19-nor C3,3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof

Abstract

To provide 19-nor C3,3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof.SOLUTION: The invention provides 19-nor C3,3-disubstituted C21-pyrazolyl steroids of Formula (I) and pharmaceutically acceptable salts thereof. The compounds are expected to be useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and / or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, and tinnitus.SELECTED DRAWING: None

Description

[Background technology]

[0001] Background of the invention Brain excitability is defined as an animal's level of alertness, which is a continuum ranging from coma to convulsions, and is controlled by a variety of neurotransmitters. In general, neurotransmitters are involved in controlling the conductance of ions across neuronal membranes. At rest, neuron membranes have a potential (or membrane voltage) of approximately -70 mV, with the interior of the cell being negative relative to the outside of the cell. The electric potential (voltage) is the ion (K + , Na + , Cl - , organic anions) balance. Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (change in potential from -70 mV to -50 mV). This effect is caused by Na + It is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, which increases membrane permeability to ions. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0002] In the case of the GABA receptor complex (GRC), its effects on brain excitability are mediated by the neurotransmitter GABA. Since up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant influence on overall brain excitability. GABA controls the excitability of individual neurons by controlling the conductance of chloride ions across neuronal membranes. GABA facilitates the flow of chloride ions down the GRC electrochemical gradient into the cell by interacting with recognition sites on GRCs. This intracellular increase in the level of anions causes hyperpolarization of the transmembrane potential and reduces the sensitivity of the neuron to excitatory inputs (ie, the excitability of the neuron decreases). In other words, the higher the chloride ion concentration within neurons, the lower the brain's excitability (arousal level).

[0003] GRCs are well established to be involved in mediating anxiety, seizure activity, and sedation. Therefore, GABA, and drugs that act like GABA or potentiate the actions of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZs), e.g., Valium®), have a specific It exerts its therapeutically useful effects by interacting with regulatory sites. Accumulating evidence now suggests that GRCs contain distinct sites for neurostimulatory steroids in addition to benzodiazepine and barbiturate binding sites (Lan, N.C. et al., Neurochem. Res. 16:347-356 (1991)).

[0004] Neurostimulatory steroids can be produced endogenously. The most potent endogenous neurostimulant steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one (respectively, the hormonal steroids progesterone and It is a metabolite of deoxycorticosterone). The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al., Science 232:1004-1007 (1986); Harrison, N.L. et al., J Pharmacol. Exp. Ther. 241:346-353(1987)).

[0005] The ovarian hormone progesterone and its metabolites have been shown to have significant effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985). ;Pfaff,D W and McEwen, B.S., 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) ). Levels of progesterone and its metabolites fluctuate depending on the time of the menstrual cycle. It is well established that levels of progesterone and its metabolites fall before the onset of menstruation. It is also well established that certain physical symptoms recur monthly before the onset of menstruation. These symptoms associated with premenstrual syndrome (PMS) include stress, anxiety, and migraines (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Subjects with PMS have recurring monthly symptoms that appear before menstruation and disappear after menstruation.

[0006] In a similar manner, decreased progesterone is also temporally correlated with increased seizure frequency in female epileptic patients (ie, menstrual epilepsy) (Laidlaw, J., Lancet, 1235-1237 (1956)). A more direct correlation was observed with a decrease in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). Furthermore, in subjects with primary generalized petit mal epilepsy, the temporal frequency of seizures correlated with the frequency of premenstrual syndrome symptoms (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2 :8-20(1983)). The steroid deoxycorticosterone has been found to be effective in treating subjects with epileptic seizures correlated with the menstrual cycle (Aird, R.B. and Gordan, G., J. Amer. Med. Soc. .145:715-719(1951)).

[0007] Also, a syndrome associated with low progesterone levels is postnatal depression (PND). Immediately after childbirth, progesterone levels drop dramatically, leading to the onset of PND. Symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe anxiety and irritability. Depression associated with PND is not amenable to treatment with traditional antidepressants, and women experiencing PND exhibit a higher incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, Vol. Edition, Chicago Yearbook, Chicago (1984)).

[0008] Taken together, these findings implicate progesterone and deoxycorticosterone, and more specifically their metabolites, in the homeostatic control of brain excitability, manifested as increased seizure activity or symptoms associated with menstrual epilepsy, PMS and PND. implying an important role. Correlation of low levels of progesterone with symptoms associated with PMS, PND and menstrual 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)) promoted the use of progesterone in those treatments (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy", Advances in Epileptology:XVth Epilepsy International Symposium, Raven Press , New York (1984), pp. 279-282 and Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not always effective in treating the syndromes mentioned above. For example, in the treatment of PMS, there is no dose-response relationship for progesterone (Maddo cks et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).

[0009] There is a need for new and improved neurostimulant steroids that act as modulators of brain excitability and agents for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are directed to this purpose. [Prior art documents] [Non-patent literature]

[0010] [Non-patent document 1] Lan, N.C. et al., Neurochem.Res.16:347-356(1991) [Non-patent document 2] Majewska, M.D. et al., Science 232:1004-1007(1986) [Non-patent document 3] Harrison, N.L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987) [Non-patent document 4] Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Supplement 130:19-24 (1985) [Non-patent document 5] Pfaff, D.W. and McEwen, B.S., Science 219:808-814 (1983) [Non-patent document 6] Gyermek et al., J Med Chem. 11:117 (1968) [Non-patent document 7] Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987) [Non-patent document 8] Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984) [Non-patent document 9] Laidlaw, J., Lancet, 1235-1237 (1956) [Non-patent document 10] Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986) [Non-patent document 11] Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983) [Non-patent document 12] Aird, R.B. and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951) [Non-patent document 13] Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy", Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279-282 [Non-patent document 14] Maddocks et al., Obstet. Gynecol. 154:573-581 (1986) [Non-patent document 15] Dennerstein et al., Brit. Med J 290:16-17 (1986) [Summary of the invention] [Means to solve the problem]

[0011] Summary of the invention The present invention provides novel 19-nor (i.e., C19 desmethyl ) compounds, e.g. Based in part on the desire to provide logesterone, deoxycorticosterone, and related metabolites thereof. One important feature of compounds as described herein is disubstitution at the C3 position (eg, one substituent is a 3α hydroxy moiety). We show that disubstitution at C-3 eliminates the possibility of oxidation of this hydroxy moiety to a ketone, prevents further metabolism, and reduces the possibility for second elimination pathways such as glucuronidation. I predict that. The inventors further believe that the overall effect of C3 disubstitution should be to improve overall PK parameters and reduce potential toxicity and side effects, thereby making certain embodiments It is anticipated that it may be possible to administer orally and / or chronically. Another important feature of the compounds as described herein is the presence of a hydrogen rather than a methyl group at the C19 position ("19-nor"). We expect the 19-nor compound to have improved physical properties, such as improved solubility, compared to its C19-methyl counterpart. We further expect that solubility will be increased when, for example, the AB ring system is in the cis configuration.

[0012] Therefore, in one aspect, formula (I):

[0013] [ka]

[0014] Provided herein are 19-nor C3,3-disubstituted C21-pyrazolyl steroids and pharmaceutically acceptable salts thereof; In formula (I): ----- represents a single or double bond; R 1 is substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or -OR A2 , where R A2 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 3a is hydrogen or -OR A3 , where R A3 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b together with form an oxo (=O) group; R 4a and R 4b Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, or halogen, with the exception that between C5 and C6 ----- If is a single bond, then C5 hydrogen and R 4a are each independently provided in the α or β configuration, and R 4b does not exist; R 5 ,R 6 , and R 7 Each example independently represents hydrogen, halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 ,-SR GA , -S(O)R GA , for example -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; and R GA Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group if attached to oxygen, oxygen protecting group if attached to nitrogen is a nitrogen protecting group or two R GA The groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0015] Steroids of formula (I), its subgenera, and pharmaceutically acceptable salts thereof are collectively referred to herein as "compounds of the invention."

[0016] In another aspect, pharmaceutical compositions are provided that include a compound of the invention and a pharmaceutically acceptable excipient. In certain embodiments, a compound of the invention is provided in an effective amount in a pharmaceutical composition. In certain embodiments, compounds of the invention are provided in a therapeutically effective amount. In certain embodiments, compounds of the invention are provided in a prophylactically effective amount.

[0017] Compounds of the invention as described herein, in certain embodiments, include, for example, GABA A Acts as a GABA modulator that effects receptors in a positive or negative manner. Such compounds include GABA A It is predicted to have CNS activity as a modulator of central nervous system (CNS) excitability as mediated by its ability to modulate receptors.

[0018] Accordingly, in another aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. Includes processes. In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, trauma. selected from the group consisting of sexual brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically.

[0019] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description, examples, and claims.

[0020] definition chemical definition Definitions of certain functional groups and chemical terms are detailed below. Chemical elements have an elemental period Identified according to the table (CAS version, Handbook of Chemistry and Physics, 75th edition, inner cover), specific functional groups are usually defined as described therein. Additionally, general rules of organic chemistry, as well as specific functional moieties and reactivities, are discussed 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. There is.

[0021] The compounds described herein may contain one or more asymmetric centers and therefore exist as different isomers, eg, enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of individual enantiomers, diastereomers, or geometric isomers, or can exist in the form of mixtures of stereoisomers (racemic mixtures, and more than one stereoisomer). (including concentrated mixtures). Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers can be prepared by asymmetric synthesis. can be done. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel editor, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers and / or as mixtures of various isomers.

[0022] When a range of values ​​is recited, it is intended to include each value and subrange within that range. For example, “C 1~6 "Alkyl" is C 1 ,C 2 ,C 3 ,C 4 ,C 5 ,C 6 ,C 1~6 ,C 1~5 ,C 1~4 ,C 1~3 ,C 1~2 ,C 2~6 ,C 2~5 ,C 2~4 ,C 2~3 ,C 3~6 ,C 3~5 ,C 3~4 ,C 4~6 ,C 4~5 , and C 5~6 is intended to include alkyl.

[0023] The following terms are intended to have the meanings set out below for them and are useful in understanding the intended scope of this specification and invention. When describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, if present, are used: , unless otherwise indicated, has the following meanings: As described herein, any of the moieties defined below may be substituted with a variety of substituents, and the definitions of each include substitutions within those scopes as described below. It should also be understood that it is intended to include the portions described above. Unless otherwise specified, the term "substituted" is defined as described below. It is further to be understood that the terms "group" and "radical" as used herein may be considered interchangeable. The articles "a" and "an" may be used herein to refer to one or more than one (ie, at least one) of the grammatical object of the article. For example, "an analogue" can mean one analog or more than one analog. Ru.

[0024] "Alkyl" means a straight-chain or branched saturated hydrocarbon radical having 1 to 20 carbon atoms ("C 1~20 "alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms (“C 1~12 Alkyl”). In some embodiments, the alkyl group has 1 to 10 carbon atoms (“C 1~10 Alkyl”). In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C 1~9 Alkyl”). In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C 1~8 Alkyl”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C 1~7 Alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl"). 1~6 Alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C 1~5 Alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C 1~4 Alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C 1~3 Alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C 1~2 Alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C 1 Alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C 2~6 Alkyl”). C 1~6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amil (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) and n-hexyl (C 6 ) can be mentioned. Further examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8), etc. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl"), or with one or more substituents; e.g., 1 to 5 substituent, 1 to 3 substituents, or 1 substituent (“substituted alkyl”). In certain embodiments, the alkyl group is an unsubstituted C 1~10 Alkyl (e.g. -CH 3 ). In certain embodiments, the alkyl group is a substituted C 1~10 It is an alkyl. Common abbreviations for alkyl include Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ), or i-Bu(-CH 2 CH(CH 3 ) 2 ) can be mentioned.

[0025] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to divalent radicals of alkyl, alkenyl, and alkynyl groups, respectively. When a range or number of carbons is given for a particular "alkylene", "alkenylene", and "alkynylene" group, that range or number is the same as that in the divalent chain of straight carbons. It is understood to refer to a range or number of carbons. "Alkylene", "alkenylene" and "alkynylene" groups may be substituted or unsubstituted with one or more groups as described herein. good.

[0026] "Alkylene" refers to an alkyl group in which two hydrogens are removed to yield a divalent radical, and which may be substituted or unsubstituted. As an unsubstituted alkylene group, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), and hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), etc., but are not limited to these. Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(C H 3 )CH 2 -,-CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -,-CH 2 C(CH 3 ) 2 -), and substituted propylene (-CH(CH 3 )CH 2 CH 2 -,-CH 2 CH(CH 3 )CH 2 -,-CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -,-CH 2 C(CH 3 ) 2 CH 2 -,-CH 2 CH 2 C(CH 3 ) 2 -), etc., but are not limited to these.

[0027] "Alkenyl" means 2 to 20 carbon atoms, 1 or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) straight-chain or Radicals of branched hydrocarbon groups (“C 2~20 refers to "alkenyl"). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C 2~10 alkenyl). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C 2~9 alkenyl). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C 2~8 alkenyl). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C 2~7 alkenyl). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C 2~6 alkenyl). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C 2~5 alkenyl). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C 2~4 alkenyl). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C 2~3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms (“C 2 alkenyl). The one or more carbon-carbon double bonds may be internal (eg, 2-butenyl) or terminal (eg, 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), etc. C 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc. Further examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), etc. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl"), or with one or more substituents, e.g. 1 to 5 substituted with a substituent, 1 to 3 substituents, or one substituent (“substituted alkenyl”). In certain embodiments, the alkenyl group is an unsubstituted C 2~10 It is alkenyl. In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0028] "Alkenylene" refers to an alkenyl group in which two hydrogens are removed to yield a divalent radical, which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH 2 -,-CH 2 -CH=CH-), but are not limited to these. Exemplary substituted alkenylene groups (e.g., substituted with one or more alkyl (methyl) groups) include substituted ethylene (-C(CH 3 )=CH-, -CH=C(CH 3 )-), and substituted propylene (e.g., -C(CH 3 )=CHCH 2 -, -CH=C(CH 3 )CH 2 -, -CH=CHCH(CH 3 )-, -CH=CHC(CH 3 ) 2 -, -CH(CH 3 )-CH=CH-, -C(CH 3 ) 2 -CH=CH-, -CH 2 -C(CH 3 )=CH-, -CH 2 -CH=C(CH 3 )-), but are not limited to these.

[0029] "Alkynyl" means 2 to 20 carbon atoms, 1 or more than 1 carbon-carbon triple bond (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) , and required Straight or branched chains, with one or more than one carbon-carbon double bond (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), depending on radical of hydrocarbon group (“C 2~20"alkynyl"). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C 2~10 Alkynyl). In some embodiments, alkynyl groups have 2 to 9 carbon atoms (“C 2~9 Alkynyl). In some embodiments, alkynyl groups have 2 to 8 carbon atoms (“C 2~8 Alkynyl). In some embodiments, alkynyl groups have 2 to 7 carbon atoms (“C 2~7 Alkynyl). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2~6 Alkynyl). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2~5 Alkynyl). In some embodiments, alkynyl groups have 2 to 4 carbon atoms (“C 2~4 Alkynyl). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2~3 Alkynyl). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 Alkynyl). The one or more carbon-carbon triple bonds may be internal (eg, 2-butynyl) or terminal (eg, 1-butynyl). C 2~4 Examples of alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), but are not limited to these. C 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups, as well as pentynyl (C 5 ), hexynyl (C 6 ), etc. Further examples of alkynyl include heptynyl (C 7 ), octinyl (C 8 ), etc. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl"), or with one or more substituents; e.g., 1 to 5 substituent, 1 to 3 substituents, or one substituent (“substituted alkynyl”). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 It is alkynyl. In certain embodiments, an alkynyl group is a substituted C 2~10 It is alkynyl.

[0030] "Alkynylene" refers to a straight chain alkynyl group in which two hydrogens are removed to yield a divalent radical, which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0031] The term "heteroalkyl," as used herein, refers to one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, , nitrogen, boron, silicon, phosphorous) in its parent chain, the one or more heteroatoms inserted between adjacent carbon atoms in its parent carbon chain, and / Alternatively, one or more heteroatoms refer to an alkyl group, as defined herein, inserted between a carbon atom and its parent molecule (i.e., between the points of attachment). refers to In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1~10 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1~9 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1~8 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1~7 "alkyl"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1~6 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1~5 Al "Kill"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC 1~4 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ((“heteroC 1~3 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ((“heteroC 1~2 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ((“heteroC 1 "alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC 2~6 "alkyl"). Unless specified otherwise, each instance of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted "heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted hetero-C 1~10 It is an alkyl. In certain embodiments, a heteroalkyl group is a substituted hetero-C 1~10 It is an alkyl.

[0032] The term "heteroalkenyl," as used herein, refers to one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur , nitrogen, boron, silicon, phosphorous), wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain, and / or one or more More than one heteroatom refers to an alkenyl group, as defined herein, inserted between a carbon atom and its parent molecule (ie, between the points of attachment). In certain embodiments, a heteroalkenyl group is a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (" Hetero C 2~10 refers to "alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“hetero C 2~9 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 (“hetero C 2~8 alkenyl). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“hetero C 2~7 alkenyl). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2~6 alkenyl). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2~5 alkenyl). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2~4 alkenyl). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and one heteroatom (“heteroC 2~3 alkenyl). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2~6 alkenyl). Unless specified otherwise, each instance of a heteroalkenyl group is independently unsubstituted (“unsubstituted heteroalkenyl”) or substituted with one or more substituents (“substituted (heteroalkenyl). In certain embodiments, a heteroalkenyl group is an unsubstituted hetero-C 2~10 It is alkenyl. In certain embodiments, a heteroalkenyl group is a substituted hetero-C 2~10 It is alkenyl.

[0033] The term "heteroalkynyl," as used herein, refers to one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur , nitrogen, boron, silicon, phosphorus), the one or more heteroatoms being inserted between adjacent carbon atoms in its parent carbon chain, and / or one or more heteroatoms are inserted between a carbon atom and its parent molecule (i.e., between the points of attachment). Refers to an inserted alkynyl group, as defined herein. In certain embodiments, a heteroalkynyl group is a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroalkynyl”) C 2~10 "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 (“heteroC 2~9 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 (“heteroC 2~8 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 (“heteroC 2~7 Alkynyl). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC 2~6 Alkynyl). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2~5 Alkynyl). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2~4 Alkynyl). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and one heteroatom (“heteroC 2~3 Alkynyl). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC 2~6 Alkynyl). Unless specified otherwise, each instance of a heteroalkynyl group is independently unsubstituted (“unsubstituted heteroalkynyl”) or substituted with one or more substituents (“substituted "heteroalkynyl"). In certain embodiments, a heteroalkynyl group is an unsubstituted hetero-C 2~10 It is alkynyl. In certain embodiments, a heteroalkynyl group is a substituted hetero-C 2~10 It is alkynyl.

[0034] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" refer to an alkyl group, an alkenyl group, an alkynyl group, respectively. refers to divalent radicals of groups, heteroalkyl groups, heteroalkenyl groups, and heteroalkynyl groups. When a range or number of carbons is given for a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", or "heteroalkynylene" group , the range or number is understood to refer to the range or number of carbons in the straight carbon divalent chain. "Alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene", and "heteroalkynylene" groups include one or more as described herein. may be substituted with more than one group, or may be unsubstituted.

[0035] "Aryl" means a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+ ring in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided in an aromatic ring system. A radical (“C 6~14 aryl). In some embodiments, the aryl group has 6 ring carbon atoms (“C 6 aryl'; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C 10 "aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C 14 aryl”; e.g., anthracyl). "Aryl" means one or more carbocyclyl rings as defined above. also includes ring systems fused with aryl or heterocyclyl groups, in which the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to be that of the carbon atoms in the aryl ring system. Point out the number of Typical aryl groups include aceantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene. , naphthalene, octacene, octaphene, octalene, obalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyrantrene, rubicene, triphenylene and trinaphthalene These include, but are not limited to: In particular, aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise specified, each occurrence of an aryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted Aryl”). In certain embodiments, the aryl group is an unsubstituted C 6~14 It is an aryl. In certain embodiments, the aryl group is a substituted C 6~14 It is an aryl.

[0036] In certain embodiments, aryl groups include halo, C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, cyano, hydroxy, C 1 ~C 8 Substituted with one or more groups selected from alkoxy and amino.

[0037] Examples of representative substituted aryls include:

[0038] [ka]

[0039] Here, R 56 and R 57 can be hydrogen, R 56 and R 57 At least one of C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 ~C 8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 C.O.R. 59 ,NR 58 SOR 59 ,NR 58 S.O. 2 R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 ,NR 58 R 59 , S.O. 2 NR 58 R 59 , S-alkyl, SO alkyl, SO 2 Alkyl, S aryl, SO aryl, SO 2 selected from aryl; or R 56 and R 57 are linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O or S) It is possible. R 60 and R 61 are independently hydrogen, C 1 ~C 8 Alkyl, C 1 ~C 4 haloalkyl, C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 aryl, substituted C 6 ~C 10 aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0040] Other representative aryl groups having a fused heterocyclyl group include:

[0041] [ka]

[0042] , where each W is C(R 66 ) 2 ,NR 66 , O, and S; and each Y is carbonyl, NR 66 , O and S; and R 66 are independently hydrogen, C 1 ~C 8 Alkyl, C 3 ~C10 Cycloalkyl, 4- to 10-membered heterocyclyl, C 6 ~C 10 aryl, and 5- to 10-membered heteroaryl.

[0043] "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.

[0044] "Aralkyl" is a subset of alkyl and aryl as defined herein and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group.

[0045] "Heteroaryl" means a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system in which a ring carbon atom and 1 to 4 ring heteroatoms are provided in the aromatic ring system (e.g., refers to a radical with 6 or 10 π electrons shared in a cyclic arrangement, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (from 5 to 10 member heteroaryl). For heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valency permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring. , in such cases, the number of ring members continues to refer to the number of ring members within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, where the point of attachment is on the aryl ring or on the heteroaryl ring; In such cases, the number of ring members refers to the number of ring members within the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g. indolyl, quinolinyl, carbazolyl, etc.), the point of attachment is on either ring, i.e. a ring containing a heteroatom (e.g. 2-indolyl) or on a ring containing no heteroatoms (eg, 5-indolyl).

[0046] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in an 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- to 8-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in an 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- to 6-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in an aromatic ring system, where each heteroatom is , independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents ( "substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl.

[0047] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. An exemplary 5-membered heteroaryl group containing 4 heteroatoms includes, but is not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, Includes, but is not limited to, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, napthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0048] Examples of typical heteroaryls are:

[0049] [ka]

[0050] , where each Y is carbonyl, N, NR 65 , O and S ;R 65 are independently hydrogen, C 1 ~C 8 Alkyl, C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 aryl and 5- to 10-membered heteroaryl.

[0051] "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. refers to

[0052] "Carbocyclyl" or "carbocyclic" means a non-aromatic ring system containing 3 to 10 ring carbon atoms ( "C 3~10 "carbocyclyl") and non-aromatic cyclic hydrocarbon radicals having 0 heteroatoms. In some embodiments, carbocyclyl groups have 3 to 8 ring carbon atoms (“C 3~8 carbocyclyl). In some embodiments, carbocyclyl groups have 3 to 6 ring carbon atoms (“C 3~6 carbocyclyl). In some embodiments, carbocyclyl groups have 3 to 6 ring carbon atoms (“C 3~6 carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms (“C 5~10 carbocyclyl). Exemplary C 3~6 As a carbocyclyl group, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), but are not limited to these. Exemplary C 3~8 As the carbocyclyl group, the above-mentioned C 3~6 Carbocyclyl group, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), but are not limited to these. Exemplary C 3~10 As the carbocyclyl group, the above-mentioned C 3~8 carbocyclyl group, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), but are not limited to these. As the foregoing example is illustrated, in certain embodiments, a carbocyclyl group is monocyclic (a "monocyclic carbocyclyl") or is a fused, bridged, or spiro ring system (e.g., It includes bicyclic systems (“bicyclic carbocyclyl”)) and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring and such , the number of carbons continues to refer to the number of carbons in the carbon ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted carbocyclyl”) or substituted with one or more substituents (“substituted carbocyclyl). In certain embodiments, the carbocyclyl group is an unsubstituted C 3~10 It is carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is carbocyclyl.

[0053] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 cycloalkyl). In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms (“C 3~8 cycloalkyl). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms (“C 3~6 cycloalkyl). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5~6 cycloalkyl). In some embodiments, cycloalkyl groups have 5 to 10 ring carbon atoms (“C 5~10 cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ) can be mentioned. C 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ) can be mentioned. C 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups, as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ) can be mentioned. Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is an unsubstituted C 3~10 It is cycloalkyl. In certain embodiments, a cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0054] "Heterocyclyl" or "heterocyclic" refers to a 3- to 10-membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as valency permits. A heterocyclyl group can be a monocyclic ring system (a "monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system (a "bicyclic heterocyclyl")) and is saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring or as defined above. A heterocyclyl ring is present on a ring system fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such case the number of ring members continues to Point out the number of ring members in the ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). ”). In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl.

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

[0056] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary five-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. but not limited to. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Not possible. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. C 6 Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to an aryl ring include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl. , benzoxazolinonyl, and the like, but are not limited to these. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. These include, but are not limited to:

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

[0058] [ka]

[0059] Here, each W is CR 67 ,C(R 67 ) 2 ,NR 67 , O and S; each Y is NR 67 , O and S;R 67 are independently hydrogen, C 1 ~C 8 Alkyl, C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 aryl, 5- to 10-membered heteroaryl. These heterocyclyl rings include acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amide), 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- may be optionally substituted with one or more groups selected from -aryl. Substituents include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0060] "Hetero" when used to describe a compound or a group present on a compound indicates that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen or sulfur heteroatom. means. Hetero means any hydrocarbyl group as described above having 1 to 5, especially 1 to 3 heteroatoms (e.g. alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocyclyl, aryl, e.g. heteroaryl, cycloalkenyl, such as cycloheteroalkenyl).

[0061] "Acyl" is -C(O)R 20 refers to a radical, where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, as defined herein. or a substituted or unsubstituted heteroaryl. "Alkanoyl" is R 20 is an acyl group which is a group other than hydrogen. Typical acyl groups include formyl (-CHO), acetyl (-C(=O)CH 3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH 2 Ph), --C(O)-C 1 ~C 8 Alkyl, -C(O)-(CH 2 ) t (C 6 ~C 10 Aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) t (C 3 ~C 10 cycloalkyl) and -C(O)-(CH 2 ) t (4-10 membered heterocyclyl) (t is an integer of 0-4), but is not limited to these. In certain embodiments, R 21 is C substituted with halo or hydroxy 1 ~C 8 alkyl; or C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl, each of which is an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 (substituted with haloalkoxy or hydroxy).

