Pharmaceutical formulations and methods for treating metabolic and liver conditions

Abstract

Disclosed herein are formulations of small molecule GIP / GLP-1 dual receptor agonists and uses thereof.

Description

[0001] Reference sequence list

[0002] This application is submitted in electronic format along with a sequence listing. The sequence listing is provided as a file named VIKNG.024WO.xml, which was created on July 17, 2023 and is 51,632 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

[0003] background

[0004] field

[0005] The present disclosure relates generally to the fields of chemistry and medicine. More specifically, the present disclosure relates to pharmaceutical formulations for treating metabolic disorders and fatty liver disease.

[0006] Description of Related Technology

[0007] Incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are metabolic hormones. Both GIP and GLP-1 are secreted within a few minutes of nutrient intake and promote rapid processing of ingested nutrients. The two peptides have a common effect on pancreatic β cells, which act through structurally different but related receptors. Incretin receptor activation leads to glucose-dependent insulin secretion, induction of β-cell proliferation and enhanced resistance to apoptosis. GIP also promotes energy storage by acting directly on adipose tissue. In contrast, GLP-1 exerts a glucose-regulating effect by slowing gastric emptying and glucose-dependent inhibition of glucagon secretion. In preclinical and clinical studies, GLP-1 also promotes satiety, and sustained GLP-1 receptor activation is associated with weight loss.

[0008] Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and is the most common cause of chronic liver disease. NAFLD may progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. GIP / GLP-1 dual receptor agonists have been developed for the treatment of NAFLD, non-alcoholic steatohepatitis (NASH), diabetes, obesity and other diseases. However, the use of GIP / GLP-1 dual receptor agonists is associated with nausea, vomiting and / or diarrhea. For example, clinical trials of GIP / GLP1 dual receptor agonist compounds have found that high-dose tolerance is limited by gastrointestinal adverse events. The dose restrictions associated with gastrointestinal adverse events may prevent administration to the desired effective dose, may impair patient compliance with treatment, and may limit the effectiveness of treatment regimens. Therefore, there is a demand for GIP / GLP1 dual agonist compounds that can be used to treat fatty liver disease and other diseases and conditions. In addition, there is a demand for suitable pharmaceutical preparations for such dual agonist compounds.

[0009] Overview

[0010] Disclosed herein are pharmaceutical compositions, some of which comprise a compound having the structure of Formula I:

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein:

[0013] Aib is 2-aminoisobutyric acid;

[0014] J 1 , J 2 and J 3 wherein each instance is independently an amino acid selected from Aib, naturally occurring amino acids, and unnatural amino acids;

[0015] U 1 For -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 -;

[0016] U 2 For -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 -;

[0017] J 4 , J 5 , J 6 , J 7 , J 8 , J 9 , J 10 and J 11 Each instance in is independently a naturally occurring amino acid or an unnatural amino acid;

[0018] Each of n1, n2, n3, n4, n5, n6, n7 and n8 is independently 0 or 1, provided that the sum of n1+n2+n3+n4+n5+n6+n7+n8 is 4;

[0019] R 1 Selected from -C(=O)(OZ 1), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0020] R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0021] Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0022] X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0023] Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryl and C 7-11 Arylalkyl;

[0024] Each R 5 are independently hydrogen or C 1-6 alkyl;

[0025] Each R 6 are independently hydrogen or C 1-6 Alkyl; and

[0026] Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl.

[0027] In some embodiments, the pharmaceutical composition does not contain a compound:

[0028]

[0029] Some embodiments include J 1 , J 2 and J 3 Each example in which is an amino acid independently selected from Aib and naturally occurring amino acids. Some embodiments include J 1 , J 2 and J 3 Each example in which is an amino acid independently selected from Aib, A, F, N, R and Q. Some embodiments include compounds of Formula I wherein J 1 is Aib or F. Some embodiments include compounds of formula I wherein J 1 is F. Some embodiments include compounds of Formula I wherein J 2 is N or Q. Some embodiments include compounds of Formula I wherein J 2 is N. Some embodiments include compounds of Formula I wherein J 3 is A or R. Some embodiments include compounds of Formula I wherein 3 Some embodiments include compounds of Formula I wherein J 4 , J 5 , J 6 and J 7 Each example in which is an amino acid independently selected from A, I, K, R, Q, S, T, and V. Some embodiments include compounds of Formula I wherein J 4 is K or R. Some embodiments include compounds of Formula I wherein J 4 Some embodiments include compounds of Formula I wherein J 5 is I, T or V. Some embodiments include compounds of Formula I wherein J 5 is T or V. Some embodiments include compounds of Formula I wherein J 6is A or S. Some embodiments include compounds of Formula I wherein J 6 Some embodiments include compounds of Formula I wherein J 7 is Q. Some embodiments include compounds of Formula I wherein J 8 , J 9 , J 10 and J 11 Each example in is an amino acid independently selected from A, I or Q. Some embodiments include compounds of formula I wherein J 8 is I or Q. Some embodiments include compounds of formula I wherein J 9 is I or Q. Some embodiments include compounds of formula I wherein J 10 is Q. Some embodiments include compounds of Formula I wherein J 11 For Q.

[0030] Some embodiments include a pharmaceutical composition wherein

[0031] In the compound of formula I, J 1 Selected from Aib or F;

[0032] In the compound of formula I, J 2 Select from Q or N;

[0033] In the compound of formula I, J 3 Selected from A or R;

[0034] U in the compound of formula I 1 is selected from -KVA-, -KIAQ-, -KTAQ-, -KTSQ-, -KVAQ-, -RIAQ-, or is absent; and

[0035] U in the compound of formula I 2 Selected from -Q-, -IAQQ-, or absent.

[0036] Some embodiments include compounds of Formula I wherein each instance of n1, n2, n3, and n4 is zero. Some embodiments include compounds of Formula I wherein each instance of n4, n6, n7, and n8 is zero. Some embodiments include compounds of Formula I wherein each instance of n4, n6, n7, and n8 is zero. Some embodiments include compounds of Formula I wherein Z 1 and Z 2 At least one of them is not hydrogen.

[0037] Some embodiments include pharmaceutical compositions comprising a compound having the structure of Formula Ia:

[0038]

[0039] or a pharmaceutically acceptable salt thereof.

[0040] Some embodiments include Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 Some embodiments include compounds of Formula Ia wherein Z 1 is hydrogen, and each R in the compound of formula Ia 4 are independently hydrogen or C 7-11 Some embodiments include compounds of Formula Ia wherein each R 4 Some embodiments include compounds of Formula Ia wherein Z 1 is hydrogen, and each R in the compound of formula Ia 4 For hydrogen.

[0041] Some embodiments include pharmaceutical compositions comprising a compound having the structure of Formula Ib:

[0042]

[0043] or a pharmaceutically acceptable salt thereof.

[0044] Some embodiments include compounds of Formula Ib wherein each R 4 are independently selected from hydrogen, C 6-10 Aryl and C 7-11 Some embodiments include compounds of Formula Ib wherein each R 4 For hydrogen.

[0045] Some embodiments include pharmaceutical compositions comprising a compound selected from the group consisting of:

[0046]

[0047]

[0048]

[0049]

[0050] or a pharmaceutically acceptable salt thereof.

[0051] Some embodiments include pharmaceutical compositions comprising a compound having the structure of Formula II:

[0052]

[0053] or a pharmaceutically acceptable salt thereof, wherein:

[0054] R 1 Selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0055] R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0056] Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0057] X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0058] Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C6-10 Aryloxy and C 6-10 Arylalkoxy;

[0059] Each R 5 are independently hydrogen or C 1-6 alkyl;

[0060] Each R 6 are independently hydrogen or C 1-6 Alkyl; and

[0061] Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl,

[0062] Where Z 1 and Z 2 At least one of them is not hydrogen.

[0063] Some embodiments include pharmaceutical compositions comprising a compound having the structure of Formula II-a:

[0064]

[0065] or a pharmaceutically acceptable salt thereof.

[0066] Some embodiments include Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 Some embodiments include Z 1 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Some embodiments include Z 1 is hydrogen, and each R 4 are independently hydrogen or C 6-10 Some embodiments include each R 4 is hydrogen. Some embodiments include Z 1 is hydrogen, and each R 4 For hydrogen.

[0067] Some embodiments include pharmaceutical compositions comprising a compound having the structure of Formula III-b:

[0068]

[0069] or a pharmaceutically acceptable salt thereof.

[0070] Some embodiments include Z 2 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 Some embodiments include Z 2 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Some embodiments include Z 2 is hydrogen, and each R 4 is hydrogen or C 6-10 Some embodiments include each R 4 is hydrogen. Some embodiments include Z 2 is hydrogen, and each R 4 For hydrogen.

[0071] Some embodiments include pharmaceutical compositions comprising a compound having the structure of Formula II-c:

[0072]

[0073] or a pharmaceutically acceptable salt thereof.

[0074] Some embodiments include X and Y are each -OR 4 Some embodiments include each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Some embodiments include each R 4 For hydrogen.

[0075] Some embodiments include a pharmaceutical composition comprising a compound having a structure selected from the group consisting of:

[0076]

[0077]

[0078]

[0079]

[0080] and pharmaceutically acceptable salts thereof.

