Compounds for the prevention and treatment of obesity and related disorders

Abstract

In certain aspects, provided herein are methods of treating or preventing obesity, assisting or inducing weight loss, suppressing appetite, or suppressing weight gain in a subject by administering to the subject a compound of the invention.

Description

Technical Field

[0001] The present invention relates to the use of compounds for treating and / or preventing obesity, inducing weight loss and / or suppressing appetite.

[0002] background

[0003] Obesity is a common clinical disorder in highly developed and emerging countries. More than 300 million adults worldwide are considered clinically obese. A large amount of clinical and epidemiological evidence accumulated to date also shows that obesity is associated with cardiovascular disease, hypertension and diabetes.

[0004] The National Institutes of Health recommends defining obesity as a body mass index (or "BMI") of 30 and above. BMI is closely related to total body fat content in adults. BMI is calculated mathematically by dividing a subject's weight (in kilograms) by the subject's height (in meters squared). A BMI of 30 generally indicates that a subject is 30 pounds overweight.

[0005] Despite all the existing research, the number of methods for producing meaningful weight loss in obese people appears to be very limited. Summary of the invention

[0006] In certain aspects, provided herein are methods for treating or preventing obesity, assisting or inducing weight loss, suppressing appetite, and / or suppressing weight gain in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., sometimes referred to herein as a compound of the present invention). In certain embodiments, the compounds of the present invention comprise the structure of any one of Formulas I to IV disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In certain embodiments, the compounds of the present invention are included in a pharmaceutical composition. In certain embodiments, the compounds of the present invention comprise the structure of Formula IV; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0007]

[0008] In certain embodiments, the subject is a human. In certain embodiments, the compound of the present invention is administered at a dosage of 0.1 mg / kg to 100 mg / kg. In certain embodiments, the compound of the present invention is administered at a dosage of 5 mg / kg to 100 mg / kg. In certain embodiments, the compound of the present invention is administered once a day or twice a day. In certain embodiments, the compound of the present invention is administered orally or intravenously. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The figures illustrate embodiments of the technology and are not intended to be limiting.

[0010] Figure 1A and 1B Shown is a graphical representation of mean body weight (y-axis) over time (x-axis; study days) for beagle dogs treated with 1 mg / kg / day (triangles), 10 mg / kg / day (circles), 30 mg / kg / day (stars) of J147, or with a control (i.e., 0 mg / kg / day of J147; squares). Figure 1A Mean weight values ​​for male dogs are shown. Figure 1B Mean weight values ​​for female dogs are shown.

[0011] Figure 1C and 1D Shown is a graphical representation of mean body weight (Y-axis) of beagle dogs during the recovery phase (i.e., after the last treatment was administered) over time (x-axis; study days) for dogs previously treated with 30 mg / kg / day of J147 (triangles) or with a control (i.e., 0 mg / kg / day of J147; squares). Figure 1C Mean weight values ​​for male dogs are shown. Figure 1D Mean weight values ​​for female dogs are shown.

[0012] Figure 2A and 2B Shown is a graphical representation of food consumption (y-axis; grams / day) over time (x-axis; study days) in beagle dogs treated with 1 mg / kg / day (triangles), 10 mg / kg / day (circles), 30 mg / kg / day (stars) of J147, or with a control (i.e., 0 mg / kg / day of J147; squares). Figure 2A Average food consumption for male dogs is shown. Figure 2B Mean food consumption for female dogs is shown.

[0013] Figure 2C and 2D Shown is a graphical representation of food consumption (Y-axis; grams / day) of beagle dogs during the recovery phase (i.e., after the last treatment was administered) over time (x-axis; study days) in dogs previously treated with 30 mg / kg / day of J147 (triangles) or with a control (i.e., 0 mg / kg / day of J147; squares). Figure 2C Average food consumption for male dogs is shown. Figure 2D Mean food consumption for female dogs is shown. DETAILED DESCRIPTION OF THE INVENTION

[0015] Provided herein are compounds useful for treating and / or preventing obesity, inducing weight loss, preventing weight gain, and / or suppressing appetite.

[0016] Compound

[0017] In certain embodiments, the compounds of the present invention comprise the structure of Formula I; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0018]

[0019] In certain embodiments of Formula I, R 2 is hydrogen (H) or methyl; R 3 L is methyl, fluoro-substituted alkyl (e.g., fluoromethyl, difluoromethyl or trifluoromethyl) or bromo-substituted alkyl (e.g., bromomethyl, dibromomethyl, tribromomethyl); 3 is a carbonyl group; and R 6 is independently selected at each occurrence from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, hydroxy, methoxy, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, mercapto, alkylthio, arylthio, carbonyl, carboxyl, aryl, substituted aryl, substituted heterocyclyl, halogen, cyano, cyanoalkyl, amine, methylamine, dimethylamine, nitro, amino, amidino, carbamate, CF3, OCF3, S(O) n R 7 and C(O)R 8 , or two R in adjacent positions 6 to form an optionally substituted heteroaryl or heteroalkyl ring fused to an adjacent phenyl moiety; wherein R 7 Selected from H, R 9 、NH2、HNR 9 and NR 9 R 10 ; R 8 Selected from OH, OR 9 、NH2、NHR 9 and NR 9 R 10 ; where R 9 and R 10 is independently at each occurrence optionally substituted alkyl; and n is 1 or 2.

[0020] In certain embodiments of Formula I, R 6 is independently selected at each occurrence from alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxy, alkoxy, methoxy, substituted alkoxy, halogen, carbonyl, carboxyl, or C(O)R 8 ; and in some such respects, R 6 is methyl, methoxy, perfluoromethyl, perfluoromethoxy, hydroxy, Cl, F, or I at each occurrence. In certain embodiments of Formula I, L 3 is a carbonyl group, R 3 It is CF 3 , R 2 is H, and R6 is absent or is H at each occurrence. In certain embodiments of Formula I, L 3 is a carbonyl group, R 3 It is CF3, R 2 is H, and R 6 In certain embodiments of Formula I, L is independently selected from methyl or methoxy at each occurrence. 3 is a carbonyl group, R 3 It is CF3, R 2 is a methyl group, and R 6 is independently selected at each occurrence from methyl or methoxy.

[0021] In certain embodiments, the compounds of the present invention comprise the structure of Formula II; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,

[0022]

[0023] in:

[0024] (i)R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is a methyl group, and R B4 It is methyl;

[0025] (ii) R A2 , R A3 , R A5 and R A6 Yes H, R A4 is methoxy, R B2 is a methyl group, and R B4 It is methyl;

[0026] (iii) R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is H, and R B4 It is H;

[0027] (iv) R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is a methyl group, and R B4 It is methyl;

[0028] (v)R A2 , RA4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is H, and R B4 It is H;

[0029] (vi)R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is H, and R B4 It is methyl;

[0030] (vii) R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is H, and R B4 It is methyl;

[0031] (viii) R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is a methyl group, and R B4 It is H;

[0032] (ix)R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is a methyl group, and R B4 It is H;

[0033] (x)R A2 , R A3 , R A5 and R A6 Yes H, R A4 is COOH, R B2 is a methyl group, and R B4 It is methyl;

[0034] (xi)R A2 , R A4 and R A5 Yes H, R A3 and R A6 is hydroxyl, R B2 is a methyl group, and R B4 It is methyl;

[0035] (xii)R A2 , R A4 and R A6 Yes H, R A3 and R A5 is hydroxyl, R B2 is a methyl group, and R B4 It is methyl;

[0036] (xiii)R A2 , R A4 and R A5 Yes H, R A3 is methoxy, R A6 It's F, R B2 is H, and R B4 It is Cl;

[0037] (xiv)R A3 and R A5 Yes H, R A2 and R A6 It's F, R A4 is hydroxyl, R A6 It's F, R B2 is H, and R B4 It is F;

[0038] (xv)R A2 , R A4 and R A6 Yes H, R A3 is hydroxyl, R A5 It's F, R B2 is H, and R B4 is F; or

[0039] (xvi)R A2 , R A5 and R A6 Yes H, R A3 and R A4 Together they are -O-CH2-O-, R A5 It's F, R B2 is H, and R B4 It's F.

[0040] In certain embodiments of the compound of Formula II, R A2 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 and R B4 is a methyl group, and R A4 is selected from H, NO2, OH, methoxy, phenol, methyl, fluorine (F), N(CH3)2, CHC(CN)2 and O-tert-butyldimethylsilyl (OTBDMS). In certain embodiments of the compound of formula II, RA2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is a methyl group, and R B4 In certain embodiments of the compound of Formula II, R A2 , R A3 , R A5 and R A6 Yes H, R A4 is methoxy, R B2 is a methyl group, and R B4 In certain embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is a methyl group, and R B4 In certain embodiments of the compound of Formula II, R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is H, and R B4 is H. In certain embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is H, and R B4 In certain embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is H, and R B4 In certain embodiments of the compound of Formula II, R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is H, and R B4 In certain embodiments of the compound of Formula II, R A2 , R A4 , R A5 and R A6 Yes H, R A3is methoxy, R B2 is a methyl group, and R B4 is H. In certain embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is a methyl group, and R B4 is H. In certain embodiments of the compound of Formula II, R A2 , R A3 , R A5 and R A6 Yes H, R A4 is carboxyl, R B2 is a methyl group, and R B4 In certain embodiments of the compound of Formula II, R A2 , R A4 , R A5 and R A6 Yes H, R A3 is carboxyl, R B2 is a methyl group, and R B4 It's methyl.

[0041] In certain embodiments, the compounds of the invention comprise the structure of Formula III; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

[0042]

[0043] Wherein R1 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl or tribromomethyl; R2 is methyl, methoxy, hydroxyl, halogen, CF3, OCH3, OCF3 or OCBr3; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen (e.g., Cl, F or Br), methyl, methoxy and amine. In certain embodiments of formula III, R1 is CF3 (trifluoromethyl), R2 is OCH3, and R3 and R4 are methyl. In certain embodiments of formula III, R1 is CF3 (trifluoromethyl), R2 is OCF3, and R3 and R4 are methyl.

