 2-alkyl, and -S (O) 2-aryl. Group substitution includes carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.
[047] "Straight" when used to describe a compound or group present in a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can be applied to any of the hydrocarbyl groups described above as alkyl, for example, heteroalkyl, cycloalkyl, for example, heterocyclyl, aryl, for example, heteroaryl, cycloalkenyl, for example, cycloheteroalkenyl, and others having from 1 to 5, and particularly 1 to 3 heteroatoms.
[048] "Acyl" refers to a radical -C (O) R20, where R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, heterocyclyl substituted or unsubstituted, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is an acyl group in which R20 is a different group than hydrogen. Representative acyl groups include, without limitation, formyl (-CHO), acetyl (-C (= O) CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (- C (= 0) Ph), benzylcarbonyl (-C (= 0) CH2Ph) , -C (O) -Ci-C8 alkyl, -C (0) - (CH2) t (Ce-Cio aryl), -C (0) - (CH2) t (5-10 membered heteroaryl), -C (0) - (CH2) t (C3-C10 cycloalkyl), and -0 (0) - (CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments , R21 is C1 -Cs alkyl, substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Cs-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each being replaced with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, C1-C4 unsubstituted haloalkyl, C1-C4 hydroxyalkyl unsubstituted, or C1-C4 haloalkoxy or unsubstituted hydroxy.
[049] "Acylamino" refers to a radical -NR22C (O) R23, where each case of R22 and R23 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, carbocyclyl substituted or unsubstituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein, or R22 is an amino protecting group. Examples of "acylamino" groups include, without limitation, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzoylamino and benzylcarbonylamino. Particular examples of "acylamino" groups are -NR24C (O) -Ci-Cg alkyl, -NR24C (O) - (CH2) t (Ce-Cio aryl), -NR24C (O) - (CH2) t (heteroaryl of 5 -10 members), -NR24C (O) - (CH2) t (C3-C10 cycloalkyl), and -NR24C (O) - (CH2) t (4-10 membered heterocyclyl), where t is an integer of 0 to 4, and each R24 independently represents H or C1-Cy alkyl. In certain embodiments, R25 is H, C2-Cg alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Cg-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each being unsubstituted C1-C4 alkyl substituted, halo, unsubstituted C1-C4 alkoxy, Unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and R26 is H, C1 -C6 alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each being 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 at least one of R25 and R26 is different from H.
[050] "Acyloxy" refers to a radical -OC (O) R27, where R27 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, heterocyclyl substituted or unsubstituted, substituted or unsubstituted or substituted heteroaryl, as defined herein. Representative examples include, without limitation, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certain embodiments, R28 is C1 -Cs alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each being substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, C1-C4 unsubstituted haloalkyl, C1X4 unsubstituted hydroxyalkyl, or C1-C4 haloalkoxy or unsubstituted hydroxy.
[051] "Aloxy" refers to the group -OR29 where R29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted aryl or unsubstituted, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, that is, with between 1 and 6 carbon atoms. Additional particular alkoxy groups have between 1 and 4 carbon atoms.
[052] In certain embodiments, R29 is a group having 1 or more substituents, for example, 1 to 5 substituents, and particularly 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino , Ce-Cio aryl, aryloxy, carboxyl, cyano, Ca-Cio cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S (O) - , aryl-S (O) -, alkyl-S (O) 2- and aryl-S (O) 2-. Examples of "substituted alkoxy" groups include, without limitation, -O- (CH2) t (Ce-Cio aryl), -0- (CH2) t (5-10 membered heteroaryl), -O- (CH2) t ( C3-C10 cycloalkyl), and -O- (CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present can be replaced by C1-C4 unsubstituted alkyl, halo, C1-C4 unsubstituted alkoxy, C1-C4 haloalkyl unsubstituted, C1-C4 hydroxyalkyl unsubstituted, or C1-C4 haloalkoxy or unsubstituted hydroxy. Particular examples of "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.
[053] "Amino" refers to the radical -NH2.
[054] "Substituted amino" refers to an amino group of formula -N (R38) 2 where R38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl substituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, in which at least one of R38 is not a hydrogen. In certain embodiments, each R38 is independently selected from hydrogen, C1 -C6 alkyl, alkenyl Ca-Cs, alkynyl Ca-Cs, Ce-C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl; or C 1 -C 6 alkyl, substituted with halo or hydroxy; Alkenyl Ca-Cs, substituted with halo or hydroxy; Alkynyl Ca-Cs, substituted with halo or hydroxy, or (CHa) t (Ce-Cio aryl), - (CHa) t (5-10 membered heteroaryl), (CHa) t (C3-C10 cycloalkyl), or - (CHa) t (4-10 membered heterocyclyl), where t is an integer between 0 and 8, each being replaced by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, C1-C4 unsubstituted haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R38 groups are joined to form an alkylene group.
[055] Examples of "substituted amino" groups include, without limitation, -NR39-Ci-Ca alkyl, -NR39- (CHa) t (Ce-Cio aryl), - NR39- (CH ) T (5- 10 members), -NR39- (CHa) t (C3-C10 cycloalkyl), and -NR39- (CHa) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, for example 1 or 2, each R39 independently represents H or C1 -C6 alkyl; and any alkyl groups present, can be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present may be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or C1- C4 haloalkoxy or unsubstituted hydroxy. For the avoidance of doubt, the term "substituted amino" includes the alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups as defined below. Substituted amino encompasses both monosubstituted amino groups and disubstituted amino groups.
[056] "Azido" refers to the radical -N3.
[057] "Carbamoil" or "starch" refers to the radical C (O) NH2.
[058] "Substituted carbamoyl" or "substituted starch" refers to the radical -C (O) N (R62) 2 where each R62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted alkynyl or unsubstituted, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, in which at least one of R62 is not a hydrogen. In certain embodiments, R62 is selected from H, C1 -C6 alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Ce-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or C 1 -C 6 alkyl substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10-membered heterocyclyl, Ce-Cio-aryl, aralkyl, 5-10-membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, C1-C4 non-alkoxy substituted, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R62 is different from H.
[059] Examples of "substituted carbamoyl" groups include, without limitation, -C (O) NR64-Ci-Cs alkyl, -C (O) NR64- (CH2) t (Ce-Cio aryl), -C (O) NR64- (CH2) t (5-10 membered heteroaryl), -C (O) NR64- (CH2) t (C3-C10 cycloalkyl), and -C (O) NR64- (CH2) t (4- 10 members), where t is an integer from 0 to 4, each R64 independently represents H or C1 -Cs alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present can be replaced by unsubstituted C1-C4 alkyl, halo , C1-C4 unsubstituted alkoxy, C1-C4 haloalkyl unsubstituted, C1-C4 hydroxyalkyl unsubstituted, or C1-C4 haloalkoxy or unsubstituted hydroxy.
[060] "Carboxy" refers to the radical -C (O) OH.
[061] "Cyan" refers to the radical -CN.
[062] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, the halo group is fluorine or chlorine.
[063] "Hydroxy" refers to the radical -OH.
[064] "Nitro" refers to the radical -NO2.
[065] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is replaced with the cycloalkyl group. Typical cycloalkylalkyl groups include, without limitation, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptymethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and others.
[066] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is replaced with a heterocyclyl group. Typical heterocyclylalkyl groups include, without limitation, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and others.
[067] "Cycloalkenyl" refers to the substituted or unsubstituted carbocyclyl group having 3 to 10 carbon atoms and having a single cyclical ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, for example, single ring structures like cyclohexenyl, cyclopentenyl, cyclopropenyl, and others.
[068] "Fused cycloalkenyl" refers to a cycloalkenyl that has two of its ring carbon atoms in common with a second aliphatic or aromatic ring and that has its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.
[069] "Etenil" refers to - (C = C) - substituted or unsubstituted. "Ethylene" refers to - (C-C) - substituted or unsubstituted. "Ethinyl" refers to - (C = C) -.
[070] "Heterocyclyl containing nitrogen" group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but not limited to, morpholino, piperidine (eg 2- piperidinyl, 3- piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.
[071] "Thiocetus" refers to the group = S.
[072] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted alkyl (e.g., "substituted" or "unsubstituted", "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" 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 in a group (for example, a carbon or nitrogen atom) is replaced with a permissible substituent, for example, a substituent that after replacement results in a stable compound, for example, a compound that does not undergo spontaneous transformation as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent in one or more substitutable positions in the group, and when more than one position in any given structure is replaced, the substituent is the same or different in each position. The term "substituted" is contemplated to include substitution with all permissible substituents on organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all combinations to arrive at a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituent as described herein that satisfy the valences of the hetero atoms and result in the formation of a stable portion.
[073] Examples of carbon atom substituents include, without limitation, halogen, -CN, -NO2, -N3, -SO2H, - SO3H, -OH, -ORaa, ON (Rbb) 2, N (Rbb) 2, N (Rbb) 3 + X ", -N (ORcc) Rbb, - SH, -SRaa, -SSRCC, -C (= O) Raa, -CO2H, -CHO, -C (ORCC) 2, -CO2Raa, - OC (= O) Raa, -OCO2Raa, -C (= 0) N (Rbb) 2, 00 (= 0) N (Rbb) 2, NRbbC (= 0) Raa, -NRbbC (= 0) N (Rbl: j 2, -0 (= NRbb) Raa, -C (= NRbb) 0Raa, - 00 (= NRbb) Raa, -0C (= NRbtj 0Raa, -C (= NRbb) N (Rbb) 2, 00 (= NRbb) ) N (Rbb) 2, -NRbbc (= NRbb) N (Rbbj 2, -C (= 0) NRbbS02Raa, NRbbS02Raa, -SO2N (Rbb) 2, -SO2Raa, -SO2ORaa, -0S02Raa, -S (= O) Raa, -OS (= O) Raa, -Si (Raa) s, -OSi (Raa) 3-C (= S) N (Rbb) 2, = C (= O) SRaa, - C (= S) SRaa , -SC (= S) SRaa, -SC (= O) SRaa, -OC (= O) SRaa, SC (= O) ORaa, -SC (= O) Raa, -P (= 0) 2Raa, -0P (= 0) 2Raa, -P (= 0) (Raa) 2, -0P (= 0) (Raa) 2, -0P (= 0) (0Rcc) 2, -P (= 0)) 2N (Rbb) 2, -0P (= 0) 2N (Rbb) 2, -P (= 0) (NRbb) 2, -0P (= 0) (NRbb) 2, -NRbbP (= 0) (0Rcc) 2, NRbbP (= 0) (NRbb) 2, -P (RCC) 2, -P (RCC) 3, -0P (RCC) 2, -OP (Rcc) 3, - B (Raa) 2, -B (0RCC) 2, - BR; "(0RCC), C i-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Cs-i4 aryl, and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 Rdcl groups; or two hydrogens on a carbon atom are replaced with the group = 0, = S, = NN (Rbb) 2, = NNRbbC (= 0) Raa, = NNRbbC (= 0) 0Raa, = NNRbbS (= 0) 2Raa, = NRbb, or = N0Rcc; each case of Raa is independently selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Co-14 aryl, and heteroaryl from 5-14 members, or two Raa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each case of Rbb is independently selected from hydrogen, -OH, -ORaa, -N (RCC) 2, -CN, -C (= O) Raa, C (= 0) N (Rcc) 2, -CO2Raa, -SO2Raa, -C (= NRCC) ORaa, -C (= NRCC) N (Rcc) 2, -SO2N (RCC) 2, -SO2RCC, -SO2ORCC, -SORaa, -C (= S) N (Rcc) 2 , C (= 0) SRCC, -C (= S) sRcc, -P (= 0) 2Raa, -P (= 0) (Raa) 2, P (= 0) 2N (Rcc) 2, -P (= 0) (NRCC) 2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 heteroaryl members, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0.1 , 2, 3, 4, or 5 Rdd groups; each case of Rcc is independently selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently replaced with 0, 1, 2, 3, 4, or 5 Rdd groups; each case of Rdcl is independently selected from halogen, -CN, -NO-, ~ N3, - SO2H, -SO3H, -OH, -ORee, ON (Rff) 2, -N (Rff) 2, -N ( Rff) 3 + X-, -N (ORθθ) Rff, -SH, -SRθθ, - SSRθθ, -C (= O) Rθθ, -CO2H, -CO2Ree, -OC (= O) Ree, -OCO2Ree, - C (= O) N (Rff) 2, -OC (= O) N (Rff) 2, -NRffC (= 0) Rθθ, -NRffCO2Ree, NRffC (= 0) N (Rff) 2, -C (= NRff) ORθθ, - OC (= NRff) Rθθ, -OC (= NRff) 0Ree, - C (= NRff) N (Rff) 2, -OC (= NRff) N (Rff) 2, - NRffC (= NRff) N ( Rff) 2, - NRffS02Ree, -SO2N (Rff) 2, -SO2Ree, -SO2ORee, -OSO2Rθθ, -S (= O) Ree, -Si (Rθθ) 3, -0Si (Rθθ) 3, - C (= S ) N (Rff) 2, -C (= 0) SRee, -C (= S) SRee, -SC (= S) SRθθ, -P (= 0) 2Rθθ, - P (= 0) (Rθθ) 2, -OP (= 0) (Rθθ) 2, OP (= 0) (0Rθθ) 2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-io carbocyclyl, 3- 10-member, Ce-10 aryl, 5-10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R groups , or two twin substituents Rdd can be joined to form = 0 or = S; each case of Rθθ is independently selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-io carbocyclyl, Cg-10 aryl, 3-10 membered heterocyclyl, and heteroaryl 3-10 members, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 groups R 2; each case of Rff θ, independently selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce 10 aryl and heteroaryl of 5-10 members, or two Rff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and each case of Rgg is independently halogen, -CN, -NO2, -Na, -SO2H, -SO3H, -OH, -OCi-and alkyl, -ON (C1-alkyl) 2, -N (CI- 6 alkyl) a, -N (C 1 -alkyl) a + X-, -NH (C 1 -alkyl) 2 ± X, -NH (C1-6 alkyl) + X ", -NH3 + X ', -N (OCi-e alkyl) (C1-6 alkyl), -N (OH) (C1-6 alkyl), -NH (OH), - SH, - SCi-6 alkyl, -SS (C1-6 alkyl), -C (= 0) (C1-6 alkyl), -CO2H, CO2 (C1-6 alkyl), -OC (= O) (C1-) and alkyl), -OCO2 (C1-6 alkyl), - C (= O) NH2, -C (= O) N (CI-6 alkyl) 2, - OC (= 0) NH (C1-6 alkyl), NHC (= O) (C1-6 alkyl), -N (C1-6 alkyl) C (= 0) (C1-6 alkyl), NHCO2 (C1-6 alkyl), -NHC (= 0) N (C1-6) and alkyl) 2, -NHC (= 0) NH (C1-6 alkyl), -NHC (= 0) NH2, -C (= NH) 0 (CI-6 alkyl), -0C (= NH) (C1-) and alkyl), -0C (= NH) OCi-e alkyl, -C (= NH) N (C1-alkyl) 2, C (= NH) NH (C1-6 alkyl), -C (= NH) NH2 , -0C (= NH) N (C1-6 alkyl) 2, - OC (NH) NH (C1-6 alkyl), -0C (NH) NH2, -NHC (NH) N (C1-6 alkyl) 2, - NHC (= NH) NH2, -NHSO2 (CI-6 alkyl), -SO2N (CI-6 alkyl) 2, SO2NH (CI-O alkyl), -SO2NH2, -SO2C1-6 alkyl, - SO2OC1-6 alkyl, -OSO2C1-6 alkyl, -SOC1-6 alkyl, -Si (C1-6 alkyl) 3, -OSi (C1-6 alkyl) 3 -C (= S) N (C] -6 alkyl, C (= S) NH (C1-6 alkyl), C (= S) NH2, -C (= 0) S (C1-6 alkyl), -C (= S) SCi-6 alkyl, SC (= S) SCi-6 alkyl, -P (= 0) 2 (Ci-e al kil), -P (= O) (C1-6 alkyl) 2, -0P (= O) (C16 alkyl) 2, -0P (= 0) (OCi-e alkyl) 2, C1-6 alkyl, C1- 6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, CG-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; where X “is a counterion.
[074] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electronic neutrality. Examples of counterions include halide ions (for example, F, Cr, Br-, I-), NCV, C1O4 ", OH“, H2POr, HSOr, sulfonate ions (for example, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate , benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and others), and carboxylate ions (for example, acetate, etanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and others).
[075] Nitrogen atoms can be substituted or unsubstituted as the valence allows, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Examples of nitrogen atom substituents include, without limitation, hydrogen, -OH, -ORaa, -N (RCC) 2, -CN, - C (= O) Raa, -C (= 0) N (Rcc) 2, -CO2Raa, -SO2Raa, - C (= NRbb) Raa, -C (= NRCC) 0Raa, -C (= NRCC) N (Rcc) 2, -SO2N (RCC) 2, SO2RCC, -SO2ORCC, -SORaa, - C (= S) N (Rcc) 2, -C (= 0) SRCC, -C (= S) SRCC, -P (= 0) 2Raa, -p (= 0) (Raa) 2, -p (= 0) 2N (Rcc) 2, -P (= 0) (NRCC) 2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl , Cs-i4 aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl , alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and in which Raa Rbb Rcc and Rdd, are as defined above.
[076] In certain embodiments, the substituent present on a nitrogen atom is an amino protecting group (also referred to as a nitrogen protecting group). Amino protecting groups include, without limitation, -OH, - ORaa, -N (RCC) 2, -C (= O) Raa, -C (= O) ORaa, - C (= 0) N (Rcc) 2 , S (= 0) 2Raa, -C (= NRCC) Raa, -C (= NRCC) 0Raa, -C (= NRCC) N (Rcc) 2, SO2N (RCC) 2, -SO2RCC, -SO2ORCC, -SORaa , -C (= S) N (Rcc) 2, C (= 0) SRCC, -C (= S) SRCC, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-alkenyl, C2-alkynyl , C3-10 carbocyclyl, 3-14 membered heterocyclyl, Cg-14 aryl, and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 groups Rdd, and where Raa, Rbb, Rcc and Rdd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis (T. W. Greene and P. G. M. Wuts, 3rd Ed., John Wiley & Sons, 1999), incorporated herein by reference.
[077] Examples of amino protecting groups include, but are not limited to, amide groups (for example, C (= O) Raa), which include, without limitation, formamide and acetamide; carbamate groups (for example, -C (= O) ORaa), which include, without limitation, 9-fluorenylmethyl carbamate (Fmoc), i-butyl carbamate (BOG), and benzyl carbamate (Cbz); sulfonamide groups (for example, -S (= O) 2Raa), which include, without limitation, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N- [2- (trimethylsilyl) ethoxy] methylamine (SEM).
[078] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protection groups include, without limitation, -Raa -N (Rbb) 2, -C (= 0) SRaa, ~ C (= O) Raa, -CO2Raa, - C (= 0) N (Rbb) 2, - C (= NRbb) Raa, -C (= NRbb) 0Raa, -C (= NRbb) N (Rbb) 2, -S (= 0) Raa, -SO2Raa, -Si (Raa) 3, -P (RCC ) 2, -P (RCC) 3, -P (= 0) 2Raa, -P (= 0) (Raa) 2, P (= 0) (0Rcc) 2, -P (= 0) 2N (Rbb) 2 , and - P (= 0) (NRbb) 2, where Raa, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis (T. W. Greene and P. G. M. Wuts, 3rd Ed., John Wiley & Sons, 1999), incorporated herein by reference.
[079] Examples of oxygen protecting groups include, without limitation, methyl, methoxymethyl (M0M), 2-methoxymethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), i-butyldimethylsilyl (TBDMS), i-butylmethoxyphenylsilyl ( TBMPS), methanesulfonate (mesylate), and tosylate (Ts).
[080] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Thiol protecting groups include, without limitation, -Raa, -N (Rbb) 2, -C (= 0) SRaa, -C (= O) Raa, -C02Raa, - C (= 0) N (Rbb) 2 , -C (= NRbb) Raa, - C (= NRbb) 0Raa, -C (= NRbb) N (Rbb) 2, -S (= 0) Raa, -SO2Raa, - Si (Raa) 3, -P ( RCC) 2, -P (RCC) 3, -P (= 0) 2Raa, -P (= 0) (Raa) 2, -P (= 0) (0Rcc) 2, - P (= 0) 2N (Rbb ) 2, e - P (= 0) (NRbb) 2, where Raa, Rbb, and Rcc are as defined herein. Thiol protecting groups are well known in the art and include those described in detail in "Protecting Groups in Organic Synthesis", T. W. GReene and p. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
[081] These and other examples of substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any way by the example listing of substituents above. Other definitions
[082] "Pharmaceutically acceptable" means approved or approved by a regulatory agency of the Federal Government or State Government or the corresponding agency in countries other than the United States, or that is listed in the "US Pharmacopoeia" or other pharmacopoeia generally recognized for use in animals, and more particularly, in humans.
[083] The term "pharmaceutically acceptable salt" refers to those salts that, within the scope of safe medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and others, and are in accordance with a reasonable cost / benefit ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of non-toxic, pharmaceutically acceptable acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid or by the use of other methods used in the technique such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanopropionate, digluconate, dodecylsulfate, glycosulfonate, glycoside, glycate, fumarate, format, salts , heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenessulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pateate, pamoate, pamoate 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, others. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal, ammonium and N + (C1-4 alkyl) salts 4. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and others. Additional pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
[084] "Solvate" refers to forms of the compound that are associated with a solvent or water (also referred to as "hydrate"), commonly by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and others. The compounds of the invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include stoichiometric solvates and non-stoichiometric solvates. In certain cases the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal structure of the crystalline solid. "Solvate" encompasses solution phase solvates and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[085] An "individual" to whom the administration is addressed includes, without limitation, human beings (that is, a man or woman of any age group, for example, a pediatric being (for example, baby, child, adolescent) or an adult being (for example, young adult, middle-aged adult or elderly) and / or a non-human animal, for example, a mammal such as primates (for example, Cynomolgus monkeys, Rhesus monkeys), cattle, pigs, horses , sheep, goats, rodents, cats, and / or dogs. In certain modalities, the individual is a human being. In certain embodiments, the individual is a non-human animal. The terms "human", "patient", and "individual" are used interchangeably in this.
[086] Illness, disorder, and condition are used interchangeably in this.
[087] As used herein, and unless otherwise specified, the terms "treat", "treating" and "treatment" include an action that occurs while an individual suffers from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or slows or slows down the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates an action that occurs before the individual begins to suffer from the specified disease, disorder or condition ("treatment" prophylactic").
[088] In general, the "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be perceived by those of ordinary skill in the art, the effective amount of a compound of the invention can vary depending on factors such as the desired end point, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and age, health , and condition of the individual. An effective amount includes therapeutic and prophylactic treatment.
[089] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount that improves general therapy, reduces or avoids symptoms or causes of disease or condition, or increases the therapeutic effectiveness of another therapeutic agent.
[090] As used herein, and unless otherwise specified, 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 prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing the disease, disorder or condition. The term "prophylactically effective amount" can encompass an amount that improves general prophylaxis or increases the prophylactic effectiveness of another prophylactic agent. Brief description of the drawings
[091] FIGS. 1-12 show representative 1 H NMR spectra of example compounds described herein. Detailed description of certain embodiments of the invention
[092] As generally described therein, the present invention provides 17-cyano substituted neuroactive steroids comprising at least one substituent at one or more positions 2, 4, or 11 on the steroid skeleton, and designed, for example, to act as GABA modulators. In some embodiments, the present invention provides 17-cyano substituted neuroactive steroids that comprise at least one substituent at one or more positions 2, 4, and 11 on the steroid backbone. In certain embodiments, such compounds are seen as useful as therapeutic agents for inducing anesthesia and / or sedation in an individual. In certain embodiments, such compounds are seen to be useful as therapeutic agents for the treatment of a CNS disorder.
[093] In one aspect, a compound of Formula

[094] where Rla is hydrogen, halo, alkyl, alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rb) (Rc) , OC (O) N (Rb) (Rc), -OC (O) ORa, -S (O) o-2Ra, -S (O) o-2ORa, or -S (O) o- 2N (Rb) (Rc); Rlb is H, halo, hydroxy, alkyl, alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rd) (Re), -OC (O) N (Rb) (Rc), OC (O) ORa, -OC (O) Ra, -S (0) o-2Ra, -S (O) o-2ORa, or -S (0) o- 2N (Rb) (Rc); where one of Rla and Rlb is hydrogen; each Ra is hydrogen or Ci-Ce alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 membered); and each Rd and RB is hydrogen, substituted methyl or C2-Ce alkyl, or Rd and Re, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) ).
[095] In some embodiments, Rla is hydrogen and Rlb is hydroxy, alkyl, or alkoxy. In some embodiments, Rlb is hydroxy or alkoxy. In some embodiments, Rlb is hydroxy. In some embodiments, Rlb is methoxy. In some embodiments, Rlb is alkyl.
[096] In some embodiments, Rlb is hydrogen and Rla is alkyl or alkoxy. In some embodiments, Rla is alkoxy. In some modalities, Rba is methoxy.
[097] In some embodiments, the compound is of Formula (la): Formula (Ia)
where Rla is hydrogen, halo, alkyl, alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rb) (Rc), ~ OC (O) N (Rb) (Rc), OC (O) ORa, -S (0) o-2Ra, -S (0) o-20Ra, or -S (O) 0-2N (Rb) (Rc) ; Rlb is hydrogen, halo, hydroxy, alkyl, alkoxy, -C (O) Ra, C (O) N (Rb) (Rc), -C (O) ORa, -N (Rd) (Re), -OC ( O) N (Rb) (Rc), OC (O) ORa, -OC (O) Ra, -S (0) o-2Ra, -S (O) o-2ORa, or -S (O) 0- 2N (Rb) (R "); where one of Rla and Rlb is hydrogen; each Ra is hydrogen or Ci-Ce alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the atom of nitrogen to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered), and each Rd and Re is hydrogen, substituted methyl or C2-C6 alkyl, or Rd and Re, along with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered).
[098] In some embodiments, Rla is hydrogen and Rlb is hydroxy, alkyl, or alkoxy. In some embodiments, Rlb is hydroxy or alkoxy. In some embodiments, Rlb is hydroxy. In some embodiments, Rlb is methoxy. In some embodiments, Rlb is alkyl.
[099] In some embodiments, R -'- '3 is hydrogen Θ R ^ a is alkyl or alkoxy. In some embodiments, Rla is alkoxy. In some modalities, Rba θ methoxy.
[100] In some embodiments, the compound is of formula (lb): Formula (Ib)
where Rla is hydrogen, halo, alkyl, alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rb) (Rc), -OC (O) N (Rb) (Rc), OC (O) ORa, -S (0) o-2Ra, -S (0) o-2ORa, or -S (O) 0-2N (Rb) (Rc) ; Rib is hydrogen, halo, hydroxy, alkyl, alkoxy, -C (O) Ra, C (O) N (Rb) (Rc), -C (O) ORa, -N (Rd) (Re), - OC ( O) N (Rb) (Rc), OC (O) ORa, -OC (O) Ra, -S (O) o-2Ra, -S (O) o-2ORa, or -S (O) o- 2N (Rb) (Rc); where one of Rla and Rlb is hydrogen; each Ra is hydrogen or C Ce alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 membered); and each Rd and Re is hydrogen, substituted methyl or C2-Ce alkyl, or Rd and Re, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) ).
[101] In some embodiments, R1a is hydrogen and R1b is hydroxy, alkyl, or alkoxy. In some embodiments, R1b is hydroxy or alkoxy. In some embodiments, R1b is hydroxy. In some embodiments, R1b is methoxy. In some embodiments, R1b is alkyl.
[102] In some embodiments, R1b is hydrogen and R1a is alkyl or alkoxy. In some embodiments, R1a is alkoxy. In some embodiments, R1a is methoxy.
[103] In one aspect, a compound selected from: is provided.

