Analogues of tripterine

Abstract

The invention relates to analogs of tripterine. Described herein are, inter alia, compositions for treating or preventing obesity and methods of using the compositions.

Description

[0001] The present invention is a divisional application of a PCT patent application entered into China with Chinese patent application number 201680076127.9, invention name “Analogues of tripterygium wilfordii” and international application date October 21, 2016.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to and the benefit of U.S. Provisional Application No. 62 / 245,356, filed on October 23, 2015, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] The present application relates to analogs of tripterygium wilfordii. Background Art

[0005] In 2008, the World Health Organization (WHO) estimated that 1.4 billion adults worldwide were overweight; of these, 200 million men and 300 million women were obese. It is predicted that by 2030, more than 1 billion people in the world will be obese. Obesity is a major cause of developing debilitating diseases such as type 2 diabetes, cardiovascular disease, osteoarthritis (a health problem that causes pain, swelling and stiffness in one or more joints), stroke, high blood pressure, cancer (breast, colon, endometrial (related to the lining of the uterus) and kidney) and non-alcoholic steatohepatitis, all of which reduce quality of life and longevity.

[0006] Among healthcare professionals worldwide, there is now consensus that the global obesity epidemic will be one of the leading causes of morbidity and mortality for current and future generations unless the irreversible rise in the prevalence of this disorder is reversed. Once considered a problem primarily in Western cultures, developing countries have now joined the ranks of obese nations. A 1999 United Nations study found that obesity is present in all developing regions and is growing rapidly, even in countries where hunger exists. The World Health Organization (WHO) defines obesity as having a body mass index (BMI = weight in kg / height in m 2 ) value>30kg m -2 (Normal BMI = 20 to 25 kg m -2 ) of subjects).

[0007] Overweight and obesity are caused by an energy imbalance. The body requires a certain amount of food energy (calories) to maintain basic life functions. When the amount of calories the body takes in equals the amount of calories the body uses or "burns," body weight tends to remain constant. Over time, when people eat and drink more calories than they burn, the energy balance moves toward weight gain, overweight and obesity.

[0008] A likely explanation for the rapid increase in obesity is that it is driven by a combination of genetic, social, and environmental factors. Although a large proportion of the population is very successful in maintaining a healthy weight through a strict diet and reasonable physical activity, for many this program does not lead to the desired health outcomes. For some obese people, pharmacological therapies will be required to provide the necessary adjunct support to diet, exercise, and lifestyle changes to achieve a clinically beneficial weight loss of >5%.

[0009] There is no single cause for all overweight and obesity. There is no single method that can help prevent or treat overweight and obesity. Treatment may include a mix of behavioral therapy, diet, exercise, and sometimes even weight loss medications. In some cases of extreme obesity, bariatric surgery may be an option. In the past 15 years, only four new drugs, dexfenfluramine, Sibutramine Orlistat and rimonabant have been registered for the treatment of obesity. Of these drugs, only three, namely dexfenflurazine, sibutramine and orlistat, have achieved global (except Japan) registration. There is a great need to develop other safe and effective anti-obesity drugs. Summary of the invention

[0010] Specifically provided herein are compositions comprising the compounds disclosed herein and methods of using the same.

[0011] In various specific embodiments, compared with tripterygium wilfordii, the compounds provided by the present invention have structural modifications.

[0012] In one aspect, the composition can promote weight loss, reduce body fat, reduce food intake, improve homeostasis, or a combination thereof. The compound has the structure of formula (I):

[0013]

[0014] in

[0015] The dashed lines between C1 and C2, C2 and R3, C3 and R4, C5 and C6, C5 and C7, C1 and C6, and C3 and C4 indicate that single or double chains may exist if valency permits;

[0016] R1 is -CN, -COOH, -COOCH2CH3, -CONHR5, -CONR5R5, -COOR5, -COOCH3, -CH2NR5R5, -CH2OCONR5R5, -CH2NR5COOR5, -CH2R5, -CH2NR5CONR5R5, -CH2OH, -CH2OR5, alkyl sulfate, alkyl sulfonate, alkyl phosphate, -CH2OSO3R5, -CH2OSO2R5, -CH2OPO3R5R5, -CH2OPO3HR5, - CH2OPO3H2, -C(=NR5)NR5R5, -NR5C(=NR5)NR5R5, -CONH2, -CH2CONR5R5, -SR5, -SO3R5, -SO2R5, -CH2NHCOR5, -CH2NHCN R5NR5R5, -CH2COSR5, CH2NR5COR5, -CH2NR5CNR5NR5R5, -CH2NR5COSR5, -CH2NHSO2R5, -CH2NR5SO2R5, -CHNR5, -CHNOR5 , -H, -NH2, -NHR5, -NR5R5, -OH, -OR5, phosphate, -OPO3R5R5, -OPO3HR5, -OPO3H2, -NCO, -NCS, -N3, -R5, -C≡CR5, -(CH=CH)R5, -SH, -SR5, -SO2H, -SO3H, -SO2NR5R5, -SO3R5, -NHCOR5, -NHCNR5NR5R5, -NHCOSR5, secondary amide, tertiary amide, -NR5COR5, -NR5C(=NH)NR 5R5, -NR5COSR5, -NHC(=NR5)R5, -NR5C(=NR5)R5, -NHSO2(NH2), -NHSO2R5, -NR5SO2R5, -NR5SO2NR5R5, -OCOR5, -OCONR5R5, -O(C=O)OR5, -SCOR5, -O(C=NH)NR5R5, -OCSNHR5, -OS(=O2)R5, -OS(=O2)NR5R5, -SCONR5R5, -CH2-aryl, -CH2-heteroaryl,

[0017]

[0018] R2 is -H, -CH3, -SCH(CH3)2, -SC(=O)CH3, -SC(=O)R5, -SCH2CH2OCOCH3, -SR5, -SOR5, -SOOR5, -SCONR5R5,

[0019]

[0020] When there are double bonds between C1 and C2, C3 and C4, and C5 and C6, R3 is –OCOCH3, –OCOOCH2CH3, –OR7, –R7, or –NR5R5;

[0021] When there are double bonds between C1 and C2, C3 and C4, and C5 and C6, R4 is –OCOCH3, –OCOOCH2CH3, –OR7, –R7, or –NR5R5;

[0022] When R4 is O and there are double bonds between C2 and R3 and between C3 and R4, R3 is O;

[0023] When R3 is O and there is a double bond between C2 and R3, R4 is -OCH3, -OP(=O)(OCH3)2, -OH, -OCOOCH2CH3, -OCONHCH2CH3, -OCOOCH(CH3)2, -OR7, -R7 or -NR5R5; R3 and R4 may also be combined to form a heterocyclic ring or a carbocyclic ring;

[0024] R5, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, amino, or heteroaryl, optionally substituted with substituents each selected from alkyl, alkoxy, cycloalkyl, ether, amino optionally substituted with one or more alkyl groups, halogen, hydroxy, ether, cyano, nitrile, CF3, ester, amide, cycloalkylamide, sugar, heteroarylamide optionally substituted with alkyl and / or alkoxy, urea, carbamate, thioether, sulfate, sulfonyl, sulfonic acid carboxylic acid, and aryl, or two R5 groups taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with substituents each selected from alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, heteroaryl, amino, halogen, hydroxy, ether, nitrile, cyano, nitro, CF3, esteramide, urea, carbamate, thioether, or carboxylic acid; and

[0025] R7 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl or heteroaryl, optionally substituted with substituents each selected from alkyl, cycloalkyl, ether, ammonia, halogen, hydroxy, ether, nitrile, cyano, nitrile, CF3, ester, amide, urea, carbamate, thioether or carboxylic acid,

[0026] or a pharmaceutically acceptable salt thereof or a prodrug thereof. In some specific embodiments, R1 is -NR5C(=NR5)NR5R5, -SR5, -SO3R5, -SO2R5, -NH2, -NHR5, -NR5R5, -OH, -OR5, -NCO, -NCS, -N3, -SH, -SR5, -SO2H, -SO3H, -SO2NR5R5, -SO3R5, -NHCOR5, -NHCNR5NR5R5, -NHCOSR5, -NR5COR5, -N R5C(=NH)NR5R5, -NR5COSR5, -NHC(=NR5)R5, -NR5C(=NR5)R5, -NHSO2(NH2), -NHSO2R5, -NR5SO2R5, -NR5SO2NR5R5, -OCOR5, -OCONR5R5, -O(C=O)OR5, -SCOR5, -O(C=NH)NR5R5, -OCSNHR5, -OS(=O2)R5, -OS(=O2)NR5R5 or -SCONR5R5.

[0027] In some embodiments, R2 is H.

[0028] In some embodiments, when R3 is O and there is a double bond between C2 and R3, R4 is -OH, -OR7 or -R7.

[0029] In one aspect, the composition comprises a compound of the structure of formula (II):

[0030]

[0031] Among them, R1 is OR a or NR a R b , where each R a and R b are independently hydrogen, R5, C(=NR5)NR5R5, -CO, -CS, -COR5, -CNR5NR5R5, -COSR5, -C(=NH)NR5R5, -C(=NR5)R5, -SO2(NH2), -SO2R5, -SO2R5, -SO2NR5R5, -COR5, -CONR5R5, -(C=O)OR5, -(C=NH)NR5R5, -CSNHR5, -S(=O2)R5, or -S(=O2)NR5R5, and

[0032] R5 are each as described in formula (I), or

[0033] A pharmaceutically acceptable salt or a prodrug thereof.

[0034] In some specific embodiments, R1 is NR a Rb , which can be represented by formula (II)-a:

[0035]

[0036] In certain embodiments, R1 is NH(CO)R5, wherein R5 is preferably alkyl, cycloalkyl or aryl.

[0037] In certain embodiments, R1 is NHAc.

[0038] Exemplary compounds include, but are not limited to, the following compounds:

[0039]

[0040]

[0041] as well as

[0042] In one aspect, provided are pharmaceutical compositions comprising a compound disclosed herein, for example, a compound of Formula (I) and Formula (II), including embodiments thereof, and a pharmaceutically acceptable excipient.

[0043] In one aspect, a method for treating obesity in a subject in need is provided. The method comprises administering to the subject a composition comprising an effective amount of a compound of formula (I), including specific embodiments thereof. Alternatively, a method for treating obesity in a subject in need comprises administering a composition comprising an effective amount of a compound of formula (II), including specific embodiments thereof. In addition, a method for treating obesity in a subject in need comprises administering a composition comprising an effective amount of a compound of formula (I), formula (II), or a combination thereof, including specific embodiments thereof.

[0044] In some embodiments, the subject comprises leptin resistance. In certain embodiments, the subject has an increased leptin level, for example in the blood. In certain embodiments, the subject does not respond well (e.g., experiences decreased appetite, improved BMI, and / or a weight loss of at least about 5%, 4%, 3%, 2%, or 1%) to leptin administration and / or the efficacy of leptin administration decreases over time (e.g., as measured by a reversal of weight loss or more frequent hunger in the subject). In some embodiments, the subject comprises a blood or serum leptin concentration of about 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100 ng / mL or more. In certain embodiments, the subject is male and has a blood or serum leptin concentration of about 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50 ng / mL or more. In some specific embodiments, the subject is female and has a blood or serum leptin concentration of about 30, 35, 40, 45, 50, 75, 100 ng / mL or more.

[0045] In one aspect, the composition for administration comprises oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intra-disease site administration, intracerebral administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, lower eyelid administration, insufflation administration, suppository administration, inhalation administration or subcutaneous administration.

[0046] In some embodiments, methods for treating obesity in a subject in need thereof comprise orally administering a composition comprising an effective amount of one or more compounds disclosed herein.

[0047] In some embodiments, methods for treating obesity in a subject in need thereof comprise intraperitoneally administering a composition comprising an effective amount of one or more compounds disclosed herein.

[0048] In some embodiments, methods for treating obesity in a subject in need thereof comprise intraperitoneally administering a composition comprising an effective amount of one or more compounds disclosed herein.

[0049] In one aspect, provided herein is a composition, wherein the composition is for treating obesity-related diseases or conditions. Obesity-related diseases or conditions are selected from the group including obesity, pre-obesity, morbid obesity, Prader-Willi syndrome, hypothalamic injury-related obesity, non-alcoholic steatohepatitis, hyperlipidemia, hypertension, diabetes, lipodystrophy, fatty liver, Bardet-Biedl syndrome, Cohen syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome and MOMO (macrosomia, macrocephaly eye abnormalities) syndrome.

[0050] On the one hand, a method for treating an obesity-related disease or condition is provided herein, comprising administering to a subject suffering from an obesity-related disease or condition or at risk of suffering from an obesity-related disease or condition one or more compositions of formula (I), formula (II) or a combination thereof. The obesity-related disease or condition is selected from obesity, pre-obesity, morbid obesity, Prader-Willi syndrome, obesity associated with hypothalamic damage, non-alcoholic steatohepatitis, hyperlipidemia, hypertension, diabetes, dyslipidemia, fatty liver, Budd-Bieder syndrome, Cohen syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome and MOMO syndrome.

[0051] In one aspect, the composition is administered in combination with another therapy.

[0052] In some aspects, administration further comprises oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intra-disease site administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intra-articular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sub-eyelid administration, insufflation administration, suppository administration, inhalation administration or subcutaneous administration.

[0053] In one aspect, the composition is administered in a form selected from the group consisting of tablets, capsules, troches, granules, powders, salts, crystals, liquids, serums, syrups, suspensions, gels, creams, pastes, films, patches, and vapors.

[0054] In one aspect, the subject is a mammal. In another aspect, the subject is a human. In yet another aspect, the subject is a human having a body mass index (BMI) greater than 30 kg / m 2 of human beings.

[0055] In one aspect, a method for treating a malignant tumor in a subject in need thereof is provided, comprising administering to the subject an effective amount of one or more compounds disclosed herein.

[0056] In one aspect, a composition is provided, wherein the composition is used to treat a malignant tumor-related disease or condition. The malignant tumor-related disease or condition is selected from the group consisting of gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung cancer, brain cancer and glioblastoma multiforme (GBM).

[0057] In one aspect, provided herein is a method for treating a malignancy-related disease or condition, comprising administering one or more of formula (I) to a subject suffering from a malignancy-related disease or condition or at risk of suffering from a malignancy-related disease or condition. The malignancy-related disease or condition is selected from the group consisting of gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non-small cell lung cancer, brain cancer, and glioblastoma multiforme (GBM).

[0058] In one aspect, a kit is provided herein, comprising a composition for treating obesity, and instructions for treating obesity. In certain specific embodiments, the kit can be used for oral administration or intraperitoneal administration of a composition for treating obesity.

[0059] Each embodiment disclosed herein is considered applicable to each other disclosed embodiment. Therefore, all combinations of the various components described herein fall within the scope of the present invention. Other aspects are disclosed below. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 is a graph of daily body weights of diet-induced obese (DIO) mice during 11 days of treatment with oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0061] Figure 2 is a graph of the area under the curve (AUC) of daily body weight change in diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0062] Figure 3 is a graph of the cumulative body weight changes of diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compounds listed in Table 13 at a dose of 2,000 μg / kg.

[0063] Figure 4 is a graph of the area under the curve (AUC) of the cumulative body weight change in diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0064] Figure 5 is a graph of the cumulative body weight changes of diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compounds listed in Table 13 at a dose of 2,000 μg / kg.

[0065] Figure 6 is a graph of cumulative food intake in diet-induced obese (DIO) mice during treatment by oral administration at a dose of 2,000 μg / kg as listed in Table 13 for 11 days.

[0066] Figure 7 is a graph of the area under the curve (AUC) of cumulative food intake in diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compounds listed in Table 13 at a dose of 2,000 μg / kg.

[0067] Figure 8 is a graph of the change in percent whole blood glucose between Day 1 and Day 11 of diet-induced obese (DIO) mice during an 11-day treatment course by oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0068] Fig. 9 Graphs are between glucose values ​​between days 1 and 11 of diet-induced obese (DIO) mice during an 11-day treatment course of oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0069] Fig.10 Shown are data for daily body weights of diet-induced obese (DIO) mice during an 11-day treatment course of oral administration of the compounds listed in Table 13 at a dose of 2,000 μg / kg.

[0070] Fig.11 Data showing daily body weight changes of diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compounds listed in Table 13 at a dose of 2,000 μg / kg.

[0071] Fig.12 Data showing the cumulative body weight changes of diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compounds listed in Table 13 at a dose of 2,000 μg / kg.

[0072] Fig.13 Data showing daily food intake of diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0073] Fig.14 Data showing the cumulative daily food intake of diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0074] Fig.15 Shown are day 1 glucose data for diet-induced obese (DIO) mice during an 11-day treatment course of oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0075] Fig.16 Glucose data are shown for diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compound listed in Table 13 at a dose of 2,000 μg / kg.

[0076] Fig.17 Data showing changes in glucose in diet-induced obese (DIO) mice during an 11-day treatment course with oral administration of the compounds listed in Table 13 at a dose of 2,000 μg / kg. DETAILED DESCRIPTION

[0077] I. Definitions

[0078] Abbreviations used herein have their conventional meanings in the chemical and biological arts.Chemical structures and formulae described herein are constructed according to standard rules of chemical coordination known in the chemical arts.

[0079] As used herein, the term "about" in the context of a numerical value or a range means ±10% of the stated or claimed numerical value or range, unless the context requires a more restricted range.

[0080] It should be understood that in the case of providing a parameter range, the present invention also provides all integers and tenths within the range. For example, "0.2 to 5 mg" is 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, etc. to and including 5.0 mg.

[0081] When substituent groups are designated by their conventional chemical formula written from left to right, they also encompass chemically identical substituents that would result from writing the structure from right to left, for example, -CH2O- is equivalent to -OCH2-.

[0082] Some compounds of the present invention can exist in unsolvated form as well as solvated form, including hydrated form. Typically, solvated form is equivalent to unsolvated form and is included in the scope of the present invention. Some compounds of the present invention can exist in multiple crystalline or amorphous forms. Typically, all physical forms are equivalent for the purposes contemplated by the present invention and are intended to be within the scope of the invention.

[0083] As used herein, the term "salt" refers to an ionic compound produced by the neutralization reaction of an acid and a base. They are composed of relevant numbers of cations (positively charged ions) and anions (negative ions) so that the product is electrically neutral (has no net charge). These component ions can be inorganic, such as chloride (Cl - ) or organic, such as acetate (C2H3O2 - ) and can be monatomic, such as fluoride (F - ) or polyatomic, such as sulfate (SO4 2- ).

[0084] Certain compounds of the invention have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined in terms of absolute stereochemistry, such as (R)- or (S)- or as (D)- or (L)- of amino acids and each isomer is included within the scope of the invention. The compounds of the invention do not include those compounds known in the art that are too unstable for synthesis and / or separation. The invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds are intended to include both E and Z geometric isomers.

[0085] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

[0086] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0087] It will be apparent to those skilled in the art that certain compounds of the present invention may exist in tautomeric forms and all such tautomeric forms of the compounds are within the scope of the present invention.

[0088] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, both the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0089] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or with13 C- or 14 Compounds having the present structure except for the substitution of a C-rich carbon for a hydrogen are also within the scope of the present invention.

[0090] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute these compounds. For example, radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeled Compounds All isotopic variations of the compounds of the present invention, whether radiolabeled or not, are encompassed within the scope of the present invention.

[0091] It should be noted that throughout the application, alternative experimental instructions are written into Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered individually, thus comprising another specific embodiment, and the Markush group should not be considered a single unit.

[0092] As used herein, the term "a" or "an" means one or more. In addition, as used herein, the phrase "substituted by" means that the specified group may be substituted by one or more of any or all of the substituents. For example, when a group such as an alkyl or heteroaryl group is substituted by an "unsubstituted C1-C 20 alkyl or unsubstituted 2 to 20-membered heteroalkyl”, the group may contain one or more unsubstituted C1-C 20 alkyl and / or one or more unsubstituted 2 to 20 membered heteroalkyl. In addition, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted". When a moiety is substituted with R, the moiety is substituted with at least one R substituent, and each R substituent may be optionally different.

[0093] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight (i.e., non-straight) or branched non-cyclic carbon chain (or carbon) or combination thereof, which may be fully saturated, mono- or polyunsaturated and may include divalent and polyvalent groups, having the specified number of carbon atoms (i.e., C1-C10 means one to ten carbons). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers thereof such as n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkoxy is an alkyl group connected to the rest of the molecule through an oxygen linker (O). The alkyl portion can be an alkenyl portion. The alkyl portion can be an alkynyl portion. The alkyl portion can be fully saturated.

[0094] Unless otherwise indicated, the term "alkyl sulfate" by itself or as part of another substituent means a sulfate ester, O(SO2)O - or an alkyl group substituted with a salt thereof.

[0095] Unless otherwise stated, the term "alkyl sulfonate" by itself or as part of another substituent means an ester of sulfonate (SO2). - or an alkyl group substituted with a salt thereof.

[0096] Unless otherwise indicated, the term "alkyl phosphate" by itself or as part of another substituent means a phosphate ester, PO4 - or an alkyl group substituted with a salt thereof.

[0097] Unless otherwise indicated, the term "cycloalkyl" by itself or as part of another substituent refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) saturated hydrocarbon composed of hydrogen and carbon atoms, arranged into a structure containing a monocyclic or polycyclic ring in which all carbon-carbon bonds are single bonds. Examples of monocyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and examples of polycyclic alkyls include norbornyl, adamantyl, and the like.

[0098] Unless otherwise indicated, the term "carbocycle" itself or as part of another substituent refers to an unsaturated cyclic carbon chain (or carbon) that can be a fully saturated monocyclic or polycyclic, and can include a divalent or polyvalent group with a specified number of carbon atoms (i.e., C1-C10 represents 1 to 10 carbons). Carbocycle can have a structure comprising a monocyclic or polycyclic ring without restriction. Examples of saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and examples of unsaturated carbocyclic groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.

[0099] Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched non-cyclic chain or combination thereof, comprising at least one carbon atom and at least one heteroatom selected from O, N, P, Si and S, wherein the nitro and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N, P, S and Si (but not limited thereto) may be located at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH2-CH2-O-CH3-, CH2-CH2-NH-CH3-, CH2-CH2-N(CH3)-CH3, CH2-S-CH2-CH3, CH2-CH2-S(O)-CH3, -CH2=CH-O-CH3, -Si(CH3)3, -CH2-CH=N(CH3)-CH3, -O-CH3, -O-CH2-CH3 and -CN. A maximum of two or three heteroatoms may be consecutive, for example -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0100] Unless otherwise stated, the term "heterocycle" by itself or in combination with another term refers to a cyclic chain comprising at least one carbon atom and at least one heteroatom selected from O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom O, N, P, S and Si may be placed at any interior position of the cycloheteroalkyl group or at the position at which the heterocyclyl group is attached to the rest of the molecule. Examples include, but are not limited to: -CO-, -OCOO-, -CH2-CH2-O-CH3-, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3-, -CH2-S-CH2-CH3-, -CH2-CH2-, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3 and -CN. Up to two or three heteroatoms may be consecutive, for example -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si or P). The heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0101]

[0046] Unless otherwise stated, the term "secondary amide" by itself or as part of another substituent means an amide in which the nitrogen atom is directly bonded to two carbon atoms.

[0102]

[0046] Unless otherwise stated, the term "tertiary amide" by itself or as part of another substituent means an amide wherein the nitrogen atom is directly bonded to three carbon atoms.

[0103] The description of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted with one or more of a number of substituents, such substitution is selected to comply with the principles of chemical bonding and to provide compounds that are not inherently unstable and / or may be unstable to one of ordinary skill in the art under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is attached to the rest of the molecule via a ring heteroatom, in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0104] The term "treating" or "treatment" refers to any marker of success in treating or ameliorating an injury, disease, pathology, or condition (including any objective or subjective parameter, such as alleviation); relief; reducing symptoms or making the patient more tolerant of the injury, pathology, or condition; slowing down or slowing the rate of deterioration; making the last point of deterioration more debilitating; improving the patient's physical or mental health. Treatment or alleviation of symptoms can be based on objective or subjective parameters; including physical examination results, neuropsychiatric examinations, and / or psychiatric assessments. For example, certain methods herein treat diseases associated with weight gain, such as obesity.

[0105] An "effective amount" is an amount sufficient for a compound to achieve the stated purpose relative to the absence of the compound (e.g., to achieve the effect of its administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signaling pathway, to reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." A "reduction" of one or more symptoms (and grammatical equivalents of this phrase) refers to a reduction in the severity or frequency of the symptoms or the elimination of the symptoms. A "prophylactically effective amount" of a drug is an amount that, when administered to a subject, will have the intended prophylactic effect, such as preventing or delaying injury, The amount of a drug that reduces the onset (or recurrence) of a disease, pathology or condition, or reduces the possibility of the onset (or recurrence) of an injury, disease, pathology or condition or its symptoms. A dose of administration does not necessarily result in a complete preventive effect, and may only occur after a series of doses. Therefore, the preventive effective amount can be administered in one or more administrations. "Activity reduction amount" used herein refers to the amount of antagonist required to reduce enzyme activity relative to the absence of antagonist. The exact amount will depend on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0106] In the context of a substance or substance activity or function associated with a disease (e.g., obesity), the term "associated" or "associated with..." means that the disease is (wholly or partially) caused by or the symptoms of the disease are (wholly or partially) caused by the substance or substance activity or function. As used herein, if a pathogen is described as being associated with a disease, it may be a target for treating the disease. For example, a disease associated with weight gain, such as obesity, can be treated with an agent (e.g., a compound described herein) that is effective in reducing weight gain.

[0107] "Control" or "control experiment" or "standard control" are used according to their ordinary, plain meaning and refer to an experiment in which the experimental subjects or agents are treated in parallel with the experimental procedure, agent or variable except that the experimental procedure, agent or variable is omitted. In some cases, the control is used as a comparison standard for evaluating the effect of the experiment.

[0108] As defined herein, the terms "inhibition", "inhibit", "inhibiting", etc., with respect to protein-inhibitor (e.g., antagonist) interactions, mean adversely affecting (e.g., reducing) the level of activity or function of the protein relative to the level of activity or function of the protein in the absence of the inhibitor. In certain embodiments, inhibition refers to reducing a disease or disease symptom. Thus, inhibition may include, at least in part, partially or completely blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing, or downregulating a signal transduction or enzyme activity or the amount of a protein.

[0109] As defined herein, the terms "activation", "activate", "activating", and the like with respect to protein-activator (e.g., agonist) interactions mean that the activity or function of a protein is positively affected (e.g., increased) relative to the activity or function of the protein in the absence of an activator (e.g., a compound described herein). Thus, activation may include, at least in part, a partial or complete increase in stimulation, an increase or initiation of activation, or activation, sensitization, or upregulation of signal transduction or enzymatic activity or a reduction in the amount of a deleterious mediator / substance in a disease. Activation may include, at least in part, a partial or complete increase in stimulation, an increase or initiation of activation, or activation, sensitization, or upregulation of signal transduction or enzymatic activity or the amount of a deleterious mediator / substance.

[0110] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule. In specific embodiments, the modulator is an anti-inflammatory agent. In specific embodiments, the modulator is an inhibitor of leptin. In specific embodiments, the modulator is a leptin ligand.

[0111] "Anti-obesity agent" refers to the property of a substance or treatment that reduces weight gain and promotes weight loss. Examples of anti-obesity drugs are sibutramine, phentermine, mazindol, diethylpropion, leptin, orlistat, beta-3 agonists, and rimonabant.

[0112] The term "obese" as used herein refers to a person with a body weight greater than 30 kg / m 2 As used herein, "overweight" and "pre-obese" refer to patients with a body mass index greater than 25 kg / m 2 As used herein, "morbid obesity" refers to a patient with a BMI greater than 40 mg / m 2 , BMI greater than 35 kg / m 2 Patients with a BMI greater than 30 kg / m2 in combination with one or more comorbidities 2 and uncontrolled diabetes or a combination thereof.

[0113] The term "prodrug" refers to a pharmacological substance, such as a drug, that is administered to a subject in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in the body (in vivo) into a compound with the desired pharmacological activity.

[0114] The terms "patient", "subject", "individual", etc. refer to a living organism suffering from or susceptible to a disease or condition that can be treated by the administration of a compound or pharmaceutical composition as described herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, cats, apes, monkeys, goats, sheep, cattle, deer, and other non-mammals. In certain specific embodiments, the subject is a companion animal, such as a dog or a cat. In some specific embodiments, the patient is a human. In some specific embodiments, the patient is pre-obesity, obese or morbidly obese. In certain specific embodiments, the patient is not pre-obesity, obese or morbidly obese, but was previously pre-obesity, obese or morbidly obese. In some specific embodiments, the patient wishes to lose weight or reduce appetite. Alternatively or in addition, the patient suffers from a disease or condition related to obesity. These examples are not limiting. The terms "subject", "patient", "individual", etc. used herein are not limiting and are generally interchangeable. That is, an individual described as a "patient" does not necessarily have a given disease or be cared for by a medical professional, but may simply seek or wish to be treated (e.g., self-treated) without medical advice. "Disease" or "disorder" refers to a physical condition or health condition of a patient or subject that can be treated with a compound, pharmaceutical composition or method. In some embodiments, the disease is a disease of weight gain. In some embodiments, the disease is obesity. Obesity may be a primary cause of a disease and / or condition that is treated or can be treated as a result of the primary disease and / or condition.

[0115] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration of an active agent and absorption by a subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solution, lactated Ringer's solution, natural sucrose, natural glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments, etc. Such preparations can be sterilized and, if desired, mixed with adjuvants that do not react harmfully with the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances, etc. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0116] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier, which provides a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier, thereby associating the active ingredient with the carrier. Likewise, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0117] As used herein, the term "administration" means oral administration, administration by suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or implantation of a sustained-release device, such as a miniature osmotic pump, into a subject. Administration is by any route, including parenteral and transmucosal (e.g., oral, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of administration include, but are not limited to, the use of liposome preparations, intravenous infusions, transdermal patches, etc. "Co-administration" refers to the simultaneous administration of the composition described herein just before or after the administration of one or more additional therapies (e.g., anti-obesity agents). The compound can be administered alone or co-administered to the patient. Co-administration means simultaneous or continuous administration of a single compound or a combination thereof (more than one compound or agent). Thus, when desired, the formulations may also be combined with other active substances (e.g., reducing metabolic degradation, increasing degradation of prodrugs and releasing drugs, detectable agents). The compositions may be delivered transdermally, by topical routes, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, coatings, powders and aerosols. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for ingestion by the patient. Solid-forming formulations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. Liquid-forming formulations include solutions, suspensions and emulsions, such as water or water / propylene glycol solutions. The compositions may additionally contain components that provide sustained release and / or comfort. These components include high molecular weight, anionic mucus analog polymers, gelling polysaccharides and finely divided drug carrier matrices. These components are described in more detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162 and 4,861,760. The entire contents of these patents are incorporated herein by reference for all purposes. The composition can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres, which are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:

[0118] 857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49: 669-674, 1997). In another specific embodiment, the formulation of the composition can be delivered by using liposomes that fuse with the cell membrane or are internalized, that is, by using receptor ligands attached to the liposomes, the liposomes bind to the surface membrane protein receptors of the cell, causing internalization. By using liposomes, especially when the liposomes carry receptor ligands specific to the target cells on their surface or preferentially target specific organs, it is possible to focus on delivering the composition to the target cells in the body (see, e.g., Al-Muhammed, J.

[0119] Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The composition can also be delivered as nanoparticles.

[0120] II.Compounds

[0121]

[0013] Specifically provided herein are compositions that promote weight loss, reduce body fat, reduce food intake, improve homeostasis, or a combination thereof.