[0044] In certain embodiments, the compounds of the present invention comprise the structure of Formula IV below, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof

[0045]

[0046] The structure of Formula IV is sometimes referred to herein as "J147".

[0047] The following terms have the respective definitions set out below.

[0048] "Alkyl" means a straight or branched chain alkyl residue having from about 1 up to about 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, etc.). "Substituted alkyl" means an alkyl further bearing one or more (e.g., 1, 2, 3, 4, or even 5) substituents as described herein. "Optionally substituted alkyl" means an alkyl or substituted alkyl.

[0049] "Cycloalkyl" means a group containing a cyclic ring, the group containing carbon atoms in the range of about 3 up to about 12. "Substituted cycloalkyl" means a cycloalkyl further bearing one or more (e.g., 1, 2, 3, 4 or even 5) substituents selected from alkyl, substituted alkyl, and any of the substituents described herein. "Optionally substituted cycloalkyl" means a cycloalkyl or substituted cycloalkyl.

[0050] "Heterocycle", "heterocyclic" and similar terms refer to cyclic (i.e., ring-containing) groups that contain one or more heteroatoms (e.g., N, O, S, etc.) as part of the ring and have carbon atoms ranging from 1 to about 14. "Substituted heterocyclic" and similar terms refer to heterocycles that further carry one or more (e.g., 1, 2, 3, 4, or even 5) substituents as described herein. Exemplary heterocyclic moieties include saturated rings, unsaturated rings, and aromatic heteroatom-containing ring systems, for example, epoxy, tetrahydrofuran, oxazoline, pyrrole, pyridine, furan, and the like. "Optionally substituted heterocycle" and similar terms refer to heterocycles or substituted heterocycles.

[0051] Reference to an "optionally substituted bicyclic ring" refers to a bicyclic ring structure as known in the art, optionally comprising substitutions as defined herein.

[0052] "Alkenyl" means a straight chain, branched or cyclic hydrocarbon radical comprising 2 to about 20 carbon atoms, having at least one, 1-3, 1-2 or 1 carbon to carbon double bond. "Substituted alkenyl" means an alkenyl substituted at one or more (e.g., 1, 2, 3, 4 or even 5) positions, with substitution as described herein. "Optionally substituted alkenyl" means an alkenyl or substituted alkenyl. In certain embodiments, alkenyl is vinyl or propenyl. In certain embodiments, substituted alkenyl is substituted vinyl or substituted propenyl. In certain embodiments, vinyl or propenyl is substituted with one or more CN moieties. For example, in certain embodiments, substituted vinyl comprises (CN)2C=CH-.

[0053] "Aryl" means an aromatic group having carbon atoms ranging from 6 up to about 14. "Substituted aryl" means an aryl residue further bearing one or more (e.g., 1, 2, 3, 4 or even 5) substituents selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, carbonyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanoalkyl, nitro, amino, amido, amidino, carboxyl, carbamate, SO2X, where X is H, R, NH2, NHR or NR2, SO3Y, where Y is H, NH2, NHR or NR2 or C(O)Z, where Z is OH, OR, NH2, NHR or NR2, etc. "Optionally substituted aryl" means aryl or substituted aryl.

[0054] "Aralkyl" means an alkyl group substituted with an aryl group. "Substituted aralkyl" means an aralkyl group further having one or more (e.g., 1, 2, 3, 4 or even 5) substituents selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and any of the substituents described herein. Thus, aralkyl groups include benzyl, diphenylmethyl, and 1-phenylethyl (-CH(C6H5)(CH3)), among others. "Optionally substituted aralkyl" means an aralkyl group or a substituted aralkyl group.

[0055] "Heteroaryl" refers to an aromatic group containing one or more heteroatoms (e.g., N, O, S, etc.) as part of the aromatic ring, typically having carbon atoms in the range of 2 to about 14, and "substituted heteroaryl" refers to a heteroaryl residue further bearing one or more (e.g., 1, 2, 3, 4 or even 5) substituents selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and any of the substituents described above.

[0056] "Heteroaralkyl" and "heteroarylalkyl" refer to alkyl groups substituted with one or more heteroaryl groups. "Substituted heteroaralkyl" refers to heteroaralkyl groups further bearing one or more (e.g., 1, 2, 3, 4, or even 5) substituents selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and any of the substituents described herein. "Optionally substituted heteroaralkyl" refers to heteroaralkyl or substituted heteroaralkyl groups.

[0057] "Halogen" and "halo" mean fluorine, chlorine, bromine or iodine.

[0058] "Hydroxyl" and "hydroxy" refer to the functional group -OH.

[0059] "Alkoxy" refers to the group -OR, where R is alkyl. "Substituted alkoxy" refers to the group -OR, where R is substituted alkyl. "Optionally substituted alkoxy" refers to alkoxy or substituted alkoxy.

[0060] "Aryloxy" refers to the group -OR, where R is aryl. "Substituted aryloxy" refers to the group -OR, where R is substituted aryl. "Optionally substituted aryloxy" refers to aryloxy or substituted aryloxy.

[0061] "Mercapto" and "thiol" refer to the functional group -SH.

[0062] "Alkylthio" and "thioalkoxy" refer to the radicals -SR, -S(0) n＝1-2 -R, wherein R is alkyl. "Substituted alkylthio" and "substituted thioalkoxy" refer to the groups -SR, -S(O) n＝1-2 -R, wherein R is substituted alkyl. "Optionally substituted alkylthio" and "optionally substituted thioalkoxy" mean alkylthio or substituted alkylthio.

[0063] "Arylthio" refers to the group -SR, where R is aryl. "Substituted arylthio" refers to the group -SR, where R is substituted aryl. "Optionally substituted arylthio" refers to arylthio or substituted arylthio.

[0064] "Amino" refers to unsubstituted, monosubstituted and disubstituted amino groups, including the substituent -NH2, "monoalkylamino" (which refers to a substituent having the structure -NHR, where R is alkyl or substituted alkyl), and "dialkylamino" (which refers to a substituent having the structure -NR2, where each R is independently alkyl or substituted alkyl).

[0065] "Amidino" refers to the group -C(=NR q )NR r R s , where R q , R r and R s is independently hydrogen or optionally substituted alkyl.

[0066] Reference to "amido" includes substituents of the structure -C(O)-NR2, wherein each R is independently H, alkyl, substituted alkyl, aryl or substituted aryl as described above. When each R is H, the substituent is also referred to as "carbamoyl" (i.e., a substituent having the structure -C(O)-NH2). When only one of the R groups is H, the substituent is also referred to as "monoalkylcarbamoyl" (i.e., a substituent having the structure -C(O)-NHR, wherein R is an alkyl or substituted alkyl as described above) or "arylcarbamoyl" (i.e., a substituent having the structure -C(O)-NH(aryl), wherein aryl is as defined above, including substituted aryl). When any one of the R groups is not H, the substituent is also referred to as "di-alkylcarbamoyl" (i.e., a substituent having the structure -C(O)-NR2, wherein each R is independently an alkyl or substituted alkyl as described above).

[0067] References to "carbamate" include substituents of the structure -OC(O)-NR2, wherein each R is independently H, alkyl, substituted alkyl, aryl, or substituted aryl.

[0068] Reference to an "ester group" includes substituents of the structure -OC(O)-OR, wherein each R is independently alkyl, substituted alkyl, aryl, or substituted aryl.

[0069] "Acyl" refers to a group having the structure -C(O)R, wherein R is hydrogen, alkyl, aryl, etc., as defined herein. "Substituted acyl" refers to an acyl group wherein the substituent R is substituted as defined herein. "Optionally substituted acyl" refers to both acyl and substituted acyl groups.

[0070] "Cyanoalkyl" means a group -R≡N, where R is optionally substituted alkylenyl.

[0071] As used herein, "substituted" means an atom or atom group that has been replaced with another atom or atom group (i.e., a substituent), and includes all levels of substitution, such as single-, two-, three-, four-, five- or even six-substitutions, where such substitutions are chemically permitted. Substitutions can occur at any chemically accessible position and any atom, such as substitutions on carbon and any heteroatoms (such as oxygen, nitrogen or sulfur). For example, substituted moieties include those in which one or more bonds to hydrogen or carbon atoms contained therein are replaced by bonds to non-hydrogen and / or non-carbon atoms. Substitutions may include, but are not limited to, halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxy, alkoxy, aryloxy, and ester groups; sulfur atoms in groups such as thiol, alkyl and aryl sulfide, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl; and heteroatoms in other groups well known in the art.