[0062] "Acylamino" means -NR 22 C(O)R 23 refers to a radical, where R 22 and each occurrence of R23 independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted carbocyclyl, as defined herein. is unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 22 is an amino protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Certain exemplary "acylamino" groups are -NR 24 C(O)-C 1 ~C 8 Alkyl, -NR 24 C(O)-(CH 2 ) t (C 6 ~C 10 aryl), -NR 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH 2 ) t (C 3 ~C 10 cycloalkyl) and -NR 24 C(O)-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and each R 24 is independently H or C 1 ~C 8 Represents alkyl. In certain embodiments, R 25 is C substituted with H, halo or hydroxy 1 ~C 8 Alkyl;C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl, each of which represents an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 Substituted with haloalkoxy or hydroxy;R 26 is C substituted with H, halo or hydroxy 1 ~C 8 Alkyl;C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl, each of which represents an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 Substituted with haloalkoxy or hydroxyl; however, R 25 and R 26 At least one of is other than H.

[0063] "Acyloxy" means -OC(O)R 27 refers to a radical, where R 27 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, as defined herein. or a substituted or unsubstituted heteroaryl. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certain embodiments, R 28 is C substituted with halo or hydroxy 1 ~C 8 Alkyl;C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 Aryl, arylalkyl, 5-10 membered heteroa aryl or heteroarylalkyl, each of which represents an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 Substituted with haloalkoxy or hydroxy.

[0064] "Alkoxy" means -OR 29 Refers to the group, where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, ie, have 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0065] In certain embodiments, R 29 is amino, substituted amino, C 6 ~C 10 Aryl, aryloxy, carboxyl, cyano, C 3 ~C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S (O) 2 - and aryl-S(O) 2 A group having one or more substituents selected from the group consisting of -, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH 2 ) t (C 6 ~C 10 aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 ~C 10 cycloalkyl) and -O-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present is itself but unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 Can be substituted by haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF 3 ,-OCH 2 C.F. 3 ,-OCH 2 Ph, -OCH 2 -cyclopropyl, -OCH 2 CH 2 OH and -OCH 2 CH 2 NMe 2 It is.

[0066] "Amino" means -NH 2 Refers to radicals.

[0067] "Substituted amino" means the formula -N(R 38 ) 2 refers to the amino group of R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or amino protecting group , where R 38 At least one of them is not hydrogen. In certain embodiments, each R 38 are independently hydrogen, C 1 ~C 8 Alkyl, C 3 ~C 8 alkenyl, C 3 ~C 8 Alkynyl, C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C 3 ~C 10 cycloalkyl; or C substituted with halo or hydroxy 1 ~C 8 Alkyl; C substituted with halo or hydroxy 3 ~C 8 alkenyl; C substituted with halo or hydroxy 3 ~C 8 Alkynyl, or -(CH 2 ) t (C 6 ~C 10 Aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 ~C 10 cycloalkyl) or -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which represents an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 substituted by haloalkoxy or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0068] Exemplary "substituted amino" groups include -NR 39 -C 1 ~C 8 Alkyl, -NR 39 -(CH 2 ) t (C 6 ~C 10 aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C 3 ~C 10 cycloalkyl) and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 is independently H or C 1 ~C 8 represents alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino or hydroxy; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by halo, substituted or unsubstituted amino or hydroxy; unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 Can be substituted by haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" means alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino, as defined below. Contains groups. Substituted amino includes both mono- and di-substituted amino groups.

[0069] "Azide" is -N 3 Refers to radicals.

[0070] "Carbamoyl" or "amide" means -C(O)NH 2 Refers to radicals.

[0071] "Substituted carbamoyl" or "substituted amide" means -C(O)N(R 62 ) 2 refers to a radical, where each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, where R 62 At least one of them is not hydrogen. In certain embodiments, R 62 H, C 1 ~C 8 Alkyl, C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 Aryl, aralkyl, 5-10 membered heteroaryl and heteroaralkyl; or C substituted with halo or hydroxy 1 ~C 8 alkyl; or C 3 ~C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 ~C 10 selected from aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each of which represents an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 substituted by haloalkoxy or hydroxy; provided that at least one R 62 is other than H.

[0072] Exemplary "substituted carbamoyl" groups include -C(O)NR 64-C 1 ~C 8 Alkyl, -C(O)NR 64 -(CH 2 ) t (C 6 ~C 10 aryl), -C(O)N 64 -(CH 2 ) t (5-10 membered heteroaryl), -C(O)NR 64 -(CH 2 ) t (C 3 ~C 10 cycloalkyl) and -C(O)NR 64 -(CH 2 ) t (4-10 membered heterocyclyl), but is not limited to these, where t is an integer from 0 to 4, and each R 64 is independently H or C 1 ~C 8 represents alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present is itself an unsubstituted C 1 ~C 4 Alkyl, halo, unsubstituted C 1 ~C 4 alkoxy, unsubstituted C 1 ~C 4 haloalkyl, unsubstituted C 1 ~C 4 Hydroxyalkyl or unsubstituted C 1 ~C 4 Can be substituted by haloalkoxy or hydroxy.

[0073] "Carboxy" refers to the -C(O)OH radical.

[0074] "Cyano" refers to -CN radical.

[0075] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, a halo group is fluoro or chloro.

[0076] "Hydroxy" refers to -OH radical.

[0077] "Nitro" means -NO 2 Refers to radicals.

[0078] "Cycloalkylalkyl" refers to an alkyl radical in which an alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl and Examples include, but are not limited to, cyclooctylethyl.

[0079] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like. These include, but are not limited to:

[0080] "Cycloalkenyl" has 3 to 10 carbon atoms and has a single cyclic ring or multiple fused rings (including fused and bridged ring systems), and at least one In particular, it refers to a substituted or unsubstituted carbocyclyl group having 1 to 2 olefinic unsaturation sites. Such cycloalkenyl groups include, by way of example, monocyclic structures (eg, cyclohexenyl, cyclopentenyl, cyclopropenyl, etc.).

[0081] A "fused cycloalkenyl" has two ring carbon atoms in common with a second aliphatic or aromatic ring and has olefinic unsaturation positioned to impart aromaticity to the cycloalkenyl ring. Refers to cycloalkenyl.

[0082] "Ethylene" refers to substituted or unsubstituted -(C-C)-.

[0083] "Ethenyl" refers to substituted or unsubstituted -(C=C)-.

[0084] "Ethynyl" refers to -(C≡C)-.

[0085] A "nitrogen-containing heterocyclyl" group includes at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-piperidinyl), pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (e.g., N-methylpiperazine). do. Specific examples include azetidine, piperidone and piperazone.

[0086] "Thioketo" refers to the =S group.

[0087] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups, as defined herein, are optionally substituted (e.g. For example, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether or not preceded by the term "optionally," means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is permissible. a substituent that, when substituted, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction); It means that. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions on the group, and when more than one position within any given structure is substituted, Substituents may be the same or different at each position. The term "substituted" is intended to include all permissible substituents of organic compounds, including substitution with any substituent described herein that forms a stable compound. For the purposes of this invention, a heteroatom such as nitrogen has hydrogen substituents and / or It can have any suitable substituents.

[0088] Exemplary carbon atom substituents include halogen, -CN, -NO 2 ,-N 3 ,-SO 2 H, -SO 3 H, -OH, -OR aa ,-ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa ,-SSR cc , -C(=O)R aa ,-CO 2 H, -CHO, -C(OR cc ) 2 ,-CO 2 R aa , -OC(=O)R aa ,-OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 ,-NR bb C(=O)R aa ,-NR bb C.O. 2 R aa ,-NR bb C(=O)N(R bb ) 2 , -C(=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2 , -OC(=NR bb )N(R bb ) 2 ,-NR bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb S.O. 2 R aa ,-NR bb S.O. 2 R aa ,-SO 2 N(R bb ) 2 ,-SO 2 R aa ,-SO 2 OR aa ,-OSO 2 R aa , -S(O)Raa (For example, -S(=O)R aa ), -OS(=O)R aa , -Si(R aa ) 3 ,-OSi(R aa ) 3 -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S)SR aa ,-SC(=S)SR aa ,-SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O) 2 R aa ,-OP(=O) 2 R aa , -P(=O)(R aa ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 ,-OP(=O) 2 N(R bb ) 2 , -P(=O)(NR bb ) 2 , -OP(=O)(NR bb ) 2 ,-NR bb P(=O)(OR cc ) 2 ,-NR bb P(=O)(NR bb ) 2 , -P(R cc ) 2 , -P(R cc ) 3 ,-OP(R cc ) 2 ,-OP(R cc ) 3 , -B(R aa ) 2 , -B(OR cc ) 2 ,-BR aa (OR cc ), C 1~10 Alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 including, but not limited to, aryl and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently 0, 1, 2, 3 , 4 or 5 R dd Is it substituted with a group; or the two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb ) 2 ,=NNR bb C(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O) 2 R aa ,=NR bb or=NOR cc replaced by a group; R aa Each existence of C 1~10 Alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 selected from aryl and 5-14 membered heteroaryl, or two R aa The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, Terocyclyl, aryl and heteroaryl independently contain 0, 1, 2, 3, 4 or 5 R dd substituted with a group; R bb Each occurrence of independently represents hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 ,-CO 2 R aa ,-SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 ,-SO 2 N(R cc ) 2 ,-SO 2 R cc ,-SO 2 OR cc ,-SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 ,C 1~10 Alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 selected from aryl and 5-14 membered heteroaryl, or two R bb The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently 0, 1 , 2, 3, 4 or 5 R dd substituted with a group; R cc Each occurrence of independently represents hydrogen, C 1~10 Alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 selected from aryl and 5-14 membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently 0, 1 , 2, 3, 4 or 5 R dd substituted with a group; R dd Each occurrence of independently represents a halogen, -CN, -NO 2 ,-N 3 ,-SO 2 H, -SO 3 H, -OH, -OR ee ,-ON(R ff ) 2 , -N(R ff ) 2 , -N(R ff ) 3 + X - , -N(OR ee )R ff , -SH, -SR ee ,-SSR ee , -C(=O)R ee ,-CO 2 H, -CO 2 R ee , -OC(=O)R ee ,-OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 ,-NR ff C(=O)R ee ,-NR ff C.O. 2 R ee ,-NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff )R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 ,-NR ff C(=NR ff )N(R ff ) 2 ,-NR ff S.O. 2 R ee ,-SO 2 N(R ff ) 2 ,-SO 2 R ee ,-SO 2 OR ee ,-OSO 2 R ee , -S(O)R ee , for example -S(=O)R ee , -Si(R ee ) 3 ,-OSi(R ee ) 3 , -C(=S)N(R ff )2 , -C(=O)SR ee , -C(=S)SR ee ,-SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 ,C 1~6 Alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently 0, 1, 2, 3, 4 or 5 R gg substituted with a group or two geminal R dd Substituents may be linked to form =O or =S; R ee Each existence of C 1~6 Alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently 0, 1, 2, 3, 4 or 5 R gg substituted with a group; R ff Each occurrence of independently represents hydrogen, C 1~6 Alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 selected from aryl and 5-10 membered heteroaryl, or two R ff The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heteroaryl ring Rosyclyl, aryl and heteroaryl independently contain 0, 1, 2, 3, 4 or 5 R gg substituted with a group; R gg Each occurrence of independently represents a halogen, -CN, -NO 2 ,-N 3 ,-SO 2 H, -SO 3 H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl) 2 , -N(C 1~6 alkyl) 2 , -N(C 1~6 alkyl) 3 + X - , -NH(C 1~6 alkyl) 2 + X - ,-NH 2 (C 1~6 alkyl) + X - ,-NH 3 + X - , -N(OC 1~6 alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO 2 H, -CO 2 (C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO 2 (C 1~6 alkyl), -C(=O)NH 2 , -C(=O)N(C 1~6 alkyl) 2 , -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO 2 (C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl) 2 , -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl) 2 , -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH 2 , -OC(=NH)N(C 1~6 alkyl) 2 , -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1~6 alkyl) 2 , -NHC(=NH)NH 2 ,-NHSO 2 (C 1~6 alkyl), -SO 2 N(C 1~6 alkyl) 2 ,-SO 2 NH(C 1~6 alkyl), -SO 2 N.H. 2 ,-SO 2 C 1~6 Alkyl, -SO 2 O.C. 1~6 Alkyl, -OSO 2 C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl) 3 ,-OSi(C 1~6 alkyl) 3 -C(=S)N(C 1~6 alkyl) 2 , C(=S)NH(C 1~6 alkyl), C(=S)NH 2 , -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O) 2 (C 1~6 alkyl), -P(=O)(C 1~6 alkyl) 2 , -OP(=O)(C 1~6 alkyl) 2 , -OP(=O)(OC 1~6 alkyl) 2 ,C 1~6 Alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - is the counterion.

[0089] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - ,Br - ,I - ), NO 3 - ,ClO 4 - ,OH - ,H 2 P.O. 4 - , H.S.O. 4 - , S.O. 4 -2 Sulfonate ions (e.g. methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2) -sulfonate, etc.) and carboxylate ions (eg, acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0090] Nitrogen atoms may be substituted or unsubstituted as valency permits, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 ,-CO 2 R aa ,-SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 ,-SO2 N(R cc ) 2 ,-SO 2 R cc ,-SO 2 OR cc ,-SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 ,C 1~10 Alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 including, but not limited to, aryl and 5-14 membered heteroaryl, or two R attached to a nitrogen atom. cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently 0, 1, 2, 3, 4 or 5 R dd substituted with a group, R aa ,R bb ,R cc and R dd is as defined above.

[0091] These and other exemplary substituents are described in detail in the Detailed Description, Examples, and Claims. It is not intended that this invention be limited in any way by the above exemplary listing of substituents.

[0092] other definitions The term "pharmaceutically acceptable salts" means salts for use in contact with human and lower animal tissues within the scope of sound medical judgment and without undue toxicity, irritation, and allergic response. refers to salts that are appropriate for use and commensurate with a reasonable benefit / risk 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 salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganic acids (e.g. hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric) or organic acids (e.g. acetic, oxalic, maleic). , tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate. , camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate salt, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonic acid Salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate , phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Examples include. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 alkyl) 4 Salt is an example. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Additional pharmaceutically acceptable salts include, where appropriate, halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and arylsulfonate ions. Contains non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions.

[0093] "Subjects" to which administration is intended include humans (i.e., any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly). adult) male or female) and / or non-human animals, such as mammals (e.g. primates (e.g. cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

[0094] Disease, disorder, and condition are used interchangeably herein.

[0095] As used herein, unless specified otherwise, the terms "treat," "treating," and "treatment" mean that a subject has a particular disease, disorder or Contemplating any action taken while suffering from a condition that reduces the severity of the disease, disorder or condition or delays or slows the progression of the disease, disorder or condition (a “therapeutic treatment”) and also contemplates actions taken before a subject begins to suffer from a particular disease, disorder or condition ("preventive treatment").

[0096] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, an effective amount of a compound of the invention will depend on the desired biological goal, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. This can vary depending on factors such as: Effective amounts include therapeutic and prophylactic treatments.

[0097] As used herein, unless specified otherwise, a "therapeutically effective amount" of a compound is one that provides a therapeutic benefit in the treatment of a disease, disorder or condition, or that provides a therapeutic benefit in the treatment of a disease, disorder or condition. in an amount sufficient to delay or minimize one or more symptoms associated with. A therapeutically effective amount of a compound means an amount of the therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of that disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids a symptom or cause of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0098] As used herein, unless specified otherwise, a "prophylactically effective amount" of a compound refers to the disease, disorder or condition, or one or more An amount sufficient to prevent the symptoms or their recurrence. A prophylactically effective amount of a compound means an amount of the therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of that disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In the embodiment of the present invention, the following items are provided, for example. (Item 1) Formula (I): [ka] or a pharmaceutically acceptable salt thereof; In formula (I): ----- represents a single or double bond; R 1 is substituted or unsubstituted C 1~6 Alkyl (e.g. haloalkyl (e.g. -CHF) 2 ,-CH 2 F), -CH 2 OCH 3 ,-CH 2 OCH 2 CH 3 ), substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or -OR A2 , where R A2 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 3a is hydrogen or -OR A3 , where R A3 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b together with form an oxo (=O) group; R 4a and R 4b Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, or halogen, with the exception that between C5 and C6 ----- If is a single bond, then C5 hydrogen and R 4a are each independently provided in the α or β configuration, and R 4b does not exist; R 5 ,R 6 , and R 7 Each example independently represents hydrogen, halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 ,-SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted C 1~6 Alkyl (e.g. haloalkyl), substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; R GA Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, is an oxygen protecting group if it is bonded to a nitrogen, or a nitrogen protecting group if it is bonded to a nitrogen, or two R GA The group together with the intervening atoms forms a substituted or unsubstituted heterocyclyl or heteroaryl ring; and R 1 is a C optionally substituted with alkoxy or one to two halo groups (e.g. fluoro) 1~6 is alkyl or R 5 ,R 6 , and R 7 At least one of them is a halogen (e.g. -F, -Cl, -Br), -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA ,-SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 ,-CH 2 CH 3 , haloalkyl (e.g. -CF 3 )), where R GA is substituted or unsubstituted C 1~2 is an alkyl, A compound or a pharmaceutically acceptable salt thereof. (Item 2) R 1 is a C optionally substituted with alkoxy or one to two halo groups (e.g. fluoro) 1~6 is alkyl, and R 5 ,R 6 , and R 7 At least one of them is a halogen (e.g. -F, -Cl, -Br), -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA ,-SR GA , -S(O)R GA , for example -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 ,-CH 2 CH 3 , haloalkyl (e.g. -CF 3 )), where R GA is substituted or unsubstituted C 1~2 A compound of formula (I) according to item 1, which is alkyl. (Item 3) The compound has the formula (I-A): [ka] A compound of formula (I) according to item 1, selected from compounds of (Item 4) The compound has the formula (I-B): [ka] A compound of formula (I) according to item 1, selected from compounds of (Item 5) R 1 is unsubstituted C 1~6 A compound according to item 1, which is alkyl. (Item 6) R 1 is C optionally substituted with alkoxy 1~6 A compound according to item 1, which is alkyl. (Item 7) R 1 is C optionally substituted with 1 or 2 halo (e.g. fluoro) 1~6 A compound according to item 1, which is alkyl. (Item 8) R 1 is -CH 3 ,-CH 2 CH 3 ,-CH 2 F, -CHF 2 ,-CH 2 OCH 2 CH 3 , or -CH 2 OCH 3 The compound according to item 1, which is (Item 9) R 1 -CH 3 The compound according to item 8, which is (Item 10) R 2 is -OH, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-CH 3 ,-CH 2 CH 3 ,-CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro. (Item 11) R 2 is -CH 3 or -OCH 3 The compound according to item 10, which is (Item 12) R 2 is-OCH 3 The compound according to item 11, which is (Item 13) R 2 The compound according to item 1, wherein is hydrogen. (Item 14) R 3a and R 3b and are both hydrogen. (Item 15) ----- represents a single bond, and R 4a and R 4b and are both hydrogen, listed in item 1 compound. (Item 16) ----- represents a single bond, and R 4a and R 4b and are both fluoro, in item 1 Compounds described. (Item 17) ----- represents a single bond, and R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 The compound according to item 1, which is (Item 18) ----- represents a single bond, and R 4a is substituted or unsubstituted C 1~6 Alkyl, ma or halogen, and R 4b The compound according to item 1, wherein is hydrogen. (Item 19) R 4a The compound according to item 18, wherein is fluoro. (Item 20) R 5 ,R 6 , and R 7 A compound according to item 1, wherein at least one of the compounds is hydrogen. (Item 21) R 5 ,R 6 , and R 7 A compound according to item 1, wherein at least two of the compounds are hydrogen. (Item 22) R 5 ,R 6 , and R 7 The compound according to item 1, wherein all of are hydrogen. (Item 23) R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , halogen, -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , or -S(=O) 2 N(R GA ) 2 , where R GA is substituted or unsubstituted C 1~2 A compound according to item 1, which is alkyl. (Item 24) R 5 ,R 6 , and R 7 The compound according to item 23, wherein at least one of the compounds is -CN. (Item 25) R 5 ,R 6 ,R 7 At least one of the -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , or -S(=O) 2 N(R GA ) 2 , where R GA is substituted or unsubstituted C 1~2 A compound according to item 23, which is alkyl. (Item 26) R 5 ,R 6 ,R 7 At least one of them is -S(=O) 2 R GA The compound according to item 25, which is (Item 27) R GA -CH 3 The compound according to item 25, which is (Item 28) R 5 and R 7 The compound according to item 1, wherein is hydrogen. (Item 29) R 6 is a halogen (e.g. -F, -Cl, -Br), -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA ,-SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 ,-CH 2 CH 3 , haloalkyl (e.g. -CF 3 )), where R GA is substituted or unsubstituted C 1~2 A compound according to item 1, which is alkyl. (Item 30) R 6 -SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , or -S(=O) 2 N(R GA ) 2 , where R GA is substituted or unsubstituted C 1~2 A compound according to item 29, which is alkyl. (Item 31) R 6 is a halogen (e.g. -F, -Cl, -Br), -NO 2 , -CN, or substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 ,-CH 2 CH 3 , haloalkyl (e.g. -CF 3 )), where R GA is substituted or unsubstituted C 1~2 A compound according to item 29, which is alkyl. (Item 32) R 2 ,R 3a ,R 3b ,R 4a , and R 4b The compound according to item 1, wherein is hydrogen. (Item 33) R 2 ,R 3a ,R 3b ,R 4a ,R 4b ,R 5 ,R 6 , and R 7 A compound according to item 1, wherein at least 3 of the compounds are hydrogen. (Item 34) R 2 ,R 3a ,R 3b ,R 4a ,R 4b ,R 5 ,R 6 , and R 7 A compound according to item 1, wherein at least 4 of the compounds are hydrogen. (Item 35) R 2 ,R 3a ,R 3b ,R 4a ,R 4b ,R 5 ,R 6 , and R 7 A compound according to item 1, wherein at least 5 of the compounds are hydrogen. (Item 36) R 6 is a halogen (e.g. -F, -Cl, -Br), -NO 2 , -CN, -C(=O)R GA , -C(=O)OR GA ,-SR GA , -S(=O)R GA , -S(=O) 2 R GA , substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 ,-CH 2 CH 3 , haloalkyl (e.g. -CF 3 )), where R GA is substituted or unsubstituted C 1~2 A compound according to item 35, which is alkyl. (Item 37) R 6 -SR GA, -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , or -S(=O) 2 N(R GA ) 2 , where R GA is substituted or unsubstituted C 1~2 A compound according to item 36, which is alkyl. (Item 38) R 6 The compound according to item 36, wherein is -CN. (Item 39) R 1 is substituted or unsubstituted C 1~6 Alkyl (e.g. haloalkyl (e.g. -CF 3 ,-CHF 2 ,-CH 2 F)) or alkoxy. (Item 40) The said compound is: [ka] [ka] [ka] A compound according to item 1 selected from the group consisting of. (Item 41) The said compound is: [ka] [ka] [ka] [ka] The compound according to item 2, selected from the group consisting of. (Item 42) The said compound is: [ka] [ka] The compound according to item 3, selected from the group consisting of. (Item 43) A pharmaceutical composition comprising a compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 44) A method for treating a CNS-related disorder in a subject in need of treatment, the method comprising: administering to the subject an effective amount of a compound according to any one of items 1 to 19; A method comprising administering a pharmaceutically acceptable salt. (Item 45) The CNS-related disorders include sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, and vascular disorders. The method of item 44, which is a disease, substance abuse disorder and / or withdrawal syndrome, or tinnitus. (Item 46) 45. The method of item 44, wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly. (Item 47) 45. The method of item 44, wherein said compound is administered chronically. [Brief explanation of the drawing]

[0099]

Figure 1

Figure 2

[0100] Detailed Description of Certain Embodiments of the Invention As described herein, the present invention relates to formula (I):

[0101] [ka]

[0102] 19-nor C3,3-disubstituted C21-pyrazolyl neurostimulant steroids and pharmaceutically acceptable salts thereof; In formula (I): ----- represents a single or double bond; R 1 is substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or -OR A2 , where R A2 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 is a carbocyclyl; R 3a is hydrogen or -OR A3 , where R A3 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C of substitution 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b together with form an oxo (=O) group; R 4a and R 4b Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, or halogen, with the exception that between C5 and C6 ----- If is a single bond, then C5 hydrogen and R 4a are each independently provided in the α or β configuration, and R 4b does not exist; R 5 ,R 6 , and R 7 Each example independently represents hydrogen, halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 ,-SR GA , -S(O)R GA , for example -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; and R GA Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group if attached to oxygen, oxygen protecting group if attached to nitrogen is a nitrogen protecting group or two R GA The groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0103] In certain embodiments, R 1 is a C optionally substituted with alkoxy or one to two halo groups (e.g. fluoro) 1~6 is alkyl or R 5 ,R 6 , and R 7 At least one of them is a halogen (e.g. -F, -Cl, -Br), -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA ,-SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 ,-CH 2 CH 3, haloalkyl (e.g. -CF 3 )), where R GA is substituted or unsubstituted C 1~2 It is an alkyl.

[0104] In certain embodiments, R 1 is a C optionally substituted with alkoxy or one to two halo groups (e.g. fluoro) 1~6 is alkyl, and R 5 ,R 6 , and R 7 At least one of them is a halogen (e.g. -F, -Cl, -Br), -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA ,-SR GA , -S(=O)R GA , -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 ,-CH 2 CH 3 , haloalkyl (e.g. -CF 3 )), where R GA is substituted or unsubstituted C 1~2 It is an alkyl.

[0105] Based on the above description, the steroid of formula (I) is a 3,3-disubstituted 19-nor neurostimulant steroid in which the A / B ring system of this compound is cis (as given in formula (I-A)). , a 3,3-disubstituted 19-nor neurostimulant steroid in which the A / B ring system of this compound is trans (as given in formula (I-B)), and the B ring of this compound is (as given in formula (I-C) 3,3-disubstituted 19-nor neurostimulant steroids containing a C5-C6 double bond (as given in ):

[0106] [ka]

[0107] [ka]

[0108] and its pharmaceutically acceptable salts.

[0109] base R 1 As generally defined herein, R 1 is substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 It is carbocyclyl.