[0122] In a preferred aspect, the composition may include a compound having the structure of formula (I):

[0123]

[0124] in

[0125] The dashed lines between C1 and C2, C2 and R3, C3 and R4, C5 and C6, C5 and C7, C1 and C6, and C3 and C4 indicate that single or double chains may exist if valency permits;

[0126] R1 is -CN, -COOH, -COOCH2CH3, -CONHR5, -CONR5R5, -COOR5, -COOCH3, -CH2NR5R5, -CH2OCONR5R5, -CH2NR5COOR5, -CH2R5, -CH2NR5CONR5R5, -CH2OH, -CH2OR5, alkyl sulfate, alkyl sulfonate, alkyl phosphate, -CH2OSO3R5, -CH2OSO2R5, -CH2OPO3R5R5, -CH2OPO3HR5, - CH2OPO3H2-C(=NR5)NR5R5, -NR5C(=NR5)NR5R5, -CONH2, -CH2CONR5R5, -SR5, -SO3R5, -SO2R5, -CH2NHCOR5, -CH2NHCN R5NR5R5, -CH2COSR5, CH2NR5COR5, -CH2NR5CNR5NR5R5, -CH2NR5COSR5, -CH2NHSO2R5, -CH2NR5SO2R5, -CHNR5, -CHNOR5 、-H、-NH2、-NHR5、-NR5R5、-OH、-OR5、phosphate、-OPO3R5R5、-OPO3HR5、-OPO3H2、-NCO、-NCS、-N3、-R5、-C≡CR5、-(CH=CH)R5、-SH、-SR5、-SO2H、-SO3H、-SO2NR5R5、-SO3R5、-NHCOR5、-、NHCNR5NR5R5、-NHCOSR5、secondary amide, tertiary amide, -NR5COR5、-NR5C(=NH)N R5R5, -NR5COSR5, -NHC(=NR5)R5, -NR5C(=NR5)R5, -NHSO2(NH2), -NHSO2R5, -NR5SO2R5, -NR5SO2NR5R5, -OCOR5, -OCONR5R5, -O(C=O)OR5, -SCOR5, -O(C=NH)NR5R5, -OCSNHR5, -OS(=O2)R5, -OS(=O2)NR5R5, -SCONR5R5, -CH2-aryl, -CH2-heteroaryl,

[0127]

[0128] R2 is -H, -CH3, -SCH(CH3)2, -SC(=O)CH3, -SC(=O)R5, –SCH2CH2OCOCH3, -SR5, -SOR5, -SOOR5, -SCONR2,

[0129]

[0130] R3 is –OCOCH3, –OCOOCH2CH3, –OR7, –R7, or –NR5R5 when double bonds exist between C1 and C2, C3 and C4, and C5 and C6;

[0131] R4 is –OCOCH3, –OCOOCH2CH3, –OR7, –R7 or –NR5R5 when there are double bonds between C1 and C2, C3 and C4, and C5 and C6;

[0132] When R4 is O and there is a double bond between C2 and R3 and between C3 and R4, R3 is O;

[0133] When R3 is O and there is a double bond between C2 and R3R4, R4 is -OCH3, -OP(=O)(OCH3)2, -OH, -OCOOCH2CH3, -OCONHCH2CH3, -OCOOCH(CH3)2, -OR7, -R7, or -NR5R5; R3 and R4 may also be combined to form a heterocyclic or carbocyclic ring;

[0134] R5, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, amino, or heteroaryl, optionally substituted with substituents each selected from alkyl, alkoxy, cycloalkyl, ether, amino optionally substituted with one or more alkyl groups, halogen, hydroxy, ether, cyano, nitrile, CF3, ester, amide, cycloalkylamide, sugar, heteroarylamide optionally substituted with alkyl and / or alkoxy, urea, carbamate, thioether, sulfate, sulfonyl, sulfonic acid carboxylic acid, and aryl, or two R5 groups taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with substituents each selected from alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, heteroaryl, amino, halogen, hydroxy, ether, nitrile, cyano, nitro, CF3, esteramide, urea, carbamate, thioether, or carboxylic acid; and

[0135] R7 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl or heteroaryl, optionally substituted with substituents each selected from alkyl, cycloalkyl, ether, ammonia, halogen, hydroxy, ether, nitrile, cyano, nitrile, CF3, ester, amide, urea, carbamate, thioether or carboxylic acid,

[0136] or a pharmaceutically acceptable salt or a prodrug thereof.

[0137] In some embodiments, the compounds of formula (I) include those that are prodrugs.

[0138] In some embodiments, the compounds of formula (I) include those wherein R1 is -CONH2, which can be represented by formula (I)-a:

[0139]

[0140] wherein each of R2, R3 and R4 is as defined in formula (I).

[0141] In a specific embodiment, R2 is -H, -SCH(CH3)2, -SC(=O)CH3,

[0142]

[0143] In some embodiments, R3 is -OC(=O)CH3 or -OC(=O)OCH2CH3. In some embodiments, R4 is -OC(=O)CH3 or -OC(=O)OCH2CH3. A subset of compounds of formula (I) includes compounds as shown below:

[0144]

[0145]

[0146] In yet another embodiment, the compounds of formula (I) include those wherein R1 is -COOH or -COOCH3.

[0147] In some embodiments, R2 is -CH3, -SC(=O)CH3, -SCH(CH3)2 or -SCH2CH2OCOCH3.

[0148] In some embodiments, R3 is -OCOCH3 or -OH.

[0149] In some embodiments, R4 is -OCOCH3 or -OH.

[0150] A subset of compounds of formula (I) includes compounds shown below:

[0151]

[0152]

[0153] In some embodiments, the compounds of formula (I) include those wherein R1 is -CN or -CH2NR5R5, such as -CH2N(CH3)2, which can be represented by formula (I)-b or formula (I)-c, respectively:

[0154]

[0155]

[0156] wherein each of R2, R3, R4 and R5 is as defined in formula (I).

[0157] In some specific embodiments, R2 is -SCH(CH3)2, -SC(=O)CH3, -H,

[0158]

[0159] In some embodiments, R3 is -OCOCH3.

[0160] In some embodiments, R4 is -OCOCH3.

[0161] In some embodiments, R3 and R4 form a five-membered heterocyclic ring including -OCOO-. In some embodiments, R5 is an alkyl group, preferably CH3.

[0162] A subset of compounds of formula (I) includes compounds shown below:

[0163]

[0164]

[0165] In some embodiments, compounds of formula (I) include those wherein R3 is O and there is a double bond between C2 and R3 and between C3 and C4.

[0166] In some specific embodiments, R1 is -C(=O)OCH2CH3, -CN, -CONH2, -CH2N(CH3)2,

[0167]

[0168] In some embodiments, R2 is -H.

[0169] In some specific embodiments, R4 is -OCH3, -OP(=O)(OCH3)2, -OCH2CH3, -OH, -OCONHCH2CH3, -OCH2COOCH3, -OCOOCH2CH3, -OCH2CH2OH, -OCOOCH(CH3)2, or -OCH(CH3)2.

[0170] A subset of compounds of formula (I) includes compounds shown below:

[0171]

[0172]

[0173]

[0174] In some embodiments, compounds of formula (I) include those wherein R3 and R4 are O and a double bond exists between C2 and R3 and C3 and R4.

[0175] In some specific embodiments, R1 is COOH, COOCH3, or

[0176]

[0177] In some embodiments, R2 is CH3.

[0178] A subset of compounds of formula (I) includes compounds shown below:

[0179]

[0180] In some specific embodiments, R1 is -NR5C(=NR5)NR5R5, -SR5, -SO3R5, -SO2R5, -NH2, -NHR5, -NR5R5, -OH, -OR5, -NCO, -NCS, -N3, -SH, -SR5, -SO2H, -SO3H, -SO2NR5R5, -SO3R5, -NHCOR5, -NHCNR5NR5R5, -NHCOSR5, -NR5COR5, -N R5C(=NH)NR5R5, -NR5COSR5, -NHC(=NR5)R5, -NR5C(=NR5)R5, -NHSO2(NH2), -NHSO2R5, -NR5SO2R5, -NR5SO2NR5R5 , -OCOR5, -OCONR5R5, -O(C=O)OR5, -SCOR5, -O(C=NH)NR5R5, -OCSNHR5, -OS(=O2)R5, -OS(=O2)NR5R5, -SCONR5R5.

[0181] In some embodiments, R2 is H.

[0182] In some embodiments, R4 is OH, -OR7, or -R7 when R3 is O and there is a double bond between C2 and R3.

[0183] A subset of compounds of formula (I) includes compounds shown below:

[0184]

[0185]

[0186] In some embodiments, the compound may include:

[0187]

[0188] In another preferred aspect, the composition may comprise a compound having formula (II):

[0189]

[0190] Where R1 is OR a or NR a R b , where each R a and R b R5, -(=NR5)NR5R5, -CO, -CS, -COR5, -CNR5NR5R5, -COSR5, -C(=NH)NR5R5, -C(=NR5)R5, -SO2(NH2), -SO2R5, -SO2R5, -SO2NR5R5, -COR5, -CONR5R5, -(C=O)OR5, -(C=NH)NR5R5, -CSNHR5, -S(=O2)R5 or -S(=O2)NR5R5,

[0191] R5 is defined in formula (I), or

[0192] A pharmaceutically acceptable salt or a prodrug thereof.

[0193] In some embodiments, R1 is NR a R b , which can be represented by formula (II)-a:

[0194]

[0195] Among them, each R a or R b is defined in formula (II).

[0196] In a specific embodiment, R1 is NH(CO)R5, wherein R5 is preferably an alkyl group, a cycloalkyl group or an aryl group, which can be represented in formula (II)-b:

[0197]

[0198] Among them, each R a or R b is defined in formula (II).

[0199] Examples of compounds of formula (II) include the compounds shown below:

[0200]

[0201]

[0202] The compounds described by formula (I) and formula (II) can be prepared using methods known in the art and are described herein. For example, tripterygium wilfordii can be obtained from commercial sources or isolated from plants, for example, by methods known in the art (Kutney et al., Can. J. Chem. 59: 2677, 1981) and Zhang et al., Acta Pharm. Sin. 212: 592, 1986). Tripterygium wilfordii can be modified to provide compounds of formula (I) or formula (II). The prepared compounds are purified using conventional methods to obtain compounds free of impurities. The prepared compounds have a purity of >75, >80, >85, >90, >95, >96, >97, >98, >99, >99.5%. Optionally, the preferred compound purity is >99%.

[0203] Further provided are compounds of Formula (I) and Formula (II) which impart the property of increased or substantially increased oral bioavailability.

[0204] In some specific embodiments, the compounds of formula (I) and formula (II) may have a greater or lesser solubility in water, aqueous solutions, and / or physiological solutions than tripterygium wilfordii available from commercial sources or isolated from plants. For example, the compounds may have a solubility in aqueous solution of about 0.001 μM to about 150 μM, 0.01 μM to about 100 μM, 0.1 μM to about 100 μM, 1 μM to about 100 μM, 10 μM to about 100 μM, 1 μM to about 50 μM, 10 μM to about 50 μM, from 10 μM to about 80 μM, 10 μM to about 25 μM, 25 μM to about 50 μM, 50 μM to about 100 μM, 50 μM to about 75 μM, 25 μM to about 50 μM, 5 ...75 μM, 25 μM to about 50 μM, 50 μM to about 75 μM, 25 μM to about 5 75 μM, or a solubility of at least about 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 μM, or less than about at least about 0.1, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 μM, such as in phosphate buffered saline (PBS), such as at a pH of about 7, 7.1, 7.2, 7.3, 7.4, 7.5, or 7 to 8.

[0205] In some embodiments, the compounds of Formula (I) and Formula (II) have increased or substantially increased stability or half-life in water, aqueous solutions or physiological solutions. For example, the compounds may have substantially increased stability or resistance in the upper or middle gastrointestinal (GI) or digestive tract under various pH conditions in the range of 2 to 8.

[0206] In some specific embodiments, when administered to a subject, the compounds of formula (I) and formula (II) produce increased or substantially increased uptake. For example, the compounds may have substantially improved permeability across biological membranes. These compounds may exhibit an appropriate balance between hydrophobicity (lipophilicity) and hydrophilicity through local ionic charge.

[0207] In one aspect, the composition of the present invention includes at least one compound having oral efficacy for treating obesity. Exemplary compounds having oral efficacy for treating obesity may include the following compounds: as well as

[0208]

[0209] In another aspect, a composition includes a compound having intraperitoneal efficacy for treating obesity.

[0210] Examples of these compounds having intraperitoneal efficacy for treating obesity may include the following compounds:

[0211]

[0212] as well as

[0213] III. Methods of treatment and diagnosis

[0214] The above compounds can be used to treat obesity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I). Obesity may be the primary cause of a disease and / or condition, or may be caused by a disease and / or condition.

[0215] In some cases, an effective amount of a compound of Formula (I) can be administered as a method of treating weight gain in a patient suffering from pre-obesity, obesity or morbid obesity.

[0216] In some cases, the method of reducing body fat in patients with pre-obesity, obesity or morbid obesity comprises administering an effective amount of a compound of formula (I). Body mass or body fat can be reduced by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, about 5 to 10%, 5 to 25%, 10 to 25%, 10 to 50%, 25 to 50%, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0217] In some cases, a method of reducing food intake in a patient with pre-obesity, obesity or morbid obesity is achieved by administering an effective amount of a compound of formula (I). Average daily food intake (calorie basis) can be reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more, or about 5 to 10%, 5 to 25%, 10 to 25%, 10 to 50%, 25 to 50%.

[0218] In some cases, an effective amount of a compound of formula (I) can be administered to reduce the body mass index (BMI) of an obese patient. The patient's BMI can be reduced to <30 kg m -2 (Normal BMI = 20 to 25 kg m -2 ).

[0219] Finally, methods of improving glucose homeostasis in patients with pre-obesity, obesity or morbid obesity can be accomplished by administering a compound of formula (I). Mean fasting plasma glucose levels can be reduced by at least 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45% or 50% or more or about 5 to 10%, 5 to 25%, 10 to 25%, 10 to 50%, 25 to 50%.

[0220] Obesity

[0221] Obesity is a medical condition in which excess body fat accumulates to an extent that may have a negative impact on health, leading to reduced life expectancy and / or increased health problems (Haslam et al., Lancet (Review) 366(9492): 1197-209, 2005). In Western countries, people become obese when their body mass index (BMI), measured by dividing their weight by the square of their height, exceeds 30 kg / m. 2 They are considered obese when the range is 25 to 30 kg / m 2 Defined as being overweight. Obesity increases the likelihood of various diseases, especially heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer and osteoarthritis (Haslam et al., Lancet (Review) 366 (9492): 1197-209, 2005). Although a few cases are mainly caused by genes, endocrine disorders, drug treatment or mental illness, the most common causes of obesity are excessive energy intake, lack of physical activity and genetic susceptibility. There is evidence to support the view that some obese people gain weight while eating little because of their slow metabolism. On average, obese people have higher energy expenditure than those who lose weight because of the energy required to maintain the increase in body mass (Kushner, Obese Patient Treatment, 2007).

[0222] Obesity is a medical condition in which excess body fat accumulates to a degree that may have adverse effects on health. It is defined by BMI, which is further assessed by waist-to-hip ratio and total cardiovascular risk factors (Sweeting et al., Nutr. J. 6(1): 32, 2007). BMI is closely related to body fat percentage and total body fat (Gray et al., J. Clin. Epidemiol. 44(6): 545-50, 1991).

[0223] BMI is defined as the subject's weight divided by the square of their height. BMI is usually expressed in kilograms per square meter, so weight is measured in kilograms and height is measured in meters. Some modifications to the definition were made when the surgical literature broke down obesity into further categories whose exact values ​​remain controversial (Sturm et al., Public Health 121(7):492-6, 2007). Any BMI ≥ 35 or 40 kg / m 2 All are severely obese. BMI ≥ 35kg / m 2 and experiencing obesity-related health conditions or ≥40 to 44.9 kg / m 2 Morbidly obese. BMI ≥ 45 or 50 kg / m 2 The World Health Organization (WHO) considers a BMI of less than 18.5 to be underweight, which may indicate malnutrition, eating disorders, or other health problems, while a BMI of 25 or more is overweight, and a BMI of more than 30 is obese (World Health Organization, Global Database on Body Mass Index (2006)). Table 1 below lists a summary of the WHO BMI classification experimental guidelines.

[0224] Table 1: Body mass index classification

[0225]

[0226]

[0227] Hypothalamic damage-related obesity

[0228] Hypothalamic obesity is a complex medical condition that can occur from the growth of rare brain tumors and other types of hypothalamic damage. Craniopharyngioma is one of the tumors that can cause obesity associated with hypothalamic damage. Damage to the hypothalamus disrupts communication between the gut and the brain, causing a constant feeling of hunger.

[0229] The hypothalamus and pituitary gland are closely integrated. Damage to the hypothalamus will affect the response and normal function of the pituitary gland. Hypothalamic disease may lead to insufficient or suppressed pituitary signaling, resulting in one or more deficiencies in the following hormones: thyroid stimulating hormone, adrenocorticotropic hormone, beta-endorphin, luteinizing hormone, follicle stimulating hormone, and melanocyte stimulating hormone. Treatment of hypopituitarism involves hormone replacement therapy (Pinkney, Pituitary News 17, 2000).

[0230] Thyroid hormones are responsible for metabolic activity. Insufficient production of thyroid hormones can lead to suppressed metabolic activity and weight gain. Therefore, hypothalamic diseases may have an impact on obesity (Pinkney, Pituitary News 17, 2000); (Ling, Trends in Obesity Research, 2004).

[0231] Fatty Liver / NASH

[0232] Non-alcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, which occurs when fat is deposited (steatosis) in the liver due to reasons other than excessive alcohol use. NAFLD is associated with insulin resistance and metabolic syndrome, and may be responsive to treatments originally developed for other insulin-resistant states (e.g., type 2 diabetes), such as weight loss, metformin, and thiazolidinediones (Adams et al., Postgrad. Med. J. 82(967): 315-22, 2006). Non-alcoholic steatohepatitis (NAH) is the most extreme form of NAFLD and is considered the leading cause of cirrhosis of unknown cause (Clark et al., JAMA 289(22): 3000-4, 2003).

[0233] Most people with NAFLD have few or no symptoms. Patients may complain of abdominal discomfort with fatigue, malaise, and weakness in the right upper quadrant. Mild jaundice may be noted, although this is rare. More commonly, NAFLD is diagnosed after abnormal liver function tests occur during routine blood work. NAFLD is associated with insulin resistance and metabolic syndrome (obesity, combined hyperlipidemia, diabetes (type II), and hypertension) (Adams et al., Postgrad. Med. J. 82(967): 315-22, 2006).

[0234] Common findings are elevated liver enzymes and liver ultrasound showing fatty degeneration. Ultrasound can also be used to rule out gallstone problems (cholelithiasis). Liver biopsy (tissue examination) is widely accepted as the only test that can definitively distinguish NASH from other forms of liver disease and can be used to assess the severity of inflammation and resulting fibrosis (Adams et al., Postgrad. Med. J. 82(967):315-22, 2006).

[0235] Other diagnostic tests are available. Relevant blood tests include erythrocyte sedimentation rate, glucose, albumin, and renal function. Since the liver is important for making proteins used for clotting, some studies related to clotting are usually performed, especially INR (International Normalized Ratio). Blood tests (serology) are usually used to rule out viral hepatitis (hepatitis A, hepatitis B, hepatitis C, and herpes viruses such as EBV or CMV), rubella, and autoimmune-related diseases. Hypothyroidism is more common in NASH patients, which can be detected by determining TSH (Liangpunsakul et al., J. Clin. Gastroenterol. 37 (4): 340-3, 2003).

[0236] Metabolic syndrome

[0237] Metabolic syndrome is a disorder of energy utilization and storage, diagnosed by the co-occurrence of three of the following five medical conditions: abdominal (central) obesity, high blood pressure, high fasting blood sugar, high serum triglycerides, and low-density lipoprotein (HDL) levels. Metabolic syndrome increases the risk of cardiovascular disease and diabetes (Kaur, Cardiology Research and Practice, 2014) (Felizola, "Ursolic acid in experimental models and human subjects: potential as an anti-obesity / overweight treatment?" Research Gate, 2015).

[0238] The main sign of metabolic syndrome is central obesity (also called visceral, androgenic or apple-shaped obesity), especially the excessive accumulation of fat tissue around the waist and trunk. Other signs of metabolic syndrome include high blood pressure, low fasting serum HDL cholesterol, elevated fasting serum triglyceride levels (VLDL triglycerides), abnormal fasting glucose, insulin resistance or prediabetes. Related conditions include hyperuricemia, fatty liver (especially with concurrent obesity), non-alcoholic fatty liver disease, polycystic ovary syndrome (women), erectile dysfunction (men) and acanthosis nigricans.

[0239] A joint interim statement from the International Diabetes Federation's Epidemiology and Prevention Working Group; the National Heart, Lung, and Blood Institute; the American Heart Association; the World Heart Federation; the International Atherosclerosis Society; and the International Association for the Study of Obesity issued guidelines for a harmonized definition of the metabolic syndrome (Alberti et al., Circulation 120(16):1640-5, 2009). This definition recognizes that the risks associated with a particular waist circumference measurement can vary in different populations.

[0240] Stroke

[0241] A stroke, also called a cerebrovascular accident (CVA), cerebrovascular injury (CVI), or brain attack, occurs when poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic due to lack of blood flow and hemorrhagic due to bleeding. They cause part of the brain to stop functioning properly. Signs and symptoms of a stroke may include an inability to move or feel on one side of the body, problems understanding or speaking, feeling like the world is spinning, or a lack of vision on one side (Donnan et al., Lancet 371(9624):1612-23, 2008). Signs and symptoms may appear soon after a stroke occurs. If symptoms last less than 1 or 2 hours, it is called a transient ischemic attack (TIA). A hemorrhagic stroke may also be associated with severe headaches.

[0242] The main risk factor for stroke is high blood pressure. Other risk factors include smoking, obesity, high blood cholesterol, diabetes, previous TIA, and atrial fibrillation (Donnan et al., Lancet 371(9624):1612-23, 2008). Ischemic stroke is usually caused by a blockage in a blood vessel. Hemorrhagic stroke is caused by bleeding directly into the brain or into the space around the brain. (Feigin et al., Stroke 36(12):2773-80, 2005). Bleeding may occur due to a brain aneurysm. Diagnosis usually involves medical imaging, such as a CT scan or MRI scan, and a physical exam. Other tests such as an electrocardiogram (ECG) and blood tests are used to determine risk factors and rule out other possible causes.

[0243] Stroke is diagnosed by several techniques: neurological examination (e.g., NIHSS), CT scan (most commonly without contrast enhancement) or MRI scan, Doppler ultrasound, and arteriography. The diagnosis of stroke itself is clinical with the help of imaging techniques. Imaging techniques also help determine the subtype and cause of stroke. Although blood tests may help discover possible causes of stroke (Hill et al., Clin. Chem. 51(11): 2001-2, 2005), there is currently no commonly used blood test for the diagnosis of stroke itself.

[0244] Cardiovascular disease

[0245] Cardiovascular disease (CVD) is a class of diseases involving the heart or blood vessels. Cardiovascular disease includes coronary artery disease (CAD), such as angina and myocardial infarction (commonly known as heart attack) (Shanthi et al., Global Atlas on Cardiovascular Disease Prevention and control 3-18, 2011). Other cardiovascular diseases include stroke, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, atrial fibrillation, congenital heart disease, endocarditis, aortic aneurysm and peripheral arterial disease.

[0246] The underlying mechanisms vary depending on the disease in question. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This can be caused by high blood pressure, smoking, diabetes, lack of exercise, obesity, high cholesterol, poor diet, and excessive alcohol consumption. High blood pressure causes 13%, while tobacco causes 9%, diabetes causes 6%, lack of exercise causes 6%, and obesity causes 5% of CVD deaths. Rheumatic heart disease can be associated with untreated strep throat (Shanthi et al., Global Atlas on Cardiovascular Disease Prevention and control 3-18, 2011).

[0247] Standard tests for the management of cardiovascular disease include: coronary artery calcification, total carotid artery plaque area, elevated low-density lipoprotein-p, and elevated blood levels of brain natriuretic peptide (also known as type B) (Bertazzo et al., Nat. Mat. 12, 576-583, 2013) (Inaba et al., Atherosclerosis 220(1):128-33, 2012) (J. Lipidol. Dec; 1(6)583-92, 2007) (Wang et al., N. Engl. J. Med. 350(7):655-63, 2004).

[0248] diabetes

[0249] Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic diseases in which high blood sugar levels exist for a long time. Symptoms of high blood sugar include frequent urination, increased thirst and increased hunger. If not treated, diabetes may cause many complications (Diabetes Fact sheet N321". WHO, 2013). Acute complications include diabetic ketoacidosis and non-ketotic hyperosmolar coma (Kitabchi et al., Diabete Care 32(7): 1335-43, 2009). Serious long-term complications include cardiovascular disease, stroke, chronic renal failure, foot ulcers and eye damage.

[0250] Diabetes is caused by the pancreas not producing enough insulin or the body's cells not being able to adapt to the insulin produced (Shoback, Greenspan's Basic & Clinical Endocrinology (9th Edition) (2011)).

[0251] Diabetes mellitus is characterized by recurrent or persistent hyperglycemia and is diagnosed by demonstration of any of the following: fasting plasma glucose level ≥7.0mmol / l (126mg / dl); plasma glucose ≥11.1mmol / l (200mg / dl) two hours after a 75g oral glucose load in a glucose tolerance test; symptoms of hyperglycemia and any blood glucose ≥11.1mmol / l (200mg / dl); and glycated hemoglobin (HbA1C) ≥48mmol / mol (≥

[0252] 6.5 DCCT%) (National Diabetes House (NDIC): National Diabetes Statistics 2011" USD Department of Health and Human Services, 2011) ("Diabetes Care" American Diabetes Association, 2010).

[0253] Positive results in the absence of unequivocal hyperglycemia should be confirmed by repeating any of the above methods on a different day. Measuring fasting blood glucose levels is preferred because of the ease of measurement and the considerable time commitment of the formal glucose tolerance test (which requires two hours to complete) and does not have a prognostic advantage over the fasting test (Saydah et al., Diabetes Care 24(8): 1397-402, 2001). According to current definitions, two fasting blood glucose measurements above 126 mg / dl (7.0 mmol / l) are considered diagnostic of diabetes.

[0254] According to the World Health Organization, people with fasting blood glucose levels of 6.1 to 6.9 mmol / l (110 to 125 mg / dl) are considered to have impaired fasting glucose; people with plasma glucose concentrations equal to or greater than 7.8 mmol / l (140 mg / dl) but not exceeding 11.1 mmol / l (200 mg / dl) 2 hours after a 75 g oral glucose load are considered to have impaired glucose tolerance (Definition and diagnosis of diabetes mellitus and moderate hyperglycemia: WHO / IDF consultation report. World Health Organization, 2006, p. 21). Of the two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes and cardiovascular disease. Since 2003, the American Diabetes Association has used a slightly different range for impaired fasting glucose of 5.6 to 6.9 mmol / l (100 to 125 mg / dl) (Bartoli et al., Eur. J. Int. Med. 22(1): 8-12, 2011). Glycated hemoglobin is superior to fasting blood glucose in determining the risk of cardiovascular disease and death from any cause (Selvin et al., N. Engl. J. Med. 362(9):800-11, 2010).

[0255] The rare disease diabetes insipidus has similar symptoms to diabetes but does not have the disordered sugar metabolism (diabetes insipidus means "tasteless" in Latin) and does not involve the same disease mechanisms. Diabetes is part of a broader group of conditions known as metabolic syndrome.

[0256] hypertension

[0257] Hypertension is diagnosed based on persistent hypertension. Traditionally, the National Institute for Clinical Excellence recommends three separate sphygmomanometer measurements every other month. The American Heart Association recommends at least three measurements at least twice during at least two separate health care visits (Aronow et al., J.Am.Soc.Hypertension:JASH 5(4):259-352,2011). An exception to this is those whose blood pressure readings are very high, especially when organ function is poor. The initial assessment of patients with hypertension should include a complete medical history and physical examination. With the introduction of 24-hour ambulatory blood pressure monitors and home blood pressure machines, the importance of not misdiagnosing patients with white coat hypertension has led to changes in experimental guidelines (protocols). In the UK, the best practice is currently to follow up with an elderly clinic reading with ambulatory blood pressure measurements, or less ideally to perform home blood pressure monitoring over the course of 7 days. Pseudohypertension or non-compressible arterial syndrome in the elderly also needs to be considered. This condition is thought to be caused by arterial calcification leading to abnormally high blood pressure readings from a blood pressure cuff, while intra-arterial measurements of blood pressure are normal (Franklin et al., Hypertension 59(2):173-8, 2012). Postural hypertension refers to elevated blood pressure when standing.

[0258] Hyperlipidemia

[0259] Hyperlipidemia involves abnormally elevated levels of any or all lipids and / or lipoproteins in the blood (Dorland's Medical Dictionary for Health Consumers, 2007). It is the most common form of dyslipidemia (including any abnormal blood lipid levels). Lipids (fat-soluble molecules) are transported in protein capsules. The size of the capsule, or lipoprotein, determines its density. The density of lipoproteins and the type of apolipoproteins it contains determine the fate of the particle and its effect on metabolism.

[0260] Hyperlipidemia is divided into primary and secondary subtypes. Primary hyperlipidemia is usually due to genetic causes (such as mutations in receptor proteins), while secondary hyperlipidemia is due to other underlying causes (such as diabetes). Lipid and lipoprotein abnormalities are common in the general population and are considered modifiable risk factors for cardiovascular disease due to their effects on atherosclerosis. In addition, some forms may predispose to acute pancreatitis.

[0261] Hyperlipidemia is a disease characterized by excessive serum cholesterol, especially excessive LDL-C and / or excessive triglycerides. Hypercholesterolemia is usually asymptomatic. Before the triglyceride level is maintained at more than 1000mg / dL, hypertriglyceridemia is usually asymptomatic-symptoms include skin disease manifestations, such as eruptive xanthomas and gastrointestinal manifestations, such as pancreatitis. Hyperlipidemia is usually determined by genes, but may be caused or amplified by abnormal diet, drugs and certain disease conditions. Drugs related to hyperlipidemia include: immunosuppressive therapy, thiazide diuretics, progestins, retinoids, anabolic steroids, glucocorticoids, HIV protease inhibitors, alcohol, retinoic acid and beta-blockers. Diseases related to secondary hyperlipidemia include: diabetes (type I and II), hypothyroidism, Cushing's syndrome, chronic kidney disease, nephrotic syndrome and cholestatic diseases. Hyperlipidemia is a major modifiable risk factor for atherosclerosis and cardiovascular disease, including coronary heart disease (Dorland's Medical Dictionary for Health Consumers, 2007).

[0262] Prader-Willi syndrome

[0263] Prader-Willi syndrome affects approximately 1 in 10,000 to 1 in 25,000 births (Killeen, Principles of Molecular Pathology 2004). More than 400,000 people worldwide have Prader-Willi syndrome (Tweed, AOL Health, September 2009). It is traditionally characterized by low muscle tone, short stature, overeating, obesity, behavioral problems (especially obsessive-compulsive behavior), small hands and feet, hypogonadism, and mild intellectual disability (Killeen, Principles of Molecular Pathology 2004). Like autism, Prader-Willi syndrome is a spectrum disorder, with symptoms ranging from mild to severe and may change throughout a person's lifetime.

[0264] Traditionally, PWS was diagnosed by clinical presentation. Currently, the syndrome is confirmed by genetic testing; testing is recommended for newborns who present with significant hypotonia. Early diagnosis of PWS allows for early intervention. The mainstay of diagnosis is genetic testing, particularly DNA-based methylation testing to detect the Prader-Willi syndrome / Angelman syndrome (PWS / AS) region on chromosome 15q11-q13 without paternal contribution. This test detects more than 97% of cases. Methylation-specific testing is important for confirming the diagnosis of PWS in all individuals, particularly those who are too young to present with sufficient features to be diagnosed on clinical grounds or those who have atypical findings (Buiting et al., Nat, Genet. 9(4):395-400, 1995).

[0265] Budd-Bieder syndrome

[0266] Budd-Beagle syndrome (BBS) is a ciliary human genetic disease that produces numerous effects and affects many body systems. The main features are obesity, retinitis pigmentosa, polydactyly, hypogonadism and renal failure (Beales et al., J. Med. Genet. 36(6):437-46, 1999).

[0267] Budd-Bieder syndrome is a pleiotropic disorder with variable expressivity and a wide range of clinical variability observed within and between families. The main clinical features are rod retinal dystrophy, visual loss before childhood onset, and night blindness; postaxial polydactyly; truncal obesity, which manifests in infancy and remains problematic throughout adulthood; specific learning difficulties in some but not all individuals; hypogenital genitalia in males and complex urogenital malformations in females; and renal dysfunction, which is a major cause of morbidity and mortality. BBS has many secondary features including: speech impairment / delay, strabismus / cataracts / astigmatism, brachydactyly / syndactyly of both hands and feet, partial syndactyly (most commonly between the second and third fingers), developmental delay, polyuria / polydipsia (nephrogenic diabetes insipidus), ataxia / incoordination / imbalance, mild hypertension (especially in the lower extremities), diabetes mellitus, crowded / missing teeth / small roots; high-arched cleft palate, cardiovascular anomalies, hepatic vein involvement, anosmia, hearing defects, and Hirschsprung disease (Ross et al., The Clinical, Molecular, and Functional Genetics of Bardet-Biedl Syndrome, in Genetics of Obesity Syndromes, 2008).

[0268] Cohen syndrome

[0269] The syndrome is believed to be a genetic mutation on chromosome 8 at the locus 8q22 gene COH1 (Kolehmainen et al., Am. J. Hum. Genet. 72(6): 1359-69, 2003). Cohen syndrome has several features such as obesity, mental retardation and craniofacial malformations. It has autosomal recessive transmission with variable expression (Kivitie-Kallio et al., Am. J. Med. Genet. 102(2): 125-35, 2001).

[0270] Cohen syndrome is diagnosed by clinical examination, but this is often difficult due to the changes in expression. Ocular complications, although rare, are listed as optic atrophy, microphthalmia, chorioretinitis pigmentosa, pupillophthalmia (reduced vision in bright light), myopia, strabismus, nystagmus, and iris / retinal nodules. The general appearance is obesity with slender / elongated arms and legs. Micrognathia, short philtrum, and high vaulted roof are common. Variable mental retardation with occasional seizures and deafness is also characteristic of Cohen syndrome.

[0271] MOMO Syndrome

[0272] MOMO syndrome is a very rare genetic disease, belonging to the category of overgrowth syndrome, diagnosed in only 6 cases worldwide and occurring in 1 in 100 million newborns. The name is an acronym for the four main aspects of the disease: macrosomia (excessive birth weight), obesity, macrocephaly (excessive head size), and eye abnormalities (Moretti-Ferreira et al., Am. J. Med. Genet. 46(5): 555-8, 1993). There are other common symptoms: downward sloping forehead, delayed bone maturation, and mental retardation. Eye abnormalities are generally retinal pigment tumors and nystagmus.