[0072] Non-limiting examples of substituents include, but are not limited to, halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR, -SR, -OC(O)R, -OC(S)R, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -S(O)R, -S(O)2R, -C(O)NHR, -C(S)NHR, -C(O)NRR, -C(S)NRR, -S(O)2NHR, -S(O)2NRR, -C(NR)NHR, -C(NH)NRR, -NH C(O)R, -NHC(S)R, -NRC(O)R, -NRC(S)R, -NHS(O)2R, -NRS(O)2R, -NHC(O)NHR, -NHC(S)NHR, -NRC(O)NH2, -NRC(S)NH2, -NRC(O)NHR, -NRC(S)NHR, -NHC(O)NRR, -NHC(S)NRR, -NRC(O)NRR, -NRC(S)NRR, -NHS(O)2NHR, -NRS(O)2NH2, -NRS(O)2NHR, -NHS(O)2NRR, -NRS(O)2NRR, -NHR, -NRR, wherein R at each occurrence is independently H, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.Also contemplated are substitutions with optionally substituted hydrocarbyl moieties containing one or more of the following chemical functionalities: -O-, -S-, -NR-, -OC(O)-, -OC(O)-O-, -OC(O)-NR-, -NR-C(O)-, -NR-C(O)-O-, -NR-C(O)-NR-, -SC(O)-, -SC(O)-O-, -SC(O)-NR-, -S(O)-, -S(O)2-, -OS(O)2-, -O S(O)2-O, -OS(O)2-NR-, -OS(O)-, -OS(O)-O-, -OS(O)-NR-, -O-NR-C(O)-, -O-NR-C(O)-O-, -O-NR-C(O)-NR -, -NR-OC(O)-, -NR-OC(O)-O-, -NR-OC(O)-NR-, -O-NR-C(S)-, -O-NR-C(S)-O-, -O-NR-C(S)-NR-, -NR-OC( S)-, -NR-OC(S)-O-, -NR-OC(S)-NR-, -OC(S)-, -OC(S)-O-, -OC(S)-NR-, -NR-C(S)-, -NR-C(S)-O-, -NR-C (S)-NR-, -SS(O)2-, -SS(O)2-O-, -SS(O)2-NR-, -NR-OS(O)-, -NR-OS(O)-O-, -NR-OS(O)-NR-, -NR-OS(O)2 -, -NR-OS(O)2-NR-, -O-NR-S(O)-, -O-NR-S(O)-O-, -O-NR-S(O)-NR-, -O-NR-S(O)2-O-, -O-NR-S(O)2-NR-, -O-NR-S(O)2-, -OP(O)R2-, -SP(O)R2-, or -NRP(O)R2-, wherein R at each occurrence is independently H, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0073] In certain embodiments, compounds of the present invention include isomers of the compounds disclosed herein, including stereoisomers (eg, enantiomers and diastereomers), constitutional isomers, tautomers, conformational isomers, and geometric isomers.

[0074] Exemplary structural isomers include, for example, but not limited to, isomers resulting from different connectivity of functional groups forming compounds of the invention, e.g., 1-propyl substituted with respect to 2-propyl, etc. Structural isomers in combination with tautomerism further include bonding rearrangements involving migration of double bonds and substituents. For example, tautomerism in combination with 1-3 polyvalent hydrogen shifts can produce structural isomerism.

[0075] Exemplary conformational isomers include, for example, but are not limited to, isomers produced by rotation about a bond where the rotation is hindered to the extent that separable isomers are produced, as is well known in the art.

[0076] Exemplary geometric isomers include double bonds in, for example, the "E" or "Z" configuration, as is well known in the art.

[0077] The compounds of the present invention can be easily prepared using suitable synthetic methods. For example, curcumin can be condensed with phenylhydrazine by warming to reflux overnight in toluene. Optionally, a catalytic amount of acid (HCl) can be used. In certain embodiments, pure curcumin (relative to technical grade) and freshly distilled phenylhydrazine can be used.

[0078] As another example, 3-methoxybenzaldehyde can be condensed with 2,4-dimethylphenylhydrazine in methanol using standard hydrazone preparation conditions (e.g., heating in a microwave to speed up the reaction time). The free NH is then acylated with TFAA (trifluoroacetic anhydride) + catalytic (0.1%) amounts of DMAP (dimethylaminopyridine), THE (tetrahydrofuran), or DCM (dichloromethane).

[0079] In certain embodiments, CF3 substituted triazoles can be prepared by 1,3-dipolar cycloaddition between suitable aryl trifluoromethyl acetylene and aryl azide. Regioselectivity can be obtained by utilizing suitable click chemistry (e.g., see Huisgen R. (1984) 1,3-Dipolar Cycloaddition Chemistry, pp. 1-176, Lodon: Wiley; Padwa (1991) Comprehensive Organic Synthesis, Vol. 4: pp. 1069-1109, Oxford: Pergamon; and Fan and Katritzky (1996) Comprehensive Heterocyclic Chemistry II, Vol. 4: pp. 101-126, Oxford: Pergamon). Additional methods for preparing compounds disclosed herein can be found in Lima et al., (2015) Chem. Commun. 51: 10784-10796 and Kim et al., (2015) Org. Biomol. Chem. 13: 9564-9569.

[0080] In certain embodiments, the compound of the present invention is provided in the form of a pharmaceutically acceptable salt. The compound of the present invention can form a complex with any suitable inorganic or organic salt. In certain embodiments, by reacting the compound of the present invention with a suitable organic or inorganic acid or base, the salt of the compound of the present invention is prepared. The non-limiting examples of organic salts used together with the compound of the present invention in this article include mesylate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate (toluenesulfonate), citrate, malate, maleate, fumarate, succinate, tartrate, naphthylsulfonate, mesylate, 2-naphthalenesulfonate, nicotinate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, glucose heptanoate, glycerophosphate, heptanoate, hexanoate, undecanoate, 2-hydroxyethanesulfonate, ethanesulfonate etc. are included. In certain embodiments, inorganic salts can be formed from inorganic acids, such as sulfates, bisulfates, hemisulfates, hydrochlorides, chlorates, perchlorates, hydrobromides, hydroiodides, etc. Non-limiting examples of base salts include ammonium salts; alkali metal salts such as sodium salts, potassium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, etc.; salts formed with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, etc.; and salts formed with amino acids such as arginine, lysine, etc. The salt forms of the compounds of the present invention can be prepared using appropriate methods.

[0081] Methods and indications

[0082] Provided herein are methods for treating and / or preventing obesity, assisting a subject in weight loss, inducing weight loss, suppressing appetite, and / or suppressing weight gain in a subject, including administering a therapeutically effective amount of a compound of the present invention to the subject. In certain embodiments, the method includes assisting him / her in the subject's efforts to lose weight, wherein the subject is administered a compound disclosed herein. In certain embodiments, the method includes inducing weight loss in a subject, wherein the subject is administered a compound disclosed herein. The term "weight" represents the subject's body weight. The term "weight loss" represents the decrease in the subject's body weight over time (e.g., measured by day, week, or month). In certain embodiments, the subject's body weight can be reduced by 0.1% or more, 0.5% or more, 1% or more, or 5% or more by the methods herein. In certain embodiments, the subject's body weight can be reduced by 0.5 pounds or more, 1 pound or more, 5 pounds or more, or 10 pounds or more by the methods herein. In certain embodiments, the subject's body weight can be reduced by 1-150 pounds, 1-100 pounds, or 1-50 pounds by the methods herein.

[0083] In certain embodiments, the method includes preventing obesity in a subject by administering a compound disclosed herein. Preventing obesity means maintaining the subject's weight at a healthy BMI (e.g., between about 18 and 29) and / or preventing the subject's BMI from exceeding a BMI of 29.9. In certain embodiments, the method includes treating obesity in a subject by administering a compound disclosed herein. Treating obesity means administering a compound of the present invention to a subject with a BMI of 30 or greater, with the goal of reducing the subject's BMI to a lower level. In certain embodiments, treating obesity includes reducing the subject's BMI by at least 0.1, at least 0.5, at least 1, or sometimes by at least 5. In certain embodiments, treating obesity includes inducing weight loss.

[0084] In certain embodiments, the method includes inhibiting, slowing or preventing weight gain in a subject by administering a compound of the present invention to the subject. In certain embodiments, the methods of inhibiting, slowing or preventing weight gain disclosed herein can inhibit, slow or prevent the increase in the subject's weight over time (e.g., over days, weeks or years).

[0085] In certain embodiments, the methods comprise suppressing appetite in a subject by administering a compound of the invention to the subject.

[0086] Subjects

[0087] The term "subject" means a mammal. Any suitable mammal can be treated by the methods or compositions described herein. Non-limiting examples of mammals include humans, non-human primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, etc.), domestic animals (e.g., dogs and cats), farm animals (e.g., horses, cattle, goats, sheep, pigs), and experimental animals (e.g., mice, rats, rabbits, guinea pigs). In certain embodiments, the subject is a non-human primate or a human. In certain embodiments, the subject is a human. The subject can be of any age or at any stage of development (e.g., an adult, a teenager, a child, an infant, or a mammal in the womb). The subject can be male or female.

[0088] In certain embodiments, the subject is overweight. In certain embodiments, the subject has a BMI of 30 or greater. In certain embodiments, the subject is obese. In certain embodiments, the subject has an eating disorder. In certain embodiments, the subject has or is suspected of having anorexia. In certain embodiments, the subject has or is suspected of having a compulsive eating disorder or binge eating disorder. In certain embodiments, the subject has a history of compulsive overeating or binge eating. In certain embodiments, the subject has a history of eating more than 3000 calories per day. In certain embodiments, the subject has a history of eating more than 5000 calories per day. In certain embodiments, the subject is a person who desires to lose weight.

[0089] In certain embodiments, the subject has or is suspected of having diabetes. In certain embodiments, the subject has or is suspected of having cardiovascular disease. In certain embodiments, the subject is at risk of having diabetes, heart disease or cardiovascular disease or at risk of developing diabetes, heart disease or cardiovascular disease.

[0090] Pharmaceutical composition

[0091] In certain embodiments, the composition or pharmaceutical composition comprises a compound of the present invention. In certain embodiments, the composition or pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention. In certain embodiments, the composition or pharmaceutical composition comprises a compound disclosed herein in an amount within the range of 1 μg to 1000 mg, 1 μg to 100 mg, or 10 μg to 100 μg. In certain embodiments, provided herein is a pharmaceutical composition comprising a compound of the present invention for treating and / or preventing obesity, assisting a subject in weight loss, inducing weight loss, suppressing appetite, and / or suppressing weight gain in a subject. In certain embodiments, the pharmaceutical composition comprises a compound of the present invention and a pharmaceutically acceptable excipient, diluent, additive, or carrier.