[104] In some modalities, from:

[105] In some embodiments, the compound is selected from

[106] In one aspect, a compound of Formula (II) is provided
where R is hydrogen, halo (e.g., chlorine, fluorine, bromine, iodine), hydroxy, alkyl, methoxy, substituted ethoxy, C3-C6 alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, N (R) (Rg), -OC (O) N (Rb) (RC) Z -OC (O) ORa, -OC (O) Ra, -S (O ) 0-2Ra, -S (0) o-2ORa, or -S (O) 0-2N (Rb) (Rc); R2b is hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy, C3-C6 alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc) '-C (O) ORa, -N ( Rb) (Rc), OC (O) N (Rb) (RC), -OC (O) ORa, -OC (O) Ra, -S (O) o-2Ra, -S (O) o-2ORa, or -S (O) o-2N (Rb) (Rc); where one of R2a θ R2b is hydrogen; each Ra is hydrogen or C 1 -C 6 alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 membered); and each hydrogen or Ci-Ce alkyl, nitrogen to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) that optionally comprises an additional heteroatom selected from nitrogen, oxygen and sulfur.
[107] In some embodiments, R2a is hydrogen and R2b is alkyl. In some embodiments, R2b is alkyl. In some embodiments, R2b is methyl. In some embodiments, R2b is methoxy.
[108] In some embodiments, R2b is hydrogen and R2a is alkyl, methoxy, substituted ethoxy, or Ca-Ce alkoxy. In some embodiments, R2a is alkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is ethyl. In some embodiments, R2a is methoxy. In some embodiments, R2a is - OCF.3. In some embodiments, R2a is substituted ethoxy. In some embodiments, R2a is -OCH2CH2OMe. In some embodiments, R: is -OCH CH2OH. In some embodiments, R2a is -OCH2CF3. In some embodiments, R2a is C3-Ce alkoxy. In some embodiments, R a is propoxy. In some embodiments, R2a is -OCH (CH3) 2. In some embodiments, R2a is -OCH2CH (CH3) 2. In some embodiments, R2a is cyclopropoxy.
[109] In some embodiments, the compound is of Formula (Ha):
wherein R = - is hydrogen, halo (e.g., chlorine, fluorine, bromine, iodine), hydroxy, alkyl, methoxy, substituted ethoxy, C3-C6 alkoxy, -C (O) R ', -C (0) N (R> -) (Rd, -C (O) OR>, -N (R9 (RS), - OC (O) N (R.ηm, -OC (O) ORa, _OC (O) R., _S (O) „. 2R / -S (0) O-2ORS OR -S (O)„. 2N (R> =) (R =); R2b is hydrogen, halo hydroxy, alkyl, methoxy, substituted ethoxy, C3- C6 alkoxy, - C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rb) (Rc), OC (O) N (Rb) (Rc) , -OC (O) ORa, -OC (O) Ra, -S (O) o-2Ra, ~ S (O) o-2ORa, or -S (O) 0-2N (Rb) (Rc); in that one of R2a and R2b is hydrogen; each Ra is hydrogen or Ci-C6 alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 membered), and each Rf and R9 is independently hydrogen or Ci-Ce alkyl, or Rf and R , along with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) comprising options an additional heteroatom selected from nitrogen, oxygen and sulfur.
[110] In some embodiments, R2a is hydrogen and R2b is alkyl. In some embodiments, R2b is alkyl. In some embodiments, R2b is methyl. In some embodiments, R2b is methoxy.
[111] In some embodiments, R2b is hydrogen and R2a is alkyl, methoxy, substituted ethoxy, or C3-C6 alkoxy. In some embodiments, R2a is alkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is ethyl. In some embodiments, R2a is methoxy. In some embodiments, R2a is - OCF3. In some embodiments, R2a is substituted ethoxy. In some embodiments, R2a is -OCJRCJbOMe. In some embodiments, R2a is -OCH2CH2OH. In some embodiments, R2a is -OCH2CF3. C3-C6 alkoxy. In some embodiments, R2a is propoxy. In some embodiments, R2a is -OCH (CHa) 2. In some embodiments, R2a is -OCH2CH (CH3) 2. In some embodiments, R2a is cyclopropoxy.
[112] In some embodiments, the compound is of Formula (Ilb):
fluorine, bromine, iodine), hydroxy, alkyl, methoxy, substituted ethoxy, C3-C6 alkoxy, —C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rf) (Rg), - OC (O) N (Rb) (Rc), -OC (O) ORa, -OC (O) Ra, -S (O) 0-2Ra, S (O) 0 2OR, or S (O) 0-2N (Rb) (Rc); R2b θ hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy, C3-C6 alkoxy, - C (O) Ra, ~ C (O) N (Rb) (Rc), ~ C (O) ORa, -N ( Rb) (Rc), OC (O) N (Rb) (RC), -OC (O) ORa, -OC (O) Ra, -S (O) 0-2Ra, -S (O) o-2ORa, or -S (O) 0-2N (Rb) (RC); wherein one of R2a and R2b is hydrogen; each Ra is hydrogen or Ci-C alkyl; each Rb and Rc is independently hydrogen or C] -c alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 members); and each Rf and Ri is independently hydrogen or C1 -C6 alkyl, or Rf and R'-J, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) which optionally comprises an additional heteroatom selected from nitrogen, oxygen and sulfur.
[113] In some embodiments, R2a is hydrogen and R2b is alkyl. In some embodiments, R2b is alkyl. In some embodiments, R2b is methyl. In some embodiments, R2b is methoxy.
[114] In some embodiments, R2b is hydrogen and R2a is alkyl, methoxy, substituted ethoxy, or CJ-C1- alkoxy. In some embodiments, R2a is alkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is ethyl. In some embodiments, R2a is methoxy. In some embodiments, R2a is - OCF3. In some embodiments, R2a is substituted ethoxy. In some embodiments, R2a is -OCH2CH2OMe. In some embodiments, R2a is -OCH2CH2OH. In some embodiments, R2a is -OCH2CF3. C3-C6 alkoxy. In some embodiments, R2a is propoxy. In some embodiments, R2a is -OCH (CH3) 2. In some embodiments, R2a is -OCH2CH (CH3) 2. In some embodiments, R2a is cyclopropoxy.
[115] In one aspect, a compound selected from:


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


[117] In some modalities, from:


[119] In one aspect, a compound of Formula (III) is provided: Formula (III)
where one of Ria and pit θ halo (for example, chlorine, fluorine, bromine, iodine), hydroxy, alkyl, alkoxy, -C (O) Ra, - C (O) N (Rb) (Rc), ~ C (O) ORa, -N (Rh) (Ra), -OC (O) N (Rb) (Rc), OC (O) ORa, -OC (O) Ra, - S (O) o-2Ra, - S (O) o-2ORa, or -S (O) o- 2N (Rb) (Rc), and the other is hydrogen; or Rla and Rlb are joined with the carbon to which they are attached to form C (= 0); one of R2a and R2b is chlorine, fluorine, hydroxy, alkyl, alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rf) (R1 !), OC (O) N (Rb) (RC) '-OC (O) ORa, -OC (O) Ra, -S (O) o-2Ra, -S (0) o-2ORa, or -S (0) 0-2N (Rb) (Rc), and the other is hydrogen; R3 is hydrogen or C1 -C6 alkyl; each Ra is hydrogen or C 1 -C 6 alkyl; each Rb and Rc is independently hydrogen or C1-6 alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered); each Rf and Rg is independently hydrogen or C1 -C6 alkyl, or Rf and Rg, together with the nitrogen atom to which they are joined to form a 3-7 membered (for example, 5-7 membered) heterocyclic ring comprising optionally an additional heteroatom selected from nitrogen, oxygen and sulfur; and each Rh is unsubstituted C1-C4 alkyl; each Ri is hydrogen, substituted methyl or C2-C6 alkyl, or Rh and Ri, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 membered).
[120] In some embodiments, Rla is hydrogen and Rlb is hydroxy, alkyl, or alkoxy.
[121] In some embodiments, Rlb is hydrogen and Rla is hydroxy, alkyl, or alkoxy. In some embodiments, Rla is hydroxy. In some embodiments, Rla is alkoxy. In some modalities, Rla is methoxy.
[122] In some embodiments, Rla and Rlb are joined with the carbon to which they are attached to form C (= 0).
[123] In some embodiments, R2a is hydrogen and R2b is hydroxy, alkyl, or alkoxy. In some embodiments, R2b is hydroxy. In some embodiments, R2b is alkyl. In some embodiments, R2b is methyl. In some embodiments, R2b is alkoxy.
[124] In some embodiments, R2b is hydrogen and R2a is hydroxy, alkyl, or alkoxy. In some embodiments, R2a is hydroxy. In some embodiments, R2a is alkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is alkoxy. In some embodiments, R2a is methoxy. In some embodiments, R2a is ethoxy. In some embodiments, R2a is propoxy. In some embodiments, R2a is -OCH2CH2OCH3. In some embodiments, R2a is -OCH (CH3) 2.
[125] In some embodiments, R3 is alkyl (for example, Ci-Ce alkyl) or alkoxy (for example, Ci-Ce alkoxy).
[126] In some embodiments, the compound is a compound of Formula (Ilia):
where one of Rla and Rlb is halo, hydroxy, alkyl, alkoxy, -C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rh) (R2 ), OC (O) N (Rb) (Ra), -OC (O) ORa, -OC (O) Ra, -S (O) 0-2Ra, -S (O) o-2ORa, or -S ( O) 0-2N (Rb) (Rc), and the other is hydrogen; or Rla and Rlb are joined with the carbon to which they are attached to form C (= 0); one of R2a and R2b is halo (e.g., chlorine, fluorine, bromine, iodine), hydroxy, alkyl, alkoxy, -C (O) Ra, C (O) N (Rb) (Rc), -C (O) ORa, -N (Rf) (R9), - OC (0) N (Rb) (Rc), - OC (O) ORa, -0C (0) Ra, -S (0) o-2Ra, -S ( 0) o-2ORa, or —S (0) o-2N (Rb) (Rc), and the other is hydrogen; R3 is hydrogen or Ci-Ce alkyl; each Ra is hydrogen or Ci-Ce alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 membered); each Rf and Rg is independently hydrogen or C1 -C6 alkyl, or Rf and R3, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) comprising optionally an additional heteroatom selected from nitrogen, oxygen and sulfur; and each Rh is unsubstituted C1-C4 alkyl; each R2 is hydrogen, substituted methyl or C2-CÓ alkyl, or Rh and R1, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered).
[127] In some embodiments, Rla is hydrogen and Rlb is hydroxy, alkyl, or alkoxy.
[128] In some embodiments, Rlb is hydrogen and Rla is hydroxy, alkyl, or alkoxy. In some embodiments, Rla is hydroxy. In some embodiments, Rla is alkoxy. In some modalities, Rla is methoxy.
[129] In some embodiments, Rla and Rlb are joined with the carbon to which they are attached to form C (= 0).
[130] In some embodiments, R2a is H and R2b is hydroxy, alkyl, or alkoxy. In some embodiments, R2b is hydroxy. In some embodiments, R2b is alkyl. In some embodiments, R2b is methyl. In some embodiments, R2b is alkoxy.
[131] In some embodiments, R2b is H and R2a is hydroxy, alkyl, or alkoxy. In some embodiments, R2a is hydroxy. In some embodiments, R2a is alkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is alkoxy. In some embodiments, R2a is methoxy. In some embodiments, R2a is ethoxy. In some embodiments, R2a is propoxy. In some embodiments, R2a is -OCH2CH2OCH3. In some embodiments, R2a is -OCH (CH3) 2.
[132] In some embodiments, R3 is hydrogen. In some embodiments, R3 is Ci-Cs alkyl.
[133] In some embodiments, the compound is a compound of Formula (IIIb):
wherein one of Rla and R2b is halo (e.g., chlorine, fluorine, bromine, iodine), hydroxy, alkyl, alkoxy, -C (O) Ra, C (O) N (Rb) (Rc), ~ C ( O) ORa, -N (Rh) (R1), -OC (O) N (Rb) (Rc), OC (O) ORa, -OC (O) Ra, -S (0) o-2Ra, ~ S (0) o-2ORa, or -S (0) o-2N (Rb) (Rc), and the other is hydrogen; or Rla and Rlb are joined with the carbon to which they are attached to form C (= 0); one of R2a and R2b is halo (e.g., chlorine, fluorine, bromine, iodine), hydroxy, alkyl, alkoxy, -C (O) Ra, -C (0) N (Rb) (Rc), - C (O ) ORa, -N (Rf) (R9), -0C (0) N (Rb) (Rc), -OC (O) ORa, -OC (O) Ra, - s (0) o-2Ra, ~ S (0) o-2ORa, or —S (0) Q-2N (Rb) (Rc), and the other is hydrogen; R3 is hydrogen or C1 -C6 alkyl; each Ra is hydrogen or Ci-C &alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5-7 membered); each Rf and R 'is independently hydrogen or Ci-Ce alkyl, or Rf and R', together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 member) which optionally comprises an additional heteroatom selected from nitrogen, oxygen and sulfur; and each Rh is unsubstituted C1-C4 alkyl; each Ri is hydrogen, substituted methyl or Cg-Ce alkyl, or Rh and R1, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered).
[134] In some embodiments, Rla is hydrogen and Rlb is hydroxy, alkyl, or alkoxy.
[135] In some embodiments, Rlb is hydrogen and Rla is hydroxy, alkyl, or alkoxy. In some embodiments, Rla is hydroxy. In some embodiments, Rla is alkoxy. In some modalities, Rla is methoxy.
[136] In some embodiments, Rla and Rlb are joined with the carbon to which they are attached to form C (= 0).
[137] In some embodiments, R2a is H and R2b is hydroxy, alkyl, or alkoxy. In some embodiments, R2b is hydroxy. In some embodiments, R2b is alkyl. In some embodiments, R2b is methyl. In some embodiments, R2b is alkoxy.
[138] In some embodiments, R2b is H and R2a is hydroxy, alkyl, or alkoxy. In some embodiments, R2a is hydroxy. In some embodiments, R2a is alkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is alkoxy. In some embodiments, R2a is methoxy. In some embodiments, R2a is ethoxy. In some embodiments, R2a is propoxy. In some embodiments, R2a is -OCH2CH2OCH3. In some embodiments, R2a is -OCH (CHJ) 2.
[139] In some embodiments, R3 is hydrogen. In some embodiments, R3 is Ci-Ce alkyl.
[140] In one aspect, a compound selected from:


[142] In one aspect, a compound selected from:


[143] In one aspect, a compound of Formula (IV) is provided:
where one of Rla and Rlb is halo, hydroxy, alkyl, alkoxy, -C (O) Ra, -c (O) N (Rb) (Rc), -C (O) ORa, -N (Rb) (Rc ), OC (O) N (Rb) (RC), -OC (O) ORa, -OC (O) Ra, -S (O) o-2Ra, -S (O) o-2ORa, or -S ( O) O-2N (Rb) (Rc), and the other is hydrogen; or Rla and Rlb are joined with the carbon to which they are attached to form C (= 0); R3 is alkyl or alkoxy; each Ra is hydrogen or Ci-Ce alkyl; each Rb and Rc is independently hydrogen or Ci-Ce alkyl, or Rb and Rc, together with the nitrogen atom to which they are joined to form a 3-7 membered heterocyclic ring (eg 5-7 membered).
[144] In some embodiments, Rlb is hydrogen and Rla is hydroxy, alkyl, or alkoxy. In some embodiments, Rla is hydroxy. In some embodiments, Rla is alkyl. In some embodiments, Rla is alkoxy. In some modalities, Rla is methoxy.
[145] In some embodiments, Rla and Rlb are joined with the carbon to which they are attached to form C (= 0).
[146] In some embodiments, R3 is alkyl. In some embodiments, R3 is methyl.
[147] In some embodiments, a compound selected from:

[148] In one aspect, a compound of Formula (V) is provided
wherein R3 is alkyl or alkoxy.
[149] In some embodiments, R3 is alkyl. In some embodiments, R3 is methyl or ethyl.
[150] In some embodiments, a compound is provided

[151] In one aspect, a pharmaceutical composition is provided that comprises a compound of Formula (I), (Ia), (lb), (II), (Ila), (lib), (III), (IHa), (Illb), (IIIc), (IV), or (V) and a pharmaceutically acceptable excipient.
[152] In one aspect, a solvate, isotopic variant, or tautomer of a compound of Formula (I), (Ia), (lb), (II), (Ila), (lib), (III), is provided, (Ilia), (Illb), (IIIc), (IV), or (V).
[153] In one aspect, a method of inducing sedation and / or anesthesia in an individual is provided, which comprises administering to the individual an effective amount of a compound of Formula (IIIc),
a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein one of Ria θ Rlb is halo (for example, chlorine, fluorine, bromine, iodine), hydroxy, alkyl, alkoxy, -C (O) Ra, - c (O ) N (Rb) (Rc), -C (O) ORa, -N (Rb) (Rc), -OC (O) N (Rb) (Rc), OC (O) ORa, -OC (O) Ra , - S (O) o-2Ra, -S (O) o-2ORa, or -S (O) o-2N (Rb) (Rc); or Ria and Rib are optionally together with the carbon to which they are attached to form C (= 0); one of R2a and R2b and halo (e.g., chlorine, fluorine, bromine, iodine), hydroxy, alkyl, methoxy, substituted ethoxy, C3-C6 alkoxy, - C (O) Ra, -C (O) N (Rb) (Rc), -C (O) ORa, -N (Rf) (Ra), OC (O) N (Rb) (RC), -OC (O) ORa, -OC (O) Ra, -S (O ) 0-3Ra, -S (O) 0-2ORa, or -S (O) 0-2N (Rb) (Rc), where one of Rla, Rlb, R2a, and R2b are not hydrogen, and when Rla and Rlb are joined with the carbon to which they are attached to form C (= 0), one of R2a and R2b is hydrogen; R3 is hydrogen or Ci-Ce alkyl; each Ra is hydrogen or C 1 -C 6 alkyl; each Rb and Rc is independently hydrogen or Ci-Cs alkyl, or Rb and Rc, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered); each R1 and R9 is independently hydrogen or CI-CR alkyl, or Rf and R'3, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (eg 5-7 membered) which optionally comprises an additional heteroatom selected from nitrogen, oxygen and sulfur; and each R3 and Rk is independently hydrogen, substituted methyl, or C3-Ce alkyl, or R3 and Rk, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclic ring (for example, 5- 7 members) optionally comprising an additional heteroatom selected from nitrogen, oxygen and sulfur.
[154] In some embodiments, Rla is hydrogen and Rlb is hydroxy, alkyl, or alkoxy. In some embodiments, Rlb is hydroxy. In some embodiments, Rlb is alkyl. In some embodiments, Rlb is methyl or ethyl. In some embodiments, Rlb is alkoxy. In some embodiments, Rlb is methoxy. In some embodiments, Rlb is ethoxy. In some embodiments, Rlb is propoxy. [136] In some embodiments, Rlb is hydrogen and Rla is hydroxy, alkyl, or alkoxy. In some embodiments, Rla is hydroxy. In some embodiments, Rla is alkyl. In some embodiments, Rla is methyl or ethyl. In some embodiments, Rla is alkoxy. In some modalities, Rla is methoxy. In some embodiments, Rla is ethoxy. In some embodiments, Rla is propoxy.
[155] In some embodiments, Rla and Rlb are joined with the carbon to which they are attached to form C (= 0).
[156] In some embodiments, R2a is hydrogen and R2b is hydroxy, alkyl, methoxy, substituted ethoxy, or Ca-Ce alkoxy. In some embodiments, R2b is methoxy. In some embodiments, R2b is -OCF3. In some embodiments, R2b is substituted ethoxy. In some embodiments, R2b is OCHaCHaOMe. In some embodiments, R2b is -OCH2CH2OH. In some embodiments, R2b is -OCH2CF3. In some embodiments, R2b is C3-C6 alkoxy. In some embodiments, R2b is propoxy. In some embodiments, R2b is -OCH (CH3) 2. In some embodiments, R2b is -OCH2CH (CH3) 2. In some embodiments, R2b is cyclopropoxy.
[157] In some embodiments, R2b is hydrogen and R2a is methoxy. In some embodiments, R2a is -OCF. In some embodiments, R2a is substituted ethoxy. In some embodiments, R2a is -OCJRCJROMe. In some embodiments, R2a is -OCH2CH2OH. In some embodiments, R2a is -OCH2CF3. In some embodiments, R2a is Cs-Ce alkoxy. In some embodiments, R2a is propoxy. In some embodiments, R2a is - OCH (CH3) 2. In some embodiments, R2a is -OCH2CH (CH3) 2. In some embodiments, R2a is cyclopropoxy.
[158] In some embodiments, R3 is hydrogen. In some embodiments, R3 is Ci-Ce alkyl.
[159] In some embodiments, the compound is administered by intravenous administration.
[160] In some embodiments, the compound is administered in combination with another therapeutic agent.
[161] In one aspect, a method is provided for the treatment of disorders related to GABA function in an individual in need thereof, the method comprises administering to the individual a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of a compound as described herein (for example, a compound of Formula (I), (Ia), (lb), (II), (Ila), (lib), (III), (Ilia), ( Illb), (IIIc), (IV), or (V)).
[162] In one aspect, a method of administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound as described herein is provided (for example, a compound of Formula (I), (Ia ), (lb), (II), (Ha), (lib), (III), (Illa), (Illb), (IIIc), (IV), or (V)), to an individual in need thereof , in which the individual experiences sedation and / or anesthesia in two hours.
[163] In some embodiments, the individual is a mammal. In some modalities, the individual is a human being.
[164] In some embodiments, the method of administration is intravenous administration.
[165] In some modalities, the individual experiences sedation and / or anesthesia within one hour of administration. In some modalities, the individual experiences sedation and / or anesthesia instantly. Pharmaceutical compositions
[166] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, for example, a composition suitable for injection, such as for intravenous (IV) administration.
[167] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suitable for the particular desired dosage form, for example , injection. General considerations in the formulation and / or manufacture of pharmaceutical composition agents can be found, for example, in Remington's Pharmaceutical Sciences, 16th Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: "The Science and Practice of Pharmacy ", 21st Edition (Lippincott Williams & Wilkins, 2005).
[168] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to the known technique using suitable dispersing or wetting agents and suspending agents. Examples of excipients that can be used include, without limitation, water, sterile saline or phosphate buffered saline, or Ringer's solution.
[169] In certain embodiments, the pharmaceutical composition also comprises a cyclodextrin derivative. The most common cyclodextrins are a-, β- and y- cyclodextrins which consist of 6, 7 and 8 a-1,4- linked glucose units, respectively, which optionally comprise one or more substituents on the linked sugar moieties, which include , without limitation, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkylether ether. In certain embodiments, cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).
[170] The injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other injectable medium sterile before use.
[171] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in view of the relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient symptoms and the like.
[172] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically distinct units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient . Typical unit dosage forms include pre-filled ampoules or syringes, pre-measured liquid compositions. In such compositions, the compound is commonly a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and delivery aids. useful for forming the appropriate dosage form.
[173] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all from about 1 to about 120 hours and from about 24 to about 96 hours. A preload cake of about 0.1 mg / kg to about 10 mg / kg or more can also be administered to achieve adequate levels of steady state. The maximum total dose should not exceed about 2 g / day for a human patient from 40 to 80 kg. An example composition can be, for example, dissolved or suspended in an aqueous injectable medium of sterile buffered saline in a concentration of approximately 5 mg / ml.
[174] The compounds provided herein can be administered as the only 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. Combined administration can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternate administration.
[175] Although the descriptions of pharmaceutical compositions provided herein are primarily directed to pharmaceutical compositions that are suitable for administration to humans, it should be understood by the skilled practitioner that such compositions are generally suitable for administration to animals of all types. The modification of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various animals is well understood, and the veterinarian of ordinary skill can design and / or perform such modification with common experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins, 2005). Methods of use and Treatment
[176] As generally described therein, the present invention is directed to 17-cyano substituted neuroactive steroids comprising at least one substituent in one or more 2, 4, and / or 11 positions on the steroid skeleton, designed, for example , to rotate as GABA modulators. In certain embodiments, such compounds are seen to be useful as therapeutic agents for inducing anesthesia and / or sedation in an individual. In some embodiments, such compounds are seen to be useful as therapeutic agents for the treatment of a CNS disorder (for example, sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory disorder and / or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in an individual in need (for example, an individual with Rett's syndrome, fragile X's syndrome, or Angelman's syndrome).
[177] Therefore, in one aspect, the present invention provides a method of inducing sedation and / or anesthesia in an individual, which comprises administering to the individual an effective amount of a compound of the present invention or a composition thereof. In certain embodiments, the compound is administered by intravenous administration.
[178] Previous studies (see, for example, Gee et al, European Journal of Pharmacology, 136: 419-423 (1987)) have shown that certain 3a-hydroxylated steroids are more potent orders of magnitude as modulators of the GABA receptor complex. (GRC) that others have reported (see, for example, Majewska et al., Science 232: 1,004-1,007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241: 346- 353 (1987)). Majewska et al, and Harrison et al, taught that 3a-hydroxylated-5-reduced steroids are only capable of much lower levels of effectiveness. Experimental data in vitro and in vivo have now shown that the high potency of these steroids allows them to be therapeutically useful in modulating brain excitability via GRC (see, for example, Gee et al., European Journal of Pharmacology, 136: 419-423 ( 1987); Wieland et al., Psychopharmacology 118 (1): 65-71 (1995)).
[179] Several synthetic steroids have also been prepared as neuroactive steroids. See, for example, US Patent No. 5,232,917, which discloses neuroactive steroid compounds useful in the treatment of stress, anxiety, insomnia, seizure disorders, and mood disorders, which are responsive to those active in the GRC, such as depression, in a therapeutically beneficial way. In addition, these steroids have previously been shown to interact at a single site in the GRC that is distinct from other known interaction sites (eg, barbiturates, benzodiazepines, and GABA) in which therapeutically beneficial effects on stress, anxiety, sleep, sleep disorders mood and seizure disorders have been previously provoked (see, for example, Gee, KW and Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxieti, Insomnia and Seizure Disorders", in Central Nervous System Disorders, Horvell, ed. , Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KG and Morselli, PL, "Psychopharmacology of GABAergic Drugs", in 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 for their duration, potency and oral activity (along with other forms of administration ).
[180] The compounds of the present invention, as described herein, are generally designed to modulate GABA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS-related conditions in an individual. Modulation, as used herein, refers to the inhibition or enhancement of the GABA receptor function. Therefore, the compounds and pharmaceutical compositions provided herein are used as therapeutic agents for the prevention and / or treatment of CNS conditions in mammals including humans and non-human mammals. Therefore, and as previously determined, the present invention includes, and extends, its scope of treatment, as well as compounds for such methods, and the use of such compounds for the preparation of medicaments useful for such methods.
[181] In one aspect, the present invention provides the method for the treatment of disorders related to GABA function in an individual in need thereof, the method comprises administering to the individual a therapeutically effective amount of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein.
[182] Examples of CNS conditions related to GABA modulation include, without limitation, sleep disorders [eg, insomnia], mood disorders [eg, depression, dysthymic disorder (eg, mild depression), bipolar disorder ( for example, I and / or II), anxiety disorders (for example, generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (for example, disorder obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorder [eg, schizophrenia, schizoaffective disorder], seizure disorders [eg epilepsy (eg, epileptic status (SE)), seizures], memory disorders and / or cognition [for example, attention disorders (for example, hyperactivity and attention deficit disorder (ADHD)), dementia (for example, Alzheimer's-type dementia, Lewis body-type dementia, vascular-type dementia], disorders of the movement [ eg Huntington's disease, Parkinson's disease], personality disorders [eg, antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorders (ASD) [eg, autism, monogenetic causes of autism such as synaptopathies, for example, Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g. neuropathic pain, injury-related pain syndromes, acute pain, chronic pain], brain injury traumatic (TBI), vascular diseases [for example, stroke, ischemia, vascular malformations], substance abuse disorders and / or withdrawal syndromes [for example, addiction to opiates, cocaine and / or alcohol] and tinnitus.
[183] In yet another aspect, a combination of a compound of the present invention and another pharmacologically active agent is provided. The compounds provided herein can be administered as the only active agent or can be administered in combination with other agents. Combined administration can occur by any technique known to those skilled in the art, including, for example, separate, sequential, concomitant and alternate administration.
[184] In another aspect, a method of treating or preventing cerebral excitability is provided in an individual susceptible or suffering from a condition associated with cerebral excitability, which comprises administering to the individual an effective amount of a compound of the present invention to the individual.
[185] In yet another aspect, a method of treating or preventing stress or anxiety in an individual is provided, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
[186] In yet another aspect, a method of relieving or preventing seizure activity in an individual is provided, which comprises administering to the individual who needs such treatment an effective amount of a compound of the present invention.
[187] In yet another aspect, a method of relieving or preventing insomnia in an individual is provided, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
[188] In yet another aspect, a method of inducing sleep and maintaining substantial REM sleep is provided which is found in normal sleep, in which the substantial rebound of insomnia is not induced, which comprises administering an effective amount of a compound of the present invention.
[189] In yet another aspect, a method of relieving or preventing PMS or PND is provided in an individual, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention.
[190] In yet another aspect, a method of treating or preventing mood disorders in an individual is provided, which comprises administering to the individual in need of such treatment an effective amount of a compound of the present invention. In some modalities, the mood disorder is depression.
[191] In yet another aspect, a method of inducing anesthesia in an individual is provided, which comprises administering to the individual an effective amount of a compound of the present invention.
[192] In yet another aspect, a method of administering an effective amount of a compound of the present invention is provided to an individual in need thereof, wherein the individual experiences sedation and / or anesthesia within two hours of administration. In some modalities, the individual experiences sedation and / or anesthesia within one hour of administration. In some modalities, the individual experiences sedation and / or anesthesia instantly.
[193] In yet another aspect, a method of increasing cognition or treating memory disorder by providing the individual with a therapeutically effective amount of a compound of the present invention is provided. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett's syndrome.
[194] In yet another aspect, a method of treating attention disorders is provided by administering to the individual a therapeutically effective amount of a compound of the present invention. In some embodiments, the attention disorder is ADHD.
[195] In certain embodiments, the compound is administered to the individual chronically. In certain embodiments, the compound is administered to the individual orally, subcutaneously, intramuscularly or intravenously. Anesthesia / sedation
[196] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of reflexes in skeletal muscles, decreased response to stress, or all of these simultaneously. These effects can be achieved by a single drug that alone provides the correct combination of effects, or occasionally with a combination of drugs (eg, hypnotics, sedatives, paralytics, analgesics) to obtain very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures, without the suffering and pain they would otherwise experience.
[197] Sedation is the reduction of irritability or agitation by administration of a pharmacological agent, usually to facilitate a medical medical procedure or diagnostic procedure.
[198] Sedation and analgesia include a continuous sequence of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.
[199] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient normally responds to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are typically not affected.
[200] Moderate sedation / analgesia (conscious sedation) is a drug-induced depression of consciousness during which the patient responds resolutely to verbal command, either alone or accompanied by tactile-light stimulation. No intervention is normally necessary to maintain a patent airway. Spontaneous ventilation is typically adequate. Cardiovascular function is normally maintained.
[201] Deep sedation / analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused, but responds resolutely (not a reflex withdrawal from a painful stimulus) after repeated or painful stimulation. Independent ventilatory function may be impaired and the patient may need assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is normally maintained.
[202] General anesthesia is a drug-induced loss of consciousness during which the patient is not arousable, even by 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 due to spontaneous depressed ventilation or drug-induced depression of neuromuscular function. Cardiovascular function may be impaired.
[203] Sedation in the intensive care unit (ICU) allows depression of the consciousness of patients in the environment and reduced response to external stimulation. It can play a role in the care of critically ill patients, and encompasses a broad spectrum of symptom control that will vary between patients, and between individuals over the course of their illnesses. Heavy sedation in intensive care has been used to facilitate endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.
[204] In some modalities, sedation (for example, long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (for example, 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedation agents can have a long duration of action. Sedation agents in the ICU can have a short elimination half-life.
[205] Procedural sedation and analgesia, also called conscious, is a technique for administering sedative or dissociative agents with or without pain relievers to induce a condition that allows an individual to tolerate unpleasant procedures while maintaining cardiorespiratory function. Anxiety disorders
[206] Anxiety disorder is a broad term that covers several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.
[207] Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not concentrated on an object or situation. Those who suffer from generalized anxiety have persistent non-specific fear and worry and become overly concerned with day-to-day concerns. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.
[208] In panic disorder, a person suffers from brief attacks of terror and intense apprehension, often marked by tremors, agitation, confusion, dizziness, nausea, difficulty breathing. These panic attacks, defined by the APA ("American Psychological Association") as fear or discomfort that arises abruptly and reaches a peak in less than ten minutes, can last for several hours and can be triggered by stress, fear or even exercise , although the specific cause is not always apparent. In addition to unexpected recurring panic attacks, a diagnosis of panic disorder also requires that such attacks have chronic consequences: concerns about the potential implications of the attacks, persistent fear of future attacks or significant changes in behavior related to the attacks. Consequently, those who suffer from panic disorder experience symptoms even outside of specific panic episodes. Often, normal changes in heart rate are noticed by those who suffer from panic, which makes them think that there is something wrong with their heart or that they are about to have another panic attack. In some cases, a heightened awareness (hypervigilance) of the body's functioning occurs during panic attacks, in which any perceived physiological change is interpreted as a potentially life-threatening illness (ie, extreme hypochondria).
[209] Obsessive-compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent and intrusive thoughts or images) and compulsions (urgency to perform specific acts or rituals). The OCD's thought pattern may be linked to superstitions, as it involves a belief in a causative relationship where, in reality, it does not exist. The process is often entirely illogical; for example, the compulsion to walk in a certain pattern can be used to alleviate the obsession with imminent danger; and in many cases, the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness. In a minority of cases, those suffering from OCD may have only obsessions, with no clear compulsions; a much smaller number of patients have only compulsions.
[210] The single largest category of anxiety disorders is that of Phobia, which includes all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate dire consequences when they find the object of their fear, which can be anything from an animal to the location of a body fluid.
[211] Post-traumatic stress disorder or PTSD is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from an extreme situation, for example, combat, rape, hostage situations, or even a serious accident. It can also result from long-term (chronic) exposure to a serious stressor, for example, soldiers who endure individual battles but cannot cope with ongoing combat. Common symptoms include flashbacks, elusive behaviors and depression. Neurodegenerative diseases and disorders
[212] The term "neurodegenerative disease" includes diseases and disorders that are associated with progressive loss of neuron structure or function, or death of neurons. Neurodegenerative diseases and disorders include, without limitation, Alzheimer's disease (including the associated symptoms of mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and seizure (including for the treatment and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; cerebral edema; cerebellar ataxia, including McLeod's neuroacanthosis syndrome (MLS); closed cranial injury; with the; blunt injuries (for example, spinal cord injury and cranial injury); dementias, including multi-infarct dementia and senile dementia; disturbances of consciousness; Down's syndrome; Drug-induced or medication-induced parkinsonism (for example, neuroleptic-induced acute akathisia, acute dystonia, Parkinsonism or tardive dyskinesia, malignant neuroleptic syndrome or medication-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; deficit and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders, including akinesias and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple systemic atrophy, ALS Parkinsonism-dementia complex, Parkinson's disease, post-encephalitic parkinsonism and progressively supranuclear paralysis); muscle spasms and disorders associated with spasticity or muscle weakness, including chorea (eg, benign hereditary chorea, drug-induced chorea, hemibalism, Huntington's disease, neuroacanthosis, Sydenham's chorea and symptomatic chorea), dyskinesia (including tics, for example , complex tics, simple tics and symptomatic tics), myoclonus (including generalized myoclonus and focal cycloclonus), tremor (for example, resting tremor, postural tremor and intentional tremor) and dystonia (including axial dystonia, dystonic cramp, hemiplegic dystonia , paroxysmal dystonia and focal dystonia such as, for example, blepharospasm, oromandibular dystonia and spasmodic dysphonia and torticollis); neuronal damage, including eye damage, retinopathy or macular degeneration of the eye; neurotoxic injury after stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; convulsions; epileptic state; Brain stroke; buzz; tubular sclerosis and neurodegeneration induced by viral infection (for example, caused by acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, without limitation, neurotoxic injury after 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 loss of neuronal function characteristic of neurodegenerative disorders. Epilepsy
[213] Epilepsy is a brain disorder characterized by repeated seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, for example, childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with major on-awake seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, by example, temporal lobe epilepsy, frontal lobe epilepsy, benign childhood focal epilepsy. Epileptic status (SE)
[214] The epileptic state (SE) can include, for example, convulsive epileptic state, for example, early epileptic state, established epileptic state, refractory epileptic state, super-refractory epileptic state; non-convulsive epileptic state, for example, generalized epileptic state, complex partial epileptic state; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. The convulsive epileptic state is characterized by the presence of convulsive epileptic status, and may include early epileptic status, established epileptic state, refractory epileptic state, super-refractory epileptic state. Early epileptic status is treated with first-line therapy. The established epileptic state is characterized by seizures of an epileptic state that persist despite treatment with first-line therapy, and second-line therapy is administered. The refractory epileptic state is characterized by seizures of an epileptic state that persist despite treatment with first-line and second-line therapy, and a general anesthetic is usually administered. The super-refractory epileptic state is characterized by seizures of an epileptic state that persist despite treatment with first-line therapy, second-line therapy and a general anesthetic for 24 hours or more.
[215] The non-convulsive epileptic state may include, for example, focal non-convulsive epileptic state, for example, complex partial non-convulsive epileptic state, simple partial non-convulsive epileptic state, subtle non-convulsive epileptic state; generalized non-convulsive epileptic state, for example, non-convulsive non-convulsive epileptic state, non-convulsive non-convulsive epileptic state or non-convulsive non-convulsive epileptic state.
[216] In one aspect, the present invention provides a method for treating epilepsy or epileptic condition in an individual, which comprises administering to the individual a therapeutically effective amount of a compound as described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one of a compound as described herein.
[217] The compounds and compositions described herein can also be administered as a prophylactic to an individual who has a CNS disorder, for example, a traumatic brain injury, epileptic state, for example, convulsive epileptic state, for example, early epileptic state , established epileptic state, refractory epileptic state, super-refractory epileptic state; non-convulsive epileptic state, for example, generalized epileptic state, complex partial epileptic state; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; before the onset of a seizure. Seizure
[218] A seizure consists of the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "seizures". Seizures are when a person's body moves quickly and uncontrollably. During seizures, the person's muscles contract and relax repeatedly.
[219] Based on the type of brain behavior and activity, seizures are divided into two broad categories: generalized and partial (also called local or focal). The seizure type classification helps doctors diagnose whether or not a patient has epilepsy.
[220] Generalized seizures are produced by electrical impulses throughout the brain, while partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that generates seizures is sometimes called the focus.
[221] There are six types of generalized seizures. The most common and dramatic, and therefore the most well-known, is the generalized seizure, also called the seizure of the great evil type. In this type of seizure, the patient loses consciousness and usually collapses. Loss of consciousness is followed by generalized body stiffness (called the "tonic" phase of the seizure) for 30 to 60 seconds, and then by violent spasms (the "clonic" phase) for 30 to 60 seconds, after which the patient passes into a deep sleep (the "post-crisis" or post-seizure phase). During seizures of the great evil type, injuries and accidents can occur, for example, biting the tongue and urinary incontinence.
[222] Absence seizures cause a short loss of consciousness (just a few seconds) with few, if any, symptoms. The patient, most often a child, typically interrupts an activity and acquires a lost look. These seizures begin and end abruptly and can occur several times a day. Patients are usually unaware that they are having a seizure, except that they may be aware of "wasting time".
[223] Myoclonic seizures consist of sporadic spasms, usually on both sides of the body. Patients sometimes describe spasms as brief electrical shocks. When violent, these seizures can result in the falling or involuntary throwing of objects.
[224] Clonic seizures are repetitive, rhythmic spasms that involve both sides of the body at the same time.
[225] Tonic seizures are characterized by tightening of the muscles.
[226] Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.
[227] The seizures described here may include epileptic seizures; acute repetitive seizures; cluster convulsions; continuous seizures; non-remitting seizures; prolonged seizures; recurrent seizures; epileptic status seizures, for example, refractory seizure status seizures, non-seizure status seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence convulsions; absence convulsions; atonic seizures; benign rolandic seizures; febrile seizures; emotional convulsions; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; seizures of massive bilateral myoclonus; multifocal seizures; neonatal onset seizures; nocturnal seizures; convulsions of the occipital lobe; post-traumatic seizures; subtle seizures; Sylvan's seizures; visual reflex seizures; or withdrawal convulsions. Equivalents and scope
[228] In the claims, articles such as "one / ones", "one (s)", "the one (s)" and "the one (s)" may mean one or more of one, unless otherwise indicated or some other way evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all members of the group are present, employed, or otherwise relevant to a certain product or process, unless otherwise indicated or otherwise evident from the context. The invention includes modalities in which exactly one member of the group is present, employed or otherwise relevant to a certain product or process. The invention includes modalities in which more than one, or all, members of the group are present, employed or otherwise relevant to a certain product or process.
[229] In addition, the invention encompasses all variations, combinations and permutations in which one or more limitations, elements, clauses and descriptive terms of one or more of the listed claims are introduced in another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same underlying claim. When elements are presented as lists, for example, in Markush group format, each subgroup of the elements is also revealed, and any elements can be removed from the group. It should be understood that, in general, when the invention, or aspects of the invention, is cited as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or basically consist of those elements and / or features. For simplicity, those modalities were not specifically described here in haec verba. It should also be noted that the terms "which comprises" and "which contains" are open and allow the inclusion of additional elements or steps. When tracks are displayed, the end points are included. In addition, unless otherwise indicated or otherwise evident by the context and understanding of those skilled in the art, values that are expressed as ranges may assume any specific value or sub-range within the ranges established in different modalities of the invention, up to the tenth of the unit of the lower limit of the range, unless the context clearly dictates differently.
[230] This specification refers to several granted patents, published patent applications, scientific journal articles and other publications, all of which are incorporated by reference. In the event of a conflict between any of the incorporated references and this specification, the specification must take precedence. In addition, any particular embodiment of the present invention that falls within the established technique can be explicitly excluded from any one or more of the claims. As these modalities are considered known to those skilled in the art, they can be excluded even if the exclusion is not explicitly described here. Any particular form of the invention can be excluded from any claim, for any reason, whether or not it relates to the existence of an established technique.
[231] Those skilled in the art will recognize or be able to verify using at most routine experimentation many equivalents for the specific modalities described here. The scope of the present modalities described herein is not intended to be limited to the above Description, but is as described in the appended claims. Those skilled in the art will observe that various changes and modifications to this description can be made, without departing from the spirit or scope of the present invention, as defined in the following claims. Examples
[232] In order for the invention described here to be more fully understood, the following examples are presented. The synthetic and biological examples described in that application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting their scope. Synthetic methods
[233] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It should be noted that when typical or preferred process conditions (ie reaction temperatures, times, mole ratio of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless determined in contrary. Optimal reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by a person skilled in the art by routine optimization.
[234] Additionally, as will be apparent to those skilled in the art, conventional protection groups may be necessary to prevent certain functional groups from suffering unwanted reactions. The choice of such a protection group suitable for a particular functional group as well as conditions suitable for protection and deprotection are well known in the art. For example, numerous protection groups, and their introduction and removal, are described in T. W. GReene and p. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1991, and references cited here.
[235] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (without limitation) recrystallization, column chromatography, HPLC or supercritical fluid chromatography (SEC). The compounds provided herein can be prepared from known or commercially available starting materials and reagents by a person skilled in the art of organic synthesis. Examples of chiral columns available for use in separating / purifying the enantiomers / diastereomers provided herein include, without limitation, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
[236] 1H-MRI reported here (for example, for intermediates) may be a partial representation of the total MRI spectrum of a compound, for example, a compound described herein. For example, the XH RNM reported can exclude the region between δ (ppm) from about 1 to about 2.5 ppm. Copies of the total spectra of 1H-NMR for representative examples are given in FIGS. 1-12.
[237] Example of general method for preparatory HPLC: Column: Waters RBridge prep 10 pm C18, 19 * 250 mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L of water, 24 g of NH4HCO3, 30 ml of NH3.H2O). Flow rate: 25 mL / min
[238] Example of general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: Acetonitrile gradient: 5 -95 B in 1.6 or 2 min Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6x50mm, 3.5 pm at 45 ° C. Example 1. Synthesis of Compounds 1 and 2.
Synthesis of compounds 1 and 2