[0081] Some embodiments include a "*" to indicate a chiral carbon having an "S" configuration. Some embodiments include a "*" to indicate a chiral carbon having an "R" configuration.

[0082] Some embodiments include a pharmaceutical composition comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0083] Some embodiments disclosed herein include pharmaceutical compositions for administration to a subject in need thereof, wherein the pharmaceutical composition comprises: one or more non-aqueous solvents or solubility enhancers, which account for less than 20% by weight of the pharmaceutical composition; and a therapeutically effective dose of a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.

[0084] Some embodiments disclosed herein include pharmaceutical compositions wherein one or more non-aqueous solvents or solubility enhancers comprise less than 10% by weight of the composition.

[0085] Some embodiments disclosed herein include pharmaceutical compositions wherein one or more non-aqueous solvents or solubility enhancers comprise less than 5% by weight of the composition.

[0086] Some embodiments disclosed herein include pharmaceutical compositions wherein the one or more non-aqueous solvents or solubility enhancers include propylene glycol.

[0087] Some embodiments disclosed herein include pharmaceutical compositions wherein propylene glycol is present in a weight percent equal to or less than about 10%.

[0088] Some embodiments disclosed herein include pharmaceutical compositions wherein propylene glycol is present at a weight percentage equal to or less than about 2%.

[0089] Some embodiments disclosed herein include pharmaceutical compositions wherein propylene glycol is present in a weight percent range of about 0.1% to about 2%.

[0090] Some embodiments disclosed herein include pharmaceutical compositions wherein propylene glycol is present in a weight percent range of about 0.4% to about 1.5%.

[0091] Some embodiments disclosed herein include pharmaceutical compositions wherein the one or more non-aqueous solvents or solubility enhancers include a polysorbate.

[0092] Some embodiments disclosed herein include pharmaceutical compositions wherein the polysorbate is present in a weight percent range of about 0.001% to about 0.1%.

[0093] Some embodiments disclosed herein include pharmaceutical compositions wherein the polysorbate is present in a weight percent range of about 0.003% to about 0.05%.

[0094] Some embodiments disclosed herein include pharmaceutical compositions wherein the polysorbate is polysorbate 80.

[0095] Some embodiments disclosed herein include pharmaceutical compositions wherein the polysorbate is polysorbate 20.

[0096] Some embodiments disclosed herein include pharmaceutical compositions wherein the one or more non-aqueous solvents or solubility enhancers include glycerol.

[0097] Some embodiments disclosed herein include pharmaceutical compositions wherein glycerol is present in an amount of about 0.5% to about 5% by weight.

[0098] Some embodiments disclosed herein include pharmaceutical compositions wherein the one or more non-aqueous solvents or solubility enhancers include m-cresol.

[0099] Some embodiments disclosed herein include pharmaceutical compositions wherein m-cresol is present in an amount of about 0.1% to about 1% by weight.

[0100] Some embodiments disclosed herein include pharmaceutical compositions wherein the one or more non-aqueous solvents or solubility enhancers include phenol.

[0101] Some embodiments disclosed herein include pharmaceutical compositions wherein phenol is present in an amount of about 0.1% to about 1% by weight.

[0102] Some embodiments disclosed herein include pharmaceutical compositions wherein phenol is present in a weight percent range of about 0.1% to about 0.6%.

[0103] Some embodiments disclosed herein include pharmaceutical compositions comprising about 0.1% to about 5% by weight propylene glycol and about 0.1% to about 1% by weight phenol.

[0104] Some embodiments disclosed herein include pharmaceutical compositions comprising from about 0.001% to about 0.01% by weight of polysorbate 80.

[0105] Some embodiments disclosed herein include pharmaceutical compositions comprising lactose and a therapeutically effective dose of a compound having the structure of Formula II or a pharmaceutically acceptable salt thereof:

[0106]

[0107] in:

[0108] R 1 Selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0109] R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0110] Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0111] X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0112] Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Arylalkyl;

[0113] Each R 5 are independently hydrogen or C 1-6 alkyl;

[0114] Each R 6 are independently hydrogen or C 1-6 Alkyl; and

[0115] Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl,

[0116] Where Z 1 and Z 2 At least one of them is not hydrogen.

[0117] Some embodiments disclosed herein include pharmaceutical compositions in which lactose is present as lactose monohydrate at a weight percentage of about 2% to about 10%. Some embodiments include a "*" representing a chiral carbon with an "S" configuration. Some embodiments include a "*" representing a chiral carbon with an "R" configuration. Some embodiments include a pharmaceutically acceptable aqueous carrier. Some embodiments include an aqueous carrier that is water or saline. Some embodiments include a pharmaceutical composition comprising a buffer. In some embodiments, the buffer comprises sodium citrate, disodium phosphate, L-histidine, methionine, tartrate, citrate, acetate, 2-(N-morpholino)ethanesulfonic acid (MES), piperazine-N,N'-bis(2-ethanesulfonic acid (PIPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TAPSO) , N-[tris(hydroxymethyl)methyl]glycine (Tricine), tris(hydroxymethyl)aminomethane (Tris), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), N-cyclohexyl-2-aminoethanesulfonic acid (CHES), phosphate, borate or any combination thereof. Some embodiments include a buffer comprising sodium citrate. Some embodiments include a buffer comprising disodium phosphate. Some embodiments include a buffer comprising L-histidine. Some embodiments include a buffer comprising methionine.

[0118] Some embodiments include pharmaceutical compositions wherein the pH of the composition is about 2 to 12. Some embodiments include pharmaceutical compositions wherein the pH of the composition is about 5.0 to 7.5. Some embodiments include pharmaceutical compositions wherein the pH of the composition is about 6.0. Some embodiments include pharmaceutical compositions wherein the composition is configured for subcutaneous administration. Some embodiments include pharmaceutical compositions wherein the composition is a liquid.

[0119] Some embodiments disclosed herein include pharmaceutical compositions wherein Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

[0120] Some embodiments disclosed herein include pharmaceutical compositions wherein Z 1Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 are independently selected from hydrogen, C 6-10 Aryl and C 6-10 Arylalkyl.

[0121] Some embodiments disclosed herein include pharmaceutical compositions wherein Z 1 is hydrogen, and each R 4 are independently hydrogen or C 6-10 Arylalkyl.

[0122] Some embodiments disclosed herein include pharmaceutical compositions wherein each R 4 For hydrogen.

[0123] Some embodiments disclosed herein include pharmaceutical compositions wherein the compound has a structure consisting of:

[0124]

[0125] Certain embodiments disclosed herein include pharmaceutical compositions, wherein "*" represents a chiral carbon having an "S" configuration.

[0126] Certain embodiments disclosed herein include pharmaceutical compositions wherein "*" represents a chiral carbon having an "R" configuration.

[0127] Some embodiments disclosed herein include pharmaceutical compositions comprising a pharmaceutically acceptable aqueous carrier.

[0128] Some embodiments disclosed herein include pharmaceutical compositions wherein the aqueous carrier is water or saline.

[0129] Some embodiments disclosed herein include pharmaceutical compositions, wherein the composition comprises a buffer.

[0130] Some embodiments disclosed herein include pharmaceutical compositions wherein the buffer comprises sodium citrate, disodium phosphate, L-histidine, methionine, tartrate, citrate, acetate, 2-(N-morpholino)ethanesulfonic acid (MES), piperazine-N,N'-bis(2-ethanesulfonic acid (PIPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid (HEPES), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TAPSO), N-[tris(hydroxymethyl)methyl]glycine (Tricine), tris(hydroxymethyl)aminomethane (Tris), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), N-cyclohexyl-2-aminoethanesulfonic acid (CHES), phosphate, borate or any combination thereof.

[0131] Some embodiments disclosed herein include pharmaceutical compositions wherein the buffer comprises sodium citrate.

[0132]

[0013] Some embodiments disclosed herein include pharmaceutical compositions wherein the buffer comprises disodium phosphate.

[0133] Some embodiments disclosed herein include pharmaceutical compositions wherein the buffer comprises L-histidine.

[0134]

[0013] Some embodiments disclosed herein include pharmaceutical compositions wherein the buffer comprises methionine.

[0135] Some embodiments disclosed herein include pharmaceutical compositions wherein the pH of the composition is about 2-12.

[0136] Some embodiments disclosed herein include pharmaceutical compositions wherein the pH of the composition is about 5.0 to 7.5.

[0137] Some embodiments disclosed herein include pharmaceutical compositions wherein the pH of the composition is about 6.0.

[0138] Some embodiments disclosed herein include pharmaceutical compositions, wherein the composition is configured for subcutaneous administration.

[0139] Some embodiments disclosed herein include pharmaceutical compositions, wherein the composition is in liquid form.

[0140] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises about 0.47% propylene glycol, about 0.18% phenol, about 0.037% anhydrous disodium phosphate, and about 1.5% of a compound of Formula I or Formula II by weight.

[0141] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises about 4.9% sorbitol, about 0.12% L-histidine, about 0.09% methionine, about 1.5% of a compound of Formula I or Formula II, and about 0.04% polysorbate 20 by weight.