[0092] The pharmaceutical composition can be formulated for a suitable route of administration. In certain embodiments, the pharmaceutical composition is formulated for oral, subcutaneous (sc), intradermal, intramuscular, intraperitoneal and / or intravenous (iv) administration. In certain embodiments, the pharmaceutical composition contains formulation materials for changing, maintaining or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption or penetration of the composition. In certain embodiments, suitable formulation materials include, but are not limited to: amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite or sodium bisulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrate, phosphate (e.g., phosphate buffered saline) or a suitable organic acid); fillers (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinyl pyrrolidone, β-cyclodextrin or hydroxypropyl-β-cyclodextrin); proteins (such as serum albumin, gelatin or immunoglobulins); colorants, flavorings and diluents; emulsifiers; hydrophilic polymers (such as polyvinyl pyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); solvents (such as glycerol, propylene glycol or polyethylene glycol); diluents; excipients and / or pharmaceutical adjuvants. Specifically, the pharmaceutical composition may contain any suitable carrier, formulation or ingredient, etc., or a combination thereof, as listed in the following documents: "Remington: The Science And Practice Of Pharmacy" Mack Publishing Co., Easton, PA, 19th edition (1995) (hereinafter referred to as Remington'95), or "Remington: The Science And Practice Of Pharmacy", Pharmaceutical Press, Easton, PA, 22nd edition (2013) (hereinafter referred to as Remington 2013), the contents of which are incorporated herein by reference in their entirety.

[0093] In certain embodiments, the pharmaceutical composition comprises suitable excipients, non-limiting examples of which include anti-adherents (e.g., magnesium stearate), binders, fillers, monosaccharides, disaccharides, other carbohydrates (e.g., glucose, mannose or dextrin), sugar alcohols (e.g., mannitol or sorbitol), coating agents (e.g., cellulose, hydroxypropylmethylcellulose (HPMC), microcrystalline cellulose, synthetic polymers, shellac, gelatin, corn protein zein, enterics or other polysaccharides), starches (e.g., potato starch), The invention relates to a pharmaceutical composition comprising a pharmaceutical composition comprising a plurality of ingredients, such as starch, starch, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches, starches,

[0094] In certain embodiments, the pharmaceutical composition comprises a suitable pharmaceutically acceptable additive and / or carrier. Non-limiting examples of suitable additives include suitable pH adjusting agents, mitigating agents, buffers, sulfur-containing reducing agents, antioxidants, etc. Non-limiting examples of sulfur-containing reducing agents include those with sulfhydryl groups (e.g., thiol), such as N-acetylcysteine, N-acetylhomocysteine, lipoic acid, thiodiethanol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salt, sodium thiosulfate, glutathione and C1-C7 thioalkanoic acid. The non-limiting examples of antioxidants include erythrosonic acid, butylated hydroxytoluene, butylated hydroxyanisole, alpha-tocopherol, tocopheryl acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, tripentyl gallate and propyl gallate, and chelating agents such as disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate and sodium metaphosphate. In addition, diluents, additives and excipients may include other common ingredients, for example, inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate and sodium bicarbonate, and organic salts such as sodium citrate, potassium citrate and sodium acetate.

[0095] Pharmaceutical compositions used herein can be stable in extended time periods (e.g., months or years). In certain embodiments, pharmaceutical compositions include one or more suitable preservatives. The non-limiting example of preservatives includes benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenylethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, hydrogen peroxide, etc. and / or its combination. Preservatives can include quaternary ammonium compounds, such as benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, sepazonium chloride, cetylpyridinium chloride or domiphene bromide. The preservative may comprise an alkylmercury salt of thiosalicylic acid, such as thimerosal, phenylmercuric nitrate, phenylmercuric acetate, or phenylmercuric borate. The preservative may comprise a paraben, such as methylparaben or propylparaben. The preservative may comprise an alcohol, such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol. The preservative may comprise a biguanide derivative, such as chlorhexidine or polyhexamethylene biguanide. The preservative may comprise sodium perborate, imidazolidinyl urea, and / or sorbic acid. The preservative may comprise a stabilized oxychloro complex, such as those known and available under the trade name The preservative may include a polyethylene glycol-polyamine condensation resin, such as those known and available under the trade name The preservative may comprise stabilized hydrogen peroxide. The preservative may be benzalkonium chloride. In certain embodiments, the pharmaceutical composition is free of a preservative.

[0096] In certain embodiments, the compositions, pharmaceutical compositions or compounds of the present invention are substantially free of pollutants (e.g., blood cells, platelets, polypeptides, minerals, blood-borne compounds or chemicals, viruses, bacteria, other pathogens, toxins, etc.). In certain embodiments, the compositions, pharmaceutical compositions or compounds of the present invention are substantially free of serum and serum pollutants (e.g., serum proteins, serum lipids, serum carbohydrates, serum antigens, etc.). In certain embodiments, the compositions, pharmaceutical compositions or compounds of the present invention are substantially free of pathogens (e.g., viruses, parasites or bacteria). In certain embodiments, the compositions, pharmaceutical compositions or compounds of the present invention are substantially free of endotoxins. In certain embodiments, the compositions, pharmaceutical compositions or compounds of the present invention are sterile. In certain embodiments, the compositions or pharmaceutical compositions disclosed herein include compounds of formula I, II, III or IV.

[0097] Pharmaceutical compositions described herein can be configured to be administered to a subject in any suitable form and / or amount according to the therapy adopted therein.For example, a pharmaceutical composition configured to be administered parenterally (for example, by injection or infusion) can be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and it can contain a preparaton, an excipient, an additive and / or a diluent such as an aqueous or non-aqueous solvent, a cosolvent, a suspending solution, a preservative, a stabilizer and / or a dispersant.In certain embodiments, the pharmaceutical composition suitable for parenteral administration can contain one or more excipients.In certain embodiments, the pharmaceutical composition is lyophilized to a dry powder form.In certain embodiments, the pharmaceutical composition is lyophilized to a dry powder form, which is suitable for reconstructing with a suitable pharmaceutical solvent (for example, water, saline, isotonic buffer solution (for example, PBS), DMSO, a combination thereof, etc.).In certain embodiments, the reconstructed form of the lyophilized pharmaceutical composition is suitable for parenteral administration (for example, intravenous administration) to mammals.

[0098] In certain embodiments, the pharmaceutical composition is configured for oral administration and can be formulated as a tablet, microtablet, minitablet, micropellet, powder, granule, capsule (e.g., capsule filled with microtablet, micropellet, powder or granule), emulsion, solution, etc., or a combination thereof. The pharmaceutical composition configured for oral administration may contain a suitable coating to delay or sustain the release of the active ingredient, non-limiting examples of which include enteric coatings such as fatty acids, waxes, shellac, plastics, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, cellulose acetate trimellitate, sodium alginate, zein, plant fibers, etc., and combinations thereof.

[0099] In certain embodiments, the pharmaceutical compositions described herein can be configured for topical administration and can include one or more of an adhesive and / or lubricant, polymeric glycol, gelatin, cocoa powder-butter or other suitable wax or fat. In certain embodiments, the pharmaceutical compositions described herein are incorporated into a topical formulation containing a topical carrier generally suitable for topical drug administration and comprising any suitable material known to those skilled in the art. In certain embodiments, the topical formulation of the pharmaceutical composition is formulated for administration of the compounds of the invention from a topical patch.

[0100] In certain embodiments, the optimal pharmaceutical composition is determined by one skilled in the art based on, for example, the intended route of administration, delivery form, and desired dosage (see, for example, Remington '95 or Remington 2013, supra). The pharmaceutical composition can be manufactured by any suitable means, including, for example, by means of conventional mixing, dissolving, granulating, dragee making, levigating, emulsifying, encapsulating, embedding, or tableting processes (see, for example, the methods described in Remington '95 or Remington 2013).

[0101] Route of administration

[0102] Any suitable method of administering the composition, pharmaceutical composition or compound of the present invention to a subject can be used. Any suitable formulation and / or route of administration can be used to administer the compound of the present invention or the composition disclosed herein (e.g., see Fingl et al. 1975, "The Pharmacological Basis of Therapeutics", which is incorporated herein by reference in its entirety). Suitable formulations and / or routes of administration can be selected by a medical professional (e.g., a physician) taking into account, for example, the risk, age and / or condition of the subject. Non-limiting examples of routes of administration include topical or topical (e.g., transdermally or dermally (e.g., on the skin or epidermis), in or on the eye, intranasally, transmucosally, in the ear, in the ear (e.g., behind the tympanic membrane)), enteral (e.g., delivered through the gastrointestinal tract, e.g., orally (e.g., as a tablet, capsule, granule, liquid, emulsion, lozenge, or a combination thereof), sublingually, through a gastric feeding tube, rectally, etc.), by parenteral administration (e.g., parenterally, e.g., intravenously, intraarterially, intramuscularly, intraperitoneally, intradermally, subcutaneously, intracavitary, intracranial, intraarticularly, in a joint space, intracardiacly (in the heart), intracavernous injection, intralesional (in a skin lesion), intraosseous infusion (in the bone marrow), intrathecally (in the spinal canal), intrauterine, intravaginally, intravesical infusion, intravitreal), etc., or a combination thereof. In certain embodiments, the compounds or compositions disclosed herein are formulated for oral administration. In certain embodiments, a compound or composition disclosed herein is administered orally.

[0103] In certain embodiments, a compound of the invention or a pharmaceutical composition described herein is administered to the lungs, bronchial passages, trachea, esophagus, sinuses, or nasal passages using a suitable method, non-limiting examples of which include intranasal administration, intratracheal instillation, and oral inhalation administration (e.g., by use of an inhaler, e.g., a single / multi-dose dry powder inhaler, a nebulizer, etc.).