[239] To a solution of 006-1, dehydroepiandrosterone (11 g, 38.17 mmol) in EtOH (150 mL) was added 10% Pd / C (1.1 g). Then the mixture was stirred under H2 (40 psi) (275, 79 kPa) at 40 ° C for 12 hours. TLC showed that the starting material was completely consumed. The mixture was filtered and the filtrate was concentrated in vacuo to generate 008-1 (11 g, 99%) as a white solid. XH RNM (008-1): (400 MHz, CDCla) δ 3.59-3.51 (m, 1H), 2.46-2.39 (m, 1H), 2.10-2.01 (m , 1H), 1.92-1.81 (m, 1H), 1.80-0, 94 (m, 19H), 0.85 (s, 3H), 0.82 (s, 3H), 0, 69-0.62 (m, 1H).
[240] To a solution of 008-1 (11 g, 37.8 mmol) in dry pyridine (150 mL) was added p-TsCl (11.4 g, 68.2 mmol) in portions. The mixture was stirred at 40 ° C for 6 hours. Water was added slowly, then a white solid precipitated. The white solid was filtered, and washed with aqueous HCl (200 ml * 3, 1M), followed by water (200 ml * 3). The solid was dried to generate 008-2 (13 g, 77%) as a white solid. 2H RNM (008-2): (400 MHz, CDCI3) δ 7.78 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.0Hz, 1H), 4.44-4 , 38 (m, 1H), 2.46-2.39 (m, 4H), 2.10-2.00 (m, 1H), 1.94-1, 87 (m, 1H), 1.80 -1.45 (m, 12H), 1.29-0, 89 (m, 8H), 0.83 (s, 3H), 0.80 (s, 3H), 0.67-0.61 (m , 1H).
[241] To a stirred solution of collidine (150 mL) was added 008-2 (12.0 g, 27.0 mmol). The mixture was stirred at 150 ° C for 4 hours. TLC showed that the starting material was completely consumed. The reaction mixture was treated with aqueous H2SO4 (500 ml, 10%) and a solid precipitated. The solid was filtered, washed with H2SO4 (500 mLx3, 10%) and water, and dried to generate the crude product. Purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 100: 1 to 50: 1) generated the mixture of 008-3 and 008-3A (7.2 g, 98%, 008-3 : 008-3A = 3.5: 1, confirmed by H-RNM) as a white solid. XH RNM (008-3 and 008-3A): (400 MHz, CDCI3) δ 5.61 - 5.59 (m, 2H), 2.47-2.40 (m, 1H), 2.11 - 1 , 60 (m, 10H), 1.59-1.20 (m, 9H), 0.99-0, 95 (m, 1H), 0.87 (m, 3H), 0.79-0.75 (m, 4H).
[242] To a stirred solution of the mixture of 008-3 and 008-3A (7.2 g, 26.4 mmol) in CH2 Cl2 (100 mL) was added m-CPBA (6.8 g, 39.6 mmol) in portions at 0 ° C. The mixture was stirred at 0 ° C for 1 hour, then at room temperature for 12 hours. The solvent was removed and the residue diluted with EtOAc; then the solution was washed successively with a saturated aqueous solution of Na2SOs (200 ml) and a saturated aqueous solution of Na2COs (200 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 50: 1 to 30: 1) to generate the mixture of 008-4 and 008-4A (7.0 g, 94 , 7%) as a white solid. 1H RNM (008-4 and 008-4A): (400 MHz, CDCI3) δ 3.16-3.15 (m, 1H), 3.12-3.11 (m, 1H), 2.46-2 , 39 (m, 1H), 2.08-2.01 (m, 1H), 1.94-0, 90 (m, 19H), 0.87-0.85 (m, 3H), 0.79 -0.77 (m, 3H), 0.69-0.68 (m, 1H).
[243] A solution of the mixture of 008-4 and 008-4A (3.0 g, 10.4 mmol) in MeOH (30 mL) was treated with 5 drops of H2SO4 (98%) at room temperature. After 1 hour, TLC showed that the starting material was completely consumed. The reaction mixture was treated with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSCg, filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15: 1 to 10: 1) to generate Al (1.7 g, 51%) and A2 (0, 5 g, 15%) as a white solid. 1H RNM (Al): (400 MHz, CDCI3) δ 3.95-3.93 (m, 1H), 3.35-3.33 (m, 4H), 2.46-2.39 (m, 1H ), 2.10-1.66 (m, 7H), 1.62-1.18 (m, 11H), 1.05-0, 98 (m, 1H), 0.95 (s, 3H), 0.85 (s, 3H), 0.79 - 0.73 (m, 1H). ! H RNM (A2): (400 MHz, CDCl3) δ 4.02-4.01 (m, 1H), 3.30 (s, 3H), 3.03-3, 02 (m, 1H), 2 , 46-2.39 (m, 1H), 2.11 - 1.60 (m, 7H), 1.59-1.43 (m, 4H), 1.33-0, 99 (m, 7H) , 0.97 (s, 3H), 0.85 (s, 3H), 0.77-0.70 (m, 1H).
[244] To a stirred solution of t-BuOK (3.5 g, 31.2 mmol) in BuOH (20 mL) was added a solution of Al (1.0 g, 3.12 mmol) in ethylene glycol dimethyl ether (20 mL) under N2. A solution of TosMic (2.5 g, 12.48 mmol) in ethylene glycol dimethyl ether (10 mL) was added in drops. The reaction mixture was stirred at room temperature for 12 hours and then treated with aqueous sodium chloride followed by hydrochloric acid (2 M) to acid. The mixture was extracted with CH2 Cl2, and the organic layer was washed with brine, dried over anhydrous Na2 SCc, and concentrated to generate a residue, which was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15: 1 to 10: 1) to generate 2 (250 mg, 24%) and 1 RNM (2): (400 MHz, (m, 4H), 2.28-2.23 (m, 8H), 1 , 42-1.23 3H), 0.90 (s, 3H), CDCl3) δ 3.95-3.93 (dd, J1 = 2.0 Hz, 2.00-1.57 (m, 9H) , (110 mg, 11%) CDCl3) δ 3.95-3.93 (m, 1H), 2.11-2.04 (m, 8H), 1.15-0.98 0.76-0, 69 (m, 1H). 1H (m, 1H), 3.35-3.30 J2 = 7.2 Hz, 1H), 1.40-1.22 (m, 10H), 0.95 (s, 3H), 0.93- 0.83 (m, 1H), 0.80 (s, 3H). Example 2. Synthesis of Compounds 3 and 38


[245] To a solution of 001-1 (20 g, 55 mmol) in pyridine (200 mL) was added in AC2O drops (8.45 g, 82.8 mmol), then the mixture was stirred at room temperature for one overnight. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the starting material was completely consumed. The mixture was poured into water (1.5 L) with stirring. The resulting solid was collected by filtration and washed with 500 ml of HCl (1 M), followed by water (500 ml x 3). The solid was dried by lyophilization, and 001-2 (19.1 g, 85.9%) was obtained as a white solid. XH RNM (001-2): (400 MHz, CDCI3) δ 5.68 (s, 1H), 5.03 (d, J = 17.6Hz, 1H), 4.84 (d, J = 17.6Hz , 1H), 4.48-4.47 (m, 1H), 2.81-2.77 (m, 1H), 2.57-2.20 (m, 5H), 2.17 (s, 3H ), 2.17-1.97 (m, 3H), 1.91-1.79 (m, 2H), 1.76-1, 64 (m, 2H), 1.54-1.46 (m , 2H), 1.42 (s, 3H), 1.30-1.07 (m, 3H), 0.98 (s, 3H), 0.90-0.89 (m, 1H).
[246] To a solution of 001-2 (17 g, 42 mmol) in EtOH (19 mL) and THF (190 mL) was added CH (OEt) (38.6 mL, 231 mmol) and p-TsOH (463 mg, 2.31 mmol). The mixture was stirred at 20 ° C for 4 h. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the starting material was completely consumed. Then the mixture was diluted with EtOAc (200 ml), and washed with aqueous NaHCO Solution. The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 7: 1) to generate 001-3 (12 g, 66 , 0%) as a white solid. 1H RNM (001-3): (300 MHz, DMSO) δ 5.39 (s, 1H), 5.13-5.07 (m, 2H), 5.07-5.01 (m, 1H), 4.77-4.71 (d, J = 23.4Hz, 1H), 4.27 (m, 1H), 4.18-4.17 (m, 1H), 3, 73-3, 67 (m , 2H), 2.50-2.19 (m, 2H), 2.09 (s, 3H), 2.03-1.92 (m, 4H), 1, 80-1, 60 (m, 4H ), 1.52-1.39 (m, 1H), 1.47-1.12 (m, 6H), 1.09 (s, 3H), 0.95-0, 92 (m, H), 0.74 (s, 3H).
[247] To a solution of 001-3 (1 g, 2.31 mmol) in EtOAc (20 mL) and EtOH (20 mL) was added 10% Pd / C (100 mg). The mixture was stirred at 20 ° C for 30 minutes under H2 (1 atm), then the mixture was filtered. To the resulting solution, aqueous HCl (12%, 50 mL) was added and stirred for 20 min. The mixture was extracted with EtOAc (50 ml). The organic phase was washed with aqueous NaHCO3 solution (50 ml). The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 2: 1) to generate 001-4 (605 mg, 64.4%) as a white solid. XH RNM (001-4): (400 MHz, CDCI3) δ 5.04 (d, J = 17.2 Hz, 1H), 4.83 (d, J = 17.2 Hz, 1H), 4.45-4 , 44 (m, 1H), 2.75-2, 65 (m, 1H), 2.52-2.40 (m, 1H), 2.35-2.20 (m, 3H), 2.18 (s, 3H), 2.10-2.02 (m, 2H), 2.00-1, 78 (m, 3H), 1.78-1, 60 (m, 3H), 1.58-1 , 30 (m, 6H), 1.26 (s, 3H), 0.94 (s, 3H), 0.83-0.79 (m, 1H).
[248] To a solution of 001-4 (5.3 g, 13.05 mmol) in THF (50 mL) was added a solution of K-selectride (19.34 mL, 19.34 mmol, IM in drops) THE) at -78 ° C. The mixture was stirred at -78 ° C for 3 h. Then the mixture was quenched with H2O2 (0.4 mL). The mixture was extracted with EtOAc (80 ml) and H2O (80 ml). The organic phase was washed with aqueous NaHCOa solution (100 ml). The organic phase was dried over Na2SO4 and evaporated to generate the crude product (5.9 g), which was used in the next step without purification.
[249] To a solution of 001-5 (5.9 g, 14.46 mmol) in EtOH (33 mL) and CH2 Cl2 (33 mL) was added NaBJR (1.1 g, 28.92 mmol) in portions. The mixture was stirred at 15 ° C overnight. The reaction mixture was quenched with acetone (33 ml) and H2O (33 ml). To the mixture was added MeOH (200 ml), H2O (200 ml) and NaICc (12.26 g, 57.56 mmol), then the mixture was stirred at 60 ° C overnight. The mixture was cooled to room temperature and extracted with EtOAc (3x100 ml). The combined organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 2: 1) to generate 001-6 (2, 5 g, 62%, two steps) as a white solid. XH RNM (001-6): (400 MHz, CDClj) δ 4.45-4.40 (m, 1H), 4.10-4.05 (m, 1H), 2.50-2.43 (m , 1H), 2.01-1.90 (m, 5H), 1.78-1.35 (m, 12H), 1.28-1.22 (m, 4H), 1.10 (s, 3H ), 1.04 (s, 3H), 0.93-0, 83 (m, 4H).
[250] To a solution of 001-6 (2.5 g, 8.17 mmol) in pyridine (25 mL) was added TsCl (2.33 g, 12.25 mmol). The mixture was stirred at 25 ° C for 10 h. TLC showed that most of the starting material was consumed. The reaction was extracted with EtOAc (50 ml x 2), washed with brine (50 ml), the organic phase dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/4) to generate 001-7 (2 g, 53%) as a white solid. XH RNM (001-7): (400 MHz, CDCls) δ 7.78 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.43 -4.37 (m, 1H), 4.35-4.30 (m, 1H), 2.44 (s, 3H), 2.00-1, 68 (m, 8H), 1.62-1 , 57 (m, 3H), 1.54-1.38 (m, 3H), 1.35-1.14 (m, 5H), 1.12 (s, 3H), 1.03 (s, 3H ), 1.01-0.95 (m, 2H).
[251] To a solution of 001-7 (8.0 g, 17.39 mmol) in CH2 Cl2 (100 mL) was added PCC (7.5 g, 34.8 mmol) in portions at room temperature, then the mixture The reaction was stirred overnight. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. The mixture was filtered, the filtrate was concentrated to generate the crude product, which was purified by flash chromatography eluting with (petroleum ether: ethyl acetate = 3: 1) to generate 018-1 (6.5 g, 81%) like a white solid.
[252] Compound 018-1 (12 g, 26.2 mmol) was dissolved in collidine (40 mL), then the solution was heated to 130 ° C and held at temperature for 2 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. After the mixture returned to room temperature, it was poured into an aqueous solution of H2SO4 (10%). The solution was extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with saturated NaHCOa solution and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated the solvent to generate almost pure 018-2 (7.0 g, 93.0%) as a white solid. XH RNM (018-2): (400 MHz, CDCI3) δ 5, 65-5, 50 (m, 2H), 2.85-2.75 (m, 1H), 2.57-2.50 (m , 1H), 2.45-2.40 (m, 2H), 2.39-2.13 (m, 3H), 2.11-2.07 (m, 1H), 1.96-1.74 (m, 3H), 1.65-1.60 (m, 2H), 1.51-1, 48 (m, 1H), 1.28-1.18 (m, 4H), 0.98 (s, 3H ), 0.84 (s, 3H).
[253] To a solution of 018-2 (7.0 g, 24.3 mmol) in CH2 Cl2 (50 mL) was added m-CPBA (6.3 g, 36.5 mmol) in portions. The resulting mixture was stirred at 10 ° C for 20 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that little starting material existed. Then saturated Na2SÜ3 solution (100 mL) was added to the solution. The organic layer was washed with saturated NaHCOs and brine. The organic layer was dried over anhydrous Na2SÜ4 and the solvent was concentrated. The residue was purified by flash chromatography eluting with (petroleum ether: ethyl acetate = 10: 1) to generate 018-3 (4.8 g, 66%) as a white solid. 1H RNM (018-3): (400 MHz, CDCI3) δ 3.17-3.10 (m, 2H), 2.84-2.78 (m, 1H), 2.56-2.22 (m , 4H), 2.10-2.00 (m, 2H), 1.98-1, 80 (m, 3H), 1.74-1.58 (m, 3H), 1.42-1.05 (m, 5H), 0.98 (s, 3H), 0.82 (s, 3H).
[254] To a solution of the mixture of 018-3 and 018-3A (0.9 g, 3 mmol) in MeOH (10 mL) was added H2SO4 (5 drops, 98%). The mixture was stirred at 20 ° C for 2 hours. TLC showed that the starting material was completely consumed. The mixture was quenched with aqueous NaHCOs (40 ml). The mixture was extracted with EtOAc (20 ml x 2) and washed with brine (20 ml). The organic phase was dried over Na2SO4 and concentrated to generate the crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1) to generate the pure 044-1 (200 mg, 20 %) and the mixture of 044-1 and 044-1A (400 mg, 40%) as a white solid. 1H RNM (044-1): (300 MHz, CDCI3) δ 3, 96-3.90 (m, 1H), 3.37 (s, 3H), 3.31-3.23 (m, 1H), 2.80-2.71 (m, 1H), 2.59-2.47 (m, 1H), 2.45-2.37 (m, 1H), 2.34-2.23 (m, 2H ), 2.20-2.15 (m, 1H), 2.14-2.04 (m, 1H), 1.98-1.71 (m, 5H), 1.68-1.57 (m , 1H), 1.44-1.39 (m, 1H), 1.38-1.23 (m, 4H), 1.17 (s, 3H), 1.15-1.09 (m, 1H ), 0.82 (s, 3H).
[255] To a stirred solution of t-BuOK (6.53 g, 58.35 mmol) in BuOH (50 mL) was added a solution of 044-1 (3.9 g, 11.67 mmol) in 1, 2-dimethoxyethane (50 ml) under Na • A solution of TosMic (3.41 g, 17.5 mmol) in 1,2-dimethoxyethane (30 ml) was then added in drops. The mixture was stirred at room temperature for 4 hours. The mixture was treated with aqueous sodium chloride followed by hydrochloric acid (2 M) until pH = 2. The mixture was extracted with CH2 Cl2, and the organic layer was washed with brine, dried over anhydrous NaaSCg, then concentrated to produce residue, which was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 4: 1) to generate 3 (1.24 g, 32%) and 38 (0.75 g, 19%) as white solids. 1H RNM: (3) (300 MHz, CDCI3) δ 3, 92 -3.89 (m, 1H), 3.30 (s, 3H), 3.30-3.25 (m, 1H), 2, 78-2.73 (m, 1H), 2.55-2.47 (m, 2H), 2.29-2.17 (m, 2H), 2.08-1.92 (m, 1H), 1.90-1.82 (m, 1H), 1.80-1.68 (m, 4H), 1.67-1.59 (m, 1H), 1.58-1.48 (m, 2H ), 1.47-1.32 (m, 1H), 1.30-1.23 (m, 3H), 1.17 (s, 3H), 1.10-1.09 (m, 1H), o, 87 (s, 3H). iH RNM: (38) (300 MHz, CDCls) δ 3.95 - 3.90 (m, 1H), 3.37 (s, 3H), 3.30-3.25 (m, 1H), 2, 78-2.70 (m, 2H), 2.52-2.45 (m, 1H), 2.33-2.30 (m, 1H), 2.30-1.21 (m, 1H), 2.20-2.19 (m, 1H), 2.07-1.92 (m, 2H), 1.88-1.78 (m, 3H), 1.77-1.68 (m, 1H ), 1.55-1.50 (m, 1H), 1.49-1.26 (m, 7H), 1.13 (s, 3H), 0.88 (s, 3H). Example 3 ._ Synthesis of Compounds 47 and 48. Synthesis of Intermediates 039-1 and 051 -1
Synthesis of Compounds 47 and 48

[256] To a solution of the mixture of 008-4 and 008-4A (2.5 g, 8.68 mmol) in EtOH (75 mL) was added H2SO4 (10 drops, 98%). The mixture was stirred at 20 ° C for 3 h. TLC showed that the starting material was completely consumed. The mixture was quenched with aqueous NaHCCc (40 ml). The mixture was extracted with EtOAc (100 ml x 2) and washed with aqueous NaCl (50 ml). The organic phase was dried over Na2SÜ4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1: 2) to generate the mixture of 039-1 and 051-1 (1.8 g, 60%) as a white solid.
[257] To a solution of t-BuOK (1.47 g, 13.16 mmol) in t-BuOH (10 mL) was added a solution of 039-1 (440 mg, 1.32 mmol) in 1.2 -dimethoxyethane (4 mL) in drops at room temperature. Then a solution of TosMic (1.0 g, 5.1 mmol) in 1,2-dimethoxyethane (6 mL) was added dropwise to the mixture. The reaction mixture was warmed to room temperature and stirred for 4 hours. After LCMS showed that the starting material was completely consumed, the mixture was quenched with aq. HCl and extracted with EtOAc (15 mL x 3). The combined organic phases were dried over Na2 SO4, and the solvent was evaporated to generate the crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20: 1) to generate products 47 (40.8 mg, 8.98%) and 48 (25, 5 mg , 5.61%). iH RNM (47): (400 MHz, CDCla) δ 3.96-3, 92 (m, 1H), 3.61-3.52 (m, 1H), 3.45-3.35 (m, 2H ), 2.32-2.22 (m, 1H), 2.18-2.05 (m, 1H), 2.00-1, 60 (m, 7H), 1.45-1.20 (m , 9H), 1.20-1.05 (m, 4H), 1.05-0.91 (m, 5H), 0.88 (s, 3H), 0.80-0.71 (m, 1H ). ! H RNM (48): (400 MHz, CDCI3) δ 3.95-3.91 (m, 1H), 3.64-3.50 (m, 1H), 3.45-3.31 (m, 2H), 2.58-2.52 (m, 1H), 2.15-2.11 (m, 1H), 2.05-1.96 (m, 1H), 1.92-1.75 ( m, 3H), 1.75-1, 62 (m, 4H), 1.48-1.23 (m, 10H), 1.20-1.11 (m, 3H), 1.10-0, 98 (m, 1H), 0.95 (s, 3H), 0.85-0, 82 (m, 4H). Example 4. Synthesis of Compound 4.