[0142] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises, by weight, approximately 0.94% propylene glycol, approximately 0.36% phenol, approximately 0.074% disodium phosphate anhydrous, approximately 1.5% of a compound of Formula I or Formula II, and approximately 0.005% polysorbate 80.

[0143] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises, by weight, approximately 0.8% sodium chloride, approximately 0.193% sodium citrate dihydrate, approximately 0.01% polysorbate 80, approximately 1.5% of a compound of Formula I or Formula II, and approximately 0.018% EDTA.2Na.

[0144] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises, by weight, approximately 5.802% trehalose dihydrate, approximately 0.005% polysorbate 80, approximately 0.0072% methionine, approximately 0.108% sodium citrate dihydrate, approximately 1.5% of a compound of Formula I or Formula II, and approximately 1.5% mannitol.

[0145] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises, by weight, approximately 1.21% glycerol, approximately 0.441% sodium citrate dihydrate, approximately 0.102% magnesium chloride hexahydrate, approximately 1.5% compound of Formula I or Formula II, and approximately 0.0039% zinc oxide.

[0146] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises about 0.3% m-cresol, about 0.441% sodium citrate dihydrate, about 1.5% of a compound of Formula I or Formula II, and about 4.54% mannitol by weight.

[0147] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises about 4.9% lactose monohydrate, about 0.113% disodium phosphate anhydrous, and about 1.5% of a compound of Formula I or Formula II by weight.

[0148] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises, by weight, approximately 1.40% propylene glycol, approximately 0.55% phenol, approximately 1.5% compound of Formula I or Formula II, approximately 0.113% disodium phosphate anhydrous, and approximately 0.005% polysorbate 80.

[0149] Some embodiments disclosed herein include pharmaceutical compositions, wherein the pharmaceutical composition comprises one or more of the following: propylene glycol, phenol, m-cresol, disodium phosphate anhydrous, glycerol, mannitol, zinc oxide, magnesium chloride hexahydrate, L-histidine, methionine, sorbitol, sodium chloride, trehalose dihydrate, lactose monohydrate, sodium citrate dihydrate, polysorbate 80, polysorbate 20, and EDTA.2Na.

[0150] Some embodiments disclosed herein include methods of preventing, treating, or ameliorating one or more fatty liver diseases in a subject, the methods comprising administering a pharmaceutical composition to a subject in need thereof.

[0151] Some embodiments disclosed herein include methods, wherein the fatty liver disease is selected from steatosis, nonalcoholic steatohepatitis, and nonalcoholic fatty liver disease.

[0152] Some embodiments disclosed herein include methods, wherein said administering of said pharmaceutical composition results in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a fibrotic symptom.

[0153] Some embodiments disclosed herein include methods, wherein said administering of said pharmaceutical composition results in a decrease in the amount of an extracellular matrix protein present in one or more tissues of said subject.

[0154] Some embodiments disclosed herein include methods, wherein said administering of said pharmaceutical composition results in a decrease in the amount of collagen present in one or more tissues of said subject.

[0155] Some embodiments disclosed herein include methods, wherein said administering of said pharmaceutical composition results in a decrease in the amount of type I, type Ia, or type III collagen present in one or more tissues of said subject.

[0156] Some embodiments disclosed herein include methods of preventing, treating, or ameliorating one or more diseases or conditions in a subject, the method comprising administering a pharmaceutical composition to a subject in need thereof, wherein the disease or condition is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

[0157] Some embodiments disclosed herein include methods, wherein the disease or disorder is nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, or primary biliary cirrhosis.

[0158] Some embodiments disclosed herein include pharmaceutical formulations wherein the therapeutically effective dose starts at about 1.0 mg / kg.

[0159] Some embodiments disclosed herein include methods wherein the route of administration is subcutaneous. BRIEF DESCRIPTION OF THE DRAWINGS

[0161] Figure 1 is a graph depicting mean plasma concentration versus time profiles following administration of Compound 4 in Formulations 1-8 in male monkeys; and

[0162] Figure 2 is a graph depicting the mean plasma concentration versus time profiles following administration of certain compounds of Formula I or Formula II in Formulations 9-13 in male monkeys.

[0163] Details

[0164] In some embodiments, a pharmaceutical preparation for administration to a subject in need is provided. Various embodiments of these pharmaceutical preparations include a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable diluent, and any combination thereof. Some embodiments of the pharmaceutical preparations include a therapeutically effective dose of a compound or a pharmaceutically acceptable salt thereof, as described in other parts of this article. Some embodiments of the pharmaceutical preparations are administered for preventing, treating, or improving one or more fatty liver diseases in a subject.

[0165] Compound

[0166] In some embodiments, the pharmaceutical formulation comprises a compound that is a non-macrocyclic functionalized peptide that is a GIP / GLP-1 dual receptor agonist. Various embodiments of these compounds include compounds having a structure of formula (I) as described herein or a pharmaceutically acceptable salt thereof. The structure of formula (I) includes all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0167]

[0168] or a pharmaceutically acceptable salt thereof. In formula (I) and the compounds described herein, "H-" represents the hydrogen on the N-terminal amine, and "-NH2" represents the amino group forming the C-terminal amide.

[0169] In some embodiments of compounds of Formula (I):

[0170] Aib is 2-aminoisobutyric acid;

[0171] J 1 , J 2 and J 3 Each instance in which is independently an amino acid selected from Aib, naturally occurring amino acids, and unnatural amino acids.

[0172] In some embodiments of compounds of Formula (I):

[0173] U 1 For -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 -;

[0174] U 2 For -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 -;

[0175] J 4 , J 5 , J 6 , J 7 , J 8 , J 9 , J 10 and J 11 Each instance in is independently a naturally occurring amino acid or an unnatural amino acid;

[0176] Each of n1, n2, n3, n4, n5, n6, n7 and n8 is independently 0 or 1, provided that the sum of n1+n2+n3+n4+n5+n6+n7+n8 is 4;

[0177] R 1 Selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0178] R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0179] Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0180] X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0181] Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryl and C 7-11 Arylalkyl;

[0182] Each R 5 are independently hydrogen or C 1-6 alkyl;

[0183] Each R 6 are independently hydrogen or C 1-6 Alkyl; and

[0184] Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl.

[0185] In some embodiments, the compound is not:

[0186]

[0187] In some embodiments of the compound of Formula (I), J 1 , J 2 and J 3 Each instance in which is independently an amino acid selected from Aib and naturally occurring amino acids.

[0188] In some embodiments of the compound of Formula (I), J 1 , J 2 and J 3 Each instance in is independently an amino acid selected from Aib, A, F, N, R, and Q. In some embodiments, J 1 is Aib or F. In some embodiments, J 1 is F. In some embodiments, J 2 is N or Q. In some embodiments, J 2 is N. In some embodiments, J 3 is A or R. In some embodiments, J 3 For R.

[0189] In some embodiments of the compound of Formula (I), J 4 , J 5 , J 6 and J 7 Each instance of J is independently an amino acid selected from A, I, K, R, Q, S, T, and V. In some embodiments, J 4 is K or R. In some embodiments, J 4 is R. In some embodiments, J 5 is I, T or V. In some embodiments, J 5 is T or V. In some embodiments, J 6 is A or S. In some embodiments, J 6 is S. In some embodiments, J 7 For Q.

[0190] In some embodiments of the compound of Formula (I), J 8 , J 9 , J 10 and J 11 Each instance in is independently an amino acid selected from A, I and Q. In some embodiments, J8 is I or Q. In some embodiments, J 9 is A or Q. In some embodiments, J 10 is Q. In some embodiments, J 11 For Q.

[0191] In some embodiments of the compound of Formula (I), J 1 Selected from Aib or F; J 2 Select from Q or N; J 3 Select from A or R; U 1 is selected from -KVA-, -KIAQ-, -KTAQ-, -KTSQ-, -KVAQ-, -RIAQ-, or is absent; U 2 Selected from -Q-, -IAQQ-, or absent.

[0192] In some embodiments of compounds of Formula (I), each instance of n1, n2, n3, and n4 is zero. In some embodiments, each instance of n4, n6, n7, and n8 is zero. In some embodiments, each instance of n5, n6, n7, and n8 is zero.

[0193] In some embodiments of the compound of Formula (I), Z 1 and Z 2 At least one of them is not hydrogen.

[0194] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (Ia):

[0195]

[0196] or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

[0198] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, Z 1 is hydrogen, and each R 4 are independently hydrogen or C 7-11 Arylalkyl.

[0199] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, each R 4 For hydrogen.

[0200] In some embodiments of the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof, Z 1 is hydrogen, and each R 4 For hydrogen.

[0201] Some embodiments of compounds of Formula (I) include compounds having the structure of Formula (Ib):

[0202]

[0203] or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, each R 4 are independently selected from hydrogen, C 6-10 Aryl and C 7-11 Arylalkyl.

[0205] In some embodiments of the compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, each R 4 For hydrogen.

[0206] Some embodiments include compounds having a structure selected from:

[0207]

[0208]

[0209]

[0210]

[0211] or a pharmaceutically acceptable salt thereof.