[0273] cancer

[0274] Cancer, also known as malignancy, malignant neoplasm or malignant tumor, is a group of diseases that involve abnormal cell growth and have the potential to invade or spread to other parts of the body (Cancer Fact sheet N°297. World Health Organization, February 2014; Defining Cancer, National Cancer Institute, 2014). Not all tumors are cancerous, as benign tumors do not spread (Defining Cancer. National Cancer Institute, 2014). Possible signs and symptoms include: new lumps, unusual bleeding, prolonged coughing, unexplained weight loss and changes in bowel movements, etc. (Cancer-Signs and symptoms, NHS Choices, 2014). Although these symptoms may indicate cancer, they can also occur due to other problems (Cancer-Signs andsymptoms, NHS Choices, 2014). There are more than 100 different known cancers that affect humans (Defining Cancer, National Cancer Institute, 2014). Cancer is a broad class of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body (Cancer Fact sheet N°297. World Health Organization. February 2014; Defining Cancer. National Cancer Institute. 2014). A polyp or tumor is a group of cells that undergo unregulated growth and usually form a mass or large tumor, but can be diffusely distributed (Cancer Glossary. Cancer.org. American Cancer Society. 2013; What is cancer? cancer.gov. National Cancer Institute. 2013). Proposed characteristics of cancer include: 1) insensitivity to anti-growth signals; 2) self-sufficiency in growth signals; 3) induction and maintenance of angiogenesis; 4) escape from apoptosis; 5) achievement of unlimited replication potential; and 6) activation of metastasis and invasion of tissues (Hanahan, Douglas; Weinberg, Robert A. (January 7, 2000). "The hallmarks of cancer". Cell 100(1):57-70).Malignant progression is a multistep process that transforms normal cells into cells capable of forming large, discernible masses called tumors (Hanahan, Douglas; Weinberg, Robert A. (January 7, 2000). "Hallmarks of cancer." Cell 100(1):57-70; Hanahan, Douglas; Weinberg, Robert A. (2011). "Hallmarks of Cancer: The Next Generation" Cell 144(5):646-74).

[0275] Cancer is a disease in which tissue growth regulation fails. Genes that regulate cell growth and differentiation must change in order for normal cells to become cancerous (Croce CM (January 2008). "Oncogenes and cancer". N. Engl. J. Med. 358 (5): 502-11). The affected genes are divided into two major categories - tumor suppressor genes and oncogenes. Tumor suppressor genes inhibit cell division and survival. Oncogenes promote cell growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and survival. Malignant transformation can occur through the following pathways: low expression or inactivation of tumor suppressor genes, inappropriate overexpression of normal oncogenes, or the formation of new oncogenes (Knudson AG (November 2001)). "Two genetic hits (more or less) to cancer". Nature Reviews Cancer 1 (2): 157-62). Cancer is driven by progressive genetic abnormalities including mutations in oncogenes, chromosomal abnormalities in tumor suppressor genes, and epigenetic changes (Baylin SB, Ohm JE (February 2006).

[0276] "Epigenetic gene silencing in cancer-a mechanism for early oncogenic pathway addiction?"). Nature Reviews Cancer6(2):107-16).

[0277] Most cancers are initially identified due to the appearance of characteristics or symptoms or through screening. A definitive diagnosis requires examination of a tissue sample by a pathologist. Patients suspected of having cancer are individually tested for diagnostic tests, including CT scans, blood tests, endoscopy, and X-rays.

[0278] Malignancies treatable by the methods and compositions described herein include gastric cancer, multiple myeloma, leukemia, lymphoma, hepatocellular carcinoma, renal cell carcinoma, prostate cancer, brain cancer, glioblastoma, melanoma, breast cancer, head and neck cancer, and non-small cell lung cancer.

[0279] Glioblastoma, also known as glioblastoma multiforme (GBM) and grade IV astrocytoma, is the most common and most aggressive malignant primary brain tumor. It involves glial cells, accounting for 52% of all brain tissue tumor cases and 20% of all tumors in the skull ("American Brain Tumor Association (ABTA) 2014"). About 50% of people diagnosed with GBM die within one year, and about 90% die within three years. Treatment can involve chemotherapy, radiotherapy and surgery. The median survival of standard of care radiotherapy and chemotherapy with temozolomide is 15 months (Johnson, Derek R.; O'Neill, Brian Patrick (2011). "Glioblastoma survival in the United States before and during the temozolomide era". Neuro-Oncology 107 (2): 359-64). The median survival without treatment is 4 and a half months. Although no randomized controlled trials have been conducted, surgery remains the standard of care (Van Meir, EG; Hadjipanayis, CG; Norden, AD; Shu, HK; Wen, PY; Olson, JJ (2010). “Exciting New Advances in Neuro-Oncology: The Avenue to a Kure for Malignant Glioma.” CA: A Cancer Journal for Clinicians 60(3):166-93).

[0280] Although common symptoms of the disease include seizures, nausea and vomiting, headaches, memory loss, and hemiparesis, the single most common symptom is progressive memory, personality, or neurological deficits involving the temporal and frontal lobes. The type of symptoms produced is highly dependent on the location of the tumor rather than its pathological nature. Tumors can begin to produce symptoms rapidly, but occasionally grow to a large volume without symptoms.

[0281] When viewed with MRI, glioblastomas typically appear as ring-enhancing lesions. However, the appearance is not specific, although other lesions such as abscesses, metastases, tumors of multiple sclerosis, and other entities may have a similar appearance (Smirniotopoulos, JG; Murphy, FM; Rushing, EJ; Rees, JH; Schroeder, JW "From the Archives of the AFIP: Patterns of Contrast Enhancement in the Brain and Meninges." Radiographics 27 (2): 525-51). A definitive diagnosis of suspected GBM on CT or MRI requires stereotactic biopsy or tumor resection and craniotomy with pathological confirmation. Because tumor grade is based on the most malignant part of the tumor, biopsy or sub-resection of the tumor may result in a downgrade of the lesion. Imaging tumor blood flow using perfusion MRI and measuring tumor metabolite concentrations by MR spectroscopy will increase the value of standard MRI in diagnosing glioblastoma by demonstrating increased relative cerebral blood volume and increased choline peak, respectively, but pathology remains the gold standard (Weerakkody, Yuranga; Gaillard, Frank, “Glioblastoma”, Radiopaedia.org, 2014).

[0282] The diagnosis of glioblastoma relies on distinguishing primary glioblastoma from secondary glioblastoma. (Bleeker, FE; Molenaar, RJ; Leenstra, S (May 2012), "Recent advances in their molecular understanding of glioblastoma", Journal of neuro-oncology 108(1): 11-27). Primary glioblastoma has a poor prognosis, and different tumor biology may respond differently to therapy, making this a critical assessment in determining patient prognosis and therapy (Weerakkody, Yuranga; Gaillard, Frank. "Glioblastoma". Radiopaedia.org 2014). More than 80% of secondary glioblastomas carry IDH1 mutations, while this mutation is rare in primary glioblastoma (5 to 10%). Therefore, IDH1 mutations may become a useful tool to distinguish primary from secondary glioblastomas in the future, as they are very similar histopathologically and the distinction is unreliable without molecular biomarkers (The driver and passenger effects ofisocitrate dehydrogenase 1and 2mutations in oncogenesis and survivalprolongation", Biochim Biophys Acta 1846(2):326-41.Dec 2014).

[0283] IV. Pharmaceutical Compositions

[0284] The above-mentioned slimming agent can be formulated into a pharmaceutical composition suitable for the present method. Such a composition comprises an active agent (a compound of formula (I)) and a pharmaceutically acceptable carrier, excipient or diluent.

[0285] In some cases, a pharmaceutical composition includes a compound of formula (I), a pharmaceutically acceptable salt or a prodrug thereof in combination with one or more pharmaceutically acceptable excipients.

[0286] In some cases, the pharmaceutical composition containing the compound of formula (I) is administered orally and exhibits higher bioavailability than tripterygium wilfordii. The oral bioavailability may be at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 80%, 90% or 95% or more of tripterygium wilfordii. In addition, the oral bioavailability can be at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or 95% of the intravenous bioavailability of the compound of (I), and / or a level of bioavailability of at least 1%, 2%, 3%, 4%, 5%, 7%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80% or 95% when the compound is administered intravenously.

[0287] The pharmaceutical compositions provided herein include compositions wherein the active ingredient contains a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend on the condition being treated, etc. When administered in a method for treating a disease, such a composition will contain an amount of active ingredient effective to achieve the desired result, such as inducing weight loss. It is within the capabilities of those skilled in the art to determine a therapeutically effective amount of compound, particularly in light of the detailed disclosure herein.

[0288] Pharmaceutically acceptable salts can be prepared by reacting the free acid or base form of the above compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of the two. Remington's Pharmaceutical Sciences, 20th edition, Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704; and Handbook of Pharmaceutical salts; Properties, Selection and Use, P. Heinrich Stahland Camille G. Wermuth, ed., Wiley-VCH, Weinheim, 2002.

[0289] Weight loss agents can also be pharmaceutically acceptable prodrugs of any of the above compounds. Prodrugs are compounds that undergo conversion into compounds with desired pharmacological activity during metabolism in vivo. Prodrugs can be prepared by replacing suitable functional groups present in the above compounds, such as the "pro-moities" described in H.Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include esters, ethers or amide derivatives of the above compounds. For further discussion of prodrugs, see Rautio, J.et al.Nat.Rev.Drug Disc.7:255-270,2008.

[0290] To prepare pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be solid or liquid. Solid-form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also serve as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0291] In powders, the carrier is a finely divided solid, a mixture with a finely divided active ingredient (e.g., a compound provided herein). In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in a suitable proportion and compressed into the desired shape and size. Powders and tablets preferably contain 5% to 70% of the active compound.

[0292] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol or sorbitol, starch from corn, wheat, rice, potato or other plants; celluloses such as methylcellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and colloids including acacia and tragacanth; and proteins including, but not limited to, gelatin and collagen. If desired, a disintegrating agent or solubilizing agent may be added, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.

[0293] The dragee core is provided with a suitable coating, for example a concentrated sugar solution, which may also contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or dragee coating to provide the amount (i.e., dosage) of the active compound for product identification or characterization. Pharmaceutical preparations may also be used in the oral cavity, for example, push-in capsules made of gelatin and soft sealed capsules made of gelatin and coatings such as glycerol or sorbitol.

[0294] To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed uniformly therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0295] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

[0296] When parenteral administration is required or desired, particularly suitable mixtures of the salts disclosed herein are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, etc. Ampoules are convenient unit doses. Salts may also be added to liposomes or administered via transdermal pumps or patches. Pharmaceutical admixtures suitable for various embodiments are well known to those skilled in the art and are described, for example, in Pharmaceutical Sciences (Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309, the teachings of which are incorporated herein by reference.

[0297] Aqueous solutions suitable for oral use can be prepared by dissolving the active salt (e.g., compounds described herein, including specific embodiments and examples) in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners as needed. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in a viscous material such as a natural or synthetic gum, resin, methylcellulose, cyclodextrin, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, and a dispersant or wetting agent, such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (e.g., heptadecyl ethoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. The osmotic pressure of the formulation may be adjusted.

[0298] Also included are solid form preparations that are intended to be converted into liquid-form preparations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these preparations may also contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0299] Oil suspensions may contain thickeners, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners may be added to provide palatable oral preparations, such as glycerol, sorbitol or sucrose. These preparations may be preserved by adding antioxidants such as ascorbic acid. As examples of injectable oil carriers, see Minto, J. Pharmacol. Exp. Ther. 281: 93-102, 1997. Pharmaceutical preparations may also form oil-in-water emulsions. The oil phase may be the above-mentioned vegetable oil or mineral oil or a mixture thereof. Suitable emulsifiers include naturally occurring gums (e.g., gum arabic and tragacanth), naturally occurring phospholipids (e.g., soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Emulsions may also contain sweeteners and flavoring agents, such as in the formulations of syrups and elixirs. Such formulations may also contain a demulcent, a preservative or a coloring agent.

[0300] The compounds disclosed herein can be administered alone or can be co-administered to a patient. Co-administration means simultaneous or sequential administration including a single or combination of compounds (more than one compound). Thus, when desired, the formulation can also be combined with other active substances (e.g., to induce weight loss).

[0301] These compounds can be administered by a variety of routes and methods, including, but not limited to: oral, intravenous, topical, parenteral, intraperitoneal, intramuscular, intrathecal, intralesional, intracranial, intranasal, intraocular, intracardiac, intravitreal, intraosseous, intracerebral, intraarterial, intraarticular, intradermal, transdermal, transmucosal, sublingual, enteral, sub-eyelid, insufflation, suppository, inhalation or subcutaneous administration.

[0302] A wide variety of oral, parenteral and topical dosage forms of the compounds can be prepared and administered. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like suitable for ingestion by a patient. Salts of the compounds disclosed herein can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. Moreover, the salts described herein can be administered by inhalation, such as intranasally. In addition, the salts can be administered transdermally. It is also contemplated that a variety of routes of administration (e.g., intramuscularly, orally, transdermally) can be used to administer the salts of the compounds disclosed herein. Therefore, pharmaceutical compositions are also provided, which include a pharmaceutically acceptable excipient or one or more salts of one or more compounds disclosed herein.

[0303] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation, the package containing discrete quantities of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. Additionally, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these packaged forms.

[0304] Depending on the specific application and efficacy of the active ingredient, the amount of the active ingredient in the unit dose formulation can be changed or adjusted from about 0.1 μg / kg to about 100,000 μg / kg, 1.0 μg / kg to 10,000 μg / kg, or 1 μg / kg to 5,000 μg / kg, based on per kg body weight. Examples of unit doses can be 1, 10, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000 or 5000 μg / kg. If desired, the composition may also contain other compatible therapeutic agents. Multiple unit doses may be administered within 24 hours. The dosage may be oral, but other routes of administration may also be used depending on the severity of the patient's disease / disorder.

[0305] In some specific embodiments, the amount of the compound of formula (I) or formula (II) can be about 1.0 μg or adjusted to 10,000 μg, such as 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000 or 5000 μg / kg body weight, to treat obesity by oral administration. In some specific embodiments, the amount of the compound of formula (I) or formula (II) can be about 1.0 μg to 10,000 μg, such as 500, 600, 700, 800, 900, 1000, 2000 or 5000 μg / kg body weight, to treat obesity by intraperitoneal administration.

[0306] Various embodiments include oral administration of the compounds disclosed herein. In some specific embodiments, the compound is administered at a dosage of about 0.05 to about 100 mg / kg, about 0.1 to about 0.5 mg / kg, about 0.1 to about 1 mg / kg, about 0.1 to about 5 mg / kg, about 0.1 to about 10 mg / kg, about 0.1 to about 25 mg / kg, about 1 to about 5 mg / kg, about 1 to about 25 mg / kg, about 5 to about 25 mg / kg, about 10 mg to about 25 mg / kg, about 25 mg / kg to about 50 mg / kg, about 25 mg / kg to about 75 mg / kg, or about 50 mg / kg to about 100 mg / kg. In certain specific embodiments, the compound is administered at a dose of about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 mg / kg. The dose can be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 times or more per day or per week. For example, the compound can be administered once, twice or three times per day. In some specific embodiments, the compound is administered before (e.g., about 1, 2, 3, 4, 5, or 6 hours before) or during meals. Non-limiting examples of methods for converting doses from animals such as mice into human equivalent doses are known in the art. See, for example, the Drug Evaluation and Research (CDER) (2005) Industry Guide of the U.S. Food and Drug Administration Center for Drug Evaluation and Research: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (available from www.fda.gov / downloads / drugs / guidances / ucm078932.pdf). For example, a mouse dose in mg / kg can be converted to a human equivalent dose (assuming a 60 kg human) based on body surface area by multiplying the mouse dose by 0.08.

[0307] Some compounds may have limited solubility in water and thus may require a surfactant or other suitable cosolvent in the composition. Such cosolvents include: polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; cyclodextrin; polyoxyl 35 castor oil; or other agents known to those skilled in the art. Such cosolvents are typically used at levels of about 0.01% by weight and about 2% by weight.

[0308] Viscosities greater than simple aqueous solutions may be desirable to reduce the variability of the dispensed formulation, reduce the physical separation of the components of the suspension or emulsion of the formulation and / or otherwise improve the formulation. Such viscosity enhancers include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, chondroitin sulfate esters and salts thereof, hyaluronic acid and salts thereof, combinations of the above substances, and other agents known to those skilled in the art. These agents are typically used at levels of about 0.01% by weight and about 2% by weight. Those skilled in the art are easily able to determine the acceptable amount of any of the above-mentioned adjuvants.

[0309] The composition may additionally contain components that provide sustained release and / or comfort. These components include high molecular weight, anionic sticky mimetic bacterial polymers, gelling polysaccharides, and finely divided drug carrier matrices. These components are discussed in more detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. For all purposes, the entire contents of these patents are incorporated herein by reference.

[0310] The dosage and frequency (single or multiple doses) of administration to a mammal may vary depending on a variety of factors, such as whether the mammal suffers from another disease and the route of administration; the capacity, age, sex, health, weight, body mass index and diet of the recipient; the type, nature and extent of the symptoms (e.g., emphysema, asthma, ARDS including oxygen toxicity, pneumonia, chronic obstructive pulmonary disease (COPD), emphysema, cystic fibrosis, bronchopulmonary dysplasia, chronic sinusitis, pulmonary fibrosis) being treated, complications of the disease being treated, or other health-related problems. The disease may be the primary cause of the weight gain disease and / or disorder. The disease may be caused by a primary weight gain and / or condition. Other therapeutic experimental guidelines or agents may be used in conjunction with the methods and compounds disclosed herein. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the capabilities of those skilled in the art.

[0311] For any compound described herein, the therapeutically effective amount can be initially determined by cell culture assays. Target concentrations will be those concentrations of active compound that are capable of achieving the methods described herein, as measured using the methods described herein or methods known in the art.

[0312] As is well known in the art, therapeutically effective amounts for humans can also be determined from animal models. For example, a human dose can be formulated to achieve a concentration that has been found to be effective in animals. As described above, the dose in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dose upward or downward. It is well within the capabilities of ordinary technicians to adjust the dose based on the above methods and other methods to achieve maximum efficacy in humans.

[0313] The dosage can vary depending on the needs of the patient and the compound used. In the case of the present disclosure, the dosage administered to the patient should be sufficient to produce a beneficial therapeutic response to the patient over time. The size of the dosage also depends on the presence, nature and extent of any adverse side effects. It is within the skill of the physician to determine the appropriate dosage for a particular situation. Typically, treatment begins with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved. In a specific embodiment, the dosage range is 0.001% to 10% weight / volume. In another specific embodiment, the dosage range is 0.1% to 5% weight / volume.

[0314] Dosage amount and interval may be adjusted individually to provide levels of the administered compound that are effective for the particular clinical manifestation being treated. This will provide a guide for therapeutic trials commensurate with the severity of the individual's disease state.

[0315] Using the teachings provided herein, an effective preventive or therapeutic treatment protocol can be planned that does not cause substantial toxicity and is effective for treating the clinical symptoms presented by a particular patient. The plan should include careful selection of active compounds by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected drug.

[0316] The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal to 50% of the population) and ED50 (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used to formulate a range of doses for use in humans. The dose of these compounds is preferably within a range of plasma concentrations that includes the ED50 with little or no toxicity. The dose can vary within this range, depending on the dose used and the route of administration used. See, for example, Fingl et al., In: The Pharmacological Basis of Therapeutics, Ch.1, p.175. The exact formulation, route of administration and dosage can be selected by an individual physician based on the patient's condition and the particular method of using the compound.

[0317] V. Kit

[0318] In one aspect, the kit described herein is provided herein, which comprises a composition for treating obesity, and instructions for treating obesity. In some specific embodiments, the kit can be used for oral administration of the composition for treating obesity, for example, the kit can further include an applicator for oral administration. In some specific embodiments, the kit can be used for intraperitoneal administration of the composition for treating obesity.

[0319] Example

[0320] The following examples illustrate certain specific embodiments of the present invention and are not intended to limit the scope of the present invention.

[0321] Specific embodiments are further illustrated by the following examples and detailed experimental instructions herein. However, these embodiments are only for the purpose of illustrating specific embodiments and cannot be construed as limiting the scope herein. The contents of all references cited throughout this application and disclosed patents and patent applications are hereby cited by reference.

[0322] Chemical

[0323] The following examples illustrate certain specific embodiments of the present invention and are not intended to limit the scope of the present invention.

[0324] Specific embodiments The steps are described in the following examples and detailed experimental instructions. However, these examples are only for illustrating specific implementations and cannot be interpreted as limiting the scope herein. The contents of all references cited throughout this application and disclosed patents and patent applications are incorporated herein by reference.

[0325] Example 1.

[0326]

[0327] EtI (104 mg, 0.054 mL, 0.67 mmol) and NaCO (70.6 mg, 0.67 mmol) were added to a solution of tripterygium wilfordii (150 mg, 0.33 mmol) in DMF (3 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with CHCl (200 mL), washed with brine (100 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 1) to give the product as a red solid (70 mg, 0.146 mmol, yield = 44%). 1 HNMRδ(400MHz, CDCl3):7.02(1H,d,J=7.2Hz),6.96(1H,s),6.54(1H,s),6.35(1H,d,J=7.2Hz ),3.90-4.05(2H,m),2.44(1H,d,J=15.5Hz),2.21(3H,s),2.13-2.25(2H,m),2.00-2.10(1H, m),1.77-1.93(3H,m),1.62-1.73(3H,m),1.47-1.55(2H,m),1.45(3H,s),1.32-1.42(1H,m), 1.26(3H,s),1.21(3H,t,J=7.2Hz),1.17(3H,s),1.10(3H,s),0.93-1.01(1H,m),0.56(3H,s); 13 CNMRδ (100MHz, CDCl3): 178.34, 178.19, 170.09, 164.71, 146.01, 134.12, 127. 37, 119.55, 118.12, 117.12, 60.26, 45.04, 44.26, 42.93, 40.24, 39.40, 38.22, 36.35, 34.76, 33.51, 32.76, 31.59, 30.69, 30.55, 29.78, 29.60, 28.66, 21.63, 18.44, 14.02, 10.26; LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.20 minutes, m / z = 479.3 [M+H] + , purity = 100% (214, 254nm).

[0328] Example 2.

[0329]

[0330] EtNH2·HCl (40 mg, 0.50 mmol), HATU (190 mg, 0.5 mmol) and NEt3 (101 mg, 0.14 ml, 1 mmol) were added to a solution of celastrol (150 mg, 0.333 mmol) in THF (3 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 1) to give the product as a red solid (23.5 mg, 0.0492 mmol, yield = 15%). 1 HNMRδ (400MHz, CDCl3): 7.01 (1H, dd, J = 7.2, 0.9Hz), 6.98 (1H, s), 6.53 (1H, d, J = 0.9Hz), 6.34 (1H, d, J = 7.2H z),5.62(1H,t,J=5.0Hz),3.13-3.20(2H,m),2.46(1H,d,J=15.8Hz),2.21(3H,s),2.10-2.17(1H,m),1.98-2 .09 (1H, m), 1.82-1.97 (4H, m), 1.47-1.74 (7H, m), 1.44 (3H, s), 1.26 (3H, s), 1.15 (3H, s), 1.13 (3H, s), 1.06 (3H, t, J = 7.2 Hz), 0.98-1.05 (1H, m), 0.65 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.7 minutes; flow rate: 2.2 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.33 minutes, m / z = 478.3 [M+H] + , purity = 100% (214, 254nm).

[0331] Example 3.

[0332]

[0333] Morpholine (78 mg, 0.88 mmol), HATU (254 mg, 0.66 mmol) were added to a solution of tripterygium wilfordii (200 mg, 0.44 mmol) in THF (5 mL), followed by DIPEA (114 mg, 0.16 ml, 0.88 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 1) to give the product as a red solid (74 mg, 0.142 mmol, yield = 32%). 1 HNMRδ (400MHz, CDCl3): 7.02 (1H, dd, J = 7.2, 1.0Hz), 6.97 (1H, s), 6.54 (1H, d, J = 1.0Hz), 6.36 (1H, d, J=7.2Hz),3.50-3.80(8H,m),2.28-2.36(2H,m),2.22(3H,s),2.16-2.23(1H,m),2.03-2.13(1H,m), 1.49-1.93 (8H, m), 1.46 (3H, s), 1.34-1.40 (1H, m), 1.25-1.33 (1H, m), 1.30 (3H, s), 1.28 (3H, s), 1.15 (3H, s), 0.96-1.02 (1H, m), 0.61 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.36 minutes, m / z = 520.3 [M+H] + , purity = 100% (214, 254nm).

[0334] Example 4.

[0335]

[0336] 1-Methylpiperazine (50 mg, 0.055 mL, 0.50 mmol), HATU (190 mg, 0.5 mmol) were added to a solution of tripterygium wilfordii (150 mg, 0.333 mmol) in THF (3 mL), followed by NEt 3 (67.4 mg, 0.093 mmol, 0.666 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product as a red solid (25.2 mg, 0.0473 mmol, yield=14.2%). 1 HNMR: δ (400MHz, CDCl3): 7.02 (1H, dd, J = 7.2, 1.0Hz), 6.98 (1H, br), 6.51 (1H, d, J = 1.0Hz), 6.35 (1H, d, J =7.2Hz),3.60-3.80(2H,m),2.31-2.45(5H,m),2.30(3H,s),2.21(3H,s),2.04-2.19(2H,m),1.65-1.92 (8H, m), 1.49-1.62 (3H, m), 1.45 (3H, s), 1.33-1.39 (1H, m), 1.29 (3H, s), 1.28 (3H, s), 1.24-1.30 (1H, m), 1.14 (3H, s), 0.95-1.01 (1H, m), 0.61 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.7 minutes; flow rate: 2.2 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 1.88 minutes, m / z = 533.3 [M+H] + , purity = 100% (214, 254nm).

[0337] Example 5.

[0338]

[0339] 1M TBAF in THF (0.22 mL, 0.22 mmol) was added to a solution of celastrol (200 mg, 0.44 mmol) and MeNO2 (54 mg, 0.88 mmol) in THF (3 mL). The reaction was stirred at room temperature overnight. H2O (50 mL) was added to quench the reaction. The solution was then extracted with Et2O (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the product as a light yellow solid (139.6 mg, 0.273 mmol, yield=62%). 1 HNMR:

[0340] δ(400MHz, CDCl3):6.77(1H,s),5.69(1H,d,J=5.9Hz),4.54

[0341] (1H, dd, J = 11.3, 4.0 Hz), 4.24-4.31 (1H, m), 4.11 (1H, t, J = 11.3 Hz), 2.38 (1H, d, J = 15.5 Hz), 2.28 (3H, s), 1.48-2.14 (9H, m), 1.45 (3H, s), 1.29-1.39 (4H, m), 1.20 (3H, s), 1.13 (3H, s), 1.05 (3H, s), 0.84-0.92 (1H, m), 0.57 (3H, s); LC-MS (gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120

[0342] EC-C18, 4.6*30mm, 2.7um): rt = 1.86 minutes, m / z = 451.2 [M-CH2NO2] + , purity = 100% (214, 254nm).

[0343] Example 6.

[0344]

[0345] To a solution of celastrol (225 mg, 0.5 mmol) in DMF (10 mL) was added NH4Cl (80 mg, 1.5 mmol), HATU (209 mg, 0.55 mmol), and then DIPEA (129 mg, 0.18 ml, 1.0 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the product as a red solid (200 mg, 0.445 mmol, yield=89%). 1 HNMR: δ (400MHz, CDCl3): 7.01 (1H, s), 7.00 (1H, d, J = 7.0Hz), 6.51 (1H, s), 6.33 (1H, dd, J = 7 .0, 2.4Hz),5.34-5.74(2H,br),2.42(1H,d,J=15.1Hz),2.22(3H,s),2.00-2.16(2H,m),1.8 2-1.98 (4H, m), 1.46-1.72 (7H, m), 1.44 (3H, s), 1.26 (3H, s), 1.20 (3H, s), 1.12 (3H, s), 0.98-1.05 (1H, m), 0.72-0.73 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 1.81 minutes, m / z = 450.4 [M+H] + , purity = 100% (214, 254nm).

[0346] Example 7.

[0347]

[0348] NEt3 (45 mg, 0.062 mL, 0.444 mmol) was added to a solution of tripterygium wilfordii (100 mg, 0.222 mmol) in CH2Cl2 (4 mL), followed by AcCl (20.9 mg, 0.019 mmol, 0.266 mmol). The reaction was stirred at 0 °C for 1 hour. The solution was then diluted with CH2Cl2 (100 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 1, then CH2Cl2 / ethyl acetate = 1: 1) to give the product as a yellow solid (17.3 mg, 0.0351 mmol, yield = 15.8%). 1 HNMR: δ (400MHz, CDCl3): 7.07 (1H, d, J = 7.0Hz), 6.60 (1H, s), 6.30 (1H, d, J = 7.0Hz), 2.24 (1H, d,J=15.5Hz),2.35(3H,s),2.15(3H,s),2.10-2.18(2H,m),1.95-2.10(2H,m),1.78-1.90(3H, m), 1.46-1.72 (4H, m), 1.45 (3H, s), 1.28-1.40 (2H, m), 1.25 (3H, s), 1.18 (3H, s), 1.08 (3H, s), 0.91-0.97 (1H, m), 0.66 (3H, s); LC-MS (mobile phase: A: H2O (0.01% TFA); B: MeCN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2 ml min; column: SunFire C18

[0349] 50*4.6mm,3.5um):rt=2.19min,m / z=493.2[M+H] + , purity = 100% (214, 254nm).

[0350] Example 8.

[0351]

[0352] Me2NH.HCl (72.4 mg, 0.888 mmol), HATU (338 mg, 0.888 mmol) and NEt3 (134.8 mg, 0.186 mmol, 1.332 mmol) were added to a solution of celastrol (200 mg, 0.444 mmol) in THF (5 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the product as a red solid (101.4 mg, 0.212 mmol, yield=48%). 1 HNMR: δ (400MHz, CDCl3): 7.02 (1H, dd, J = 7.2, 1.2Hz), 6.96 (1H, s), 6.53 (1H, d, J = 1.2Hz), 6.36 ( 1H,d,J=7.2Hz),3.00-3.25(3H,br),2.70-3.00(3H,br),2.32-2.46(2H,m),2.22(3H,s),2.06-2 .20 (2H, m), 1.48-1.93 (9H, m), 1.46 (3H, s), 1.30-1.36 (1H, m), 1.29 (3H, s), 1.28 (3H, s), 1.14 (3H, s), 0.95-1.01 (1H, m), 0.54 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 1.96 minutes, m / z = 478.4 [M+H] + , purity = 100% (214, 254nm).

[0353] Example 9.

[0354]

[0355] K2CO3 (115 mg, 0.836 mmol) was added to a solution of celastrol ethyl ester ERX1001 (200 mg, 0.418 mmol) in acetone (4 mL), followed by MeI (1 mL). The reaction was heated at 40 °C overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to give the product as a red solid (120 mg, 0.244 mmol, yield

[0356] =58%). 1 HNMRδ (400MHz, CDCl3): 6.98 (1H, d, J = 7.2, 1.2Hz), 6.43 (1H, d, J = 1.2Hz), 6.30 (1H, d, J = 7.2Hz), 3.90 -4.06(2H,m),3.85(3H,s),2.44(1H,d,J=15.8Hz),2.22(3H,s),2.00-2.22(3H,m),1.77-1.92(3H,m), 1.48-1.72 (6H, m), 1.45 (3H, s), 1.32-1.42 (1H, m), 1.26 (3H, s), 1.21 (3H, t, J = 7.0 Hz), 1.17 (3H, s), 1.10 (3H, s), 0.93-1.00 (1H, m), 0.58 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.78 minutes, m / z = 493.3 [M+H] + , purity = 100% (214, 254nm).

[0357] Example 10.

[0358]

[0359] LiAlH4 (50.8 mg, 1.33 mmol) was added in batches to a solution of ethyl tripterygium wilfordii ERX1001 (160 mg, 0.33 mmol) in THF (20 mL). The reaction was stirred at room temperature overnight. The reaction was quenched by adding H2O (5 mL) and acidified to pH 6-7 with 0.1M HCl. The solution was then diluted with EtOAc (200 mL) and the solid was removed by filtration. The filtrate was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give a crude intermediate. The crude intermediate was dissolved in MeOH (10 mL) and oxidized with an O2 balloon and heated at 40 ° C overnight. The solution was concentrated in vacuo and the residue was purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to give the product as a red solid (58.5 mg, 0.134 mmol, yield=41% (2 steps)). 1HNMR: δ (400MHz, CDCl3): 7.03 (1H, dd, J = 7.1, 1.2Hz), 6.97 (1H, s), 6.53 (1H, d, J = 1.2Hz), 6.38 (1H, d,J=7.1Hz),3.43(1H,dd,J=10.5,5.5Hz),3.22(1H,dd,J=10.5,4.3Hz),2.21(3H,s),2.09-2.16(1H ,m), 2.01(1H,s), 1.54-1.94(9H,m), 1.45(3H,s), 1.38(3H,s), 1.24-1.50(4H,m), 1.19(3H,s), 1.00(3H,s), 0.94-1.00(1H,m), 0.80(3H,s); LC-MS (mobile phase: A: water (0.01% TFA), B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.7 minutes; flow rate: 2.2 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.48 minutes, m / z = 437.3 [M+H] + , purity = 100% (214, 254nm).

[0360] Example 11.