[0104] In certain embodiments, the compound of the present invention or the pharmaceutical composition disclosed herein is provided to the subject. For example, sometimes the composition provided to the subject is provided to the subject for self-administration or for administration to the subject by another person (e.g., non-medical professional). As another example, the composition can be provided according to the instructions written by the medical practitioner, and the medical practitioner authorizes the patient to provide the composition described herein or treatment (e.g., prescription). In another example, the composition can be provided to the subject, wherein the subject self-administers the composition, for example, orally, intravenously or by an inhaler.

[0105] Alternatively, the compounds or compositions of the invention may be administered in a local rather than systemic manner, for example, via direct application to the skin, mucosa, or target area of ​​treatment, including the use of depot or sustained release formulations.

[0106] In certain embodiments, a pharmaceutical composition comprising a compound of the invention is administered alone (e.g., as a single active ingredient (AI, or, e.g., as a single active pharmaceutical ingredient (API)). In other embodiments, a pharmaceutical composition comprising a compound of the invention is administered in combination with one or more additional AI / APIs, e.g., as two separate compositions or as a single composition, wherein the one or more additional AI / APIs are mixed or formulated together with the compound of the invention in the pharmaceutical composition.

[0107] Dosage and therapeutically effective amount

[0108] In certain embodiments, the amount of the compound of the present invention (e.g., in a pharmaceutical composition) is a therapeutically effective amount. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein. In certain embodiments, a therapeutically effective amount of the compound of the present invention is administered to a subject. In certain embodiments, the therapeutically effective amount of the compound of the present invention is the amount required to obtain an effective therapeutic result. In certain embodiments, the therapeutically effective amount of the compound of the present invention is an amount sufficient to treat and / or prevent obesity, assist a subject in weight loss, induce weight loss, suppress appetite, and / or suppress weight gain in a subject, as contemplated herein. The determination of a therapeutically effective amount is fully within the capabilities of those skilled in the art, particularly according to the detailed disclosure provided herein.

[0109] In certain embodiments, the therapeutically effective amount is an amount high enough to provide an effective therapeutic effect (e.g., a beneficial therapeutic effect) and low enough to minimize the amount of undesirable adverse reactions. Therefore, in certain embodiments, the therapeutically effective amount of the compounds of the present invention may vary from subject to subject, often depending on the age, weight, general health, severity of obesity and / or the specific drug combination administered to the subject. Thus, in certain embodiments, the therapeutically effective amount is determined empirically. Therefore, those of ordinary skill in the art can determine the therapeutically effective amount of a compound or composition based on, for example, finding effective amounts in animals or clinical studies, physician's experience, and / or the dosage range or administration guidelines of advice.

[0110] In certain embodiments, a therapeutically effective amount of a compound of the invention is administered with an appropriate dose (e.g., at an appropriate volume, frequency, and / or concentration, which often depends on the weight, age, and / or condition of the subject) intended to obtain an acceptable therapeutic result. In certain embodiments, a therapeutically effective amount of a compound of the invention comprises one or more doses selected from at least 0.01 mg / kg (e.g., mg compound of the invention / kg subject body weight), at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1 mg / kg, at least 10 mg / kg, or at least 100 mg / kg. In certain embodiments, a therapeutically effective amount of a compound of the invention is selected from one or more of about 0.001 mg / kg (e.g., mg of the compound of the invention per kilogram of subject body weight) to about 5000 mg / kg, 0.1 mg / kg to 5000 mg / kg, 1 mg / kg to 5000 mg / kg, 10 mg / kg to 5000 mg / kg, 0.01 mg / kg to 1000 mg / kg, 0.1 mg / kg to 1000 mg / kg, 1 mg / kg to 1000 mg / kg, 100 mg / kg to 1000 mg / kg, 0.01 mg / kg to 1000 mg / kg.

[0014] In some embodiments, the present invention provides a dosage of 0.1 mg / kg to 500 mg / kg, 0.1 mg / kg to 500 mg / kg, 1 mg / kg to 500 mg / kg, 0.1 mg / kg to 250 mg / kg, 0.1 mg / kg to 150 mg / kg, 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 100 mg / kg, 0.1 mg / kg to 75 mg / kg, 0.1 mg / kg to 50 mg / kg, 0.1 mg / kg to 25 mg / kg, 0.1 mg / kg to 10 mg / kg, 0.1 mg / kg to 5 mg / kg, 0.5 mg / kg to 5 mg / kg, intervening amounts, and combinations thereof. In some aspects, the therapeutically effective amount of the compound of the present invention administered to a subject comprises one or more about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, 500 mg / kg and the dosage of the amount and combinations thereof between. In certain embodiments, the therapeutically effective amount of the compound of the present invention is between about 0.1 mg / kg and about 50 mg / kg.

[0111] In certain embodiments, the compound of the present invention or the pharmaceutical composition disclosed herein is administered at the appropriate frequency or interval required to obtain effective treatment results. In certain embodiments, administering a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition disclosed herein includes hourly, every 2 hours, every 4 hours, every 6 hours, three times a day, twice a day, once a day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, with its combination, and / or with its regular or irregular intervals, and / or simply with the frequency or interval required or recommended by medical professionals, administering a suitable dose. In certain embodiments, for example, by intravenous administration in a suitable time period, the compound of the present invention or the pharmaceutical composition disclosed herein is continuously administered with a therapeutically effective amount. In certain embodiments, the compound of the present invention is administered for 1-30 days, 1-52 weeks, 1-5 years, or other suitable time periods. In certain embodiments, the compound of the present invention is administered until the subject reaches a suitable healthy body mass index (BMI), which can be determined by a medical professional. In certain embodiments, the compound of the present invention is administered until the subject reaches a BMI of 18.5-25 or a BMI of 18.5-29. In certain embodiments, administering a therapeutically effective amount of a compound of the invention comprises administering a dose of about 1-1000 mg / kg, about 1-100 mg / kg, or about 1-30 mg / kg, administered at a frequency of once per day.

[0112] In certain embodiments, a therapeutically effective amount of the compound of the present invention is administered to a subject before, during, and / or after exercise. In certain embodiments, a therapeutically effective amount of the compound of the present invention is administered to a subject up to 1 day, up to 20 hours, up to 15 hours, up to 10 hours, up to 5 hours, up to 2 hours, or up to 1 hour before exercise or strenuous activity. In certain embodiments, a therapeutically effective amount of the compound of the present invention is administered to a subject 0-72 hours, 0 and 48 hours, 0-24 hours, 0-12 hours, 0-6 hours, 0-4 hours, or 0-2 hours before exercise or strenuous activity. In certain embodiments, a therapeutically effective amount of the compound of the present invention is administered during exercise or strenuous activity. In certain embodiments, a therapeutically effective amount of a compound of the invention is administered intermittently or continuously for up to 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 1 week, 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, or up to 36 months after exercise or strenuous activity.

[0113] Reagent test kit

[0114] In certain embodiments, kits are provided herein, which include compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention. In certain embodiments, the kit includes one or more doses of pharmaceutical compositions comprising compounds of the present invention. In certain embodiments, the kit includes one or more packs and / or one or more dispensing devices, which may contain one or more doses of compounds of the present invention as described herein or pharmaceutical compositions thereof. Non-limiting examples of packages include metal, glass or plastic containers, syringes or blister packs, which include compounds of the present invention or compositions described herein. In certain embodiments, the kit includes dispensing devices such as syringes or inhalers, which may or may not include compounds of the present invention or compositions described herein. The package and / or dispensing device may be accompanied by instructions for use. The package or dispenser may also be accompanied by a notice associated with the container, which is in the form prescribed by a government agency that manages the manufacture, use or sale of the drug, and the notice reflects the approval of the agency for the form of the drug for human or veterinary administration. For example, such a notice may be a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert.

[0115] In certain embodiments, the kit or pack contains an amount of a compound of the invention sufficient to treat a patient for 1 day to 1 year, 1 day to 180 days, 1 day to 120 days, 1 day to 90 days, 1 day to 60 days, 1 day to 30 days, 1-24 hours, 1-12 hours, 1-4 hours, or a period of time therebetween.

[0116] The kit optionally includes a product label and / or one or more package inserts, which provide a description of the component or the in vitro, in vivo or ex vivo instructions for use of the component. Exemplary instructions may include instructions for a treatment plan (protocol) or a treatment regimen (regime). In certain embodiments, the kit includes packaging materials, which represent the physical structure of the components of the kit. The packaging materials can maintain the components aseptically, and can be made of materials (e.g., paper, corrugated fiber (corrugated fiber), glass, plastic, foil, ampoule, vial (vial), tube, etc.) that are commonly used for such purposes. The product label or insert includes "printed matter", e.g., paper or cardboard, or individually or attached to a component, a kit or packaging material (e.g., box), or attached to an ampoule, tube or vial containing a kit component. The label or insert may additionally include a computer-readable medium, an optical disc such as CD- or DVD-ROM / RAM, DVD, MP3, a magnetic tape or an electrical storage medium such as RAM and ROM or a hybrid of these such as magnetic / optical storage media, FLASH media or a memory card. The product label or insert may include identification information, dosage, clinical pharmacology of active ingredients, including mechanism of action, pharmacokinetics (PK) and pharmacodynamics (PD) of one or more components. The product label or insert may include information identifying manufacturer information, batch number, manufacturer location, date, information about specified conditions, disorders, diseases or symptoms for which kit components may be used. The product label or insert may include instructions for clinicians or subjects to use one or more kit components in methods, treatment plans or treatment regimens. Instructions may include dosage, frequency or duration, and instructions for implementing any method, treatment plan or treatment regimen described herein. The kit may additionally include labels or instructions for implementing any method described herein. The product label or insert may include information about potential adverse side effects and / or warnings. Example

[0117] Example 1

[0118] J147 or vehicle was administered to Sprague-Dawley rats via oral gavage once a day at a daily dose of 0,30,100 or 300 mg / kg for 28 consecutive days.J174 was prepared in a vehicle formulation comprising 5% ethanol, 5% DMSO and 90% corn oil (v / v / v).Proven rodent diet and water were available at will.Groups 1-4 contained 10 animals / sex / groups.Groups 1 (control) and 4 (high dose) also included 5 other animals / sex / groups for use as recovery animals.Recovery animals maintained a 14-day post-administration recovery period in the study.Monitoring group 1-4 animals for morbidity and mortality, clinical signs, detailed clinical observations, body weight, food consumption, ophthalmology parameters, neurobehavioral assessment, hematology, coagulation, serum chemistry and urinalysis parameters composed of functional observation combined test (Functional ObservationalBattery, FOB) and motor activity test. The necropsy assessment included microscopic evaluation of autopsy, measurement of selected organ weights, and standard groups of tissues. Plasma samples for bioanalysis were collected from satellite toxicokinetics animals in groups 5 to 8 on the 1st and 28th days. The animals in these groups were euthanized after the last blood sampling, and the carcasses were discarded without inspection. The study protocol is shown in Table 1 below.