[0212] Other embodiments of the pharmaceutical formulations described herein include compounds having a structure of Formula II or a pharmaceutically acceptable salt thereof. The structure of Formula II includes all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0213]

[0214] In some embodiments of the compound of Formula II:

[0215] R 1 Selected from -C(=O)(OZ 1), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0216] R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0217] Each R 7 can be independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl;

[0218] X and Y can each independently be selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0219] Each R 4 can be independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Arylalkyl;

[0220] Each R 5 can be independently hydrogen or C 1-6 alkyl;

[0221] Each R 6 can be independently hydrogen or C 1-6 Alkyl; and

[0222] Z 1 and Z 2 can be independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl,

[0223] The condition is Z 1 and Z 2 At least one of them is not hydrogen.

[0224] Some embodiments of compounds of Formula II include compounds having the structure of Formula II-a:

[0225]

[0226] or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments of the compound of Formula II-a or a pharmaceutically acceptable salt thereof, Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

[0228] In some embodiments of the compound of Formula II-a or a pharmaceutically acceptable salt thereof, Z 1 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 can be independently selected from hydrogen, C 6-10 Aryl and C 6-10 Arylalkyl.

[0229] In some embodiments of the compound of Formula II-a or a pharmaceutically acceptable salt thereof, Z 1 is hydrogen, and each R 4 can be independently hydrogen or C 6-10 Arylalkyl.

[0230] In some embodiments of the compound of Formula II-a or a pharmaceutically acceptable salt thereof, each R4 For hydrogen.

[0231] In some embodiments of the compound of Formula II-a or a pharmaceutically acceptable salt thereof, Z 1 is hydrogen, and each R 4 For hydrogen.

[0232] Some embodiments of compounds of Formula II include compounds having the structure of Formula II-b:

[0233]

[0234] or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments of the compound of Formula II-b or a pharmaceutically acceptable salt thereof, Z 2 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

[0236] In some embodiments of the compound of Formula II-b or a pharmaceutically acceptable salt thereof, Z 2 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 can be independently selected from hydrogen, C 6-10 Aryl and C 6-10 Arylalkyl.

[0237] In some embodiments of the compound of Formula II-b or a pharmaceutically acceptable salt thereof, Z 2 is hydrogen, and each R 4 can be independently hydrogen or C 6-10 Arylalkyl.

[0238] In some embodiments of the compound of Formula II-b or a pharmaceutically acceptable salt thereof, each R 4 For hydrogen.

[0239] In some embodiments of the compound of Formula II-b or a pharmaceutically acceptable salt thereof, Z 2 is hydrogen, and each R 4 For hydrogen.

[0240] Some embodiments of compounds of Formula II include compounds having the structure of Formula II-c:

[0241]

[0242] or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments of the compound of Formula II-c or a pharmaceutically acceptable salt thereof, X and Y are each -OR 4 .

[0244] In some embodiments of the compound of Formula II-c or a pharmaceutically acceptable salt thereof, each R 4 can be independently selected from hydrogen, C 6-10 Aryl and C 6-10 Arylalkyl.

[0245] In some embodiments of the compound of Formula II-c or a pharmaceutically acceptable salt thereof, each R 4 For hydrogen.

[0246] Some embodiments include compounds having a structure selected from:

[0247]

[0248]

[0249]

[0250]

[0251]

[0252] and pharmaceutically acceptable salts thereof.

[0253] Some embodiments include compounds wherein "*" represents a chiral carbon having an "S" configuration.

[0254] Some embodiments include compounds wherein "*" represents a chiral carbon having an "R" configuration.

[0255] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers (including racemates). The separation of individual isomers or the selective synthesis of individual isomers is achieved by applying various methods well known to those skilled in the art. Unless otherwise stated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. In addition, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise stated, all such forms are included in the scope of the compounds disclosed herein (including any polymorphic forms). In addition, some compounds disclosed herein can form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise stated, such solvates are included in the scope of the compounds disclosed herein.

[0256] Those skilled in the art will recognize that some structures described herein may be resonance forms or tautomers of compounds, even though they may be reasonably represented kinetically by other chemical structures; the skilled artisan recognizes that such structures may represent only a very small portion of a sample of such compounds. Such compounds are considered to be within the scope of the described structures, even though such resonance forms or tautomers are not represented herein.

[0257] preparation

[0258] Some embodiments include pharmaceutical preparations comprising compounds of Formula I or Formula II (e.g., Compound 4). In some embodiments, the pharmaceutical preparation includes one or more non-aqueous solvents or solubility enhancers. In some embodiments, the pharmaceutical preparation also includes an aqueous carrier, and may be suitable for subcutaneous injection. In some embodiments, one or more non-aqueous solvents or solubility enhancers include one or more of propylene glycol, phenol, meta-cresol, glycerol, polysorbate 80 or polysorbate 20. In some embodiments, one or more non-aqueous solvents or solubility enhancers are non-aqueous solvents (e.g., propylene glycol, phenol, meta-cresol or glycerol). In some embodiments, one or more non-aqueous solvents or solubility enhancers are solubility enhancers (e.g., propylene glycol, phenol, polysorbate 80 or polysorbate 20).

[0259] In some embodiments, one or more non-aqueous solvents or solubility enhancers include propylene glycol. In some embodiments, one or more non-aqueous solvents or solubility enhancers include phenol. In some embodiments, one or more non-aqueous solvents or solubility enhancers are glycerol. In some embodiments, one or more non-aqueous solvents or solubility enhancers include polysorbate 80. In some embodiments, one or more non-aqueous solvents or solubility enhancers include polysorbate 20. In some embodiments, one or more non-aqueous solvents or solubility enhancers include meta-cresol.In some embodiments, the one or more non-aqueous solvents or solubility enhancers are present in an amount equal to or less than about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.020%, 0.030%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.050%, 0.051%, 0.052%, 0.053%, 0.054%, 0.055%, 0.056%, 0.057%, 0.058%, 0.059%, 0.060%, 0.061%, 0.062%, 0.063%, 0.064%, 0.065%, 0.066%, 0.067%, 0.068%, 0.069%, 0.070%, 0.071%, 0.072%, 0.073%, 0.074%, 0.075%, 0.076%, 0.077%, 0.078%, 0.079%, 0.080%, 4%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, 0.060%, 0.070%, 0.080%, 0.090%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0. 18%, 0.19%, 0.20%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.65%, 0.70%, 0.7 5%, 0.80%, 0.85%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.0%, 1.10%, 1.11%, 1.12%, 1.13%, 1.14%, 1.15%, 1.16%, 1. %, 1.24%, 1.25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.0%, 5.0%, 10%, 20%, 30%, 33%, 35%, 37%, 39%, and 40%, or a weight percentage including and / or a range encompassing the above values ​​is present in the formulation.In some embodiments, one or more non-aqueous solvents or solubility enhancers account for less than 10% by weight of the formulation. In some embodiments, one or more non-aqueous solvents or solubility enhancers account for less than 5% by weight of the formulation. In some embodiments, one or more non-aqueous solvents or solubility enhancers are present in the formulation at a weight percentage of about 0.1% to 2.0% by weight. In some embodiments, one or more non-aqueous solvents or solubility enhancers are present in the formulation at a weight percentage of about 0.001% to 5.0%. In some embodiments, one or more non-aqueous solvents or solubility enhancers are present in the formulation at a weight percentage of about 0.01% to 0.1%. In some embodiments, one or more non-aqueous solvents or solubility enhancers are present in the formulation at a weight percentage of about 0.01% to 0.5%.

[0260] In some embodiments, the amount of a compound of Formula I or Formula II (e.g., Compound 4) in a pharmaceutical formulation is equal to or less than about 0.50%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 1.0%, 1.10%, 1.20%, 1.21%, 1.22%, 1.23%, 1.24%, 1.25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.31%, 1.32%, 1.33%, 1.34%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.46%, 1.47%, 1.48%, 1.49%, 1.50%, 1.51%, 1.52%, 1.53%, 1.54%, 1.55%, 1.56%, 1.57%, 1.58%, 1.59%, 1.60%, 1.61%, 1.62%, 1.63%, 1.64%, 1.65%, 1.66%, 1.67%, 1.68%, 1.69%, 1.70%, %, 1.28%, 1.29%, 1.30%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.0%, 5.0%, or a weight percentage including and / or covering the range of the above values. In some embodiments, the amount of the compound of Formula I or Formula II (e.g., Compound 4) in the pharmaceutical preparation ranges from about 0.05 weight % to about 0.5 weight %. In some embodiments, the amount of the compound of Formula I or Formula II (e.g., Compound 4) in the pharmaceutical preparation is about 1.5 weight %. In some embodiments, the amount of the compound of Formula I or Formula II (e.g., Compound 4) in the pharmaceutical preparation is about 0.2 weight %.