[258] A solution of 008-4 (1.0 g, 3.46 mmol) in 2-methoxyethanol (10 mL) was treated with 3 drops of H2SO4 at room temperature. After 1 hour, the reaction mixture was treated with aqueous NaHCCç. The resulting solution was extracted with 2x100 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to generate product 063-1 (330 mg, 26%) as a white solid. XH RNM (063-1): (400 MHz, CDCI3) δ 3, 97-3, 96 (m, 1H), 3.67-3.63 (m, 1H), 3.53-3.51 (m , 3H), 3.50-3.45 (m, 1H), 3.38 (s, 3H), 2.46-2.41 (m, 1H), 1.92-1, 65 (m, 8H ), 1.54-1.21 (m, 11H), 1.02-0, 98 (m, 1H), 0.96 (s, 3H), 0.85 (s, 3H), 0.78- 0.75 (m, 1H).
[259] To a stirred solution of t-BuOK (1.01 g, 9.00 mmol) in BuOH (3 mL) was added a solution of 063-1 (330 mg, 0.90 mmol) in 1.2- dimethoxyethane (3 ml) under N2. A solution of TosMic (720 mg, 3.60 mmol) in 1,2-dimethoxyethane (3 ml) was then added in drops. The mixture was stirred at room temperature for 12 hours. The mixture was treated with aqueous sodium chloride followed by hydrochloric acid (2 M) until pH = 2. The mixture was extracted with CH2 Cl2, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15: 1 to 10: 1) to generate 4 (25 mg, 12%). XH RNM (4): (400 MHz, CDCI3) δ 3, 97-3, 96 (m, 1H), 3, 68-3, 64 (m, 1H), 3.53 - 3.51 (m, 3H ), 3.50-3.46 (m, 1H), 3.38 (s, 3H), 2.28-2.23 (m, 1H), 2.11-2.07 (m, 1H), 1.95-1, 60 (m, 7H), 1.53-1.23 (m, 10H), 1.15-1.11 (m, 1H), 1.02-0, 97 (m, 1H ), 0.96 (s, 3H), 0.92 (s, 3H), 0.76-0, 70 (m, 1H). Example 5. Synthesis of Compounds 5 and 6.

[260] To a solution of 008-4 (2 g, 6.9 mmol) in isopropanol (20 mL) was added concentrated H2SO4 (10 drops). The solution was stirred at room temperature for 3 h. After TLC showed that the starting material was completely consumed, the mixture was quenched with aqueous NaHCOa, and extracted with EtOAc (25 ml x 3). The combined organic layers were dried over Na2SÜ4, concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20: 1) to generate 062-1 (430 mg, 17.77%) as a white solid. : H RNM (062-1): (400 MHz, CDCls) δ 3, 85-3, 80 (m, 1H), 3.70-3, 60 (m, 1H), 3.50- 3.45 ( m, 1H), 2.50-2.35 (m, 1H), 2.10-1.75 (m, 5H), 1.35-1.25 (m, 9H), 1.15-1, 06 (m, 5H), 0.95 (s, 3H), 0.85-0.86 (m, 9H), 0.8-0.7 (m, 1H).
[261] To a solution of t-BuOK (1.38 g, 12.35 mmol) in t-BuOH (10 mL) was added a solution of 062-1 (430 mg, 1.23 mmol) in 1.2 -dimethoxyethane (4 mL) in drops at room temperature. Then a solution of TosMic (964 mg, 4.94 mmol) in 1,2-dimethoxyethane (6 mL) was added dropwise to the mixture. Then the reaction mixture was warmed to room temperature and stirred for 4 hours. After LCMS showed that the starting material was completely consumed, the mixture was quenched with aqueous HCl solution and extracted with EtOAc (15 mL * 3). The combined organic phases were dried over Na2SÜ4, and the solvent was evaporated to generate the crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20: 1) to generate product 5 (27.1 mg, 6.1%) as a white powder and 6 ( 12.7 mg, 2.86%), ifi RNM (5): (400 MHz, CDCla) δ 3.87-3.80 (m, 1H), 3, 68-3, 60 (m, 1H), 3.52-3.46 (m, 1H), 2.30-2.20 (m, 1H), 2.15-2.05 (m, 1H), 2.0-1.6 (m, 7H ), 1.55-1.45 (m, 2H), 1.45-1.19 (m, 9H), 1, 1.19-1.03 (m, 7H), 1.03-0.92 (m, 5H), 0.92-0.88 (m, 4H), 0.75-0.65 (m, 1H). : H RNM (6): (400 MHz, CDCI3) δ 3, 86-3, 80 (m, 1H), 3, 68-3, 60 (m, 1H), 3.52- 3.47 (m, 1H), 2.58-2.52 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.90-1.60 ( m, 7H), 1.55-1.45 (m, 2H), 1.45-1.20 (m, 9H), 1.20-1.05 (m, 6H), 1.05-1, 00 (m, H), 0.95 (s, 3H), 0.85-0.75 (m, 4H). Example 6. Synthesis of Compound 7. Synthesis of intermediates 066-1 and 066-1ª
Synthesis of compound 7

[262] To a solution of the mixture 008-4 and 008-4A (4.0 g, 13.87 mmol) in THF (10 ml) was added ethane-1,2-diol (30 ml). Then 4 drops of H2SO4 were added slowly. The mixture was stirred at room temperature for 1 hour. TLC (petroleum ether: ethyl acetate = 1: 3) indicated that the reaction was complete, so the reaction mixture was treated with aqueous NaHCCç. The resulting solution was extracted with 3 x 100 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 3: 1) to generate product 066-1 (2.8 g, 57.6%) and 066-1A (0, 6 g, 12.3%) as white solids. 1H RNM (066-l): (400 MHz, CDCla) δ 3, 97-3, 96 (m, 1H), 3.71-3.65 (m, 2H), 3.64-3.60 (m , 1H), 3.51-3.46 (m, 2H), 2.46-2.39 (m, 1H), 2.10-2.01 (m, 1H), 1.95-1.45 (m, UH), 1.34-1.21 (m, 7H), 1.03-0.98 (m, 1H), 0.95 (s, 3H), 0.85 (s, 3H), 0.79-0.76 (m, 1H). U RNM (O66-1A): (400 MHz, CDCI3) δ 3.99-3.98 (m, 1H), 3.70-3.67 (m, 3H), 3.45-3.43 (m , 1H), 3.21 - 3.20 (m, 1H), 2.46 - 2.39 (m, 1H), 2.08-1.45 (m, 11H), 1.42-1.20 (m, 6H), 1.04-1.01 (m, 1H), 0.99-0.95 (m, 3H), 0.85 (s, 3H), 0.79-0.75 (m , 1H).
[263] To a stirred solution of t-BuOK (1.28 g, 11.4 mmol) in t-BuOH (3 mL) was added a solution of 066-1 (400 mg, 1.14 mmol) in 1, 2-dimethoxyethane (3 ml) under N2. A solution of TosMic (890 mg, 4.56 mmol) in 1,2-dimethoxyethane (3 ml) was then added in drops. The mixture was stirred at room temperature for 12 hours. The mixture was treated with aqueous sodium chloride followed by hydrochloric acid (2 M) until it was acidic. The mixture was extracted with 3x100 ml of CH2 Cl2, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated to generate the residue, which was purified by column chromatography on silica gel (petroleum ether: acetate). ethyl = 5: 1 to 2: 1) to generate the crude product, then the crude product was purified by pre-HPLC to generate 7 (60 mg, 14.5%). XH RNM (7): (400 MHz, CDCla) δ 3.97-3.96 (m, 1H), 3.71-3.65 (m, 2H), 3.64-3.61 (m, 1H ), 3.51-3.48 (m, 2H), 2.28-2.24 (m, 1H), 2.09-2.08 (m, 1H), 1.95-1.61 (m , 9H), 1.50-1.21 (m, 10H), 1.18-1.05 (m, 1H), 1.03-0, 98 (m, 1H), 0.95 (s, 3H ), 0.92 (s, 3H), 0.79-0.76 (m, 1H). Example 7. Synthesis of Compounds 8 and 14. Synthesis of Intermediates A3 and A4
Synthesis of compounds 8 and 14

[264] The solution of 001-7 (2 g, 4.35 mmol) in collidine (10 mL) was stirred at 140 ° C for 4 h. TLC showed that the starting material was completely consumed. To the mixture was added H2SO4 (10 ml, 1 M) and extracted with EtOAc (30 ml x 2) and aqueous NaCl (30 ml). The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/20) to generate the mixture of 001-8 and 001 -8A (1.1 g, 88%) as a white solid.
[265] To a solution of the mixture of 001-8 and 001-8A (1.1 g, 3.82 mmol) in CH2 Cl2 (10 mL) was added m-CPBA (0.99 g, 5.73 mmol) in portions at 0 ° C. The mixture was stirred at 0 ° C by warming it to room temperature and stirred overnight. TLC showed that the starting material was completely consumed. The mixture was quenched with aqueous NazSgCg (30 ml) and aqueous NaHCOs (30 ml), extracted with EtOAc (30 ml x 2) and washed with brine (30 ml). The organic phase was dried over Na2SOá and evaporated to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/15) to generate the mixture of 001-9 and 001-9A (1.0 g, 86%).
[266] To a solution of the mixture of 001-9 and 001-9A (1 g, 3.29 mmol) in MeOH (25 mL) was added H2SO4 (10 drops, 98%). The mixture was stirred at 20 ° C for 1h. TLC showed that the starting material was completely consumed. The mixture was quenched with aqueous NaHCO3 (40 ml). The mixture was extracted with EtOAc (50 ml x 2) and washed with brine (50 ml). The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/2) to generate A3 (550 mg, 42.6%) and A4 (240 mg, 18.6%) as a white solid. 1H RNM (A3): (400 MHz, CDClj) δ 4.45-4.42 (m, 1H), 3.98-3.94 (m, 1H), 3.42-3.39 (m, 1H ), 3.34 (s, 3H), 2.50-2.43 (m, 1H), 2.10-1.78 (m, 7H), 1.65-1.20 (m, 10H), 1.19 (s, 4H), 1.12 (s, 3H), 1.10-1.00 (m, 1H), 0.86-0, 79 (m, 1H). 2H RNM (A4): (400 MHz, CDClj) δ 4.41 - 4.40 (m, 1H), 4, 04-4, 03 (m, 1H), 3.34 (s, 3H), 3, 05-3.01 (m, 1H), 2.51-2.44 (m, 1H), 2.08-1.96 (m, 5H), 1.95-1.94 (m, 1H), 1.82-1.78 (m, 1H), 1.65-1.55 (m, 3H), 1.53-1.48 (m, 5H), 1.27 (s, 3H), 1, 10 (s, 3H), 1.10-1.00 (m, 1H), 0.77-0, 74 (m, 1H).
[267] To a stirred solution of t-BuOK (830 mg, 7.4 mmol) in BuOH (4 mL) was added a solution of A3 (250 mg, 0.74 mmol) in 1,2-dimethoxyethane (3 mL ) under N2. A solution of TosMic (290 mg, 1.48 mmol) in 1,2-dimethoxyethane (3 mL) was then added in drops. The mixture was stirred at room temperature for 12 hours. The mixture was treated with aqueous sodium chloride followed by hydrochloric acid (2 M) to acid. The mixture was extracted with CH2 Cl2, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, then concentrated to generate the residue, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10 : 1 to 8: 1) to generate 8 (43 mg, 16%) and 14 (15 mg, 6%) as white powders. 1H RNM (8): (400 MHz, CDCI3) δ 4.40-4.39 (m, 1H), 3.96-3.95 (m, 1H), 3.37-3.34 (m, 4H ), 2.22-2.18 (m, 1H), 2.11-1.76 (m, 8H), 1.53-1.52 (m, 1H), 1.46-1.18 (m , 7H), 1.14-1.13 (m, 6H), 1.00-0, 94 (m, 1H), 0.80-0.77 (m, 1H). XH RNM (14): (300 MHz, CDCI3) δ 4.48-4.46 (m, 1H), 3, 96-3, 95 (m, 1H), 3.35-3.33 (m, 4H ), 2.55-2.51 (m, 1H), 2.20-2.16 (m, 1H), 2.05-1.59 (m, 8H), 1.50-1.22 (m , 7H), 1.21-1.18 (m, 1H), 1.15 (s, 3H), 1.03 (s, 3H), 0.92-0, 83 (m, 1H). Example 8. Synthesis of Compounds 9 and 15.

[268] To a solution of compound 001-1 (4 g, 11.02 mmol) in DMF (50 mL) was added 10% Pd / C (400 mg). The mixture was stirred under H2 (50 psi) (344.73 MPa) at 30 ° C overnight. Then the mixture was filtered and evaporated to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/2) to generate compound 005-1 (4 g, 100%) like a white solid. XH RNM (005-1): (400 MHz, CDClj) δ 5.06 (d, J = 17.2 Hz, 1H), 4.83 (d, J = 17.2 Hz, 1H), 4.45-4 , 40 (m, 1H), 2.79-2, 62 (m, 1H), 2.35-2.34 (m, 1H), 2.27-2.21 (m, 3H), 2.13 -1.96 (m, 3H), 2.83-1, 80 (m, 2H), 1.76-1.72 (m, 1H), 1, 67-1, 63 (m, 2H), 1 , 63-1.59 (m, 1H), 1.51-1.42 (m, 3H), 1.27 (s, 3H), 1.23-1.21 (m, 1H), 1.20 -1.17 (m, 1H), 0.96 (s, 3H).
[269] To a solution of compound 005-1 (4 g, 11.02 mmol) in pyridine (40 mL) was added AC2O (2.2 g, 22 mmol). The mixture was stirred at room temperature overnight. The mixture was poured into cold water (200 ml). The solid was collected by filtration and washed with 200 ml of HCl (1 M). The resulting solid was washed with water (100 ml x 3). The solid was dried in air to generate 005-2 (3.0 g, 69%) as a white solid used without further purification. To a solution of compound 005-2 (2.4 g, 5.35 mmol) in EtOH (20 ml) and CH2 Cl2 (20 ml) was added NaBH4 (404 mg, 10.7 mmol). The mixture was stirred at 15 ° C overnight. Then the mixture was quenched with acetone (20 ml) and H2O (20 ml). NaICç (3.3 g, 21.4 mmol) was added to the reaction mixture. The mixture was stirred at 30 ° C overnight. Then the mixture was extracted with EtOAc (50 ml) and H2O (50 ml). The organic phase was dried over Na2SÜ4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/2) to generate compound 005-3 (1.3 g , 79.7%) as a white solid. 1H RNM (005-3): (400 MHz, CDCI3) δ 4.42-4.29 (m, 1H), 3.67-3.56 (m, 1H), 2.51- 2.44 (m , 1H), 2.10-1.94 (m, 5H), 1.73-1, 65 (m, 2H), 1.62-1.50 (m, 5H), 1.48-1.37 (m, 5H), 1.19 (s, 3H), 1.10 (s, 3H), 0.96-0.82 (m, 2H).
[270] To a solution of t-BuOK (2.2 g, 19.58 mmol) in t-BuOH (10 mL) was added a solution of compound 005-3 (600 mg, 1.958 mmol) in 1 drops, 2-dimethoxyethane (5 ml) at room temperature under N2. The mixture was stirred at room temperature for 20 minutes. Then TosMic (574 mg, 2.94 mmol) in 1,2-dimethoxyethane (5 mL) was added in drops and the mixture was stirred at room temperature for 3 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. The reaction was quenched with water (50 mL). The resulting solution was extracted with 2x50 ml of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5.5: 1) to generate product 9 (170 mg, 23%) and 15 (200 mg, 27%) as a white solid. ÍH RNM (9): (300 MHz, CDCI3) δ 4.22-4.18 (m, 1H), 3.66-3.55 (m, 1H), 2.19-2.12 (m, 1H ), 2.06-1.55 (m, 10H), 1.49-1.12 (m, 9H), 1.11 (s, 3H), 1.08 (s, 3H), 1.05- 0.94 (m, 2H). ifi RNM (15): (300 MHz, CDCI3) δ 4.31 - 4.24 (m, 1H), 3.68-3.51 (m, 1H), 2.52-2.45 (m, 1H ), 2.19-1.41 (m, 16H), 1.31-1.17 (m, 5H), 1.11 (s, 3H), 1.01-1.02 (m, 1H), 0.96 (s, 3H). Example 9. Synthesis of Compounds 10 and 11.

[271] To a solution of 001-9 (500 mg, 1.64 mmol) in EtOH (10 mL) was added concentrated H2SO4 (5 drops). The solution was stirred at room temperature for 3 h. TLC showed that the starting material was completely consumed. The mixture was quenched with aqueous NaHCO3 (20 ml), and extracted with EtOAc (15 ml x 3). The combined organic layers were dried over NarSOí, concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 6: 1) to generate 075-1 (160 mg, 28%) as a white solid. 2H RNM (075-1): (400 MHz, CDCI3) δ 4.45-4.40 (m, 1H), 3, 96-3.90 (m, 1H), 3, 65-3.55 (m , 1H), 3.50-3.35 (m, 2H), 2.55-2.42 (m, 1H), 2.10-1.70 (m, 8H), 1.48-1.40 (m, 2H), 1.40-1.20 (m, 6H), 1.20-1.12 (m, 6H), 1.12-1.10 (m, 4H), 1, 08-0 , 98 (m, 1H), 0.85-0, 80 (m, 1H).
[272] To a solution of t-BuOK (511.17 mg, 4.57 mmol) in t-BuOH (8 mL) was added a solution of 075-1 (160 mg, 0.56 mmol) in 1.2 -dimethoxyethane (3 mL) in drops at room temperature. Then a solution of TosMic (178.38 mg, 0.91 mmol) in 1,2-dimethoxyethane (5 ml) was added dropwise to the mixture. The reaction mixture was warmed to room temperature and stirred for 4 hours. After LCMS showed that the starting material was completely consumed, the mixture was quenched with water and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over NSΩSOJ, and the solvent was evaporated to generate the crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 6: 1) to generate product 10 (56.8 mg, 33.41%) as a white powder and 11 ( 32.8 mg, 19.29%). iH RNM (10): (400 MHz, CDC13) δ 4.45-4.35 (m, 1H), 3.98- 3.90 (m, 1H), 3.65-3.55 (m, 1H ), 3.50-3.35 (m, 2H), 2.25-2.15 (m, 1H), 2.10-1.80 (m, 8H), 1.45-1.10 (m , 19H), 1.05-0.95 (m, 1H), 0.82-0.75 (m, 1H). TH RNM (11): (400 MHz, CDCI3) δ 4.5-4.45 (m, 1H), 3, 98-3, 90 (m, 1H), 3, 65-3.55 (m, 1H ), 3.50-3.35 (m, 2H), 2.56-2.50 (m, 1H), 2.25-2.15 (m, 1H), 2.00-1.80 (m , 7H), 1.45-1.15 (m, 16H), 1.05-1.02 (m, 4H), 0.95-0, 85 (m, 1H). Example 10. Synthesis of Compounds 12 and 13.
Synthesis of compounds 12 and 13

[273] To a solution of mixture 003-2 and 003-2A (2.2 g, 5.67 mmol) in acetone (20 mL) was added TSOH.H2O (975 mg, 5.67 mmol). The mixture was stirred at 10 ° C for 3 h. TLC (petroleum ether: ethyl acetate = 10: 1) showed that the starting material was completely consumed. Then the mixture was quenched with aqueous NaHCOa solution (40 ml) and diluted with EtOAc (80 ml x 2). The organic phase was dried over Na2SÜ4 and evaporated to generate the mixture of 003-3 and 003-3A (2.1 g, crude) as a yellow oil, which was used directly in the next step without any purification.
[274] To a solution of mixture 003-3 and 003-3A (2.1 g, crude) in CH2 Cl2 (20 ml) was added 3-chlorobenzoperoxoic acid (1.7 g, 10.43 mmol). The mixture was stirred at 10 ° C for 3 h. TLC (petroleum ether: ethyl acetate = 5: 1) showed that the starting material was completely consumed. Then the mixture was quenched with a solution of Na2S2θ3 / NaHCθ3 (3/1, 40 g) in water (40 ml) and extracted with EtOAc (70 ml x 2). The organic phase was dried over Na2SÜ4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1) to generate the mixture of 003-4 and 003-4A (1.35 g, 61%) as a white solid. : H RNM (003-4 and 003-4A): (400 MHz, CDCI3) δ 3.68- 3.67 (m, 1H), 3.24 (s, 3H), 3.20-3.13 ( m, 2H), 2.49-2.42 (m, 1H), 2.30-2.23 (m, 1H), 2.04-1.31 (m, 12H), 1.20-1, 10 (m, 1H), 1.04-0, 97 (m, 6H), 0.95-0, 92 (m, 1H), 0.70-0.65 (m, 1H).
[275] To a solution of mixture 003-4 and 003-4A (1 g, 3.1 mmol) in MeOH (25 mL) was added concentrated H2SO4 (10 drops, 98%). The mixture was stirred at 10 ° C for 2 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the starting material was completely consumed. Then the mixture was quenched with a mixture of aqueous NaHCO3 solution (30 ml) and diluted with EtOAc (60 ml x 2). The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 7: 1) to generate 003-5 (600 mg, 55% ) and 003-5A (250 mg, 25%) as a white solid. 1H RNM (003-5): (400 MHz, CDCla) δ 3.96-3, 95 (m, 1H), 3.73-3.72 (m, 1H), 3.36-3.35 (m , 4H), 3.26 (s, 3H), 2.49-2.42 (m, 1H), 2.29-2.25 (m, 1H), 2.09-1.80 (m, 6H ), 1.61-1.50 (m, 3H), 1.43-1.16 (m, 6H), 1.10 (s, 3H), 1.04 (s, 3H), 0, 80- 0.77 (m, 1H). ÍH RNM (003-5A): (400 MHz, CDCI3) δ 4.03-4.01 (m, 1H), 3.71-3.69 (m, 1H), 3.35 (s, 3H), 3.20 (s, 3H), 3.02-3.01 (m, 1H), 2.49-2.42 (m, 1H), 2.27-2.23 (m, 1H), 2, 07-2.00 (m, 4H), 1.91-1.79 (m, 1H), 1.60-1.21 (m, 8H), 1.19 (s, 3H), 1.02 ( s, 3H), 0.99-0, 97 (m, 1H), 0.74-0.71 (m, 1H).
[276] To a stirred solution of t-BuOK (324 mg, 2.9 mmol) in BuOH (10 mL) was added a solution of 003-5 (100 mg, 0.29 mmol) in 1,2-dimethoxyethane ( 5 mL) under N2. A solution of TosMic (84 mg, 0.43 mmol) in 1,2-dimethoxyethane was then added in drops. The mixture was stirred at room temperature (15 ° C) for 4 hours. The mixture was treated with aqueous sodium chloride followed by hydrochloric acid (2M) until it was acidic. The mixture was extracted with CH2Cl2, and the organic layer was washed with brine, dried over anhydrous Na2SÜ4, then concentrated to generate the residue, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 8 : 1) and HPLC prep to generate 12 (25 mg, 24.3%) and 13 (20 mg, 19.4%) as a white solid. : H RNM (12): (400 MHz, CDCI3) δ 3, 97-3, 93 (m, 1H), 3.72-3, 68 (m, 1H), 3.39-3.32 (m, 4H), 3.23 (s, 3H), 2.44-2.38 (m, 1H), 2.23-2.18 (t, J = 9.6 Hz, 1H), 2.12-2.02 (m, 1H), 1.97-1, 88 (m, 2H), 1.86-1.72 (m, 4H), 1.53-1.17 (m, 9H), 1.09 (s , 3H), 1.07 (s, 3H), 0.97-0.90 (m, 3H), 0.79-0.72 (m, 1H). 2H RNM (13): (400 MHz, CDCla) 53.97-3.93 (m, 1H), 3, 72-3, 68 (m, 1H), 3.39-3.32 (m, 4H), 3 , 23 (s, 3H), 2.52-2.50 (m, 1H), 2.21-2.12 (m, 2H), 1.98-1.71 (m, 6H), 1.60 -1.43 (m, 3H), 1.41-1.18 (m, 8H), 1.07 (s, 3H), 1.04-0, 99 (m, 1H), 0.96 (s , 3H), 0.89-0.84 (m, 1H). Example 11. Synthesis of compounds 16 and 18

[277] To a solution of 008-4 (1.0 g, 3.47 mmol) in n-PrOH (20 mL) was added H2SO4 (5 drops, 98%). The mixture was stirred at room temperature for 5 h. TLC (petroleum ether / ethyl acetate = 3/1) showed that the starting material was completely consumed. The mixture was quenched with the addition of aqueous saturated NaHCCc (10 ml). The mixture was extracted with EtOAc (15 ml x 3). The combined organic layers were washed with brine (20 ml) and dried over anhydrous Na2 SO4 and concentrated to generate the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20/1) to generate pure 061-1 (360 mg, 30%) as a white solid. XH RNM (061-1): (400 MHz, CDCI3) δ 3.89-3, 97 (m, 1H), 3.37-3.49 (m, 2H), 3.26-3.32 (m , 1H), 2.39-2.48 (m, 1H), 2.01-2.11 (m, 1H), 1.73-1.97 (m, 6H), 1.14-1.71 (m, 22H), 0.71-1.05 (m, 16H).
[278] To a solution of t-BuOK (1.16 g, 10.33 mmol) in t-BuOH (10 mL) was added 061-1 (0.36 g, 1.03 mmol) in 1.2- dimethoxyethane (7 mL) at room temperature under N2 atmosphere. The mixture was stirred at room temperature for 30 minutes. Then a solution of TosMic (0.405 g, 2.07 mmol) in 1,2-dimethoxyethane (7 mL) was added and the resulting solution was stirred at room temperature overnight. TLC (petroleum ether / ethyl acetate = 3/1) showed that the starting material was completely consumed. To the resulting mixture, saturated aqueous NaCl (10 ml) was added and the resulting mixture was extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with brine (15 ml x 2) and dried over anhydrous Na2SÜ4 and concentrated in vacuo to generate the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 12 / 1) and also purified by Prep-HPLC to generate 16 (39.7 mg, 10.7%) and 18 (46.2 mg, 12.4%) as white solids. 1H RNM (16): (400 MHz, CDClj) δ 3, 89-3, 96 (m, 1H), 3.41-3.47 (m, 1H), 3.37- 3.42 (m, 1H ), 3.26-3.32 (m, 1H), 2.22-2.39 (m, 1H), 2.03-2.15 (m, 1H), 1.88-1.95 (m , 2H), 1.81-1.87 (m, 2H), 1.60-1.79 (m, 3H), 1.48-1.59 (m, 5H), 1.19-1.44 (m, 9H), 1.02-1.17 (m, 1H), 0.77-1.02 (m, 11H), 0.68-0.75 (m, 1H). RNM (18): (400 MHz, CDCla) δ 3, 89-3, 95 (m, 1H), 3.37-3.48 (m, 2H), 3.27-3.32 (m, 1H) , 2.52-2.56 (m, 1H), 2.11-2.21 (m, 1H), 1.92-2.01 (m, 2H), 1.77-1.89 (m, 3H), 1.62-1.76 (m, 4H), 1.19-1.40 (m, 10H), 0.95-1, 09 (m, 1H), 0.86-0, 97 ( m, 5H), 0.76-0, 87 (m, 4H). Example 12. Synthesis of Compounds 17.