[0110] In certain embodiments, R 1 is substituted or unsubstituted C 1~6 alkyl, e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. Exemplary R 1 C 1~6 As an alkyl group, substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amil (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), n-hexyl (C 6 ), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups 1~6 Alkyl (e.g. -CF 3 ,-CH 2 F, -CHF 2 , difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), 1, 2, 3, 4, 5, 6, 7, 8, 9, C substituted with 10 or more chloro groups 1~6 Alkyl (e.g. -CH 2 Cl, -CHCl 2 ), as well as C substituted with an alkoxy group 1~6 Alkyl (e.g. -CH 2 OCH 3 and -CH 2 OCH 2 CH 3 ), but are not limited to these. In certain embodiments, R 1 is the substituted C 1~6 Alkyl, for example R 1 is haloalkyl, alkoxyalkyl, or aminoalkyl. specific In embodiments, R 1 is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1 -dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.

[0111] In certain embodiments, R 1 is unsubstituted C 1~3 Alkyl, for example R 1 is -CH 3 ,-CH 2 CH 3 , or -CH 2 CH 2 CH 3 It is.

[0112] In certain embodiments, R 1 is C substituted with one or more fluorine atoms 1~6 It is an alkyl. For example, R 1 is -CH 2 F, -CHF 2 , or -CF 3 It is. In certain embodiments, R 1 is C substituted with 1 or 2 fluorine atoms 1~6 It is an alkyl. For example, R 1 is -CH 2 F or -CHF 2 It is.

[0113] In certain embodiments, R 1 is 1 or more than 1 -OR A1 C substituted with group 1~6 is alkyl, where R A1 is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 1 is -CH 2 OR A1 and, for example, here R A1 is hydrogen, -CH 3 ,-CH 2 CH 3 , or -CH 2 CH 2 CH 3 and, for example, the formula -CH 2 OH, -CH 2 OCH 3 ,-CH 2 OCH 2 CH 3 , or -CH 2 OCH 2 CH 2 CH 3 R of 1 Provide base.

[0114] In certain embodiments, R 1 is substituted or unsubstituted C 2~6 alkenyl, e.g. substituted or unsubstituted C 2~3 alkenyl, substituted or unsubstituted C 3~4 alkenyl, substituted or unsubstituted C 4~5 alkenyl, or substituted or unsubstituted C 5~6 It is alkenyl. In certain embodiments, R 1 is ethenyl (C 2 ), propenyl (C 3 ), or butenyl (C 4 ), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 1 is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R 1 is ethenyl.

[0115] In certain embodiments, R 1 is substituted or unsubstituted C 2~6 Alkynyl, e.g. substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4 Alkynyl, substituted or unsubstituted C 4~5 alkynyl, or substituted or unsubstituted C 5~6 It is alkynyl. In certain embodiments, R 1 is ethynyl, propynyl, or butynyl, unsubstituted or alkyl, halo, haloalkyl (e.g., CF 3 ), alkoxyalkyl, cycloalkyl (eg, cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R 1 is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. In certain embodiments, R 1 is ethynyl (C 2 ), propynyl (C 3 ), or butynyl (C 4 ), selected from the group consisting of unsubstituted or substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl, or Substituted with more than one substituent. In certain embodiments, R 1 is ethynyl (C 2 ), propynyl (C 3 ), or butynyl (C 4 ) and is substituted with phenyl. In certain embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amido. . In certain embodiments, R 1 is ethynyl (C 2 ), propynyl (C 3 ), or butynyl (C 4 ), substituted or unsubstituted pyrrolyl, imidazolyl , pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

[0116] In certain embodiments, R 1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted aryl. In certain embodiments, R 1 is ethynyl or propynyl substituted with phenyl, which is unsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain embodiments, R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted carbocyclyl. In certain embodiments, R 3a is ethynyl or propynyl substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyridinyl or pyrimidinyl. In certain embodiments, R 1 is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl There is. In certain embodiments, R 1 is ethynyl or propynyl, substituted with substituted or unsubstituted heterocyclyl. In certain embodiments, R 1 is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In certain embodiments, R 1 is propynyl or butynyl substituted with hydroxyl or alkoxy. In certain embodiments, R 1 is propynyl or butynyl substituted with methoxy or ethoxy. In certain embodiments, R 1 is ethynyl or propynyl substituted with chloro. In certain embodiments, R 1 is ethynyl or propynyl substituted with trifluoromethyl.

[0117] In certain embodiments, R 1 is substituted or unsubstituted C 3~6 carbocyclyl, e.g. substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 carbocyclyl, or substituted or unsubstituted C 5~6 It is carbocyclyl. In certain embodiments, R 1 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.

[0118] basis ----- ,R 2 ,R 3a ,R 3b ,R 4a , and R 4b As generally defined herein, R 2 is hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, or -OR A2 , where R A2 is hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 It is carbocyclyl.

[0119] In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halogen, for example fluoro, chloro, bromo, or iodo. In certain embodiments, R 2 is fluoro or chloro. In certain embodiments, R 2 is substituted or unsubstituted C 1~6 alkyl, e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 alkyl , substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. For example, in some embodiments, R 2 is halo (e.g., bromo, chloro, fluoro (i.e., formula -CH 2 F, -CHF 2 ,-CF 3 The group R 2 )) or -OR A2 C replaced as necessary with 1~6 It is an alkyl. In certain embodiments, R A2 is -CH 3 ,-CH 2 CH 3 , or -CH 2 CH 2 CH 3 , i.e. the formula -OH, -OCH 3 ,-OCH 2 CH 3 , or -OCH 2 CH 2 CH 3 The group R 2 give. In certain embodiments, R 2 is substituted or unsubstituted C 2~6 alkenyl, and in certain embodiments, R 2 is substituted or unsubstituted C 2~6 Alkynyl, e.g. substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4 Alkynyl, substituted or unsubstituted C 4~5 alkynyl, or substituted or unsubstituted C 5~6 It is alkynyl. In certain embodiments, R 2 is substituted or unsubstituted C 3~6 carbocyclyl, e.g. substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 carbocyclyl, or substituted or unsubstituted C 5~6 It is carbocyclyl. In certain embodiments, R 2 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In certain embodiments, R 2 is -CH 3 ,-CH 2 CH3 ,-CH 2 CH 2 CH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 -OR A2 It is. In certain embodiments, R A2 is hydrogen. In certain embodiments, R A2 is substituted or unsubstituted alkyl, for example substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. In certain embodiments, R A2 is hydrogen, -CH 3 ,-CH 2 CH 3 , or -CH 2 CH 2 CH 3 , i.e. the formula -OH, -OCH 3 ,-OCH 2 CH 3 , or -OCH 2 CH 2 CH 3 base R 2 I will provide a. In certain embodiments, R 2 is a non-hydrogen substituent in the α configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration.

[0120] As generally defined herein, R 3a is hydrogen or -OR A3 , where R A3 is hydrogen, or substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, or substituted or unsubstituted C 3~6 carbocyclyl, and R 3b is hydrogen; or R 3a and R 3b Together, they form an oxo (=O) group.

[0121] In certain embodiments, R 3a and R 3b Both are hydrogen.

[0122] In certain embodiments, R 3a and R 3b Together, they form an oxo (=O) group.

[0123] In certain embodiments, R 3a -OR A3 and R 3b is hydrogen. R 3a is-OR A3 In certain embodiments, R 3a is an α configuration or a β configuration. R 3a is-OR A3 In certain embodiments, R 3a is in the α configuration. R 3a is-OR A3 In certain embodiments, R 3a is in the β configuration. In certain embodiments, R A3 is hydrogen. In certain embodiments, R A3 is substituted or unsubstituted C 1~6 alkyl, e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. In certain embodiments, R A3 is hydrogen, -CH 3 ,-CH 2 CH 3 , or -CH 2 CH 2 CH 3 , i.e. the formula -OH, -OCH 3 ,-OCH 2 CH 3 , or -OCH 2 CH 2 CH 3 The group R 3a I will provide a.

[0124] As generally defined herein, R 4a and R 4b Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, or halogen, with the exception that between C5 and C6 ----- If is a single bond, the hydrogen of C5 and R 4a are each independently α configuration or is provided in the β configuration, and R 4b does not exist.

[0125] In certain embodiments, ----- is a single bond and R 4a and R 4b less of One of both is hydrogen. In certain embodiments, ----- is a single bond and R 4a and R 4b at least one of them is a substituted or unsubstituted C 1~6 alkyl, e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. In certain embodiments, ----- is a single bond Yes, R 4a and R 4b At least one of them is C 1 Alkyl, for example -CH 3 or -CF 3 It is. In certain embodiments, ----- is a single bond and R 4a and R 4b At least one of them is a halogen (eg, fluoro).

[0126] In certain embodiments, ----- is a single bond, and R 4a and R 4b and both are water It is basic. In certain embodiments, ----- is a single bond, and R 4a and R 4b with Both are independently substituted or unsubstituted C 1~6 alkyl, e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. In certain embodiments, ----- is a single bond, and R 4 a and R 4b and both independently, C 1 Alkyl, for example -CH 3 or -CF 3 It is. In certain embodiments, ----- is a single bond, and R 4a and R 4b and both The other is halogen (eg fluoro).

[0127] ----- In certain embodiments where R represents a single bond, R 4a is a non-hydrogen substituent in α configuration. Ru. ----- In certain embodiments where R represents a single bond, R 4a is a non-hydrogen substituent in β configuration. be.

[0128] In certain embodiments, ----- is a double bond, and R 4a is hydrogen. identification In an embodiment of ----- is a double bond, and R 4a is a substituted or unsubstituted C 1~6 alkyl, e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. In certain embodiments, ----- is a double bond, and R 4a is C 1 Alkyl, e.g. ba,-CH 3 or -CF 3 It is. In certain embodiments, ----- is a double bond , and R 4a is a halogen (eg, fluoro).

[0129] base R 5 ,R 6 , and R 7 As generally defined herein, R 5 ,R 6 , and R 7 Each example independently represents hydrogen, halogen, -NO 2 , -CN, -OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA , -N(R GA )C(=O)N(R GA ) 2 ,-SR GA , -S(O)R GA (For example, -S(=O)R GA ), -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , -N(R GA )S(=O) 2 R GA , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl.

[0130] Furthermore, as generally defined herein, R GA Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group if attached to oxygen, oxygen protecting group if attached to nitrogen is a nitrogen protecting group or two R GA The groups together with the intervening atoms form a substituted or unsubstituted heterocyclyl or heteroaryl ring. In certain embodiments, R GA Each example of independently represents hydrogen, substituted or unsubstituted C 1~6 Alkyl (e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R GA Each example is hydrogen, -CH 3 ,-CH 2 CH 3 , or substituted or unsubstituted phenyl.

[0131] In certain embodiments, R 5 ,R 6 , and R 7 At least one of them is hydrogen. In certain embodiments, R 5 ,R 6 , and R 7 At least two of them are hydrogen. In certain embodiments, R 5 ,R 6 , and R 7 are all hydrogen, giving unsubstituted pyrazolyl.

[0132] In certain embodiments, R 5 ,R 6 ,R 7 At least one of them is a non-hydrogen substituent. As used herein, R 5 ,R 6 , and R 7 “Non-hydrogen substituent” means R 5 ,R 6 , and R 7 is hydrogen, not halogen, -NO 2 , -CN, -CF 3 ,-OR GA , -N(R GA ) 2 , -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA ) 2 , -N(R GA )C(=O)R GA , -OC(=O)N(R GA ) 2 , -N(R GA )C(=O)OR GA ,-SR GA , -S(O)R GA (For example, -S(=O)R GA ), -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , or -N(R GA )S(=O) 2 R GA ;replaced or unreplaced C 1~6 Alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 It means any one of carbocyclyl or substituted or unsubstituted 3- to 6-membered heterocyclyl.

[0133] In certain embodiments, R 5 ,R 6 ,R 7 At least one of them is halogen, such as fluoro, bromo, iodo, or chloro. In certain embodiments, R 5 ,R 6 , and R 7 One of them is a halogen. In certain embodiments, R 5 is halogen, such as fluoro, bromo, iodo, or chloro. In certain embodiments, R 6 is halogen, such as fluoro, bromo, iodo, or chloro. In certain embodiments, R 7 is halogen, such as fluoro, bromo, iodo, or chloro.

[0134] In certain embodiments, R 5 ,R 6 ,R 7 At least one of the -NO 2 It is. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -NO 2 It is. In certain embodiments, R 5 -NO 2 It is. In certain embodiments, R 6 -NO 2 It is. In certain embodiments, R 7 -NO 2 It is.

[0135] In certain embodiments, R 5 ,R 6 , and R 7 At least one of them is -CN. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -CN. In certain embodiments, R 5 is -CN. In certain embodiments, R 6 is-CN It is. In certain embodiments, R 7 is -CN.

[0136] In certain embodiments, R 5 ,R 6 ,R 7 At least one of them is -OR GA and, for example, here R GA is hydrogen, or substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 or -CF 3 ). In certain embodiments, R 5 ,R 6 , and R 7 One of them is -OR GA For example, -OH, -OCH 3 , or -OCF 3 It is. In certain embodiments, R 5 -OR GA For example, -OH, -OCH 3 , or -OCF 3 It is. In certain embodiments, R6 -OR GA It is. In certain embodiments, R 7 -OR GA For example, -OH, -OCH 3 , or -OCF 3 It is.

[0137] In certain embodiments, R 5 ,R 6 ,R 7 At least one of them is -N(R GA ) 2 , where R GA is hydrogen, or substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 or -CF 3 ). In certain embodiments, R 5 ,R 6 , and R 7 One of them is -N(R GA ) 2 For example, -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is. In certain embodiments, R 5 -N(R GA ) 2 For example, -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is. In certain embodiments, R 6 -N(R GA ) 2 For example, -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is. In certain embodiments, R 7 -N(R GA ) 2 For example, -NH 2 , -NHCH 3 , or -N(CH 3 ) 2 It is.

[0138] In certain embodiments, R 5 ,R 6 , and R 7 At least one of them is -C(=O)R GA , -C(=O)OR GA , or -C(=O)N(R GA ) 2 and, for example, here R GA is hydrogen, or substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 or -CF 3 ). In certain embodiments, R 5 ,R 6 , and R 7 One of them is -C(=O)R GA For example, -CHO, -C(=O)CH 3 , or -C(=O)CH 2 CH 3 It is. In certain embodiments, R 5 -C(=O)R GA For example, -CHO, -C(=O)CH 3 , or -C(=O)CH 2 CH 3 It is. In certain embodiments, R 6 -C(=O)R GA For example, -CHO, -C(=O)CH 3 , or -C(=O)CH 2 CH 3 It is. In certain embodiments, R 7 -C(=O)R GA For example, -CHO, -C(=O)CH 3 , or -C(=O)CH 2 CH 3 It is. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -C(=O)OR GA For example, -C(=O)OH, -C(=O)OCH 3 , or -C(=O)OCH 2 CH 3 It is. In certain embodiments, R 5 is -C(=O)OR GA For example, -C(=O)OH, -C(=O)OCH 3 , or -C(=O)OCH 2 CH 3 It is. In certain embodiments, R 6 is -C(=O)OR GA For example, -C(=O)OH, -C(=O)OCH 3 , or -C(=O)OCH 2 CH 3 It is. In certain embodiments, R 7 is -C(=O)OR GA For example, -C(=O)OH, -C(=O)OCH 3 , or -C(=O)OCH 2 CH 3 It is. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -C(=O)N(R GA ) 2 For example, -C(=O)NH 2 , -C(=O)NHCH 3 , or -C(=O)N(CH 3 ) 2 It is. In certain embodiments, R 5 -C(=O)N(R GA ) 2 For example, -C(=O)NH 2 , -C(=O)NHCH 3 , or -C(=O)N(CH 3 ) 2 It is. In certain embodiments, R 6 -C(=O)N(R GA ) 2 For example, -C(=O)NH 2 , -C(=O)NHCH 3 , or -C(=O)N(CH 3 ) 2 It is. In certain embodiments, R 7 -C(=O)N(R GA ) 2 For example, -C(=O)NH 2 , -C(=O)NHCH 3 , or -C(=O)N(CH 3 ) 2 It is.

[0139] In certain embodiments, R 5 ,R 6 ,R 7 At least one of the -OC(=O )R GA , -OC(=O)OR GA , or -OC(=O)N(R GA ) 2 and, for example, here R GA is hydrogen, or substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 or -CF 3 ). In certain embodiments, R 5 ,R 6 , and R 7 One of them is -OC(=O)R GA For example, -OC(=O)CH 3 It is. In certain embodiments, R 5 is-OC(=O)R GA For example, -OC(=O)CH 3 It is. In certain embodiments, R 6 is-OC(=O)R GA For example, -OC(=O)CH 3 It is. In certain embodiments, R 7 is-OC(=O)R GA For example, -OC(=O)CH 3 It is. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -OC(=O)OR GA For example, -OC(=O)OCH 3 It is. In certain embodiments, R 5 is -OC(=O)OR GA For example, -OC(=O)OCH 3 It is. In certain embodiments, R 6 is -OC(=O)OR GA For example, -OC(=O)OCH 3 It is. In certain embodiments, R 7 is -OC(=O)OR GA For example, -OC(=O)OCH 3 It is. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -OC(=O)N(R GA ) 2 and, for example, -OC(=O)NHCH 3 or -OC(=O)N(CH 3 ) 2 It is. In certain embodiments, R 5 -OC(=O)N(R GA ) 2 and, for example, -OC(=O)NHCH 3 or -OC(=O)N(CH 3 ) 2 It is. In certain embodiments, R 6 -OC(=O)N(R GA ) 2and, for example, -OC(=O)NHCH 3 or -OC(=O)N(CH 3 ) 2 It is. In certain embodiments, R 7 -OC(=O)N(R GA ) 2 and, for example, -OC(=O)NHCH 3 or -OC(=O)N(CH 3 ) 2 It is.

[0140] In certain embodiments, R 5 ,R 6 ,R 7 At least one of -N(R GA )C(=O)R GA , -N(R GA )C(=O)OR GA , or -N(R GA )C(=O)N(R GA ) 2 and, for example, here R GA is hydrogen, or substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 or -CF 3 ). In certain embodiments, R 5 ,R 6 , and R 7 One of them is -N(R GA )C(=O)R GA For example, -NHC(=O)CH 3 It is. In certain embodiments, R 5 -N(R GA )C(=O)R GA For example, -NHC(=O)CH 3 It is. In certain embodiments, R 6 -N(R GA )C(=O)R GA For example, -NHC(=O)CH 3 It is. In certain embodiments, R 7 -N(R GA )C(=O)R GA For example, -NHC(=O)CH 3 It is. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -N(R GA )C(=O)OR GA For example, -NHC(=O)OCH 3 It is. In certain embodiments, R 5 -N(R GA )C(=O)OR GA For example, -NHC(=O)OCH 3 It is. In certain embodiments, R 6 -N(R GA )C(=O)OR GA For example, -NHC(=O)OCH 3 It is. In certain embodiments, R 7 -N(R GA )C(=O)OR GA For example, -NHC(=O)OCH 3 It is. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -N(R GA )C(=O)N(R GA ) 2 For example, -NHC(=O)NH 2 or -NHC(=O)N(CH 3 ) 2 It is. In certain embodiments, R 5 -N(R GA )C(=O)N(R GA ) 2 For example, -NHC(=O)NH 2 or -NHC(=O)N(CH 3 ) 2 It is. In certain embodiments, R 6 -N(R GA )C(=O)N(R GA ) 2 For example, -NHC(=O)NH 2 or -NHC(=O)N(CH 3 ) 2 It is. In certain embodiments, R 7 -N(R GA )C(=O)N(R GA ) 2 For example, -NHC(=O)NH 2 or -NHC(=O)N(CH 3 ) 2 It is.

[0141] In certain embodiments, R 5 ,R 6 ,R 7 At least one of the -SR GA , -S(O)R GA (For example, -S(=O)R GA ), -S(=O) 2 R GA , -S(=O) 2 OR GA , -OS(=O) 2 R GA , -S(=O) 2 N(R GA ) 2 , or -N( R GA )S(=O) 2 R GA and, for example, here R GA is hydrogen, substituted or unsubstituted C 1~6 Alkyl (e.g. -CH 3 or -CF 3 ), substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -SR GA (For example, -SCH 3 ), or -S-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -S(O)R GA , for example -S(=O)R GA , for example, -S(=O)CH 3 , -S(=O)CF 3 , or -S(=O)-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -S(=O) 2 R GA , for example -S(=O) 2 CH 3 , -S(=O) 2 C.F. 3 , or -S(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 -SR GA , for example -SCH 3 ,-SCF 3 ;-S(O)R GA , for example -S(=O)R GA , for example, -S(=O)CH 3 , -S(=O)CF 3 ;-S(=O) 2 R GA , for example -S(=O) 2 CH 3 , -S(=O) 2 C.F. 3 , or -S(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 -SR GA , for example -SCH 3 ,-SCF 3 ;-S(O)R GA , for example -S(=O)R GA , for example, -S(=O)CH 3 , -S(=O)CF 3 ;-S(=O) 2 R GA , for example -S(=O) 2 CH 3 , -S(=O) 2 C.F. 3 , or -S(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 -SR GA , for example -SCH 3 ,-SCF 3 ;-S(O)R GA , for example -S(=O)R GA , for example, -S(=O)CH 3 , -S(=O)CF 3 ;-S(=O) 2 R GA , for example -S(=O) 2 CH 3 , -S(=O) 2 C.F. 3 , or -S(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -S(=O) 2 OR GA It is. In certain embodiments, R 5 is -S(=O) 2 OR GA , for example -S(=O) 2OCH 3 , -S(=O) 2 O.C.F. 3 , or -S(=O) 2 Oaryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -S(=O) 2 OR GA , for example -S(=O) 2 OCH 3 , -S(=O) 2 O.C.F. 3 , or -S(=O) 2 Oaryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -S(=O) 2 OR GA , for example -S(=O) 2 OCH 3 , -S(=O) 2 O.C.F. 3 , or -S(=O) 2 Oaryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -OS(=O) 2 R GA It is. In certain embodiments, R 5 is -OS(=O) 2 R GA , for example -OS(=O) 2 CH 3 , -OS(=O) 2 C.F. 3 , or -OS(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -OS(=O) 2 R GA , for example -OS(=O) 2 CH 3 , -OS(=O) 2 C.F. 3 , or -OS(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -OS(=O) 2 R GA , for example -OS(=O) 2 CH 3 , -OS(=O) 2 C.F. 3 , or -OS(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -S(=O) 2 N(R GA ) 2 It is. In certain embodiments, R 5 is -S(=O) 2 N(R GA ) 2 , for example -S(=O) 2 NHCH 3 , -S(=O) 2 NHCF 3 , or -S(=O) 2 -NH-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -S(=O) 2 N(R GA ) 2 , for example -S(=O) 2 NHCH 3 , -S(=O) 2 NHCF 3 , or -S(=O) 2 -NH-aryl, Aryl here is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -S(=O) 2 N(R GA ) 2 , for example -S(=O) 2 NHCH 3 , -S(=O) 2 NHCF 3 , or -S(=O) 2 -NH-aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 5 ,R 6 , and R 7 One of them is -N(R GA )S(=O) 2 R GA It is. In certain embodiments, R 5 is -N(R GA )S(=O) 2 R GA , for example -NHS(=O) 2 CH 3 ,-NHS(=O) 2 C.F. 3 , or -NHS(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 6 is -N(R GA )S(=O) 2 R GA , for example -NHS(=O) 2 CH 3 ,-NHS(=O) 2 C.F. 3 , or -NHS(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl. In certain embodiments, R 7 is -N(R GA )S(=O) 2 R GA , for example -NHS(=O) 2 CH 3 ,-NHS(=O) 2 C.F. 3 , or -NHS(=O) 2 -aryl, where aryl is substituted or unsubstituted aryl or heteroaryl.

[0142] In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~6 alkyl, e.g. substituted or unsubstituted C 1~2 Alkyl, substituted or unsubstituted C 2~3 Alkyl, substituted or unsubstituted C 3~4 Alkyl, substituted or unsubstituted C 4~5 alkyl, or substituted or unsubstituted C 5~6 It is an alkyl. Exemplary C 1~6 As an alkyl group, substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amil (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), n-hexyl (C 6 ), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluoro groups 1~6 Alkyl (e.g. -CF 3 ,-CH 2 F, -CHF 2 , difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), 1, 2, 3, 4, 5, 6, 7, 8, 9, C substituted with 10 or more chloro groups 1~6 Alkyl (e.g. -CH 2 Cl, -CHCl 2 ), as well as C substituted with an alkoxy group 1~6 Alkyl (e.g. -CH 2 OCH 3 and -CH 2 OCH 2 CH 3 ), but are not limited to these. In certain embodiments, R 5 ,R 6 ,R 7 at least one of the substituted C 1~6 Alkyl, for example R 5 ,R 6 ,R 7 At least one of them is haloalkyl, alkoxyalkyl, or aminoalkyl. In certain embodiments, R 5 ,R 6 ,R 7 At least one of Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoroethyl, trifluoroethyl, difluoroethyl, 2,2,2- Trifluoro-1,1-dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl.

[0143] In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 2~6alkenyl, e.g. substituted or unsubstituted C 2~3 alkenyl, substituted or unsubstituted C 3~4 alkenyl, substituted or unsubstituted C 4~5 alkenyl, or substituted or unsubstituted C 5~6 It is alkenyl. In certain embodiments, R 5 ,R 6 ,R 7 At least one of them is ethenyl (C 2 ), propenyl (C 3 ), or butenyl (C 4 ), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 5 ,R 6 ,R 7 at least one of them is ethenyl, propenyl, or butenyl, unsubstituted or alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy has been replaced by shi.

[0144] In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 2~6 Alkynyl, e.g. substituted or unsubstituted C 2~3 Alkynyl, substituted or unsubstituted C 3~4 Alkynyl, substituted or unsubstituted C 4~5 alkynyl, or substituted or unsubstituted C 5~6 It is alkynyl. In certain embodiments, R 5 ,R 6 ,R 7 at least one of the is ethynyl, propynyl, or butynyl and is unsubstituted or alkyl, halo, haloalkyl (e.g., CF 3 ), alkoxyalkyl, cycloalkyl (eg, cyclopropyl or cyclobutyl), or hydroxyl.

[0145] In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 3~6 carbocyclyl, e.g. substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted C 4~5 carbocyclyl, or substituted or unsubstituted C 5~6 It is carbocyclyl. In certain embodiments, R 5 ,R 6 , and R 7 At least one of them is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.