[0261] In some embodiments, the one or more non-aqueous solvents or solubility enhancers include propylene glycol. In various embodiments, the amount of propylene glycol in the pharmaceutical formulation is equal to or less than about 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, , 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.65%, 0.70%, 0.75%, 0. .80%, 0.85%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.0%, 1.10%, 1.11%, 1.12%, 1.13%, 1.14%, 1.15%, 1.16%, 1.17%, 1.18%, 1.19%, 1.20%, 1.21%, 1.22%, 1.23%, 1.24 %, 1.25%, 1.26%, 1.27%, 1.28%, 1.29%, 1.30%, 1.35%, 1.36%, 1.37%, 1.38%, 1.39%, 1.40%, 1.41%, 1.42%, 1.43%, 1.44%, 1.45%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.0%, 5.0%, or a weight percentage including and / or covering the range of the above values. In some embodiments, propylene glycol is present in a weight percentage equal to or less than about 10%. In some embodiments, propylene glycol is present in a weight percentage equal to or less than about 2%. In some embodiments, propylene glycol is present in a weight percentage of about 0.1% to about 2%. In some embodiments, propylene glycol is present in a weight percentage of about 0.1% to about 0.5%. In some embodiments, propylene glycol is present in a weight percentage of about 0.4% to about 1.5%. In some embodiments, the amount of propylene glycol in the pharmaceutical preparation is about 1.40 weight %. In some embodiments, propylene glycol is present in a weight percentage of about 0.9% to about 1%. In some embodiments, the amount of propylene glycol in the pharmaceutical preparation is about 0.94 weight %.

[0262] In some embodiments, the one or more non-aqueous solvents or solubility enhancers include phenol. In various embodiments, the amount of phenol in the pharmaceutical formulation is equal to or less than about 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, %, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.0%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 2.0%, or a weight percentage that includes and / or covers the above values. In some embodiments, phenol is present in an amount of about 0.1% to about 1% by weight. In some embodiments, phenol is present in an amount of about 0.1% to about 0.6% by weight. In some embodiments, phenol is present in an amount of about 0.1% to about 0.5% by weight. In some embodiments, the amount of phenol in the pharmaceutical preparation is about 0.55% by weight. In some embodiments, phenol is present in an amount of about 0.3% to about 0.4% by weight. In some embodiments, the amount of phenol in the pharmaceutical preparation is about 0.36% by weight.

[0263] In some embodiments, one or more non-aqueous solvents or solubility enhancers include meta-cresol. In various embodiments, the amount of meta-cresol in the pharmaceutical formulation has a weight percentage equal to or less than about 0.01%, 0.03%, 0.05%, 0.07%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 5%, 10%, or a range including and / or covering the above values. In some embodiments, meta-cresol is present in a weight percentage of about 0.1% to about 1%. In some embodiments, meta-cresol is present in a weight percentage of about 0.01% to about 0.05%. In some embodiments, m-cresol is present at about 0.3% by weight. In some embodiments, m-cresol is present at about 0.02% by weight.

[0264] In some embodiments, one or more non-aqueous solvents or solubility enhancers include glycerol. In various embodiments, the amount of glycerol in the pharmaceutical preparation has equal to or less than 0.1%, 0.3%, 0.5%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 5%, 10%, or the weight percentage of the scope including and / or covering the above values. In some embodiments, glycerol exists with a weight percentage of about 0.5% to about 5%. In some embodiments, glycerol exists with a weight percentage of about 0.01% to about 0.05%. In some embodiments, glycerol exists with a weight percentage of about 1.2% (e.g., 1.21%). In some embodiments, glycerol exists with a weight percentage of about 0.02%.

[0265] In some embodiments, the one or more non-aqueous solvents or solubility enhancers include polysorbate. In various embodiments, the amount of polysorbate in the pharmaceutical formulation is equal to or less than about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.020%, 0.021%, 0.022%, 0.023%, 0.024%, 0.025%, 0.026%, 0.027%, 0.028%, 0.029%, 0.030%, 0.031%, 0.032%, 0.033%, 0.034%, 0.035%, 0.036%, 0.037%, 0.038%, 0.039%, 0.040%, 0.041%, 0.042%, 0.043%, 0.044%, 0.045%, 0.046%, 0.047%, 0.048%, 0.049%, 0.050%, 0.051%, 0.052%, 0.053%, 0.054%, 0.055%, 0.056%, 0.057%, 0.058%, 0.059%, 0.060%, 0.061%, 0.062%, 0.063%, 0.064%, 0.065%, 0.066%, 0 In some embodiments, the amount of polysorbate in the pharmaceutical preparation accounts for about 0.005% by weight of the preparation. In other embodiments, the amount of polysorbate in the pharmaceutical preparation accounts for about 0.005% to 0.01% by weight of the preparation. In some embodiments, polysorbate is present in a weight percentage of about 0.001% to about 0.1%. In some embodiments, polysorbate is present in a weight percentage of about 0.003% to about 0.05%. In some embodiments, polysorbate is present in a weight percentage of about 0.0003% to about 0.005%. In some embodiments, polysorbate is present in a weight percentage of about 0.004% to about 0.006%. In some embodiments, polysorbate is present in a weight percentage of about 0.005%.

[0266] In some embodiments, the polysorbate is polysorbate 80. In some embodiments, polysorbate 80 is present at a weight percentage of about 0.005%. In some embodiments, polysorbate 80 is present at a weight percentage of about 0.01%. In some embodiments, the polysorbate is polysorbate 20. In some embodiments, polysorbate 20 is present at a weight percentage of about 0.04%.

[0267] In some embodiments, the pharmaceutical preparation may contain one or more of the following: propylene glycol, phenol, m-cresol, disodium phosphate anhydrous, glycerol, mannitol, zinc oxide, magnesium chloride hexahydrate, L-histidine, methionine, sorbitol, sodium chloride, trehalose dihydrate, lactose monohydrate, sodium citrate dihydrate, polysorbate 80, polysorbate 20, and EDTA.2Na.

[0268] In some embodiments, the pharmaceutical formulation may contain propylene glycol, phenol, anhydrous disodium phosphate, polysorbate 80, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical formulation may contain approximately 1.40% propylene glycol, 0.55% phenol, 1.5% of a compound of Formula I or Formula II (e.g., Compound 4), 0.113% anhydrous disodium phosphate, and 0.005% polysorbate 80 by weight. In another example, the pharmaceutical formulation may contain approximately 0.94% propylene glycol, 0.36% phenol, 0.074% anhydrous disodium phosphate, 1.5% of a compound of Formula I or Formula II (e.g., Compound 4), and 0.005% polysorbate 80 by weight. In some embodiments, the pharmaceutical formulation may contain about 0.9% to about 1% propylene glycol, about 0.3% to about 0.4% phenol, about 0.004% to about 0.006% polysorbate 80, and about 1 mg / ml to about 5 mg / ml (e.g., about 1 mg / ml to about 2 mg / ml) of Compound 4 by weight.

[0269] In some embodiments, the pharmaceutical formulation may contain glycerol, zinc oxide, magnesium chloride hexahydrate, sodium citrate dihydrate, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical formulation may contain approximately 1.21% glycerol, 0.441% sodium citrate dihydrate, 0.102% magnesium chloride hexahydrate, 1.5% of a compound of Formula I or Formula II (e.g., Compound 4), and 0.0039% zinc oxide by weight.

[0270] In some embodiments, the pharmaceutical preparation may contain one or more of meta-cresol, mannitol, sodium citrate dihydrate, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical preparation may contain approximately 0.3% meta-cresol, 0.441% sodium citrate dihydrate, 1.5% of a compound of Formula I or Formula II (e.g., Compound 4), and 4.54% mannitol by weight.

[0271] In some embodiments, the pharmaceutical formulation may contain one or more of anhydrous disodium phosphate, lactose monohydrate, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical formulation may contain approximately 4.9% lactose monohydrate, 0.113% anhydrous disodium phosphate, and 1.5% of a compound of Formula I or Formula II (e.g., Compound 4) by weight.

[0272] In some embodiments, the pharmaceutical preparation may contain one or more of mannitol, methionine, trehalose dihydrate, sodium citrate dihydrate, polysorbate 80, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical preparation may contain approximately 5.802% trehalose dihydrate, 0.005% polysorbate 80, 0.0072% methionine, 0.108% sodium citrate dihydrate, 1.5% of a compound of Formula I or Formula II (e.g., Compound 4), and 1.5% mannitol by weight.

[0273] In some embodiments, the pharmaceutical preparation may contain one or more of sodium chloride, sodium citrate dihydrate, polysorbate 80, EDTA.2Na, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical preparation may contain approximately 0.8% sodium chloride, 0.193% sodium citrate dihydrate, 0.01% polysorbate 80, 1.5% of a compound of Formula I or Formula II (e.g., Compound 4), and 0.018% EDTA.2Na by weight.

[0274] In some embodiments, the pharmaceutical formulation may contain one or more of L-histidine, methionine, sorbitol, polysorbate 20, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical formulation may contain approximately 4.9% sorbitol, 0.12% L-histidine, 0.09% methionine, 1.5% of a compound of Formula I or Formula II (e.g., Compound 4), and 0.04% polysorbate 20 by weight.

[0275] In some embodiments, the pharmaceutical formulation may contain one or more of propylene glycol, phenol, anhydrous disodium phosphate, and a compound of Formula I or Formula II (e.g., Compound 4). For example, the pharmaceutical formulation may contain approximately 0.47% propylene glycol, 0.18% phenol, 0.037% anhydrous disodium phosphate, and 1.5% of a compound of Formula I or Formula II (e.g., Compound 4) by weight.