[0361]

[0362] To a solution of celastrol (500 mg, 1.11 mmol) in EtOH (10 mL) was added NaHSO 3 (127 mg, 1.22 mmol) in 5 mL of H2O solution. The reaction was stirred at room temperature for 3 hours. The solution became nearly colorless and transparent. The solution was concentrated to dryness in vacuo at 40 ° C to give a white powder. Enough EtOH was added to dissolve the crude product. The solution was filtered and the filtrate was concentrated in vacuo (<40 ° C) to about 10 mL. The solution was stored in a refrigerator overnight. The solid was filtered and dissolved in water. After freeze drying, the pure product (114.7 mg, 0.207 mmol, yield = 18.6%) was obtained as a white solid. 1HNMR: δ (400 MHz, d6-DMSO): 12.10 (1H, br), 8.84 (1H, br), 7.69 (1H, br), 6.56 (1H, br), 5.78 (1H, d, J = 6.3 Hz), 4.44 (1H, d, J = 6.3 Hz), 2.30-2.38 (1H, m), 2.20 (3H, s), 1.75-2.07 (4H, m), 1.61 (3H, s), 1.20-1.60 (9H, m), 1.17 (3H, s), 1.08 (3H, s), 1.05 (3H, s), 0.80-0.88 (1H, m), 0.60 (3H, s); LC-MS (mobile phase: A: water (10 mM ammonium bicarbonate); B: ACN; gradient: 5% to 95% B at 1.5 minutes; flow rate: 2.0 ml / min; column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 1.48 minutes, m / z = 530.8 [M-Na] - (Negative ion), purity = 95.47% (214nm).

[0363] Example 12.

[0364]

[0365] To a solution of ethyl tripterygium wilfordii (500 mg, 1.045 mmol) in EtOH (10 mL) was added NaHSO (119.6 mg, 1.149 mmol) in 5 mL H2O solution. The reaction was stirred at room temperature overnight. The solution turned light yellow. The solution was concentrated to dryness in vacuo at 40 °C. The residue was washed with CH2Cl2 (4×10 mL), dissolved in sufficient water, and lyophilized overnight to give a light yellow solid product (487.6 mg, 0.837 mmol, yield = 80%). The product may gradually oxidize in the air. 1HNMR: δ (400MHz, d6-DMSO): 8.78 (1H, s), 7.62 (1H, s), 6.57 (1H, s), 5.80 (1H, d, J = 5.9Hz), 4.46(1H,d,J=5.9Hz),3.80-3.94(2H,m),2.34(1H,d,J=15.5Hz),2.20(3H,s),1.76-2.10( 4H, m), 1.62 (3H, s), 1.27-1.65 (9H, m), 1.18 (3H, s), 1.10 (3H, s), 1.08 (3H, t, J = 7.2 Hz), 1.06 (3H, s), 0.84-0.92 (1H, m), 0.45 (3H, s); LC-MS (mobile phase: A: water (10 mM ammonium bicarbonate); B: ACN; gradient: 5% to 95% B in 1.5 minutes; flow rate: 2.0 ml min; column: XBridge; C18, 4.6*50 mm, 3.5 um): rt = 1.83 minutes, m / z = 558.8 [M-Na] - (Negative ion), purity = 95.93% (214nm).

[0366] Example 13.

[0367]

[0368] K2CO3 (184 mg, 1.332 mmol) was added to a solution of celastrol (200 mg, 0.444 mmol) in acetone (5 mL), followed by PhCH2Br (83.5 mg, 0.058 mL, 0.488 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 3:1) to give a crude product. But it was not pure enough. The crude product was then washed with petroleum ether heated twice at 60 ° C to give the product as a yellow solid (40.6 mg, 0.0751 mmol, yield = 17%). 1HNMR:δ(4 00MHz, CDCl3):7.27-7.36(5H,m),7.01(1H,d,J=6.9Hz),6.98(1H,s),6.48(1H,s),6.33(1H,d,J=6.9H z),5.01(1H,AB,J=12.3Hz),4.94(1H,AB,J=12.3Hz),2.44(1H,d,J=15.7Hz),2.20-2.28(1H,m),2.22(3 H, s), 1.82-2.12 (3H, m), 1.46-1.74 (8H, m), 1.42 (3H, s), 1.35-1.44 (1H, m), 1.24 (3H, s), 1.21 (3H, s), 1.09 (3H, s), 0.95-1.01 (1H, m), 0.51 (3H, s); LC-MS: (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.91 minutes, m / z = 541.3 [M+H] + , purity = 97.41% (214nm), 100% (254nm).

[0369] Example 14.

[0370]

[0371] K2CO3 (123 mg, 0.888 mmol) was added to a solution of tripterygium wilfordii (200 mg, 0.444 mmol) in DMF (2 mL), followed by MeOCH2Br (61 mg, 0.04 mL,

[0372] 0.488 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 5:2) to give the product as a yellow solid (10.0 mg, 0.0202 mmol, yield = 4.6%). 1HNMR: δ (400MHz, CDCl3): 7.02 (1H, d, J = 7.0Hz), 6.97 (1H, s), 6.52 (1H, s), 6.35 (1H, d, J=7.0Hz),5.20(1H,AB,J=5.9Hz),5.07(1H,AB,J=5.9Hz),3.44(3H,s),2.45(1H,d,J=1 5.6Hz), 2.21(3H,s), 1.30-2.26(13H,m), 1.45(3H,s), 1.27(3H,s), 1.23(3H,s), 1.11(3H,s), 0.96-1.02(1H,m), 0.60(3H,s); LC-MS (mobile phase: A: water (10mM ammonium bicarbonate); B: ACN; gradient: 5% to 95% B in 1.5 minutes; flow rate: 2.0ml min; column: XBridge C18, 4.6*50mm, 3.5um; rt=2.75min, m / z=463.3[M-OMe] + , purity = 100% (214, 254nm).

[0373] Example 15.

[0374]

[0375] NEt3 (449 mg, 0.62 mL, 4.44 mmol) was added to a solution of ERX1006 (1.0 g, 2.22 mmol) in CH2Cl2 (10 mL), followed by AcCl (261 mg, 0.24 mL, 3.33 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched by adding H2O (5 mL). The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give an intermediate (910 mg, 1.92 mmol, yield = 90%) as a yellow solid.

[0376] To a solution of the intermediate (590 mg, 1.2 mmol) in CH2Cl2 (20 mL) was added ClCO2CCl3 (475 mg, 2.4 mmol) and then NEt3 (242 mg, 0.33 mL, 2.4 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by adding H2O (5 mL). The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2: 1) and then reverse phase preparative-HPLC to obtain the intermediate (120 mg, 0.278 mmol, yield = 23%) as a red solid.

[0377] To a solution of ERX1006 (650 mg, 1.446 mmol) in CH2Cl2 (20 mL) was added (MeO)2P(O)Cl (1044 mg, 0.78 mL, 7.23 mmol) followed by NEt3 (732 mg, 0.726 mL, 7.23 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of H2O (5 mL). The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=30:1) to give the product (321 mg, 0.744 mmol, yield) as a red solid.

[0378] =51%). 1 HNMR: δ (400 MHz, CDCl3): 7.02 (1H, dd, J = 7.1, 1.4 Hz), 6.97 (1H, s), 6.53 (1H, d, J = 1.3 Hz), 6.37 (1H, d, J = 7.5 Hz), 2.22 (3H, s), 1.55-2.20 (14H, m), 1.47 (3H, s), 1.44 (3H, s), 1.29 (3H, s), 1.09-1.15 (1H, m), 1.09 (3H, s), 1.03 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50mm, 3.5um): rt = 2.38 minutes, m / z = 432.3 [M+H] + , purity = 100% (214, 254nm).

[0379] Example 16.

[0380]

[0381] K2CO3 (184 mg, 1.332 mmol) was added to a solution of celastrol (300 mg, 0.666 mmol) in DMF (4 mL), followed by 1-chloroethyl cyclohexyl carbonate (151 mg, 0.134 mL, 0.732 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified twice by preparative TLC (petroleum ether / ethyl acetate = 5:2) to provide isomer 1 (less polar, 29.7 mg, 0.0478 mmol, yield = 7.2%) and isomer 2 (more polar, 20.0 mg, 0.0322 mmol, yield = 4.8%) as yellow solids. Isomer 1: 1 HNMR:

[0382] δ(400MHz, CDCl3):7.02(1H,dd,J=7.3,1.1Hz),6.98(1H,s),

[0383] 6.74 (1H, q, J = 5.5Hz), 6.55 (1H, d, J = 1.1Hz), 6.35 (1H, d, J = 7.3Hz), 4.45-4.53 (1H, m), 2.41 (1H,d,J=16.1Hz),2.20(3H,s),1.00-2.20(23H,m),1.46(3H,s),1.45(3H,d,J=5.5Hz),1.27 (3H, s), 1.20 (3H, s), 1.09 (3H, s), 0.93-1.00 (1H, m), 0.61 (3H, s); LC-MS: SP-0012508-089-1-01262-LCMSA043 Mobile phase: A: water (10 mM ammonium bicarbonate); B: ACN; Gradient: 5% to 95% B in 1.5 minutes; Flow rate: 2.0 ml min; Column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 3.11 minutes, m / z = 477.4 [M-C6H11OCO2] + , purity = 100% (214, 254nm). Isomer 2: 1 HNMR:

[0384] δ(400MHz, CDCl3):7.02(1H,dd,J=7.1,1.1Hz),6.97(1H,s),

[0385] 6.67 (1H, q, J = 5.4Hz), 6.52 (1H, d, J = 1.1Hz), 6.35 (1H, d, J = 7.1Hz), 4.52-4.58 (1H ,m),2.41(1H,d,J=15.9Hz),2.21(3H,s),1.05-2.25(23H,m),1.46(3H,d,J=5.4Hz) ,1.45(3H,s),1.26(3H,s),1.19(3H,s),1.10(3H,s),0.94-1.01(1H,m),0.60(3H,s); LC-MS(mobile phase: A: water (10mM ammonium bicarbonate); B: ACN; gradient: 5% to 95% B in 1.5min; flow rate: 2.0mlmin; column: XBridge C18,4.6*50mm,3.5um): rt=3.12min, m / z=477.3[M-C6H 11 OCO2] + , purity = 94.91% (254nm).

[0386] Example 17.

[0387]

[0388] At 0°C, NaBH4 (1.52 g, 40 mmol) was added in batches to a solution of celastrol (1.8 g, 4.0 mmol) in MeOH (20 mL). The reaction was stirred at room temperature for 30 minutes. The solution turned red and then colorless. The reaction was quenched with 0.1 M HCl and neutralized to pH = 7. The mixture was then extracted with CH2Cl2 (2×100 mL), and the combined organic layers were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the crude intermediate (500 mg, 400 mg) as a white solid.

[0389] 1.104 mmol, Yd=28%).

[0390] To a solution of the crude intermediate (300 mg, 0.66 mmol) in CH2Cl2 (20 mL) was added (MeO)2CMe2 (690 mg, 6.6 mmol) followed by TsOH (12 mg, 0.066 mmol). The reaction was stirred at room temperature overnight. The solution was diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over Mg2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1) to give the product as a white solid (230 mg, 0.467 mmol, yield = 71%). 1HNMR: δ (400MHz, CDCl3): 6.64 (1H, s), 5.73 (1H, dd, J = 6.0, 1.5Hz), 3.27 (1H, dd, J = 20.8, 6. 3Hz),2.98(1H,d,J=20.8Hz),2.41(1H,d,J=15.7Hz),2.10(3H,s),1.95-2.15(4H,m),1.69( 3H, s), 1.64 (3H, s), 1.24-1.85 (9H, m), 1.30 (3H, s), 1.20 (3H, s), 1.17 (3H, s), 1.05 (3H, s), 0.84-0.91 (1H, m), 0.68 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.34 minutes, m / z = 493 [M+H] + , purity = 100% (214, 254nm).

[0391] Example 18.

[0392]

[0393] Pyrrolidine (63 mg, 0.074 mL, 0.888 mmol), HATU (185 mg, 0.48 mmol) were added to a solution of tripterygium wilfordii (200 mg, 0.444 mmol) in DMF (10 mL), followed by DIPEA (115 mg, 0.16 mL, 0.88 mmol). The reaction was stirred at room temperature for 1 hour. The solution was then diluted with CH2Cl2 (200 mL), washed with H2O (2×100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product as a red solid (140 mg, 0.278 mmol, yield=63%). 1HNMRδ (400MHz, CDCl3): 7.03 (1H, dd, J = 7.2, 1.0Hz), 6.96 (1H, s), 6.53 (1H, d, J = 1.0Hz), 6.35 (1H, d, J=7.2Hz),3.56-3.70(2H,m),3.39-3.50(1H,m),3.19-3.29(1H,m),2.34-2.44(2H,m),2.22(3H,s), 2.09-2.20 (2H, m), 1.47-1.97 (12H, m), 1.46 (3H, s), 1.23-1.33 (2H, m), 1.27 (3H, s), 1.22 (3H, s), 1.13 (3H, s), 0.94-1.10 (1H, m), 0.55 (3H, s); LC-MS: mobile phase: A: water (0.01% TFA): B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.01 minutes, m / z = 504.4 [M+H] + , purity = 100% (214, 254nm).

[0394] Example 19.

[0395]

[0396] Piperidine (76 mg, 0.088 mL, 0.888 mmol), HATU (185 mg, 0.48 mmol) were added to a solution of tripterygium wilfordii (200 mg, 0.444 mmol) in DMF (10 mL), followed by DIPEA (115 mg, 0.16 mL, 0.88 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with water (2×100 mL), then with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product as a yellow solid (95 mg, 0.188 mmol, yield=42%). 1HNMR: δ (400MHz, CDCl3): 7.04 (1H, d, J = 7.2Hz), 6.97 (1H, s), 6.54 (1H, s), 6.36 (1H ,d,J=7.2Hz),2.90-4.10(4H,br),2.28-2.42(2H,m),2.22(3H,s),2.05-2.21(2H,m ), 1.24-1.92 (16H, m), 1.46 (3H, s), 1.29 (3H, s), 1.27 (3H, s), 1.14 (3H, s), 0.94-1.01 (1H, m), 0.60 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.63 minutes, m / z = 518.5 [M+H] + , purity = 100% (214, 254nm).

[0397] Example 20.

[0398]

[0399] 3-Hydroxyazetidine hydrochloride (97 mg, 0.888 mmol), HATU (338 mg, 0.888 mmol) were added to a solution of celastrol (200 mg, 0.444 mmol) in THF (5 mL), followed by NEt3 (180 mg, 0.25 mL, 1.776 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:4) and reverse phase preparative-HPLC to give the product as a red solid (80.5 mg, 0.159 mmol, yield = 36%). 1HNMR: δ (400MHz, CDCl3): 7.05 (1H, d, J = 7.2Hz), 6.93 (1H, s), 6.54 (1H, s), 6.36 (1H, d ,J=7.2Hz),4.50-4.60(2H,m),3.55-4.30(4H,m),2.23(3H,s),1.82-2.28(6H,m),1.4 6-1.74 (6H, m), 1.43 (3H, s), 1.20-1.34 (2H, m), 1.25 (3H, s), 1.14 (3H, s), 1.11 (3H, s), 0.94-1.01 (1H, m), 0.64 & 0.60 (3H, s); LC-MS (mobile phase: A: water (10 mM ammonium bicarbonate); B: ACN; gradient: 5% to 95% B in 1.5 minutes; flow rate: 2.0 ml min; column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 2.34 minutes, m / z = 556.4 [M+H] + , purity = 100% (214, 254nm).

[0400] Example 21.

[0401]

[0402] 4-Hydroxypiperidine (135 mg, 1.33 mmol), HATU (507 mg, 1.33 mmol) were added to a solution of celastrol (300 mg, 0.666 mmol) in THF (7.5 mL), followed by NEt3 (202 mg, 0.28 mL, 2.0 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (300 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:3) and reverse phase preparative-HPLC to give the product as a yellow solid (34.8 mg, 0.0652 mmol, yield = 9.8%). 1HNMR: δ (400 MHz, CDCl3): 7.03 (1H, d, J = 7.1 Hz), 6.96 (1H, s), 6.53 (1H, s), 6.36 (1H, d, J = 7.1 Hz), 4.0-4.4 (1H, br), 3.94 (1H, s), 3.0-3.9 (2H, br), 2.00-2.40 (3H, m), 2.22 (3H, s), 1.20-1.95 (17H, m), 1.46 (3H, s), 1.29 (3H, s), 1.28 (3H, s), 1.15 (3H, s), 0.95-1.02 (2H, m), 0.58 (3H, s); LC-MS (mobile phase: A: water (10 mM ammonium bicarbonate); B: ACN; gradient: 5% to 95% B at 1.5 minutes; flow rate: 2.0 ml / min; column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 2.41 minutes, m / z = 534.3 [M+H] + , purity = 96.7% (214nm), 100% (254nm).

[0403] Example 22.

[0404]

[0405] Azetidine hydrochloride (62 mg, 0.67 mmol), HATU (139 mg, 0.36 mmol) were added to a solution of celastrol (150 mg, 0.33 mmol) in DMF (10 mL), followed by DIPEA (86 mg, 0.12 mL, 0.67 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:4) and reverse phase preparative-HPLC to give the product as a yellow solid (96 mg, 0.196 mmol, yield = 52%). 1HNMR: δ (400MHz, CDCl3): 7.04 (1H, d, J = 7.1Hz), 6.97 (1H, s), 6.56 (1H, s), 6.36 (1H ,d,J=7.1Hz),4.35-4.45(2H,m),3.75-3.95(2H,m),2.22(3H,s),1.50-2.30(14H, m), 1.47 (3H, s), 1.28 (3H, s), 1.24-1.34 (2H, m), 1.15 (3H, s), 1.10 (3H, s), 0.93-1.00 (1H, m), 0.66 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.38 minutes, m / z = 490.4

[0406] [M+H] + , purity = 100% (214, 254nm).

[0407] Example 23.

[0408]

[0409] 3-Hydroxypyrrolidine (116 mg, 1.33 mmol), HATU (279 mg, 0.73 mmol) were added to a solution of tripterygium wilfordii (300 mg, 0.666 mmol) in DMF (10 mL), followed by DIPEA (172 mg, 0.24 mL, 1.33 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (300 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:5) to give the product as a yellow solid (110 mg, 0.212 mmol, yield = 32%). 1HNMR: δ(400MHz, CDCl3):7.04(1H,d,J=7.0Hz),6.95(1H,s),6.51&6.46(1H,s),6.35(1 H,d,J=7.0Hz),4.33-4.55(1H,m),3.15-3.95(1H,m),2.50-3.05(1H,m),2.20(3H,s),1 .20-2.50 (16H, m), 1.27 (3H, s), 1.25 (3H, s), 1.20 (3H, s), 1.13 (3H, s), 0.93-1.01 (1H, m), 0.61 & 0.59 & 0.53 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.23 minutes, m / z = 520.3 [M+H] + , purity = 100% (214, 254nm).

[0410] Example 24.

[0411]

[0412] To a solution of celastrol (200 mg, 0.444 mmol) in DMF (15 mL) was added N-hydroxysuccinimide (153 mg, 1.33 mmol), HATU (185 mg, 0.48 mmol), and then DIPEA (115 mg, 0.16 mL, 0.89 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (300 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=40:1) to give the product as a yellow solid (80 mg, 0.146 mmol, yield=33%). 1HNMR: δ (400MHz, CDCl3): 7.01 (1H, dd, J = 7.2, 1.0Hz), 6.98 (1H, s), 6.57 (1H, d, J = 1.0Hz) ,6.35(1H,d,J=7.2Hz),2.70-2.90(4H,m),2.57(1H,d,J=15.9Hz),2.28-2.35(1H,m),2.2 1 (3H, s), 1.48-2.20 (11H, m), 1.46 (6H, s), 1.25-1.30 (1H, m), 1.28 (3H, s), 1.12 (3H, s), 0.99-1.06 (1H, m), 0.71 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 1.97 minutes, m / z = 548.3 [M+H] + , purity = 100% (214nm), 97.26% (254nm).

[0413] Example 25.

[0414]

[0415] To a solution of ERX1005 (500 mg, 0.97 mmol) in CH2Cl2 (10 mL) was added (MeO)2CMe2 (1.01 g, 9.7 mmol) followed by p-TsOH.H2O (18 mg, 0.1 mmol). The reaction was stirred at room temperature overnight. The solution was diluted with CH2Cl2 (200 mL), washed with saturated NaHCO3 (100 mL) solution, followed by brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=10:1) to give the intermediate (350 mg, 0.635 mmol, yield=65%) as a white solid.

[0416] Pd / C (50 mg) was added to a solution of the intermediate (300 mg, 0.54 mmol) in EtOH (20 mL), followed by H2NNH2.H2O (270 mg, 5.4 mmol). The reaction was stirred at 75 ° C overnight. The reaction solution was filtered and concentrated in vacuo. The residue was diluted with CH2Cl2 (200 mL), washed with water (2×100 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 / MeOH=30:1) to give the product as a white solid (160 mg, 0.29 mmol, yield=57%). 1 HNMRδ (400MHz, d4-MeOD): 6.63 (1H, s), 5.90 (1H, d, J = 5.9Hz), 3.53-3.60 (1H, m), 3.01 (1H, dd, J = 12.0 ,3.4Hz),2.43-2.55(2H,m),2.02-2.26(3H,m),2.06(3H,s),1.79-1.95(3H,m),1.54-1.76(6H,m),1.6 7 (3H, s), 1.61 (3H, s), 1.47 (3H, s), 1.43-1.51 (1H, m), 1.30-1.40 (2H, m), 1.29 (3H, s), 1.12 (3H, s), 1.10 (3H, s), 0.85-0.92 (1H, m), 0.82 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.7 minutes; flow rate: 2.2 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 1.98 minutes, m / z = 522.3

[0417] [M+H] + , purity = 100% (214, 254nm).

[0418] Example 26.

[0419]

[0420] To a solution of ERX1025 (90 mg, 0.17 mmol) in CH2Cl2 (10 mL) was added NEt3 (34 mg, 0.34 mmol) followed by AcCl (20 mg, 0.26 mmol). The reaction was stirred at room temperature for 30 min. The solution was diluted with CH2Cl2 (100 mL), washed with saturated NaHCO3 solution (50 mL), then with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=10:1) to give the product as a white solid (60 mg, 0.106 mmol, yield=63%). 1 HNMR: δ (400MHz, CDCl3): 6.64 (1H, s), 6.24 (1H, t, J = 5.6Hz), 5.67 (1H, d, J = 6.5Hz), 3.68-3.7 5(1H,m),3.45-3.53(1H,m),3.05-3.14(1H,m),2.39(1H,d,J=16.0Hz),2.27(3H,s),1.98-2.1 2 (2H, m), 2.05 (3H, s), 1.68 (3H, s), 1.66 (3H, s), 1.47 (3H, s), 1.04-1.82 (12H, m), 1.16 (6H, s), 1.01 (3H, s), 0.72-0.80 (1H, m), 0.45 (3H, s); LC-MS (mobile phase: A: water (10 mM ammonium bicarbonate); B: ACN; gradient: 5% to 95% B in 1.5 minutes; flow rate: 2.0 ml min; column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 2.17 minutes, m / z = 564.4 [M+H] + , purity = 100% (214, 254nm).

[0421] Example 27.

[0422]

[0423] 3,5-Dimethylpyrazole (336 mg, 3.492 mmol) was added to a solution of SM (860 mg, 1.746 mmol) in CH2Cl2 (20 mL), followed by PDC (647 mg, 1.746 mmol). The reaction was stirred at room temperature overnight. The solution was filtered through celite and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 4:1) to give the product as a white solid (410 mg, 0.809 mmol, yield = 46%). 1HNMR: δ (400 MHz, CDCl3): 6.72 (1H, s), 6.24 (1H, s), 2.55 (3H, s), 2.41 (1H, d, J = 15.6 Hz), 1.25-2.20 (13H, m), 1.70 (3H, s), 1.67 (3H, s), 1.52 (3H, s), 1.28 (3H, s), 1.16 (3H, s), 1.09 (3H, s), 0.91-0.99 (1H, m), 0.66 (3H, s); LC-MS (mobile phase: A: H2O (0.01% TFA); B: MeCN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2 ml min; column: SunFire C18

[0424] 50*4.6mm,3.5um):rt=2.39min,m / z=507.3[M+H] + , purity = 99.28% (214nm), 100% (254nm).

[0425] Example 28.

[0426]

[0427] LiAlH4 (70 mg, 1.83 mmol) was added in batches to a solution of ERX1017 (300 mg, 0.61 mmol) in THF (10 mL). The reaction was stirred at room temperature for 1 hour. Water (5 mL) was added to quench the reaction. The solution was diluted with EtOAc (200 mL) and filtered. The filtrate was separated, and the organic layer was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=10:1) to give an intermediate (180 mg, 0.376 mmol, yield=62%) as a white solid.

[0428] To a solution of the intermediate (150 mg, 0.31 mmol) in CH2Cl2 (10 mL) was added NEt3 (63 mg, 0.62 mmol), followed by MsCl (71 mg, 0.62 mmol). The reaction was stirred at room temperature overnight. The solution was diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=10:1) to give the intermediate (160 mg, 0.287 mmol, yield=93%) as a white solid.

[0429] KCN (99 mg, 1.528 mmol) and 18-crown-6 (403 mg, 1.528) were added to a solution of the intermediate (170 mg, 0.305 mmol) in DMF (5 mL). The reaction was heated at 120 ° C for 6 hours in a microwave reactor. The solution was diluted with EtOAc (200 mL), washed with water (2×100 mL) and brine (100 mL) in sequence, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the product as a white solid (110 mg, 0.226 mmol, yield = 74%). 1 HNMR: δ (400MHz, CDCl3): 6.65 (1H, s), 5.80 (1H, d, J = 4.7Hz), 3.30 (1H, dd, J = 20.8, 6.3Hz), 3.01 (1H, d,J=20.1Hz),2.46(1H,AB,J=16.5Hz),2.19(1H,AB,J=16.5Hz),2.11(3H,s),2.00-2.07(2H,m),1.50 -1.85 (9H, m), 1.68 (3H, s), 1.64 (3H, s), 1.25-1.38 (3H, m), 1.31 (3H, s), 1.29 (3H, s), 1.16 (3H, s), 1.14 (3H, s), 0.97-1.03 (1H, m), 0.87 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.35 minutes, no MS peak integration, purity = 100% (214, 254 nm).

[0430] Example 29.

[0431]

[0432] 2-Amino-1,3-propanediol (91 mg, 1.0 mmol), HATU (139 mg, 0.36 mmol), followed by DIPEA (129 mg, 0.17 mL, 1.0 mmol) were added to a solution of celastrol (150 mg, 0.33 mmol) in DMF (10 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=8:1) to give the product as a red solid (60 mg, 0.115 mmol, yield=35%). 1 HNMR

[0433] δ(400MHz, CDCl3):7.03(1H,d,J=7.1Hz),7.00(1H,s),6.61

[0434] (1H, d, J = 3.0 Hz), 6.53 (1H, s), 6.35 (1H, d, J = 7.1 Hz), 3.45-3.90 (5H, m), 3.00-3.45 (2H, m), 2.43 (1H, d, J = 15.7 Hz), 2.21 (3H, s), 1.47-2.18 (12H, m), 1.43 (3H, s), 1.26 (3H, s), 1.24-1.28 (1H, m), 1.18 (3H, s), 1.12 (3H, s), 0.95-1.05 (1H, m), 0.66 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B at 1.4 minutes; flow rate: 2.3 ml / min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.08 minutes, m / z = 524.3 [M+H] + , purity = 95.73% (214nm).

[0435] Example 30.

[0436]

[0437] Concentrated hydrochloric acid HCl (1 mL) was added to a solution of SM (90 mg, 0.178 mmol) in THF (5 mL). The reaction was stirred at 70 ° C for 2 days. Most of the THF solvent was then removed in vacuo. The residue was diluted with CH2Cl2 (200 mL), the aqueous layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product (4.4 mg, 0.00943 mmol, yield=5.3%) as a light yellow solid. 1 HNMRδ(400MHz,CD3OD):6.86(1H,s),6.18(1H,s),4.62(2H,br),2.55(3H,s),1.40-2.50(14H,m),1.54(3H,s),1.35(3H,s),1.18(3H,s),1.13(3H,s),0.93-1.00(1H,m),0.76(3H,s);LC-MS(mobile phase:A:H2O(0.01%TFA);B:MeCN(0.01%TFA);gradient:5%to95%Bin1.2min;flow rate:2mlmin;column:SunFire C18 50*4.6mm,3.5um):rt=2.05min,m / z=467[M+H] + , purity = 97.30% (9214nm), 97.25% (254nm).

[0438] Example 31.

[0439]

[0440] K2CO3 (37 mg, 0.267 mmol) was added to a solution of ERX1006 (60 mg, 0.133 mmol) in acetone (2 mL), followed by MeI (1 mL). The reaction was stirred at 40 ° C overnight. The mixture was diluted with CH2Cl2 (300 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:2) to give the product as a yellow solid (38.4 mg, 0.0826 mmol, yield=62%). 1HNMRδ (400MHz, CDCl3): 6.96 (1H, dd, J = 7.0, 1.0Hz), 6.40 (1H, d, J = 1.0Hz), 6.27 (1H, d,J=7.0Hz),5.72(1H,br),5.55(1H,br),3.84(3H,s),2.40(1H,d,J=15.7Hz),2.22( 3H, s), 1.45-2.13 (13H, m), 1.44 (3H, s), 1.25 (3H, s), 1.20 (3H, s), 1.11 (3H, s), 0.97-1.04 (1H, m), 0.73 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.16 minutes, m / z = 464.3

[0441] [M+H] + , purity = 100% (214, 254nm).

[0442] Example 32.

[0443]

[0444] To a solution of ERX1006 (100 mg, 0.22 mmol) in THF (15 mL) was added K2CO3 (46 mg, 0.33 mmol), followed by BrCH2CO2Me (51 mg, 0.032 mL, 0.33 mmol). The reaction was stirred at 50 °C overnight. The mixture was diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the product as a yellow solid (40 mg, 0.077 mmol, yield=35%). 1HNMRδ (400MHz, CDCl3): 7.01 (1H, d, J = 7.1Hz), 6.36 (1H, s), 6.29 (1H, d, J = 7.1Hz), 5.70 ( 1H, br), 5.39 (1H, br), 4.85 (2H, s), 3.77 (3H, s), 2.40 (1H, d, J = 15.4Hz), 2.31 (3H, s), 1.8 0-2.12 (7H, m), 1.46-1.72 (6H, m), 1.43 (3H, s), 1.26 (3H, s), 1.20 (3H, s), 1.11 (3H, s), 0.88-1.05 (1H, m), 0.74 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.16 minutes, m / z = 522.3

[0445] [M+H] + , purity = 100% (214, 254nm).

[0446] Example 33.

[0447]

[0448] At 0°C, ERX1006 (300 mg, 0.667 mmol) in CH2Cl2 (5 mL) was added dropwise with Et3N (135 mg, 0.19 mL, 1.334 mmol), followed by dropwise addition of ClCO2Et (145 mg, 0.13 mL, 1.334 mmol) ℃. The reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product (150.6 mg, 0.289 mmol, yield=43%) as a yellow solid. 1HNMRδ (500MHz, CDCl3): 7.06 (1H, dd, J = 7.0, 1.0Hz), 6.47 (1H, d, J = 1.0Hz), 6.33 (1H, d, J = 7.0 Hz), 5.67 (1H, br), 5.26 (1H, br), 4.32 (2H, q, J = 7.2Hz), 2.39 (1H, d, J = 15.6Hz), 2.21 (3H, s), 1.49-2.04 (13H, m), 1.46 (3H, s), 1.39 (1H, t, J = 7.2 Hz), 1.27 (3H, s), 1.21 (3H, s), 1.12 (3H, s), 0.99-1.05 (1H, m), 0.76 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.15 minutes, m / z = 522.3 [M+H] + , purity = 100% (214, 254nm).

[0449] Example 34.

[0450]

[0451] To a solution of ERX1006 (300 mg, 0.667 mmol) in (CH2Cl)2 (10 mL) was added Et3N (202 mg, 0.28 mL, 2.0 mmol) followed by EtNCO (142 mg, 0.158 mL, 2.0 mmol). The reaction was stirred at 55°C overnight. The mixture was diluted with CH2Cl2 (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=20:1) to remove unreacted SM. The crude product was then heated at 80°C with 20 mL of ethyl acetate. The solid was filtered and purified in one step by preparative TLC (ethyl acetate / CH2Cl2=3:1) to give the product as a yellow solid (74.7 mg, 0.143 mmol, yield = 22%). 1HNMR: δ (400MHz, CDCl3): 7.03 (1H, d, J = 7.2Hz), 6.45 (1H, s), 6.31 (1H, d, J = 7.2Hz), 5.70 (1H, b r),5.38(1H,br),5.26(1H,t,J=5.0Hz),3.26-3.45(2H,m),2.38(1H,d,J=15.7Hz),2.18(3H,s ), 1.47-2.15 (13H, m), 1.45 (3H, s), 1.26 (3H, s), 1.22 (3H, t, J = 7.2 Hz), 1.20 (3H, s), 1.12 (3H, s), 0.98-1.05 (1H, m), 0.75 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um; rt = 2.06 minutes, m / z = 521.4 [M+H] + , purity = 100% (214, 254nm).

[0452] Example 35.