[0119] Table 1

[0120]

[0121] Groups 1-4 = Toxicity groups

[0122] Groups 5-8 = Toxicokinetic groups

[0123] Toxic females were dosed one day later than toxic males and toxicokinetic males / females (staggered starts).

[0124] * TK animals were terminated on these days without gross necropsy.

[0125] Detailed results

[0126] weight

[0127] Mean body weights are shown in Table 2 (males) and Table 3 (females).

[0128] Table 2 - Average Weight - Males

[0129] Weight (g)

[0130]

[0131] Statistical tests: Anova and Dunnett's test

[0132] 1 [aa-Statistical test: ANOVA p<0.01]

[0133] 2 [dd-Statistical test: Dunnett 2-sided p<0.01]

[0134] Table 2-(Continued)

[0135] Weight (g)

[0136]

[0137] Statistical tests: Anova and Dunnett's test

[0138] 1 [aa-Statistical test: ANOVA p<0.01]

[0139] 2 [a-Statistical test: ANOVA p<0.05]

[0140] 3 [dd-Statistical test: Dunnett 2-sided p<0.05]

[0141] 4 [d-statistical test: Dunnett 2-sided p<0.01]

[0142] Table 3 - Average weight - females

[0143] Weight (g)

[0144]

[0145] Statistical tests: Anova and Dunnett's test

[0146] 1 [aa-Statistical test: ANOVA p<0.01]

[0147] 2 [d-statistical test: Dunnett 2-sided p<0.05]

[0148] 3 [dd-Statistical test: Dunnett 2-sided p<0.01]

[0149] Table 3-(Continued)

[0150]

[0151] Statistical tests: Anova and Dunnett's test

[0152] Mean body weight gains are shown in Table 4 (males) and Table 5 (females).

[0153] Table 4 - Average Weight Gain - Males

[0154] Weight gain (g)

[0155]

[0156] Statistical tests: Anova and Dunnett's test

[0157] 1 [aa-Statistical test: ANOVA p<0.01]

[0158] 2 [d-statistical test: Dunnett 2-sided p<0.05]

[0159] 3 [dd-Statistical test: Dunnett 2-sided p<0.01]

[0160] Table 5 - Average Weight Gain - Females

[0161] Weight (g)

[0162]

[0163] Statistical tests: Anova and Dunnett's test

[0164] 1 [aa-Statistical test: ANOVA p<0.01]

[0165] 2 [a-Statistical test: ANOVA p<0.05]

[0166] 3 [d-statistical test: Dunnett 2-sided p<0.05]

[0167] 4 [dd-Statistical test: Dunnett 2-sided p<0.01]

[0168] The final mean body weights are shown in Table 6.

[0169] Table 6 - Final average body weight

[0170]

[0171] The group mean body weights of males decreased by 5.9% and 16.2% at 100 and 300 mg / kg / day males on Day 28 compared to Group 1 controls. The group mean body weights of females decreased by 6.9% and 12.4% at 100 and 300 mg / kg / day females on Day 28 compared to Group 1 controls. The group mean body weight gains from Day -1 to Day 28 for males in Groups 1 and 2 were 175 and 180 grams, respectively, while the mean body weight gains for males in Groups 3 and 4 were 150 and 101 grams, respectively.

[0172] The group mean weight gains from day -1 to day 28 for females in Groups 1 and 2 were 47 and 45 grams, respectively, while the mean weight gains for females in Groups 3 and 4 were 28 and 13 grams, respectively.

[0173] These changes in body weight and body weight gain were often statistically significant, particularly at the high dose levels, and were considered to be related to test article exposure.

[0174] During the recovery period, mean body weight gains in the 300 mg / kg / day group for both males and females exceeded that seen in vehicle treated controls. Complete restoration of body weight and body weight gain was seen during the recovery period.

[0175] Food consumption

[0176] Mean food consumption is shown in Table 7 (males) and Table 8 (females).

[0177] Table 7 - Average Food Consumption - Males

[0178]

[0179] Statistical tests: Anova and Dunnett's test

[0180] 1 [aa-Statistical test: ANOVA p<0.01]

[0181] 2 [dd-Statistical test: Dunnett 2-sided p<0.01]

[0182] Table 8 - Average food consumption - females

[0183] Average food consumption (g / animal / day)

[0184]

[0185]

[0186] Statistical tests: Anova and Dunnett's test

[0187] 1[aa-Statistical test: ANOVA p<0.01]

[0188] 2 [a-Statistical test: ANOVA p<0.05]

[0189] 3 [dd-Statistical test: Dunnett 2-sided p<0.01]

[0190] 4 [d-statistical test: Dunnett 2-sided p<0.05]

[0191] Compared with group 1 control, food consumption decreased in both sexes at 100 and 300 mg / kg / days. The food consumption decrease at 300 mg / kg / days in both sexes was often statistically significant, and sometimes statistically significant at 100 mg / kg / days. Compared with group 1 control, the group average food consumption from the 21st to 28th day in males decreased by 4.9% and 16.7% at 100 and 300 mg / kg / days, respectively. Compared with group 1 control, the group average food consumption from the 21st to 28th day in females decreased by 8.6% and 15.6% at 100 and 300 mg / kg / days, respectively.

[0192] These changes in food consumption are considered to be related to test article exposure.

[0193] Group mean food consumption during the recovery period was similar between vehicle treated controls and 300 mg / kg / day animals, indicating complete restoration of food consumption during the recovery period.

[0194] Summary and discussion of results

[0195] The dose formulation analysis showed that the formulation was accurately prepared, homogeneous, and stable during use. The incurred sample reanalysis (ISR) of the bioanalytical plasma sample did not pass the acceptance criteria. In addition, the analysis of the day 28 sample was also performed outside the known long-term stability (LTS) range of the validated bioanalytical method. Therefore, the bioanalytical and toxicokinetic results of J147 are considered for reference only. In view of the fact that the day 28 sample was analyzed outside its LTS, the bioanalytical and toxicokinetic analysis results should also be considered.

[0196] The clinical observations worth noting in the 28-day treatment phase were limited to the soft feces noted in some animals of both sexes at 300mg / kg / day. Body weight, weight gain and food consumption of both sexes were reduced at 100 and 300mg / kg / day. It was noted that the general reduction of activity was manifested as the reduction of travel distance, walking time, horizontal count, vertical count and vertical interruption (vertical break) in the motor activity part of the functional observation combined test (FOB) performed on the 1st day, and the increase of rest time. These changes were obvious in the males of all dosage levels and the females of 100 and 300mg / kg / day. Although relevant to treatment, these neurobehavioral findings were not considered to be unfavorable. There were no clinical observations worth noting in the recovery phase, and the effects of J147 related to body weight and food consumption were reversible after stopping treatment. At the end of the 28-day treatment phase, males at all dosage levels and females at 100 and 300mg / kg / day, mean red blood cell count, hematocrit and hemoglobin values ​​were reduced. The mean platelet and reticulocyte counts of both sexes at all dose levels were increased. At all dose levels, the prothrombin time of both sexes was reduced. Note the reduction in the mean serum glucose concentration of males at 100mg / kg / day and both sexes at 300mg / kg / day. Note the reduction in the mean serum triglyceride concentration of males at 100 and 300mg / kg / day. The effect on serum glucose and triglyceride concentrations is considered to be secondary to the reduction in food consumption during the treatment phase. Urinalysis showed that the urine ketone level of males at 300mg / kg / day was elevated. There was no anatomical pathology associated with these clinical pathological findings. At the end of the 14-day recovery period, in animals previously administered 300mg / kg / day J147 for 28 days, the test substance-related effects on serum triglyceride concentrations and red blood cell mass continued.

[0197] No changes considered to be related to the administration of the test article were noted at 30 mg / kg / day. The decrease in activity seen in the motor activity test of FOB, and the increase in platelets and reticulocytes seen at this dose level, are not considered adverse findings. Although there were indicators of decreased activity in FOB, the decrease in activity was never referred to as a clinical observation at any dose level, and other than a few instances of hair loss, there were no clinical observations of any kind at 30 mg / kg / day. The increase in platelet counts in females at 30 mg / kg / day was small (3.8%), and the increase in males was not proportional to the dose. The increase in reticulocyte counts is considered an adaptive response to the decrease in RBC parameters.

[0198] At the time of terminal necropsy, enlarged livers and small thymus were seen in one or two animals at a dose of 300mg / kg / day. The average liver weight of the group increased in males at all dose levels and females at 100 and 300mg / kg / day. At 100 and 300mg / kg / day, a decrease in the average thymus weight of the group was observed in both sexes. Under the microscope, subacute perivascular inflammation was noted in the liver of both sexes at 300mg / kg / day, and hepatocyte hypertrophy was observed in both sexes at 100 and 300mg / kg / day. The incidence of single cell necrosis of acinar cells in the pancreas increased in both sexes at 300mg / kg / day, and increased in males at 100mg / kg / day. In addition, thymic lymphoid depletion was noted in both sexes at 300mg / kg / day. The findings of increased liver weight and hepatocyte hypertrophy are considered to represent adaptive responses, rather than adverse or toxicological effects. At day 43 following a 2-week treatment-free recovery period, there were no J147-related organ weights, macroscopic or microscopic findings in the high-dose (300 mg / kg / day) animals.