[0276] The pharmaceutical preparation may include at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is aqueous. In some embodiments, the pharmaceutically acceptable carrier includes saline or sterile water.

[0277] In some embodiments, the pharmaceutically acceptable carrier is present in the formulation at a weight percentage equal to or less than about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 53%, 55%, 57%, 59%, 60%, 61%, 63%, 65%, 67%, 70%, 75%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or a range including and / or covering the above values. In some embodiments, the pharmaceutically acceptable carrier is present in the formulation at a weight percentage of about 20% to 99% by weight. In some embodiments, the pharmaceutically acceptable carrier is present in the formulation at a weight percentage of about 90% to 98%. In some embodiments, the pharmaceutically acceptable carrier is present in the formulation at a weight percentage of about 94% to 98%.

[0278] In some embodiments, the mass ratio of an aqueous pharmaceutically acceptable carrier (e.g., water) to a non-aqueous solvent or solubility enhancer is equal to or less than 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 300:1, 500:1, 700:1, 1000:1, 1500:1, 2000:1, 2500:1, 3000:1, 4000:1, or a range including and / or encompassing the above values. In some embodiments, the mass ratio of an aqueous pharmaceutically acceptable carrier (e.g., water) to a non-aqueous solvent or solubility enhancer is 10:1 to 50:1.

[0279] In some embodiments, the pharmaceutical formulation comprises a pH buffer. In some embodiments, the pH buffer is selected from tartrate, L-histidine, methionine, disodium phosphate, citrate (e.g., sodium citrate), acetate, 2-(N-morpholino)ethanesulfonic acid (MES), piperazine-N,N'-bis(2-ethanesulfonic acid (PIPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 3-[ N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TAPSO), N-[tris(hydroxymethyl)methyl]glycine (Tricine), tris(hydroxymethyl)aminomethane (Tris), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), N-cyclohexyl-2-aminoethanesulfonic acid (CHES), phosphate, borate, and any combination thereof. In some embodiments, the pharmaceutically acceptable carrier comprises a pH buffer.

[0280] In some embodiments, the pharmaceutical preparation comprises propylene glycol and a pH buffer compound. In some embodiments, the pH buffer comprises tartrate. In some embodiments, the pH buffer comprises disodium phosphate. In some embodiments, the pH buffer comprises tartrate. In some embodiments, the pH buffer comprises citrate (e.g., sodium citrate). In some embodiments, the pH buffer comprises acetate. In some embodiments, the pH buffer compound comprises 2-(N-morpholinyl)ethanesulfonic acid (MES). In some embodiments, the pH buffering compound comprises piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES). In some embodiments, the pH buffering compound comprises L-histidine. In some embodiments, the pH buffering compound comprises methionine. In some embodiments, propylene glycol is present in the formulation at a weight percentage equal to or less than about 10%, and the pH buffering compound is present in the formulation at a weight percentage equal to or less than about 5%. In some embodiments, propylene glycol is present in the formulation at a weight percentage of about 0.2% to 1.5%. In some embodiments, propylene glycol is present in the formulation at a weight percentage of about 0.1% to 2.0%. In some embodiments, propylene glycol is present in the formulation at a weight percentage of about 0.4% to 1.4%. In the preparation. In some embodiments, the pH buffer compound is present in the preparation at a weight percentage of about 0.01% to 5.0%. In some embodiments, the pH buffer compound is present in the preparation at a weight percentage of about 0.01% to 1.0%. In some embodiments, the pH buffer compound is present in the preparation at a weight percentage of about 0.03% to 1.0%. In some embodiments, the pH of the preparation is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or a range including and / or covering the above values. In some embodiments, the pH of the preparation is about 3 to 7. In some embodiments, the pH of the preparation is about 4 to 6.8. In some embodiments, the pH of the preparation is about 5 to 6.8.

[0281] Pharmaceutical preparations include therapeutically effective doses or therapeutically effective amounts.Terms as used herein " therapeutically effective dose " or " therapeutically effective amount " depend on the judgment of the object treated and the disease state, the severity of pain, the mode of administration and the timetable and the doctor who prescribes a prescription.In some embodiments, the therapeutically effective dose can be about 0.0125mg / kg to about 120mg / kg body weight or more, about 0.025mg / kg or less to about 70mg / kg, about 0.05mg / kg to about 50mg / kg body weight or about 0.075mg / kg to about 10mg / kg body weight daily dosage.Therefore, for using to the people of 70kg, dosage range will be about 0.88mg / day to about 8000mg / day, about 1.8mg / day or less to about 7000mg / day or more, about 3.6mg / day to about 6000mg / day, about 5.3mg / day to about 5000mg / day or about 11mg / day to about 3000mg / day. In some embodiments, the therapeutically effective dose is about 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.12 mg / kg, 0.14 mg / kg, 0.15 mg / kg, 0.16 mg / kg, 0.18 mg / kg, 0.19 mg / kg, 0.20 mg / kg, 0.21 mg / kg, 0.22 mg / kg, 0.24 mg / kg, 0.25 mg / kg, 0.26 mg / kg, 0.28 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, 200 mg / kg, 500 mg / kg, or a range including and / or encompassing the above values. In some embodiments, the therapeutically effective dose is about 0.01 mg / kg to about 5 mg / kg. In some embodiments, the therapeutically effective dose is about 0.05 mg / kg to about 1 mg / kg. In some embodiments, the therapeutically effective dose is about 0.15 mg / kg to about 0.25 mg / kg.

[0282] The pharmaceutical preparation can be administered using a route of administration including, but not limited to, enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, intranasal, topical, intrapulmonary, vaginal, rectal, transdermal, and transmucosal. In some embodiments, the route of administration is selected from enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, and transmucosal. In some embodiments, the pharmaceutical preparation is administered subcutaneously. In some embodiments, the pharmaceutical preparation is administered intravenously. In some embodiments, the pharmaceutical preparation is administered orally.

[0283] Pharmaceutical preparations can be provided in dosage forms. In some embodiments, the dosage form is selected from solid form and liquid form. Solid dosage forms include tablets, capsules, granules and bulk powders. Liquid dosage forms include solutions, emulsions and suspensions. In some embodiments, the dosage form is in solid form. In some embodiments, the dosage form is in liquid form. In some embodiments, the preparation is provided in two parts, a solid part and a liquid part. The final preparation can be prepared by mixing the solid part and the liquid part. In some embodiments, the final preparation is prepared by further diluting the initial preparation (for example, by further diluting one of the preparations described herein). The dilution ratio can be at least 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50 or the range between any two of these values. In some embodiments, the dilution ratio is 10 to 20 (for example, 15).

[0284] In some embodiments, the pharmaceutical formulation comprises one or more additional pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" as used herein includes, but is not limited to, solvents, dispersants, coatings, antimicrobial agents, adjuvants, isotonic and absorption delaying agents, and the like. In some embodiments, pharmaceutically acceptable excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol, and glycerol. and polyethylene glycol; alginic acid; emulsifiers and surfactants, such as TWEENS; wetting agents, such as sodium lauryl sulfate; colorants; flavorings; tablets, stabilizers; antioxidants; preservatives, such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric and phenylmercuric nitrate; tension regulators, such as sodium chloride, potassium chloride, mannitol and glycerol; vehicles, such as polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose and hydroxyethyl cellulose; and pyrogen-free water. In some embodiments, pharmaceutically acceptable excipients are selected based on the route of administration and may include solid or liquid fillers, diluents, cosolvents, surfactants and encapsulating materials. For example, in the case of intravenous administration, excipients may include gelatin; carbohydrates, such as glucose, mannitol and dextran; and antioxidants, such as sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea and EDTA. In some embodiments, pharmaceutically acceptable excipients include antimicrobial agents such as phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol. Additional examples of suitable pharmaceutically acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, each of which is incorporated herein by reference in its entirety.

[0285] In some embodiments, the pharmaceutical formulation is administered to a mammalian subject.

[0286] In some embodiments, the pharmaceutical formulation is administered to a human subject.

[0287] definition

[0288] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the case where there are multiple definitions for a term in this article, unless otherwise stated, the definitions in this section shall prevail.

[0289] "Solvate" refers to a compound formed by the interaction of a solvent with a compound described herein or a salt thereof. Suitable solvates are pharmaceutically acceptable solvates, including hydrates.

[0290] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound, which is not biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds herein are capable of forming acid and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in Johnston et al. WO 87 / 05297, published September 11, 1987 (incorporated herein by reference in its entirety).

[0291] As used herein, “C a To C b " or "C a-b” (where “a” and “b” are integers) refers to the number of carbon atoms in a given group. That is, the group may contain from “a” to “b” (inclusive) carbon atoms. Thus, for example, “C1 to C4 alkyl” or “C 1-4 The term "alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0292] As used herein, the term "halogen" or "halo" means any of the radiostable atoms of column 7 of the periodic table, such as fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred.