[279] To a solution of 018-3 (950 mg, 3.13 mmol) in 2-methoxyethanol (15 mL) was added concentrated H2SO4 (5 drops). The mixture was stirred at 30 ° C for 2 hours. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. The solvent was evaporated and the residue was diluted with EtOAc (50 ml) and washed with aqueous NaHCCg. The organic layer was dried over anhydrous Na2SC> 4 and the solvent was concentrated. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 3: 1) to generate 022-1 (680 mg, 57%) as a white solid. XH RNM (022-1): (400 MHZ, CDC13) δ 3.95-3.91 (m, 1H), 3.85-3.78 (m, 1H), 3.48- 3.57 (m , 3H), 3.45-3.37 (m, 4H), 2.72-2, 68 (m, 1H), 2.58-2.49 (m, 1H), 2.42-2.36 (m, 1H), 2.31 - 2.18 (m, 2H), 2.14 - 2.07 (m, 1H), 1.95-1.83 (m, 4H), 1.78-1 , 51 (m, 2H), 1.36-1.14 (m, 9H), 0.81 (s, 3H).
[280] To a solution of t-BuOK (888 mg, 7.94 mmol) in t-BuOH (10 mL) was added a solution of 022-1 (300 mg, 0.79 mmol) in 1,2-dimethoxyethane dropwise. (5 mL) at room temperature under N . The mixture was stirred at room temperature for 20 minutes. Then TosMic (300 mg, 1.58 mmol) in 1,2-dimethoxyethane (5 mL) was added in drops. The mixture was stirred at room temperature for 3 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. The reaction was quenched with water (50 mL). The resulting mixture was extracted with 2 x 100 ml of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5.5: 1) to generate product 17 (82 mg, 27%) as an oil yellow. XH RNM (17): (400 MHz, CDCI3) δ 3, 98-3, 96 (m, 1H), 3.74-3, 68 (m, 1H), 3, 56-3, 45 (m, 3H ), 3.42-3.36 (m, 4H), 2.73-2, 68 (m, 1H), 2.52-2.46 (m, 2H), 2.30-2.20 (m , 2H), 2,08-1,98 (m, 1H), 1,94-1,71 (m, 6H), 1,49-1,38 (m, 2H), 1,35-1,26 (m, 4H), 1.18-1.15 (m, 4H), 0.88 (s, 3H). Example 13. Synthesis of Compounds 19 and 20

[281] To a solution of 001-7 (8.0 g, 17.39 mmol) in CH2 Cl2 (100 mL) was added PCC (7.5 g, 34.8 mmol) in portions at room temperature, then the mixture The reaction was stirred overnight. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. The mixture was filtered, the filtrate was concentrated to generate the crude product, which was purified by flash chromatography eluting with (petroleum ether: ethyl acetate = 3: 1) to generate 018-1 (6.5 g, 81%) like a white solid.
[282] Compound 018-1 (12 g, 26.2 mmol) was dissolved in collidine (40 mL), then the solution was heated to 130 ° C and held at temperature for 2 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. After the mixture returned to room temperature, it was poured into an aqueous solution of H2SO4 (10%). The solution was extracted with ethyl acetate (100 ml * 3). The combined organic layer was washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent was concentrated to generate almost pure 018-2 (7.0 g, 93.0%) as a white solid. 1H RNM (018-2): (400 MHz, CDCI3) δ 5, 65-5, 50 (m, 2H), 2.85-2.75 (m, 1H), 2.57-2.50 (m , 1H), 2.45-2.40 (m, 2H), 2.39-2.13 (m, 3H), 2.11-2.07 (m, 1H), 1.96-1.74 (m, 3H), 1.65-1.60 (m, 2H), 1.51-1.48 (m, 1H), 1.28-1.18 (m, 4H), 0.98 (s, 3H ), 0.84 (s, 3H).
[283] To a solution of 018-2 (7.0 g, 24.3 mmol) in CH2 Cl2 (50 mL) was added m-CPBA (6.3 g, 36.5 mmol) in portions. The resulting mixture was stirred at 10 ° C for 20 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that some starting material has always existed. Then saturated Na2SOa solution (100 mL) was added to the solution. The organic layer was washed with saturated NaHCOs and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent was concentrated. The residue was purified by flash chromatography eluting with (petroleum ether: ethyl acetate = 10: 1) to generate 018-3 (4.8 g, 66%) as a white solid. 1H RNM (018-3): (400 MHz, CDC13) δ 3.17-3.10 (m, 2H), 2.84-2.78 (m, 1H), 2.56-2.22 (m , 4H), 2.10-2.00 (m, 2H), 1.98-1, 80 (m, 3H), 1.74-1.58 (m, 3H), 1.42-1.05 (m, 5H), 0.98 (s, 3H), 0.82 (s, 3H).
[284] To a solution of compound 018-3 (0.95 g, 3.13 mmol) in EtOH (20 mL) was added H2SO4 (98%, 5 drops). The mixture was stirred at 30 ° C for 2 h. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. The mixture was quenched with aqueous NaHCOa and extracted with ethyl acetate (30 ml x 2). The combined organic layer was dried over anhydrous Na2SÜ4 and the solvent was concentrated. The residue was purified by flash chromatography eluting with (petroleum ether: ethyl acetate = 6: 1) to generate 018-4 (500 mg, 47%) as a white solid. 1H RNM (018-4): (400 MHz, CDCI3) δ 3.95 - 3.91 (m, 1H), 3.76-3, 69 (m, 1H), 3.40-3.31 (m , 2H), 2.73-2.69 (m, 1H), 2.56-2.49 (m, 1H), 2.42-2.20 (m, 3H), 2.12-2.07 (m, 1H), 1.96-1, 60 (m, 5H), 1.42-1.12 (m, 12H), 0.72 (s, 3H).
[285] In an oven-dried flask, t-BuOH (5 mL) and t-BuOK (644 mg, 5.70 mmol) were added. It was evaporated and filled with N2. Then TosMic (224 mg, 1.14 mmol) in 1,2-dimethoxyethane (4 mL) was added and the mixture turned yellow. Compound 018-4 (200 mg, 0.57 mmol) in 1,2-dimethoxyethane (4 ml) was added to the suspension. The resulting mixture was stirred at room temperature (10 ° C) for 16 h. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. Water was added and the mixture was stirred then extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SÜ4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel ethyl acetate = 6: 1) to generate 19 (43 mg, 21%) and 20 (14 mg, 7%) as a white solid. 1H RNM (19): (400 MHz, CDCl3) δ 3.91-3.86 (m, 1H), 3.74-3.66 (m, 1H), 3.40-3.30 (m, 2H ), 2.73-2.68 (m, 1H), 2.53-2.44 (m, 2H), 2.30-2.18 (m, 2H), 2.08-1.95 (m , 1H), 1.93-1.70 (m, 5H), 1.68-1.58 (m, 1H), 1.51-1.40 (m, 2H), 1.33-1.22 (m, 3H), 1.20-1.11 (m, 8H), 0.87 (s, 3H). 1H RNM (20): (400 MHz, CDCl3) δ 3.92-3.88 (m, 1H), 3.76-3.69 (m, 1H), 3.41-3.33 (m, 2H ), 2.78-2.65 (m, 2H), 2.65-2.54 (m, 1H), 2.38-2.30 (m, 1H), 2.28-2.10 (m , 2H), 2.04-1.92 (m, 2H), 1.90-1.70 (m, 4H), 1.42-1.26 (m, 6H), 1.21-1.14 (m, 7H), 0.78 (s, 3H). Example 14. Synthesis of Compound 21.

[286] To a solution of the mixture of 018-3 and 018-3A mg, 1.65 mmol) in 1-propanol (10 mL) was added H2SO4 (5 drops, 98%). The mixture was stirred at 15 ° C for 3 h. TLC showed that the starting material was completely consumed. The mixture was quenched with aqueous NaHCOs (20 ml), extracted with EtOAc (20 ml x 2) and aqueous NaCl (20 ml). The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 6: 1) to generate the mixture of 080-1 and 080- 1A (250 mg, 41.7%) as a white solid.
[287] To a stirred solution of t-BuOK (773 mg, 6.9 mmol) in BuOH (10 mL) was added a solution of the mixture of 080-1 and 080-1A (250 mg, 0.69 mmol) in 1,2-dimethoxyethane (5 ml) under N2. A solution of TosMic (269 mg, 1.38 mmol) in 1,2-dimethoxyethane (5 ml) was then added in drops. The mixture was stirred at room temperature for 16 h. To the mixture, water (20 ml) was added, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NagSCU, then concentrated to generate a residue, which was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 8: 1) and prep HPLC for generate white solid c. 1H RNM (21): (m, 1H), 3.64-3.57 (m, 1H), (m, 1H), 2.74-2, 67 (m, 1H), (m, 2H), 2.03-1.70 (m, 6H), (m, 2H), 1.48-1.23 (m, 6H), 1H), 0.92 (t, J = 9 Hz, 3H), 0 , Example 15. Synthesis of Compound 22

[288] To a solution of the mixture of 018-3 and 018-3A (500 mg, 1.65 mmol) in isopropanol (10 mL) was added H2SO4 (5 drops, 98%). The mixture was stirred at 15 ° C for 3 h. TLC showed that the starting material was completely consumed. The mixture was quenched with aqueous NaHCOa (20 ml). The mixture was extracted with EtOAc (20 ml x 2) and aqueous NaCl (20 ml). The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by silica gel column on silica gel (petroleum ether: ethyl acetate = 6: 1) to generate the mixture of 081-1 and 081-1A (150 mg, 25%) as a white solid.
[289] To a stirred solution of t-BuOK (459 mg, 4.1 mmol) in BuOH (10 mL) was added a solution of the mixture of 081-1 and 081-1A (150 mg, 0.41 mmol) in 1,2-dimethoxyethane (3 ml) under N2. A solution of TosMic (162 mg, 0.83 mmol) in 1,2-dimethoxyethane was then added in drops. The mixture was stirred at room temperature for 12 hours. The mixture was added water (20 ml) and extracted with EtOAc (20 ml x 2), and the organic layer was washed with brine, dried over anhydrous Na2SÜ4, then concentrated to generate the residue, which was purified by flash column chromatography over silica gel (eluent: petroleum ether: ethyl acetate = 7: 1) and prep. to generate 22 (31.3 mg, 20.2%) as a yellow oil. XH RNM (22): (300 MHz, CDCla) δ 3.86-3.81 (m, 1H), 3.80-3.71 (m, 1H), 3.47-3.40 (m, 1H ), 2.63-2.56 (m, 1H), 2.55-2.45 (m, 2H), 2.30-2.21 (m, 2H), 2.08-1, 64 (m , 7H), 1.58-1.24 (m, 6H), 1.20-1.05 (m, 11H), 0.86 (s, 3H). Example 16. Synthesis of Compound 23.

[290] To a solution of 001-9 (500 mg, 1.64 mmol) in propan-2-ol (10 mL) was added a solution of concentrated H2SO4 (0.125 mL) in drops. The solution was stirred at room temperature for 3 h. After TLC showed that the starting material was completely consumed, the mixture was quenched with aqueous NaHCCH, then the mixture was concentrated under reduced pressure. The mixture was poured into water (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were dried over Na2SO4, concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 6: 1) to generate 077-1 (150 mg, 25.05%) as a white solid. XH RNM (077-1): (400 MHz, CDCI3) δ 4.45-4.38 (m, 1H), 3, 95-3, 85 (m, 1H), 3.72-3.62 (m , 1H), 3.55-3.45 (m, 2H), 2.55-2.40 (m, 1H), 2.12-1.85 (m, 8H), 1.45-1.38 (m, 3H), 1.30-1.24 (m, 5H), 1.18-1.05 (m, 13H), 0.85-0.75 (m, 1H).
[291] To a solution of t-BuOK (461.33 mg, 4.12 mmol) in t-BuOH (6 mL) was added a solution of 077-1 (150 mg, 0.41 mmol) in 1.2 -dimethoxyethane (2 mL) in drops at room temperature. Then a solution of TosMic (160.80 mg, 0.82 mmol) in 1,2-dimethoxyethane (4 mL) was added dropwise to the mixture. The reaction mixture was warmed to room temperature and stirred for 4 hours. After LCMS showed that the starting material was completely consumed, the mixture was extracted with EtOAc (10 ml x 3). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to generate the crude product. The crude product was first purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 7: 1), and then purified by prep HPLC. to generate 23 (16.6 mg, 11.07%) as a white powder. : H RNM (23): (400 MHz, CDClj) δ 4.44-4.36 (m, 1H), 3.95-3.82 (m, 1H), 3.74-3, 64 (m, 1H), 3.55-3.50 (m, 1H), 2.25-2.18 (m, 1H), 2.14-2.04 (m, 2H), 2.00-1.75 ( m, 6H), 1.49-1.18 (m, 8H), 1.18-1.08 (m, 13H), 1.02-0, 94 (m, 2H), 0, 84-0, 75 (m, 1H) Example 17. Synthesis of compounds 24 and 25

[292] To a solution of 001-9 (500 mg, 1.64 mmol) in 2-Methoxy-ethanol (10 mL) was added sulfuric acid (3 drops). The solution was stirred at room temperature for 3 hours. After TLC showed that the starting material was completely consumed, the reaction mixture was quenched with aqueous NaHCO3 (30 ml) and extracted with EtOAc (10 ml x 3). The combined organic layer was dried over Na2SO4, concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: 6: 1 ether) to generate 078-1 (270 mg, XH RNM (078-1 ): (400 MHz, 3.99-3.97 (m, 1H), 3.72-3.64 3.37 (s, 3H), 2.51-2.41 (m, 1H), 2, 09-1.82 (m, 8H), 1. 63-0, 98 (m, 20H), 0.84-0.77 (m, 1H).
[293] To a solution of t-BuOK (795.46 mg, 7.10 mmol) in t-BuOH (10 mL) was added a solution of 078-1 (270 mg, 0.71 mmol) in 1.2 -dimethoxyethane (4 mL) in drops at room temperature. Then a solution of TosMic (277.26 mg, 1.42 mmol) in 1,2-dimethoxyethane (6 mL) was added in drops. Then the reaction mixture was warmed to room temperature and stirred for 4 hours. After LC-MS showed that the starting material was completely consumed, the mixture was extracted with EtOAc (10 ml * 3). The combined organic phases were dried over NagSCU, and the solvent was evaporated to generate the crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 3: 1) 3 times to generate the product 24 (22.2 mg, 7.93%) and 25 (10 , 6 mg, 3.79%). ÍH RNM (25): (400 MHz, CDC13) δ 4.45- 4.35 (m, 1H), 4.02-3, 95 (m, 1H), 3.75-3, 65 (m, 1H ), 3.58 - 3.46 (m, 4H), 3.38 (s, 3H), 2.35-2.16 (m, 1H), 2.12-1.76 (m, 8H), 1.46-1.18 (m, 10H), 1.18-1.10 (m, 6H), 1.06-0.86 (m, 3H), 0.82-0.75 (m, 1H ). XH RNM (24): (400 MHz, CDCI3) δ 4.55-4.45 (m, 1H), 4.05-3, 95 (m, 1H), 3.75-3, 65 (m, 1H ), 3.60-3.50 (m, 4H), 3.38 (s, 3H), 2.58-2.52 (m, 1H), 2.26-2.24 (m, 1H), 2.12-1.92 (m, 3H), 1.88-1.72 (m, 4H), 1.40-1.10 (m, 13H), 1.06-0, 98 (m, 4H ), 0.95-0.86 (m, 1H). Example 18. Synthesis of Compound 26. Synthesis of intermediates 076-1 and 0761A
Synthesis of Compound 26

[294] To a solution of mixture 001-9 and 001-9A (500 mg, 1.64 mmol) in Propan-l-ol (10 mL) was added a solution of H2SO4 (0.125 mL) in drops. The solution was stirred at room temperature for 3 h. After TLC showed that the starting material was completely consumed, the mixture was quenched with aqueous NaHCO3 and concentrated under reduced pressure. The mixture was poured into water (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were dried over Na2SÜ4, concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 6: 1) to generate the 076-1 mixture and 076-1A (250 mg, 41.8%) as a white solid.
[295] To a solution of t-BuOK (768 mg, 6.86 mmol) in t-BuOH (10 mL) was added a solution of 076-1 (250 mg, 0.686 mmol) in 1,2-dimethoxyethane (5 mL) in drops at room temperature under N2 atmosphere. Then a solution of TosMic (267 mg, 1.372 mmol) in 1,2-dimethoxyethane (5 mL) was added dropwise to the mixture. The reaction mixture was stirred for 4 hours. After LC-MS showed that the starting material was completely consumed, the mixture was extracted with EtOAc (10 ml x 3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 6: 1) to generate crude 26 (110 mg), which was purified by prep-HPLC to generate pure 26 (36 mg, 27.9%) as a white powder. iH RNM (26): (400 MHz, CDClj) δ 4.42-4.38 (m, 1H), 3, 96-3, 90 (m, 1H), 3.53-3.40 (m, 2H ), 3.33-3.26 (m, 1H), 2.23-2.17 (m, 1H), 2.15-1.72 (m, 8H), 1.63-1, 48 (m , 5H), 1.46-1.10 (m, 14H), 1.04-0.85 (m, 5H), 0.83-0.76 (m, 1H). Example 19. Synthesis of Compounds 27 and 39.

[296] To a solution of t-BuOK (1.83 g, 16.32 mmol) in t-BuOH (10 mL) was added 001-6 (0.5 g, 1.63 mmol) in 1.2- dimethoxyethane (7 mL) at room temperature under Nj. The mixture was stirred at room temperature for 30 min, then the solution of TosMic (0. 640 g, 3.26 mmol) in 1,2-dimethoxyethane (7 mL) was added and the solution was stirred at room temperature for one day To the other. TLC (ethyl acetate / petroleum ether = 1/3) showed that the starting material was completely consumed. To the mixture, saturated aqueous NaCl (10 ml) was added and extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with brine (15 ml x 2), dried over anhydrous NajSOj and concentrated in vacuo to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 5) and also purified by ELSD-HPLC to generate 27 (110.6 mg, 21%) and 39 (63, 8 mg, 12.3%) as a white solid. 1H RNM (27): (400 MHz, CDCI3) δ 4.43-4.39 (m, 1H), 4.09-4, 04 (m, 1H), 2.25-2.18 (m, 1H ), 2.16-2.03 (m, 1H), 1.99-1, 88 (m, 1H), 1.87-1.76 (m, 3H), 1.74-1, 68 (m , 1H), 1, 64-1, 68 (m, 1H), 1.64-1.61 (m, 4H), 1.60-1.57 (m, 1H), 1.56-1.50 (m, 2H), 1.49-1.32 (m, 4H), 1.32-1.27 (m, 1H), 1.27-1.18 (m, 2H), 1.16 (s, 3H ), 1.10 - 1.07 (m, 1H), 1.01-0.91 (m, 1H), 0.86-0.78 (m, 1H). Hl RNM (39): (400 MHz, CDCI3) δ 4.45-4.38 (m, 1H), 4.01-3.97 (m, 1H), 2.50-2.44 (m, 1H ), 2.19-2.07 (m, 1H), 1.98-1.64 (m, 7H), 1.64-1.58 (m, 1H), 1.58-1.53 (m , 1H), 1.52-1.49 (m, 4H), 1.39-1.21 (m, 4H), 1.21-1.08 (m, 3H), 1, 06-0, 90 (m, 7H), 0.89-0.80 (m, 1H). Example 20. Synthesis of Compound 28.

[297] To a solution of 9 (800 mg, 2.52 mmol) in DMF (10 mL) was added TBSCI (569 mg, 3.78 mmol) and imidazole (343 mg, 5.04 mmol) at room temperature. The mixture was stirred overnight at room temperature. TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. The reaction was quenched with water (50 ml) and the resulting solution was extracted with 3 x 30 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20: 1) to generate product 069-1 (800 mg, 73%) as a white solid.
[298] ÍH RNM (069-1): (300 MHz, CDCI3) δ 4.28-4.15 (m, 1H), 3.63-3.51 (m, 1H), 2.19-1, 52 (m, 11H), 1.52-1.48 (m, 3H), 1.42-1.12 (m, 7H), 1.12 (s, 3H), 1.08 (s, 3H) , 0.84 (s, 9H), 0.00 (s, 3H).
[299] To a solution of 069-1 (800 mg, 1.86 mmol) in THF (10 mL) was added NaH (372 mg, 9.3 mmol) at 0 ° C. The mixture was stirred at room temperature for 30 minutes. Then Honey (528 mg, 3.72 mmol) was added in drops and the mixture was stirred overnight at 40 ° C. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the reaction was complete. The reaction was quenched with NH4Cl solution (50 ml) and the resulting mixture was extracted with 3 x 30 ml of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo to generate the crude product (700 mg, crude) as a yellow solid, which was used in the next step directly.
[300] To a solution of 069-2 (700 mg, crude) in THE (10 mL) was added TBAF (9 mL, 1 M in THE) at room temperature. The mixture was stirred overnight at 30 ° C. TLC (petroleum ether: ethyl acetate = 5: 1) showed that the reaction was complete. The reaction was quenched with NaHCOa solution (20 ml) and the resulting solution was extracted with 3 x 30 ml of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo to generate the crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 3: 1) to generate product 28 (230 mg, 37% two-step) like a white solid. XH RNM (28): (400 MHz, CDCI3) δ 3.72-3.62 (m, 1H), 3.56-3.55 (m, 1H), 3.25 (s, 3H), 2, 43-2.39 (m, 1H), 2.25-2.22 (m, 1H), 2.16 (m, 1H), 2.15-2.04 (m, 1H), 1.99- 1.87 (m, 2H), 1.84-1, 62 (m, 5H), 1.55-1.13 (m, 8H), 1.11 (s, 3H), 1.08 (s, 3H), 1.03-0, 96 (m, 2H). Example 21. Synthesis of compounds 29 and 37

[301] To a solution of 008-4 (2 g, mmol) in 2-Methylpropan-l-ol (10 mL) was added a solution of H2SO4 (10 drops, 98%) in drops. The solution was stirred at room temperature for 2 h. After TLC showed that the starting material was completely consumed, the mixture was quenched with aqueous NaHCCb, and then it was concentrated under reduced pressure. The mixture was poured into water (20 ml) and extracted with EtOAc (20 ml x 3). The combined organic layers were dried over NaaSCç, concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 30: 1) to generate 094-1 (1 g, 40%) as a white solid. XH RNM (094-1): (400 MHz, CDCI3) δ 4.00-3, 90 (m, 1H), 3.40-3.35 (m, 1H), 3.30-3.24 (m , 1H), 3.15-3.06 (m, 1H), 2.50-2.36 (m, 1H), 2.14-2.00 (m, 1H), 1.98-1, 60 (m, 8H), 1.50-1.10 (m, 10H), 1.10-0.92 (m, 4H), 0, 92-0, 80 (m, 9H), 0.80-0 , 70 (m, 1H).
[302] To a solution of t-BuOK (3.1 g, 27.58 mmol) in t-BuOH (25 mL) was added a solution of 094-1 (1 g, 2.76 mmol) in 1.2 -dimethoxyethane (10 mL) in drops at room temperature. Then a solution of TosMic (1.08 mg, 5.51 mmol) in 1,2-dimethoxyethane (15 mL) was added dropwise to the mixture. The reaction mixture was warmed to room temperature and stirred for 4 hours. After LCMS showed that the starting material was completely consumed, the mixture was extracted with EtOAc (10 ml x 3). The combined organic phases were dried over NaaSOa, and the solvent was evaporated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 7: 1) to generate the crude product. 29 and 37, then the mixture of the two products was purified by prep-HPLC respectively to generate 29 (130.3 mg, 12.7%) and 37 (14.1 mg, 1.2%) as a white powder. XH RNM (29): (400 MHz, CDCla) δ 3, 95-3, 90 (m, 1H), 3.40-3.35 (m, 1H), 3.30-3.22 (m, 1H ), 3.15-3.06 (m, 1H), 2.30-2.24 (m, 1H), 2.16-2.04 (m, 1H), 1.96-1, 62 (m , 8H), 1.42-1.22 (m, 8H), 1.16-1.06 (m, 1H), 1.06-0, 94 (m, 5H), 0, 94-0, 84 (m , 10H), 0.76-0.68 (m, 1H). XH RNM (37): (400 MHz, CDCla) δ 3, 95-3, 90 (m, 1H), 3.41-3.35 (m, 1H), 3.30-3.20 (m, 1H ), 3.15-3.05 (m, 1H), 2.60-2.50 (m, 1H), 2.20-2.08 (m, 1H), 2.02-1.92 (m , 1H), 1.88-1, 68 (m, 8H), 1.42-1.22 (m, 9H), 1.10-0.80 (m, 15H).
[303] Example 22. Synthesis of Compounds 30 and 35.