[0199] in conclusion

[0200] Given the fact that the plasma samples incurred sample reanalysis that did not meet the acceptance criteria and that the day 28 samples were analyzed outside of their long-term stability window, an accurate measure of test article exposure could not be obtained as the toxicokinetic data were taken into account. Given the clear evidence of toxicity in the mid and high dose groups, the study director believes that the study met the objective of examining the toxicity profile of J147. The study did not meet the objective of examining the toxicokinetic profile of J147 following oral exposure. Under the conditions of this study, the no observed adverse effect level (NOAEL) for J147 was considered to be 30 mg / kg / day. The Cmax and AUC0-last on day 1 at the NOAEL were 146 ng / mL and 835 hr*ng / mL, respectively, in males and 50.8 ng / mL and 233 hr*ng / mL, respectively, in females. The Cmax and AUC0-last values ​​should be considered in light of the caveats mentioned in the previous paragraph. The lowest observed adverse effect level (LOAEL) was 100 mg / kg / day in both sexes based on test article-related decreases in body weight / weight gain and food consumption, decreased activity, decreased measures of red blood cell mass, decreased prothrombin time, decreased serum glucose and triglycerides, decreased thymus weights, and single cell necrosis of pancreatic acinar cells in males.

[0201] Example 2

[0202] J147 or vehicle is administered to beagle dogs via oral gavage once a day for up to 28 days with a daily dose of 0, 30, 100 and 300 mg / kg. J174 is prepared in a vehicle formulation comprising 5% ethanol, 5% DMSO and 90% corn oil (v / v / v). Block Lab Diet (Certified CanineDiet #5007, PMI Nutrition International, Inc.) is provided via limited feeding except for the specified stage. Animals are provided with food for 2-5 hours 2 hours after administration on each administration day. Food is provided every day for 2-5 hours in the adaptation period and in the recovery period. Tap water can be obtained arbitrarily via an automatic water supply system. The research scheme is shown in Table 9 below.

[0203] Table 9

[0204]

[0205] Compared with the vehicle-treated control group, body weight and weight gain decreased in all J147-treated groups (both sexes). At 30 and 100 mg / kg / days, the average body weight values ​​of the 28th day group of males decreased by 23% and 26% respectively. The average body weight of the 300 mg / kg / day males at the 22nd day group decreased by 18% relative to the 28th day control value. The average body weight of the 28th day group of females decreased by 19% and 21% at 30 and 100 mg / kg / days respectively. The average body weight of the 300 mg / kg / day females at the 21st day group decreased by 23% relative to the 28th day control value. High doses (300 mg / kg / days) recovered animals (male and female) and increased weight rapidly in the recovery period, indicating the complete recovery of body weight and weight gain in the 14-day recovery period.

[0206] Compared with the vehicle-treated control group, food consumption is reduced in the group (two sexes) of all J147 treatments.Male's average food consumption value on the 28th day group was reduced by 31% and 39% at 30 and 100mg / kg / days.300mg / kg / days male's average food consumption on the 22nd day group was reduced by 48% relative to the 28th day control value.Female's average food consumption value on the 28th day group was reduced by 45% and 48% at 30 and 100mg / kg / days.300mg / kg / days female's average food consumption on the 21st day group was reduced by 38% relative to the 28th day control value.High dose (300mg / kg / days) recovery animals (male and female) show the sharp and immediate increase of food consumption in the recovery period, indicating the rapid and complete recovery of food consumption in the 14-day recovery period.

[0207] Example 3

[0208] J147 was administered to beagle dogs via oral gavage once a day at a daily dose of 0, 1, 10 and 30 mg / kg for up to 28 days. J174 was prepared in a vehicle formulation comprising 5% ethanol, 5% DMSO and 90% corn oil (v / v / v). In addition to the specified stage, Block Lab Diet (Certified Canine Diet #5007, PMI Nutrition International, Inc.) was provided via limited feeding. Animals were provided with food for 2-5 hours 2 hours after administration on each dosing day. Food was provided for 2-5 hours every day during the adaptation period and during the recovery period. Tap water can be obtained arbitrarily via an automatic water supply system. The research scheme is shown in Table 10 below.

[0209] Table 10

[0210]

[0211] At the 10 mg / kg / day and 30 mg / kg / day dose levels, weight loss and less food consumption were noted in Groups 3 and 4. At 10 mg / kg / day, 3 of 4 males and 4 of 4 females lost weight (up to -9% compared to pre-test levels). At 30 mg / kg / day, 5 of 6 males and 6 of 6 females lost weight (up to -12% and -17% of pre-test levels, respectively). The results are summarized in Table 11 (males), Table 12 (females) and Figures 1 and 2. Body weight gain during the 14-day recovery period was comparable to control values ​​for both sexes at 30 mg / kg / day (see, e.g., Figure 1C and 1D ). It is noteworthy that, although the animals in Group 3 experienced only moderate weight loss, they did not experience the weight gain observed for the control animals in Group 1. Therefore, it is concluded that J147 induces weight loss and inhibits weight gain. This result may be due, at least in part, to the appetite suppression observed in Figure 2.

[0212] Table 11

[0213] MPI Research Study No. 2382-001

[0214] J147: 28-day oral (gavage) toxicity study in beagle dogs with a 14-day recovery period

[0215] Summary of Weight Values ​​- Males

[0216]

[0217] N = number of measurements used to calculate the mean.

[0218] AD = standard deviation

[0219] Table 12

[0220] MPI Research Study No. 2382-001

[0221] J147: 28-day oral (gavage) toxicity study in beagle dogs with a 14-day recovery period

[0222] Summary of Weight Values ​​- Females

[0223]

[0224]

[0225] N = number of measurements used to calculate the mean.

[0226] AD = Standard Deviation

[0227] a-Significantly different from control, p<0.05

[0228] b-Significantly different from control, p<0.01

[0229] Example 4 - Certain non-limiting embodiments

[0230] A1. A method for treating or preventing obesity, assisting or inducing weight loss, suppressing appetite, or suppressing weight gain in a subject, the method comprising administering a therapeutically effective amount of a compound having a structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0231]

[0232] in:

[0233] R 2 is selected from H and methyl;

[0234] R 3 is trifluoromethyl or other fluorine-substituted alkyl;

[0235] L 3 is a carbonyl group; and

[0236] R 6 is independently selected at each occurrence from alkyl, methyl, methoxy, perfluoromethyl, perfluoromethoxy, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxy, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, mercapto, alkylthio, arylthio, carbonyl, aryl, substituted aryl, substituted heterocyclyl, halogen, cyano, cyanoalkyl, nitro, amino, amidino, carbamate, S(O) n R 7 and C(O)R 8, or two R in adjacent positions 6 combines to form an optionally substituted heteroaryl or heteroalkyl ring fused to an adjacent phenyl moiety;

[0237] R 7 It is H, R 9 、NH2、HNR 9 or NR 9 R 10 ;

[0238] R 8 It is OH, OR 9 、NH2、NHR 9 or NR 9 R 10 ;

[0239] R 9 and R 10 is independently at each occurrence optionally substituted alkyl; and

[0240] n=1 or 2.

[0241] A2. The method of embodiment A1, wherein R 6 is selected at each occurrence from alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, halogen, and C(O)R 8 .

[0242] A3. The method of embodiment A2, wherein R 6 is selected at each occurrence from methyl, methoxy, perfluoromethyl, perfluoromethoxy, hydroxy, Cl, F and I.

[0243] A4. The method of embodiment A1, wherein the compound has the structure of Formula II; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,

[0244]

[0245] in:

[0246] (i)R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is a methyl group, and R B4 is methyl; or

[0247] (ii) R A2 , R A3 , R A5 and R A6 Yes H, R A4 is methoxy, R B2is a methyl group, and R B4 is methyl; or

[0248] (iii) R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is H, and R B4 is H; or

[0249] (iv) R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is a methyl group, and R B4 is methyl; or

[0250] (v)R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is H, and R B4 is H; or

[0251] (vi)R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is H, and R B4 is methyl; or

[0252] (vii) R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is H, and R B4 is methyl; or

[0253] (viii) R A2 , R A3 , R A4 , R A5 and R A6 Yes H, R B2 is a methyl group, and R B4 is H; or

[0254] (ix)R A2 , R A4 , R A5 and R A6 Yes H, RA3 is methoxy, R B2 is a methyl group, and R B4 is H; or

[0255] (x)R A2 , R A3 , R A5 and R A6 Yes H, R A4 is COOH, R B2 is a methyl group, and R B4 is methyl; or

[0256] (xi)R A2 , R A4 and R A5 Yes H, R A3 and R A6 is hydroxyl, R B2 is a methyl group, and R B4 is methyl; or

[0257] (xii)R A2 , R A4 and R A6 Yes H, R A3 and R A5 is hydroxyl, R B2 is a methyl group, and R B4 is methyl; or

[0258] (xiii)R A2 , R A4 and R A5 Yes H, R A3 is methoxy, R A6 It's F, R B2 is H, and R B4 is Cl; or

[0259] (xiv)R A3 and R A5 Yes H, R A2 and R A6 It's F, R A4 is hydroxyl, R A6 It's F, R B2 is H, and R B4 is F; or

[0260] (xv)R A2 , R A4 and R A6 Yes H, R A3 is hydroxyl, R A5 It's F, R B2 is H, and R B4 is F; or

[0261] (xvi)RA2 , R A5 and R A6 Yes H, R A3 and R A4 Together they are -O-CH2-O-, R A5 It's F, R B2 is H, and R B4 It's F.