[0293] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). An alkyl group can have 1 to 20 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 20" refers to each integer in a given range; for example, "1 to 20 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 20 carbon atoms, but this definition also covers the occurrence of the term "alkyl" in the case of an unspecified numerical range). The alkyl group can also be a medium-sized alkyl group with 1 to 9 carbon atoms. The alkyl group can also be a low alkyl group with 1 to 4 carbon atoms. The alkyl group of a compound can be designated as "C 1-4 Alkyl" or similar designations. By way of example only, "C 1-4 "Alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0294] As used herein, "haloalkyl" refers to a straight or branched alkyl group having 1 to 12 carbon atoms in the chain, wherein a halogen replaces one or more hydrogens. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3 and other groups that would be considered equivalent to any one of the aforementioned examples according to those of ordinary skill in the art and the teachings provided herein.

[0295] As used herein, "alkoxy" refers to a radical of the formula -OR, wherein R is an alkyl radical as defined above, e.g., "C 1-9"Alkoxy" includes, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, etc.

[0296] As used herein, "polyethylene glycol" refers to Wherein n is an integer greater than 1, and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by citing multiple members. Therefore, for example, "2 to 5-membered polyethylene glycol" means that n is an integer selected from 2 to 5. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0297] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen and sulfur) in the backbone. The heteroalkyl group can have 1 to 20 carbon atoms, but this definition also encompasses the appearance of the term "heteroalkyl" in the case of an unspecified numerical range. The heteroalkyl group can also be a medium-sized heteroalkyl group with 1 to 9 carbon atoms. The heteroalkyl group can also be a low-order heteroalkyl group with 1 to 4 carbon atoms. In various embodiments, the heteroalkyl group can have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms or 1 heteroatom. The heteroalkyl group of a compound can be named "C 1-4 Heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1-4 "Heteroalkyl" means that there are 1 to 4 carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms are present in the backbone of the chain.

[0298] The term "aromatic" refers to a ring or ring system having a conjugated π electron system, and includes carbocyclic aromatics (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0299] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, each ring in the system is aromatic. Aryl groups can have 6 to 18 carbon atoms, but this definition also covers the occurrence of the term "aryl" in the case of an unspecified numerical range. In some embodiments, aryl groups have 6 to 10 carbon atoms. Aryl groups can be named "C 6-10 Aryl", "C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0300] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, wherein R is an aryl group as defined above, for example, "C 6-10 Aryloxy" or "C 6-10 "Arylthio" and the like, including but not limited to phenoxy.

[0301] "Aralkyl" or "arylalkyl" is an aryl group attached as a substituent through an alkylene group, for example "C 7-14 "Aralkyl" and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene group).

[0302] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen and sulfur) in the ring backbone. When heteroaryl is a ring system, each ring in the system is aromatic. The heteroaryl group can have 5-18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses the appearance of the term "heteroaryl" in the case of an unspecified numerical range. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group can be named "5-7 yuan heteroaryl", "5-10 yuan heteroaryl" or similar names. In various embodiments, the heteroaryl group includes 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms or 1 heteroatom. For example, in various embodiments, the heteroaryl group comprises 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0303] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group attached as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene group).

[0304] As used herein, "carbocyclyl" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the main chain of the ring system. When the carbocyclyl is a ring system, two or more rings can be connected together in a fused, bridged or spirally connected manner. The carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Therefore, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. The carbocyclyl group can have 3 to 20 carbon atoms, but this definition also covers the occurrence of the term "carbocyclyl" in the case of an unspecified numerical range. The carbocyclyl group can also be a medium-sized carbocyclyl with 3 to 10 carbon atoms. The carbocyclyl group can also be a carbocyclyl with 3 to 6 carbon atoms. The carbocyclyl group can be named "C 3-6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydroindane, bicyclo[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0305] "(Carbocyclyl)alkyl" is a carbocyclyl group attached as a substituent via an alkylene group, for example "C 4-10 "(Carbocyclyl)alkyl" and the like, including but not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl and the like. In some cases, the alkylene group is a lower alkylene group.

[0306] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0307] As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0308] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. The heterocyclyl group can be connected together in a fused, bridged or spirally connected manner. The heterocyclyl group can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom can be present in a non-aromatic ring or aromatic ring in the ring system. The heterocyclyl group can have 3 to 20 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses the appearance of the term "heterocyclyl" in the case of an unspecified numerical range. The heterocyclyl group can also be a medium-sized heterocyclyl with 3 to 10 ring members. The heterocyclyl group can also be a heterocyclyl with 3 to 6 ring members. The heterocyclyl group can be named "3-6 heterocyclyl" or similar names.

[0309] In various embodiments, the heterocyclic radical contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclic radical contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred six-membered monocyclic heterocyclic radicals, the heteroatoms are selected from one to three of O, N, or S, and in preferred five-membered monocyclic heterocyclic radicals, the heteroatoms are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,2-oxazinyl, , 3,5-triazine, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrophenylthio, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0310] "(Heterocyclyl)alkyl" is a heterocyclyl group attached as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0311] As used herein, "acyl" refers to -C(=O)R, wherein R is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

[0312] An "O-carboxyl" group refers to a "-OC(=O)R" group, wherein R is selected from hydrogen, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0313] A "C-carboxyl" group refers to a "-C(=O)OR" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl are as defined herein. Non-limiting examples include carboxyl (ie, -C(=O)OH).

[0314] A "cyano" group refers to a "-CN" group.

[0315] A "cyanato" group refers to a "-OCN" group.

[0316] An "isocyanato" group refers to a "-NCO" group.

[0317] A "thiocyanato" group refers to a "-SCN" group.

[0318] An "isothiocyanato" group refers to a "-NCS" group.

[0319] A "sulfinyl" group refers to a "-S(=O)R" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0320] A "sulfonyl" group refers to a "-SO2R" group where R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0321] The "S-sulfonylamino" group refers to the "-SO2NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0322] An "N-sulfonylamino" group refers to an "-N(R A )SO2R B " group, where R A and R b are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0323] An "O-carbamoyl" group refers to a "-OC(=O)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0324] An "N-carbamoyl" group refers to an "-N(R A )OC(=O)R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0325] An "O-thiocarbamoyl" group refers to an "-OC(=S)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0326] An "N-thiocarbamoyl" group refers to an "-N(R A )OC(=S)R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0327] A "C-amido" group refers to a "-C(=O)NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0328] An "N-amido" group refers to an "-N(R A )C(=O)R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0329] An "amino" group refers to an "-NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl are as defined herein.

[0330] An "aminoalkyl" group refers to an amino group attached through an alkylene group.

[0331] An "alkoxyalkyl" group refers to an alkoxy group attached through an alkylene group, for example, "C 2-8 "Alkoxyalkyl" and the like.

[0332] As used herein, a substituted group is derived from an unsubstituted parent group in which there is an exchange of one or more hydrogen atoms with another atom or group. Unless otherwise specified, when a group is considered to be "substituted", it means that the group is substituted by one or more substituents independently selected from the following: C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 assorted alkyl, C3-C7 carbocyclyl (optionally substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl ... C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6 alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6) alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted), 5-10 membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6) alkyl (i.e., ether), aryloxy, mercapto (thiol), halo (C1-C6) alkyl (e.g., -CF3), halo (C1-C6) alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino (C1-C6) alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, acyl, cyano, isocyano, thiocyano, isothiocyano, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted", the group may be substituted by the above substituents.

[0333] In some embodiments, the substituted group is substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxyl, and halogen.

[0334] It is understood that certain radical naming conventions may include monoradicals or diradicals, depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, a substituent identified as an alkyl group that requires two points of attachment includes a diradical, such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene".

[0335] When two R groups are considered to form a "ring (e.g., a carbocyclyl, heterocyclyl, aryl, or heteroaryl ring)" together with the atoms to which they are attached, it is meant that the collective unit of the atoms and the two R groups is the ring. The ring is not limited by the definition of each R group when used alone. For example, when the following substructure is present:

[0336]

[0337] And R 1 and R 2 is defined as being selected from hydrogen and alkyl, or R 1 and R 2 Together with the nitrogen to which they are attached, they form a heterocyclic group, which means that R 1 and R 2 can be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0338]

[0339] wherein Ring A is a heterocyclyl ring containing the depicted nitrogen.

[0340] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," this means that the collective unit of atoms, the intervening bond, and the two R groups is the ring. For example, when the following substructure is present:

[0341]

[0342] And R 1 and R 2 is defined as being selected from hydrogen and alkyl, or R 1 and R 2 Together with the atoms to which they are attached, they form an aryl or carbocyclic group, which means that R 1 and R 2can be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0343]

[0344] wherein A is an aryl ring or a carbocyclic group containing a double bond as depicted.

[0345] Where a substituent is depicted as a diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise specified. Thus, for example, a substituent depicted as -AE- or Substituents include substituents that are directed such that A is attached at the leftmost attachment point of the molecule, as well as cases where A is attached at the rightmost attachment point of the molecule.

[0346] The term "mammal" is used in its ordinary biological sense. Thus, it specifically includes, but is not limited to, primates (including great apes (chimpanzees, apes, monkeys) and humans), cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, but also includes many other species.

[0347] As used herein, "subject" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any other vertebrate or invertebrate.