[0146] In certain embodiments, R 5 ,R 6 , and R 7 At least one of them is substituted or unsubstituted 3- to 6-membered heterocyclyl, for example, substituted or unsubstituted 3- to 4-membered heterocyclyl, substituted or unsubstituted 4- to 5-membered heterocyclyl. , or a substituted or unsubstituted 5- to 6-membered heterocyclyl.

[0147] In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ).

[0148] R as a non-hydrogen substituent 5 ,R 6 , and R 7 Exemplary combinations of are contemplated herein.

[0149] For example, in certain embodiments, the formula

[0150] [ka]

[0151] C21-pyrazolyl has the formula:

[0152] [ka]

[0153] is a monosubstituted pyrazolyl ring, where R 5 ,R 6 , and R 7 are each referred to herein as is a non-hydrogen substituent as defined in

[0154] In certain embodiments, the formula

[0155] [ka]

[0156] C21-pyrazolyl has the formula:

[0157] [ka]

[0158] is a disubstituted pyrazolyl ring, where R 5 ,R 6 , and R 7 are each non-hydrogen substituents as defined herein.

[0159] In certain embodiments, the formula

[0160] [ka]

[0161] C21-pyrazolyl is a trisubstituted pyrazolyl ring, where R 5 ,R 6 , and R 7 each of is a non-hydrogen substituent as defined herein.

[0162] Various combinations of specific embodiments Various combinations of specific embodiments are further envisioned herein.

[0163] For example, R 2 In certain embodiments, where is hydrogen or a non-hydrogen alpha substituent, formula (I-A1), (I-B1), or (I-C1):

[0164] [ka]

[0165] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 1 is -CH 3 ,-CH 2 CH 3 ,-CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 is -OH, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-CH 3 ,-CH 2 CH 3 ,-CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R 3a and R 3b Both are hydrogen. In certain embodiments, R 3a and R 3b Combines with to form =O (oxo). In certain embodiments where ring B comprises a C5-C6 double bond, R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are hydrogen. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b and both -CH 3 or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4bBoth are fluoro. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is di-substituted pyrazolyl. In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ). In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 ,R 6 , and R 7 Each example of is hydrogen.

[0166] R 2 In certain embodiments, where is hydrogen or a non-hydrogen β substituent, formula (I-A2), (I-B2), or (I-C2):

[0167] [ka]

[0168] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 1 is -CH 3 ,-CH 2 CH 3 ,-CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 is -OH, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-CH 3 ,-CH 2 CH 3 ,-CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R 3a and R 3b Both are hydrogen. In certain embodiments, R 3a and R 3b Combines with to form =O (oxo). In certain embodiments where ring B comprises a C5-C6 double bond, R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are hydrogen. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b and both -CH 3 or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are fluoro. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is di-substituted pyrazolyl. In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ). In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 ,R 6 , and R 7 Each example of is hydrogen.

[0169] R 3a is hydrogen or a non-hydrogen α substituent, and R 3b In certain embodiments where is hydrogen, formula (I-A3), (I-B3), or (I-C3):

[0170] [ka]

[0171] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 1 is -CH 3 ,-CH 2 CH 3 ,-CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 is -OH, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-CH 3 ,-CH 2 CH 3 ,-CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R 2 is a non-hydrogen substituent in the α configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments where ring B comprises a C5-C6 double bond, R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are hydrogen. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b and both -CH 3 or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are fluoro. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is di-substituted pyrazolyl. In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ). In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 ,R 6 , and R 7 Each example of is hydrogen.

[0172] R 3a is a hydrogen or non-hydrogen β substituent, and R 3b In certain embodiments where is hydrogen, formula (I-A4), (I-B4), or (I-C4):

[0173] [ka]

[0174] [ka]

[0175] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 1 is -CH 3 ,-CH 2 CH 3,-CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 is -OH, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-CH 3 ,-CH 2 CH 3 ,-CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R 2 is a non-hydrogen substituent in the α configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments where ring B comprises a C5-C6 double bond, R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are hydrogen. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b and both -CH 3 or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are fluoro. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is di-substituted pyrazolyl. In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ). In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 ,R 6 , and R 7 Each example of is hydrogen.

[0176] R 3a and R 3b are taken together to form an oxo group, formula (I-A5), (I-B5), or (I-C5):

[0177] [ka]

[0178] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 1 is -CH 3 ,-CH 2 CH 3 ,-CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 is -OH, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-CH 3 ,-CH 2 CH 3 ,-CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R 2 is a non-hydrogen substituent in the α configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments where ring B comprises a C5-C6 double bond, R 4a is hydrogen, fluoro, -CH 3 , or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are hydrogen. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b and both -CH 3 or -CF 3 It is. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a and R 4b Both are fluoro. In certain embodiments where ring B does not contain a C5-C6 double bond, R 4a is a non-hydrogen substituent, and R 4b is hydrogen. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is di-substituted pyrazolyl. In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ). In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 ,R 6 , and R 7 Each example of is hydrogen.

[0179] R 4a In certain embodiments where is a non-hydrogen substituent, formula (I-A6) or (I-B6):

[0180] [ka]

[0181] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 1 is -CH 3 ,-CH 2 CH 3 ,-CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, R 2 is -OH, -OCH 3 ,-OCH 2 CH 3 ,-OCH 2 CH 2 CH 3 ,-CH 3 ,-CH 2 CH 3 ,-CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro. In certain embodiments, R 2 is a non-hydrogen substituent in the α configuration. In certain embodiments, R 2 is a non-hydrogen substituent in the β configuration. In certain embodiments, R 3a and R 3b Both are hydrogen. In certain embodiments, R 3a and R 3b Combines with to form =O (oxo). In certain embodiments, R 4a is fluoro, -CH 3 , or -CF 3 and R 4b is hydrogen. In certain embodiments, R 4b is fluoro, -CH 3 , or -CF 3 and R 4a is hydrogen. In certain embodiments, R 4a and R 4b and both -CH 3 or -CF 3 It is. In certain embodiments, R 4a and R 4b Both are fluoro. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is di-substituted pyrazolyl. In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ). In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 ,R 6 , and R 7 Each example of is hydrogen.

[0182] R 4a In certain embodiments where is a non-hydrogen substituent, formula (I-A6) or (I-B6):

[0183] [ka]

[0184] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 1 is -CH 3 ,-CH 2 CH 3 ,-CH 2 F, -CHF 2 ,-CF 3 ,-CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl. In certain embodiments, the C21-pyrazolyl ring is monosubstituted pyrazolyl. In certain embodiments, the C21-pyrazolyl ring is di-substituted pyrazolyl. In certain embodiments, R 5 ,R 6 , and R 7 at least one of them is a substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ), -CO 2 R GA , -C(=O)R GA , -CN, -NO 2 , or halogen, where R GA is substituted or unsubstituted C 1~2 Alkyl (e.g. -CH 3 ,-CF 3 ). In certain embodiments, the C21-pyrazolyl ring is unsubstituted pyrazolyl, where R 5 ,R 6 , and R 7 Each example of is hydrogen.

[0185] In certain embodiments, the steroid of formula (I) is:

[0186] [ka]

[0187] [ka]

[0188] [ka]

[0189] [ka]

[0190] and a pharmaceutically acceptable salt thereof.

[0191] In certain embodiments, the steroid of formula (I) is:

[0192] [ka]

[0193] [ka]

[0194] and pharmaceutically acceptable salts thereof.

[0195] In certain embodiments, the steroid of formula (I) is:

[0196] [ka]

[0197] [ka]

[0198] and pharmaceutically acceptable salts thereof.

[0199] In certain embodiments, the steroid of formula (I) is:

[0200] [ka]

[0201] [ka]

[0202] and pharmaceutically acceptable salts thereof.

[0203] In certain embodiments, the steroid of formula (I) is:

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] [ka]

[0208] [ka]

[0209] and pharmaceutically acceptable salts thereof.

[0210] In certain embodiments, the steroid of formula (I) is:

[0211] [ka]

[0212] [ka]

[0213] [ka]

[0214] and pharmaceutically acceptable salts thereof.

[0215] pharmaceutical composition In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.

[0216] The pharmaceutical compositions provided herein can be administered by various routes including oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous ( (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration).

[0217] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by the circumstances involved (the condition being treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, the patient's symptoms, etc.). (including the severity of the disease) and is determined by the doctor.

[0218] When used to prevent the development of CNS disorders, the compounds provided herein are typically administered at the dosage levels described above, on the advice and under the supervision of a physician. , may be administered to a subject at risk of developing the condition. Subjects at risk for developing a particular condition generally include those who have a family history of the condition or who have been identified through genetic testing or screening as being particularly susceptible to developing the condition. It will be done.

[0219] The pharmaceutical compositions provided herein are also administered chronically (“chronic administration”). Chronic administration may be continued for an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely, e.g., for the remainder of the subject's life. Refers to the administration of a compound or pharmaceutical composition thereof. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, eg, within a therapeutic window, over an extended period of time.

[0220] Pharmaceutical compositions of the invention may further be delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, eg, to increase the concentration of the compound in the blood to an effective level. Bolus dose placement is Depending on the systemic levels of the active ingredient desired throughout the body, e.g. an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, whereas a bolus delivered directly into a vein (e.g. IV (by instillation) allows for faster delivery, which quickly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, such as by IV instillation, to provide maintenance of a steady state concentration of the active ingredient within the subject's body. Furthermore, in yet still other embodiments, the pharmaceutical composition may be initially administered as a bolus dose, followed by continuous infusion.

[0221] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as a unit dosage for human subjects and other mammals, each unit containing the desired amount of pharmaceutically excipients, and a suitable pharmaceutical excipient. Contains a predetermined amount of active material calculated to provide a therapeutic effect. Typical unit dosage forms include premeasured and prefilled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc. for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), with the remainder being in various vehicles or excipients and as desired. It is a processing aid that helps form the dosage form.

[0222] For oral administration, 1 to 5, especially 2 to 4, typically 3 oral doses per day is a typical regimen. When using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, with preferred doses each providing about 0.1 to about 10 mg / kg, particularly about yielding 1 to about 5 mg / kg.

[0223] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injectable doses, generally from about 0.01% to about 20% by weight, preferably from about 0.01% to about 20% by weight. Amounts range from about 0.1% to about 20%, preferably from about 0.1% to about 10%, and more preferably from about 0.5% to about 15%.

[0224] Dose levels for injections range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve appropriate steady state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0225] Liquid forms suitable for oral administration include buffers, suspending agents and dispensing agents. agents), colorants, fragrances, and the like. Solid forms may, for example, contain any of the following ingredients or compounds of a similar nature: binders (e.g. microcrystalline cellulose, gum tragacanth or gelatin); excipients (e.g. starch or lactose); agents (e.g. alginic acid, Primogel or corn starch); lubricants (e.g. magnesium stearate); lubricants (e.g. colloidal silicon dioxide); sweeteners (e.g. sucrose or saccharin); or flavorants (e.g. peppermint). , methyl salicylate or orange flavor).

[0226] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable excipients known in the art. As is conventional, the active compounds in such compositions are typically minor ingredients, often about 0.05-10% by weight, with the remainder being injectable excipients and the like.

[0227] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, including, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0228] The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be accomplished using patches of the reservoir or porous membrane type or of the solid matrix type.

[0229] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, etc. are shown in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, incorporated herein by reference.

[0230] Compounds of the invention may also be administered in sustained release form or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0231] The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation includes water. In another embodiment, the formulation includes a cyclodextrin derivative. The most common cyclodextrins contain one or more optional substituents on the sugar moiety to which they are linked, including methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, including, but not limited to, α-1,4-linked glucose units. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, eg, US Pat. No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (eg, 10-50% in water).

[0232] The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the invention. Acids that can be used to prepare pharmaceutically acceptable salts include non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, Hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para- toluenesulfonate).

[0233] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0234] Exemplary Formulation 1 - Tablets: The compounds of the invention may be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg active compound per tablet) in a tablet press.

[0235] Exemplary Formulation 2 - Capsules: Compounds of the invention are prepared as a dry powder with a starch diluent. They can be mixed in a 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg active compound per capsule).

[0236] Exemplary Formulation 3 - Liquid: A compound of the invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture is mixed and passed through a No. 10 mesh U.S. sieve and then , mixed with a pre-prepared aqueous solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. The total volume can then be brought to 5 mL by adding enough water.

[0237] Exemplary Formulation 4 - Tablets: The compounds of the invention may be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0238] Exemplary Formulation 5 - Injection: The compounds of the invention may be dissolved or suspended in a sterile buffered saline injectable aqueous medium to a concentration of approximately 5 mg / mL.

[0239] Exemplary Formulation 6 - Tablets: The compounds of the invention may be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg active compound per tablet) in a tablet press.

[0240] Exemplary Formulation 7 - Tablets: The compounds of the invention may be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg active compound per tablet) in a tablet press.

[0241] Exemplary Formulation 8 - Tablets: The compounds of the invention may be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg active compound per tablet) in a tablet press.

[0242] Exemplary Formulation 9 - Tablets: The compounds of the invention may be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg active compound per tablet) in a tablet press.

[0243] Exemplary Formulation 10 - Tablets: The compounds of the invention may be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg active compound per tablet) in a tablet press.

[0244] Methods of use and treatment As generally described herein, the present invention relates to C21-substituted neurostimulant steroids designed to act, for example, as GABA modulators. In certain embodiments, such compounds are expected to be useful as therapeutic agents for inducing anesthesia and / or sedation in a subject. In some embodiments, such compounds are effective for treating CNS-related disorders (e.g., sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism). spectrum disorder, pain Subjects requiring treatment for pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, or tinnitus (e.g., subjects with Rett syndrome, Fragile X syndrome, or Angelman syndrome) It is predicted that it will be useful as a therapeutic agent for the treatment of cancer.

[0245] Accordingly, in one aspect, the invention provides a method of inducing anesthesia and / or sedation in a subject, the method comprising administering to the subject an effective amount of a compound of the invention or a composition thereof. Includes processes. In certain embodiments, the compound is administered by intravenous administration.

[0246] Previous studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) have shown that certain 3α-hydroxylated steroids act as modulators of the GABA receptor complex (GRC). , than what others have reported (see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Proved to be powerful in high digits. Majewska et al. and Harrison et al. taught that 3α-hydroxylated-5-reduced steroids are capable of much lower levels of efficacy. In vitro and in vivo experimental data have demonstrated that high potencies of these steroids make them therapeutically useful in regulating GRC-mediated brain excitability (e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); see Wieland et al., Psychopharmacology 118(l):65-71 (1995)).

[0247] Various synthetic steroids have also been prepared as neurostimulant steroids. See, for example, U.S. Patent No. 5,232,917 (U.S. Pat. (discloses neurostimulatory steroid compounds). Additionally, these steroids have previously been shown to interact at unique sites on GRCs that are distinct from other known interaction sites (e.g., barbiturates, benzodiazepines, and GABA); Therapeutically beneficial effects on sleep, mood disorders, and seizure disorders have been elicited previously (e.g., Gee, K.W. and Yamamura, H.I., "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure"). Lloyd, K.G. and Morselli, P.L., "Psychopharmacology of GABAergic Drugs", Psychopharmacology: The Third Generation of Progress, See H. Y. Meltzer, editor, Raven Press, N.Y. (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). Desirable for efficacy and oral activity (in addition to other forms of administration).

[0248] The compounds of the invention as described herein are generally designed to modulate GABA function and, therefore, to act as neurostimulatory steroids for the treatment and prevention of CNS-related conditions in a subject. be done. Modulation, as used herein, refers to inhibition or synergism of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein can be used to treat the CNS in mammals, including humans and non-human mammals. It finds use as a therapy for the prevention and / or treatment of symptoms. Thus, as previously stated, the present invention provides the recited methods of treatment, as well as compounds for such methods, and the use of such compounds to prepare medicaments useful for such methods. It includes within its scope and extends to them.

[0249] Exemplary CNS conditions associated with GABA regulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymia disorders (e.g., mild depression), bipolar disorders (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorders (e.g., obsessive-compulsive disorder (OCD)) ], schizophrenia spectrum disorders [e.g. schizophrenia, schizoaffective disorder], convulsive disorders [e.g. epilepsy (e.g. status epilepticus (SE)), seizures], disorders of memory and / or cognition [e.g. For example, attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewis body type dementia, cerebrovascular dementia), movement disorders [e.g., Huntington's disease], Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorder (ASD) [e.g., autism, forms of autism such as synaptophathy Host-related causes (e.g., Rett syndrome, fragile X syndrome, Angelman syndrome), pain [e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain], traumatic brain injury (TBI), vascular disease [ Examples include, but are not limited to, stroke, ischemia, vascular malformations], substance abuse disorders and / or withdrawal syndromes [eg, opiate, cocaine, and / or alcohol addiction], and tinnitus.

[0250] In yet another aspect, combinations of a compound of the invention and another pharmacologically active agent are provided. The compounds provided herein can be administered as the single active agent or in combination with other agents. Administration in combination may proceed by any technique apparent to those skilled in the art, such as separate administration, sequential administration, simultaneous administration, and alternating administration.

[0251] In another aspect, a method of treating or preventing brain agitation in a subject susceptible to or suffering from a condition associated with brain agitation is provided, the method comprising administering to the subject an effective amount of administering a compound of the invention to the subject.

[0252] In yet another aspect, a method of treating or preventing stress or anxiety in a subject is provided, which method comprises administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof. the step of administering.

[0253] In yet another aspect, a method of reducing or preventing seizure activity in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. do.

[0254] In yet another aspect, a method of reducing or preventing insomnia in a subject is provided, which method comprises administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof. It includes the step of

[0255] In yet another aspect, a method is provided for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, the method not inducing substantial rebound insomnia, the method comprising: , comprising administering an effective amount of a compound of the invention.

[0256] In yet another aspect, a method of reducing or preventing PMS or PND in a subject. is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.

[0257] In yet another aspect, a method of treating or preventing a mood disorder in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. do. In certain embodiments, the mood disorder is depression.

[0258] In yet another aspect, a method of inducing anesthesia in a subject is provided, the method comprising administering to the subject an effective amount of a compound of the invention.

[0259] In yet another aspect, a method of treating cognitive enhancement or memory impairment by administering to a subject a therapeutically effective amount of a compound of the invention is provided. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0260] In yet another aspect, methods of treating attention disorders are provided by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0261] In certain embodiments, the compound is administered chronically to a subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to a subject.

[0262] anesthesia / sedation Anesthesia is a pharmacologically induced reversible state of amnesia, analgesia, loss of reactivity, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. These effects can be obtained from one drug that provides the right combination of effects alone, or sometimes drugs (e.g. hypnotics, sedatives, can be obtained using a combination of paralytics, analgesics). Anesthesia allows patients to undergo surgery and other procedures without experiencing the difficulty and pain they would otherwise experience.

[0263] Sedation is the reduction of nervousness or agitation, typically by the administration of pharmacological agents to facilitate a medical or diagnostic procedure.

[0264] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0265] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are typically unaffected.

[0266] Moderate sedation / analgesia (conscious sedation) is a drug-induced state of consciousness in which the patient intentionally responds to verbal commands, either alone or accompanied by mild tactile stimulation. This is a decrease in Usually no intervention is required to maintain the patient's airway. Spontaneous ventilation is typically sufficient. Cardiovascular function is usually preserved.

[0267] Deep sedation / analgesia is a drug-induced condition in which the patient is unable to awaken easily but responds intentionally (as opposed to reflexively withdrawing from the painful stimulus) after repeated or painful stimuli. This is an induced decrease in consciousness. The patient may require assistance to maintain the patient's airway, as independent ventilatory function may be impaired. Spontaneous ventilation may be inadequate. heart Visceral vascular function is usually maintained.

[0268] General anesthesia is a drug-induced loss of consciousness in which the patient is unable to awaken even to painful stimuli. Because the ability to maintain independent ventilatory function is often impaired, assistance is often required to maintain the patient's airway. Positive pressure ventilation may be required due to decreased spontaneous ventilation or drug-induced decreases in neuromuscular function. Cardiovascular function may be impaired.

[0269] Sedation in the intensive care unit (ICU) allows for decreased patient awareness of the environment and decreased response to external stimuli. This encompasses a wide range of symptom control that can play a role in the treatment of critically ill patients and varies from patient to patient and individual to individual throughout the course of the patient's disease. Heavy sedation in intensive care has been used to facilitate endotracheal tube tolerability and ventilator synchronization (often accompanied by neuromuscular blockers).

[0270] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced in the ICU and for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks). , 3 weeks, 1 month, 2 months). Long-term sedatives may have a long duration of action. Sedatives in the ICU can have short elimination half-lives.

[0271] Procedural sedation and analgesia (also referred to as conscious sedation) is the use of analgesics with analgesics to allow the subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function. A technique in which a sedative or dissociative agent is administered, with or without sedatives.

[0272] anxiety disorder Anxiety disorder is an umbrella term that covers several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0273] Generalized anxiety disorder is a common chronic disorder characterized by prolonged anxiety that is unable to focus on any one object or situation. People who suffer from generalized anxiety experience nonspecific, persistent fear and worry, and become overly concerned about mundane situations. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0274] In panic disorder, a person suffers brief bouts of intense fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as fear or discomfort that occur suddenly and peak in less than 10 minutes) can last for several hours and can be triggered by stress, fear, or even exercise, but The specific cause is not always obvious. In addition to recurrent, unpredictable panic attacks, a diagnosis of a phobic disorder also indicates that the attack is associated with chronic consequences (worry about the attack's potential implications, persistent fear of future attacks, or anxiety about the attack). any significant change in behavior). Thus, patients with phobic disorders experience symptoms even outside of a specific panic episode. Often, normal changes in heartbeat are noticed by panic sufferers, leading them to believe that something is wrong with their heart or that they are about to have another panic attack. In some cases, an increased perception of bodily functions (hypervigilance) occurs during a panic attack, in which case any perceived physiological changes are interpreted as a possible life-threatening illness ( i.e. excessive hypochondria).

[0275] Obsessive-compulsive disorder is a type of anxiety disorder characterized by recurrent obsessions (demanding, persistent , intrusive thoughts or images) and threatening behavior (the urge to perform certain actions or rituals). OCD thought patterns can be linked to superstitions insofar as they involve the person believing in causal relationships that do not actually exist. Often the process is completely illogical. For example, a compulsion to walk in a particular pattern may be used to reduce the compulsion of imminent danger. And in many cases, this compulsion is not entirely inexplicable, but simply a nervously induced urge to complete a ritual. In a minority of cases, patients with OCD may only experience obsessions without overt compulsions, and a smaller number of patients experience only compulsions.

[0276] One of the largest categories of anxiety disorders is that of phobias, which encompasses all cases in which fear and anxiety are provoked by specific stimuli or situations. Patients typically anticipate fearful outcomes from encountering the object of their fear (this can be anything ranging from animals, places, bodily fluids).

[0277] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations (eg, war, rape, hostage situations, or even major disasters). It can also result from long-term (chronic) exposure to severe stressors (eg, soldiers who can withstand individual combat but cannot cope well with continuous warfare). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0278] Neurodegenerative diseases and disorders The term "neurodegenerative disease" encompasses diseases and disorders that are associated with a progressive loss of neuronal structure or function, or death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic damage; ataxia and convulsions (including for the treatment and prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; brain hydrops; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head trauma; coma; contusion injuries (e.g., spinal and head injuries); dementia (multiple infarcts); disorders of consciousness; Down syndrome; drug-induced or drug-induced tremor paralysis (e.g., psycholeptic-induced acute akathisia, acute ataxia, tremor paralysis); vertebral palsy or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma); hearing loss and Hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesias; mental retardation; movement disorders including akinesia and akinesia (rigidity) syndromes (brainstem neurocalcification, corticobasal degeneration, multisystem atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitis tremor palsy, and progressive supranuclear palsy); muscle spasticity and disorders associated with muscle spasticity or weakness (e.g. chorea); benign hereditary chorea, drug-induced chorea, unilateral ballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesias (simple tics, complex tics, and symptomatic tics) tics (such as tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (such as resting tremor, postural tremor, and intention tremor), and ataxia (axial including blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis). ); neuronal damage (including ocular damage, ocular retinopathy or macular degeneration); stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia , neurotoxic disorders following hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizures; These include status epilepticus; stroke; tinnitus; tubulosclerosis; and neurodegeneration induced by viral infections (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and brain disorders). Not limited. Neurodegenerative diseases also include post-stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. including, but not limited to, neurotoxic disorders. Methods of treating or preventing neurodegenerative diseases also include treating or preventing loss of neuronal function that is characteristic of neurodegenerative disorders.

[0279] epilepsy Epilepsy is a brain disorder characterized by repeated seizures over long periods of time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with waking grand mal seizures, West syndrome, Lennox-Gastaut syndrome, Partial epilepsies may be included, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0280] Status epilepticus (SE) Status epilepticus (SE) includes, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory epileptic seizures. status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial epilepticus; generalized periodic epileptic discharge; and periodic unilateral epileptic discharge. can be included. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus, including early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Can include intussusception. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus seizures despite treatment with first-line therapy, and second-line therapy is used. Refractory status epilepticus is characterized by persistent status epilepticus seizures despite treatment with first-line and second-line therapy, and general anesthetics are commonly administered. Extremely refractory status epilepticus is characterized by persistent status epilepticus despite first-line therapy, second-line therapy, and treatment with general anesthetics for more than 24 hours.

[0281] Non-convulsive status epilepticus includes, for example, focal non-convulsive status epilepticus, complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, and microscopic Convulsive status epilepticus; generalized nonconvulsive status epilepticus, such as late-onset absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical Absence non-convulsive status epilepticus may be included.

[0282] The compositions described herein may also be used to treat CNS disorders prior to the onset of seizures, such as traumatic brain injury, status epilepticus, such as convulsive status epilepticus, such as early epilepsy. status epilepticus, established status epilepticus, refractory status epilepticus, extremely refractory status epilepticus; non-convulsive status epilepticus, e.g. generalized status epilepticus, complex It can be administered prophylactically to subjects with partial seizure status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges.

[0283] seizure A seizure is a physical finding or change in behavior that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." Convulsions are when a person's body shakes rapidly and uncontrollably. During a spasm, a person's muscles contract and relax repeatedly.

[0284] Based on the type of behavior and brain activity, seizures are divided into two broad categories: systemic and partial (also called focal or focal). Classifying seizure types assists physicians in diagnosing whether a patient has epilepsy.