[304] To a solution of 001-6 (4 g, 13 mmol) in toluene (80 mL) was added TsOH.lAO (745 mg, 3.9 mmol). The mixture was stirred at 70 ° C overnight. The mixture was quenched with aqueous NaHCO3 solution (100 ml) and extracted with EtOAc (100 ml x 2). The organic phase was dried over Na2SÜ4 and evaporated to generate the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to generate 1.5 g of 074-1 (yield: 40% ) as a white solid. 1H RNM (074-1): (400 MHz, CDCla) 55, 38-5, 37 (m, 1H), 4, 06-4.05 (m, 1H), 2.49- 2.42 (m, 1H), 2.22-2.15 (m, 1H), 2.13-1.98 (m, 7H), 1.75-1.54 (m, 6H), 1.52-1.25 ( m, 9H), 1.11-1.03 (m, 2H), 0.96 (s, 3H), 0.82 (s, 3H).
[305] To a solution of 074-1 (1.5 g, 5.2 mmol) in toluene (30 mL) was added 2,2-dimethylpropane-1,3-diol (2.16 g, 20.8 mmol ), CH (OEt) 3 (2.26 g, 15.6 mmol) and TSOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 40 ° C overnight. Then the mixture was quenched with NaHCCç solution (50 ml) and extracted with EtOAc (50 ml x 2). The organic phase was dried over Na2SO4 and evaporated to generate the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 25: 1) to generate 1.3 g of 074-2 (Yield: 67% ) as a white solid. XH RNM (074-2): (400 MHz, CDCI3) δ 5, 38-5, 36 (m, 1H), 4.03-4, 02 (m, 1H), 3, 66-3, 64 (m , 1H), 3.47-3.45 (m, 1H), 3.39-3.34 (m, 2H), 2.65-2.61 (m, 1H), 2.32-2.29 (m, 1H), 2.03-2.01 (m, 1H), 1.89-1, 84 (m, 1H), 1.78-1.41 (m, 14H), 1.36-1 , 24 (m, 5H), 1.14 (s, 3H), 1.03-0, 95 (m, 2H), 0.91 (s, 3H), 0.74 (s, 3H), 0, 71 (s, 3H).
[306] To a solution of 074-2 (1.3 g, 3.47 mmol) in THF (15 mL) was added catecholate (2.49 g, 10.4 mmol) and LÍBH4 (113 mg, 5.2 mmol). The mixture was stirred at 14 ° C overnight. To the mixture was added NaOH (1.6 g in 5 ml H2O), EtOH (16 ml) and H2O2 (11 ml) at 0 ° C and stirred at 14 ° C for 5 h. The mixture was extracted with ethyl acetate (30 ml x 2). The organic phase was dried over Na2SÜ4 and evaporated to generate the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to generate 1.0 g of 074-3 (Yield: 76% ) as a white solid. 'H RNM (074-3): (400 MHz, CDCI3) δ 4.01-4.00 (m, 1H), 3, 93-3.92 (m, 1H), 3, 63-3, 62 ( m, 1H), 3.44-3.41 (m, 1H), 3.36-3.34 (m, 1H), 2.28-2.20 (m, 1H), 2.16-2, 10 (m, 1H), 1.85-1.81 (m, 1H), 1.76-1.32 (m, 15H), 1.21-1.15 (m, 2H), 1.12 ( s, 3H), 0.91 (s, 3H), 0.90-0.85 (m, 1H), 0.79 (s, 3H), 0.70 (s, 3H).
[307] To a solution of 074-3 (1 g, 2.55 mmol) in acetone (10 mL) was added TSOH.H2O (485 mg, 1.27 mmol). The mixture was stirred at 15 ° C for 1 h. Then the reaction mixture was quenched with NaHCOs solution (30 ml) and extracted with EtOAc (50 ml x 2). The organic phase was dried over Na2SÜ4 and evaporated to generate 750 mg of 074-4 (Yield: 94%) as a white solid. XH RNM (074-4): (400 MHz, CDCI3) δ 4.01-4.00 (m, 1H), 3, 93-3, 92 (m, 1H), 2.48 - 2.40 (m , 1H), 2.14-2.05 (m, 3H), 1.95-1.48 (m, 12H), 0.93 (s, 3H), 0.91 (s, 3H), 0, 84 (s, 3H).
[308] To a solution of t-BuOK (1.65 g, 14.7 mmol) in t-BuOH (10 mL) was added a solution of 074-4 (450 mg, 1.47 mmol) in 1.2 -dimethoxyethane (5 mL) in drops at room temperature. Then a solution of TosMic (573 mg, 2.94 mmol) in 1,2-dimethoxyethane (5 mL) was added dropwise to the mixture. The reaction mixture was warmed to room temperature and stirred for 16 hours. After LCMS showed that the starting material was completely consumed, the mixture was extracted with EtOAc (10 ml x 3). The combined organic phases were dried over NagSCg, and the solvent was evaporated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 1: 1) to generate 30 (220 mg, 47%) and 35 (51 mg, 12%) as a white powder. 'H RNM (30): (400 MHz, CDC13) δ 4.03-4.02 (m, 1H), 4.01-3.95 (m, 1H), 2.35-2.30 (m, 1H), 2.29-2.25 (m, 1H), 2.20-2.02 (m, 2H), 2.00-1.90 (m, 1H), 1.80-1.61 ( m, 5H), 1.57-1.49 (m, 2H), 1.45-1.10 (m, 10H), 0.92 (s, 3H), 0.90 (s, 3H).
[309] XH RNM (35): (400 MHz, CDCI3) δ 4.03-4.01 (m, 1H), 3, 95-3, 93 (m, 1H), 2.57 -2.55 ( m, 1H), 2.19-2.00 (m, 4H), 1.90-1.80 (m, 1H), 1.75-1.50 (m, 11H), 1.50-1, 08 (m, 10H), 1.57-1.49 (m, 2H), 1.45-1.10 (m, 10H), 0.93 (s, 3H), 0.82 (s, 3H) . Example 23. Synthesis of compound 31

[310] To a solution of 27 (650 mg, 2.05 mmol) and 1H-imidazole (278.77 mg, 4.09 mmol) in DMF (8 mL) was added TBSC1 (462.9 mg, 4.09 mmol) in DMF (4 mL) at room temperature under N2 atmosphere. The mixture was stirred at room temperature overnight. TLC showed that the starting material was completely consumed. To the resulting mixture, saturated brine (10 ml) was added and the resulting solution was extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with saturated brine (15 mL x 3) and dried over anhydrous Na2SÜ4 and concentrated in vacuo to generate the crude, which was purified by column chromatography eluting with (ethyl acetate / petroleum ether = 1/150 ) to generate 070-1 (500 mg, 56.6%) as a white solid.
[311] ÍH RNM (070-1): (400 MHz, CDCI3) δ 4.44-4.38 (m, 1H), 3, 98-3, 94 (m, 1H), 2.14-2, 06 (m, 2H), 2.03-1, 87 (m, 1H), 1.85-1.73 (m, 3H), 1.62-1, 47 (m, 7H), 1.47- 1.28 (m, 4H), 1.28-1.17 (m, 2H), 1.17-1.12 (m, 4H), 1.07-1.02 (m, 2H), 1, 01-0.92 (m, 4H), 0.91-0.84 (m, 12H), 0.83-0.78 (m, 1H), 0.02 (s, 6H).
[312] To a suspension of NaH (463.21 mg, 11.58 mmol) in THF (10 mL) a solution of compound 070-1 (0.5 g, 1.16 mmol) in THF ( 5 mL) at 0 ° C under N2. The mixture was stirred at 0 ° C for 30 min. Then Honey (1.64 g, 11.58 mmol) was added in drops and the mixture was stirred at 30 ° C overnight. TLC showed that the reaction was complete. The reaction was quenched with aqueous NH4Cl (10 ml), the resulting solution was extracted with ethyl acetate (15 ml x 2) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1/50) to generate the product 070-2 (270 mg, 52.3%) as a white solid, ifi RNM (070-2): ( 400 MHz, CDC13) δ 3.98-3.92 (m, 1H), 3.72-3, 68 (m, 1H), 3.21 (s 3), 2.40-2.37 (m, 1H) , 2.26-2.18 (m, 1H), 1.98-1.82 (m, 1H), 1.82-1.71 (m, 4H), 1.47-1.31 (m, 5H), 1.23-1.16 (m, 2H), 1.08 (s, 3H), 1.02-0.91 (m, 7H), 0.88 (s, 12H), 0.78 -0.72 (m, 1H), 0.06-0.02 (m, 7H).
[313] A mixture of 070-2 (270 mg, 605, 72 pmol) and TBAF (1.58 g, 6.06 mmol) in THF (6 mL) was stirred at 30 ° C for 2 days. TLC showed that the reaction was complete. To the reaction mixture, saturated brine (10 ml) was added and the resulting solution was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with saturated brine (10 ml x 2), dried over anhydrous Na ^ SCc and concentrated in vacuo to generate the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether) = 1/5) to generate 31 (65.4 mg, 24.2%) as a white solid. XH RNM (31): (400 MHz, CDCl3) δ 4, 06-4.02 (m, 1H), 3.71 - 3.68 (m, 1H), 3.23 (s, 3H), 2, 41-2.37 (m, 1H), 2.24-2.18 (m, 1H), 2.14-2.06 (m, 1H), 1.98-1, 87 (m, 1H), 1.84-1, 68 (m, 5H), 1.78-1.79 (m, 1H), 1.59-1.48 (m, 3H), 1.48-1.32 (m, 5H ), 1.32-1.13 (m, 4H), 108 (s, 3H), 0.99-0, 89 (m, 7H), 0.82-0.77 (m, 1H). Example 24. Synthesis of Compound 32.


[314] To a mixture of 008-4 (2 g, 6, 934 mmol) in CF3CH2OH (20 mL) at room temperature under N2 atmosphere was added a catalytic amount of concentrated H2SO4 (one drop). The reaction mixture was stirred at room temperature for 16 h. TLC showed that the reaction was complete. The reaction mixture was diluted with EtOAc (30 ml) and aqueous NH4 Cl (50 ml), extracted with EtOAc (30 ml). The combined organic layers were washed with aqueous NaHCO3 (2 x 50 mL), dried over Na2SÜ4, and concentrated to generate the crude product, which was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 6: 1) to generate the product A5 (720 mg, 26.6% yield).
[315] To a mixture of t-BuOK (1.73 g, 15.44 mmol) in t-BuOH (10 mL) was added a solution of 093-1 (600 mg, 1.544 mmol) in 1,2-dimethoxyethane (5 mL) under an N2 atmosphere. A solution of TosMic (603 mg, 3.089 mmol) in 1,2-dimethoxyethane (5 ml) was added. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with CH2 Cl2 (30 ml) and H2O (50 ml) and extracted with CH2 Cl2 (30 ml). The combined organic layers were washed with aqueous NH4Cl (50 ml) and dried over Na2SÜ4, then concentrated to generate the crude product, which was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 10: 1) to generate the crude product A5 (250 mg, 40.5% yield, 17-CN epimer mixture).
[316] To a suspension of A5 (300 mg, 0.751 mmol) in pyridine (10 mL) at room temperature under N2 atmosphere was added PhCOCl (316 mg, 2.253 mmol) in drops. The reaction mixture was heated to 100 ° C and stirred for 3 h. TLC showed that the reaction was complete. The reaction mixture was diluted with CH2 Cl2 (30 ml) and H2O (50 ml), extracted with CH2 Cl2 (30 ml). The combined organic layers were washed with IN HCl (30 ml x 2), dried over Na2SÜ4, and concentrated to generate the crude product. This was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 25: 1) to generate the pure target product A6 (100 mg, 2.4% yield). XH RNM (A6): (400 MHz, CDCla) δ 5.20 (m, 1H), 3, 99-3, 86 (m, 2H), 3.73 (m, 1H), 2.29-2, 22 (m, 1H), 2.18-1.88 (m, 5H), 1.79-1.21 (m, 14H), 1.20-0.72 (m, 11H).
[317] To a solution of A6 (100 mg, 0.2 mmol) in MeOH (5 mL) was added a solution of LiOH.H2O (20 mg, 1 mmol) in H2O (1 mL). The reaction mixture was stirred at room temperature for 16h. TLC showed that the reaction was complete. The reaction mixture was diluted with EtOAc (10 ml) and aqueous NH 4 Cl (10 ml), extracted with EtOAc (10 ml). The combined organic layers were washed with H2O (10 ml), dried over Na2SO4, and concentrated to generate the crude product. The crude product was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 10: 1) to generate 32 (67 mg, 85% yield). XH RNM (32): (400 MHz, CDCI3) δ 3.99 (m, 1H), 3.89-3.70 (m, 2H), 3.58 (m, 1H), 2.30-2, 22 (m, 1H), 2.15-2.02 (m, 1H), 1.97-1, 60 (m, 7H), 1.44-1.20 (m, 9H), 1.18- 0.70 (m, 11H). Example 25. Synthesis of Compounds 33 and 36.

[318] To a solution of 104-1 (10 g, 34 mmol) in toluene (100 mL) was added sodium hydride, mmol) and ethyl formate (3.7 g, 51 mmol). The mixture was then stirred at 10 ° C for 16 hours. The mixture was then filtered. The solid was washed with petroleum ether, added to HCl (IN, aq.), Filtered and washed with water. The solid was dried under vacuum to generate 20 g of crude 104-2 as a white solid. XH RNM (104-2): (400 MHz, CDCI3) δ 14.37 (brs, 1H), 8.62 (s, 1H), 3.64 (t, J = 8.6Hz, 1H), 2, 39-2.20 (m, 2H), 2.14-1.94 (m, 3H), 1.88-1.79 (m, 1H), 1.54-1.32 (m, 7H), 1.31-1.16 (m, 3H), 1.13-0.80 (m, 5H), 0.77 (s, 3H), 0.75 (s, 3H).
[319] To a solution of 104-2 (20 g of crude product) in methanol (400 ml) was added Pd / C (3 g). The mixture was then stirred at 10 ° C for 16 hours under hydrogen (1 atm.). The mixture was then filtered, concentrated in vacuo, purified by column chromatography (petroleum ether: ethyl acetate = 8: 1 for ethyl acetate) to generate 104-3 (3.1 g, 30% above 2 steps) as a colorless oil. XH RNM (104-3): (400 MHz, CDClj) δ 3.63 (t, J = 8.6 Hz, 1H), 2.66-2.40 (m, 1H), 2.38-2.20 (m, 1H), 2.10-1.92 (m, 3H), 1.85-1.75 (m, 1H), 1.70-1.20 (m, 12H), 1.10-0 , 81 (m, 7H), 0.80-0.75 (m, 6H).
[320] To a solution of 104-3 (3.1 g, 10.1 mmol) in dichloromethane (30 mL) was added pyridinium chlorochromate (4.8 g, 22.3 mmol) at 15 ° C and stirred at 15 ° C for 2 hours. To the mixture, water was then added and filtered. The organic layer was then separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to generate 104-4 (2.6 g, 84% ) as a white solid. ! H RNM (104-4): (400 MHz, CDClj) δ 2.67-2.55 (m, 1H), 2.48-2.41 (m, 1H), 2.32-1.24 ( m, 1H), 2.12-1.95 (m, 5H), 1.83-1, 79 (m, 2H), 1.58-1.36 (m, 5H), 1.32-1, 23 (m, 4H), 1.03-0.98 (m, 4H), 0.88-0.76 (m, 4H), 0.78 (s, 3H).
[321] To a solution of 104-4 (2.1 g, 7 mmol) in tetrahydrofuran (20 mL) was added K-selectride (10 mL, 1 M in THF, 10 mmol) in drops at -78 ° C. The mixture was stirred at -78 ° C for 5 hours and hydrogen peroxide (2 mL, 30% in water) was then added in drops at -78 ° C. The mixture was then heated to 10 ° C and aqueous sodium thiosulfate was added. The mixture was then extracted with ethyl acetate (30 mL x 3), the organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to generate 104-5 (700 mg, 30%) as a white solid. 1H RNM (104-5): (400 MHz, CDCI3) δ 3, 82-3.75 (m, 1H), 2.42 (dd, J = 19.4 Hz, J = 9.0 Hz, 1H) , 2.12-2.00 (m, 1H), 1.97-1, 89 (m, 1H), 1.82-1.67 (m, 4H), 1.56-1.44 (m, 5H), 1.37-1.20 (m, 7H), 1.07-0.97 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.85 (s , 3H), 0.81 (s, 3H), 0.79-0.73 (m, 1H).
[322] To a solution of potassium tert-butylate (1.4 g, 13 mmol) in tert-butanol (5 mL) was added a solution of 104-5 (400 mg, 1.3 mmol) in 1, 2 -dimethoxyethane (5 ml) and a solution of TosMic (600 mg, 3.3 mmol) in 1,2-dimethoxyethane (5 ml). The mixture was stirred at 15 ° C for 16 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo and the resulting crude solid purified by column chromatography (petroleum ether: ethyl acetate = 15: 1) to generate 33 (87.2 mg, 21%) and 36 (70.3 mg, 17%) as a white solid. XH RNM (33): (400 MHz, CDCI3) δ 3, 82-3.75 (m, 1H), 2.26 (t, J = 9.6Hz, 1H), 2.18-2.04 (m , 1H), 1.98-1, 87 (m, 2H), 1.79-1.62 (m, 4H), 1.56-1.40 (m, 3H), 1.39-1.10 (m, 8H), 1.10-0.95 (m, 3H), 0.93 (d, J = 7.2Hz, 3H), 0.90 (s, 3H), 0.79 (s, 3H ), 0.78-0.71 (m, 1H). ÍH RNM (36): (400 MHz, CDCI3) δ 3.81 - 3.75 (m, 1H), 2.55 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 2 , 20 - 2.11 (m, 1H), 2.02-1.91 (m, 1H), 1.89-1, 80 (m, 1H), 1.77-1, 62 (m, 5H ), 1.53-1.41 (m, 3H), 1.38-1.13 (m, 8H), 1.08-0, 98 (m, 2H), 0.93 (d, J = 6 , 8Hz, 3H), 0.89-0, 82 (m, 1H), 0.80 (s, 3H), 0.79 (s, 3H). Example 26. Synthesis of Compound 34.

[323] To a solution of 30 (170 mg, 0.53 mmol) in DMF (2 mL) was added imidazole (73 mg, 1.07 mmol) and TBSC1 (121 mg, 0.80 mmol). The reaction was stirred at 15 ° C for 16 h. TLC (petroleum ether: EtOAc = 1: 2) showed that the starting material was completely consumed. The reaction was extracted with EtOAc (20 ml) and aqueous NaCl (20 ml). The organic layer was dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and purified by chromatography on silica gel eluting with ethyl acetate / petroleum ether (1/60) to generate 150 mg of 071-1 (65%) as a white solid.
[324] To a solution of 071-1 (150 mg, 0.35 mmol) in THF (2 mL) was added NaH (56 mg, 1.39 mmol). The mixture was stirred at 12 ° C for 30 minutes. To the reaction mixture was added honey (197 mg, 1.39 mmol) and stirred at 40 ° C for 16 h. TLC (petroleum ether: EtOAc = 5: 1) showed that the starting material was completely consumed. The reaction was quenched with aqueous NH4Cl (5 ml) and extracted with EtOAc (20 ml). The organic layer was dried over anhydrous sodium sulfate and the organic phase was concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with ethyl acetate / petroleum ether (1/30) to generate 100 mg 071-2 (65%) as a white solid.
[325] To a solution of 071-2 (100 mg, 0.22 mmol) in CH2 Cl2 (3 mL) was added TEA (0.5 mL). The mixture was stirred at 15 ° C for 15 minutes. TLC (petroleum ether: EtOAc = 5: 1) showed that the starting material was completely consumed. The reaction was quenched with aqueous NaHCO3 (5 ml) and extracted with EtOAc (20 ml). The organic layer was dried over anhydrous sodium sulfate and the organic phase was concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with ethyl acetate / petroleum ether (1/1) to generate 66 mg of 34 (88%) as a white solid. 1H RNM (34): (400 MHz, CDCI3) δ 4.00 (m, 1H), 3.41-3.35 (m, 1H), 2.25 (s, 3H), 2.46-2, 42 (m, 1H), 2.34-2.29 (m, 1H), 2.19-2.09 (m, 1H), 2.00-1.88 (m, 1H), 1.82- 1.56 (m, 7H), 1.53-0, 98 (m, 12H), 0.90 (s, 3H), 0.89 (s, 3H). Example 27. Synthesis of Compounds 40 and 49. Synthesis of intermediates 105-7 and 105-7A

Synthesis of compound 40
Synthesis of compound 49

[326] To a solution of 008-1 (20 g, 69 mmol) in toluene (200 mL) was added Me2C (CH2OH) 2 (22 g, 211 mmol), HC (OEt) 3 (40 g, 270 mmol) and TsOH.H2O (2.5 g, 13 mmol). The mixture was then stirred at 50 ° C. NaHCO3 aq dried over Na2SO2, concentrated in vacuo, purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1) was added to generate 105-1 (23 g, 88%) as a white solid.
[327] RNM (105-1): (400 MHz, CDC13) δ 3, 65-3.30 (m, 5H), 2.25-2.15 (m, 1H), 1.84-1.18 (m, 16H), 1.15-0.62 (m, 18H).
[328] To a solution of 105-1 (23 g, 61 mmol) in pyridine (100 mL) was added TsCl (20 g, 105 mmol). The mixture was then stirred at 50 ° C for 4 hours. The mixture was then poured into water and filtered. The resulting solid was washed with water, dissolved in CH2Cl2, dried over Na2SÜ4 and concentrated in vacuo to generate 105-2 (35 g, 100%) as an off-white solid. XH RNM (105-2): (400 MHz, CDCI3) δ 7, 80-7, 74 (m, 2H), 7.38-7.28 (m, 2H), 4.45-4.33 (m , 1H), 3.65-3.58 (m, 1H), 3.47-3.30 (m, 3H), 2.43 (s, 3H), 2.25-2.15 (m, 1H ), 1.80-0.57 (m, 33H).
[329] A solution of 105-2 (35 g, 66 mmol) in collidine (60 mL) was stirred at 180 ° C for 2 hours. The mixture was then poured into water, acidified with IN HCl at pH = 3 and extracted with CH2 Cl2. The organic layer was dried over Na2SÜ4 and concentrated in vacuo to generate 105-3 and crude 105-3A (23 g, 100%) as an off-white solid. XH RNM (105-3 and 105-3A): (400 MHz, CDCI3) δ 5, 63-5.50 (m, 1.75H, alkene-2,3-CH), 5, 30-5,24 ( m, 0.25 H, alkene-4-CH), 3.67-3.60 (m, 1H), 3.48-3.40 (m, 1H), 3.38-3.30 (m, 2H), 2.27-2.16 (m, 1H), 2.05-1.05 (m, 16H), 0.95-0.65 (m, 15H).
[330] To a solution of 105-3 and 105-3A (23 g, 64 mmol) in CH2 Cl2 (100 mL) was added m-CPBA (18 g, 105 mmol). The mixture was then stirred at 15 ° C for 16 hours. To the mixture was added NaHCθ3 / Na2S2θ3 (aq.). The organic layer was dried over Na2SÜ4 and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to generate 105-4 and 105-4A (8 g, 32%) as a white solid. XH RNM (105-4 and 105-4A): (400 MHz, CDCI3) δ 3, 67-3.57 (m, 1H), 3.48-3.40 (m, 1H), 3.38-3 , 30 (m, 2H), 3.17-3.03 (m, 1.75 H, epoxy-2,3-CH), 2.70-2, 65 (m, 0.25 H, epoxy-4 -CH), 2.27-2.14 (m, 1H), 2.06-0.55 (m, 31H).
[331] To a suspension of CuCN (2.3 g, 26 mmol) in THF (20 mL) was added MeLi (53 mL, 1M in 2-Me-THF, 53 mmol) at -78 ° C in drops. The mixture was heated to 0 ° C and then cooled to -78 ° C. A solution of BF3.Et2O (1.5 g, 10.6 mmol) in THF (10mL) was added in drops and then stirred at -78 ° C for 30 minutes. A solution of 105-4 and 105-4A (2 g, 5.3 mmol) in THF (10 mL) was then added in drops and stirred at -78 ° C for an additional 3 hours. To the mixture was then added a mixture of MeOH (15 ml) and EtaN (15 ml). The mixture was then heated to 10 ° C. To the mixture, NH4Cl (aq.) And ethyl acetate were added. The mixture was then filtered. The organic layer was separated, dried over Na2SÜ4 and concentrated in vacuo to generate 105-5 and 105-5A (3.1 g, crude) as a light yellow oil. XH RNM (105-5 and 105-5 A): (400 MHz, CDCl3) δ 3.72-3.67 (m, 0.4 H, 4-methyl compound 3-CHOH), 3.67 - 3 62 (m, 0.6H, 2-methyl compound 3-CHOH), 3.58-3.52 (m, 1H), 3.41-3.34 (m, 1H), 3.32-3 , 25 (m, 2H), 2.20-2.03 (m, 2H), 1.86-0.58 (m, 35H).
[332] To a solution of 105-5 and 105-5A (3.1 g, crude) in acetone (30 ml) was added TsOH.H2O (1.5 g, 7.9 mmol). The mixture was stirred at 15 ° C for 1 hour. To the mixture was added NaHCOs (aq.) At pH = 7. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1 to 5: 1) to generate 105-6 and 105-6A (1,2 g, 70% two-step) as a white solid. : H RNM (105-6 and 105-6A): (400 MHz, CDCI3) δ 3.72-3.67 (m, 0.4H, 4-methyl compound 3-CHOH), 3.67-3, 62 (m, 0.6H, 2-methyl compound 3-CHOH), 2.48 - 2.38 (m, 1H), 2.13-1.98 (m, 1H), 1.97-1, 15 (m, 18H), 1.05-0, 63 (m, 11H).
[333] To a solution of t-BuOK (2.2 g, 20 mmol) in t-BuOH (20 mL) was added a solution of TosMic (900 mg, 5 mmol) in 1,2-dimethoxyethane (10 mL) and a solution of 105-6 and 105-6A (600 mg, 2 mmol) in 1,2-dimethoxyethane (10 ml). The mixture was stirred at 15 ° C for 3 hours. To the mixture, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SÜ4 and purified by column chromatography (petroleum ether: ethyl acetate = 15: 1 to 10: 1) to generate A7 and A8 (600 mg, crude) as a white solid. 1H RNM (A7 and A8): (400 MHz, CDCl3) δ 3.72-3.67 (m, 0.25 H, 4-methyl compound 3-CHOH), 3.67 - 3.62 (m, 0.75H, 2-methyl compound 3-CHOH), 2.26 (t, J = 9.2 Hz, 1H), 2.15-0.68 (m, 31H).
[334] To a solution of A7 and A8 (600 mg, 1.9 mmol) in pyridine (6 mL) was added BzCl (1 g, 7 mmol). The mixture was then stirred at 15 ° C for 3 days. To the mixture, NaHCOs (aq.) Were then added and then extracted with ethyl acetate. The organic layer was concentrated in vacuo and purified by prep-HPLC and then SBC to generate 105-7 (90 mg) and 105-7A (40 mg, total two-step yield: 30%) as white solids. 2H RNM (105-7): (400 MHz, CDCla) δ 8, 08-8.03 (m, 2H), 7.61-7.55 (m, 1H), 7.51-7.44 (m , 2H), 5, 08-5, 00 (m, 1H), 2.29 (t, J = 9.6 Hz, 1H), 2.22-0.90 (m, 29H), 0.83- 0.74 (m, 1H). XH RNM (105-7A): (400 MHz, CDCI3) δ 8.10-8.05 (m, 2H), 7, 63-7.55 (m, 1H), 7.52-7.44 (m , 2H), 5.11-5.04 (m, 1H), 2.29 (t, J = 9.6 Hz, 1H), 2.23-1.13 (m, 18H), 1.07- 0.88 (m, 11H), 0.85-0.75 (m, 1H).
[335] To a solution of 105-7 (90 mg, 0.2 mmol) in THF (2 mL) was added MeOH (1 mL) and a solution of LiOH.H2O (0.1 g, 2.4 mmol) in water (1 mL). The mixture was stirred at 40 ° C for 16 hours. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SÜ4 and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1 to 5: 1) to generate 40 (72 mg, 100%) as an off-white solid. 1H RNM (40): (400 MHz, CDCI3) δ 3.74-3, 67 (m, 1H), 2.24 (t, J = 9, 6 Hz, 1H), 2.24-2.00 ( m, 1H), 1.97-1.81 (m, 3H), 1.78-1.45 (m, 7H), 1.43-0.75 (m, 19H), 0.75-0, 65 (m, 1H).
[336] To a solution of compound 105-7A (40 mg, 0.1 mmol) in THF (2 mL) was added MeOH (1 mL) and a solution of LiOH.H2O (0.1 g, 2.4 mmol ) in water (1 mL). The mixture was stirred at 40 ° C for 16 hours. Then the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1 to 5: 1) to generate 49 (25 mg, 100%) as an off-white solid. H RNM (49): (400 MHz, CDCI3) δ 3.83-3.77 (m, 1H), 2.27 (t, J = 9.6 Hz, 1H), 2.17-2.03 ( m, 1H), 1.99-1.50 (m, UH), 1.50-0.73 (m, 19H). Example 28. Synthesis of Compounds 41 and 50. Synthesis of intermediates 107-3 and 107-3A

Synthesis of compound 41
Synthesis of compound 50

[337] To a suspension of CuCN (1.88 g, 21.2 mmol) in THF (150 mL) was added EtLi (85 mL, 0.5 M in benzene / cyclohexane, 42.5 mmol) at -78 ° C in drops. The mixture was heated to 0 ° C and then cooled to -78 ° C. A solution of BF3.Et2O (1.5 g, 10.6 mmol) in THF (q0 mL) was added in drops and then stirred at -78 ° C for 30 minutes. A solution of 105-4 and 105-4A (2 g, 5.3 mmol) in THF (10 mL) was added in drops and stirred at -78 ° C for an additional 3 hours. To the mixture was then added a mixture of MeOH (15 ml) and EtjN (15 ml). The mixture was heated to 10 ° C. To the mixture, NH4CI (aq.) And ethyl acetate were added. The mixture was filtered and the organic layer was separated, dried over Na2SO4 and concentrated in vacuo to generate 107-1 and 107-1A (2.5 g, crude) as a light yellow oil, a mixture of the 2β-Et, 3 isomers -αOH and 3-αOH, 4β- Et. XH RNM (107-1 and 107-1A): (400 MHz, CDCl3) δ 3.94-3.90 (m, 0, 1H, 4-ethyl compound 3-CHOH), 3.85-3.74 (m, 0.6H, 2-ethyl compound 3-CHOH), 3.68-3.62 (m, 1H), 3.51-3.43 (m, 1H), 3.41-3.33 (m, 2H), 2.28-2.18 (m, 1H), 1.78-0.70 (m, 38H).
[338] To a solution of 107-1 and 107-1A (2.5 g, crude) in acetone (20 ml) was added TSOH.H2O (0.5 g, 2.6 mmol). The mixture was stirred at 15 ° C for 3 hours. To the mixture, NaHCOa (aq.) Was added at pH = 7. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SÜ4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to generate 107-2 and 107-2A (1.2 g, 70% two-stage) as a white solid. XH RNM (107-2 and 107-2A): (400 MHz, CDCl3) δ 3.93-3.88 (m, 0.2H, 3-CHOH of 4-ethyl compound), 3.83-3.77 (m, 0.8H, 2-ethyl compound 3-CHOH), 2.46-2.34 (m, 1H), 2.10-1.97 (m, 1H), 1.95-1.13 (m, 20H), 1.06-0.70 (m, 11H).
[339] To a solution of t-BuOK (4.2 g, 38 mmol) in t-BuOH (20 mL) was added a solution of TosMic (1.8 g, 9.5 mmol) in 1,2-dimethoxyethane (20 ml) and a solution of 107-2 and 107-2A (1.2 g, 3.8 mmol) in 1,2-dimethoxyethane (20 ml). The mixture was stirred at 15 ° C for 5 hours. To the mixture, water was added and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1 to 8: 1) to generate A9 and AIO (1 g, crude) as a white solid. XH RNM (A9 and AIO): (400 MHz, CDCI3) δ 3.97-3.93 (m, 0.15H, 3-CHOH of 4-ethyl compound), 3.87-3.80 (m, 0 , 8H, 2-ethyl compound 3-CHOH), 2.28 (t, J = 9.2 Hz, 1H), 2.17-2.06 (m, 1H), 1.98-1, 90 ( m, 2H), 1.82-0.70 (m, 30H).
[340] To a solution of A9 and A10 (1 g, 3 mmol) in pyridine (10 mL) was added BzCl (1.5 g, 10.6 mmol). The mixture was stirred at 20 ° C for 16 hours. To the mixture, NaHCOa (aq.) Was added and extracted with ethyl acetate. The organic layer was concentrated in vacuo, purified by prep-HPLC and then SFC to generate 107-3 (450 mg) and 107-3A (80 mg, total two-step yield: 40%) as white solids. XH RNM (107-3): (400 MHz, CDCI3) δ 8, 07-8.00 (m, 2H), 7.59-7.52 (m, 1H), 7.50-7.42 (m , 2H), 5.15-5.10 (m, 1H), 2.27 (t, J = 9.6 Hz, 1H), 2.15-2.05 (m, 1H), 1.98- 0.85 (m, 30H), 0.82-0.73 (m, 1H). ÍH RNM (107-3A): (400 MHz, CDC13) δ 8.10-8.02 (m, 2H), 7.58-7.52 (m, 1H), 7.50-7.42 (m , 2H), 5.25-5.18 (m, 1H), 2.26 (t, J = 9.6 Hz, 1H), 2.18 - 2.05 (m, 1H), 1.98- 1.50 (m, 13H), 1.45-1.10 (m, 6H), 1.07-0.84 (m, 11H), 0.84-0.74 (m, 1H).
[341] To a solution of 107-3 (450 mg, 1 mmol) in THF (4 mL) was added MeOH (2 mL) and a solution of LiOH.H2O (0.4 g, 10 mmol) in water (2 mL). The mixture was stirred at 40 ° C for 16 hours. The mixture was then extracted with ethyl acetate. The organic layer was dried over Na2SÜ4, purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1 to 5: 1) to generate 41 (233 mg, 80%) as a white solid.
[342] 2H RNM (41): (400 MHz, CDCI3) δ 3.86-3.70 (m, 1H), 2.26 (t, J = 9.6 Hz, 1H), 2.16-2 , 03 (m, 1H), 1, 97-1, 84 (m, 2H), 1.79-1, 06 (m, 18H), 1.05-0, 88 (m, 8H), 0.83 (s, 3H), 0.77-0.67 (m, 1H).
[343] To a solution of 107-3A (80 mg, (1 mL) and a solution of LiOH.H2O (0.1 g, 2.4 mmol) in water (1 mL). The mixture was stirred at 40 ° C for 16 hours The mixture was extracted with ethyl acetate The organic layer was dried over Na2SOi, purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1 to 5: 1) to generate the compound 50 (40 mg, 80%) as a white solid XH RNM (50): (400 MHz, CDCl3) δ 3, 95-3, 90 (m, 1H), 2.26 (t, J = 9, 6 Hz, 1H), 2.16 - 2.03 (m, 1H), 1, 98-0, 85 (m, 28H), 1.82-0.70 (m, 4H) Example 29. Synthesis of Compound 42.