[0453]

[0454] At 0°C, ClCO2CCl3 (341 mg, 0.21 mL, 1.725 mmol) was added dropwise to a solution of SM (160 mg, 0.345 mmol) in CH2Cl2 (5 mL), followed by dropwise addition of NEt3 (175 mg, 0.24 mL, 1.725 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=30:1) to give the product (71 mg, 0.159 mmol, yield=46%) as a yellow solid. 1HNMRδ(400MHz,CDCl3):6.97(1H,d,J=6.9Hz),6.42(1H,s),6.32(1H,d,J=6.9Hz),3.85(3H,s),2.22(3H,s),2.09-2.18(3H,m),1.89-2.01(3H,m),1.53-1.81(8H,m),1.47(3H,s),1.44(3H,s),1.29(3H,s),1.08-1.15(1H,m),1.09(3H,s),1.05(3H,s); LC-MS(mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B at 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.33 minutes, m / z = 446.3 [M+H] + , purity = 100% (214, 254nm).

[0455] Example 36.

[0456]

[0457] To a solution of SM (100 mg, 0.232 mmol) in acetone (2 mL) was added K2CO3 (64 mg, 0.463 mmol), followed by BrCH2CO2Me (71 mg, 0.044 mL, 0.463 mmol). The reaction was stirred at 55 ° C overnight. The mixture was diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / EtOAc=10:1) to give a crude product. The crude product was further washed with Et2O (2×2 mL) to give the pure product (55 mg, 0.109 mmol, yield=47%) as a yellow solid. 1HNMRδ (400MHz, CDCl3): 7.03 (1H, dd, J = 7.0, 1.0Hz), 6.38 (1H, d, J = 1.0Hz), 6.33 (1H, d, J = 7.0Hz), 4.8 5(1H,AB,J=16.5Hz),4.84(1H,AB,J=16.5Hz),3.77(3H,s),2.32(3H,s),2.08-2.18(3H,m),1.89-2.00 (3H, m), 1.52-1.81 (8H, m), 1.46 (3H, s), 1.44 (3H, s), 1.29 (3H, s), 1.08-1.15 (1H, m), 1.09 (3H, s), 1.04 (3H, s); LC-MS (mobile phase: A: water (0.1% TFA); B: ACN (0.1% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120

[0458] EC-C18, 4.6*30mm, 2.7um): rt = 1.94 minutes, m / z = 504.3 [M+H] + , purity = 100% (214, 254nm).

[0459] Example 37.

[0460]

[0461] At 0°C, Et3N (84 mg, 0.12 mL, 0.834 mmol) was added dropwise to a solution of ERX1015 (120 mg, 0.278 mmol) in CH2Cl2 (5 mL), followed by dropwise addition of ClCO2Et (91 mg, 0.834 mL, 0.834 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=50:1) to give the product (97.3 mg, 0.193 mmol, yield=69%) as a yellow solid. 1HNMR: δ (400MHz, CDCl3): 7.08 (1H, d, J = 7.2Hz), 6.49 (1H, s), 6.36 (1H, d, J = 7.2Hz), 4 .32(2H, q, J=7.2Hz),2.22(3H,s),2.09-2.20(3H,m),1.89-2.03(3H,m),1.51-1.81(8 H, m), 1.49 (3H, s), 1.44 (3H, s), 1.39 (3H, t, J = 7.2 Hz), 1.30 (3H, s), 1.07-1.15 (1H, m), 1.09 (3H, s), 1.05 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 1.92 minutes, m / z = 504.4 [M+H] + , purity = 98.02% (214nm), 97.42% (254nm).

[0462] Example 38.

[0463]

[0464] To a solution of ERX1015 (100 mg, 0.232 mmol) in (CH2Cl)2 (5 mL) was added Et3N (117 mg, 0.16 mL, 1.158 mmol) followed by EtNCO (82 mg, 0.0917 mL, 1.158 mmol). The reaction was stirred at 50 °C overnight. The mixture was diluted with CH2Cl2 (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=20:1) to give the product as a yellow solid (59.6 mg, 0.119 mmol, yield=51%). 1HNMRδ (400MHz, CDCl3): 7.04 (1H, d, J = 7.0Hz), 6.47 (1H, s), 6.34 (1H, d, J = 7.0Hz), 5.17&4. 71(1H,br),3.19-3.36(2H,m),2.19(3H,s),2.09-2.17(3H,m),1.89-2.02(4H,m),1.54-1. 81 (8H, m), 1.48 (3H, s), 1.44 (3H, s), 1.29 (3H, s), 1.20-1.27 (3H, m), 1.23 & 1.14 (3H, t, J = 7.2 Hz), 1.09 (3H, s), 1.05 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 1.83 minutes, m / z = 503.4 [M+H] + , purity = 95.00% (214nm), 98.55% (254nm).

[0465] Example 39.

[0466]

[0467] To a solution of ERX1015 (100 mg, 0.23 mmol) in CH2Cl2 (10 mL) was added NEt3 (47 mg, 0.065 mL, 0.46 mmol) followed by (MeO)2P(O)Cl (70 mg, 0.052 mL, 0.46 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to give the product as a yellow solid (28 mg, 0.0519 mmol, yield=23%). 1HNMRδ (500MHz, CDCl3): 7.06 (1H, d, J = 7.0Hz), 6.47 (1H, s), 6.35 (1H, d, J = 7.0Hz), 4.00 (3H,d,J=11.4Hz),3.96(3H,d,J=11.2Hz),2.30(3H,d,J=1.5Hz),2.10-2.18(3H,m),1.9 0-2.00 (3H, m), 1.54-1.80 (8H, m), 1.47 (3H, s), 1.44 (3H, s), 1.29 (3H, s), 1.09-1.14 (1H, m), 1.09 (3H, s), 1.05 (3H, s); LC-MS (mobile phase: A: water (0.1% TFA); B: ACN (0.1% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 1.82 minutes, m / z = 540.3 [M+H] + , purity = 94.11% (254nm).

[0468] Example 40.

[0469]

[0470] 1M BH3.THF (1.67 mL, 1.67 mmol) was added to a solution of ERX1006 (250 mg, 0.56 mmol) in THF (15 mL). The reaction was stirred at room temperature for 1 hour. Water (5 mL) was added to quench the reaction. Most of the solvent was removed in vacuo, and the solution was acidified to pH 5 to 6 with 0.1 M HCl. The mixture was diluted with CH2Cl2 (200 mL) and filtered. The filtrate was washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the crude product (250 mg, 1.67 mmol) as a white solid.

[0471] 0.554 mmol, Yd=100%). The starting material was used in the next step without further purification.

[0472] To a solution of the intermediate (250 mg, 0.56 mmol) in CH2Cl2 (15 mL) was added NEt3 (224 mg, 0.31 mL, 2.21 mmol), followed by AcCl (174 mg, 2.21 mmol). The reaction was stirred at room temperature overnight. Water (5 mL) was added to quench the reaction. The mixture was diluted with CH2Cl2 (200 mL), washed with saturated Na2CO3 (2×100 mL) followed by brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=10:1) to give the product as a white solid (40 mg, 0.0773 mmol, Yd=14%). 1 HNMRδ (400MHz, CDCl3): 7.00 (1H, s), 5.78 (1H, d, J = 6.0Hz), 3.35 (1H, dd, J = 21.0, 6.0Hz) ,3.07(1H,d,J=21.0Hz),2.31(3H,s),2.27(3H,s),2.03-2.20(4H,m),2.07(3H,s),1.85 -1.97 (2H, m), 1.48-1.72 (8H, m), 1.43 (3H, s), 1.36 (3H, s), 1.24 (3H, s), 1.02-1.10 (1H, m), 1.07 (3H, s), 1.06 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA); B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.06 minutes, m / z = 518.3 [M+H] + , purity = 97.21% (214nm).

[0473] Example 41.

[0474]

[0475] In the CH2C l2To the (10 mL) solution was added NEt3 (134 mg, 0.18 mL, 1.32 mmol), followed by (Cl3CO)2CO (395 mg, 1.32 mmol). The reaction was stirred at room temperature overnight. Water (5 mL) was added to quench the reaction. The mixture was diluted with CH2Cl2 (200 mL), washed with saturated Na2CO3 (2×100 mL) followed by brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=10:1) to give the product as a white solid (70 mg, 0.152 mmol, Yd=18%). 1 HNMRδ(500MHz,CDCl3):7.11(1H,s),5.83(1H,d,J=6.4Hz),3.41(1H,dd,J=21.0,6.4Hz),3.09(1H,d,J=21.0Hz),2.28(3H,s),2.09-2.18(4H,m),1.87-1.96(2H,m),1.49-1.72(8H,m),1.44(3H,s),1.34(3H,s),1.25(3H,s),1.06-1.11(1H,m),1.07(3H,s),1.06(3H,s).;LC-MS(mobile phase:A:water(0.1%TFA);B:ACN(0.1%TFA);gradient:5%to95% B at 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.23 minutes, m / z = 460.3 [M+H] + , purity = 97.77% (214nm).

[0476] Example 42.

[0477]

[0478] LiAlH4 (2.38 g, 75 mmol) was added to a solution of ERX1008 (477 mg, 1.0 mmol) in anhydrous THF (40 mL). The mixture was refluxed overnight. The reaction was quenched by a saturated solution of NH4Cl solution. The mixture was heated at 50 ° C for 2 hours and filtered through a thin layer of silica gel. The solid was washed with THF (3×50 mL). The combined filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 10: 1) to give the product as a red solid (23.9 mg, 0.0515 mmol, Yd = 5%). 1HNMRδ(500MHz,CDCl3):7.03(1H,d,J=7.1Hz),6.96(1H,s),6.52(1H,s),6.39(1H,d,J=7.1Hz),2.34(6H,br),2.22(3H,s),1.95-2.25(4H,m),1.35-1.88(12H,m),1.44(3H,s),1.42(3H,s),1.24(3H,s),1.09(3H,s),0.97-1.03(1H,m),0.79(3H,s); LC-MS(mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B at 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 1.83 minutes, m / z = 480.4 [M+H] + , purity = 98.20% (214nm), 99.51% (254nm).

[0479] Example 43.

[0480]

[0481] i-C3H7SH (84.5 mg, 0.10 mL, 1.11 mmol) was added to a solution of tripterygium wilfordii (100 mg, 0.222 mmol) in MeOH (3 mL). The reaction was stirred at room temperature for 3 hours. The solution changed from red to light reddish yellow. The solution was then concentrated in vacuo to obtain a crude mixture, which was used in the next step without further purification.

[0482] Pyridine (0.5 mL) was added to the crude mixture (117 mg, 0.222 mmol, theoretical amount) in Ac2O (4 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=5:2) to give the product as a white solid (85.2 mg, 0.139 mmol, total yield=63%). 1HNMRδ (400MHz, CDCl3): 7.01 (1H, s), 5.97 (1H, d, J = 6.2Hz), 4.57 (1H, d, J = 6.2Hz), 3.11-3.22 (1H,m),2.39(1H,d,J=15.8Hz),2.30(3H,s),2.27(3H,s),2.26(3H,s),1.25-2.15(13H,m),1 .58 (3H, s), 1.39 (1H, d, J = 6.5 Hz), 1.27 (1H, d, J = 6.5 Hz), 1.25 (3H, s), 1.16 (3H, s), 1.07 (3H, s), 0.89-0.96 (1H, m), 0.67 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.7 minutes; flow rate: 2.2 ml min, column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.68 minutes, m / z = 535.2 [M-C3H7S] + , purity = 100% (214, 254nm).

[0483] Example 44.

[0484]

[0485] i-C3H7SH (44 mg, 0.58 mmol) was added to a solution of celastrol (50 mg, 0.111 mmol) in MeOH (10 mL). The reaction was stirred at room temperature for 1 hour. The solution changed from red to almost colorless. The solution was then concentrated in vacuo to obtain a crude mixture, which was used in the next step without further purification.

[0486] Pyridine (91 mg, 1.2 mmol) was added to the crude mixture (56.3 mg, 0.111 mmol, theoretical amount) of Ac2O (3 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=4:1) to give the product as a white solid (35 mg, 0.059 mmol, total yield=49%). 1HNMRδ (500MHz, CDCl3): 7.02 (1H, s), 6.01 (1H, d, J = 6.2Hz), 4.59 (1H, d, J = 6.2Hz), 3.13-3. 22(1H,m),2.30(3H,s),2.28(3H,s),2.26(3H,s),1.88-2.18(6H,m),1.50-1.74(8H,m),1. 64 (3H, s), 1.43 (3H, s), 1.40 (3H, d, J = 6.7 Hz), 1.29 (3H, d, J = 6.7 Hz), 1.27 (3H, s), 1.06-1.11 (1H, m), 1.07 (3H, s), 1.04 (3H, s); LC-MS (mobile phase: A: water (0.1% TFA) B: ACN (0.1% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min

[0487] Column: Poroshell 120EC-C18, 4.6*30mm, 2.7um): rt=2.11min, m / z=516.3[M-C3H7S] + , purity = 100% (214, 254nm).

[0488] Example 45.

[0489]

[0490] 4-Methylphenylsulfide (144 mg, 1.16 mmol) was added to a solution of SM (50 mg, 0.116 mmol) in THF (3 mL). The reaction was stirred at room temperature for 3 hours. The solution changed from dark red to light red. The solution was then concentrated in vacuo to obtain a crude mixture, which was used in the next step without further purification.

[0491] Pyridine (0.25 mL) was added to the crude mixture (64.5 mg, 0.116 mmol, theoretical amount) in Ac2O (2 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=5:2) to give the product as a white solid (62.4 mg, 0.0975 mmol, total yield=84%). 1HNMRδ (400MHz, CDCl3): 7.36 (1H, d, J = 8.0Hz), 7.12 (1H, d, J = 8.0Hz), 7.03 (1H, s), 5.7 7(1H,d,J=6.1Hz),4.79(1H,d,J=6.1Hz),2.35(3H,s),2.32(3H,s),2.28(3H,s),1.84 -2.15 (6H, m), 1.35-1.68 (8H, m), 1.51 (3H, s), 1.42 (3H, s), 1.26 (3H, s), 1.02-1.08 (1H, m), 1.06 (3H, s), 1.00 (3H, s); LC-MS (mobile phase: A: water (0.1% TFA) B: ACN (0.1% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.17 minutes, m / z = 516.3 [M-C7H7S] + , purity = 98.54% (214nm), 96.35% (254nm).

[0492] Example 46.

[0493]

[0494] 4-Acetamidothiophenol (58 mg, 0.348 mmol) was added to a solution of SM (50 mg, 0.116 mmol) in THF (2 mL). The reaction was stirred at room temperature for 1 hour. The solution changed from dark red to light red. The solution was then concentrated in vacuo to give a crude mixture, which was used in the next step without further purification.

[0495] Pyridine (0.5 mL) was added to the crude mixture (69.4 mg, 0.116 mmol, theoretical amount) in Ac2O (2 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the product as a white solid (45.1 mg, 0.066 mmol, total yield=57%). 1HNMRδ(400MHz, CDCl3):7.47(1H,d,J=8.6Hz),7.40(1H,d,J=8.6Hz),7.20(1H,s),7.03(1H,s ),5.76(1H,d,J=6.2Hz),4.80(1H,d,J=6.2Hz),2.33(3H,s),2.31(3H,s),2.28(3H,s),2.19( 3H, s), 1.82-2.14 (7H, m), 1.30-1.66 (7H, m), 1.49 (3H, s), 1.42 (3H, s), 1.26 (3H, s), 1.02-1.09 (1H, m), 1.06 (3H, s), 1.00 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.26 minutes, m / z = 684.4 [M+H] + , purity = 100% (214, 254nm).

[0496] Example 47.

[0497]

[0498] To a solution of ERX1006 (90 mg, 0.2 mmol) in MeOH (3 mL) was added i-C3H7SH (23 mg, 0.3 mmol). The reaction was stirred at room temperature for 2 hours. The solution turned from red to light yellow. The solution was then concentrated in vacuo to give a crude mixture.

[0499] Pyridine (0.5 mL) was added to the crude mixture prepared above in Ac2O (4 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2 × 100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative HPLC (petroleum ether / acetone = 1: 1) to give the product as a white solid (46.6 mg, 0.0764 mmol, total yield = 38%). 1HNMRδ (400MHz, CDCl3): 7.00 (1H, s), 5.97 (1H, d, J = 6.3Hz), 5.63 (1H, br), 5.24 (1H, br), 4.57 (1H, d, J=6.3Hz),3.12-3.22(1H,m),2.40(1H,d,J=15.3Hz),2.30(3H,s),2.27(3H,s),2.26(3H,s),1.42-2 .10 (13H, m), 1.57 (3H, s), 1.40 (3H, d, J = 6.7 Hz), 1.28 (3H, d, J = 6.7 Hz), 1.26 (3H, s), 1.19 (3H, s), 1.11 (3H, s), 0.95-1.02 (1H, m), 0.74 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.7 minutes; flow rate: 2.2 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.50 minutes, m / z = 610.3 [M+H] + ,purity

[0500] =96.87% (214nm).

[0501] Example 48.

[0502]

[0503] p-MeC6H4SH (82 mg, 0.66 mmol) was added to a solution of tripterygium wilfordii (200 mg, 0.44 mmol) in MeOH (6 mL). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to obtain a crude mixture.

[0504] To the crude mixture prepared above was added pyridine (1 mL) in Ac2O (8 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL) and washed with water (2×

[0505] 100 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:1) to give the product (30 mg, 0.0457 mmol, yield=10%) as a white solid.

[0506] To a solution of compound 2 (100 mg, 0.15 mmol) in DMF (10 mL) was added NH4Cl (18 mg, 0.34 mmol), HATU (65 mg, 0.17 mmol), and then DIPEA (39 mg, 0.3 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with EtOAc (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to give the product as a white solid (30 mg, 0.0456 mmol, yield = 30%). 1 HNMRδ (500MHz, CDCl3): 7.35 (1H, d, J = 7.7Hz), 7.12 (1H, d, J = 7.7Hz), 7.02 (1H, s), 5.73 (1H, d, J = 6 .1Hz),5.61(1H,br),5.15(1H,br),4.76(1H,d,J=6.1Hz),2.38(1H,d,J=15.2Hz),2.35(3H,s),2.3 2 (3H, s), 2.31 (3H, s), 2.28 (3H, s), 1.30-2.06 (13H, m), 1.48 (3H, s), 1.24 (3H, s), 1.18 (3H, s), 1.09 (3H, s), 0.94-0.99 (1H, m), 0.70 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.47 minutes, purity = 98.43% (214 nm), 100% (254 nm).

[0507] Example 49.

[0508]

[0509] To a solution of ERX1006 (500 mg, 11.0 mmol) in MeOH (15 mL) was added 4-acetamidothiophenol (250 mg, 16.0 mmol). The reaction was stirred at room temperature for 1 hour. The solution changed from dark red to light red. The solution was then concentrated in vacuo to give a crude mixture.

[0510] Pyridine (2.5 mL) was added to the crude mixture prepared above in AcO (20 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2 × 100 mL), brine (100 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to give the product (250 mg, 0.357 mmol, yield = 51%) as a white solid. 1 HNMRδ(500MHz, CDCl3):7.45(1H,d,J=8.5Hz),7.39(1H,d,J=8.5Hz),7.30(1H,s),7.01(1H,s),5.71(1H,d,J= 6.3Hz),5.63(1H,br),5.21(1H,br),4.76(1H,d,J=6.3Hz),2.39(1H,d,J=16.1Hz),2.32(3H,s),2.30(3H,s),2 .28 (3H, s), 2.18 (3H, s), 1.30-2.06 (13H, m), 1.48 (3H, s), 1.23 (3H, s), 1.18 (3H, s), 1.09 (3H, s), 0.92-0.99 (1H, m), 0.69 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.13 minutes, m / z = 701.3 [M+H] + , purity = 99.36% (214nm), 97.26% (254nm).

[0511] Example 50.

[0512]

[0513] 4-Fluorobenzenesulfide (74 mg, 0.579 mmol) was added to a solution of SM (50 mg, 0.116 mmol) in THF (3 mL). The reaction was stirred at room temperature for 1 hour. The solution changed from dark red to light red. The solution was then concentrated in vacuo to obtain a crude mixture, which was used in the next step without further purification.

[0514] Pyridine (0.5 mL) was added to Ac2O (2 mL) of the crude mixture (74.7 mg, 0.116 mmol, theoretical amount). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=3:1) to give the product as a white solid (18.2 mg, 0.0283 mmol, yield=24%).

[0515] 1 HNMRδ(400MHz,CDCl3):7.38-7.43(2H,m),6.98-7.04(3H,m),5.72(1H,d,J=6.0Hz),4.81(1H,d,J=6.0Hz),2.33(3H,s),2.31(3H,s),2.28(3H,s),1.84-2.14(6H,m),1.32-1.66(8H,m),1.44(3H,s),1.42(3H,s),1.25(3H,s),1.02-1.10(1H,m),1.06(3H,s),1.00(3H,s); LC-MS(mobile phase: A: water (0.1% TFA) B: ACN (0.1% TFA); gradient: 5% to 95% B at 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.10 minutes, m / z = 516.3 [M-FC6H4S] + , purity = 97.87% (214nm), 99.10% (254nm).

[0516] Example 51.

[0517]

[0518] 4-Hydroxyphenylsulfide (44 mg, 0.348 mmol) was added to a solution of tripterygium wilfordii (50 mg, 0.116 mmol) in MeOH (5 mL). The reaction was stirred at room temperature for 1 hour. The solution changed from red to almost colorless. The solution was then concentrated in vacuo to obtain a crude mixture, which was used in the next step without further purification.

[0519] Pyridine (0.3 mL) was added to the crude mixture (61.9 mg, 0.116 mmol, theoretical amount) in Ac2O (3 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=3:1) to give the product as a white solid (20 mg, 0.0292 mmol, yield=18%). 1 HNMRδ (400MHz, CDCl3): 7.43 (2H, d, J = 8.4Hz), 7.04 (2H, d, J = 8.4Hz), 7.03 (1H, s), 5.7 9(1H,d,J=6.3Hz),4.85(1H,d,J=6.3Hz),2.32(3H,s),2.30(6H,s),2.28(3H,s),1.82 -2.14 (6H, m), 1.32-1.66 (9H, m), 1.47 (3H, s), 1.42 (3H, s), 1.25 (3H, s), 1.02-1.10 (1H, m), 1.06 (3H, s), 1.00 (3H, s); LC-MS (mobile phase: A: water (0.1% TFA) B: ACN (0.1% TFA); gradient: 5% to 95% B in 1.2 minutes; flow rate: 2.2 ml min; column: Poroshell 120EC-C18, 4.6*30 mm, 2.7 um): rt = 2.01 minutes, m / z = 516.3 [M-MeCO2C6H4S] + , purity = 100% (214nm), 99.7% (254nm).

[0520] Example 52.

[0521]

[0522] HSCH2CH2OH (53 mg, 0.67 mmol) was added to a solution of tripterygium wilfordii (200 mg, 0.44 mmol) in MeOH (6 mL). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to obtain a crude mixture.

[0523] To the crude mixture prepared above was added pyridine (1 mL) in Ac2O (8 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL) and washed with water (2×

[0524] The residue was purified by preparative TLC (EtOAc) to give the product (20 mg, 0.0305 mmol, yield = 7%) as a white solid. 1 HNMRδ (500MHz, CDCl3): 7.02 (1H, s), 5.98 (1H, d, J = 6.0Hz), 4.63 (1H, d, J = 6.0Hz), 4.20- 4.34(2H,m),2.96-3.01(1H,m),2.74-2.83(1H,m),2.38(1H,d,J=15.5Hz),2.30(3H,s),2 .27(3H,s),2.07(3H,s),1.30-2.14(11H,m),1.58(3H,s),1.25(3H,s),1.12(3H,s),1.07 (3H,s),0.82-0.94(3H,m),0.65(3H,s); LC-MS: rt=2.33 minutes, m / z=535.3[M-MeCO2CH2CH2S] + , purity = 95.75% (214nm).

[0525] Example 53.

[0526]

[0527] K2CO3 (184 mg, 1.332 mmol) was added to a solution of celastrol (300 mg, 0.666 mmol) in DMF (3 mL), followed by CH3I (141 mg, 0.061 ml, 0.732 mmol). The reaction was stirred at room temperature for 2 hours. A lot of solids appeared. The mixture was diluted with H2O (30 mL) and filtered. The solid was dissolved with CH2Cl2 (300 mL), washed with H2O (2×100 mL) and then with brine (100 mL), dried with MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=3:1) to give the product (87.6 mg, 0.189 mmol, yield=28%) as a red-yellow solid. 1HNMRδ(400MHz,CDCl3):7.02(1H,dd,J=7.0,1.2Hz),6.96(1H,s),6.53(1H,d,J=1.2Hz),6.35(1H,d,J=7.0Hz),3.55(3H,s),2.42(1H,d,J=15.6Hz),2.18(3H,s),2.00-2.20(3H,m),1.30-1.93(10H,m),1.45(3H,s),1.26(3H,s),1.18(3H,s),1.10(3H,s),0.94-1.01(1H,m),0.53(3H,s); LC-MS(mobile phase:A:water(10mM ammonium bicarbonate)B:ACN; gradient:5% to 95% B at 1.5 minutes; flow rate: 2.0 ml / min; column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 2.77 minutes, m / z = 465.4 [M+H] + , purity = 97.25% (214nm), 99.77% (254nm).

[0528] Example 54.

[0529]

[0530] MeCOSH (51 mg, 0.67 mmol) was added to a solution of tripterygium wilfordii (200 mg, 0.44 mmol) in MeOH (20 mL). The reaction was stirred at room temperature for 0.5 hours. The solution turned from red to light yellow. The solution was then concentrated in vacuo to obtain a crude mixture.

[0531] To the crude mixture prepared above was added pyridine (1 mL) in Ac2O (8 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL) and washed with water (2×

[0532] The residue was purified by preparative TLC (EtOAc) to give the product as a white solid (131 mg, 0.214 mmol, yield = 49%). 1HNMRδ (500MHz, CDCl3): 7.02 (1H, s), 5.94&5.95 (1H, d, J = 6.4Hz), 5.36 & 5.37 (1H, d, J = 6.4Hz), 2. 39(1H,d,J=15.4Hz),2.34(3H,s),2.303&2.307(3H,s),2.269&2.273(3H,s),2.074&2.077(3H,s ),1.30-2.20(13H,m),1.438&1.451(3H,s),1.215&1.253(3H,s),1.169&1.201(3H,s),1.062&1.083(3H,s),0.90-1.00(1H,m),0.666&0.702(1H,s); LC-MS(mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA)

[0533] Gradient: 5% to 95% B in 1.7 minutes; flow rate: 2.2 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt=2.49 & 2.52 minutes, two peaks.

[0534] Example 55.

[0535]

[0536] NaBH4 (168 mg, 4.445 mmol) was added in portions to a solution of ERX1006 (200 mg, 0.445 mmol) in MeOH (10 mL). The solution turned red to colorless. The reaction was stirred at room temperature for 1 hour. The reaction was then quenched with 0.1 M HCl and acidified to pH 5 to 6 with 0.1 M HCl. The mixture was diluted with CH2Cl2 (300 mL), filtered, and separated. The organic layer was washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo to give the crude intermediate, which was used in the next step without further purification.

[0537] The crude mixture (201 mg, 0.445 mmol, theoretical amount) was added NEt (180 mg, 0.25 mL, 1.78 mmol) in CH Cl (10 mL), followed by EtCO Cl (193 mg, 0.17 mmol, 1.78 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was then diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried over MgSO and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=2:3) to give the product as a white solid (89.3 mg, 0.150 mmol, yield=34%).1 HNMRδ (400MHz, CDCl3): 7.09 (1H, s), 5.75 (1H, d, J = 6.1Hz), 5.65 (1H, br), 5.21 (1H, br), 4.31 (2H, q, J = 7.1H z), 4.31 (2H, q, J = 7.1Hz), 3.33 (1H, dd, J = 20.9, 6.1Hz), 3.06 (1H, d, J = 20.9Hz), 2.41 (1H, d, J = 15.6Hz), 2.12 (3H, s), 1.40-2.12 (13H, m), 1.38 (3H, t, J = 7.1 Hz), 1.38 (3H, t, J = 7.1 Hz), 1.33 (3H, s), 1.22 (3H, s), 1.19 (3H, s), 1.10 (3H, s), 0.94-1.10 (1H, m), 0.77 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min; column: SunFire C18, 4.6*50 mm, 3.5 um): rt = 2.39 minutes, m / z = 596.3 [M+H] + , purity = 97.29% (214nm).

[0538] Example 56.

[0539]

[0540] To a solution of ERX1006 (200 mg, 0.445 mmol) in MeOH (10 mL) was added i-PrSH (101.7 mg, 0.124 mL, 1.335 mmol). The solution turned red to pale yellow. The reaction was stirred at room temperature for 0.5 h. The solution was diluted with CH2Cl2 (200 mL), washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the crude intermediate which was used in the next step without further purification.

[0541] The crude mixture (234 mg, 0.445 mmol, theoretical amount) was added NEt3 (225 mg, 0.31 mL, 2.225 mmol) in CH2Cl2 (10 mL), followed by EtCO2Cl (241 mg, 0.21 mmol, 2.225 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was then diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=2:3) to give the product as a white solid (145.6 mg, 0.217 mmol, yield=49%). 1 HNMRδ (400MHz, CDCl3): 7.11 (1H, s), 5.97 (1H, d, J = 6.3Hz), 5.64 (1H, br), 5.18 (1H, br), 4.58 (1H, d, J = 6.3H z), 3.32 (2H, q, J = 7.2Hz), 3.31 (2H, q, J = 7.2Hz), 3.14-3.23 (1H, m), 2.40 (1H, d, J = 15.0Hz), 2.34 (3H, s), 1. 42-2.12 (13H, m), 1.56 (3H, s), 1.38 (6H, t, J = 7.2 Hz), 1.37 (3H, d, J = 6.9 Hz), 1.28 (3H, d, J = 6.9 Hz), 1.26 (3H, s), 1.19 (3H, s), 1.11 (3H, s), 0.96-1.03 (1H, m), 0.74 (3H, s); LC-MS (mobile phase: A: water (10 mM ammonium bicarbonate) B: ACN; gradient: 5% to 95% B in 1.5 minutes; flow rate: 2.0 ml min; column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 2.69 minutes, m / z = 594.2 [M-C3H7S] + , purity = 100% (214, 254nm).

[0542] Example 57.

[0543]

[0544] i-PrSH (144 mg, 0.176 mL, 1.892 mmol) was added to a solution of ERX1036 (329 mg, 0.631 mmol) in MeOH (6 mL). The reaction was stirred at room temperature for 1 hour. The mixture was then diluted with EtOAc (300 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified twice by preparative-TLC (petroleum ether / EtOAc=1:3) to give an unseparated 3:1 mixture of A and B as a yellow solid (181.8 mg, 0.304 mmol, yield=48%).

[0545] 1 HNMR: C3-OCO2Et isomers:

[0546] δ(400MHz, CDCl3):6.87(1H,s),5.97(1H,d,J=6.2Hz),5.70(1H,br),5.70(1H,s),5.26(1H, br), 4.56 (1H, d, J = 6.2Hz), 4.32 (2H, q, J = 7.2Hz), 3.11-3.22 (1H, m), 2.43 (1H, d, J = 15.1Hz), 2.30(3H,s),1.42-2.10(13H,m),1.57(3H,s),1.39(3H,t,J=7.2Hz),1.39(3H,d,J=7.0Hz),1 .27(3H,d,J=7.0Hz),1.26(3H,s),1.19(3H,s),1.11(3H,s),0.95-1.03(1H,m),0.74(3H,s).

[0547] C2-OCO2Et Isomers:

[0548] δ(400MHz, CDCl3):7.04(1H,s),5.97(1H,d,J=6.2Hz),5.70(1H,br),5.38(1H,s),5.26(1H, br), 4.60 (1H, d, J = 6.2Hz), 4.34 (2H, q, J = 7.2Hz), 3.11-3.22 (1H, m), 2.43 (1H, d, J = 15.1Hz), 2.41(3H,s),1.42-2.10(13H,m),1.57(3H,s),1.39(3H,t,J=7.2Hz),1.39(3H,d,J=7.0Hz),1 .27(3H,d,J=7.0Hz),1.26(3H,s),1.19(3H,s),1.11(3H,s),0.95-1.03(1H,m),0.73(3H,s).

[0549] LC-MS (mobile phase: A: water (10 mM ammonium bicarbonate) B: ACN

[0550] ; Gradient: 5% to 95% B in 1.5 minutes; Flow rate: 2.0 ml min; Column: XBridge C18, 4.6*50 mm, 3.5 um): rt = 2.58 minutes, m / z = 522.3 [M-C3H7S] + , purity = 97.47% (214nm).

[0551] Example 58.

[0552]

[0553] i-PrSH (118 mg, 0.144 mL, 1.551 mmol) was added to a solution of ERX1090 (277 mg, 0.517 mmol) in MeOH (6 mL). The reaction was stirred at room temperature for 1 hour. The mixture was then diluted with EtOAc (300 mL), washed with water (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified twice by preparative TLC (petroleum ether / EtOAc=1:3) to give an unseparated 3:1 mixture of A and B as a yellow solid (180.4 mg, 0.295 mmol, yield=57%).

[0554] 1 HNMR: C3-OCO2Pr-i isomer:

[0555] δ(400MHz, CDCl3):6.87(1H,s),5.97(1H,d,J=6.4Hz),5.73(1H,s),5.69(1H,br),5.29(1H, br),4.94-5.02(1H,m),4.56(1H,d,J=6.4Hz),3.10-3.22(1H,m),2.42(1H,d,J=15.6Hz),2. 30(3H,s),1.42-2.10(13H,m),1.56(3H,s),1.39(3H,d,J=6.8Hz),1.37(6H,d,J=6.8Hz),1. 27(3H,d,J=6.8Hz),1.25(3H,s),1.19(3H,s),1.11(3H,s),0.94-1.02(1H,m),0.74(3H,s).