[0285] Generalized seizures are caused by electrical impulses from the entire brain, whereas focal seizures are caused (at least initially) by electrical impulses from a smaller portion of the brain. The part of the brain that generates seizures is sometimes called the lesion.

[0286] There are six types of generalized seizures. The most common and dramatic, and therefore the best known, are generalized seizures (also called grand mal seizures). In this type of attack, the patient loses consciousness and usually collapses. This loss of consciousness is followed by 30 to 60 seconds of general body rigidity (called the "tonic" phase of the attack), followed by 30 to 60 seconds of severe convulsions (the "clonic" phase), after which the patient experiences deep Falling into sleep (the "postictal" or after-seizure stage). During grand mal seizures, disorders and accidents (eg, tongue biting and urinary incontinence) can occur.

[0287] Absence seizures cause a brief loss of consciousness (just a few seconds) with few or no symptoms. The patient, most often a child, typically suspends activities and stares blankly. These attacks start and end unexpectedly and can occur several times a day. Patients usually do not realize they are having a seizure, unless they can notice that they are "losing time."

[0288] Myoclonic seizures consist of sporadic spasms, usually on both sides of the body. Patients sometimes describe these contractions as short electric shocks. If severe, these attacks can result in dropping objects or involuntary throwing.

[0289] Clonic seizures are repetitive, rhythmic spasms that involve both sides of the body at the same time.

[0290] Tonic seizures are characterized by muscle stiffness.

[0291] Atonic attacks consist of a sudden loss of muscle tone throughout the body (particularly in the arms and legs), often resulting in a fall.

[0292] Seizures as described herein include: epileptic seizures; acute recurrent seizures; cluster seizures; continuous seizures; continuous seizures; persistent seizures; recurrent seizures; status epilepticus, e.g. Status epilepticus, nonconvulsive status epilepticus; intractable seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence Seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; laughter seizures; generalized onset seizures; cephalic seizures; Jaxon seizures; generalized bilateral myoclonic seizures; May include focal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; microseizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.

Example

[0293] In order that the invention described herein may be more fully understood, the following examples are presented. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are in no way intended to limit the scope thereof. It should not be interpreted as such.

[0294] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Although typical or preferred process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressure, etc.) are given, it is understood that other process conditions may also be used, unless otherwise stated. Ru. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization.

[0295] Additionally, as may be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of suitable protecting groups for particular functional groups and conditions suitable for protection and deprotection are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991 and references cited therein. There is.

[0296] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail for the preparation of representative pyrazoles listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL( Registered trademark) OB-H, CHIRALCEL (registered trademark) OD, CHIRALCEL (registered trademark) OD-H, CHIRALCEL (registered trademark) OF, CHIRALCEL (registered trademark) OG, CHIRALCEL (registered trademark) OJ and CHIRALCEL (registered trademark) OK These include, but are not limited to:

[0297] as reported herein (e.g. for intermediates) 1 H-NMR can be a partial representation of the entire NMR spectrum of a compound (eg, a compound described herein). For example, reported 1 H NMR can exclude a region of δ(ppm) between about 1 ppm and about 2.5 ppm. Full details about representative examples 1 A copy of the H-NMR spectrum is given in the drawing.

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

[0299] General method for analytical HPLC: Mobile phase: A: Water (10mM NH 4 HCO 3 ), B: Acetonitrile gradient: 5% to 95% B for 1.6 min or 2 min. Flow rate: 1.8 or 2mL / min; Column: XBridge C18, 4.6 x 50mm, 3.5μm, 45C.

[0300] Synthesis procedure Compounds of the invention can be prepared using appropriate reagents, starting materials and purification methods known to those skilled in the art, using methods reported in the art (Upasani et al., J. Med. Chem. 1997, 40:73-84). ; and Hogenkamp et al., J.Med.Chem.199 7,40:61-72). In some embodiments, the compounds described herein are prepared using the methods depicted in General Schemes 1-4, which involve nucleophilic substitution of 19-norpregnane bromide with a nucleophile. , can be prepared. In certain embodiments, the nucleophile is 19-norpregnane bromide and K in THF. 2 C.O. 3 reacts in the presence of

[0301] [ka]

[0302] [ka]

[0303] Example 1. Synthesis of SA and SA intermediates

[0304] [ka]

[0305] Synthesis of compound SA-B. Compound SA (50 g, 184 mmol) and palladium black (2.5 g) in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL) were hydrogenated with 10 atm hydrogen. After stirring for 24 hours at room temperature, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give the crude compound. Recrystallization from acetone gave compound SA-B (42.0 g, yield: 83.4%) as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24 (s, 3H), 2.18-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H), 1.53-1.37 (m, 7H), 1.29-1.13 (m, 3H), 1.13-0.90 (m, 2H), 0.89 (s, 3H).

[0306] Synthesis of compound SA-C. A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL of anhydrous toluene was added to methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide (MAD)) (459.19 mmol, 3.0 eq, freshly (prepared) solution with N 2 It was added dropwise at -78°C. After the addition was complete, the reaction mixture was stirred at -78°C for 1 hour. Then, 3.0M MeMgBr (153.06mL, 459.19mmol) was added to the above mixture with N 2 It was added slowly dropwise at -78°C. The reaction mixture was then stirred at this temperature for 3 hours. TLC (petroleum ether / ethyl acetate=3:1) showed the reaction was complete. Then saturated aqueous NH 4Cl was slowly added dropwise to the above mixture at -78°C. After the addition is complete, the mixture is filtered, the filter cake is washed with EtOAc, the organic layer is washed with water and brine, and anhydrous Na 2 S.O. 4 dried, filtered and concentrated on silica gel. Purification by flash chromatography (petroleum ether / ethyl acetate 20:1 to 3:1) gave compound SA-C (40.2 g, yield: 90.4%) as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 2.47-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.96-1.74 (m, 6H), 1.70-1.62 (m, 1H), 1.54-1.47 ( m, 3H), 1.45-1.37 (m, 4H), 1.35-1.23 (m, 8H), 1.22-1.10 (m, 2H), 1.10-1.01 (m, 1H), 0.87 (s, 3H).

[0307] Synthesis of compound SA-D. PPh 3 To a solution of EtBr (204.52 g, 550.89 mmol) in THF (500 mL) was added a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0°C. After the addition was complete, the reaction mixture was stirred at 60°C for 1 hour, then SA-C (40.0g, 137.72mmol) dissolved in THF (300mL) was added dropwise at 60°C. The reaction mixture was heated at 60°C for 18 hours. The reaction mixture was cooled to room temperature and Sat.NH 4 Quenched with Cl and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine, dried, and concentrated to give the crude product, which was purified by flash column chromatography (petroleum ether / ethyl acetate 50:1 to 10:1) to give compound SA-D (38.4 g, yield: 92%) was obtained as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H), 1.89-1.80 (m, 3H), 1.76-1.61 ( m, 6H), 1.55-1.43 (m, 4H), 1.42-1.34 (m, 3H), 1.33-1.26 (m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).

[0308] Synthesis of compound SA-E. A solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL) was added with BH 3 .Me 2 A solution of S (126 mL, 1.26 mol) was added dropwise under an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature (14° C.-20° C.) for 3 hours. TLC (petroleum ether / ethyl acetate 3:1) showed the reaction was complete. The mixture was cooled to 0 °C and treated with 3.0 M aqueous NaOH (400 mL) followed by 30% aqueous H 2 O 2 (30%, 300mL) was added. The mixture was stirred at room temperature (14° C.-20° C.) for 2 hours, then filtered and extracted with EtOAc (3×500 mL). The combined organic layers were hydrated with saturated aqueous Na 2 S 2 O 3 , washed with brine, Na 2 S.O. 4 and concentrated in vacuo to give the crude product (43 g, crude) as a colorless oil. This crude product was used in the next step without further purification.

[0309] Synthesis of compound SA-F. To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL) at 0° C. was added PCC (53.8 g, 268.32 mmol) in portions. This reaction mixture was then stirred at room temperature (16°C to 22°C) for 3 hours. TLC (petroleum ether / ethyl acetate 3:1) showed the reaction was complete, so the reaction mixture was filtered and washed with DCM. The organic phase is saturated with aqueous Na 2 S 2 O 3 , washed with brine, Na 2 S.O. 4 and concentrated in vacuo to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate 50:1 to 8:1) to yield compound SA-F (25.0 g, yield: 62.5%, over two steps) as a white powder. Obtained. 1 H NMR (SA-F):(400 MHz, CDCl3) δ 2.57-2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 3H) , 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m, 10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).

[0310] Synthesis of compound SA. To a solution of SA-F (10 g, 31.4 mmol) and aq.HBr (5 drops, 48% in water) in 200 mL of MeOH, bromine (5.52 g, 34.54 mmol) was added dropwise. The reaction mixture was stirred at 17°C for 1.5 hours. The resulting solution was saturated with aqueous NaHCO 3 Quenched at 0° C. and extracted with EtOAc (150 mL×2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel eluting with (PE:EA=15:1 to 6:1) to give compound SA (9.5 g, yield: 76.14%) as a white solid. LC / MS: rt 5.4min; m / z 379.0, 381.1, 396.1.

[0311] Example 2. Synthesis of SB and SB intermediates

[0312] [ka]

[0313] [ka]

[0314] Synthesis of compounds SB-B and SB-C. A small piece of lithium (7.63 g, 1.1 mol) was added to 2.7 L of concentrated ammonia at -70° C. in a three-necked flask. all lithium Once dissolved, the blue solution was warmed to -50°C. A solution of 19-norandrost-4-ene-3,17-dione SB-A (1,30 g, 110 mmol) and tert-BuOH (8.14 g, 110 mmol) in 800 ml of anhydrous tetrahydrofuran is added dropwise and The reaction mixture was stirred for 90 minutes until it turned light yellow. Ammonium chloride (70g) was added and excess ammonia was evaporated. The residue was extracted with 0.5N HCl (500 mL) and dichloromethane (500 mL x 2). Saturate the combined organic layers with NaHCO 3 Wash with Na 2 S.O. 4 , filtered, and concentrated to give a mixture of SB-B and SB-C (21 g, 70%), which was used directly in the next step without further purification. A solution of SB-B and SB-C (21 g, 76 mmol) in 50 mL of anhydrous dichloromethane was added to a suspension of pyridinium chloroformate (PCC) (32.8 g, 152 mmol) in 450 mL of dichloromethane. After stirring for 2 hours at room temperature, 2N NaOH solution (500 mL) was added to the dark brown reaction mixture and stirred for an additional 10 minutes. The resulting solution was extracted with dichloromethane and the combined organic layers were washed with 2N HCl, brine and Na 2 S.O. 4 dried, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 20:1 to 10:1) to give the title compound SB-C (16.8 g, 80%) as a white solid. SB-B's 1 H NMR(400 MHz, CDCl 3 ), δ (ppm), 3.65 (t, 1H, 1H), 0.77 (s, 3H). SB-C's 1 H NMR(400 MHz, CDCl 3 ), δ (ppm), 0.88 (s, 3H).

[0315] Synthesis of compound SB-D. To a solution of compound SB-C (16.8 g. 61.3 mmol) in methanol (250 mL) was added iodine (1.54 g, 6.1 mmol). After stirring at 60°C for 12 hours, the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (200 mL) and saturated NaHCO 3 (150 mL), washed with brine, Na 2 S.O. 4 dried, filtered and concentrated. The residue was purified by chromatography on basic alumina (petroleum ether / ethyl acetate=100:1) to obtain compound SB-D (14 g, 43.8 mmol, 71%). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 3.18 (s, 3H), 3.12 (s, 3H), 0.85 (s, 3H).

[0316] Synthesis of compound SB-E. To a suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL) at 0°C was slowly added ethyltriphenylphosphonium bromide (26 g, 70 mmol). After stirring at 60°C for 3 hours, compound SB-D (7g, 21.9mmol) was added and the mixture was stirred at 60°C for an additional 2 hours. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield crude compound SB-E (7.36 g, 100%). This crude product was used in the next step without further purification.

[0317] Synthesis of compound SB-F. A solution of crude compound SB-E (7.36 g, 21.9 mmol) in THF (50 mL) was acidified to pH=3 with 1N aqueous HCl. After stirring at room temperature for 12 hours, the reaction mixture was extracted with ethyl acetate (250 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30:1 to 20:1) to obtain compound SB-F (4.8 g, 16.7 mmol, 76% for 2 steps). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 5.12-5.10 (m, 1H), 0.77 (s, 3H).

[0318] Synthesis of compound SB-G. MeMgBr (28 mmol, 1 M in THF) in THF (50 A solution of compound SB-F (4.8 g, 16.8 mmol) in dry THF (10 mL) was added via syringe pump over 30 minutes at 0°C. After stirring at 0° C. for 5 hours, the reaction mixture was warmed up and stirred at room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was purified by flash column chromatography (petroleum ether / ethyl acetate=20:1 to 10:1) to yield compound SB-G (2.5 g, 8.28 mmol, 49%; Rf=0.35, petroleum ether / acetic acid Ethyl=10:1) was obtained. 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 5.05-5.03 (m, 1H), 1.21 (s, 3H), 0.90 (s, 3H).

[0319] Synthesis of compound SB-H. To a solution of compound SB-G (2 g, 6.62 mmol) in dry THF (50 mL) was added borane-tetrahydrofuran complex (20 mL; 1.0 M solution in THF). After stirring for 1 h at room temperature, the reaction mixture was cooled in an ice bath and then treated with 10% aqueous NaOH (10 mL) followed by H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution (12 mL) of . After stirring at room temperature for 1 h, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (100 mL), washed with brine (100 mL), MgSO 4 , filtered, and concentrated to give crude compound SB-H (2 g, 100%). This crude product was used in the next step without further purification.

[0320] Synthesis of compound SB-I. The crude compound SB-H (2 g, 6.62 mmol) was dissolved in 60 mL of wet dichloromethane (dichloromethane was mixed with a few milliliters of H 2 Dess-Martin periodinate (5.5 g, 13 mmol) was added to the solution in water (shaken with O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (100 mL), washed with brine (100 mL), MgSO 4 dried, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 10:1 to 5:1) to give compound SB-I (1 g, 3.14 mmol, 47% for 2 steps) as a white solid. . 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 2.56 (t, 1H), 2.11 (s and m, 4H), 2.0 (dt, 1H), 1.8 (dm, 2H), 1.54 (m, 6 H) 1.43 (m, 1H) , 1.34 (m, 2H),1.20 (m, 12H), 0.7 (m, 2H), 0.62(s, 3H).

[0321] Synthesis of compound SB. To a solution of compound SB-I (600 mg, 1.89 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) followed by bromine (302 mg, 1.89 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL) and MgSO 4 dried, filtered and concentrated to give crude compound SB (600 mg).

[0322] Synthesis of compound SB-J. A solution of compound SB (600 mg, 1.5 mmol) in 10 mL of acetone was added to CF 3 COOH (6.8mL) and Et 3 Treated with N (9.5 mL). After refluxing for 30 min, CF 3 COONa salt (4.49g, 33mmol) was added in portions over 10 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate and MgSO 4 dried, filtered and concentrated. The mixture was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 10:1 to 3:1) to give SB-J (300 mg, yield: 50% for 2 steps). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 4.23-4.13 (m, 2H), 2.48-2.44 (m), 0.64 (s, 3H).

[0323] Example 3. Synthesis of SA-V compound

[0324] [ka]

[0325] Synthesis of compound SA-K. Compound SA-J (10 g, 36.7 mmol) was added to 50 mL of acetyl chloride and 50 mL of acetic anhydride. The reaction mixture was heated at 120° C. for 5 hours and evaporated in vacuo to give SA-K as a white solid (10 g, 87% yield). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 5.7 8 (s, 1H), 5.55 (s, 1H),2.4(2H,dd),2.13 (s, 3H), 0.90 (s, 3H).

[0326] Synthesis of compound SA-L. Reactant SA-K (10 g, 31.8 mmol) in 200 mL THF and 20 mL H 2 To a solution in O was added mCPBA (11 g, 63.6 mmol) at 0 °C and stirred at room temperature for 15 h, the reaction mixture was extracted with 500 mL of EtOAc and 100 mL of saturated Na 2 S.O. 3 , 100mL saturated NaHCO 3 and 100 mL brine and evaporated in vacuo and then purified by silica gel flash chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give SA-L-1 as a white solid (2.2 g, yield 24%) (first elute), and SA-L as a white solid (1.1 g, yield 12%) (second elute). SA-L-1:1H NMR (400 MHz, CDCl3), δ (ppm), 5.92 (s, 1H), 4.44 (s, 1H), 0.95 (s, 3H). SA-L:1H NMR (400 MHz, CDCl3), δ (ppm), 6.25 (s, 1H), 4.28-4.25 (m, 1H), 0.93 (s, 3H).

[0327] Synthesis of compound SA-M. To a solution of SA-L (2 g, 6.94 mmol) in 50 mL of EtOAc was added 200 mg of Pd\C. Add this reaction mixture to 1 atm H 2 The mixture was hydrogenated for 15 hours. The reaction mixture was evaporated in vacuo and then purified by chromatography (petroleum ether / ethyl acetate=1:2) to give SA-M as a white solid (1.5 g, 75% yield). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 3.97 (td, 1H), 0.88 (s, 3H).

[0328] Synthesis of compound SA-N. To a solution of SA-M (1 g, 3.4 mmol) in 100 mL of MeOH was added 50 mg of TsOH and heated at 60° C. for 2 hours. The reaction mixture was extracted with 500 mL of EtOAc and 100 mL of sat.NaHCO 3 , washed with 100 mL brine solution and evaporated in vacuo to give SA-N as a white solid (1 g, 91% yield).

[0329] Synthesis of compound SA-O. To a solution of ethyltriphenylphosphonium bromide (10.67g, 28.84mmol) in 30mL of THF was added KOt-Bu (3.23g, 28.80mmol). The reaction was heated at 60°C for 1 hour. SA-N (3.23g, 9.6mmol) was added to this mixture and stirred at 60°C for 15 hours. The reaction mixture was extracted with 500 mL of EtOAc, washed with brine solution and evaporated in vacuo, then purified by chromatography (petroleum ether / ethyl acetate = 3:1) to give SA-O as a white solid. (2 g, yield 62%). 1 H NMR (400 MHz, MeOD), δ (ppm) 5.15-5.12 (m, 1H), 3.80-3.78 (m, 1H), 3.21 (s, 3H), 3.15 (s, 3H), 1.67 (d, 3H), 0.95 (s, 3H).

[0330] Synthesis of compound SA-P. To a solution of SA-O (0.5 g, 1.43 mmol) in 10 mL of DCM was added 0.5 mL of DAST at -78 °C. The reaction mixture was stirred at -78 °C for 30 min, then 5 mL of sat.NaHCO 3 , extracted with 50 mL of DCM, washed with brine, dried and concentrated in vacuo and purified by chromatography (petroleum ether / ethyl acetate = 30:1) to give SA-P as a white solid. 175 mg was obtained in a yield of 35%.

[0331] Synthesis of compound SA-Q. To a solution of SA-P (350 mg, 1 mmol) in 20 mL of THF was added 2 mL of 2M HCl and stirred at room temperature for 1 hour. Add this reaction mixture to 5 H in mL 2 Quenched with O and extracted with 100 mL of EtOAc, washed with brine and evaporated in vacuo, then purified by chromatography (petroleum ether / ethyl acetate = 10:1) to yield SA-Q as a white solid. (210 mg, yield 60%). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm) 5.17-5.14 (m, 1H), 4.80-4.66 (m, 1H), 2.61-2.57 (m, 1H), 1.79 (d, 3H), 0.93 (s, 3H).

[0332] Synthesis of compound SA-R. To a stirred solution of trimethylsulfonium iodide (3.2 g, 16 mmol) in 10 mL of DMSO was added NaH (60%; 400 mg, 16 mmol). After stirring for 1 hour at room temperature, a suspension of SA-Q (486 mg, 1.6 mmol) in 5 mL of DMSO was added dropwise. After 15 hours, the reaction mixture was poured into ice-cold water (100 mL) and extracted with 300 mL of EtOAc, washed with 100 mL of brine solution and evaporated in vacuo, then chromatographed (petroleum ether / ethyl acetate = 10 :1) to obtain SA-R and its isomer as a white solid (290 mg, yield 58%).

[0333] Synthesis of compound SA-S. A solution of SA-R and its isomers (300 mg, 0.94 mmol) in 10 mL of THF was added with LiAH 4 (100 mg, 2.7 mmol) was added and stirred at room temperature for 1 hour. Transfer this reaction mixture to 5 mL of H 2 Quenched with O and extracted with 100 mL of EtOAc, washed with brine and evaporated in vacuo, then purified by chromatography (petroleum ether / ethyl acetate = 3:1) to yield SA-S as a white solid. (140 mg, yield 48%). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm) 5.15-5.12 (m, 1H), 4.72-4.60 (m, 1H), 1.70 (apparent d within m), 1.27 (apparent s within m), 0.92 (s, 3H).

[0334] Synthesis of compound SA-T. To a solution of SA-S (100 mg, 0.3 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then treated with 10% aqueous NaOH (1 mL), followed by H 2 O 2 was slowly quenched with a 30% aqueous solution (1 mL) of After stirring at room temperature for 1 h, the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (100 mL), washed with brine (100 mL), MgSO 4 dried, filtered, and concentrated to give SA-T as a white solid (100 mg, 91%). This crude product was used in the next step without further purification.

[0335] Synthesis of compound SA-U. To a solution of SA-T (100 mg, 0.29 mmol) in 20 mL of DCM was added PCC (190 mg, 0.87 mmol) and stirred at room temperature for 2 hours. Add this reaction mixture to 5 mL of H 2 Quenched with O and extracted with 100 mL of EtOAc, washed with brine and evaporated in vacuo, then purified by chromatography (petroleum ether / ethyl acetate = 3:1) to yield SA-U as a white solid. (53 mg, yield 53%). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm) 4.71-4.57 (m, 1H), 2.54(1H, t), 1.28 (apparent s within m), 0.58 (s, 3H).

[0336] Synthesis of compound SA-V. To a solution of SA-U (40 mg, 0.11 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%) followed by bromine (150 mg, 0.33 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with EtOAc (10 mL x 3). Combined organic layers with brine (20 mL) Wash and MgSO 4 , filtered, and concentrated to give the crude compound SA-V as a white solid (40 mg, 80% yield). This crude product was used in the next step without further purification.

[0337] Example 4. Synthesis of SB-W compound

[0338] [ka]

[0339] To a stirred solution of trimethylsulfonium iodide (8.1 g, 36.9 mmol) in 100 mL of DMSO was added NaH (60%; 1.26 g, 31.5 mmol). After stirring for 1 hour at room temperature, a suspension of compound SB-F (2.2 g, 7.2 mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred for an additional 2.5 hours, then poured into ice-cold water and extracted with ether (100 mL x 3). The combined ether layers were then washed with brine (100 mL x 3) and MgSO 4 dried, filtered and concentrated to give the crude product SB-S (2.2g). This crude product was used in the next step without further purification.

[0340] Synthesis of compound SB-T. Compound SB-S (2.2 g, 7.3 mmol) was dissolved in dry ethanol (250 mL) and Na (672 mg, 29.2 mmol) was added. The solution was stirred at reflux for 6 hours. Ethanol was removed by evaporation and the residue was dissolved in dichloromethane and H 2 Wash with O (3 x 50 mL) and brine (100 mL), MgSO 4 dried, filtered and concentrated. The crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:1 to 5:1) and concentrated to give SB-T (1.8 g, 82%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 5.03-5.01 (m, 1H), 3.43 (q, 2H), 3.13 (s, 2H), 0.80 (s, 3H).

[0341] Synthesis of compound SB-U. To a solution of compound SB-T (1.8 g, 5.2 mmol) in dry THF (50 mL) was added borane-tetrahydrofuran complex (1.0 M solution in 20 mL of THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then treated with 10% aqueous NaOH (10 mL), then H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution (12 mL) of . The mixture was stirred at room temperature for 1 h, then extracted with EtOAc (3 x 100 mL). The combined organic layers were diluted with 10% aqueous Na 2 S2 O 3 (100 mL), washed with brine (100 mL), MgSO 4 dried, filtered and concentrated, Crude compound SB-U (1.8 g, 100%) was obtained. This crude product was used in the next step without further purification.

[0342] Synthesis of compound SB-V. Crude compound SB-U (1.8 g, 5.2 mmol) was added to 60 mL of H 2 O saturated dichloromethane (dichloromethane with a few milliliters of H 2 Dess-Martin periodinate (4.4 g, 10.4 mmol) was added to the solution dissolved in the solution (shaken with O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (100 mL), washed with brine (100 mL), MgSO 4 dried, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 10:1 to 5:1) to give SB-V (1 g, 2.8 mmol, 56% for 2 steps) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 3.52 (q, 2H), 3.21 (s, 2H), 2.54 (t, 2H), 2.11 (s, 3H), 1.20 (t, 3H), 0.61 (s, 3H). LCMS:Rt=7.25min.m / z=345.1[M-17] + .

[0343] Synthesis of compound SB-W. To a solution of compound SB-V (600 mg, 1.65 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) followed by bromine (264 mg, 1.65 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL) and MgSO 4 dried, filtered, and concentrated to give crude compound SB-W (600 mg, 100%). This crude product was used in the next step without further purification. LCMS:Rt=7.25min.m / z=463.1[M+Na] + .

[0344] Example 5. Synthesis of SA-AA compound

[0345] [ka]

[0346] Synthesis of compound SA-X. To a solution of EtMgBr (5 mmol, 1 M in THF) in THF (20 mL) at 0 °C was added a solution of compound SA-W (858 mg, 3 mmol) in dry THF (5 mL) via a syringe pump for 30 min. and added. After stirring at 0° C. for 5 hours, the reaction mixture was warmed up and stirred at room temperature overnight. Pour this reaction mixture into ice-cold water. and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 20:1 to 10:1) to obtain compound SA-X (900 mg).

[0347] Synthesis of compound SA-Y. To a solution of compound SA-X (200 mg, 0.66 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.0 M solution in 2 mL of THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then treated with 10% aqueous NaOH (1 mL), followed by H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution (1.2 mL) of . The mixture was stirred at room temperature for 1 h, then extracted with EtOAc (3 x 10 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (10 mL), washed with brine (10 mL), MgSO 4 dried, filtered, and concentrated to give compound SA-Y (260 mg, crude). This crude product was used in the next step without further purification.