[344] A mixture of 008-4 (20g, 69.34 mmol) and AcOH (200 mL) was stirred at 120 ° C for 3 hours. TLC showed that the starting material was completely consumed. The solvent was removed, and the mixture was adjusted to pH = 7 with a saturated aqueous solution of Na2COa (100 ml). The mixture was treated with water and extracted with EtOAc (200mL x 2). The organic phase was washed with brine, dried over anhydrous Na2SÜ4 and then concentrated to generate the crude product. The crude product was purified by flash column chromatography on silica gel (PE: EtOAc = 5: 1) to generate 032-1 (17g, 70%) as a white solid. 1H RNM (032-1): (400 MHz, CDCla) δ 4.89-4, 88 (m, 1H), 3.88-3.87 (m, 1H), 2.48-2.41 (m , 1H), 2.13-2.03 (m, 4H), 1.96 -1.93 (m, 1H), 1.87-1.76 (m, 5H), 1, 69-1.50 (m, 5H), 1.49-1.23 (m, 6H), 1.07-1.02 (m, 1H), 0.95 (s, 3H), 0.87 (s, 3H), 0.84-0.81 (m, 1H).
[345] To a stirred solution of 032-1 (16 g, 45.6 mmol) in dry DMF (150 mL) was added imidazole (6.2 g, 91.8 mmol) and TBSC1 (13.8 g, 91 , 8 mmol) and the mixture was stirred at 50 ° C for 12 hours. The mixture was treated with water and extracted with EtOAc (200 ml x 2). The combined organic layer was washed with water (200 ml x 4). The organic layer was dried over anhydrous Na2SO4, and concentrated to generate the crude product, which was purified by flash column chromatography on silica gel (PE: EtOAc = 40: 1) to generate 032-2 (18, 6 g, 88 %) as a white solid. 2H RNM (032-2): (400 MHz, CDC13) δ 4.78-4, 77 (m, 1H), 3.79-3.78 (m, 1H), 2.46-2.41 (m , 1H), 2.10-2.05 (m, 4H), 1.96-1.93 (m, 1H), 1.83-1, 60 (m, 6H), 1.51-1.22 (m, 9H), 1.10-1.00 (m, 1H), 0.93 (s, 3H), 0.91-0.89 (m, 9H), 0.87 (s, 3H), 0.84-0.81 (m, 1H), 0.12-0.001 (m, 6H)
[346] To a stirred solution of 032-2 (18 g, 38.9 mmol) in THF (150 mL) was added LiOH.H2O (4.6 g, 194.6 mmol), MeOH (30 mL) and H2O (30 mL). The mixture was stirred at 50 ° C for 12 hours. The solvent was removed under reduced pressure and the solid separated. The solid was filtered and the cake was washed with EtOAc, dried in vacuo. A white solid 092-1 (10.8 g, 66%) was obtained. : H RNM (092-1): (400 MHz, CDCls) δ 3, 82-3, 80 (m, 1H), 3.79-3.76 (m, 1H), 2.46-2.41 ( m, 1H), 2.10-2.05 (m, 1H), 1.95-1.92 (m, 2H), 1.83-1.80 (m, 2H), 1.79-1, 64 (m, 2H), 1.54-1.51 (m, 2H), 1.41-1.20 (m, 8H) 1.11-0.98 (m, 4H), 0.95 (s, 9H ), 0.93 (s, 3H), 0, 80-0.72 (m, 1H), 0, 07-0.001 (m, 6H)
[347] To a stirred solution of t-BuOK (13.4 g, 119 mmol) in t-BuOH (80 mL) was added a solution of 092-1 (10 g, 23.8 mmol) in THF (40 mL) ) under nitrogen. A solution of Tosylmethyl isocyanide (9.3 g, 47.6 mmol) in 1,2-dimethoxyethane (40 ml) was added in drops. The mixture was stirred at room temperature for 12 hours. The mixture was then treated with dilute aqueous sodium chloride followed by hydrochloric acid (1 M) to acid. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over anhydrous Na2SOq, concentrated to generate the residue, which was purified by flash column chromatography on silica gel (PE: EtOAc = 10: 1) to generate 092 -2 (4.2 g, 41%) as a white solid. 2H RNM (092-2): (400 MHz, CDClj) δ 3, 82-3, 80 (m, 1H), 3.79-3.76 (m, 1H), 2.30-2.23 (m , 1H), 2.20-2.00 (m, 1H), 1.94-1, 88 (m, 3H), 1.80-1.61 (m, 5H), 1.52-1.23 (m, 10H), 1.15-1.04 (m, 2H), 0.99 (s, 3H), 0, 97-0, 89 (m, 12H), 0.73-0, 65 (m , 1H), 0, 07-0, 001 (m, 6H)
[348] To a stirred solution of 092-2 (2.0 g, 1.16 mmol) in ethoxyethylene (20 mL) was added Hg (AcO) 2 (2.2 g, 6.95 mmol). The mixture was stirred at 25 ° C for 12 hours. The mixture was filtered, and the filtrate was evaporated to generate a residue, which was purified by flash column chromatography in Al2Oa (PE: EtOAc - 100: 1) to generate 092-3 (672 mg, 32%) as a solid. White. XH RNM (092-3): (400 MHz, CDCI3) δ 6, 32-6, 27 (m, 1H), 4.34-4.30 (dd, Ji = 1.6, J2 = 14, 1H) , 4.05-4.03 (dd, Ji = 1.6, J2 = 6.8, 1H), 3.94-3.93 (m, 1H), 3, 78-3.77 (m, 1H ), 2.27-2.251 (m, 1H), 2.18-2.10 (m, 1H), 2.07-1.93 (m, 1H), 1.90-1.65 (m, 5H ), 1.43-1.20 (m, 10), 1.18-1.10 (m, 1H), 1.00 (s, 3H), 0.99-0.93 (m, 1H), 0.92-0.91 (m, 12H), 0, 80-0.70 (m, 1H), 0.07-0.01 (m, 6H).
[349] To a stirred solution of 092-3 (600 mg, 1.31 mmol) in dry toluene (6 mL) was added diethylzinc (3.93 mL, 3.93 mmol) at -40 ° C under nitrogen. After 1 hour, chloroiodomethane (461 mg, 2.62 mmol) was added in drops. The reaction mixture was stirred at -40 ° C for 2 hours, then warmed to room temperature and stirred for 12 hours. The mixture was quenched with a saturated aqueous solution of NH4 Cl (20 mL). The mixture was treated with water and extracted with EtOAc (20 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SÜ4, evaporated to dryness and purified by flash column chromatography on silica gel (PE: EtOAc = 200: 1) to generate 092-4 (252 mg, 41%) as a white solid. XH RNM (092-4): (400 MHz, CDCI3) δ 3, 94-3, 93 (m, 1H), 3.44 -3.43 (m, 1H), 3.29-3.27 (m , 1H), 2.24-2.22 (m, 1H), 2.18-2.04 (m, 1H), 1.92-1.89 (m, 2H), 1.75-1, 60 (m, 6H), 1.52-1.15 (m, 9), 1.14-1.03 (m, 2H), 1.00-0, 98 (m, 5H), 0.92-0 , 91 (m, 12H), 0.77-0, 68 (m, 1H), 0.60-0.45 (m, 4H), 0.02-0.01 (m, 6H).
[350] To a stirred solution of 092-4 (252 mg, 0.36 mmol) in dry CH2 Cl2 (3 mL) was added trifluoroacetic acid (0.27 mL, 3.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then quenched with a saturated aqueous NaHCO3 solution (15 mL). The mixture was treated with water and extracted with CH2 Cl2 (30 ml x 2). The combined organic layer was washed with brine, dried over anhydrous NaΩSCg and evaporated to dryness, and purified by flash column chromatography on silica gel (PE: EtOAc 8: 1) to generate 42 (38 mg, as a white solid. 2H RNM (42): (400 MHz CDCI3) δ 4.03-4.02 (m 1H) 3, 57 -3.56 (m 1H), 3.32-3.29 1H) 2.28-2.25 (m 1H) 2.20-2.04 (m 1H), 1.93-1.61 2H) 1.73-1.60 (m 5H), 1.52-1.25 (m 10H), 1 , 20-1.02 1H) 0.99 (s, 3H), 0.98-0, 92 (m, 1H) 0.90 3H) 0.87-0.80 (m, 5H), 0.60 -0.47 (m, 4H). Example 30. Synthesis of Compound 43.

[351] To a CN suspension of NaH (220 mg, 5.55 mmol) in THF (5 mL) a solution of 092-2 (800 mg, 1.85 mmol) in THF (5 mL) was added dropwise. . The resulting mixture was heated to reflux for 1 hour, then cooled to room temperature, and CS2 (560 mg, 7.4 mmol) was added slowly to the reaction mixture. The resulting mixture was stirred for 30 min. Honey (1.31 g, 9.25 mmol) was added in drops. The reaction mixture was stirred overnight at room temperature. Ice water was added at 0 ° C and the mixture was treated with aqueous hydrochloric acid (1M, 5 ml). The mixture was extracted with EtOAc and the combined organic phase was washed with saturated NaHCOa solution, then with brine, dried over anhydrous Na2SÜ4 and concentrated under reduced pressure. The residue was purified by flash chromatography (PE: EtOAc = 150: 1) to generate 096-1 (450 mg, 46%) as a white solid. 1H RNM (096-1): (400 MHz, CDCla) δ 5.10-5.05 (m, 1H), 4.03- 4.01 (m, 1H), 2.58 (s, 3H), 2.30-2.25 (m, 1H), 2.20-2.11 (m, 1H), 2.00-1.91 (m, 4H), 1.84-1, 62 (m, 6H ), 1.53-1.20 (m, 12H), 1.19-1.10 (m, 2H), 1.04 (s, 3H), 1.03-0, 90 (m, 14H), 0.78-0, 72 (m, 1H), 0.98 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H)
[352] To a stirred solution of 1,3-dibromo-5,5-dimethylhydantoin (245 mg, 0.86 mmol) in CHaCla (2 ml) was added pyridine (1.5 ml) and HF / pyridine (1, 5mL) in drops at -78 ° C. The mixture was stirred at room temperature for 10 min and cooled to 0 ° C. A solution of 096-1 (450 mg, 0.86 mmol) in CHaCla (2 mL) was added in drops. The resulting mixture was stirred for 1 hour at 0 ° C. The mixture was quenched by a saturated aqueous solution of NaHCOa (20 ml). The mixture was extracted with CH2 Cl2 (20 ml x 2) and the organic layer was washed with aqueous hydrochloric acid (0.5 M, 10 ml) then with brine. The combined organic layer was dried over anhydrous Na2SÜ4 and evaporated to dryness, and purified by flash column chromatography on silica gel (PE: EtOAc = 20: 1) to generate 096-2 (120 mg, 28%) as a colorless oil . 1H RNM (096-2): (400 MHz, CDC13) δ 4.13-4.11 (m, 1H), 3.95-3.94 (m, 1H), 2.26-2.23 (m , 1H), 2.11 - 2.08 (m, 1H), 2.00-1.58 (m, 9H), 1.55-1.01 (m, 16H), 0.98 (s, 3H ), 0.92-0, 80 (m, 13H), 0.78-0.70 (m, 2H), 0.10-0.02 (m, 6H).
[353] To a stirred solution of 096-2 (120 mg, 0.24 mmol) in dry CH2 Cl2 (3 mL) was added trifluoroacetic acid (0.09 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched with a saturated aqueous solution of NaHCCb (10 ml). The mixture was then treated with water and extracted with CH2 Cl2 (10 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SCç and evaporated to dryness and purified by flash column chromatography on silical gel (PE: EtOAc = 20: 1) to generate 43 (31 mg, 32%) as a solid White. XH RNM (43) :( 400 MHz, CDCI3) δ 4.31 - 4.30 (m, 1H), 4. 07-4.03 (m, 1H), 2.29-2.24 (m, 1H ), 1.96-1.92 (m, 1H), 1.80-1.57 (m, 5H), 1.50-1.25 (m, 8H), 1.20-1.10 (m , 1H), 1.01 (s, 3H), 0.99-0, 92 (m, 1H), 0.91 (s, 3H), 0.76-0.72 (m, 1H). Example 31. Synthesis of Compound 44.


[354] To a mixture of t-BuOK (15.45 g, 138 mmol) in t-BuOH (50 mL) was added a solution of 008-1 (4 g, 14 mmol) in 1,2-dimethoxyethane (20 mL) under ft. Then a solution of TosMic (5.38 g, 28 mmol) in 1,2-dimethoxyethane (30 ml) was added. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was diluted with CH2 Cl2 (50 ml), H2O (50 ml), and extracted with CH2 Cl2 (50 ml). The combined organic layers were washed with aqueous NH4Cl (50 ml), dried over NacSO4, and concentrated to generate the crude product, which was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 20: 1) to generate the product 108-1 (1.52 g, 36.63% yield). 2H RNM (108-1 crude): (400 MHz, CDCI3) δ 4.72-4, 62 (m, 1H), 2.30-2.22 (m, 1H), 2.18-2.03 ( m, 1H), 1.98-1.58 (m, 8H), 1.41-1.10 (m, 8H), 1.06-0.79 (m, 8H), 0, 70-0, 62 (m, 1H).
[355] To a solution of 108-1 (2.3 g, 7.64 mmol) in pyridine (15 mL) was added TsCl (1.7 g, 9.17 mmol). The reaction mixture was heated to 50 ° C and stirred for 6 h. TLC showed that the reaction was complete. The reaction mixture was concentrated to remove pyridine. The residue was diluted with H2O (20 ml), extracted with EtOAc (30 ml x2). The combined organic layers were washed with IN HCl (20 ml x 2), dried over NacSOo and concentrated to generate crude product 108-2 (3.5 g) as a yellow oil. XH RNM (108-2 crude): (400 MHz, CDC13) δ 7.80-7.77 (d, 2H), 7.33- 7.30 (d, 2H), 4.45-4.35 ( m, 1H), 2.45 (s, 3H), 2.28-2.21 (m, 1H), 2.18-2.03 (m, 1H), 1.98-1.85 (m, 2H), 1.80-1.50 (m, 11H), 1.40-0.75 (m, 18H), 0.63-0.57 (m, 1H).
[356] A solution of 108-2 (3.5 g, 7.68 mmol) in collidine (10 mL) was heated to 140 ° C and stirred for 5 h. TLC showed that the reaction was complete. After cooling, the reaction mixture was poured into 2N HCl, then extracted with EtOAc (30 ml x2). The combined organic layers were washed with IN HCl (20 ml x2) and dried over Na2SO4, then concentrated to generate crude product 108-3 (2.1 g) as a yellow oil.
[357] To a solution of OsÜ4 (50 mg, 1.64 mmol) and NMO (1.8 g, 15, 876 mmol) in t-BuOH (20 mL), THF (20 mL) and H2O (2 mL) a solution of 108-3 (1.5 g, 5.292 mmol) in THF (5 mL) was added. The solution was stirred at room temperature for 3 h. After TLC showed that the starting material was completely consumed, the mixture was quenched with aqueous NaHS and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with aqueous Na2SOa, dried over Na2SO4 and concentrated to generate the crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: EtOAc = 3: 1) to generate 108-4 ( 1.1 g, 65.4%) as a white solid. XH RNM (108-4 crude): (400 MHz, CDCI3) δ 3.98-3.93 (m, 1H), 3.81-3.75 (m, 1H), 2.30-2.23 ( m, 1H), 2.15-1.50 (m, 14H), 1.49-0.78 (m, 18H).
[358] To a mixture of 108-4 (800 mg, 2.524 mmol) in toluene (15 ml) were added Novozym 435 (2 g) and vinyl ester acetic acid (5 ml). The reaction mixture was heated to 50 ° C and stirred for 3 days. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 5: 1) to generate product 108-5 (330 mg, 36.4% yield). 1H RNM (crude 108-5): (400 MHz, CDCI3) δ 5.13 (m, 1H), 3.88-3.81 (m, 1H), 2.30-2.22 (m, 1H) , 2.18-2.05 (m, 4H), 1.98-1.52 (m, 12H), 1.43-1.10 (m, 9H), 1.03-0.78 (m, 10H).
[359] To a solution of 108-5 (250 mg, 0.695 mmol) in THF (5 mL) was added NaH (278 mg, 6.95 mmol). The reaction mixture was stirred for 10 minutes. Then Honey (987 mg, 6.95 mmol) was added. The reaction mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched with aqueous NH4Cl (10 ml) and extracted with EtOAc (30 ml x2). The combined organic layers were washed with aqueous NaCl (20 ml) and dried over Na2SÜ4, then concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 10: 1) to generate crude product 108-6 (80 mg, 30.8% yield).
[360] To a solution of 108-6 (80 mg, 0.214 mmol) in MeOH (2 mL) and THF (2 mL) was added a solution of NaOH (26 mg, 0.642 mmol) in H2O (1 mL). The reaction mixture was stirred at room temperature for 16 h. TLC showed that the reaction was complete. The reaction mixture was diluted with EtOAc (10 ml) and aqueous NH 4 Cl (10 ml), and extracted with EtOAc (10 ml). The combined organic layers were washed with H2O (10 ml), dried over Na2SO4, and concentrated to generate the crude product. The crude product was purified by column chromatography on silica gel (Petroleum ether: EtOAc = 8: 1) to generate purified product 44 (17 mg, (m, 9H), 1.07-0.90 (m, 5H ), 0.87-0.80 (m, 4H) Example 32. Synthesis of Compounds 45 and 46. Synthesis of Intermediates 106-7 and 106-7th
Synthesis of compounds 45 and 46


[361] To a solution of 001-6 (10 g, 30 mmol) in toluene (200 mL) was added Me2C (CH2OH) 2 (9.4 g, 90 mmol), HC (OEt) to (13.3 g , 90 mmol) and TsOH.OH (280 mg, 1.5 mmol). The mixture was stirred at 40 ° C for 3 hours. To the mixture was then added MeOH (100 ml) and a solution of LiOH.HgO (8 g, 200 mmol) in water (100 ml). The mixture was stirred for an additional 4 hours at 20 ° C. The mixture was extracted with ethyl acetate. The combined organic layer was separated, dried over Na2SÜ4, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to generate 106-1 (9 g, 70%) as a colorless oil.
[362] 1H RNM (106-1): (400 MHz, CDC13) δ 4.45-4.35 (m, 1H), 3.75-3.20 (m, 5H), 2.20-2, 10 (m, 1H), 1.90-0, 80 (m, 30H), 0.70 (s, 3H).
[363] To a solution of 106-1 (9 g, 23 mmol) in DMF (30 mL) was added imidazole (3.1 g, 46 mmol) and TBSC1 (5.1 g, 34 mmol). The mixture was stirred at 20 ° C for 5 hours. To the mixture, water was then added and extracted with ethyl acetate. The organic layer was washed with water, dried over NajSCg, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 100: 1 to 25: 1) to generate 106-2 (9 g, 80%) like a white solid. XH RNM (106-2): (400 MHz, CDCI3) δ 4.46-4.38 (m, 1H), 4.02-3, 95 (m, 1H), 3, 68-3, 62 (m , 1H), 3.48-3.42 (m, 1H), 3.40-3.30 (m, 2H), 2.25-2.15 (m, 1H), 2.08-2.00 (m, 1H), 1.90-0, 95 (m, 27H), 0.92-0, 85 (m, 10H), 0.73 (s, 3H), 0.08-0.00 (m, 6H ).
[364] To a suspension of NaH (4 g, 60%, 100 mmol) in DMF (60 mL) was added a solution of 106-2 (9 g, 16 mmol) in DMF (40 mL) and tetrahydrofuran (10 mL) ). The mixture was stirred at 20 ° C for 30 minutes. Honey (20 ml) was then added and the mixture was stirred at 40 ° C for 5 hours. The mixture was poured into NFLC1 (aq), extracted with petroleum ether and ethyl acetate (1: 1). The organic layer was separated, washed with water, dried over Na2SÜ4 and concentrated in vacuo to generate 106-3 (10.6 g, crude product) as a white solid. XH RNM (106-3): (400 MHz, CDCla) δ 4.00-3.95 (m, 1H), 3.78-3.72 (m, 1H), 3.70-3, 65 (m , 1H), 3.50-3.35 (m, 3H), 3.25-3.20 (m, 3H), 2.25-2.15 (m, 1H), 1.80-0.80 (m, 37H), 0.75-0.70 (m, 4H).
[365] To a solution of 106-3 (10 g, 19 mmol) in tetrahydrofuran (20 ml) was added TBAF (30mL, 1M in tetrahydrofuran). The mixture was stirred at 60 ° C for 3 days. Then The mixture was concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 15: 1 to 10: 1) to generate 106-4 (6.1 g, 75% 2 steps) as a solid White. XH RNM (106-4): (400 MHz, CDCl3) δ 4.10-3.30 (m, 6H), 3.22 (s, 3H), 2.23-2.15 (m, 1H), 1.98-1.92 (m, 1H), 1.85-0, 80 (m, 28H), 0.70 (s, 3H).
[366] To a solution of 106-4 (5.1 g, 12.5 mmol) in CH2 Cl2 (50 mL) was added Dess-Matin reagent (15 g, 35 mmol). The mixture was stirred at 20 ° C for 2 hours. To the mixture was added NaHCO3 / Na2S2Oj (aq.). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1 to 25: 1) to generate 106-5 (4.5 g, 75%) like a white solid. XH RNM (106-5): (400 MHz, CDCla) δ 3.75-3, 60 (m, 2H), 3.50-3.33 (m, 3H), 3.25 (s, 3H), 2.50-2.40 (m, 1H), 2.35-2.20 (m, 3H), 2.08-1.95 (m, 3H), 1.90-1.25 (m, 11H ), 1.20 (s, 3H), 1.15 (s, 3H), 0.98 (s, 3H), 0.95-0.78 (m, 23H), 0.71 (s, 3H) .
[367] To a suspension of 106-5 (3.5 g, 8.6 mmol) in toluene (35 mL) was added NaH (1.03 g, 60%, 26 mmol) and HCOOEt (1.28 g, 17.3 mmol). The mixture was stirred at 20 ° C for 16 hours. To the mixture, NH4CI (aq) was then added and the mixture extracted with ethyl acetate. The combined organic layer was dried over Na2SÜ4, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1) to generate 106-6 (3.5 g, 95%) as a white solid. XH RNM (106-6): (400 MHz, CDCI3) δ 14.37 (brs, 1H), 8.66 (s, 1H), 3, 78-3, 70 (m, 1H), 3.70-3, 60 (m, 3H), 3.26 (m, 3H), 2.40-0, 78 (m, 27H), 0.71 (s, 3H).
[368] To a solution of 106-6 (4.5 g, 10 mmol) in methanol (50 ml) was added Pd / C (2 g). The mixture was then stirred at 30 ° C for 3 days under hydrogen (30 psi = 206.84 KPa). The mixture was then filtered, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 80: 1 to 40: 1) to generate 106-7 (0.7 g, 20%) and compound 106- 7A (0.8 g, 22%) and 0.4 g of a mixture. XH RNM (106-7): (400 MHz, CDCI3) δ 3.78-3.72 (m, 1H), 3.70-3.63 (m, 1H), 3.48-3.44 (m , 1H), 3.40-3.33 (m, 2H), 3.26 (s, 3H), 2.55-2.50 (m, 1H), 2.35-2.28 (m, 1H ), 2.25-2.24 (m, 1H), 2.08-1.95 (m, 3H), 1.90-0.75 (m, 25H), 0.71 (s, 3H). : H RNM (106-7A): (400 MHz, CDCI3) δ 3.78-3.72 (m, 1H), 3.70-3.63 (m, 1H), 3, 48-3, 44 ( m, 1H), 3.40-3.33 (m, 2H), 3.23 (s, 3H), 2.60-2.55 (m, 1H), 2.25-2.15 (m, 3H), 2.05-1.95 (m, 2H), 1.85-0, 80 (m, 25H), 0.71 (s, 3H).
[369] To a solution of 106-7 (0.7 g, 1.9 mmol) in tetrahydrofuran (12 mL) was added K-selectride (4 mL, IM in tetrahydrofuran, 4 mmol) in drops at -78 ° C . The mixture was stirred at -78 ° C for 5 hours and H2O2 (2 mL, 30% in water) was then added in drops at -78 ° C. The mixture was then heated to 10 ° C and Na2S2θ3 (aq.) Was added. The mixture was extracted with ethyl acetate. The combined organic layer was dried over Na2SÜ4, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 40: 1) to generate 106-8 (600 mg, 85%) as a white solid. 1H RNM (106-8): (400 MHz, CDClj) δ 3, 80-3.70 (m, 2H), 3, 68-3, 60 (m, 1H), 3.48-3.44 (m , 1H), 3.40-3.33 (m, 2H), 3.23 (s, 3H), 2.20-2.15 (m, 1H), 1.98-1, 90 (m, 1H ), 1.72-1.50 (m, 6H), 1.45-1.05 (m, 12H), 1.00-0, 80 (m, 12H), 0.71 (s, 3H).
[370] To a solution of 106-8 (0.66 g, 1.4 mmol) in acetone (5 mL) was added TSOH.H2O (0.1 g, 0.3 mmol). The mixture was stirred at 25 ° C for 1 hour. To the mixture was added NaHCO3 (aq.), Extracted with ethyl acetate. The organic layer was separated, combined and purified by column chromatography (petroleum ether: ethyl acetate = 12: 1 to 8: 1) to generate 106-9 (0.5 g, 100%) as a white solid. XH RNM (106-9): (400 MHz, CDClj) δ 3, 82-3.72 (m, 2H), 3.23 (s, 3H), 2.52-2.42 (m, 1H), 2.30-2.25 (m, 1H), 2.08-1.70 (m, 5H), 1.60-1.10 (m, 9H), 1.05-0.75 (m, 13H ).
[371] To a solution of t-BuOK (0.5 g, 4.5 mmol) in t-BuOH (4 mL) was added DME (4 mL), TosMic (0.21 g, 1.07 mmol) and then 106-9 (0.15 g, 0.45 mmol). The mixture was stirred at 25 ° C for 16 hours. To the mixture, NH4CI (aq.) Was added and extracted with ethyl acetate. The combined organic layers were separated, dried over Na2SÜ4, concentrated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 8: 1) to generate 45 (67 mg, 45%) and 46 ( 23 mg, 15%) as white solids. XH RNM (45): (400 MHz, CDCl3) δ 3, 82-3.74 (m, 1H), 3, 73-3, 68 (m, 1H), 3.25 (s, 3H), 2, 44-2.35 (m, 1H), 2.25-2.28 (m, 1H), 2.10-2.00 (m, 1H), 1.98-1, 88 (m, 1H), 1.85 - 1.60 (m, 4H), 1.56-1.50 (m, 1H), 1.48-1.06 (m, 11H), 1.00 - 0.90 (m, 9H ), 0.78-0.75 (m, 1H). XH RNM (46): (400 MHz, CDCI3) δ 3, 82-3.74 (m, 2H), 3.24 (s, 3H), 2.55-2.48 (m, 1H), 2, 25-2.15 (m, 2H), 2.00-1.70 (m, 5H), 1.60-1.10 (m, 11H). Example 33. Synthesis of Compounds 51 and 52.