[0556] C2-OCO2Pr-i Isomer:

[0557] δ(400MHz, CDCl3):7.04(1H,s),5.97(1H,d,J=6.4Hz),5.69(1H,br),5.42(1H,s),5.29(1H, br),4.94-5.02(1H,m),4.60(1H,d,J=6.4Hz),3.10-3.22(1H,m),2.42(1H,d,J=15.6Hz),2. 37(3H,s),1.42-2.10(13H,m),1.56(3H,s),1.39(3H,d,J=6.8Hz),1.37(6H,d,J=6.8Hz),1. 27(3H,d,J=6.8Hz),1.25(3H,s),1.19(3H,s),1.11(3H,s),0.94-1.02(1H,m),0.74(3H,s).

[0558] LC-MS (Phase: A: Water (10 mM ammonium bicarbonate) B: ACN

[0559] ; Gradient: 5% to 95% B in 1.5 minutes; Flow rate: 2.0 ml min; Column: XBridge C18, 4.6*50 mm, 3.5 um; rt = 2.62 minutes, m / z = 536.4 [M-C3H7S] + , purity = 95.39% (214nm).

[0560] Example 59.

[0561]

[0562] At 0 ° C, ERX1006 (300 mg, 0.667 mmol) was added to a solution of CH2Cl2 (6 mL) and Et3N (135 mg, 0.19 mL, 1.334 mmol) was added, followed by a 1M ClCO2Pr-i (163 mg, 1.33 mL, 1.334 mmol) solution in PhMe. The reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (300 mL), washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1: 3) to give the product as a yellow solid (302.6 mg, 0.565 mmol, yield = 85%). 1HNMRδ (500MHz, CDCl3): 7.06 (1H, dd, J = 7.4, 1.3Hz), 6.47 (1H, d, J = 1.3Hz), 6.32 (1H, d, J = 7.4Hz), 5.67 ( 1H, br),5.23(1H, br),4.93-5.01(1H,m),2.39(1H,d,J=15.4Hz),2.21(3H,s),1.82-2.14(7H,m),1.48- 1.73 (6H, m), 1.46 (3H, s), 1.39 (3H, d, J = 6.0 Hz), 1.39 (3H, d, J = 6.4 Hz), 1.27 (3H, s), 1.21 (3H, s), 0.99-1.05 (1H, m), 0.76 (3H, s); LC-MS (mobile phase: A: water (0.01% TFA) B: ACN (0.01% TFA); gradient: 5% to 95% B in 1.4 minutes; flow rate: 2.3 ml min

[0563] Column: Hypersil GOLD, 4.6*50mm, 3um): rt=2.11min, m / z=536.3[M+H] + , purity = 97.63% (214nm), 100% (254nm).

[0564] Example 60.

[0565]

[0566] K2CO3 (3.05 g, 22.06 mmol) was added to a solution of ERX1074 (2.05 g, 4.412 mmol) in Me2CO (30 mL), followed by PhCH2Br (3.77 g, 2.62 mL, 22.06 mmol). The reaction was heated at 50 °C overnight. Most of the acetone was removed in vacuo. The residue was dissolved in EtOAc (300 mL), washed with H2O (200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1) to give the product 2 (2.45 g, 4.416 mmol, Yd = 100%) as a yellow solid.

[0567] At 0°C, a 3M THF solution of MeMgBr (7.5 mL, 22.5 mmol) was added to a solution of 2 (2.5 g, 4.51 mmol) in anhydrous THF (100 mL). The reaction was stirred at 0°C for 1 hour. The reaction was quenched by adding H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=2:1) ​​to give a crude product (2.0 g, 3.53 mmol, Yd=78%) as a white solid.

[0568] The solution was hydrogenated with a hydrogen balloon. The solution was filtered through celite. After filtration, it was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to give the product ERX1095 (1.5 g, 3.26 mmol, Yd=89%) as a white solid.

[0569] Ag2CO3 (148 mg, 0.54 mmol) was added to a solution of ERX1095 (130 mg, 0.27 mmol) in benzene (5 mL). The reaction was heated at room temperature overnight. The solution was filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=2:1) ​​to give the final product (80 mg, 0.167 mmol, Yd=62%) as a red solid.

[0570] ERX1095 data:

[0571] 1 HNMRδ(500MHz, CDCl3):6.78(1H,s),5.77(1H,d,J=6.2Hz),5.15(1H,s),5.07(1H,s),3.52(3 H,s),3.44-3.50(1H,m),2.42(1H,d,J=15.7Hz),2.22(3H,s),2.14-2.20(1H,m),2.01-2.11( 2H, m), 1.80-1.89 (2H, m), 1.30-1.70 (8H, m), 1.47 (3H, s), 1.21 (3H, s), 1.16 (3H, s), 1.16 (3H, d, J = 6.8 Hz), 1.08 (3H, s), 0.91-0.97 (1H, m), 0.55 (3H, s); LC-MS: rt = 2.19 min, m / z = 481 [M+H] + , purity = 97.35% (214nm).

[0572] ERX1096 data:

[0573] 1 HNMRδ (500MHz, CDCl3): 6.28 (1H, s), 5.70 (1H, d, J = 6.0Hz), 3.58 (3H, s), 3.39 -3.46(1H,m),2.39(1H,d,J=15.7Hz),2.15-2.24(1H,m),2.02-2.10(1H,m),2. 00(3H,s),1.78-1.92(3H,m),1.59(3H,s),1.24-1.74(8H,m),1.28(3H,d,J=7 .3Hz),1.18(3H,s),1.17(3H,s),1.08(3H,s),0.93-0.98(1H,m),0.60(3H,s); 13 CNMRδ (125MHz, CDCl3): 181.32, 180.57, 178.83, 167.19, 149.49, 146.44, 132.47, 122.64, 122.32, 51.58, 44.25, 43.88, 40. 39, 38.68, 37.18, 36.59, 36.00, 34.77, 34.71, 32.75, 32.54, 31.57, 30.61, 30.48, 29.90, 28.77, 22.77, 20.50, 18.13, 11.35.

[0574] LC-MS: rt = 2.21 min, m / z = 479 [M+H] + , purity = 100% (214nm).

[0575] Example 61.

[0576]

[0577] K2CO3 (276 mg, 2.0 mmol), NaI (6 mg, 0.04 mmol) were added to a solution of ERX1018 (503 mg, 1.0 mmol) in EtOH (50 mL), followed by PhCH2Br (187 mg, 1.1 mmol). The reaction was heated at 80 °C overnight. Most of the EtOH was removed in vacuo. The residue was dissolved in CH2Cl2 (200 mL), washed with H2O (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:1) to give the product 2 (255 mg, 0.43 mmol, Yd=43%) as a yellow solid.

[0578] At 0°C, a solution of 2 (100 mg, 0.17 mmol) in anhydrous THF (10 mL) was added with a 3M THF solution of MeMgBr (0.57 mL, 1.7 mmol). The reaction was stirred at 0°C for 1 hour. The reaction was quenched by the addition of H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to give the crude product (50 mg, 0.0824 mmol, Yd=48%) as a white solid.

[0579] 10% Pd / C (5 mg) was added to a solution of crude product 3 (50 mg, 0.0824 mmol) in MeOH (10 mL). The solution was hydrogenated with a hydrogen balloon. The solution was filtered through celite. The filtered solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=1:1) to give product 4 (20 mg, 0.0385 mmol, Yd=47%) as a white solid.

[0580] To a solution of 4 (40 mg, 0.0771 mmol) in benzene (10 mL) was added Ag2CO3 (43 mg, 0.154 mmol). The reaction was heated at 60 ° C for 1 hour. The reaction was quenched by H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 10: 1) to give the final product (33 mg, 0.0637 mmol, Yd = 83%) as a red solid. 1 HNMRδ (500MHz, CDCl3): 6.27 (1H, s), 5.70 (1H, d, J = 6.4Hz), 3.58-3.68 (2H, m), 3.4 0-3.51(2H,m),3.25-3.33(1H,m),2.34-2.41(2H,m),2.09-2.18(1H,m),2.00(3H, s), 1.42-1.96 (15H, m), 1.59 (3H, s), 1.26 (3H, d, J = 7.1 Hz), 1.22 (3H, s), 1.19 (3H, s), 1.11 (3H, s), 0.93-0.99 (1H, m), 0.62 (3H, s); LC-MS: rt = 2.57 min, m / z = 518 [M+H] + , purity = 97.84% (214nm).

[0581] Example 62.

[0582]

[0583] K2CO3 (276 g, 2.0 mmol) was added to a solution of ERX1001 (478 mg, 1.0 mmol) in DMF (10 mL), followed by PhCH2Br (187 mg, 1.1 mmol). The reaction was heated at 80 °C for 2 h. The reaction was quenched with icy H2O (50 mL) and filtered. The solid was dissolved in CH2Cl2 (200 mL), washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1) to give the product 2 (300 mg, 0.528 mmol, Yd = 53%) as a yellow solid.

[0584] At 0 ° C, a 3M MeMgBr solution in THF (2.33 mL, 7.0 mmol) was added dropwise to a solution of 2 (568 g, 1.0 mmol) in anhydrous THF (20 mL). The reaction was stirred at 0 ° C for 1 hour. The reaction was quenched by adding H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=2:1) ​​to give a crude product (400 mg, 0.685 mmol, Yd=69%) as a white solid.

[0585] 10% Pd / C (58 mg) was added to a solution of crude product 3 (584 mg, 1.0 mmol) in MeOH (10 mL). The solution was hydrogenated with a hydrogen balloon. The solution was filtered through celite. After filtration, it was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=3:1) to give the product ERX1100 (450 mg, 0.911 mmol, Yd=91%) as a white solid.

[0586] Ag2CO3 (548 mg, 2.0 mmol) was added to a solution of ERX1100 (494 mg, 1.0 mmol) in benzene (20 mL). The reaction was heated at 60°C overnight. The solution was filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=3:1) to provide the final product (200 mg, 0.813 mmol, Yd=81%) as a red solid.

[0587] ERX1100 Data:

[0588] 1HNMR: δ (500MHz, d6-DMSO): 8.85 (1H, s), 7.86 (1H, s), 6.60 (1H, s), 5.73 (1H, d, J = 6.2 Hz), 3. 82-3.94(2H,m),3.32-3.40(1H,m),2.34(1H,d,J=15.2Hz),2.06(3H,s),1.91-2.09(3H,m), 1.20-1.85(10H,m),1.39(3H,s),1.17(3H,s),1.11(3H,t,J=7.2Hz),1.11(3H,s),1.06(3H, d, J=6.7Hz), 1.06 (3H, s), 0.85-0.91 (1H, m), 0.49 (3H, s); LC-MS: rt=2.85 minutes, m / z=495[M+H] + , purity = 100% (214nm).

[0589] ERX1099 data:

[0590] 1 HNMRδ (500MHz, CDCl3): 6.28 (1H, s), 5.70 (1H, d, J = 5.6Hz), 3.93-4.08 (2H, m), 3.39-3.4 6(1H,m),2.41(1H,d,J=15.6Hz),2.18-2.23(1H,m),2.01-2.09(1H,m),2.00(3H,s),1.15 -1.92(11H,m),1.59(3H,s),1.27(3H,d,J=7.2Hz),1.22(3H,t,J=7.3Hz),1.18(3H,s),1. 17(3H,s),1.08(3H,s),0.92-0.98(1H,m),0.63(3H,s); LC-MS: rt=2.81 minutes, m / z=493[M+H] + , purity = 100% (214, 254nm).

[0591] Example 63.

[0592]

[0593] K2CO3 (276 mg, 2.0 mmol) was added to a DMF (10 mL) solution of celastrol (450 mg, 1.0 mmol), followed by PhCH2Br (374 mg, 2.2 mmol). The reaction was heated at 80 °C for 2 h. The reaction was quenched with ice water (50 mL). The mixture was filtered. The solid was dissolved in CH2Cl2 (200 mL), washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3:1) to give a yellow solid product 2 (400 mg, 0.635 mmol, Yd = 64%).

[0594] At 0°C, a 3M MeMgBr solution in THF (3.3 mL, 10 mmol) was added to a solution of 2 (630 mg, 1.0 mmol) in anhydrous THF (20 mL). The reaction was stirred at 0°C for 1 hour. The reaction was quenched by adding H2O (50 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=2:1) ​​to give a crude product (500 mg, 0.774 mmol, Yd=77%) as a white solid.

[0595] 10% Pd / C (6 mg) was added to a solution of compound 3 (64.6 mg, 0.1 mmol) in MeOH (10 mL). The solution was hydrogenated with a hydrogen balloon. The solution was filtered through celite. After filtration, it was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the product ERX1101 (30 mg, 0.0644 mmol, Yd=64%) as a white solid.

[0596] Ag2CO3 (55 mg, 0.2 mmol) was added to a solution of ERX1101 (47 mg, 0.1 mmol) in benzene (10 mL). The reaction was heated at 60°C overnight. The solution was filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the final product ERX1098 (40 mg, 0.0862 mmol, Yd=86%) as a red solid.

[0597] ERX1101 Data:

[0598] 1HNMRδ(500MHz, d6-DMSO):11.9-12.2(1H,br),8.80-9.10(1H,br),7.80-8.10(1H, br),6.60(1H,s),5.72(1H,d,J=5.6Hz),2.35(1H,d,J=15.3Hz),2.05(3H,s),1.94- 2.05(3H,m),1.20-1.85(1H,m),1.38(3H,s),1.17(3H,s),1.08(3H,s),1.07(3H,s ), 1.04 (3H, s), 0.80-0.88 (1H, m), 0.65 (3H, s); LC-MS: rt=2.03 minutes, m / z=467.3[M+H] + , purity = 100% (214nm).

[0599] ERX1098 data:

[0600] 1 HNMRδ (400MHz, CDCl3): 6.27 (1H, s), 6.65 (1H, d, J = 6.5Hz), 3.36-3.45 (1H, m), 2.38(1H,d,J=13.9Hz),2.07-2.16(1H,m),2.00(3H,s),1.93-2.03(1H,m),1.3 2-1.90(13H,m),1.58(3H,s),1.29(3H,d,J=7.3Hz),1.17(3H,s),1.16(3H,s), 1.05(3H,s),0.86-0.94(1H,m),0.69(3H,s); LC-MS: rt=2.04 minutes, m / z=467[M+H] + , purity = 100% (214nm).

[0601] Example 64.

[0602]

[0603] MeCOSH (51 mg, 0.67 mmol) was added to a solution of ERX1006 (200 mg, 0.44 mmol) in MeOH (6 mL). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to give a crude mixture.

[0604] Pyridine (1 mL) was added to the crude mixture prepared above in Ac2O (8 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with EtOAc (200 mL) and washed with water (2×

[0605] The mixture was washed with 4% paraformaldehyde (0.144 g, 0.144 mmol, yield = 37%), 1% paraformaldehyde (0.144 g, 0.144 mmol), 1% paraformaldehyde (0.144 g, 0.144 mmol, yield = 37%), ... 1 HNMRδ (500MHz, CDCl3): 7.02 (1H, s), 5.94 (1H, d, J = 6.4Hz), 5.68 (1H, br), 5.45 (1 H, br),5.36(1H,d,J=6.4Hz),2.43(1H,d,J=15.9Hz),2.34(3H,s),2.31(3H,s),2 .28(3H,s),2.07(3H,s),1.45-2.06(13H,m),1.43(3H,s),1.21(3H,s),1.19(3H, s), 1.09 (3H, s), 0.96-1.02 (1H, m), 0.73 (3H, s); LC-MS: rt=1.90 minutes, m / z=610[M+H] + , purity = 97.73% (214nm).

[0606] Example 65.

[0607]

[0608] LiAlH4 (28 mg, 0.76 mmol) was added to a solution of ERX1033 (200 mg, 0.58 mmol) in THF (5.0 mL). The reaction was stirred at 0 ° C for 0.5 hours. The reaction was quenched by saturated NH4Cl solution. The solution was heated at 50 ° C in air for 2 hours. The mixture was diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product as a red solid (6 mg, 0.0122 mmol, yield=3%). 1HNMRδ (400MHz, CDCl3): 7.06 (1H, dd, J = 7.1, 0.9Hz), 6.47 (1H, d, J = 0.9Hz), 6.34 (1H, d, J = 7 .1Hz),5.68(1H,br),5.24(1H,br),5.09(1H,t,J=5.2Hz),3.98-4.10(2H,m),3.78-3.86(2H ,m), 2.39 (1H, d, J = 15.8 Hz), 2.26 (3H, s), 1.47-2.20 (13H, m), 1.45 (3H, s), 1.27 (3H, s), 1.21 (3H, s), 1.12 (3H, s), 0.99-1.06 (1H, m), 0.76 (3H, s); LC-MS: rt = 2.05 min, m / z = 494.3 [M+H] + , purity = 93.7% (214nm), 100% (254nm).

[0609] Example 66.

[0610]

[0611] To a solution of ERX1006 (200 mg, 0.444 mmol) in MeOH (20 mL) was added N-acetyl-L-cysteine ​​ethyl ester (157 mg, 0.888 mmol). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to give a crude mixture.

[0612] Ac2O (1 mL) was added to the crude mixture prepared above in pyridine (2 mL). The reaction was stirred at room temperature overnight. The mixture was then poured into H2O (100 mL) and filtered. The solid was dissolved in EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to give the product (184.2 mg, 0.259 mmol, total yield = 58%) as a white solid. 1HNMRδ (400MHz, CDCl3): 7.01 (1H, s), 6.26 (1H, d, J = 7.5Hz), 5.94 (1H, d, J = 6.3Hz), 5.65 (1H, br), 5.19 (1H, br), 4.88 ( 1H, q, J = 6.0Hz), 4.63 (1H, d, J = 6.3Hz), 3.74 (3H, s), 3.31 (1H, dd, J = 13.5, 4.8Hz), 2.93 (1H, dd, J = 13.5, 5.9Hz), 2.42 (1H,d,J=15.2Hz),2.31(3H,s),2.27(3H,s),2.25(3H,s),2.06(3H,s),1.45-2.10(13H,m),1.56(3H,s),1.26(3H,s) ,1.19(3H,s),1.11(3H,s),0.97-1.04(1H,m),0.73(3H,s); LC-MS:rt=2.00 minutes, m / z=534.4[M-SCH2CH(CO2Me)NHCOMe] + , purity = 100% (214, 254nm).

[0613] Example 67.

[0614]

[0615] i-C3H7SH (11.4 mg, 0.15 mmol) was added to a solution of ERX1033 (52 mg, 0.1 mmol) in MeOH (5.0 mL). The reaction was stirred at room temperature for 2.0 hours. The solution was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product (16 mg, 0.0268 mmol, yield=27%) as a yellow solid. 1HNMRδ(500MHz, d4-MeOD): 6.73(1H,s), 6.06(1H,d,J=6.2Hz), 4.61(1H,d,J=6.2Hz), 3.80(3H,s ),3.14-3.22(1H,m),2.47(1H,d,J=15.7Hz),2.39(3H,s),2.04-2.15(3H,m),1.79-1.95(3H,m) ,1.45-1.71(8H,m),1.54(3H,s),1.40(3H,d,J=6.6Hz),1.27(3H,s),1.25(3H,d,J=6.4Hz),1.16(3H,s),1.12(3H,s),0.92-0.98(1H,m),0.77(3H,s); LC-MS:rt=2.02min,m / z=522.2[M-C3H7S] + , purity = 94.01% (214nm), 86.66% (254nm).

[0616] Example 68.

[0617]

[0618] To a solution of ERX1006 (45 mg, 0.1 mmol) in DMF (5 mL) was added KCO (28 mg, 0.2 mmol), followed by EtI (156 mg, 1.0 mmol). The reaction was stirred at 40 ° C for 4 hours. The reaction was quenched with ice water (50 mL) and filtered. The solid was dissolved in CHCl (200 mL), washed with brine (100 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (25 mg, 0.0523 mmol, yield = 52%). 1 HNMRδ (500MHz, CDCl3): 6.94 (1H, dd, J = 7.1, 1.2Hz), 6.39 (1H, d, J = 1.2Hz), 6.28 (1H, d, J=7.1Hz),5.66(1H,br),5.20(1H,br),4.10(2H,q,J=7.1Hz),2.39(1H,d,J=16.1Hz),2 .22 (3H, s), 1.45-2.15 (13H, m), 1.44 (3H, s), 1.34 (3H, t, J = 7.0 Hz), 1.26 (3H, s), 1.20 (3H, s), 1.12 (3H, s), 0.99-1.05 (1H, m), 0.76 (3H, s); LC-MS: rt = 1.83 minutes, m / z = 478.3 [M+H] +, purity = 100% (214, 254nm).

[0619] Example 69.

[0620]

[0621] To a solution of ERX1006 (45 mg, 0.1 mmol) in DMF (5 mL) was added KCO (28 mg, 0.2 mmol) followed by i-CHI (170 mg, 1.0 mmol). The reaction was stirred at 40 °C for 4 hours. The reaction was quenched with ice water (50 mL) and filtered. The solid was dissolved in CHCl (200 mL), washed with brine (100 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (20 mg, 0.0407 mmol, yield = 41%). 1 HNMRδ (500MHz, CDCl3): 6.92 (1H, dd, J = 7.1, 1.2Hz), 6.36 (1H, d, J = 1.3Hz), 6.27 (1H, d, J = 7. 1Hz),5.68(1H,br),5.25(1H,br),4.69-4.75(1H,m),2.39(1H,d,J=15.9Hz),2.20(3H,s),1 .47-2.13 (13H, m), 1.44 (3H, s), 1.28 (3H, d, J = 6.0 Hz), 1.26 (3H, d, J = 6.0 Hz), 1.26 (3H, s), 1.20 (3H, s), 1.12 (3H, s), 0.99-1.04 (1H, m), 0.77 (3H, s); LC-MS: rt = 1.90 min, m / z = 492.4 [M+H] + , purity = 100% (214, 254nm).

[0622] Example 70.

[0623]

[0624] K2CO3 (72 mg, 0.522 mmol) was added to a solution of ERX1015 (80 mg, 0.174 mmol) in EtI (1 mL) and DMF (2 mL). The reaction was stirred at 50 °C overnight. The solution was diluted with CH2Cl2 (300 mL), washed with saturated LiCl.H2O (2×100 mL), H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=2:1) ​​to give the product as a yellow solid (33.5 mg, 0.0729 mmol, yield=42%). 1 HNMR: δ (400MHz, CDCl3): 6.96 (1H, dd, J = 7.1, 1.1Hz), 6.41 (1H, d, J = 1.2Hz), 6.31 (1H, d, J = 7.2Hz), 4.06-4.16 (2H, m), 2.22 (3H, s), 1.54-2.18 (14, m),1.47(3H,s),1.44(3H,s),1.35(3H,t,J=7.1Hz),1.29(3H,s),1.08-1. 15(1H,m),1.09(3H,s),1.05(3H,s).; LC-MS: rt=1.98 minutes, m / z=460.2[M+H] + , purity = 100% (214, 254nm).

[0625] Example 71.

[0626]

[0627] i-C3H7SH (7.6 mg, 0.1 mmol) was added to a solution of ERX1060 (30 mg, 0.0647 mmol) in MeOH (1 mL). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light reddish yellow. The solution was then concentrated in vacuo to give a crude mixture, which was used in the next step without further purification.

[0628] Pyridine (0.5 mL) was added to Ac2O (4 mL) of the crude mixture prepared above. The reaction was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (100 mL), washed with water (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 / MeOH=10:1) to give the product (5 mg, 0.00801 mmol, total yield=12%) as a light yellow solid. 1HNMR: δ (500MHz, CDCl3): 7.02 (1H, s), 6.01 (1H, d, J = 6.0Hz), 4.59 (1H, d, J = 6.1Hz), 3.1 6-3.23(1H,m),2.20-2.50(6H,br),2.31(3H,s),2.29(3H,s),2.27(3H,s),1.20-2.05( 16H, m), 1.57 (3H, s), 1.42 (3H, s), 1.41 (3H, d, J = 7.0 Hz), 1.31 (3H, d, J = 7.0 Hz), 1.22 (3H, s), 1.10 (3H, br), 0.95-1.01 (1H, m), 0.77 (3H, s); LC-MS: rt = 1.76 min, m / z = 624.3 [M+H] + , purity = 95.93% (214nm), 95.26% (254nm).

[0629] Example 72.

[0630]

[0631] To a solution of ERX1060 (70 mg, 0.15 mmol) in MeOH (1 mL) was added NaBH4 (5.7 mg, 0.15 mmol). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to give a crude mixture which was used in the next step without further purification.

[0632] Pyridine (0.5 mL) was added to Ac2O (0.5 mL) of the crude mixture prepared above. The reaction was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (100 mL), washed with water (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 / MeOH=10:1) to give the product (10 mg, 0.0182 mmol, yield=12%) as a light yellow solid. 1HNMR: δ (500MHz, CDCl3): 7.00 (1H, s), 5.80 (1H, dd, J = 6.4, 1.9Hz), 3.36 (1H, dd, J=20.5, 6.4Hz),3.09(1H,d,J=20.5Hz),2.30-2.50(6H,br),2.32(3H,s),2.20(3 H,s),2.08(3H,s),1.33-2.07(16H,m),1.39(3H,s),1.31(3H,s),1.22(3H,s),1 .11 (3H, br), 0.95-1.01 (1H, m), 0.80 (3H, s); LC-MS: rt=1.66 minutes, m / z=550.4[M+H] + , purity = 94.27% (214nm).

[0633] Example 73.

[0634]

[0635] iC3H7SH (5 mg, 0.0647 mmol) was added to a solution of ERX1060 (20 mg, 0.0431 mmol) in MeOH (1 mL). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light reddish yellow. The solution was then concentrated in vacuo to give a crude mixture, which was used in the next step without further purification.

[0636] Pyridine (0.5 mL) was added to Ac2O (0.5 mL) of the crude mixture prepared above. The reaction was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (100 mL), washed with water (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 / MeOH=10:1) to give the product (10 mg, 0.016 mmol, total yield=37%) as a light yellow solid. 1 HNMR: δ (500MHz, CDCl3): 7.03 (1H, s), 5.95 (1H, d, J = 6.4 Hz), 5.39 (1H, d, J =6.4Hz),2.26-2.50(6H,br),2.36(3H,s),2.31(3H,s),2.28(3H,s),2.08( 3H,s),1.25-2.06(16H,m),1.42(3H,s),1.37(3H,s),1.21(3H,s),1.11(3 H, br), 0.94-1.00 (1H, m), 0.77 (3H, s); LC-MS: rt=1.65 minutes, m / z=624.3[M+H] +, purity = 92.90% (214nm), 97.84% (254nm).

[0637] Example 74.

[0638]

[0639] LiAlH4 (494 mg, 13 mmol) was added to a solution of ERX1003 (90 mg, 0.174 mmol) in anhydrous THF (15 mL). The mixture was refluxed overnight. The reaction was quenched by saturated NH4Cl solution. The mixture was heated at 50 ° C for 2 hours and filtered through a thin layer of silica gel. The solid was washed with THF (3×50 mL). The combined filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 10: 1) to give the product as a red solid (10 mg, 0.0198 mmol, Yd = 11%). 1 HNMR: δ (500MHz, CDCl3): 7.03 (1H, dd, J = 7.3, 1.2Hz), 6.97 (1H, s), 6.53 (1H, d, J = 1.0H z),6.39(1H,d,J=6.9Hz),3.66(1H,t,J=4.4Hz),2.46-2.53(4H,m),2.22(3H,s),2.06- 2.20 (2H, m), 2.00-2.04 (1H, m), 1.30-1.91 (13H, m), 1.44 (3H, s), 1.40 (3H, s), 1.22 (3H, s), 1.01 (3H, s), 0.94-0.99 (1H, m), 0.79 (3H, s); LC-MS: rt = 1.60 min, m / z = 506.3 [M+H] + , purity = 100% (214, 254nm).

[0640] Example 75.

[0641]

[0642] LiAlH4 (54 mg, 1.5 mmol) was added to a solution of ERX1004 (150 mg, 0.282 mmol) in anhydrous THF (10 mL). The mixture was refluxed overnight. The reaction was quenched by saturated NH4Cl solution. The mixture was heated at 50 ° C for 2 hours and filtered through a thin layer of silica gel. The solid was washed with THF (3×50 mL). The combined filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 10: 1) to give the product as a red solid (10 mg, 0.0193 mmol, Yd = 7%). 1HNMR: δ (500MHz, CDCl3): 7.03 (1H, dd, J = 7.4, 1.4Hz), 6.96 (1H, s), 6.53 (1H, d, J = 1.0Hz), 6.39 (1H, d, J = 6.9Hz), 2.42-2.70 (8H, m), 2.37 (3H, s), 2.22 (3H,s),1.23-2.23(16H,m),1.44(3H,s),1.40(3H,s),1.21(3H,s),1.01( 3H, s), 0.93-0.99 (1H, m), 0.78 (3H, s); LC-MS: rt=1.69 minutes, m / z=519.3[M+H] + , purity = 100% (214nm), 97.88% (254nm).

[0643] Example 76.

[0644]

[0645] PhCOSH (46 mg, 0.333 mmol) was added to a solution of ERX1006 (100 mg, 0.222 mmol) in MeOH (10 mL). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to give a crude mixture.

[0646] To the crude mixture prepared above in Ac2O (4 mL) was added pyridine (0.5 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (200 mL) and washed with water (2×

[0647] The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product (50 mg, 0.0744 mmol, yield=34%) as a white solid. 1HNMR: δ (500MHz, CDCl3): 7.95 (2H, t, J = 7.4Hz), 7.56 (1H, t, J = 7.4Hz), 7.44 (2H, t, J = 7.4Hz), 7.06 ( 1H,s),6.06(1H,d,J=6.5Hz),5.68(1H,br),5.60(1H,d,J=6.5Hz),5.24(1H,br),2.44(1H,d,J=14. 9Hz), 2.30(3H,s), 2.28(3H,s), 2.12(3H,s), 1.40-2.10(13H,m), 1.51(3H,s), 1.20(3H,s), 1.19(3H,s), 1.09(3H,s), 0.96-1.02(1H,m), 0.76(3H,s); LC-MS: rt = 2.01 min, mass peak not integrated, purity = 99.59% (254nm).

[0648] Example 77.

[0649]

[0650] K2CO3 (123 mg, 0.890 mmol) was added to a solution of ERX1006 (200 mg, 0.445 mmol) in DMF (5 mL), followed by CH3CH2CH2I (756 mg, 0.43 mL, 4.45 mmol). The reaction was stirred at 50 ° C overnight. The mixture was diluted with EtOAc (200 mL), washed with saturated LiCl.H2O solution (3×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:3, twice) to give the product as a yellow solid (101 mg, 0.205 mmol, yield=46%). 1 HNMRδ (400MHz, CDCl3): 6.94 (1H, dd, J = 7.0, 1.4Hz), 6.38 (1H, d, J = 1.4Hz), 6.28 (1H, d, J=7.0Hz),5.70(1H,br),5.35(1H,br),4.00(1H,t,J=6.8Hz),2.39(1H,d,J=15.5Hz),2 .22(3H,s),1.45-2.15(15H,m),1.44(3H,s),1.26(3H,s),1.20(3H,s),1.12(3H,s),1. 00 (3H, t, J=7.6Hz), 0.98-1.05 (1H, m), 0.75 (3H, s); LC-MS: rt=1.89 minutes, m / z=492.4[M+H] +, purity = 100% (214nm), 97.59% (254nm).

[0651] Example 78.

[0652]

[0653] To a solution of ERX1006 (200 mg, 0.445 mmol) in DMF (5 mL) was added K2CO3 (123 mg, 0.890 mmol), followed by Me2CHCH2CH2I (881 mg, 0.59 mL, 4.45 mmol). The reaction was stirred at 50 °C overnight. The mixture was diluted with CH2Cl2 (200 mL), washed with saturated LiCl.H2O solution (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:3) to give the product as a yellow solid (88.8 mg, 0.171 mmol, yield=38%). 1 HNMRδ (400MHz, CDCl3): 6.94 (1H, d, J = 7.1Hz), 6.38 (1H, s), 6.28 (1H, d, J = 7.1Hz), 5 .69(1H,br),5.30(1H,br),4.06(1H,t,J=6.9Hz),2.39(1H,d,J=15.7Hz),2.21(3H, s), 1.45-2.14 (16H, m), 1.44 (3H, s), 1.26 (3H, s), 1.20 (3H, s), 1.12 (3H, s), 0.98-1.05 (1H, m), 0.94 (6H, d, J = 6.4 Hz), 0.76 (3H, s); LC-MS: rt = 2.00 min, m / z = 520.4 [M+H] + , purity = 98.46% (214nm), 98.77% (254nm).

[0654] Example 79.

[0655]

[0656] To a solution of ERX1006 (100 mg, 0.222 mmol) in DMF (10 mL) was added KCO (61 mg, 0.44 mmol) followed by iodocyclopentane (217 mg, 1.11 mmol). The reaction was stirred at 40 °C overnight. The mixture was diluted with CHCl (100 mL), washed with saturated LiCl.H0 solution (2 x 50 mL), brine (50 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (56 mg, 0.108 mmol, yield = 50%). 1 HNMRδ (500MHz, CDCl3): 6.91 (1H, dd, J = 7.0, 1.1Hz), 6.36 (1H, d, J = 1.1Hz), 6.27 (1H,d,J=7.0Hz),5.70(1H,br),5.36(1H,br),5.15-5.19(1H,m),2.39(1H,d,J=1 5.6Hz),2.18(3H,s),1.46-2.12(21H,m),1.44(3H,s),1.26(3H,s),1.20(3H,s), 1.11(3H,s),0.98-1.04(1H,m),0.76(3H,s); LC-MS: rt=1.44 minutes, m / z=518.4[M+H] + , purity = 97.22% (214nm), 99.30% (254nm).