[0348] Synthesis of compound SA-Z. PCC (449 mg,) was added to a solution of compound SA-Y (260 mg, crude) in 10 mL of dichloromethane. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with 10% aqueous NaCl (10 mL), brine (10 mL), and MgSO 4 dried, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 4:1 to 2:1) to give the title SA-Z (15 mg,) as a white solid. 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 2.49 (1H, t), 0.84(,t 3H), 0.59 (s, 3H).

[0349] Synthesis of compound SA-AA. To a solution of compound SA-Z (30 mg, 0.09 mmol) in MeOH (5 mL) were added 2 drops of HBr (48%) followed by bromine (100 mg, 0.62 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water, then extracted with ethyl acetate (15 mL x 3), the combined organic layers were washed with brine (20 mL), and MgSO 4 dried, filtered, and concentrated to yield compound SA-AA (36 mg crude). This crude product was used in the next step without further purification.

[0350] Example 6. Synthesis of SA-JJ compound

[0351] [ka]

[0352] Synthesis of compounds SA-DD and SA-EE. Compound mixture SA-BB and SA-CC (5.0 g, 16.7 mmol) was dissolved in dry methanol (250 mL) and metallic Na (1.2 g, 50.0 mmol) was added and the solution was refluxed for 16 hours. Methanol is then removed by evaporation and the residue is dissolved in dichloromethane and H 2 Wash with O (3 x 50 mL) and brine (100 mL), MgSO 4 dried, filtered and concentrated. The crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) and concentrated to yield product mixtures SA-DD and SA-EE (4.6 g, 83%). was obtained as a white solid.

[0353] Synthesis of compounds SA-FF and SA-GG. A solution of reactant mixtures SA-DD and SA-EE (4.6 g, 13.9 mmol) in anhydrous THF (30 mL) was added with BH 3 .THF (1.0M, 27.7mL, 27.7mmol) was added and the solution was stirred at 25°C overnight, then the reaction was quenched by the addition of water (5mL). Add 2M NaOH solution (30mL) followed by 30% H 2 O 2 (30 mL) was added. This mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product mixture was used directly in the next step without further purification.

[0354] Synthesis of compounds SA-HH and SA-II. To a solution of the crude reactant mixtures SA-FF and SA-GG (4.9 g, 13.9 mmol, theoretical) in dichloromethane (40 mL) was added pyridinium chloroformate (PCC) in portions (6.0 g, 27.8 mmol). The solution was stirred at 25° C. overnight, then the mixture was filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3×50 mL). All filtrates were combined and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15:1) to give the product SA-HH (2.1 g, 6.03 mmol, yield = 43% (2 steps)) as a white solid, and The product SA-II (2.2 g, 6.32 mmol, yield=45% (2 steps)) was obtained as a white solid. Compound SA-HH: 1 HNMR (500 MHz, CDCl3) δ (ppm):3.40 (s, 3H), 3.20 (s, 2H), 2.62-2.51 (m, 2H), 2.11 (s, 3H), 2.02-1.99 (m, 2H), 0.62 (s, 3H). Compound SA-II: 1 HNMR (500 MHz, CDCl3) δ (ppm):3.42 (AB, 1H), 3.38 (AB, 1H), 3.40 (s, 3H), 2.65 (s, 1H), 2.54 (t, 1H), 2.16-2.14 (m, 1H), 2.11 (s, 3H), 2.02-1.98 (m, 1H), 0.61 (s, 3H).

[0355] Synthesis of compound SA-JJ. To a solution of reactant SA-II (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine (241 mg, 0.077 mL, 1.51 mmol). was added. The solution was heated at 25° C. for 1.5 hours, then the mixture was poured into cold water (50 mL) and the resulting solid was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SA-JJ was used directly in the next step without further purification.

[0356] Example 8. Synthesis of SB-R compound

[0357] [ka]

[0358] Synthesis of compound SB-K. To a solution of compound SB-E (5 g, 15 mmol) in dry THF (20 mL) was added borane-tetrahydrofuran complex (30 mL of a 1.0 M solution in THF) and the reaction mixture was stirred at ambient temperature for 1 h. , then 10% aqueous NaOH (56 mL) was added slowly. The mixture was cooled in ice and H 2 O 2 A 30% aqueous solution (67 mL) of was slowly added. The mixture was stirred at ambient temperature for 1 h, then extracted with EtOAc (3 x 100 mL). The combined EtOAc extracts were diluted with 10% aqueous Na 2 S 2 O 3 (100 mL), washed with brine (100 mL), MgSO 4 It was dried with. Filtration and removal of solvent gave 3.2 g of crude product for next step reaction.

[0359] Synthesis of compound SB-L. To a solution of compound SB-K (3.2 g, 9 mmol) in THF (40 mL) was added 2M HCl (3 mL). The reaction solution was stirred at room temperature for 12 hours, then the solvent was removed under reduced pressure. The crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:1 to 5:1) to obtain 2.2 g of product as a white solid. Yield: 81.40%.

[0360] Synthesis of compound SB-M. To a stirred solution of trimethylsulfonium iodide (6.43 g, 31.5 mmol) in 100 mL of DMSO was added 60 wt% NaH (1.26 g, 31.5 mmol). After stirring for 1 hour at room temperature (15° C.), a solution of compound SB-L (2.2 g, 7.2 mmol) in 20 mL of DMSO was added dropwise. After 2.5 hours, the reaction mixture was poured into ice-cold water and extracted with ether (100 mL x 3). The combined ether layers were then washed with brine (100 mL x 3) and dried (MgSO 4 ), filtered and concentrated to obtain 1.6 g of crude product for next step reaction.

[0361] Synthesis of compound SB-N. Compound SB-M (1.6 g, 5 mmol) was added to 60 mL of H 2 O saturated CH 2 Cl 2 It was dissolved in (Using a separatory funnel, CH 2 Cl 2 A few milliliters of H 2 shaken with O and then separated from the aqueous layer). DMP was added (4.2g, 10mmol) and the resulting reaction mixture was stirred vigorously for 24 hours. This reaction solution diluted with DCM (100 mL) and added with 10% aqueous Na 2 S 2 O 3 (100 mL), washed with brine (100 mL), MgSO 4 dried, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 20:1 to 10:1) to yield 1.2 g, 3.79 mmol, 75% of the title compound as a white solid. 1 H NMR (400 MHz, CDCl3) δ (ppm): 2.63 (s, 1H), 2.59 (s, 1H), 2.12 (s, 3H), 0.63 (s, 3H).

[0362] Synthesis of SB-P and SB-Q. Compound SB-N (1.2 g, 3.8 mmol) was dissolved in dry methanol (250 mL) and Na (262 mg, 11.4 mmol) was added. This solution was refluxed for 16 hours. Methanol was removed by evaporation and the residue was dissolved in dichloromethane and H 2 Wash with MgSO (3 x 50 mL) and brine (100 mL). 4 dried, filtered and concentrated. This crude target compound was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain SB-P (300 mg, 25%) and SB-Q (300 mg, 25%) as white solids. Obtained as SB-P:1H NMR (400 MHz, CDCl3) δ (ppm):3.39 (s, 3H), 3.19 (s, 2H), 2.54 (t, 1H), 0.61 (s, 3H). SB-Q:1H NMR (400 MHz, CDCl3) δ (ppm): 3.39 (s, 5H),3.37 (s, 2H), 2.52 (t, 1H), 0.62 (s, 3H).

[0363] Synthesis of compound SB-R. To a solution of reactant SB-P (190 mg, 0.545 mmol) in methanol (15 mL) was added 48% hydrobromic acid (275 mg, 1.635 mmol) followed by bromine (435 mg, 0.139 mL, 2.725 mmol). was added. This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solution was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0364] Example 9. Synthesis of SB-FF compound

[0365] [ka]

[0366] Synthesis of compound SB-KK. SA-K (68g,216.27mmol) in 600mL CH 3 Selectflour (90.22g, 324.4mmol) was added in portions to the solution in CN at -4°C. The resulting reaction mixture was stirred at -4°C for 3 hours. After the TLC showed the reaction was complete, the mixture was filtered and concentrated. The product was purified by column chromatography on silica gel eluting with (petroleum ether / ethyl acetate 20:1~15:1~10:1~8:1~6:1~5:1) and SB -KK (26.3 g, yield 41.8%) was obtained as a white solid. 1 H NMR (SB-KK) (400 MHz, CDCl 3 ), δ (ppm), 6.02-5.94 (m, 1H,), 5.20-5.01 (m, 1H), 2.55-2.26 (m, 6H), 2.16-2.05 (m, 1H), 2.01-1.83 (m, 4H), 1.48-1.22 (m, 5H), 0.98-0.78 (m, 6H).

[0367] Synthesis of compound SB-X. To a solution of SB-KK (27 g, 92.98 mmol) in EtOAc (350 mL) at 20° C., Pd / C (2.7 g, 5%) was added into this mixture. The solution was stirred under hydrogen at 20° C. and 1 atm for 10 hours. After the LCMS showed the reaction was complete, the mixture was filtered and concentrated. The product was eluted with a column of silica gel (petroleum ether / ethyl acetate 40:1~35:1~30:1~25:1~20:1~15:1~10:1~6:1). Purification by chromatography gave SB-X (15.6 g, 56.38%) as a white solid. 1 H-NMR (SB-X) (400 MHz, CDCl 3 ), δ (ppm)=4.68-4.56 (m, 1H), 2.64-2.51 (m, 1H), 2.53-2.03 (m, 8H), 1.97-1.80 (m, 4H), 1.49-1.20 (m, 6H) ), 0.96-0.92 (m, 2H), 0.88-0.78 (m, 1H).

[0368] Synthesis of compound SB-Y. MeOH(60 0 mL) at 23° C., then 2.35 g of TsOH was added into this mixture. This solution was stirred at 60°C for 1.5 hours. After the TLC showed the reaction was complete, the mixture was filtered and concentrated to give SB-Y (35 g, 64.33%) as a white solid. 1 H NMR (SB-Y) (400 MHz, CDCl 3), δ (ppm)=4.74-4.57 (m, 1H), 3.16 (s, 3H), 3.10 (s, 3H), 2.47-2.35 (m, 1H), 2.15-2.09 (m, 1H), 2.06- 1.82 (m, 6H), 1.77-1.15 (m, 11H), 1.05-0.96 (m, 1H), 0.89 (s, 3H), 0.83-0.77 (m, 1H).

[0369] Synthesis of compound SB-Z. To a solution of ethyltriphenylphosphonium bromide (115.17g, 310.23mmol) in 150mL of THF was added KOt-Bu (34.81g, 310.23mmol). The reaction mixture was heated at 60°C for 1 hour and SB-Y (35g, 103.41 mmol) was added to the mixture, which was stirred at 60°C for an additional 15 hours. The reaction mixture was cooled and extracted with 1500 mL of EtOAc, washed with brine, and concentrated to give SB-Z as a white solid (120 g, crude). 1 H NMR (SB-Z) (400 MHz, CDCl 3 ), δ (ppm)=5.13-5.07 (m, 1H), 4.67-4.54 (m, 1H), 3.14 (s, 3H), 3.09 (s, 3H), 2.42-2.15 (m, 3H), 1.92- 1.79 (m, 3H), 1.67-1.61 (m, 4H), 1.57-1.50 (m, 2H), 1.45-1.15 (m, 10H), 1.01-0.94 (m, 1H), 0.92 (s, 3H), 0.90-0.84 (m, 1H).

[0370] Synthesis of compound SB-AA. To a solution of SB-Z (120 g, crude) in 600 mL of THF was added 90 mL of 2M aqueous HCl. The reaction mixture was stirred at 22°C for 1 hour. After the TLC shows that the reaction is complete, convert the reaction into aq.NaHCO 3 I quenched it. The reaction was extracted with 500 mL of EtOAc, washed with brine, and evaporated in vacuo. The obtained residue was purified by chromatography (petroleum ether / ethyl acetate = 150:1~125:1~100:1~80:1~60:1~50:1) to obtain SB-AA as a white solid. (24 g, yield 76.23%). 1 H NMR (SB-AA) (400 MHz, CDCl 3 ), δ (ppm)=5.13 (m, 1H), 4.65-4.48 (m, 1H), 2.62-2.42 (m, 1H), 2.44-2.07 (m, 8H), 1.92-1.80 (m, 1H), 1.72-1.55 (m, 8H), 1.36-1.08 (m, 6H), 0.92 (s, 3H), 0.83-0.73 (m, 1H).

[0371] Synthesis of compound SB-BB. Me 3 To a solution of SOI (78.07 g, 354.75 mmol) in 50 mL of THF was added a solution of t-BuOK (39.81 g, 354.75 mmol) in 50 mL of THF. The reaction mixture was stirred at 60°C for 1.5 hours. A solution of SB-AA (24 g, 78.83 mmol) in THF (300 mL) was then added to the reaction. The reaction was stirred at 23°C for 2.5 hours. After the TLC showed the reaction was complete, the reaction was quenched with ice water. The reaction was extracted with 500 mL of EtOAc, washed with brine, and evaporated in vacuo to give SB-BB as the crude product (50 g). 1 H NMR (SB-BB) (400 MHz, CDCl 3 ), δ (ppm)=5.20-5.11 (m, 1H), 4.65-4.52 (m, 1H), 2.74-2.68 (m, 2H), 2.48-1.81 (m, 9H), 1.72-1.64 (m, 4H), 1.55-1.06 (m, 10H), 0.97-0.89 (m , 3H) , 0.85-0.77 (m, 1H).

[0372] Synthesis of compound SB-CC. A solution of SB-BB (50 g, crude) in 300 mL of THF was added with LiAlH 4 (8.99g, 236.49mmol) was added at 0°C. The reaction mixture was stirred at 23°C for 1.5 hours. After the TLC showed the reaction was complete, the reaction was quenched with water. The reaction was extracted with 1000 mL of EtOAc, washed with brine, and evaporated in vacuo. The obtained residue was purified by chromatography (petroleum ether / ethyl acetate = 100:1~80:1~60:1~50:1~40:1~30:1) to obtain SB-CC as a white solid. (19 g, yield 75.19%). 1 H NMR (SB-CC) (400 MHz, CDCl 3 ), δ (ppm)=5.17-5.07 (m, 1H), 4.66-4.48 (m, 1H), 2.41-2.32 (m, 1H), 2.28-2.15 (m, 2H) , 2.09-2.05 (m, 1H) , 1.88-1.75 (m, 2H) , 1.68-1.64 (m, 3H) , 1.40-1.31 (m, 1H) , 1.25-1.13 (m, 9H), 0.89 (s, 3H), 0.81-0.72 (m, 1H).

[0373] Synthesis of compound SB-DD. A solution of SB-CC (19 g, 59.29 mmol) in dry THF (500 mL) was added with C 2 H 9 BS (59.29 mL; 10M solution in THF) was added at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was cooled in an ice bath and then treated with 3M aqueous NaOH (160 mL) followed by H 2 O 2 was slowly quenched with a 30% aqueous solution (100 mL) of After stirring at 20° C. for 1.5 hours, the mixture was filtered and extracted with EtOAc (300 mL). The combined organic layer is aq.Na 2 S 2 O 3 , filtered, dried, and concentrated to give SB-DD as crude material (21 g, crude). This crude product was used in the next step without further purification.

[0374] Synthesis of compound SB-EE. SB-DD (21g,59.29mmol) in 200mL CH 2 Cl 2 PCC (25.56 g, 118.58 mmol) was added to the solution at 0°C, and the mixture was stirred at 22°C for 2 hours. Filter the reaction mixture and add 20 mL of CH 2 Cl 2 Extract with aq.NaHCO 3 , aq.Na 2 S 2 O 3 , washed with brine and evaporated in vacuo. The residue was purified by chromatography (petroleum ether / ethyl acetate = 15:1~10:1~6:1) to obtain SB-EE as a white solid (12 g, yield 60.15%). 1 H NMR (SB-EE) (400 MHz, CDCl 3 ), δ (ppm)=4.65-4.46 (m, 1H), 2.55-2.51 (m, 1H), 2.22-2.09 (m, 4H), 2.06-1.97 (m, 32H), 1.88-1.77 (m, 2H), 1.69-1.54 (m, 5H), 1.48-1.30 (m, 3H), 1.28-1.05 (m, 11H), 0.83-0.72 (m, 1H) , 0.63 (s, 3H).

[0375] Synthesis of compound SB-FF. A solution of SB-EE (12 g, 35.66 mmol) in 1500 mL of MeOH was added with HBr (5 drops) and Br. 2 (2.01 mL, 39.23 mmol) was added at 0°C. The reaction was stirred at 16°C for 2 hours. Add this reaction mixture to aq.NaHCO 3 and concentrated. The mixture was then extracted with 1000 ml of EtOAc, washed with brine and evaporated in vacuo. The product was purified by column chromatography on silica gel eluting with (petroleum ether / ethyl acetate = 12:1~10:1~8:1~6:1~3:1) to obtain SB-FF. Obtained as a white solid (12.3g, yield 83.03%). 1 H NMR (SB-FF) (400 MHz, CDCl 3 ), δ (ppm)=4.64-4.47 (m, 1H), 3.95-3.86 (m, 2H), 2.89-2.80 (m, 1H), 2. 23-2.16 (m, 1H), 2.07-1.64 (m, 8H) 1.46-1.06 (m, 14H), 0.83-0.74 (m, 1H), 0.67 (s, 3H).

[0376] Example 12. Synthesis of SC-O compound

[0377] [ka]

[0378] Synthesis of compound SC-B. Reactant SC-A (10.0g, 36.44mmol) To a solution in gin (30 mL) was added acetic anhydride (5.0 mL, 52.89 mmol). This mixture was stirred at 60°C overnight. This solution was then poured into ice water (200 mL). The white precipitate was filtered and dissolved in ethyl acetate (300 mL). To remove residual pyridine, the resulting solution was saturated with sat.CuSO 4 .5H 2 Washed with O solution (2 x 200 mL). The organic layer was further washed with brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=4:1) to give the product SC-B (11.125 g, 35.16 mmol, yield=96%) as a white solid. 1 HNMR (500 MHz, CDCl 3 ) δ(ppm):5.83 (1H, s), 4.62 (1H, dd), 2.05 (3H, s), 0.86 (3H, s).

[0379] Synthesis of compound SC-C. To a solution of reactant SC-B (4.68 g, 14.79 mmol) in THF (150 mL) was added LiHMDS (1.0 M solution in THF, 17.74 mL, 17.74 mmol) at -78 °C. The solution was stirred at -78°C for 30 minutes. Then HMPA (3.09mL, 17.74mmol) was added. The solution was stirred for an additional 30 minutes at -78°C. Then iodomethane (2.76mL, 44.37mmol) was added. The solution was further stirred at −78° C. for 2 hours, then warmed to room temperature and stirred for 1 hour. The reaction was quenched by the addition of water (10 mL). Most of the THF solvent was removed in vacuo. The residue was then diluted with ethyl acetate (300 mL) and the resulting solution was washed with brine (2 x 200 mL) and dried over magnesium sulfate. The solvent was removed in vacuo to give the crude product SC-C (4.50 g, 13.62 mmol, yield=92%) as a sticky oil. This crude product was used in the next step without further purification. 1 HNMR (500 MHz, CDCl 3 ) δ(ppm):5.75 (1H, s), 4.62 (1H, t), 2.05 (3H, s), 1.10 (3H, d), 0.86 (3H, s).

[0380] Synthesis of compounds SC-D and SC-E. To a solution of crude reactant SC-C (11.62 g, 35.16 mmol, theoretical) in methanol (100 mL) and water (20 mL) was added sodium hydroxide (2.81 g, 70.32 mmol). This solution was heated at 60°C for 1 hour. Most of the methanol solvent was then removed in vacuo. The remaining solution was acidified to pH 5-6 with 2M HCl. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=5:1) to give pure product SC-D (2.354 g, 8.162 mmol, yield=23%) and pure product SC-E. (5.306g, 18.40mmol, yield=50%) was obtained as a white solid. Compound SC-D: 1 HNMR (500 MHz, CDCl 3 ) δ(ppm):5.81 (1H, s), 3.67 (1H, t), 1.11 (3H, d), 0.81 (3H,s).

[0381] Compound SC-E: 1 HNMR (500 MHz, CDCl 3 ) δ(ppm):5.74 (1H, s), 3.67 (1H, t, J=8.5 Hz), 1.11 (3H, d), 0.81 (3H, s).

[0382] Synthesis of compound SC-F. Lithium (1.80 g, 260 mmol) was added to liquid ammonia (200 mL) at -78°C. The liquid turned deep blue. A solution of reactant SC-D (3.0 g, 10.40 mmol) in t-BuOH (1.0 mL, 10.40 mmol) and THF (100 mL) was then added to the Li-ammonia solution. This mixture was stirred at -78°C for 4 hours. Then solid NH 4 The reaction was quenched by adding Cl (20g). The mixture turned from deep blue to white. this mixture Warmed to room temperature and the ammonia was allowed to evaporate in the hood overnight. Water (300 mL) was added to the residue. The mixture was acidified to pH 6-7 with conc. HCl. Ethyl acetate (300 mL) was then added. The separated aqueous layer was further extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (300 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-F was used directly in the next step without further purification.

[0383] Synthesis of compound SC-G. To a solution of crude reactant SC-F (1.749 g, 6.022 mmol) in dichloromethane (60 mL) was added pyridinium dichromate (PDC) (3.398 g, 9.033 mmol). This mixture was stirred at room temperature overnight. The solution was filtered through a short pad of Celite. CH this celite 2 Cl 2 (3 x 50 mL). Combined CH 2 Cl 2 The solution was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=5:1) to give the product SC-G (1.298 g, 4.50 mmol, yield=75%) as a white solid. Compound SC-G: 1 HNMR (400 MHz, CDCl 3 ) δ(ppm):1.02 (3H, d), 0.91 (3H, s).

[0384] Synthesis of compound SC-H. To a solution of reactant SC-G (1.948 g, 6.754 mmol) in anhydrous methanol (50 mL) was added p-toluenesulfonic acid monohydrate (128 mg, 0.6754 mmol). This solution was heated at 70°C for 3 hours. This reaction is sat.Na 2 C.O. 3 Quenched by addition of solution (10 mL). Most of the methanol solvent was removed in vacuo. The residue was then diluted with ethyl acetate (200 mL) and the resulting solution was diluted with sat.Na 2 C.O. 3 solution (2 x 100 mL). The combined aqueous layers were extracted with ethyl acetate (50 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 10:1, 0.1% NEt 3 The product SC-H (652 mg, 1.949 mmol, yield=29%) was obtained as a white solid. Additionally, starting material (1.338g) was also recovered. The yield based on recovered starting material is therefore 92%. 1 H NMR (500 MHz, d6-acetone) δ(ppm):3.079 (3H, s), 3.075 (3H, s), 2.38 (1H, dd), 1.98 (1H, dd), 0.91 (3H, d), 0.85 (3H, s).

[0385] Synthesis of compound SC-I. To a solution of ethyltriphenylphosphonium bromide (8.795g, 23.69mmol) in anhydrous THF (20mL) was added t-BuOK (2.658g, 23.69mmol). The solution turned reddish. Heated at 70°C for 2 hours. Reactant SC-H (1.642 g, 4.909 mmol) was then added in one portion. This solution was heated at 70°C overnight. The reaction was quenched by the addition of water (10 mL). The mixture was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-I was used directly in the next step without further purification.

[0386] Synthesis of compound SC-J. To the crude product SC-I (1.702 g, 4.909 mmol, theory) in THF (30 mL) was added 2M HCl (3 mL). The solution was stirred at ambient temperature for 1 hour. This mixture was diluted with ethyl acetate (300 mL) and the resulting solution was 2 C.O. 3 solution (2 x 100 mL) and the combined aqueous layers were extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=100:3) to give the crude product SC-J (1.746 g) as a white solid. This means that some non-isolated PPh 3 dirty It was stained. 1 Judging from the integration of the HNMR spectrum, the desired product versus PPh 3 Since the ratio of is 3:1, the amount of desired product SC-J is 1.354 g (4.506 mmol) and its yield is 92%. 1 H NMR (500 MHz, CDCl3) δ(ppm): 5.13 (1H, qt), 1.66 (3H, dt), 1.02 (3H, d), 0.91 (3H, s).

[0387] Synthesis of compound SC-K. To a solution of trimethylsulfoxonium iodide (5.213g, 23.69mmol) in anhydrous DMSO (30mL) was added sodium hydride (60%wt, 948mg, 23.69mmol). This mixture was stirred at 25°C for 1 hour. A solution of the crude reactant (1.746 g, theoretical amount, 1.354 g, 4.506 mmol, which was contaminated with some residual PPh3) in anhydrous THF (10 mL) was then added. This mixture was stirred at 25°C overnight. The reaction was quenched by the addition of water (5 mL). The mixture was diluted with ethyl acetate (300 mL) and the resulting solution was washed with water (2 x 100 mL), then brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-K was used directly in the next step without further purification.

[0388] Synthesis of compound SC-L. To a solution of the crude reactant SC-K (theoretical amount, 1.417 g, 4.506 mmol) in anhydrous THF (30 mL) was added lithium aluminum hydride (342 mg, 9.012 mmol) in portions. This suspension was stirred at 25°C for 1 hour. The reaction was then quenched by the addition of ethyl acetate (5 mL) followed by water (5 mL). The white solid was filtered and washed thoroughly with ethyl acetate (5 x 100 mL). The combined filtrates were washed with brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=20:1) to give the product SC-L (458 mg, 1.447 mmol, total yield for 2 steps=32%) as a white solid.

[0389] Synthesis of compound SC-M. A solution of reactant SC-L (458 mg, 1.447 mmol) in anhydrous THF (15 mL) was added with BH 3 .THF (1.0M, 7.23mL, 7.23mmol) was added and the solution was stirred at 25°C overnight. The reaction was then quenched by the addition of water (5 mL). Add 2M NaOH solution (10mL) followed by 30% H 2 O 2 (10 mL) was added. This mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0390] Synthesis of compound SC-N. To a solution of the crude reactant SC-M (484 mg, 1.447 mmol, theoretical) in dichloromethane (40 mL) was added pyridinium dichromate (PDC) in portions (1633 mg, 4.341 mmol). This solution was stirred at 25°C overnight. The mixture was then filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3 x 50 mL). All filtrates were combined and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=8:1) to give the product SC-N (305 mg, 0.917 mmol, yield=63% (2 steps)) as a white solid. 1 H NMR (500 MHz, CDCl3) δ(ppm):2.54 (1H, t,), 2.12-2.19 (1H, m), 2.12 (3H, s 0.92 (3H, d), 0.61 (3H, s). 13 CNMR (100 MHz, CDCl3) δ(ppm):209.75, 71.09, 63.96, 55.89, 47.96, 47.80, 47.00, 44.35, 41.19, 40.22, 39.05, 37.95, 34.49, 33.14, 31 .54, 30.92, 28.46, 25.82, 2 4.22, 22.76, 15.14, 13.45.