[372] To a solution of 31 (1.2 g, 3.6 mmol) in pyridine (6 mL) was added TsCl (1.4 g, 7.2 mmol). The mixture was then stirred at 50 ° C for 2 hours. The mixture was then poured into water and filtered. The solid was washed with water, dissolved in CH2Cl2, dried over Na2SÜ4, concentrated in vacuo to generate 150-1 (1.4 g, 80%) as an off-white solid. XH RNM (150-1): (400 MHz, CDCI3) δ 7.80-7.75 (m, 2H), 7.35-7.28 (m, 2H), 4.45-4, 68 (m , 1H), 3.65-3.60 (m, 1H), 3.25-3.15 (m, 3H), 2.44 (s, 3H), 2.42-2.35 (m, 1H ), 2.25-2.15 (m, 1H), 2.15-0.75 (m, 25H).
[373] A solution of 150-1 (1.4 g, 2.9 mmol) in collidine (6 mL) was stirred at 180 ° C for 1 h. The mixture was then poured into H2SO4 (aq.). The mixture was extracted with CH2 Cl2. The organic layer was dried over Na2SÜ4, concentrated in vacuo to generate 150-2 and 150-2A (1 g, crude) as a light yellow oil. XH RNM (150-2 and 150-2A): (400 MHz, CDCI3) δ 5.65-5.58 (m, 1.75H, alkene-2,3-CH), 5.30-5, 24 ( m, 0.25H, alkene-4-CH), 3.75-3, 66 (m, 1H), 3.30-3.20 (m, 3H), 2.45-2.38 (m, 1H ), 2.27-2.18 (m, 1H), 2.15-1.65 (m, 8H), 1.45-0.65 (m, 15H).
[374] To a solution of 150-2 (1 g, 3.2 mmol) in CH2 Cl2 (5 mL) was added m-CPBA (1 g, 1.8 mmol). The mixture was then stirred at 25 ° C for 1 hour. To the mixture was added NaHCθ3 / Na2S2θ3 (aq.). The organic layer was dried over Na2SÜ4, purified by column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to generate 150-3 and 150-3A (0.65 g, 60% 2 steps ) as a white solid. XH RNM (150-3 and 150-3A): (400 MHz, CDCI3) δ 3, 67-3, 60 (m, 1H), 3.28-3.12 (m, 5H), 2.45-2 , 35 (m, 1H), 2.25-2.17 (m, 1H), 2.14-1.17 (m, 12H), 1.07-0.6 (m, 11H).
[375] To a suspension of CuCN (667 mg, 7.5 mmol) in THF (20 mL) was added MeLi (15 mL, IM in 2-Me-THF, 15 mmol) at -78 ° C in drops. The mixture was heated to 0 ° C and then cooled to -78 ° C. A solution of BFj.Et2O (426 mg, 3 mmol) in THF (5 mL) was added in drops and then stirred at -78 ° C for 30 minutes. A solution of 150-3 and 150-3A (500 mg, 1.5 mmol) in THF (5 mL) was then added in drops and stirred at -78 ° C for an additional 1 hour. To the mixture was then added a mixture of MeOH (6 ml) and EtsN (6 ml). The mixture was then heated to 10 ° C. To the mixture, NH4CI (aq.) And ethyl acetate were added. The mixture was then filtered. The organic layer was separated, dried over Na ^ SCL, concentrated in vacuo, purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to generate 51 and 52 (420 mg, 82%, including a mixture of 4-methyl) as a white solid. XH RNM (51 and 52): (400 MHz, CDCI3) δ 3.78-3, 66 (m, 2H), 3.27-3.20 (m, 3H), 2.42-2.35 (m , 1H), 2.24-2.16 (m, 1H), 2.14-2.02 (m, 1H), 1.97-1.63 (m, 6H), 1.55-0.70 (m, 21H).

[376] To a solution of 51 and 52 (550 mg, 1.6 mmol) in pyridine (6 mL) was added BzCI (500 mg, 3.5 mmol). The mixture was then stirred at 25 ° C for 16 hours. To the mixture was then added NaHCCCç (aq.), Extracted with ethyl acetate. The organic layer was concentrated in vacuo, purified by column chromatography (petroleum ether: ethyl acetate = 15: 1) and then SFC to generate 150-4 (430 mg) and 150-4A (170 mg, total yield: 85 %) as a white solid. XH RNM (150-4): (400 MHz, CDCI3) δ 8, 06-8.02 (m, 2H), 7.59-7.50 (m, 1H), 7.48-7.41 (m , 2H), 5, 05-5, 00 (m, 1H), 3.74-3, 67 (m, 1H), 3.27 (s, 3H), 2.45-2.36 (m, 1H ), 2.25-1.73 (m, 7H), 1.68-1.13 (m, 12H), 1.12- 0.74 (m, 9H). XH RNM (150-4A): (400 MHz, CDCI3) δ 8.07-8.00 (m, 2H), 7, 60-7.52 (m, 1H), 7.50-7.41 (m , 2H), 5.09-5.05 (m, 1H), 3.75-3, 67 (m, 1H), 3.24 (s, 3H), 2.44-2.35 (m, 1H ), 2.25-2.18 (m, 7H), 2.13-0.73 (m, 27H).

[377] To a solution of 150-4 (430 mg, 0.96 mmol) in THF (1 mL) and a solution of LiOH.H2O (0.2 g, 4.7 mmol) in water (1 mL). The mixture was stirred at 50 ° C for 16 hours. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SOt, purified by column chromatography (petroleum ether: ethyl acetate = 8: 1 to 5: 1) to generate 51 (236 mg, 70%) as an off-white solid. The absolute configuration was confirmed by 2D-RNM. 1H RNM (51): (400 MHz, CDCl3) δ 3.80-3.76 (m, 1H), 3.74-3.67 (m, 1H), 3.27 (s, 3H), 2, 44-2.35 (m, 1H), 2.26-2.17 (m, 1H), 2.15-2.04 (m, 1H), 1.99-1.88 (m, 2H), 1.75-1.50 (m, 7H), 1.46-1.15 (m, 5H), 1.10-1.05 (m, 6H), 1.04-0.88 (m, 6H ), 0.80-0.74 (m, 1H).

[378] To a solution of 150-4A (170 mg, 0.38 mmol) in THF (2 mL) was added MeOH (1 mL) and a solution of LiOH.H2O (0.2 g, 4.7 mmol) in water (1 mL). The mixture was stirred at 50 ° C for 16 hours. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, purified by column chromatography (petroleum ether: ethyl acetate = 8: 1 to 5: 1) to generate 52 (79 mg, 61)% as an off-white solid. The absolute configuration was confirmed by 2D-RNM. 2H RNM (52): (400 MHz, CDCla) δ 3, 82-3.78 (m, 1H), 3, 75-3.65 (m, 1H), 3.22 (s, 3H), 2, 40-2.33 (m, 1H), 2.24-2.15 (m, 1H), 2.12-2.02 (m, 1H), 1.97-1.30 (m, 13H), 1.13-1.02 (m, 7H), 1.00-0, 82 (m, 6H), 0.78-0.70 (m, 1H). Example 34. Synthesis of Compounds 53 and 54. Synthesis of Compound 54Synthesis of Intermediates 151-5 and 151-5ª
Synthesis of compound 53
Synthesis of compound 54

[379] To a solution of 27 (2 g, 6.3 mmol) in pyridine (8 mL) was added TsCl (1.8 g, 9.5 mmol). The mixture was then stirred at 25 ° C for 16 hours. To the mixture was added NaHCCg (aq.), Extracted with ethyl acetate. The organic layer was dried over NazSCt, concentrated in vacuo to generate 151-1 (3.5 g, crude) as a brown solid. XH RNM (151-1): (400 MHz, CDC13) δ 7, 80- 7.75 (m, 2H), 7.35-7.28 (m, 2H), 4.85-4, 65 (m , 1H), 4.45-4.32 (m, 1H), 3.25-3.15 (m, 3H), 2.44 (s, 3H), 2.25-0, 80 (m, 28H ).
[380] A solution of 151-1 (3.5 g, 6.3 mmol) in collidine (10 mL) was stirred at 180 ° C for 1 hour. To the mixture was added HCl (aq.) Extracted with ethyl acetate. The organic layer was dried over Na2 SCu, concentrated in vacuo to generate 151-2 and 151-2A (2 g, 100% two-stage) as a light yellow solid. XH RNM (151-2 and 151-2A): (400 MHz, CDCI3) δ 5, 65-5, 57 (m, 2H), 4.50-4.35 (m, 1H), 2.25-2 , 17 (m, 1H), 2.15-0.66 (m, 25H).
[381] To a solution of 151-2 and 151-2A (2 g, 6.7 mmol) in CH2 Cl2 (15 mL) was added m-CPBA (1.8 g, 10.5 mmol). The mixture was then stirred at 25 ° C for 1 hour. To the mixture was added NaHCθ3 / Na2S2θ3 (aq.). The organic layer was dried over Na2SCL, purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to generate 151-3 and 151-3A (1.5 g, 75%) as a white solid. XH RNM (151-3 and 151-3A): (400 MHz, CDC13) δ 4.46-4.30 (m, 1H), 3.24-3.12 (m, 2H), 2.25-0 , 60 (m, 26H).
[382] To a suspension of CuCN (2.1 g, 23.5 mmol) in THF (30 mL) was added MeLi (47 mL, 1M in 2-Me-THF, 47 mmol) at -78 ° C in drops . The mixture was heated to 0 ° C and then cooled to -78 ° C. A solution of BF3.Et2O (1.33 g, 9.4 mmol) in THF (10 mL) was added in drops and then stirred at -78 ° C for 30 minutes. A solution of 151-3 and 151-3A (1.5 g, 4.7 mmol) in THF (10 mL) was then added in drops and stirred at -78 ° C for an additional 1 hour. To the mixture was then added a mixture of MeOH (10 ml) and EtsN (10 ml). The mixture was then heated to 10 ° C. To the mixture, NH4CI (aq.) And ethyl acetate were added. The mixture was then filtered. The organic layer was separated, dried over Na2SÜ4, concentrated in vacuo, purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to generate 151-4 and 151-4A (560 mg, 33 %) as a white solid. XH RNM (151-4 and 151-4A): (400 MHz, CDCI3) δ 4.45-4.35 (m, 1H), 3.86-3.75 (m, 1H), 2.25-2 , 15 (m, 1H), 2.15-0.70 (m, 30H).
[383] To a solution of 151-4 and 151-4A (0.56 g, 1.6 mmol) in pyridine (5 mL) was added BzCl (0.5 g, 3.5 mmol). The mixture was then stirred at 30 ° C for 16 hours. To the mixture was then added NaHCOs (aq.), Extracted with ethyl acetate. The organic layer was concentrated in vacuo, purified by column chromatography (petroleum ether: ethyl acetate = 15: 1 to 5: 1) and then SFC to generate 151-5 (310 mg) and 151-5A (170 mg, total yield: 69%) as a white solid. The absolute configuration of the two compounds was confirmed by 2D-RNM. 1H RNM (151-5): (400 MHz, CDClj) δ 8, 06-8, 02 (m, 2H), 7.59-7.50 (m, 1H), 7.48-7.41 (m , 2H), 5, 05-5.00 (m, 1H), 4.45-4.38 (m, 1H), 2.25-0.74 (m, 30H). ÍH RNM (151-5A): (400 MHz, CDC13) δ 8, 06-8.02 (m, 2H), 7.59-7.50 (m, 1H), 7.48-7.41 (m , 2H), 5, 09-5, 05 (m, 1H), 4.45-4.38 (m, 1H), 2.25-0, 74 (m, 30H).
[384] To a solution of 151-5 (20 mg, 0.46 mmol) in CH2 Cl2 (5 mL) was added PCC (300 mg, 1.4 mmol). The mixture was stirred at 30 ° C for 1 hour. To the mixture, MgSCg was added, and filtered. The filtrate was concentrated in vacuo, purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to generate 151-6 (170 mg, 85%) as an off-white solid. XH RNM (151-6): (400 MHz, CDCI3) δ 8, 06-8.02 (m, 2H), 7.59-7.50 (m, 1H), 7.48-7.41 (m , 2H), 5.03-4.95 (m, 1H), 2.55-2.45 (m, 2H), 2.30-1.65 (m, 11H), 1.60-1.40 (m, 4H), 1.35-1.10 (m, 9H), 0.89 (s, 3H).
[385] To a solution of 151-6 (200 mg, 0.46 mmol) in THF (4 mL) was added MeOH (2 mL) and a solution of LiOH.H2O (150 mg, 3.6 mmol) in water (1 mL). The mixture was stirred at 50 ° C for 16 hours. The mixture was extracted with ethyl acetate. The organic layer was dried over Na2SÜ4, purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to generate 53 (112 mg, 74%) as an off-white solid. XH RNM (53): (400 MHz, CDCI3) δ 3.80-3.70 (m, 1H), 2.57-2.45 (m, 2H), 2.32-2.20 (m, 2H ), 2.15-1.55 (m, 10H), 1.45-1.12 (m, 7H), 1.10-1.03 (m, 6H), 0.89 (s, 3H).
[386] To a solution of 151-5 (80 mg, 0.18 mmol) in THF (2 mL) was added MeOH (2 mL) and a solution of LiOH.H2O (70 mg, 1.6 mmol) in water (0.5 mL). The mixture was stirred at 50 ° C for 16 hours. The mixture was extracted with ethyl acetate. The organic layer was dried over NasSCg, purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to generate 54 (39 mg, 63%) as an off-white solid. 1H RNM (54): (400 MHz, CDCI3) δ 4.42-4.37 (m, 1H), 3, 82-3.75 (m, 1H), 2.25-2.17 (m, 1H ), 2.15-2.05 (m, 2H), 2.00-1, 88 (m, 2H), 1.85-1.50 (m, 10H), 1.45-1.18 (m , 6H), 1.15 (s, 3H), 1.10-0.90 (m, 8H), 0.82-0.74 (m, 1H). Example 35. Synthesis of Compounds 55 and 56.

[387] To a solution of 151-5A (120 mg, 0.28 mmol) in CH2 Cl2 (4 mL) was added PCC (180 mg, 0.84 mmol). The mixture was stirred at 30 ° C for 1 hour. To the mixture, MgSCg was added, and filtered. The filtrate was concentrated in vacuo, purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to generate 151-6A (110 mg, 90%) as an off-white solid. XH RNM (151-6A): (400 MHz, CDCI3) δ 8, 06-8.02 (m, 2H), 7.59-7.50 (m, 1H), 7.48-7.41 (m , 2H), 5.05-5.00 (m, 1H), 2.55-2.45 (m, 3H), 2.30-2.20 (m, 2H), 2.05-1.85 (m, 5H), 1, 80-1, 60 (m, 4H), 1.50-1.10 (m, 8H), 1.03 (d, J = 7.6Hz, 3H), 0, 90- 0.76 (m, 4H).
[388] To a solution of 151-6A (110 mg, 0.25 mmol) in THF (4 mL) was added MeOH (2 mL) and a solution of LiOH.H2O (150 mg, 3.6 mmol) in water (1 mL). The mixture was stirred at 50 ° C for 16 hours. The mixture was extracted with ethyl acetate. The organic layer was dried over NaΩSCt, purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to generate 55 (21 mg, 26%) as an off-white solid. 1H RNM (55): (400 MHz, CDCla) δ 3, 85-3.74 (m, 1H), 2.55-2.45 (m, 2H), 2.35-2.20 (m, 3H ), 2.10-1.85 (m, 4H), 1.78-1, 60 (m, 4H), 1.50-1.37 (m, 4H), 1.33-1.15 (m , 4H), 1.09 (s, 1H), 0.94 (d, J = 7.6 Hz, 3H), 0.89 (s, 3H).

[389] To a solution of 151-5A (50 mg, 0.11 mmol) in THF (2 mL) was added MeOH (2 mL) and a solution of LiOH.HaO (70 mg, 1.6 mmol) in water (0.5 mL). The mixture was stirred at 50 ° C for 16 hours. The mixture was extracted with ethyl acetate. The organic layer was dried over NaaSOj, purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to generate 56 (11 mg, 27%) as an off-white solid. V RNM (56): (400 MHz, CDCla) δ 4.45-4.36 (m, 1H), 3, 85-3.78 (m, 1H), 2.25-2.16 (m, 1H ), 2.14-1.70 (m, 8H), 1.50-1.25 (m, 7H), 1.20-1.10 (m, 7H), 1.00-0.75 (m , 8H). Example 36. Synthesis of Compound 57.


[390] To a stirred solution of t-BuOK (4.54 g, 40.5 mmol) in t-BuOH (30 mL) was added (3.4 g, 8.1 mmol) in THF (15 Tosylmethyl solution isocyanide (3.16 g, 16.2 mmol) in 1,2-dimethoxyethane (15 mL) was added in drops. The mixture was stirred at 25 ° C for 12 hours. The mixture was treated with dilute aqueous sodium chloride ( 50 ml) followed by hydrochloric acid (1 M) to acid The mixture was extracted with EtOAc (100 ml x 2), and the organic layer was washed with brine (100 ml), dried over anhydrous Na2 SO4, then concentrated. was purified by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 12: 1) to generate 092-2A (530 mg, 15%) as a white solid. XH RNM: (400 MHz, CDCI3) δ 3.81-3.80 (m, 1H), 3.74-3.73 (m, 1H), 2.56-2.53 (m, 1H), 2.22-2.11 ( m, 1H), 2.00 -1, 80 (m, 3H), 1.71-1.61 (m, 5H), 1.53-1.23 (m, 10H), 1.15-1, 04 (m, 1H), 0.97 (s, 3H), 0.89-0, 88 (m, 12H), 0, 87-0, 86 (m, 4H), 0.07-0.01 ( m, 6H).
[391] To a stirred solution of 092-2A (530 mg, 1.22 mmol) in ethoxyethene (10 mL) was added Hg (AcO) 2 (585.6 mg, 1.83 mmol). The mixture was stirred at 25 ° C for 12 hours. The mixture was filtered, and the filtrate was evaporated. The residue was purified by flash column chromatography on AI2O3 (eluent: petroleum ether: ethyl acetate = 100: 1) to generate 092-3A (230 mg, 41%) as a colorless oil. ifi RNM: (400 MHz, CDC13) δ 6.30-6.25 (m, 1H), 4.33-4.29 (dd, Ji = 1.6, J2 = 14, 1H), 4.03- 4.01 (dd, = 1.6, J2 = 6.8, 1H), 3.92-3.91 (m, 1H), 3.75 -3.74 (m, 1H), 2.56-2.253 (m, 1H), 2.20-2.10 (m, 1H), 1.99 -1.90 (m, 1H), 1.88-1.63 (m, 7H), 1.41-1.00 ( m, 12), 0.97-0, 80 (m, 13H), 0.79 (s, 3H), 0.07-0.01 (m, 6H).
[392] To a stirred solution of 092-3A (230 mg, 0.5 mmol) in dry toluene (3 mL) was added diethylzinc (2.0 mL, 2.0 mmol) at -40 ° C under nitrogen. After stirring for 1 hour, chloroiodomethane (351.8 mg, 2.0 mmol) was added in drops. The reaction mixture was stirred at -40 ° C for 2 hours, then heated to 25 ° C and stirred for 12 hours. The mixture was quenched by a saturated aqueous NH4 Cl solution (20 ml), extracted with EtOAc (30 ml x 2). The combined organic layer was washed with brine (30 ml), dried over anhydrous Na2SÜ4 and evaporated to dryness. Purification by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 100: 1) to generate 092-4A (100 mg, 42%) as a colorless oil. RNM: (400 MHz, CDCI3) δ 3, 94-3, 93 (m, 1H), 3.44 -3.43 (m, 1H), 3.29-3.27 (m, 1H), 2, 56-2.53 (m, 1H), 2.23-1.90 (m, 2H), 1.85-1.60 (m, 4H), 1.53-1.00 (m, 10H), 0.97- 0.65 (m, 14H), 0.64-0.40 (m, 4H), 0.02-0.01 (m, 6H).
[393] To a stirred solution of 092-4A (100 mg, 0.21 mmol) in dry CH2 Cl2 (4 mL) was added 2,2,2-trifluoroacetic acid (1 mL). The reaction mixture was stirred at 25 ° C for 1 hour. The mixture was quenched by a saturated aqueous solution of NaHCOs (15 ml), extracted with CH2Q2 (20 ml x 2). The combined organic layer was washed with brine (20 ml), dried over anhydrous Na2SÜ4 and evaporated to dryness. Purification by flash column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10: 1) to generate the crude product, which was purified by prep HPLC to generate 57 (6 mg, 9%) as a solid White. iH RNM: (400 MHz, CDClj) δ 4, 06-4, 05 (m, 1H), 3.58 -3.57 (m, 1H), 3.33-3.30 (m, 1H), 2 , 58-2.55 (m, 1H), 2.16-2.10 (m, 1H), 2.01-1.90 (m, 1H), 1.85-1.58 (m, 8H) , 1.50-1.25 (m, 9H), 1.01 (s, 3H), 0, 90-0, 82 (m, 4H), 0, 60-0.48 (m, 4H) Test methods
[394] The compounds provided here can be evaluated using several assays, examples of which are described below. Steroid inhibition of TBPS binding
[395] [35S] -t-butylbicyclophosphorothionate (TBPS) binding assays have been described using rat brain cortical membranes in the presence of 5 µM GABA (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241 , 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985.
[396] In short, cortices are quickly removed after decapitation of Sprague-Dawley rats anesthetized with carbon dioxide (200-250 g). Cortices are homogenized in 10 volumes of chilled 0.32 M sucrose using a glass / teflon homogenizer and centrifuged at 1,500 x g for 10 min at 4 ° C. The resulting supernatants are centrifuged at 10,000 x g for 20 min at 4 ° C to obtain the P2 pellets. The P2 pellets are resuspended in 200 mM NaCl / 50 mM Na-K phosphate buffer pH 7.4 and centrifuged at 10,000 x g for 10 min at 4 ° C. This washing procedure is repeated twice and the pellets are resuspended in 10 volumes of buffer. Aliquots (100 pL) of the membrane suspensions are incubated with 3 nM [35S] -TBPS and 5 pL aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (0.5% final) in the presence of 5 pM of GABA. The incubation is brought to a final volume of 1.0 ml with buffer. Non-specific binding is determined in the presence of 2 pM of unlabeled TBPS and ranged from 15 to 25%. After a 90 min incubation at room temperature, the tests are terminated by filtration through glass fiber filters (Schleicher and Schuell N ° 32) using a cell harvester (Brandel) and rinsed three times with cold buffer. The radioactivity linked to the filter is measured by liquid scintillation spectrometry. The non-linear curve that adjusts the global data for each drug weighted for each concentration is made using Prism (GraphPad). Data are fitted to a partial inhibition model, instead of a full inhibition model, if the sum of squares is significantly smaller by F test. Similarly, data are fitted to a two-component inhibition model, rather than a component inhibition model, if the sum of squares is significantly less per test F. The concentration of test compound that produces 50%. of inhibition (IC50) of specific binding and the maximum extent of inhibition (Imax) are determined for the individual experiments with the same model used for the global data and then the means ± SEMs of the individual experiments are calculated.
[397] Several compounds are or can be evaluated to determine their potential as modulators of [35S] -TBPS binding in vitro. These tests are or can be performed according to the procedures discussed above. Table 1. Data from the 35S-TBPS displacement test of example compounds, where "A" indicates an IC 50 <10 nM, "B" indicates an IC 50 10 to 50 nM, "C" indicates an IC 50 from 50 nM to 100 nM, "D" indicates an IC50 of 100 nM to 500 nM and
Patch clamp electrophysiology of αiβ: y2 and coβsδ recombinant GABA receptors
[398] Cell electrophysiology is used to measure the pharmacological properties of the compounds described in heterologous cell systems. Each compound is tested for its ability to affect currents mediated by GABA at a submaximal agonist dose (GABA EC20 = 2 pM). LTK cells are stably transfected with αiβ2Y subunits! of the GABA receptor and CHO cells are transiently transfected with the ogβsδ subunits using the Lipofectamine method. The cells were passed at a confluence of about 50-80%, and then plated on sterile 35 mm culture plates containing 2 ml of complete culture medium without antibiotics or antimycotics. Confluent groups of cells are electrically joined (Pritchett et al., Science (1988), 242: 1,306-1,308). Because responses in distant cells are not properly voltage clamped and due to uncertainties about the extent of union (Verdoorn et al, Neuron (1990), 4: 919-928), the cells were grown at a density that allows single cells (with no visible connections to neighboring cells) are measured.
[399] Whole cell currents were measured with HEKA EPC-10 amplifiers using the PatchMaster program or using the high performance QPatch platform (Sophion). The batch solution for all experiments contained (in mM): NaCl - 137 mM, KC1 - 4 mM, CaCl2 - 1.8 mM, MgC12 - 1 mM, HEPES - 10 mM, D-Glucose - 10 mM, pH ( NaOH) 7.4. In some cases, Cremophor 0.005% has also been added. The intracellular solution (pipette) contained: KC1 - 130 mM, MgCl2 - 1 mM, Mg-ATP - 5 mM, HEPES - 10 mM, EGTA - 5 mM, pH 7.2. During the experiments, the cells and solutions were kept at room temperature (19 ° C-30 ° C). For manual patch clamp records, the cell culture plates were placed in a microscope plate holder and continuously perfused (1 mL / min) with batch solution. After the formation of a Gigaohm seal between the patch electrodes and the cell (variation of the pipette resistance: 2.5 MΩ - 6.0 MΩ; variation of the seal resistance:> 1 GΩ), the cell membrane through the tip of the pipette was broken to ensure electrical access to the interior of the cell (whole cell patch configuration). For experiments using the QPatch system, the cells were transferred as a suspension to the QPatch system in the batch solution and automated full cell records were performed.
[400] The cells had voltage set at a potential of -80 mV. For the analysis of test articles, NMDA receptors were stimulated by 2 pM GABA after sequential pre-incubation of increasing concentrations of the test article. The duration of the pre-incubation was 30 s and the duration of stimulation with GABA was 2s. The test articles were dissolved in DMSO to form stock solutions (10 mM). The test articles were diluted to 0.01, 0.1, 1 and 10 pM in bath solution. All concentrations of test articles were tested in each cell. The percentage of relative potentiation was defined as the peak amplitude in response to GABA EC20 in the presence of the test article divided by the peak amplitude in response to GABA EC20 alone, multiplied by 100. Table 2. Electrophysiological evaluation of exemplary compounds against receptors GABA αiβ2X2 and αiβjβ, where "A" indicates 10-100% effectiveness, "B" indicates 100-500% effectiveness, "C"indicates> 500% effectiveness, and D indicates that data is not available or not have been determined. Name GABA (di β 272) Qpatch in Ltk,% effective at 10 pM GABA (α4β3β) Manual patch in CHO,% effective at 10 pM

Loss of straightening reflex in rats
[401] Plasma pharmacokinetics and a qualitative assessment of sedation were obtained in male Sprague-Dawley rats according to the following procedure. The rats were dosed by intravenous bolus dose (60 seconds) through the dorsal vein of the foot at a dose of 5 mg / kg in an appropriate vehicle. In order to assess sedation, the rats were gently restrained manually in a lateral position for dose administration. If decreased muscle tone was observed during dose administration, restraint was gradually reduced. If the animal was unable to return to an upright position, time was recorded as the onset of loss of the straightening reflex (LRR). If the LRR does not occur during dosing, the animals were evaluated at intervals of 5 minutes later after being placed in dorsal recline. Slow or incomplete straightening twice consecutively within a 30 second interval qualifies as a loss of the straightening reflex. After the appearance of LRR, the animals were evaluated every 5 minutes in the same way. The recovery of the straightening reflex is defined as the ability of a rat to straighten up completely within 20 seconds after being placed on a dorsal recline. LRR duration is defined as the time interval between LRR and the return of the straightening reflex. Table 3. Measurement of the loss of straightening reflex (LRR) in male Sprague Dawley rats, where "A" indicates LRR duration as <10 min, "B" indicates LRR duration as 10-20 minutes , and "C" indicates the LRR duration as> 20 minutes.

Lateral reclining duration in dogs
[402] Plasma pharmacokinetics and a qualitative assessment of sedation were obtained in male beagle dogs according to the following procedure. The dogs were dosed by intravenous bolus dose (60 seconds) through the cephalic vein in doses ranging from 2 to 5 mg / kg in an appropriate vehicle. In order to assess sedation, the dogs were gently restrained for dose administration. If decreased muscle tone, muscle weakness, or head fall was observed during dose administration, the appearance of lateral reclining was recorded. If lateral reclining did not occur during dosing, the animals were evaluated at 5-minute intervals later after being placed in lateral recline. Straight, slow or incomplete to the sternal position qualifies as lateral recline. After the appearance of lateral reclining, the animals were evaluated every 5 minutes in the same way. The duration of lateral reclining was recorded as the time interval between the appearance of lateral reclining and the return to the sternal position. Table 4. Measurement of lateral reclining in males of beagle dogs, where "A" indicates the duration as> 20 minutes. Length of lateral recline (minutes)
* Administered at 2 mg / kg; ** administered at 5 mg / kg.

权利要求:
Claims (7)
[0001]
1. Compound, characterized by the fact that it is of Formula (II): in which:
[0002]
2. Compound according to claim 1, characterized by the fact that the compound is a compound of Formula (Ilb): in which:
[0003]
Compound according to claim 1, characterized by the fact that R2a or R2b is alkyl, methoxy, substituted ethoxy, or Ca-Ce alkoxy.
[0004]
Compound according to claim 3, characterized in that R2a is alkyl, methoxy, substituted ethoxy, or Cj-Ce alkoxy.
[0005]
5. Compound according to claim 2, characterized by the fact that R2b is hydrogen.
[0006]
6. Compound according to claim 1, characterized by being selected from:
[0007]
7. Pharmaceutical composition, characterized by the fact that it comprises the compound as defined in claim 1 and a pharmaceutically acceptable excipient.

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法律状态:
2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-12-17| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-01-28| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-10-06| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/07/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201361856592P| true| 2013-07-19|2013-07-19|

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US61/856.592|2013-07-19|

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PCT/US2014/047246|WO2015010054A2|2013-07-19|2014-07-18|Neuroactive steroids, compositions, and uses thereof|

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