[0657] Example 80.

[0658]

[0659] To a solution of ERX1006 (180 mg, 0.4 mmol) in DMF (10 mL) was added KCO (110 mg, 0.8 mmol) followed by allyl bromide (242 mg, 2.0 mmol). The reaction was stirred at 40 °C overnight. The mixture was diluted with CHCl (100 mL), washed with saturated LiCl.H0 solution (2 x 50 mL), brine (50 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product (98 mg, 0.2 mmol, yield = 50%) as a yellow solid. 1HNMRδ (500MHz, CDCl3): 6.95 (1H, dd, J = 7.0, 1.0Hz), 6.39 (1H, d, J = 1.0Hz), 6.28 (1H, d, J = 7.0Hz ),6.02-6.12(1H,m),5.68(1H,br),5.34(1H,dd,J=17.2,1.4Hz),5.20(1H,d,J=10.4Hz),4.60(1 H, d, J = 5.1 Hz), 2.39 (1H, d, J = 16.1 Hz), 2.21 (3H, s), 1.45-2.12 (13H, m), 1.44 (3H, s), 1.26 (3H, s), 1.20 (3H, s), 1.12 (3H, s), 0.98-1.05 (1H, m), 0.76 (3H, s); LC-MS: rt = 1.84 min, m / z = 490.2 [M+H] + , purity = 100% (214, 254nm).

[0660] Example 81.

[0661]

[0662] To a solution of ERX1006 (100 mg, 0.22 mmol) in DMF (10 mL) was added K2CO

[0663] 3 (61 mg, 0.44 mmol) was added, followed by 3,3-dimethylallyl bromide (217 mg, 1.11 mmol). The reaction was stirred at 40 ° C overnight. The mixture was diluted with CH2Cl2 (100 mL), washed with saturated LiCl.H2O solution (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (56 mg, 0.11 mmol, yield = 50%). 1HNMRδ (500MHz, CDCl3): 6.94 (1H, dd, J = 7.0, 1.1Hz), 6.38 (1H, d, J = 1.1Hz), 6.27 (1H, d, J = 7.0H z),5.72(1H,br),5.52(1H,tt,J=7.2,1.3Hz),5.46(1H,br),4.54-4.63(2H,m),2.40(1H,d,J= 15.7Hz), 2.20 (3H, s), 1.45-2.12 (13H, m), 1.75 (3H, s), 1.69 (3H, s), 1.43 (3H, s), 1.25 (3H, s), 1.20 (3H, s), 1.11 (3H, s), 0.98-1.04 (1H, m), 0.75 (3H, s); LC-MS: rt = 2.43 minutes, m / z = 518.3 [M+H] + , purity = 100% (214, 254nm).

[0664] Example 82.

[0665]

[0666] To a solution of ERX1006 (200 mg, 0.44 mmol) in DMF (10 mL) was added KCO (121 mg, 0.88 mmol) followed by propargyl bromide (263 mg, 2.23 mmol). The reaction was stirred at 40 °C overnight. The mixture was diluted with CHCl (100 mL), washed with saturated LiCl.H0 solution (2 x 50 mL), brine (50 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (100 mg, 0.205 mmol, yield = 47%). 1HNMRδ (500MHz, CDCl3): 7.00 (1H, dd, J = 7.0, 1.0Hz), 6.39 (1H, d, J = 1.0Hz), 6.30 (1H, d, J = 7.5Hz), 5.68 (1H, br), 5.34 (1H, br), 4.88 (1H, AB × d, J = 15.9, 2.4Hz), 4.85 (1H, AB × d, J = 15.9, 2.4Hz), 2.42 (1H, t, J = 2.3Hz), 2.40 (1H, d, J = 16.0Hz), 2.28 (3H, s), 1.46-2.13 (13H, m), 1.45 (3H, s), 1.26 (3H, s), 1.20 (3H, s), 1.12 (3H, s), 0.99-1.05 (1H, m), 0.76 (3H, s); LC-MS: rt=1.78 minutes, m / z=488.3[M+H] + , purity = 100% (214nm), 93.38% (254nm).

[0667] Example 83.

[0668]

[0669] Me2CHCOCl (4.0 g, 37.6 mmol) was added dropwise to a solution of NaSH (2.0 g, 35.7 mmol) in EtOH (20 mL). The solution was stirred at room temperature for 1 hour. The solution was concentrated in vacuo and used in the next step without further purification.

[0670] To a solution of ERX1006 (50 mg, 0.11 mmol) in MeOH (5 mL) was added a solution of Me2CHCOSH (23 mg, 0.22 mmol) in EtOH (2 mL). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to give a crude mixture (45 mg, 0.081 mmol, Yd = 74%).

[0671] Pyridine (1 mL) was added to the above prepared crude mixture (45 mg, 0.081 mmol) in AcO (1 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with CHCl (50 mL), washed with water (2×30 mL), brine (30 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product as a white solid (10 mg, 0.0157 mmol, yield=20%). 1HNMRδ (500MHz, CDCl3): 7.01 (1H, s), 5.92 (1H, d, J = 6.5Hz), 5.67 (1h, br), 5.34 (1H, d, J = 6.5Hz),5.24(1H,br),2.68-2.77(1H,m),2.30(3H,s),2.27(3H,s),2.06(3H,s),1.30-2. 08 (13H, m), 1.44 (3H, s), 1.20 (3H, s), 1.20 (3H, d, J = 6.7 Hz), 1.19 (3H, s), 1.19 (3H, d, J = 5.5 Hz), 1.09 (3H, s), 0.95-1.01 (1H, m), 0.74 (3H, s); LC-MS: rt = 1.99 min, m / z = 638.3 [M+H] + , purity = 96.8% (214nm), 97.11% (254nm).

[0672] Example 84.

[0673]

[0674] To a solution of ERX1006 (200 mg, 0.445 mmol) in DMF (5 mL) was added KCO (123 mg, 0.890 mmol) followed by FCHCHI (774 mg, 0.36 mL, 4.45 mmol). The reaction was stirred at 50 °C for 1 day. The mixture was diluted with EtOAc (200 mL), washed with saturated LiCl.H0 solution (3 x 100 mL), brine (100 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product (79.4 mg, 0.160 mmol, yield = 36%) as a yellow solid. 1 HNMRδ (400MHz, CDCl3): 7.00 (1H, dd, J = 7.0, 1.2Hz), 6.39 (1H, d, J = 1.0Hz), 6.30 (1H, d, J = 7 .2Hz), 5.69 (1H, br), 5.31 (1H, br), 4.66 (2H, d×t, J=47.8, 4.0Hz), 4.37 (2H, d×t, J=31.0, 4. 0Hz), 2.40 (1H, t, J = 16.1Hz), 2.25 (3H, s), 1.46-2.14 (13H, m), 1.44 (3H, s), 1.26 (3H, s), 1.20 (3H, s), 1.12 (3H, s), 0.98-1.05 (1H, m), 0.75 (3H, s); LC-MS: rt = 1.77 minutes, m / z = 496.4 [M+H]+ , purity = 98.76% (214nm), 98.72% (254nm).

[0675] Example 85.

[0676]

[0677] To a solution of ERX1006 (200 mg, 0.445 mmol) in DMF (5 mL) was added KCO (123 mg, 0.890 mmol) followed by FCHCHI (854 mg, 0.39 mL, 4.45 mmol). The reaction was stirred at 50 °C for 1 day. The mixture was diluted with EtOAc (200 mL), washed with saturated LiCl.H0 solution (3 x 100 mL), brine (100 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (72.2 mg, 0.141 mmol, yield = 32%). 1 HNMRδ (400MHz, CDCl3): 7.02 (1H, dd, J = 7.0, 1.3Hz), 6.40 (1H, d, J = 1.3Hz), 6.32 (1H, d, J = 7 .3Hz), 6.10 (1H, tt, J = 55.5, 4.1Hz), 5.68 (1H, br), 5.28 (1H, br), 4.31 (1H, td, J = 14.0, 4.0 Hz), 2.41 (1H, d, J = 15.7 Hz), 2.24 (3H, s), 1.46-2.15 (13H, m), 1.45 (3H, s), 1.27 (3H, s), 1.21 (3H, s), 1.13 (3H, s), 0.99-1.06 (1H, m), 0.76 (3H, s); LC-MS: rt = 2.19 min, m / z = 514.4 [M+H] + , purity = 100% (214, 254nm).

[0678] Example 86.

[0679]

[0680] To a solution of ERX1006 (50 mg, 0.11 mmol) in DMF (5 mL) was added K2CO3 (45 mg, 0.33 mmol) and then F3CCH2OSO2CF3 (30 mg, 0.13 mmol). The reaction was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (100 mL), washed with saturated LiCl.H2O solution (3×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (30 mg,

[0681] 0.0564 mmol, yield = 51%). 1 HNMRδ (500MHz, CDCl3): 7.04 (1H, dd, J = 7.5, 1.2Hz), 6.40 (1H, d, J = 1.2Hz), 6.31 ( 1H,d,J=7.5Hz),5.68(1H,br),5.32(1H,br),4.57(1H,q,J=8.8Hz),2.40(1H,d,J= 15.9Hz),2.24(3H,s),1.47-2.14(13H,m),1.44(3H,s),1.27(3H,s),1.20(3H,s) ,1.12(3H,s),0.99-1.05(1H,m),0.75(3H,s); LC-MS:rt=1.27 minutes, m / z=532.4[M+H] + , purity = 100% (214, 254nm).

[0682] Example 87.

[0683]

[0684] CF3CH2COCl (161 mg, 1.1 mmol) was added dropwise to a solution of NaSH (56 mg, 1.0 mmol) in EtOH (5 mL) at 0°C. The solution was stirred at room temperature for 1 hour. The solution was concentrated in vacuo and used in the next step without further purification.

[0685] To a solution of ERX1006 (50 mg, 0.11 mmol) in MeOH (5 mL) was added Et2O (2 mL) in Me2CHCOSH (80 mg, 0.55 mmol). The reaction was stirred at room temperature for 1 hour. The solution turned from red to light yellow. The solution was then concentrated in vacuo to give a crude mixture (50 mg, 0.0842 mmol, Yd = 77%).

[0686] Pyridine (1 mL) was added to the crude mixture (50 mg, 0.0842 mmol) prepared above in AcO (1 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with CHCl (50 mL), washed with water (2×30 mL), brine (30 mL), dried over MgSO and concentrated in vacuo. The residue was purified by preparative TLC (PE:EA=1:1) to give the product (11 mg, 0.0162 mmol, total yield=20%) as a white solid. 1 HNMRδ (500MHz, CDCl3): 7.04 (1H, s), 5.96 (1H, d, J = 6.4Hz), 5.68 (1H, br), 5.49 (1H, d ,J=6.4Hz),5.31(1H,br),3.35(2H,q,J=10.0Hz),2.43(1H,d,J=15.3Hz),2.31(3H,s ), 2.28 (3H, s), 2.07 (3H, s), 1.44-2.05 (13H, m), 1.43 (3H, s), 1.20 (3H, s), 1.18 (3H, s), 1.09 (3H, s), 0.95-1.01 (1H, m), 0.73 (3H, s); LC-MS: rt = 1.88 minutes, m / z = 678.2 [M+H] + , purity = 100% (214, 254nm).

[0687] Example 88.

[0688]

[0689] MeNHOMe.HCl (131 mg, 1.33 mmol), HATU (186 mg, 0.49 mmol) and DIPEA (115 mg, 0.89 mmol) were added to a solution of celastrol (200 mg, 0.44 mmol) in DMF (5 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc=1:1) to give the product as a red solid (150 mg, 0.304 mmol, yield=69%). 1HNMRδ (500MHz, CDCl3): 7.03 (1H, dd, J = 7.2, 1.1Hz), 6.96 (1H, s), 6.54 (1H, d, J = 1.1 Hz),6.35(1H,d,J=7.2Hz),3.71(3H,s),3.05(3H,s),2.81(1H,d,J=16.2Hz),2.22( 3H,s),2.04-2.32(3H,m),1.24-1.90(10H,m),1.46(3H,s),1.26(3H,s),1.22(3H,s ),1.12(3H,s),0.94-1.00(1H,m),0.50(3H,s); LC-MS: rt=2.56 minutes, m / z=494.2[M+H] + , purity = 96.78% (214nm), 91.29% (254nm).

[0690] Example 89.

[0691]

[0692] N-acetyl-L-cysteine ​​ethyl ester (393 mg, 2.22 mmol) was added to a solution of tripterygium wilfordii (500 mg, 1.11 mmol) in MeOH (20 mL). The reaction was stirred at room temperature for 1 hour. The solution changed from red to light yellow. The solution was then concentrated in vacuo to obtain a crude mixture.

[0693] Ac2O(3mL) was added to the pyridine (5mL) solution of the crude mixture prepared above. The reaction was stirred at room temperature overnight. The mixture was then poured into H2O(100mL) and filtered. The solid was dissolved in CH2Cl2(200mL), washed with water (100mL), brine (100mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to give the product (408mg, 0.573mmol, overall yield = 52%) as a white solid. 1HNMRδ (400MHz, CDCl3): 7.02 (1H, s), 6.29 (1H, d, J = 6.8Hz), 5.93 (1H, d, J = 6.1Hz), 4.89 (1H, q, J = 5.8Hz), 4.61 (1H,d,J=6.0Hz),3.73(3H,s),3.29(1H,dd,J=13.6,4.9Hz),2.92(1H,dd,J=13.6,6.0Hz),2.39(1H,d,J=15.9 Hz),2.31(3H,s),2.27(3H,s),2.23(3H,s),2.05(3H,s),1.30-2.16(13H,m),1.56(3H,s),1.25(3H,s),1.15( 3H,s),1.07(3H,s),0.89-0.97(1H,m),0.66(3H,s); LC-MS:rt=1.78 minutes, m / z=535.2[M-SCH2CH(CO2Me)NHCOMe] + , purity = 97.44% (214nm), 100% (254nm).

[0694] Example 90.

[0695]

[0696] i-PrSH (77 mg, 1.01 mmol) was added to a solution of ERX1128 (125 mg, 0.252 mmol) in MeOH (10 mL). The reaction was stirred at room temperature for 1 hour. The solution was then concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:3) to give the product. The crude product was partially oxidized in air to the starting material.

[0697] K2CO3 (70 mg, 0.504 mmol) was added to the MeOH (10 mL) solution of the crude mixture prepared above. The reaction was stirred at room temperature overnight. Most of the MeOH was removed in vacuo. The mixture was then dissolved in CH2Cl2 (200 mL), washed with water (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1: 2) to give the product as a white solid (29.4 mg, 0.0533 mmol, two-step total yield = 21%). 1HNMRδ (400MHz, CDCl3): 6.72 (1H, s), 5.98 (1H, d, J = 6.3Hz), 5.63 (1H, br), 5.16 (1H, br), 4.60 (1H,d,J=6.3Hz),4.19-4.28(4H,m),3.13-3.23(1H,m),2.39(1H,d,J=15.2Hz),2.29(3H,s), 1.43-2.10 (13H, m), 1.56 (3H, s), 1.40 (3H, d, J = 6.8 Hz), 1.28 (3H, d, J = 6.8 Hz), 1.25 (3H, s), 1.19 (3H, s), 1.11 (3H, s), 0.96-1.02 (1H, m), 0.74 (3H, s); LC-MS: rt = 2.18 minutes, m / z = 552.3 [M+H] + , purity = 99.56% (214nm), 100% (254nm).

[0698] Example 91.

[0699]

[0700] To a solution of ERX1006 (50 mg, 0.11 mmol) in CH2Cl2 (10 mL) was added Mg(ClO4)2 (7.4 mg, 0.03 mmol) followed by Boc2O (84 mg, 0.39 mmol). The reaction was stirred at 40 °C overnight. The mixture was diluted with CH2Cl2 (100 mL), washed with water (3×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (ethyl acetate) to give the product as a yellow solid (20 mg, 0.0364 mmol, yield = 33%). 1 HNMRδ (500MHz, CDCl3): 7.04 (1H, d, J = 7.2Hz), 6.46 (1H, s), 6.31 (1H, d, J = 7.2Hz), 5.66 (1H, br), 5.22 (1H, br), 2.39 (1H, d, J = 15.3Hz), 2.20 (3H, s), 1. 47-2.15(13H,m),1.54(9H,s),1.45(3H,s),1.27(3H,s),1.21(3H,s),1.12 (3H,s),0.99-1.05(1H,m),0.76(3H,s); LC-MS:rt=2.30 minutes, m / z=550.2[M+H] + , purity = 100% (214, 254nm).

[0701] Example 92.

[0702]

[0703] K2CO3 (462 mg, 3.35 mmol) was added to a solution of ERX1008 (800 mg, 1.68 mmol) in acetone (5 mL), followed by MeI (1.2 g, 8.4 mmol). The reaction was heated at 40 ° C overnight. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1: 1) to give the product 2 (530 mg, 1.078 mmol, yield = 64%) as a yellow solid.

[0704] 1.0M LiAlH4 in THF (5.4 mL, 5.4 mmol) was added to a solution of 2 (530 mg, 1.08 mmol) in THF (10 mL). The reactant was refluxed overnight. The reaction was quenched by a saturated solution. NH4Cl solution, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate = 1: 1) to give the product 3 (400 mg, 0.834 mmol, yield = 77%) as a white solid.

[0705] AcCl (651 mg, 8.4 mmol) and NEt (840 mg, 8.4 mmol) were added to a solution of 3 (400 mg, 0.84 mmol) in CH2Cl2 (10 mL). The mixture was then stirred at room temperature. Continued for 2 hours. Water was added to quench the reaction. The mixture was extracted with CH2Cl2 (3×20 mL). The combined layer was washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product 4 (190 mg, 0.364 mmol, yield=43%) as a white solid. 1 HNMRδ (400MHz, CDCl3): 6.89 (1H, s), 5.81 (1H, dd, J = 6.3, 2.1Hz), 3.72 (3H, s), 3.35 (1H, dd, J = 20.9, 6.3Hz), 3.06 (1H, dd, J = 20.9, 2.1Hz), 2.87 (6H, br), 2.33(3H,s),2.20(3H,s),1.24-2.05(19H,m),1.39(3H,s),1.29(3H,s),1.2 3(3H,s),1.02-1.08(1H,m),0.79(3H,s); LCMS:rt=1.73 minutes, m / z=522.3[M+H] + , purity = 100% (214, 254nm).

[0706] Example 93.

[0707]

[0708] Et2NH.HCl (241 mg, 2.2 mmol), HATU (418 mg, 1.1 mmol) and then DIPEA (645 mg, 5.0 mmol) were added to a solution of celastrol (450 mg, 1.0 mmol) in DMF (10 mL). The reaction was stirred overnight at room temperature. The solution was then diluted with CH2Cl2 (200 mL) and washed with saturated NaHCO3 solution. LiCl.H2O solution (2×200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product as a red solid (101 mg, 0.20 mmol, yield=20%). 1 HNMR δ (400 MHz, CDCl3): 7.03 (1H, dd, J = 7.0, 1.1 Hz), 6.95 (1H, br), 6.52 (1H, d, J = 1.1 Hz), 6.36 (1H, d, J = 7.1 Hz), 3.62-3.80 (1H, m), 3.10-3.42 (3H, m), 2.22 (3H, s), 1.98-2.40 (5H, m), 0.95-1.90 (16H, m), 1.45 (3H, s), 1.30 (3H, s), 1.26 (3H, s), 1.15 (3H, s), 0.63 (3H, s); LC-MS: rt = 1.98 min, m / z = 506.3 [M+H] + , purity = 98.77% (214nm), 100% (254nm).

[0709] Example 94.

[0710]

[0711] LiAlH4 (38 mg, 1.0 mmol) was added to a solution of ERX1137 (100 mg, 0.198 mmol) in THF (20 mL). The reactant was refluxed overnight. The reaction was quenched by saturated NH4Cl solution. The mixture was heated at 60 ° C for 3 hours. The color turned brown. The solution was then diluted with CH2Cl2 (200 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=5:1) to give the product as a black solid (30 mg, 0.061 mmol, yield=31%). 1HNMR: δ (400MHz, CDCl3): 7.04 (1H, d, J = 7.0Hz), 6.98 (1H, s), 6.54 (1H, s), 6.41 (1H, d, J = 7.0Hz), 2.90-3.20 (2H, m), 2.48-2.62 (3H, m), 2.24 (3H, s),1.30-2.20(15H,m),1.46(3H,s),1.45(3H,.s),1.27(3H,s),1.26(3H ,s),0.92-1.04(7H,m),0.81(3H,s); LC-MS:rt=1.34 minutes, m / z=492.3[M+H] + , purity = 95.35% (214nm), 100% (254nm).

[0712] Example 95.

[0713]

[0714] HATU (101 mg, 0.266 mmol) was added to a solution of celastrol (100 mg, 0.222 mmol) in DMF (5 mL), followed by DIPEA (57 mg, 0.076 mL, 0.444 mmol). The solution was stirred at room temperature for 1 hour. Piperazine (23 mg, 0.266 mmol) was then added. The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with saturated LiCl.H2O solution (2×200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product as a red solid (35 mg, 0.0675 mmol, yield=30%). 1 HNMRδ (400MHz, CDCl3): 7.02(1H,d,J=7.2Hz), 6.54(1H,s), 6.35(1H,d,J=7.2Hz), 3.55-3.75(2H,m), 2.80-2.90(3H,m), 2.28-2.39(2H,m), 2.21(3 H,s),1.25-2.25(17H,m),1.46(3H,s),1.29(3H,s),1.28(3H,s),1.14(3 H,s),0.95-1.02(1H,m),0.62(3H,s); LC-MS:rt=1.21 minutes, m / z=519.3[M+H] + , purity = 95.17% (214nm), 96.74% (254nm).

[0715] Example 96.

[0716]

[0717] To a solution of celastrol (100 mg, 0.22 mmol) in DMF (5 mL) was added 2,6-dimethylpiperazine (30 mg, 0.26 mmol), HATU (91 mg, 0.24 mmol), and then DIPEA (57 mg, 0.44 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (100 mL), washed with saturated LiCl.H2O solution (2×50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product as a red solid (60 mg, 0.11 mmol, yield=50%). 1 HNMRδ (400MHz, CDCl3): 7.03 (1H, d, J = 7.1Hz), 6.97 (1H, br), 6.55 (1H, s), 6.36 ( 1H,d,J=7.1Hz),4.00-4.60(2H,m),2.60-2.90(2H,m),2.28-2.40(2H,m),2.22(3 H,s),1.30-2.20(15H,m),1.46(3H,s),1.29(3H,s),1.27(3H,s),1.14(3H,s),1. 12 (6H, br), 0.94-1.02 (1H, m), 0.59 (3H, br); LC-MS: rt=1.38 minutes, m / z=547.3[M+H] + , purity = 100% (214, 254nm).

[0718] Example 97.

[0719]

[0720] LiAlH4 (30 mg, 0.8 mmol) was added to a solution of ERX1142 (88 mg, 0.16 mmol) in THF (10 mL). The reactant was refluxed overnight. The reaction was quenched by saturated NH4Cl solution. The mixture was heated at 60 ° C for 3 hours. The color turned brown. The solution was then diluted with CH2Cl2 (200 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=5:1) to give the product as a red solid (20 mg, 0.0375 mmol, yield=23%). 1HNMRδ(400MHz,CDCl3):7.03(1H,d,J=7.1Hz),6.53(1H,s),6.39(1H,d,J=7.1Hz),2.94-3.06(2H,m),2.65-2.74(2H,m),2.22(3H,s),0.92-2.20(21H,m),1.44(3H,s),1.40(3H,s),1.21(3H,s),1.10(6H,br),1.00(3H,s),0.78(3H,s); LC-MS:rt=1.25min,m / z=533.3[M+H] + , purity = 97.84% (214nm), 96.36% (254nm).

[0721] Example 98.

[0722]

[0723] MeNH2·HCl (220 mg, 3.3 mmol), HATU (464 mg, 1.2 mmol) were added to a solution of celastrol (500 mg, 1.11 mmol) in DMF (10 mL), followed by DIPEA (287 mg, 2.2 mmol). The reaction was stirred overnight at room temperature. The solution was then diluted with CH2Cl2 (200 mL) and washed with saturated NaHCO3 solution. The mixture was washed with LiCl.H2O solution (2×200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product as a red solid (420 mg, 0.906 mmol, yield=82%). 1 HNMRδ (400MHz, CDCl3): 7.00 (1H, dd, J = 7.2, 1.2Hz), 6.97 (1H, br), 6.53 (1H, d, J = 1. 2Hz), 6.33 (1H, d, J = 7.2Hz), 5.72 (1H, q, J = 4.7Hz), 2.67 (3H, d, J = 4.7Hz), 2.46 (1H, d, J = 15.4 Hz), 2.21 (3H, s), 1.47-2.17 (13H, m), 1.44 (3H, s), 1.26 (3H, s), 1.15 (3H, s), 1.12 (3H, s), 0.99-1.06 (1H, m), 0.62 (3H, s); LC-MS: rt = 1.66 min, m / z = 464.2 [M+H] + , purity = 99.0% (214nm), 100% (254nm).

[0724] Example 99.

[0725]

[0726] BnNHMe (363 mg, 3.0 mmol), HATU (420 mg, 1.1 mmol) were added to a solution of celastrol (450 mg, 1.0 mmol) in DMF (10 mL), followed by DIPEA (260 mg, 2.0 mmol). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with saturated LiCl.H2O solution (2×200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product as a red solid (370 mg, 0.669 mmol, yield=67%). 1 HNMRδ(400MHz, CDCl3):7.15-7.30(5H,m),7.03(1H,dd,J=7.2,1.1Hz),6.98(1H,s),6.5 3(1H,s),6.36(1H,d,J=7.2Hz),4.85(1H,br),4.00(1H,br),3.08(3H,br),2.35-2.48(2H ,m), 2.23 (3H, s), 2.06-2.18 (2H, m), 1.32-1.89 (10H, m), 1.46 (3H, s), 1.31 (3H, s), 1.29 (3H, s), 1.15 (3H, s), 0.97-1.04 (1H, m), 0.55 (3H, s); LC-MS: rt = 2.04 min, m / z = 554.2 [M+H] + , purity = 100% (214, 254nm).

[0727] Example 100.

[0728]

[0729] LiAlH4 (34 mg, 0.9 mmol) was added to a solution of ERX1150 (100 mg, 0.18 mmol) in THF (5 mL). The reactant was refluxed overnight. The reaction was quenched by saturated NH4Cl solution. The solution was then diluted with CH2Cl2 (100 mL) and filtered. The filtrate was separated, and the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in PhMe (5 mL) and Ag2CO3 (61 mg, 0.22 mmol) was added. The mixture was stirred at room temperature overnight, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:1) to give the product as a red solid (15 mg, 0.0278 mmol, yield=25%). 1 HNMRδ(400MHz, CDCl3):7.19-7.36(5H,m),7.03(1H,dd,J=7.1,0.9Hz),6.96(1H,s),6.53(1H,d,J=0.9H z), 6.38 (1H, d, J = 7.1Hz), 3.56 (1H, AB, J = 13.8Hz), 3.55 (1H, AB, J = 13.8Hz), 2.37 (1H, AB, J = 13.5Hz), 2. 23(3H,s),2.22(3H,s),2.17(1H,AB,J=13.5Hz),2.07-2.13(1H,m),1.17-1.90(15H,m),1.44(3H,s),1. 41(3H,s),1.23(3H,s),1.06(3H,s),0.91-0.97(1H,m),0.75(3H,s); LC-MS: rt=1.48 minutes, m / z=540.4[M+H] + , purity = 100% (214, 254nm).

[0730] Example 101.

[0731]

[0732] 2,2-Dimethylpiperazine (62 mg, 0.54 mmol), HATU (184 mg, 0.48 mmol) and then DIPEA (114 mg, 0.88 mmol) were added to a solution of celastrol (200 mg, 0.44 mmol) in DMF (10 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (200 mL), washed with saturated LiCl.H2O solution (2×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2 / MeOH=10:1) to give the product as a red solid (100 mg, 0.183 mmol, yield=42%). 1 HNMRδ (400MHz, CDCl3): 7.02 (1H, d, J = 7.0Hz), 6.54 (1H, s), 6.35 (1H, d, J = 7.0Hz) ),3.35-4.20(2H,br),2.95-3.10(2H,m),2.27-2.38(2H,m),2.21(3H,s),1.35- 2.20(16H,m),1.45(3H,s),1.32(3H,s),1.30(3H,s),1.19(3H,s),1.18(3H,s), 1.15(3H,s),0.95-1.02(1H,m),0.55(3H,s); LC-MS: rt=1.39 minutes, m / z=547.3[M+H] + ,purity = 97.82% (214nm), 98.76%, (254nm).

[0733] Example 102.

[0734]

[0735] To a solution of 1 (240 mg, 0.54 mmol) in THF (10 mL) and H2O (1 mL) was added LiOH.H2O (113 mg, 2.68 mmol). The reaction was heated at 50°C for 4 hours. Most of the THF was removed in vacuo. The residue was extracted with CH2Cl2 (100×3 mL). The combined extracts were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2:MeOH=5:1) to give a brown solid product (120 mg, 0.284 mmol, yield=53%). 1HNMRδ (400MHz, CDCl3): 7.03 (1H, dd, J = 7.2, 1.3Hz), 6.53 (1H, d, J = 1.3Hz), 6.37 (1H, d, J = 7.2Hz), 2.22 (3H, s), 2.12-2.18 (1H, m), 1.50 -2.05(16H,m),1.46(3H,s),1.30(3H,s),1.14(3H,s),1.10(3H,s),0.94-1.01(1H,m),0.96(3H,s); LC-MS: rt=1.43 minutes, m / z=422.3[M+H] + , purity = 100% (214, 254nm).

[0736] Example 103.

[0737]

[0738] To a solution of ERX1146 (80 mg, 0.18 mmol) in MeCN (5 mL) was added acetic acid N-hydroxysuccinimide ester (112 mg, 0.72 mmol). The reaction was stirred at room temperature overnight. The solution was filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1: 1) to give the product as a red solid (32 mg, 0.065 mmol, yield = 36%).

[0739] 1H NMR (mixture of two atropisomers) i) major isomer δ (400 MHz, d6-DMSO): 8.71 (1H, s), 7.10 (1H, d, J = 7.1 Hz), 6.40 (1H, d, J = 7.1 Hz), 6.37 (1H, s), 3.61 (1H, AB, J = 13.2 Hz), 3.00 (3H, s), 2.79 (1H, AB, J = 13.2 Hz), 2.11-2.17 (1H, s), 2.10 (3H, s), 1.98 (3H, s), 1.20-1.85 (13H, m), 1.38 (3H, s), 1.35 (3H, s), 1.17 (3H, s), 0.95 (3H, s), 0.84-0.92 (1H, m), 0.7 4 (3H, s); ii) minor isomer δ (400 MHz, d6-DMSO): 8.71 (1H, s), 7.10 (1H, d, J = 7.1 Hz), 6.40 (1H, d, J = 7.1 Hz), 6.37 (1H, s), 3.30 (1H, AB, J = 14.8 Hz), 3.08 (1H, AB, J = 14.8 Hz), 2.85 (3H, s), 2.11-2.17 (1H, s), 2.10 (3H, s), 1.99 (3H, s), 1.20-1.85 (13H, m), 1.38 (3H, s), 1.35 (3H, s), 1.22 (3H, s), 1.00 (3H, s), 0.84-0.92 (1H, m), 0.74 (3H, s). LC-MS: rt = 1.88 min, m / z = 492.3 [M+H] + , purity = 100% (214, 254nm).

[0740] Embodiment 104

[0741]

[0742] To a solution of celastrol (500 mg, 1.11 mmol) in PhMe (25 mL) was added DIPEA (430 mg, 0.57 mL, 3.33 mmol) followed by (PhO)2P(O)N3 (458 mg, 0.36 mL, 1.66 mmol). The reaction was heated at 100 °C overnight. The solution was diluted with CH2Cl2 (200 mL), washed with H2O (200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3: 1) to give the crude product as a red solid (342 mg, 0.764 mmol, yield = 69%).

[0743] To a solution of crude 2 (342 mg, 0.764 mmol) in THF (20 mL) was added EtNH2.HCl (312 mg, 3.82 mmol) and DIPEA (494 mg, 0.65 mL, 3.82 mmol). The reaction was heated at 50 °C for 3 hours. Most of the THF was removed in vacuo. The residue was dissolved in CH2Cl2 (200 mL), washed with H2O (200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 10: 1) to give the product as a red solid (233.6 mg, 0.474 mmol, yield = 62%) 1 HNMRδ (400MHz, CDCl3): 7.02 (1H, dd, J = 7.1, 1.1Hz), 6.98 (1H, s), 6.53 (1H, d, J = 1. 0Hz),6.36(1H,d,J=7.3Hz),3.96(1H,t,J=5.5Hz),3.85(1H,s),2.95-3.15(2H,m) ,2.89(1H,d,J=13.8Hz),2.21(3H,s),1.45-2.20(13H,m),1.44(3H,s),1.40(3H,s),1.27(3H,s),1.12(3H,s),1.03(3H,t,J=7.1Hz),0.94-1.01(1H,m),0.77(3H,s). LC-MS:rt=1.79min,m / z=493.3[M+H] + , purity = 100% (214, 254nm).