[0391] Synthesis of compound SC-O. To a solution of reactant SC-N (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine (241 mg, 0.077 mL, 1.505 mmol). was added. This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-O was used directly in the next step without further purification.

[0392] Example 13. Synthesis of SC-Y compound

[0393] [ka]

[0394] Synthesis of compound SC-P. N.H. 3 Lithium (7.0 g, 1 mol) was added to (liquid, 2.0 L) at -78°C. After the liquid turned deep blue, a solution of compound SC-A (27.0 g, 100 mmol) in t-BuOH (7.4 g, 100 mmol) and THF (20 mL) was added dropwise. This mixture was stirred at -78°C for 4 hours. Then solid NH 4 The reaction was quenched by adding Cl (50g). The mixture turned from deep blue to white. The mixture was warmed to room temperature and the ammonia was allowed to evaporate overnight. The residue was dissolved in 0.5N aqueous HCl (50 mL) and extracted with dichloromethane (200 mL x 3). Saturate the combined organic layers with NaHCO 3 (200 mL) and brine (200 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (petroleum ether / ethyl acetate=4:1) to give the product SC-P (18.98 g, 68.7%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ(ppm):3.66 (1H, t), 2.29-2.27 (2H, m), 2.12-2.07 (2H, m), 1.83-1.81 (2H, m), 1.50 (1H, s), 0.77 (3H, s).

[0395] Synthesis of compound SC-Q. 19.0g sample of compound SC-P (68.84mmol ) was dissolved in 50 mL of THF at 0°C. Then 70 mL of MeMgBr in THF (3M) was added dropwise over 30 minutes. The reaction was maintained at 0°C for 8 hours. The reaction mixture was quenched with ice-cold water and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was purified by flash column chromatography (petroleum ether / ethyl acetate=5:1) to give the product SC-Q (19.0 g, 94%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ (ppm):5.78 (1H, br), 5.36 (1H, t), 3.67 (1H, t), 1.73 (3H, s), 0.77 (3H, s).

[0396] Synthesis of compound SC-R. To a solution of compound SC-Q (19.0 g, 65.07 mmol) in dichloromethane (100 mL) was added pyridinium dichromate (PDC) (48.9 g, 130.14 mmol). This mixture was stirred at room temperature overnight. The solution was filtered through a short pad of Celite. CH this celite 2 Cl 2 (3 x 100 mL). Combined CH 2 Cl 2 The solution was concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=5:1) to give the product SC-R (10.0 g, 53%) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ (ppm):2.44 (1H, dd), 2.07 (1H, m), 1.21 (3H, s), 0.87 (3H, s).

[0397] Synthesis of compound SC-S. A solution of compound SC-R (5.0 g, 17.2 mmol) in anhydrous toluene (100 mL) was added to the p-toluenesulfonic acid precipitated with silica gel (80 g) and the mixture was stirred below 45° C. for 1 hour. Insoluble by-products were removed from the silica gel by elution with petroleum ether / ethyl acetate (10 / 1). The crude product SC-S (3.20 g, 11.75 mmol) was used in the next step without further purification.

[0398] Synthesis of compound SC-T. To a solution of compound SC-S (3.20 g, 11.75 mmol) in 10 mL of anhydrous dichloromethane was added mCPBA (4.04 g, 23.50 mmol) and the reaction mixture was stirred at room temperature overnight. This reaction mixture was then converted into CH 2 Cl 2 The combined organic layers were extracted with NaHCO 3 (100 mL) and brine twice, then 2 S.O. 4 and concentrated. The crude product SC-T was used in the next step without further purification.

[0399] Synthesis of compound SC-U. A solution of compound SC-T (11.75 mmol) in methanol was added with H 2 S.O. 4 (0.5 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. This reaction solution was then converted into CH 2 Cl 2 (200mL x 3), and the combined organic layers were extracted with NaHCO 3 (100 mL) and brine, Na 2 S.O. 4 and concentrated. The residue was purified by chromatography (petroleum ether / ethyl acetate=10:1) to give compound SC-U (3.30 g, 10.30 mmol, yield=87% for 2 steps) as a white solid.

[0400] Synthesis of compound SC-V. To a solution of ethyltriphenylphosphonium bromide (11.52 g, 31.0 mmol) in anhydrous THF (20 mL) was added t-BuOK (3.48 g, 31.0 mmol). The solution turned reddish. Heated at 70°C for 3 hours. Compound SC-U (3.30 g, 10.30 mmol) was then added in one portion. The reaction solution was heated at 70° C. overnight and then quenched by the addition of water (10 mL). The mixture was diluted with EtOAc (200 mL) and the resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-V (1.90 g) was used directly in the next step without further purification.

[0401] Synthesis of compound SC-W. A solution of compound SC-V (1.90 g, 5.72 mmol) in dry THF (20 mL) was added with BH 3 -THF (18 mL of a 1.0 M solution in THF) was added. After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then treated with 10% aqueous NaOH (12 mL), followed by 30% H 2 O 2 (20 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EA (100 mL x 3). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (50 mL), washed with brine, Na 2 S.O. 4 , filtered and concentrated to give the crude compound SC-W (1.86 g, 5.31 mmol). This crude product was used in the next step without further purification.

[0402] Synthesis of compound SC-X. To a solution of crude compound SC-W (1.86 g, 5.31 mmol) in dichloromethane (50 mL) was added pyridinium dichromate (PDC) in portions (3.98 g, 10.62 mmol). This solution was stirred at 25°C overnight. The mixture was then filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3 x 50 mL). All filtrates were combined and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=10:1) to give the product SC-X (1.20 g, 3.45 mmol, 65%) as a white solid. 1 HNMR (500 MHz, CDCl3) δ(ppm):3.33 (3H, s), 3.04 (1H, s), 2.53 (1H, t), 2.12 (3H, s within m), 1.26 (3H, s within m) , 0.62 (3H, s).

[0403] Synthesis of compound SC-Y. To a solution of reactant SC-X (100 mg, 0.287 mmol) in methanol (10 mL) was added 48% HBr (152 mg, 0.903 mmol) followed by bromine (0.08 mL, 1.505 mmol). This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-Y was used directly in the next step without further purification.

[0404] Example 14. Synthesis of SC-EE compound

[0405] [ka]

[0406] Synthesis of compounds SC-Z and SC-AA. Compound SA-E (800mg, 2.79mmol) and PhSO 2 C.F. 2 A solution of H (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL) at -78 °C 2 At the bottom LHMDS (4 mL, 1M in THF) was added dropwise. After stirring for 2 h at -78 °C, the reaction mixture was dissolved in saturated aqueous NH 4 Quench with Cl solution (10 mL) and warm to room temperature, then Et 2 Extracted with O (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain a mixture (700 mg) of compounds SC-Z and SC-AA. This mixture was further purified by chiral-HPLC to obtain compound SC-Z (200 mg, t=4.31 min). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 7.99-7.97 (d, 2H), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.08 (m, 1H), 0.88 (s, 3H); Compound SC-AA (260mg,t=5.66min). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 8.00--7.98 (d, 2H), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.09 (m, 1H), 0.88 (s, 3H) .

[0407] Synthesis of compound SC-BB. Compound SC-AA (100mg, 0.209mmol) and anhydrous Na 2 HPO 4 (100 mg) in anhydrous methanol (5 mL) at -20 °C N 2 Na / Hg amalgam (500 mg) was added below. After stirring for 1 hour at -20°C to 0°C, the methanol solution was decanted and the solid residue was dissolved in Et 2 Washed with O (5 x 3 mL). The combined organic layers were washed with brine (20 mL) and MgSO 4 dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound SC-BB (36 mg, 0.106 mmol, 51%). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 6.02-5.88 (t, 1H), 5.17-5.15 (m, 1H), 0.88 (s, 3H).

[0408] Synthesis of compound SC-CC. To a solution of compound SC-BB (150 mg, 0.443 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.0 M solution in THF, 1.34 mL). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then treated with 10% aqueous NaOH (1 mL), followed by H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution (1.2 mL) of . The mixture was stirred at room temperature for 1 h, then extracted with EtOAc (3 x 10 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (10 mL), washed with brine (10 mL), MgSO 4 , filtered and concentrated to give the crude compound SC-CC (210 mg). This crude product was used in the next step without further purification.

[0409] Synthesis of compound SC-DD. Crude compound SC-CC (210 mg) was added to 10 mL of H 2 O saturated dichloromethane (dichloromethane with a few milliliters of H 2 Dess-Martin periodinate (380 mg, 0.896 mmol) was added to the solution dissolved in the solution (shaken with O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (10 mL), washed with brine (10 mL), MgSO 4 dried, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to obtain compound SC-DD (90 mg, 0.254 mmol, 57%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 6.01-5.73 (t, 1H), 2.55-2.54 (m, 1H), 2.12 (s, 3H), 0.62 (S, 3H).

[0410] Synthesis of compound SC-EE. To a solution of compound SC-DD (80 mg, 0.226 mmol) in MeOH (5 mL) were added 2 drops of HBr (48%) followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3), the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and Concentration gave crude compound SC-EE (95 mg). This crude product was used in the next step without further purification.

[0411] Example 15. Synthesis of SC-II compound

[0412] [ka]

[0413] Synthesis of compound SC-FF. To a solution of reactant SB-F (4.4 g, 15.38 mmol) in dry THF (50 mL) was added ethylmagnesium bromide (3M in THF, 51.28 mL) dropwise at 0°C. The solution was then slowly warmed up and stirred at ambient temperature for 15 hours. sat.NH 4 The reaction was quenched by adding Cl solution (20 mL) and the resulting solution was extracted with ethyl acetate (3 x 100 mL). The extract was washed with brine and Na 2 S.O. 4 and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the product SC-FF (3.15 g, 10.00 mmol, 64.8%) as a white solid.

[0414] Synthesis of compound SC-GG. A solution of reactant SC-FF (500 mg, 1.58 mmol) in anhydrous THF (10 mL) was added with BH 3 .THF (1.0M, 7.23mL, 7.23mmol) was added at room temperature and the solution was stirred at 25°C overnight. The reaction was then quenched by the addition of water (5 mL), 2M NaOH solution (10 mL), followed by 30% H 2 O 2 (10 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-GG was used directly in the next step without further purification.

[0415] Synthesis of compound SC-HH. Pyridinium chloroformate (8.48 g, 39.34 mol) was added in portions to a solution of reactant SC-GG (6.53 g, 19.67 mmol) in anhydrous DCM (100 mL) being cooled in an ice-water cooling bath. The mixture was stirred at ambient temperature overnight. The solution was then diluted with DCM (50 mL) and filtered. The combined organic solution was washed with brine (100 mL) and Na 2 S.O. 4 and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether:ethyl acetate=10:1) to give the product SC-HH (2.5 g, 7.53 mmol, 39% yield) as a white solid. 1 HNMR(500 MHz, CDCl3) δ(ppm):2.54 (1H, t), 2.11 (3H,s), 1.42-1.45 (2H, q), 0.91 (3H, t), 0.62 (3H, s).

[0416] Synthesis of compound SC-II. To a solution of reactant SC-HH (80 mg, 0.24 mmol) in methanol (5 mL) was added 48% hydrobromic acid (148 mg, 0.884 mmol) followed by bromine (241 mg, 0.077 mL, 1.505 mmol). was added. The solution was heated at 25° C. for 1.5 hours, then the mixture was poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-II was used directly in the next step without further purification.

[0417] Example 16. Synthesis of SC-SS compound

[0418] [ka]

[0419] Synthesis of compounds SC-MM and SC-NN. Dry (Bu) to the reactant mixture SA-KK and SA-LL mixture (3.0g, 10.0mmol, 1:1) 4 NF was added and the mixture was then heated at 100°C overnight. Add the remaining mixture to 50 mL of H 2 Poured into O and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (petroleum ether / ethyl acetate=20:1) to give the product mixture SC-MM and SC-NN (2.1 g, 6.5 mmol, 65%) as a white solid.

[0420] Synthesis of compounds SC-OO and SC-PP. A solution of reactant mixtures SC-MM and SC-NN (2.1 g, 6.5 mmol) in anhydrous THF (30 mL) was added with BH 3 .THF (1.0M, 13.0mL, 13.0mmol) was added and the solution was stirred at 25°C overnight. The reaction was then quenched by the addition of water (5 mL). Add 2M NaOH solution (20mL) followed by 30% H 2 O 2 (20 mL) was added. This mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate (200 mL) and the resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product mixture was used directly in the next step without further purification.

[0421] Synthesis of compounds SC-QQ and SC-RR. To a solution of the crude reactant mixtures SC-OO and SC-PP (2.2 g, 6.5 mmol, theoretical) in dichloromethane (40 mL) was added pyridinium chloroformate (Pcc) in portions (2.8 g, 13.0 mmol). This solution was stirred at 25°C overnight. The mixture was then filtered through a short pad of silica gel and the silica gel was washed with dichloromethane (3 x 50 mL). All filtrates were combined and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15:1) to give the product SC-QQ (910 mg, 2.7 mmol, yield = 41% (2 steps)) as a white solid and the product The product SC-RR (850 mg, 2.5 mmol, yield = 39% (2 steps)) was obtained as a white solid. Compound SC-QQ: 1 HNMR (500 MHz, CDCl3) δ(ppm):4. 17 (d, 2H), 2.53 (t, 1H), 2.17-2.13 (m, 2H), 2.11 (s, 3H), 2.03-2.00 (m, 1H), 0.62 (s, 3H). Compound SC-RR: 1 HNMR (500 MHz, CDCl3) δ(ppm): 4.45 (AB×d, 1H), 4.39 (AB×d, 1H), 2.54 (t, 1H), 0.62 (s, 3H).

[0422] Synthesis of compound SC-SS. To a solution of reactant SC-RR (100 mg, 0.301 mmol) in methanol (10 mL) was added 48% hydrobromic acid (152 mg, 0.903 mmol) followed by bromine (241 mg, 0.077 mL, 1.505 mmol). was added. This solution was heated at 25°C for 1.5 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product SC-SS was used directly in the next step without further purification.

[0423] Example 17. Synthesis of SA-ZZ compound

[0424] [ka]

[0425] Synthesis of compounds SC-TT and SC-UU. Compound SB-F (1.3g, 4.5mmol) and PhSO 2 CH 2 A solution of F (790 mg, 4.5 mmol) in THF (25 mL) and HMPA (0.5 mL) at -78 °C 2 At the bottom LHMDS (5.5 mL, 1M in THF) was added dropwise. After stirring for 2 h at -78 °C, the reaction mixture was dissolved in saturated aqueous NH 4 Quench with Cl solution (10 mL) and warm to room temperature, then Et 2 Extracted with O (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to produce compounds SC-TT and SC-UU. A mixture (1.53 g) was obtained. This mixture was further purified by chiral-HPLC to obtain compound SC-TT-1 (220 mg, t=3.41 min). 1H NMR (500 MHz, CDCl3), δ (ppm), 7.99-7.97 (m, 2H), 7.75-7.74 (m, 1H), 7.62-7.55 (m, 2H), 5.13-5.09 (m, 1H), 4.86-4.78 (d, 1H,), 0.88 (s, 3H);SC-TT-2 (200mg,t=3.66min); 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.96-7.95 (m, 1H), 7.71-7.69 (m, 1H), 7.62-7.58 (m, 2H), 5.13-5.09 (m, 1H), 4.87-4.77 (d, 1H), 0.88 (s, 3H);SC-UU-1 (235mg,t=4.9min). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.99-7.97 (m, 1H), 7.72-7.70 (m, 1H), 7.62-7.59 (m, 2H), 5.29-5.20 (d, 1H), 4.88-4.78 (m, 1H), 0.88 (s, 3H);SC-UU-2 (220mg,t=5.2min). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.99-7.97 (m, 2H), 7.72 (m, 1H), 7.62-7.59 (m, 2H), 5.30-5.20 (d, 1H), 5.09-5.08 (m,1H), 0.88 (s, 3H).

[0426] Synthesis of compound SC-WW. Compound SC-TT-1 (200mg, 0.434mmol) and anhydrous Na 2 HPO 4 (100 mg) in anhydrous methanol (15 mL) at -20 °C N 2 Na / Hg amalgam (400 mg) was added below. After stirring for 1 hour at -20°C to 0°C, the methanol solution was decanted and the solid residue was dissolved in Et 2 Washed with O (5 x 3 mL). The solvent of the combined organic phases was removed under reduced pressure and 20 ml of brine was added followed by extraction with Et2O. The combined ether phase was dried over MgSO4 and the ether was removed to obtain the crude product, which was further purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1) to yield 99 mg of product, Obtained 69%. 1 H NMR (500 MHz, CDCl3), δ (ppm), 5.12-5.10 (m, 1H,), 4.21-24.11 (d, 2H), 0.88 (s, 3H).

[0427] Synthesis of compound SC-XX. To a solution of compound SC-WW (95 mg, 0.296 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.0 M solution in 1 mL of THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then treated with 10% aqueous NaOH (1 mL), followed by H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution (1.2 mL) of . The mixture was stirred at room temperature for 1 h, then extracted with EtOAc (3 x 10 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (10 mL), washed with brine (10 mL), MgSO 4 dried, filtered, and concentrated to give compound SC-XX (120 mg crude). This crude product was used in the next step without further purification.

[0428] Synthesis of compound SC-YY. Compound SC-XX (120 mg crude) was dissolved in 10 mL of wet dichloromethane (dichloromethane was mixed with several milliliters of H 2 Dess-Martin periodinate (300 mg, 707 mmol) was added to the solution dissolved in the solution (shaken with O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were diluted with 10% aqueous Na 2 S 2 O 3 (10 mL), washed with brine (10 mL), MgSO 4 dried, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to give compound SC-YY (70 mg, 70% for 2 steps) as a white solid. 1 H NMR (500 MHz, CDCl3), δ (ppm ), 4.21-4.11 (d, 2H), 2.19 (s, 3H), 0.62 (s, 3H).

[0429] Synthesis of compound SC-ZZ. To a solution of reactants (200 mg, 0.594 mmol) in methanol (5 mL) was added 48% hydrobromic acid (300 mg, 1.782 mmol) followed by bromine (475 mg, 0.152 mL, 2.97 mmol). . This solution was heated at 25°C for 2 hours. The mixture was then poured into cold water (50 mL). The resulting solid was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0430] Example 18. Synthesis of compounds SA-1 and SA-2

[0431] [ka]

[0432] K 2 C.O. 3 To a suspension of (50 mg, 0.36 mmol) in THF (5 mL) was added 5-(trifluoromethyl)-1H-pyrazole (80 mg, 0.59 mmol) and SA (100 mg, 0.25 mmol). This mixture was stirred at room temperature for 15 hours. Transfer this reaction mixture to 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid SA-1 (15 mg, 13.2%). SA-2 (5mg, 4.4%). SA-1: 1 H NMR(500MHz, CDCl 3 ), δ (ppm), 7.47 (d,1H),6.59 (d,1H), 4.99 (1H, AB), 4.95(1H, AB), 2.58 (1H, t), 1.00-2.20 (m, 24H) ,0.68 (s, 3H). SA-2: 1 H NMR(500MHz, CDCl 3 ), δ (ppm), 7.57 (d,1H), 6.66 (d,1H), 5.03 (1H, AB), 4.93(1H, AB), 2.77 (1H, t), 1.00-2.2 (m, 24H), 0.9 (s, 3H).

[0433] Example 19. Synthesis of compound SA-3

[0434] [ka]

[0435] K 2 C.O. 3 To a suspension of (50 mg, 0.36 mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4-carboxylate (100 mg, 0.71 mmol) and SA (72 mg, 0.18 mmol). This mixture was stirred at room temperature for 15 hours. Transfer this reaction mixture to 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid (18 mg, 21.6%). 1 H NMR (500 MHz, CDCl 3 ), δ (ppm) 7.93 (s, 1H), 7.91 (s, 1H), 4.97 (1H, AB), 4.86 (1H, AB), 4.28 (q, 2H), 2.60 (1H, t) ,1.34 (t ,3H), 1.00-2.25 (m, 24H), 0.67 (s,3H).

[0436] Example 20. Synthesis of compound SA-4

[0437] [ka]

[0438] K 2 C.O. 3 To a suspension of (50 mg, 0.36 mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol) and SA (50 mg, 0.12 mmol). This mixture was stirred at room temperature for 15 hours. Add this reaction mixture to 5 mL of H 2Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid (9 mg, 17.4%). 1 H NMR (500 MHz, CDCl 3 ), δ (ppm) 7.87 (1H, s), 7.82 (1H, s), 5.02 (1H, AB), 4.92 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, d×t), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H , m), 1.28 (3H , s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS:rt=2.24min,m / z=410.1[M+H] + .

[0439] Example 21. Synthesis of compound SA-5

[0440] [ka]

[0441] K 2 C.O. 3 To a suspension of (50 mg, 0.36 mmol) in THF (5 mL) was added ethyl 1-(1H-pyrazol-5-yl)ethanone (100 mg, 0.91 mmol) and SA (50 mg, 0.12 mmol). This mixture was stirred at room temperature for 15 hours. Add this reaction mixture to 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid (37 mg, 65%): 1 H NMR (500 MHz, CDCl 3 ), δ (ppm) 7.41 (d,1H), 6.85 (d,1H), 4.98 (1H, AB), 4.86 (1H, AB), 2.59 (t, 1H), 2.55 (s,3H), 1.00-2.25 (m, 24H), 0.69 (s,3H).

[0442] Example 22. Synthesis of compound SA-6

[0443] [ka]

[0444] SA (350mg,0.88mmol) and K 2 C.O. 3 To a solution of (243.5 mg, 1.76 mmol) in 10 mL of dry DMF was added 4-methyl-1H-pyrazole (144.6 mg, 1.76 mmol) with N 2 It was added at room temperature. The reaction mixture was stirred at this temperature for 18 hours. The reaction mixture was poured into water, extracted with EtOAc (2 x 50 mL), and the organic layer was washed with brine and anhydrous Na 2 S.O. 4 dried, filtered and concentrated and purified by flash chromatography silica column (petroleum ether / ethyl acetate 10:1 to 2:1) to give SA-6 (230 mg, yield: 65.5%) as a white powder. obtained as Ta. 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 7.35 (s, 1H), 7.18 (s, 1H), 4.92-4.79 (m, 2H), 2.59-2.55 (m, 1H), 2.23-2.15 (m, 1H), 2.10 (s, 3H), 2.07-2.03 (m, 1H), 1.88-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.49-1.22 (m, 16H), 1.13-1.05 (m, 3H) ), 0.68 (s, 3H). LCMS:rt=1.29min,m / z=399.2[M+H] + .

[0445] Example 23. Synthesis of compound SA-7

[0446] [ka]

[0447] K 2 C.O. 3 (25 mg, 0.18 mmol) in THF (5 mL) was added 4-chloro-4H-pyrazole (21 mg, 0.21 mmol) and SA (36 mg, 0.09 mmol). This mixture was stirred at room temperature for 15 hours. Pour the residue mixture into 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid (8 mg, 21%): 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 7.45 (s, 1H), 7.41 (s, 1H), 4.90 (AB, 1H), 4.81 (AB, 1H), 2.57 (t, 1H), 2.22-2.16 (m, 1H), 2.05-2.01 (m, 1H), 1.00-1.90 (m, 22H), 0.67 (s, 3H). LCMS:rt=2.52min,m / z=419.1[M+H]+.

[0448] Example 24. Synthesis of compound SA-8

[0449] [ka]

[0450] K 2 C.O. 3 To a suspension of (25 mg, 0.18 mmol) in THF (5 mL) was added 4-nitro-4H-pyrazole (20 mg, 0.18 mmol) and SA (36 mg, 0.09 mmol). This mixture was stirred at room temperature for 15 hours. 5 of that residue mixture H in mL 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid (12 mg, 31%): 1 H NMR (500 MHz, CDCl 3 ), δ (ppm) 8.11 (s, 1H), 8.01 (s, 1H), 4.93 (AB, 1H), 4.83 (AB, 1H), 2.55 (t, 1H), 2.15-2.10 (m, 1H), 1.99-1.96 (m, 1H), 1.00-1.80 (m, 22H), 0.68 (s, 3H).

[0451] Example 25. Synthesis of compound SA-9

[0452] [ka]

[0453] K 2 C.O. 3 (25 mg, 0.18 mmol) in THF (5 mL) was added 4-bromo-4H-pyrazole (26 mg, 0.18 mmol) and SA (36 mg, 0.09 mmol). This mixture was stirred at room temperature for 15 hours. Pour the residue mixture into 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give SA-9 as a white solid (9 mg, 22%): 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 7.41 (s, 1H), 7.37 (s, 1H), 4.85 (AB, 1H), 4.77 (AB, 1H), 2.59 (t, 1H), 2.22-2.18 (m, 1H) , 2.06-2.01 (m, 1H), 0.90-1.80 (m, 22H), 0.68 (s, 3H). 0.90-1.80 (m, 22H).

[0454] Example 26. Synthesis of compounds SA-10 and SA-11

[0455] [ka]

[0456] K 2 C.O. 3 (55 mg, 0.4 mmol) in THF (5 mL) was added with 3-methyl-4H-pyrazole (33 mg, 0.4 mmol) and SA (79 mg, 0.2 mmol) in THF (5 mL). ol) was added. This mixture was stirred at room temperature for 15 hours. Pour the residue mixture into 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give SA-10 as a white solid (9 mg, 11%) and SA-11 as a white solid (11 mg, 14%). Compound SA-10: 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 7.41 (d, 1H), 6.07 (s, 1H), 4.85 (s, 2H), 2.84-2.83 (m, 1H), 2.59 (t, 1H), 2.17 (s, 3H) , 2.07-2.04 (m, 1H), 1.00-1.90 (m, 22H), 0.69 (s, 3H). Compound SA-11: 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 7.28 (s, 1H), 6.09 (d, 1H), 4.84 (AB, 1H), 4.83 (AB, 1H), 2.56 (t, 1H), 2.27 (s, 3H), 2.22-2.14 (m, 1H), 2.05-2.02 (m, 1H), 1.00-1.90 (m, 22H), 0.67 (s, 3H), 1.00-1.90 (m, 22H).