[0262] A5. The method of embodiment A4, wherein R A2 , R A4 , R A5 and R A6 Yes H, R A3 is methoxy, R B2 is a methyl group, and R B4 It's methyl.

[0263] B1. A method for preventing or treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula IV, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0264] C1. A method for preventing or treating obesity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound selected from any one of Formulae I to IV, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0265] C1.1 A method for preventing weight gain in a subject, comprising administering to the subject a therapeutically effective amount of a compound selected from any one of Formulae I to IV, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0266] C1.2 A method for inducing weight loss in a subject, comprising administering to the subject a therapeutically effective amount of a compound selected from any one of Formulae I to IV, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0267] C1.3 A method for suppressing appetite in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound selected from any one of Formulae I to IV, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

[0268] C1.4. The method of any one of embodiments C1 to C1.3, wherein the subject is a human.

[0269] C2. The method of any one of embodiments C1 to C1.4, wherein the compound comprises the structure of Formula I.

[0270] C3. The method of embodiment C2, wherein the compound comprises the structure of Formula III; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof,

[0271]

[0272] wherein R1 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl or tribromomethyl; R2 is methyl, methoxy, hydroxyl, halogen, CF3, OCH3, OCF3 or OCBr3; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen (e.g., Cl, F or Br), methyl, methoxy or amine.

[0273] C4. The method of embodiment C3, wherein the compound comprises a structure of Formula IV; or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof;

[0274]

[0275] C5. The method of any one of embodiments C1 to C4, wherein the compound is administered once a day, twice a day, or three times a day.

[0276] C6. The method of any one of embodiments C1 to C5, wherein the compound is administered at a dose of 0.1 mg / kg to 100 mg / kg.

[0277] C7. The method of any one of embodiments C1 to C6, wherein the compound is administered orally or intravenously.

[0278] C8. The method of any one of embodiments C1 to C7, wherein the subject is obese.

[0279] C9. The method of any one of embodiments C1 to C8, wherein the subject has or has had a BMI of 30 or greater.

[0280] C10. The method of any one of embodiments C1 to C9, wherein the subject has a desire to lose weight.

[0281] C11. The method of any one of embodiments C1 to C10, wherein the subject has an eating disorder.

[0282] C12. The method of any one of embodiments C1 to C11, wherein the subject has or is suspected of having hyperphagia.

[0283] C13. The method of any one of embodiments C1 to C12, wherein the subject has or is suspected of having compulsive eating disorder or binge eating disorder.

[0284] C14. The method of any one of embodiments C1 to C13, wherein the subject has a history of compulsive overeating or binge eating.

[0285] C15. The method of any one of embodiments C1 to C14, wherein the subject has a history of eating more than 3000 calories per day.

[0286] C16. The method of any one of embodiments C1 to C15, wherein the subject is a human desiring to lose weight.

[0287] C17. The method of any one of embodiments C1 to C16, wherein the subject has or is suspected of having diabetes.

[0288] C18. The method of any one of embodiments C1 to C17, wherein the subject has or is suspected of having cardiovascular disease.

[0289] C19. The method of any one of embodiments C1 to C18, wherein the subject is at risk of having or developing diabetes, heart disease, or cardiovascular disease.

[0290] C20. The method of any one of embodiments C1 to C19, wherein the subject is a mammal.

[0291] C21. The method of C20, wherein the subject is human.

[0292] C22. The method of C20, wherein the subject is a non-human primate.

[0293] C23. The method of C20, wherein the subject is a dog.

[0294] C24. The method of C20, wherein the subject is a cat.

[0295] D1. A compound comprising a structure selected from any one of Formula I, Formula II, Formula III, and Formula IV, for performing the method of any one of Embodiments C1 to C19.

[0296] D2. A pharmaceutical composition containing a compound comprising a structure selected from any one of Formula I, Formula II, Formula III and Formula IV for use in performing the method of any one of Embodiments C1 to C19.

[0297] ***

[0298] The entire contents of each patent, patent application, publication or any other reference or document cited herein are hereby incorporated by reference. In case of conflict, the specification, including definitions, will control.

[0299] Citation of any patent, patent application, publication or any other document is not an admission that any of the foregoing is relevant prior art nor does it constitute any admission as to the contents or date of such publication or document.

[0300] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.

[0301] All features disclosed herein can be combined in any combination. Each feature disclosed in the specification can be replaced by an alternative feature for the same, equivalent or similar purpose. Thus, unless explicitly stated otherwise, the disclosed feature (e.g., antibody) is an example of a type of equivalent or similar feature.

[0302] All numerical values ​​or numerical ranges used herein include integers within such ranges and fractions of values ​​or integers within the ranges, unless the context clearly indicates otherwise. In addition, when a list of values ​​is described herein (e.g., about 50%, 60%, 70%, 80%, 85%, or 86%), the list includes all intermediate values ​​and fractional values ​​thereof (e.g., 54%, 85.4%). Thus, for illustration, references to 80% or more entities include 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, etc., as well as 81.1%, 81.2%, 81.3%, 81.4%, 81.5%, etc., 82.1%, 82.2%, 82.3%, 82.4%, 82.5%, etc., and so on.

[0303] References to integers having a plural number (greater than) or a plural number (less than) include any number greater than or less than the referenced number, respectively. Thus, for example, reference to less than 100 includes 99, 98, 97, etc., up to the number one (1); and less than 10 includes 9, 8, 7, etc., up to the number one (1).

[0304] As used herein, all numerical values ​​or ranges include fractions of values ​​and integers within such ranges, as well as fractions of integers within such ranges, unless the context clearly indicates otherwise. Thus, for illustration, reference to numerical ranges, such as 1-10, includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 1.1, 1.2, 1.3, 1.4, 1.5, etc., and the like. Reference to a range of 1-50 therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., up to and including 50, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., 2.1, 2.2, 2.3, 2.4, 2.5, etc., and the like.

[0305] Reference to a series of ranges includes ranges combining the boundary values ​​of different ranges within the series. Thus, to illustrate reference to a series of ranges, for example, 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-75, 75-100, 100-150, 150-200, 200-250, 250-300, 300-400, 400-500, 500-750, 750-1,000, 1,000-1,500, 1,500-2,000, 2,000-2,000, 3,000-4,000, 5,000-6,000, 6,000-7,000, 7,000-8,000, 8,000-9,000, 9,000-10,000-11,000, 9,000-12,000, 9,000-13,000, 9,000-14,000, 9,000-15,000, 9,000-1 -9,000, including ranges of 10-50, 50-100, 100-1,000, 1,000-3,000, 2,000-4,000, etc.

[0306] The foregoing may be modified without departing from the basic aspects of the technology. Although the technology has been described in considerable detail with reference to one or more specific embodiments, those skilled in the art will recognize that changes may be made to the embodiments specifically disclosed in this application, but such modifications and improvements are within the scope and spirit of the technology.

[0307] The present invention is generally disclosed herein using positive language to describe numerous embodiments and aspects. The present invention also specifically includes embodiments in which specific themes (such as substances or materials, method steps and conditions, schemes or procedures) are excluded in whole or in part. For example, in certain embodiments or aspects of the present invention, materials and / or method steps are excluded. Therefore, even if the present invention generally does not express the aspects that the present invention does not include in this article, the aspects that are not explicitly excluded in the present invention are still disclosed in this article. Some embodiments of the technology described herein can be appropriately practiced without the presence of elements that are not specifically disclosed herein. Therefore, in certain embodiments, the term "including" or "comprising" can be replaced with "essentially consisting of..." or "consisting of..." or its grammatical variants. The term "one" or "a kind" can represent one / kind or more / kind (for example, "a reagent" can refer to one or more reagents) of the elements it modifies, unless the context clearly describes one of the elements or more than one element. As used herein, the term "about" refers to a value within 10% of the underlying parameter (i.e., plus or minus 10%), and the term "about" is used at the beginning of a string of values ​​to modify each value (i.e., "about 1, 2, and 3" refers to about 1, about 2, and about 3). For example, a weight of "about 100 grams" can include a weight between 90 grams and 110 grams. As used herein, the term "substantially" refers to a value modifier, meaning "at least 95%, "at least 96%, "at least 97%, "at least 98%", or "at least 99%, and can include 100%. For example, a composition that is substantially free of X can include less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of X, and / or X can be absent or undetectable in the composition.

Claims

1. Use of a compound having a structure of formula IV or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in the preparation of a medicament for treating or preventing obesity, assisting or inducing weight loss, suppressing appetite or suppressing weight gain in a subject, (IV).

2. The use of claim 1, wherein the subject is a human.

3. The use of claim 1, wherein the compound is administered at a dose of 0.1 mg / kg to 1000 mg / kg.

4. The use of claim 1, wherein the compound is administered at a dose of 1 mg / kg to 300 mg / kg.

5. The use of claim 1, wherein the compound is administered orally or intravenously.

6. The use of claim 1, wherein the compound is formulated as a tablet or a capsule.

7. The use of claim 6, wherein the tablet or capsule contains 1, 5, 10, 50, 100 or 500 mg of the compound.

8. The use of claim 1, wherein the subject is an adult with a body mass index of 25 or greater.

9. The use of claim 8, wherein the subject has a body mass index of 30 or greater.

10. The use of claim 1, wherein the subject has diabetes or is at risk of having diabetes.

11. The use according to claim 10, wherein the diabetes is type II diabetes.

12. The use of claim 1, wherein the subject has hypertension.

13. The use of claim 1, wherein the subject has fatty liver disease.

14. The use of claim 1, wherein the subject has heart disease or cardiovascular disease, or is at risk of having heart disease or cardiovascular disease.

15. The use of claim 1, wherein the compound is administered once a day.

16. The use of claim 1, wherein the compound is administered 0.1-3 hours before exercise.

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