[0744] Embodiment 105

[0745]

[0746] EtONa (38 mg, 0.559 mmol) was added to a solution of isocyanate (50 mg, 0.112 mmol) in THF (2 mL). The reaction was heated at room temperature for 1 hour. The reaction was quenched by NH4Cl (10 mL). The mixture was diluted in CH2Cl2 (100 mL), washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 20: 1) to give the product (11.8 mg, 0.0239 mmol, yield = 21%) as a red solid. 1HNMRδ (400MHz, CDCl3): 7.03 (1H, dd, J = 7.2, 0.9Hz), 6.98 (1H, s), 6.54 (1H, d, J = 0 .9Hz),6.37(1H,d,J=7.2Hz),4.39(1H,s),3.90-4.07(2H,m),2.74(1H,d,J=14.8H z),2.22(3H,s),2.11-2.18(1H,m),1.20-2.05(12H,m),1.45(3H,s),1.37(3H,s) ,1.27(3H,s),1.14(3H,t,J=7.0Hz),1.12(3H,s),0.95-1.01(1H,m),0.75(3H,s). LC-MS: rt = 1.99 min, m / z = 494.3 [M+H] + , purity = 100% (214, 254nm).

[0747] Embodiment 106

[0748]

[0749] LiOH.H2O (220 mg, 5.24 mmol) was added to a solution of isocyanate 1 (478 mg, 1.068 mmol) in THF (20 mL) and H2O (2 mL). The reaction was heated at 50°C for 4 hours. Most of the THF was removed in vacuo. The residue was diluted in CH2Cl2 (100 mL) and washed with 0.1 M HCl (100 mL). All the solution was filtered and the organic layer was washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue and solid obtained by filtration were dissolved in 200 mL of CH2Cl2:MeOH=10:1 solution and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2:MeOH=5:1) to give the intermediate (50 mg, 0.119 mmol, yield=11%) as a brown solid.

[0750] To a solution of intermediate 2 (50 mg, 0.119 mmol) in THF (3 mL) was added acetic acid N-hydroxysuccinimide ester (93 mg, 0.594 mmol) and DIPEA (77 mg, 0.10 mL, 0.594 mmol). The reaction was stirred at room temperature overnight. Most of the THF was removed in vacuo. The residue was diluted in CH2Cl2 (100 mL), washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1:3) to give the product as a red solid (17.5 mg, 0.0377 mmol, yield=32%)1 HNMRδ (400MHz, CDCl3): 7.01 (1H, dd, J = 7.2, 1.2Hz), 6.98 (1H, s), 6.54 (1H, d, J = 1.2Hz), 6.36 (1H, d, J = 7.2Hz), 5.04 (1H, s), 2.82 (1H, d, J = 13.9Hz), 2 .21(3H,s),2.12-2.18(1H,m),1.60-2.05(12H,m),1.81(3H,s),1.45(3H, s),1.42(3H,s),1.28(3H,s),1.12(3H,s),0.97-1.03(1H,m),0.77(3H,s). LC-MS: rt = 1.81 min, m / z = 464.3 [M+H] + , purity = 100% (214, 254nm).

[0751] Embodiment 107

[0752]

[0753] PhCOSH (71 mg, 0.06 mL, 0.516 mmol) was added to a solution of ERX1168 (116 mg, 0.258 mmol) in MeOH (5 mL). The mixture immediately changed from red to light yellow. The reaction was stirred at room temperature for 10 minutes. The solution was concentrated in vacuo. The crude intermediate 2 was used in the next step without further purification.

[0754] Ac2O (1 mL) was added to a solution of intermediate 2 (155 mg, 0.258 mmol, theoretical amount) in pyridine (3 mL). The reaction was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 (100 mL), washed with saturated CuSO4·5H2O (2×100 mL), H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=2:3) and then recrystallized from MeCN (5 mL) to give the product as a white solid (59.9 mg, 0.0873 mmol, yield=34%).

[0755] 1HNMRδ(400MHz, CDCl3):7.93-7.97(2H,m),7.54-7.60(1H,m),7.41-7.48(2H,m),7 .07(1H,s),6.07(1H,d,J=6.4Hz),5.60(1H,d,J=6.4Hz),5.08(1H,s),2.77-2.86( 1H, m), 2.30 (3H, s), 2.30 (3H, s), 2.12 (3H, s), 1.81 (3H, s), 1.43-2.10 (13H, m), 1.51 (13H, s), 1.41 (3H, s), 1.20 (3H, s), 1.08 (3H, s), 0.93-1.00 (1H, m), 0.79 (3H, s). LC-MS: rt = 2.42 minutes, m / z = 686.4 [M+H] + , purity = 97.26% (214nm), 100% (254nm).

[0756] Embodiment 108

[0757]

[0758] NEt3 (105 mg, 1.04 mmol) was added to a solution of ERX1077 (220 mg, 0.52 mmol) in CH2Cl2 (10 mL), followed by Ms2O (109 mg, 0.63 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by H2O (20 mL). The solution was extracted with CH2Cl2 (3×20 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC (hexane: EtOAc = 1: 3) to give the product as a red solid (22 mg, 0.044 mmol, yield = 8.4%). 1 HNMRδ(400MHz, CDCl3):7.08(1H,s),7.02(1H,d,J=6.2Hz),6.51(1H,s),6.37(1H,d,J=6.2Hz),4.42(1H,s),2.96(3H,s),2.21(3 H,s),2.14-2.23(2H,m),1.45-2.05(12H,m),1.49(3H,s),1.46(3H,s),1.29(3H,s),1.12(3H,s),1.00-1.06(1H,m),1.00(3H,s). LC-MS: rt=1.52 minutes, m / z=500.3[M+H] + , purity = 100% (214, 254nm).

[0759] Embodiment 109

[0760]

[0761] To a solution of ERX1077 (880 mg, 2.087 mmol) in MeCN (20 mL) was added 37% HCHO solution (7.0 mL) in portions followed by NaBH3CN (656 mg, 10.44 mmol). The reaction was stirred at room temperature overnight. The solution was diluted with CH2Cl2 (200 mL), washed with 0.1 M HCl (320 mL), H2O (3×100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the crude intermediate 2 (653 mg, 1.446 mmol, yield = 69%) as a white solid.

[0762] 1 HNMR:T242-T242-H1-20160216-SP-0012627-016-CDCL3

[0763] δ(400MHz, CDCl3):6.83(1H,s),5.77(1H,d,J=4.5Hz),

[0764] 3.29 (1H, dd, J = 20.7, 6.2Hz), 3.01 (1H, dd, J = 20.3Hz), 2.63 (6H, s), 2.15 (3H, s), 2. 01(3H,s),1.25-2.00(17H,m),1.38(3H,s),1.23(3H,s),1.19(3H,s),0.67(3H,s).

[0765] To a solution of crude intermediate 2 (600 mg, 1.328 mmol) in CH2Cl2 (50 mL) was added Ag2CO3 (733 mg, 2.657 mmol). The reaction was stirred at room temperature overnight. The solution was filtered and concentrated in vacuo. The residue was purified by preparative TLC (CH2Cl2: MeOH = 5: 1) to give the product as a red solid (86 mg, 0.191 mmol, yield = 14%). 1HNMRδ (400MHz, CDCl3): 7.02 (1H, dd, J = 7.1, 1.3Hz), 6.95 (1H, s), 6.51 (1H, d, J = 7.2Hz), 6.40 (1H, d, J = 1. 2Hz),2.67(6H,s),2.22(3H,s),1.47-2.13(15H,m),1.46(3H,s),1.43(3H,s),1.27(6H,s),0.85(3H,s). LC-MS: rt=1.27 minutes, m / z=450.3[M+H] + , purity = 100% (214, 254nm).

[0766] Biological research: intraperitoneal administration

[0767] The following test compounds were studied to determine any anti-obesity effects when administered to rodents. First, the test compounds were intraperitoneally administered for many days at 50, 100, 200, 400, 500, 1000 and 2000 μg / kg dosages and 2 mL / kg dosages once daily. The test compounds were compared with mice administered with a dosing vehicle. The experiment consists of two phases: a pre-dose phase and a dosing phase. The body weight of the animals in each test group was measured once a day. Fluid samples were also collected. Tables 2 to 5 summarize the research parameters. Table 6 shows the results of the compounds tested, their administration and anti-obesity effects.

[0768] Table 2: Study parameters

[0769]

[0770]

[0771] Table 3: Pre-dose period

[0772]

[0773] Table 4: Dosage Phase

[0774]

[0775] Table 5: Fluid Sample Collection

[0776]

[0777] Abbreviation: P = before administration

[0778] Euthanize the animal by carbon dioxide (or anesthesia) followed by decapitation, bilateral thoracotomy, exsanguination, or removal of vital organs to ensure death after the last blood draw or at termination of the program. Cervical dislocation is acceptable for animals not requiring examination or gavage.

[0779] Any animal that did not proceed to study termination was discarded without an evaluation.

[0780] Descriptive statistics (n, mean, standard error of the mean, standard deviation) were performed. In addition, one-way ANOVA followed by Dunnett's post hoc test was performed for body weight (cumulative body weight change), glucose (glucose percentage change), and food consumption (cumulative food consumption). Areas under the curves (body weight, cumulative body weight change, daily body weight change, and food consumption) were calculated for the treatment groups. Appropriate comparison tests, such as one-way ANOVA and Dunnett's, were performed on the group means of the area under the curve calculations.

[0781] All procedures in this experimental guide conform to the United States Department of Agriculture (USDA) Animal Welfare Act (9 CFR Parts 1, 2, and 3); the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Research, National Academy Press, Washington, DC); and the National Institutes of Health, Office of Laboratory Animal Welfare (for NIH-funded research). Whenever possible, the procedures in this study were designed to avoid or minimize discomfort, suffering, and pain to the animals.

[0782] This nonclinical laboratory study was not intended to be performed in full compliance with the U.S. Food and Drug Administration (FDA) Good Laboratory Practice (GLP) regulations 21 CFR Part 58, but rather was performed in accordance with Covance standard operating procedures.

[0783] This study followed all applicable sections of the Guide for the Care and Use of Laboratory Animals. The procedures used in this study avoided or minimized discomfort, distress, and pain to the animals as much as possible. All procedures were described in the study protocol or written laboratory procedures. These procedures are based on the latest state-of-the-art information on proper laboratory animal use and management.

[0784] Table 6-A: In vivo activity of compounds (intraperitoneal administration)

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829] Table 6-B: Summary of compound solubility

[0830]

[0831] N / A: Not required

[0832] Test concentration 100μM (1% of DMSO)

[0833] Test system PBS (pH 7.4)

[0834] Incubate at room temperature with shaking (1000 rpm) for 1 hour

[0835] Sample size: two replicates (n=2)

[0836] Bioanalytical LC-MS / MS

[0837] Comment:

[0838] As summarized in Table 6-B, solubility values ​​less than 10 μM suggest that these compounds exhibit low solubility; solubility values ​​between 10 μM and 80 μM suggest that these compounds show moderate solubility; and solubility values ​​above 80 μM suggest that these compounds exhibit high solubility.

[0839] Table 6-C: Summary of compound solubility

[0840]

[0841] Test concentration: 100μM (1% of DMSO)

[0842] Test system: PBS (pH 7.4)

[0843] Incubation conditions: Shake at room temperature (1000 rpm) for 1 hour

[0844] Sample size: two replicates (n=2)

[0845] Bioanalysis: LC-MS / MS

[0846] Comment:

[0847] As summarized in Table 6-C, solubility values ​​less than 10 μM suggest that these compounds exhibit low solubility;

[0848] Solubility values ​​between 10 μM and 80 μM suggest that these compounds display moderate solubility;

[0849] Solubility values ​​above 80 μM indicate that these compounds exhibit high solubility.

[0850] Table 6-D: Summary of compound solubility

[0851] Test object Test system Solubility (μM) RSD Propranolol PBS (pH 7.4) 97.45 0.009432928 Ketoconazole PBS (pH 7.4) 35.7 0.007922765 Tamoxifen PBS (pH 7.4) 0.8155 0.047689605 ERX1077 PBS (pH 7.4) 16.7 0.016936689 ERX1107 PBS (pH 7.4) 11.4 0.074432293 ERX1115 PBS (pH 7.4) 0.5575 0.244792123 ERX1117 PBS (pH 7.4) 0.914 0.030945592 ERX1116 PBS (pH 7.4) 0.4705 0.368206507 ERX1121 PBS (pH 7.4) 1.55 0.018247917 ERX1169 PBS (pH 7.4) 0.1235 0.257650244 ERX1124 PBS (pH 7.4) 1.035 0.00683195 ERX1066 PBS (pH 7.4) 0.6275 0.043947672 ERX1076 PBS (pH 7.4) 6.435 0.023075746 ERX1170 PBS (pH 7.4) 13.4 0.08443066 ERX1171 PBS (pH 7.4) 3.175 0.01113554 ERX1174 PBS (pH 7.4) 3.895 0.03086217 ERX1175 PBS (pH 7.4) 4.03 0.028073718 ERX1177 PBS (pH 7.4) 49.5 0.002856997 ERX1187 PBS (pH 7.4) 91.95 0.003845061 ERX1074 (Pyrrolidone) PBS (pH 7.4) 4.19 0.067504227 ERX1188 PBS (pH 7.4) 3.3 0.051425948 ERX1037 PBS (pH 7.4) 23.5 0.02407172 ERX1047 PBS (pH 7.4) 1.13 0.08760615 ERX1060 PBS (pH 7.4) 1.11 0.025481325 ERX1006 PBS (pH 7.4) 1.145 0.018526815 ERX1015 PBS (pH 7.4) 0.7915 0.058069413 ERX1020 PBS (pH 7.4) 0.5405 0.451344754 ERX1029 PBS (pH 7.4) 1.605 0.110141243 ERX1031 PBS (pH 7.4) 8.56 0.026433898 ERX1000 (tripterygium wilfordii) PBS (pH 7.4) 3.89 0.010906531 ERX1008 PBS (pH 7.4) 0.0841 0.040358056 ERX1010 PBS (pH 7.4) 0.644 0.052703611 ERX1007 PBS (pH 7.4) 48.75 0.01595523

[0852] Biological Studies: Oral (PO) Administration 1. Overview

[0853] The aim of this study was to evaluate the test articles in diet-induced obese (DIO) mice.

[0854] Male C57BL / 6DIO mice were divided into 12 groups and groups 2 to 12 were dosed with 2 mg / kg of tripterine (ERX1000-4), ERX1006, ERX1007, ERX1037, ERX1060, ERX1077, ERX1107, ERX1149, ERX1168, ERX1177 and pyrrolidone, respectively. Animals were dosed once daily for 10 days by oral gavage with a volume of 2 mL / kg. The vehicle control contained 1% methylcellulose (400 cps) in citric acid and phosphate buffer.

[0855] Parameters assessed included mortality, clinical observations, body weight and food consumption, and glycemic assessment.

[0856] All animals survived to the scheduled termination time. Statistically significant changes in body weight, food consumption, and changes in glucose values ​​were noted for animals dosed with ERX1000-4 and ERX1168. Statistically significant changes in body weight were noted for animals dosed with ERX1006.

[0857] 2. Methods

[0858] 2.1 Test system and study design

[0859] 2.1.1 Animal specifications and adaptation

[0860] Male C57BL 6 diet-induced obese (DIO) mice were obtained from Taconic. Animals were acclimated to housing conditions for at least 1 week prior to vehicle acclimation dosing. On days 11 to 14 of the pre-dosing period, animals were acclimated to oral gavage with vehicle once daily dosing.

[0861] At the start of dosing, animals were 21 to 22 weeks of age and their body weights ranged from 29.8 to 40.1 g.

[0862] 2.1.2 Environmental conditions, diet and water

[0863] 2.1.2.1 Feeding

[0864] Animals were housed individually in shoebox cages with wood chip bedding and kennels.

[0865] 2.1.2.2 Water

[0866] Water was provided ad libitum.

[0867] 2.1.2.3 Diet

[0868] Animals were provided TD95217 ad libitum unless fasted for study procedures.

[0869] 2.1.2.4 Environment

[0870] Environmental controls were set to maintain the following animal room conditions: temperature range 68 to 79°F, relative humidity range 30 to 70%, and 12-hour light / 12-hour dark cycle. Any changes to these conditions were maintained in the original data and had no effect on the study results.

[0871] 2.1.2.5 Dietary fortification

[0872] The animals received no special food fortification.

[0873] 2.1.3 Animal identification and study allocation

[0874] Identify animals using indelible ink on tail and cage card.

[0875] Animals were assigned to the study using a computerized program designed to achieve weight balancing and group assignment.

[0876] 2.1.4 Study Design: Table 7

[0877] Groups Test object Dosage (mmg / kg) Animal No. 1 Carrier 0 15 2 ERX10004 2 610 3 ERX1006 2 1115 4 ERX1007 2 1620 5 ERX1037 2 2125 6 ERX1060 2 2630 7 ERX1077 2 3135 8 ERX1107 2 3640 9 ERX1149 2 4145 10 ERX1168 2 4650 11 ERX1177 2 5155 12 Pseudomonas aeruginosa 2 5660

[0878] 2.2 Test objects and carriers

[0879] 2.2.1 Test objects

[0880]

[0881] 2.2.2 Carrier

[0882] The vehicle was 1% methylcellulose (400 cps) in citric acid and phosphate buffer.

[0883] 2.2.3 Test Items Formulations Formulations

[0884] Test article formulations were prepared twice according to the mixing procedure. Dosage concentrations were based on the test article as provided.

[0885] The dosage formulation was kept refrigerated and protected from light.

[0886] 2.3 Survival Phase Procedure

[0887] 2.3.1 Dosage

[0888] The dose formulation was administered by oral gavage once daily for 10 days in a dose volume of 2 mL / kg. Dosage was based on the most recently recorded planned body weight.

[0889] 2.3.2 Weight

[0890] Body weights were recorded daily during the pre-dose period on days 11 to 14. Pre-dose Body weights were collected daily for all animals during the dosing period.

[0891] 2.3.3 Food consumption

[0892] Quantitative assessments of food consumption were recorded daily on days 11 to 14 of the pre-dosing phase and prior to dosing during the dosing phase.

[0893] 2.3.4 Blood glucose level

[0894] Blood was collected from all animals for blood glucose by tail clip on day 14 of the pre-dose phase and on day 11 of the dosing phase after a 6-hour fast. One drop of blood from each animal was placed in two different The Aviva blood glucose meter is used to assess the glucose value and, if necessary, a third value is taken.

[0895] 2.4 Terminal Programs

[0896] All animals were anesthetized with carbon dioxide, sacrificed and discarded without evaluation on day 11.

[0897] 2.5 Data evaluation and statistical analysis

[0898] Descriptive statistics (n, mean, standard error of the mean, standard deviation) were performed. In addition, one-way ANOVA followed by Dunnett's post hoc test was performed for body weight (cumulative weight change), glucose (percent change in glucose), and food consumption (cumulative food consumption). Areas under the curves were calculated for treatment groups (body weight, cumulative weight change, daily weight change, and food consumption). Appropriate comparison tests, such as one-way ANOVA and Dunnett's, were performed on the group means of the area under the curve calculations. Any additional statistical analysis and interpretation of the results are the responsibility of the sponsor.

[0899] result

[0900] 3.1 Survival stage assessment

[0901] 3.1.1 Animal fate

[0902] The animal fate data are listed in Tables 11-1 to 11-12.

[0903] All animals survived until the planned termination time.

[0904] 3.1.2 Clinical observation

[0905] No changes in clinical status were noted for any treatment group.

[0906] 3.1.3 Weight

[0907] The weight data are summarized in Tables 9-1 to 9-12 and Figure 1-5 Personal data are listed in Tables 12-1 to 12-36 and Figure 10-12 (Daily weight, daily weight change and cumulative weight change).

[0908] ERX1000-4 demonstrated statistically significant decreases in the area under the curve (AUC) for daily and cumulative body weight change compared to the control group.

[0909] ERX1168 demonstrated statistically significant decreases in the area under the curve (AUC) for daily and cumulative body weight change compared to control.

[0910] ERX1008 resulted in a statistically significant decrease in cumulative body weight change compared to the control group.

[0911] 3.1.4 Food consumption

[0912] Food consumption data are summarized in Tables 10-1 to 10-6 and Figures 6 to 7 Personal data in Figures 13 to 14 Presented in.

[0913] There was a statistically significant decrease in cumulative food intake in the ERX1000-4 group compared to the control group.

[0914] ERX1168 showed statistically significant decreases in the area under the curve (AUC) of cumulative food intake and cumulative food intake compared with the control group.

[0915] 3.1.5 Blood glucose concentration

[0916] Blood glucose data are summarized in Figures 8 to 9 Personal data in Figures 15 to 17 Presented in.

[0917] ERX1000-4 produced a statistically significant decrease in percent change in glucose values ​​compared to the control group.

[0918] ERX1168 produced a statistically significant decrease in percent change in glucose values ​​compared to the control group.

[0919] 4. Related research information

[0920] 4.1 Research bias

[0921] 4.1.1 Experimental Guidelines Deviation

[0922] Table 8

[0923]

[0924] These research biases neither affect the overall interpretation of the findings nor the integrity of the study.

[0925] 5. Summary of results

[0926] Table 9: Summary of in vivo activity of compounds (PO dosing).

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997] 6. Experimental Guide

[0998] 6.1 Test subjects and study design

[0999] Table 13

[1000] Study Design

[1001] Groups Test subjects Dosage (mg / kg) Animal No. 1 Carrier 0 1-5 2 ERX1000 2 6-10 3 ERX1006 2 11-15 4 ERX1007 2 16-20 5 ERX1037 2 21-25 6 ERX1060 2 26-30 7 ERX1077 2 31-35 8 ERX1107 2 36-40 9 ERX1149 2 41-45 10 ERX1168 2 46-50 11 ERX1177 2 51-55 12 Pseudomonas aeruginosa 2 56-60

[1002] The vehicle contained 1% methylcellulose (400 cps) in citrate / phosphate buffer.

[1003] 6.2. Dosage Preparation Details

[1004] Table 14

[1005]

[1006]

[1007] 6.3 Test animals and husbandry details

[1008] Table 15

[1009]

[1010]

[1011] 6.4 Survival Phase Parameters

[1012] 6.4.1 Pre-dose phase

[1013] Table 16

[1014]

[1015] 6.4.2. Drug administration phase

[1016] Table 17

[1017]

[1018]

Claims

1. A compound of formula (I): in The dashed lines between C1 and C2, C2 and R3, C3 and R4, C5 and C6, C5 and C7, C1 and C6 and C3 and C4 indicate that single or double chains may exist if valency permits; R1 is -CN, -COOH, -COOCH2CH3, -CONHR5, -CONR5R5, -COOR5, -COOCH3, -CH2NR5R5, -CH2OCONR5R5, -CH2NR5COOR5, -CH2R5, -CH2NR5CONR5R5, -CH2OH, -CH2OR5, alkyl sulfate, alkyl sulfonate, alkyl phosphate, -CH2OSO3R5, -CH2OSO2R5, -CH2OPO3R5R5, -CH2OPO3HR5, - CH2OPO3H2-C(=NR5)NR5R5, -NR5C(=NR5)NR5R5, -CONH2, -CH2CONR5R5, -SR5, -SO3R5, -SO2R5, -CH2NHCOR5, -CH2NHCN R5NR5R5, -CH2COSR5, CH2NR5COR5, -CH2NR5CNR5NR5R5, -CH2NR5COSR5, -CH2NHSO2R5, -CH2NR5SO2R5, -CHNR5, -CHNOR5 , -H, -NH2, -NHR5, -NR5R5, -OH, -OR5, phosphate, -OPO3R5R5, -OPO3HR5, -OPO3H2, -NCO, -NCS, -N3, -R5, -C≡CR5, -(CH=CH)R5, -SH, -SR5, -SO2H, -SO3H, -SO2NR5R5, -SO3R5, -NHCOR5, -NHCNR5NR5R5, -NHCOSR5, secondary amide, tertiary amide, -NR5COR5, -NR5C(=NH)NR 5R5, -NR5COSR5, -NHC(=NR5)R5, -NR5C(=NR5)R5, -NHSO2(NH2), -NHSO2R5, -NR5SO2R5, -NR5SO2NR5R5, -OCOR5, -OCONR5R5, -O(C=O)OR5, -SCOR5, -O(C=NH)NR5R5, -OCSNHR5, -OS(=O2)R5, -OS(=O2)NR5R5, -SCONR5R5, -CH2-aryl, -CH2-heteroaryl, R2 is -H, -CH3, -SCH(CH3)2, -SC(=O)CH3, -SC(=O)R5, –SCH2CH2OCOCH3, -SR5, -SOR5, -SOOR5, -SCONR5R5, When there are double bonds between C1 and C2, C3 and C4, and C5 and C6, R3 is –OCOCH3, –OCOOCH2CH3, –OR7, –R7, or –NR5R5; When there are double bonds between C1 and C2, C3 and C4, and C5 and C6, R4 is –OCOCH3, –OCOOCH2CH3, –OR7, –R7, or –NR5R5; When R4 is O and there are double bonds between C2 and R3 and between C3 and R4, R3 is O; When R3 is O and there is a double bond between C2 and R3, R4 is -OCH3, -OP(=O)(OCH3)2, -OH, -OCOOCH2CH3, -OCONHCH2CH3, -OCOOCH(CH3) 2、 -OR7, -R7 or -NR5R5; R3 and R4 may also be combined to form a heterocyclic ring or a carbocyclic ring; R5, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, amino, or heteroaryl, optionally substituted with substituents each selected from alkyl, alkoxy, cycloalkyl, ether, amino optionally substituted with one or more alkyl groups, halogen, hydroxy, ether, cyano, nitrile, CF3, ester, amide, cycloalkylamide, sugar, heteroarylamide optionally substituted with alkyl and / or alkoxy, urea, carbamate, thioether, sulfate, sulfonyl, sulfonic acid carboxylic acid, and aryl, or two R5 groups taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with substituents each selected from alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, heteroaryl, amino, halogen, hydroxy, ether, nitrile, cyano, nitro, CF3, esteramide, urea, carbamate, thioether, or carboxylic acid; and R7 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl or heteroaryl, optionally substituted with substituents each selected from alkyl, cycloalkyl, ether, ammonia, halogen, hydroxy, ether, nitrile, cyano, nitrile, CF3, ester, amide, urea, carbamate, thioether or carboxylic acid, or a pharmaceutically acceptable salt or a prodrug thereof.

2. The compound according to claim 1, wherein R1 is -NR5C(=NR5)NR5R5, -SR5, -SO3R5, -SO2R5, -NH2, -NHR5, -NR5R5, -OH, -OR5, -NCO, -NCS, -N3, -SH, -SR5, -SO2H, -SO3H, -SO2NR5R5, -SO3R5, -NHCOR5, -NHCNR5NR5R5, -NHCOSR5, -NR5COR5, -N R5C(=NH)NR5R5, -NR5COSR5, -NHC(=NR5)R5, -NR5C(=NR5)R5, -NHSO2(NH2), -NHSO2R5, -NR5SO2R5, -NR5SO2NR5R5 , -OCOR5, -OCONR5R5, -O(C=O)OR5, -SCOR5, -O(C=NH)NR5R5, -OCSNHR5, -OS(=O2)R5, -OS(=O2)NR5R5, -SCONR5R5.

3. The compound according to claim 1, wherein R1 is NH(CO)R5. The compound according to claim 3 , wherein R 5 is alkyl, cycloalkyl or aryl.

5. The compound according to claim 3, wherein R5 is CH3.

6. The compound of claim 3, wherein when R3 is O and there is a double bond between C2 and R3, R2 is H; and R4 is -OH, -OR7 or -R7.

7. The compound of claim 2, wherein the compound is selected from the group consisting of: as well as 8. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, wherein R1 is NHCOR5.

10. The pharmaceutical composition according to claim 8, wherein R5 is an alkyl group, a cycloalkyl group or an aryl group. The pharmaceutical composition according to claim 8 , wherein the composition is for oral administration.

12. The pharmaceutical composition according to claim 11, wherein the composition comprises at least one compound selected from the group consisting of: as well as 13. The pharmaceutical composition according to claim 8, wherein the composition is administered intraperitoneally.

14. The pharmaceutical composition of claim 13, wherein the composition comprises at least some compounds selected from the group consisting of: as well as 15. The pharmaceutical composition according to claim 8, wherein the composition has higher oral bioavailability than that of tripterygium wilfordii.

16. A method for treating obesity in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1.

17. A method for treating an obesity-related disease or condition comprising administering the composition of claims 8 to 15 to a subject suffering from or at risk of suffering from an obesity-related disease or condition.

18. The method of claim 17, wherein the obesity-related disease or condition is selected from obesity, pre-obesity, morbid obesity, Prader-Willi syndrome, obesity associated with hypothalamic damage, non-alcoholic steatohepatitis, hyperlipidemia, hypertension, diabetes, lipodystrophy, fatty liver, Budd-Bieder syndrome, Cohen syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome and MOMO syndrome.

19. The method of claims 16 to 17, wherein the compound or the composition is administered in combination with another therapy.

20. The method of claims 16 to 17, wherein the administration comprises oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intra-disease site administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, insufflation administration, suppository administration, inhalation administration, or subcutaneous administration.

21. The method of claims 16-17, wherein the composition is administered in a form selected from the group consisting of tablets, capsules, troches, granules, powders, salts, crystals, liquids, serums, syrups, suspensions, gels, creams, pastes, films, patches and vapors.

22. The method of claims 16-17, wherein the subject is a mammal.

23. The method of claim 22, wherein the subject is a human.

24. The method of claim 23, wherein the subject has a body mass index (BMI) greater than 30 kg / m 2 of human beings.

25. The method of claims 16 to 17, wherein the compound or the composition is administered orally.

26. The method of claims 16-17, wherein the compound or the composition is administered orally at a dose of about 0.1 to about 0.5 mg / kg, about 0.1 to about 1 mg / kg, about 0.1 to about 5 mg / kg, about 0.1 to about 10 mg / kg.

27. A composition comprising a compound of formula (II): Where R1 is OR a or NR a R b , where each R a and R b R5, -(=NR5)NR5R5, -CO, -CS, -COR5, -CNR5NR5R5, -COSR5, -C(=NH)NR5R5, -C(=NR5)R5, -SO2(NH2), -SO2R5, -SO2R5, -SO2NR5R5, -COR5, -CONR5R5, -(C=O)OR5, -(C=NH)NR5R5, -CSNHR5, -S(=O2)R5 or -S(=O2)NR5R5; and R5, at each occurrence, is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, amino, or heteroaryl, optionally substituted with substituents each selected from alkyl, alkoxy, cycloalkyl, ether, amino optionally substituted with one or more alkyl groups, halogen, hydroxy, ether, cyano, nitrile, CF3, ester, amide, cycloalkylamide, sugar, heteroarylamide optionally substituted with alkyl and / or alkoxy, urea, carbamate, thioether, sulfate, sulfonyl, sulfonic acid carboxylic acid, and aryl, or two R5 groups taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with substituents each selected from alkyl, cycloalkyl, alkoxy, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, heteroaryl, amino, halogen, hydroxy, ether, nitrile, cyano, nitro, CF3, esteramide, urea, carbamate, thioether, or carboxylic acid; and A pharmaceutically acceptable salt or a prodrug thereof.

28. The composition according to claim 27, wherein R1 is NR a R b .

29. The composition of claim 27, wherein R1 is NHCOR5.

30. The composition of claim 29, wherein R5 is alkyl, cycloalkyl or aryl.

31. The composition of claim 27, comprising at least one compound selected from the group consisting of: as well as 32. A method for treating an obesity-related disease or condition comprising administering to a subject suffering from or at risk of suffering from an obesity-related disease or condition the composition of claims 27 to 31.

33. The method of claim 32, wherein the obesity-related disease or condition is selected from obesity, pre-obesity, morbid obesity, Prader-Willi syndrome, obesity associated with hypothalamic damage, non-alcoholic steatohepatitis, hyperlipidemia, hypertension, diabetes, lipodystrophy, fatty liver, Budd-Bieder syndrome, Cohen syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome and MOMO syndrome.

34. The method of claim 32, wherein the composition is administered in combination with another therapy.

35. The method of claim 32, wherein the administration comprises oral administration, intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intra-disease site administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, insufflation administration, suppository administration, inhalation administration, or subcutaneous administration.

36. The method of claim 32, wherein the composition is administered in a form selected from the group consisting of tablets, capsules, troches, granules, powders, salts, crystals, liquids, serums, syrups, suspensions, gels, creams, pastes, films, patches, and vapors.

37. The method of claim 32, wherein the subject is a mammal.

38. The method of claim 37, wherein the subject is a human.

39. The method of claim 38, wherein the subject has a body mass index (BMI) greater than 30 kg / m 2 of human beings.

40. The method of claim 32, wherein the composition is administered orally.

41. The method of claim 32, wherein the composition is orally administered at a dose of about 0.1 to about 0.5 mg / kg, about 0.1 to about 1 mg / kg, about 0.1 to about 5 mg / kg, or about 0.1 to about 10 mg / kg.

42. A kit comprising the compound of claims 1 to 7.

43. The kit of claim 42, further comprising an oral applicator.

44. The kit of claim 42, further comprising an intraperitoneal applicator.

45. A kit comprising the composition of claims 27 to 31.

46. ​​The kit of claim 45, further comprising an oral applicator.

47. The kit of claim 45, further comprising an intraperitoneal applicator.

Images