[0457] Example 27. Synthesis of compound SA-12

[0458] [ka]

[0459] K 2 C.O. 3 (25 mg, 0.18 mmol) in THF (5 mL) was added 3,5-dimethyl-4H-pyrazole (17 mg, 0.18 mmol) and SA (36 mg, 0.09 mmol). This mixture was stirred at room temperature for 15 hours. Pour the residue mixture into 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid (11 mg, 30%): 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 5.86 (s, 1H), 4.79 (AB, 1H), 4.74 (AB, 1H), 2.57 (t, 1H), 2.21(s, 3H), 2.18-2.16 (m, 1H) , 2.11(s, 3H), 2.05-2.02 (m, 1H), 0.90-1.80 (m, 22H), 0.68 (s, 3H).

[0460] Example 28. Synthesis of compound SA-13

[0461] [ka]

[0462] K 2 C.O. 3 (50 mg, 0.36 mmol) in THF (6 mL) was added 3H-pyrazole (16 mg, 0.23 mmol) and SA (36 mg, 0.09 mmol). This mixture was stirred at room temperature for 15 hours. Transfer this reaction mixture to 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase prep-HPLC to give the title compound as a white solid (11 mg, 31.3%). 1 HNMR(400 MHz, CDCl 3 ), δ (ppm), 7.56 (d,1H), 7.44 (d, 1H), 6.35 (s,1H), 4.95 (AB, 1H), 4.92 (AB,1H), 2.60 (1H, t), 1.00-2.25 (m, 24H), 0.68 (s, 3H).

[0463] Example 29. Synthesis of compound SA-14

[0464] [ka]

[0465] To a solution of the crude reactant (124.8 mg, 0.315 mmol, theoretical) in anhydrous THF (2.5 mL) was added 4-(trifluoromethyl)-1H-pyrazole (85.5 mg, 0.628 mmol) followed by carbonic acid Potassium (86.8 mg, 0.628 mmol) was added. The solution was heated at room temperature overnight, then the solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2 x 50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:1) to give the product (69 mg, 0.152 mmol, yield=48% (2 steps)) as a white solid. 1 HNMR(500 MHz, CDCl 3 ) δ(ppm):7.72 (2H, s), 4.99 (1H, AB), 4.89 (1H, AB), 2.61 (1H, t), 2.2 (bq, 1H), 1.00-2.10 (23H, m), 0.69 (3H, s). 1.00-2.10 (24H, m). 19 FNMR (376 MHz, CDCl 3 ) δ(ppm):-56.46. LCMS:rt=2.52min,m / z=453.2[M+H] + .

[0466] Example 30. Synthesis of compound SA-15

[0467] [ka]

[0468] To a solution of the crude reactant (249.5 mg, 0.629 mmol, theoretical) in anhydrous THF (5 mL) was added 3.4-dimethyl-1H-pyrazole (120.7 mg, 1.256 mmol) followed by potassium carbonate (173.6 mg, 1.256 mmol) was added. The solution was stirred at 25° C. overnight, then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:3) to give the product (56 mg, 0.136 mmol, yield=22% (2 steps)) as a white solid. 1 HNMR (400 MHz, CDCl 3 ) δ(ppm):7.08 (1H, s), 4.77 (1H, AB), 4.76 (1H, AB), 2.55 (1H, t), 2.18 (3H, s), 1.00-2.20 (24H, m). 0.67 (3H, s). LCMS:rt=2.41min,m / z=413.2[M+H] + .

[0469] Synthesis of 4-ethyl-1H-pyrazole

[0470] [ka]

[0471] Synthesis of 4-ethynyltrimethylsilane-1H-pyrazole. Reactant (3.88g, 20mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (2.45g,3mmol), CuI(0.571g,3mmol), Et 2 Ethynyltrimethylsilane (9.823g, 14.1mL, 100mmol) was added to a solution in NH (30mL) and THF (30mL) with N 2 was added under atmosphere and the mixture was stirred at room temperature overnight. The black solution was then diluted with ethyl acetate (300 mL) and the resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=7.5:1) to give the product (1.90 g, 11.57 mmol, yield=58%) as a brownish solid. 1 HNMR(500 MHz, DMSO-d6) δ(ppm):13.12 (1H, br), 8.07 (1H, s), 7.65 (1H, s), 0.19 (9H, s).

[0472] Synthesis of 4-ethynyl-1H-pyrazole. To a solution of the reactant (1.90 g, 11.57 mmol) in THF (20 mL) and water (4 mL) was added lithium hydroxide hydrate (970 mg, 23.14 mmol). The solution was stirred at room temperature overnight, then most of the THF solvent was removed in vacuo. The solution was neutralized by the addition of acetic acid and the resulting mixture was diluted with dichloromethane (200 mL) and brine (50 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=4:1) to obtain the product (828 mg, 8.99 mol, yield=78%) as a light brown solid. 1 HNMR (500 MHz, DMSO-d6) δ(ppm): 13.11 (1H, br), 8.05 (1H, s), 7.65 (1H, s), 3.95 (1H, s).

[0473] Synthesis of 4-ethyl-1H-pyrazole. To a solution of the reactants (828 mg, 8.99 mmol) in ethanol (50 mL) was added 10 wt% Pd / C on carbon (165.6 mg, 0.16 mmol). The reaction mixture was hydrogenated with a hydrogen balloon overnight. Filter a small sample solution, concentrate in vacuo, and 1 The reaction was determined to be complete as characterized by HNMR. The entire reaction mixture was filtered through Celite and the Celite was washed with ethanol (20 mL). The combined filtrates were concentrated in vacuo. The residue was purified by a short pad of silica gel (petroleum ether / ethyl acetate=3:1) to obtain the product (643 mg, 6.69 mmol, yield=74%) as a pale yellow liquid. 1 HNMR (500 MHz, DMSO-d6) δ(ppm):12.48 (1H, s), 7.39 (2H, s), 2.43 (2H, q, J=7.6 Hz), 1.13 (3H, t, J=7.6 Hz ).

[0474] Example 31. Synthesis of compound SA-16

[0475] [ka]

[0476] To a solution of the crude reactant (249.5 mg, 0.629 mmol, theoretical) in anhydrous THF (5 mL) was added 4-ethyl-1H-pyrazole (120.7 mg, 1.256 mmol) followed by potassium carbonate (173.6 mg, 1.256 mmol) was added. The solution was stirred at 25° C. overnight, then the solution was diluted with ethyl acetate (200 mL). The resulting solution was washed with brine (2 x 100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2:3) to obtain the product (29.5 mg, 0.0714 mmol, yield = 11% (2 steps)) as a white solid. . 1 HNMR (400 MHz, CDCl 3 ) δ(ppm):7.38 (1H, s), 7.18 (1H, s), 4.89 (1H, AB), 4.82 (1H, AB), 2.57 (1H, t), 2.51 (2H, q), 0.80-2.20 (24H, m), 0.68 (3H, s). LCMS:rt =2.34min,m / z=413.1[M+H] + .

[0477] Synthesis of 4-methylsulfonyl-1H-pyrazole

[0478] [ka]

[0479] Synthesis of 4-methylthio-1H-pyrazole. To a solution of 4-bromo-1H-pyrazole (200 mg, 1.361 mmol) in anhydrous THF (5 mL) was added n-BuLi (2.5 M, 1.8 mL, 4.5 mmol) at 0 °C. This solution was stirred at room temperature for 1 hour. MeSSMe (128 mg, 0.12 mL, 1.361 mmol) was added at 0° C. and the reaction solution was stirred at room temperature for 2 hours. The reaction was poured into ethyl acetate (50 mL) and water (50 mL). The separated organic layer was washed with brine (50 mL), dried over magnesium sulfate, and concentrated in vacuo. Due to its odor, the crude product was used in the next oxidation step without further purification.

[0480] Synthesis of 4-methylsulfonyl-1H-pyrazole. To a solution of the crude reactant (155.4 mg, 1.361 mmol, theoretical) in dichloromethane (2.7 mL) was added trifluoroacetic acid (0.1 mL) at 0°C. 3-chloroperbenzoic acid (m-CPBA, 85% wt, 863 mg, 4.25 mmol) was then added in portions and the solution was stirred at room temperature overnight. Dilute this solution with ethyl acetate (100 mL) and convert the resulting solution to sat.Na 2 C.O. 3 The solution (3 x 50 mL) was then washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate to ethyl acetate:methanol=10:1) to give the product (51 mg, 0.349 mmol, yield=26% (2 steps)) as a pale yellow thick oil. obtained as. 1 HNMR (500 MHz, CDCl 3 ) δ(ppm):8.04 (2H, s), 3.14 (3H, s).

[0481] Example 32. Synthesis of compound SA-17 (a)

[0482] [ka]

[0483] To a solution of the crude reactant (124.8 mg, 0.315 mmol, theoretical) in anhydrous THF (2.5 mL) was added 4-(methylsulfonyl)-1H-pyrazole (51 mg, 0.349 mmol) followed by potassium carbonate ( 48mg, 0.349mmol) was added. The solution was heated at 40° C. for 2 hours, then the solution was diluted with ethyl acetate (100 mL). The resulting solution was washed with brine (2 x 50 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by reverse phase prep-HPLC to give the product SA-17 (4 mg, 0.00865 mmol, yield=2.8% (2 steps) as a white solid. 1 HNMR (400 MHz, CDCl 3 ) δ(ppm):7.93 (1H, s), 7.87 (1H, s), 5.02 (1H, AB), 4.92 (1H, AB), 3.14 (3H, s), 2.63 (1H, t), 2.17- 2.26 (1H, s), 2.04 (1H, d×t), 1.70-1.89 (6H, m), 1.56-1.69 (1H, m), 1.20-1.54 (12H, m), 1.27 (3H, s), 1.04-1.18 (3H, m), 0.68 (3H, s). LCMS:rt=2.35min,m / z=463.1[M+H] + .

[0484] (b)

[0485] [ka]

[0486] To a solution of SA (200 mg, 0.46 mmol) in 30 mL of DCM was added m-CPBA (236 mg, 1.16 mmol) at room temperature (15° C.-19° C.). The reaction mixture was stirred at the same temperature for 6 hours. TLC showed the reaction was complete. This reaction mixture was mixed with saturated aqueous Na 2 S 2 O 3 and extracted with DCM (50 mL x 2). Saturate the organic layer with aqueous Na 2 S 2 O 3 (10 mL), washed with brine (10 mL), and anhydrous Na 2 S.O. 4 and concentrated in vacuo. The residue was purified by a silica gel column (petroleum ether / ethyl acetate 5 / 1-1 / 2) to obtain SA-17 (140.5 mg, yield: 65%) as a white solid. 1 H NMR:(400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (s, 1H), 5.04-4.89 (m, 2H), 3.13 (s, 3H), 2.64-2.59 (m, 1H), 2.24 -2.16 (m, 1H), 2.06-2.03 (m, 1H), 1.87-1.75 (m, 6H), 1.64-1.42 (m, 11H), 1.35-1.27 (m, 7H), 1.16-1.06 (m, 3H), 0.67 (s, 3H).

[0487] Example 33. Synthesis of compound SA-18

[0488] [ka]

[0489] SA (200mg,0.50mmol) and K 2 C.O. 3(138.2 mg, 1.00 mmol) in 5 mL dry DMF was added 4-(methylthio)-1H-pyrazole (114.2 mg, 1.00 mmol) with N 2 It was added at lower room temperature (25°C). The reaction mixture was stirred at the same temperature for 18 hours. The reaction mixture was poured into water and extracted with EtOAc (50 mL x 2). Wash the organic layer with brine and Na 2 S.O. 4 dried, filtered and concentrated in vacuo. The residue was purified by a silica gel column (petroleum ether / ethyl acetate 10 / 1 to 2 / 1) to obtain compound SA-18 (165 mg, yield: 76%) as a white powder. 1 H NMR:(400 MHz, CDCl3) δ 7.53 (s, 1H), 7.42 (s, 1H), 4.94-4.80 (m, 2H), 2.60-2.56 (m, 1H), 2.34 (s, 3H), 2.23-2.16 (m, 1H), 2.06-2.02 (m, 1H), 1.87-1.58 (m, 12H, contained H 2 O), 1.49-1.27 (m, 14H), 1.15-1.07 (m, 2H), 0.67 (s, 3H). LCMS:rt=1.32min,m / z=431.2[M+H] + .

[0490] Example 35. Synthesis of compound SA-20

[0491] [ka]

[0492] To a solution of SA (100.0 mg, 0.23 mmol) in 10 mL of DCM was added m-CPBA (51.86 mg, 0.26 mmol) at -78 °C. The reaction mixture was then stirred at -78°C for 3 hours. LCMS showed the reaction was complete. Then saturated aqueous Na 2 S 2 O 3 was added to this mixture at -78°C. The reaction was then warmed to room temperature (16-22°C). The resulting mixture was extracted with EtOAc (50 mL x 2), washed with water (10 mL), brine (10 mL), and anhydrous Na 2 S.O. 4 and concentrated in vacuo. The residue was purified by a silica gel column (petroleum ether / ethyl acetate = 1 / 1 to EtOAc) to obtain SA-20 (90 mg, yield: 72.3%) as a white solid. 1 H NMR:(400 MHz, CDCl3) δ 7.82 (s, 1H), 7.81 (s, 1H), 5.05-4.88 (m, 2H), 2.89 (d, 3H), 2.64-2.59 (m, 1H), 2.25-2.17 (m, 1H), 2.06-2.03 (m, 1H), 1.87-1.74 (m, 6H), 1.65-1.58 (m, 2H, contained H 2 O), 1.48-1.40 (m, 7H), 1.33-1.28 (m, 8H), 1.15-1.07 (m, 3H), 0.68 (s, 3H). LCMS:rt=1.14min,m / z=429.2[M-H 2 O], 469.2[M+Na].

[0493] Example 36. Synthesis of compound SA-21

[0494] [ka]

[0495] A suspension of compound SA (100 mg, 0.25 mmol) in THF (25 mL) was added with 4-fluoro-1H-pyrazole (64.5 mg, 0.75 mmol) and K 2 C.O. 3 (103 mg, 0.75 mmol) was added. This mixture was stirred at 35°C for 15 hours. The reaction mixture was then extracted with 50 mL of EtOAc and 100 mL of H 2 Washed with O and 100 mL brine and evaporated in vacuo. The residue was purified by reverse phase prep-HPLC to obtain SA-21 as a white solid (19 mg, 0.05 mmol, 20% yield). 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 7.37 (1H,d), 7.30 (1H,d), 4.85(1H,AB), 4.77(1H,AB), 2.57 (t,1H), 2.2 (bq, 1H), 2.1 (bd, 1H), 1.00-1.9 (22H, m), 0.67 (s, 3H). LCMS:Rt=2.31min,MS (ESI) m / z:403.4[M+H] + .

[0496] Example 37. Synthesis of compound SA-22

[0497] [ka]

[0498] A suspension of compound SA (100 mg, 0.25 mmol) in THF (25 mL) was added with 1H-pyrazole-3-carbonitrile (70 mg, 0.75 mmol) and K 2 C.O. 3 (103 mg, 0.75 mmol) was added. This mixture was stirred at 35°C for 15 hours. The reaction mixture was then extracted with 50 mL of EtOAc and 100 mL of H 2 O and Washed with 100 mL brine and evaporated in vacuo. The resulting residue was purified by reverse phase prep-HPLC to obtain SA-22 as a white solid (23 mg, 0.056 mnol, yield 24%). 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 7.48 (d, 1H), 6.73 (d, 1H), 5.03(1H,AB), 4.93(1H,AB), 2.60 (t,1H), 1.00-2.25 (24H, m) , 0.68 (s, 3H). LCMS:Rt=2.38min,MS (ESI) m / z:410.2[M+H] + .

[0499] Example 38. Synthesis of compound SA-23

[0500] [ka]

[0501] K 2 C.O. 3 To a suspension of (55 mg, 0.4 mmol) in THF (5 mL) was added 1H-pyrazole (28 mg, 0.4 mmol) and compound SA-JJ (85 mg, 0.2 mmol). The mixture was stirred at room temperature for 15 h, then the residual mixture was dissolved in 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give SA-23 as a white solid (29 mg, 35%). 1 HNMR(500 MHz, CDCl3) δ (ppm):7.55 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.88 (AB, 1H), 3.42-3.37 (m, 5H), 2.58 (t, 1H), 2.22-2.16 (m, 1H), 2.06-2.03 (m, 1H), 1.00-1.90 (m, 22H), 0.68 (s, 3H). LC-MS:rt=2.27min,m / z=415.3[M+H] + .

[0502] Example 39. Synthesis of compound SA-24

[0503] [ka]

[0504] A solution of compound SA-JJ (120 mg, 0.28 mmol) in THF (3 mL) was added with K 2 C.O. 3 (190 mg, 1.4 mmol) and 1H-pyrazole-4-carbonitrile (130 mg, 1.4 mmol) were added. The resulting solution was stirred at room temperature overnight, then The reaction was diluted with EtOAc (20 mL). The resulting solution was washed with brine (10 mL) and 2 S.O. 4 and concentrated in vacuo. The residue was purified by prep-HPLC to give SA-24 (30 mg, 24%) as a white solid. 1H NMR:(500 MHz, CDCl 3 ), δ (ppm), 7.86 (1H, s), 7.81 (1H, s), 5.0 (1H, AB), 4.88 (1H, AB), 3.39 (3H, s), 3.19 (2H, s), 2.59 (1H, t), 2.2 (m, 1H), 0.69 (3H, s), 0.60-2.1 (23H, m). LC-MS:rt=2.25min;m / z=440.4(M+H) + .

[0505] Example 40. Synthesis of compound SA-25

[0506] [ka]

[0507] A suspension of SA-V (20 mg, 0.04 mmol) in THF (5 mL) was added with pyrazole (30 mg, 0.45 mmol) and K 2 C.O. 3 (60 mg, 0.45 mmol) was added. This mixture was stirred at 25°C for 15 hours. The reaction mixture was then purified by reverse phase prep-HPLC to obtain SA-25 as a white solid (11 mg, 57% yield). 1 H NMR (500 MHz, CDCl 3 ), δ (ppm), 7.56 (s, 1H), 7.42 (s, 1H), 6.33 (s, 1H), 4.97(1H,AB), 4.89(1H,AB), 4.86-4.69 (m, 1H) , 2.60 (1H, t), 1.00-2.20 (22H, m), 0.72 (s, 3H).

[0508] Example 42. Synthesis of compound SA-27

[0509] [ka]

[0510] K 2 C.O. 3 To a suspension of (25 mg, 0.18 mmol) in THF (5 mL) was added 3H-pyrazole (16 mg, 0.23 mmol) and SC-EE (36 mg, 0.08 mmol). This mixture was stirred at room temperature for 15 hours. Add this reaction mixture to 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give the title compound as a white solid (12 mg, 34.3%). 1 HNMR(500MHz,CDCl3)δ(ppm), 7.55(d,1H),7.42-7.41(d,1H), 6.34 (t,1H), 5.87 (t,1H), 4.97 (1H, AB), 4.88 ( 1H, AB), 2.55(t,1H), 0.69 (s, 3H), 1.10-2.25 (m, 24H), 0.69 (s, 3H).

[0511] Example 43. Synthesis of compound SA-28

[0512] [ka]

[0513] K 2 C.O. 3 To a suspension of (25 mg, 0.18 mmol) in THF (5 mL) was added 1H-pyrazole-4-carbonitrile (20 mg, 0.23 mmol) and SC-EE (36 mg, 0.09 mmol). This mixture was stirred at room temperature for 15 hours. Add this reaction mixture to 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase prep-HPLC to give the title compound as a white solid (22 mg, 61.6%). 1 HNMR(400 MHz, CDCl 3 ), δ (ppm):7.86 (s, 1H), 7.81(s, 1H), 5.87 (t, 1H), 5.02 (AB, 1H), 4.90 (AB, 1H), 2.61 (t, 1H), 1.00 -2.25 (m, 24H), 0.68 (s, 3H). LC-MS:rt=2.30min,m / z=446.2(M + +1).

[0514] Example 44. Synthesis of compound SA-29

[0515] [ka]

[0516] K 2 C.O. 3 (127 mg, 0.92 mmol) in THF (5 mL) was added 4-(methylsulfonyl)-1H-pyrazole (67 mg, 0.46 mmol) and the reactants (200 mg, 0.46 mmol) and the resulting The mixture was stirred at room temperature for 15 hours. This mixture was then diluted with 20 mL of H 2 Poured into O and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue mixture was purified by reverse phase prep-HPLC to give the title compound SA-29 as a white solid (46 mg, 0.0923 mmol, yield=20%). 1 HNMR (500 MHz, CDCl 3 ) δ (ppm):7.93 (s, 1H), 7.87 (s, 1H), 5.87 (t, 1H), 5.02 (AB, 1H), 4.92 (AB, 1H), 3.14 (s, 3H), 2.63 ( t, 1H), 2.25-2.17 (m, 1H), 2.08-2.04 (m, 1H), 1.00-2.00 (m, 22H), 0.69 (s, 3H). LC-MS:rt=2.10min,m / z=499.3[M+H] + .

[0517] Example 61. Synthesis of compound SA-30

[0518] [ka]

[0519] K 2 C.O. 3 (25 mg, 0.18 mmol) in THF (5 mL) was added 1H-pyrazole-4-carbonitrile (20 mg, 0.21 mmol) and SA-AA (36 mg, 0.087 mmol). This mixture was stirred at room temperature for 15 hours. This reaction mixture was then diluted with 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase prep-HPLC to give the title compound as a white solid. (10 mg, 27.0%). 1 HNMR(400 MHz, CDCl 3 ), δ (ppm):7.86(s, 1H), 7.81(s, 1H), 5.99 (AB, 1H), 5.85 (AB, 1H), 2.65 (t, 1H),1.59 (q, 2H), 0.88 (t, 3H), 1.00-2.25 (m, 24H), 0.89 (t, 3H), 0.68 (s, 3H). LC-MS:rt=2.45min,m / z=424.3(M + +1).

[0520] Example 45. Synthesis of compound SA-31

[0521] [ka]

[0522] K 2 C.O. 3 To a suspension of (55 mg, 0.4 mmol) in THF (5 mL) was added 1H-pyrazole (28 mg, 0.4 mmol) and compound SC-SS (83 mg, 0.2 mmol). The mixture was stirred at room temperature for 15 h, then the residual mixture was dissolved in 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give SA-31 as a white solid (7 mg, 9%). Compound SA-31: 1 HNMR (500 MHz, CDCl3) δ (ppm):7.55 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.88 (AB, 1H), 4.48 (AB ×d, 1H), 4.38 (AB×d, 1H), 2.59 (t, 1H), 2.23-2.16 (m, 1H), 2.09-2.05 (m, 1H), 1.00-1.90 (22H, m), 0.68 (s, 3H). LC-MS:rt=2.15min,m / z=403.3[M+H] + .

[0523] Example 46. Synthesis of compound SA-32

[0524] [ka]

[0525] K 2 C.O. 3 (55 mg, 0.4 mmol) in THF (5 mL) was added to Razol-4-carbonitrile (37 mg, 0.4 mmol) and compound SC-SS (83 mg, 0.2 mmol) were added. The mixture was stirred at room temperature for 15 h, then the residual mixture was dissolved in 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue mixture was purified by reverse phase prep-HPLC to give SA-32 as a white solid (20 mg, 23%). Compound SA-32: 1 HNMR (500 MHz, CDCl3) δ (ppm):7.86 (s, 1H), 7.81 (s, 1H), 5.02 (AB, 1H), 4.91 (AB, 1H), 4.48 (AB×d, 1H), 4.38 (AB×d, 1H), 2.61 (t, 1H), 2.23 (s, 1H), 2.21-2.17 (m, 1H), 2.07-2.03 (m, 1H), 1.00-1.90 (m, 21H), 0.67 (s, 3H). LC-MS:rt=2.22min,m / z=428.3[M+H] + .

[0526] Example 47. Synthesis of compound SA-33

[0527] [ka]

[0528] K 2 C.O. 3 (119 mg, 0.86 mmol) in THF (5 mL) was added 4-(methylsulfonyl)-1H-pyrazole (63 mg, 0.43 mmol) and reactant SC-SS (180 mg, 0.43 mmol), The mixture was then stirred at room temperature for 15 hours. Add the remaining mixture to 20 mL of H 2 Poured into O and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue mixture was purified by reverse phase prep-HPLC to give the title compound SA-33 as a white solid (53 mg, 0.110 mmol, yield=25.6%). 1 HNMR(500 MHz, CDCl 3 ) δ (ppm):7.93 (s, 1H), 7.87 (s, 1H), 5.02 (AB, 1H), 4.92 (AB, 1H,), 4.48 (AB×d), 4.39 (AB×d, 1H), 3.14 (s, 1H), 2.63 (t, 1H), 2.24-2.17 (m, 1H), 2.07-2.04 (m, 1H), 1.00-1.90 (m, 24H), 0.68 (s, 3H). LC-MS:rt=2.06min,m / z=481.2[M+H] + .

[0529] Example 49. Synthesis of compound SA-35

[0530] [ka]

[0531] K 2 C.O. 3 To a suspension of (25 mg, 0.18 mmol) in THF (5 mL) was added 1H-pyrazole (20 mg, 0.23 mmol) and SA-AA (36 mg, 0.09 mmol). This mixture was stirred at room temperature for 15 hours. Transfer this reaction mixture to 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase prep-HPLC to give SA-35 as a white solid (8 mg, 21.6%). 1 H NMR (400 MHz, CDCl 3 ), δ (ppm), 7.53(1H,s), 7.41(1H,s) 6.33 (s,1H), 4.97(AB,1H), 4.88(AB,1H), 2.58(1H, t), 1.00- 2.25 (24H, m), 0.88(3H, t), 0.68(s, 3H). LC-MS:rt=2.39min,m / z=399.4(M + +1).

[0532] Example 50. Synthesis of compound SB-1

[0533] [ka]

[0534] K 2 C.O. 3 (25 mg, 0.18 mmol) in THF (5 mL) was added pyrazole (13 mg, 0.18 mmol) and compound SB (36 mg, 0.09 mmol). After stirring at room temperature for 15 h, the reaction mixture was dissolved in 5 mL of H 2 Poured into O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse phase prep-HPLC to give 7.54 (d, 1H), 7.41 (d, 1H), 6.33 (t, 1H), 4.97 (AB, 1H), 4.87 (AB, 1H), 2.58 (t, 1H), 0.90-2.25 (m, 21H), 0.69 (s, 3H).

[0535] Example 51. Synthesis of compound SB-2

[0536] [ka]

[0537] To a solution of crude SB (...

Claims

[Claim 1] Coma.

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