[0348] As used herein, an "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent effective to alleviate or reduce the likelihood of onset of one or more symptoms of a disease or condition to some extent, and includes a cure for the disease or condition. "Cure" means eliminating the symptoms of the disease or condition; however, even after a cure is achieved there may be certain long-term or permanent effects (e.g., extensive tissue damage).

[0349] As used herein, "treat," "treatment," or "treating" refers to the administration of a pharmaceutical composition for preventive and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet show symptoms of a disease or condition, but who is susceptible to or at risk for a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who already has a disease or condition.

[0350] Preparation method

[0351] Compounds disclosed herein can be synthesized by the methods described below or by improvements to these methods. The method of improving the method particularly includes temperature, solvent, reagent, etc. known to those skilled in the art. Generally, during any process for preparing compounds disclosed herein, it may be necessary and / or necessary to protect sensitive or reactive groups on any related molecules. This can be achieved by means of conventional protecting groups, such as Protective Groups in Organic Chemistry (ed. JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are incorporated herein by reference in their entirety. Protecting groups can be removed using methods known in the art in appropriate subsequent stages. Synthetic chemical transformations for synthesizing appropriate compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, which are incorporated herein by reference in their entirety. The approaches shown and described herein are illustrative only and are neither intended nor should be construed as limiting the scope of the claims in any way. Those skilled in the art will be able to identify modifications to the disclosed synthesis and will be able to design alternative approaches based on the disclosure herein; all such modifications and alternative approaches are within the scope of the claims.

[0352] In the following schemes, protecting groups for oxygen atoms were chosen for their compatibility with the necessary synthetic steps and for the compatibility of the introduction and deprotection steps with the overall synthetic scheme (PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0353] If the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or separated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers, or as mixtures enriched in stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present technology. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0354] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or reasonable modifications thereof. For example, many starting materials can be obtained from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures or rational modifications thereof, which are described in standard reference textbooks, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0355] Preparation of compounds of formula (I)

[0356] Scheme 1 depicts a method for preparing a compound according to formula (I). The method may include constructing a peptide backbone using solid phase peptide synthesis techniques to provide a resin-bound peptide. The side chain of the central lysine containing a Dde group may then be extended with a linker comprising two PEG2 amide linkers and an isoglutamic acid (or related analogs) linker to provide an intermediate (A). The method includes a coupling reaction between the amino group of the isoglutamic acid (or related analogs) of the intermediate (A) and the intermediate (B) to provide a resin-bound intermediate (C). In formulas (A)-(C), R 1 ' and R 2 ' is the R described in this article 1 and R 2 In one embodiment, the method comprises hydrolyzing the intermediate (C) under acidic conditions to remove the resin and the protecting group, and then purifying to obtain the final product (I). The peptide backbone disclosed herein can be synthesized by the solid phase peptide synthesis technique described in Methods in Molecular Biology, 298, Peptide Synthesis and Applications, (ed. J. Howl, Humana Press, 2005) and Amino Acids, Peptides and Proteins in Organic Chemistry, Volume 3, Building Blocks, Catalysts and Coupling Chemistry, (ed. AB Hughs, Wiley-VCH, 2011) (which are all incorporated herein by reference in their entirety) or obvious improvements thereof.

[0357] Scenario 1:

[0358]

[0359] Preparation of compounds of formula II

[0360] In one embodiment, the method disclosed herein may include using solid phase peptide synthesis technology to construct a 39 amino acid peptide backbone to provide an intermediate (A'). The peptide backbone includes two PEG2 amide linkers. The method includes an amide coupling reaction between the amine of the terminal PEG2 amide of the intermediate (A') and a suitably substituted carboxylic acid (B') to provide a resin-bound intermediate (C'). In one embodiment, the method includes subjecting the intermediate (C') to hydrolysis under acidic conditions and then purifying to obtain the final product (Formula II). (Scheme 2).

[0361] Scenario 2:

[0362]

[0363] The pharmaceutical preparations disclosed herein can be prepared using standard pharmaceutical preparation techniques, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, each of which is incorporated herein by reference in its entirety. In some embodiments, the pharmaceutical preparations can be prepared in unit dosage form. Techniques and compositions for preparing unit dosage forms are described in Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004), each of which is incorporated herein by reference in its entirety.

[0364] The above exemplary schemes are provided for the guidance of the reader and collectively represent exemplary methods for preparing the compounds included herein. In addition, other methods for preparing the compounds described herein will be apparent to those of ordinary skill in the art based on the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0365] Treatment

[0366] The pharmaceutical preparation disclosed herein comprises a compound that is effective as a GIP / GLP1 dual receptor agonist or its tautomer and / or its pharmaceutically acceptable salt. The pharmaceutical preparation further comprises one or more pharmaceutically acceptable carriers and one or more pharmaceutically acceptable diluents.

[0367] Some embodiments provide methods of preventing, treating, or ameliorating one or more fatty liver diseases in a subject. In some embodiments, the method comprises administering one or more pharmaceutical formulations disclosed herein to a subject in need thereof.

[0368] Some embodiments provide methods for preventing, treating or ameliorating steatosis, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. In some embodiments, the method comprises administering one or more pharmaceutical formulations disclosed herein to a subject in need thereof.

[0369] In some embodiments, the methods of administering one or more pharmaceutical formulations disclosed herein result in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a symptom of fibrosis.

[0370] In some embodiments, the pharmaceutical formulations described herein can be used to treat a number of conditions resulting from fibrosis or inflammation, and specifically include those conditions associated with myofibroblast differentiation. Example conditions include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic, and genetic chronic diseases), renal fibrosis (e.g., caused by chronic inflammation, infection, or type II diabetes), pulmonary fibrosis (idiopathic or caused by environmental insults, including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections (including tuberculosis), drugs, etc.), interstitial fibrosis, systemic sclerosis (an autoimmune disease in which many organs become fibrotic), macular degeneration (a fibrotic disease of the eye), pancreatic fibrosis (caused by, for example, alcohol abuse and chronic inflammatory diseases of the pancreas), splenic fibrosis (due to sickle cell anemia, other blood disorders), cardiac fibrosis (caused by infection, inflammation, and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, nonalcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, cirrhosis), fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or conditions.

[0371] In some embodiments, the methods of administering one or more pharmaceutical formulations disclosed herein result in a decrease in the amount of extracellular matrix protein present in one or more tissues of the subject.

[0372] In some embodiments, the methods of administering one or more pharmaceutical formulations disclosed herein result in a decrease in the amount of collagen present in one or more tissues of the subject.

[0373] In some embodiments, the methods of administering one or more pharmaceutical formulations disclosed herein result in a decrease in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

[0374] Some embodiments provide a method of preventing, treating or ameliorating one or more of liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis or idiopathic fibrosis in a subject. In some embodiments, the method comprises administering one or more pharmaceutical preparations disclosed herein to a subject in need thereof.

[0375] Some embodiments provide a method of preventing, treating or ameliorating one or more non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis or primary biliary cirrhosis in a subject. In some embodiments, the method comprises administering one or more pharmaceutical preparations disclosed herein to a subject in need thereof.

[0376] Some embodiments provide methods for preventing, treating or improving one or more metabolic disorders or metabolic syndromes. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity or Prader-Willi syndrome. In some embodiments, the method comprises administering one or more pharmaceutical preparations disclosed herein to a subject in need thereof.

[0377] In some embodiments, the methods of administering one or more pharmaceutical formulations disclosed herein result in activation of the glucose-dependent insulinotropic polypeptide (GIP) receptor. In some embodiments, the methods of administering one or more pharmaceutical formulations disclosed herein result in activation of the glucagon-like peptide-1 (GLP-1) receptor. In some embodiments, the methods of administering one or more pharmaceutical formulations disclosed herein result in activation of the GIP receptor and the GLP-1 receptor.

[0378] Some embodiments include co-administering a pharmaceutical formulation and / or compound as described herein or a pharmaceutically acceptable salt thereof with an additional drug. By "co-administering," it is meant that two or more medicaments can be found simultaneously in the patient's bloodstream, regardless of when or how they are actually administered. In one embodiment, the medicaments are administered simultaneously. In one such embodiment, combined administration is accomplished by combining the medicaments in a single dosage form. In another embodiment, the medicaments are administered sequentially. In one embodiment, the medicaments are administered by the same route (e.g., oral). In another embodiment, the medicaments are administered by different routes, such as a subcutaneous administration, another oral administration, and another intravenous administration.

[0379] To further illustrate the present invention, the following examples are included. These examples should certainly not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the purview of those skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that those skilled in the art who understand the present disclosure and have mastered the technology in the art are able to prepare and use the present invention without the detailed examples. The following examples will further describe the present invention and are used for illustrative purposes only and should not be considered limiting.

[0380] Administration and pharmaceutical compositions

[0381] Some embodiments provide pharmaceutical compositions comprising a therapeutically effective amount of at least one compound described elsewhere herein and a pharmaceutically acceptable excipient.

[0382] Compound is administered with therapeutically effective dose. Although human dosage level has not been optimized for compounds described herein, generally, daily dose can be about 0.0125mg / kg to about 120mg / kg body weight or more, about 0.025mg / kg or less to about 70mg / kg, about 0.05mg / kg to about 50mg / kg body weight or about 0.075mg / kg to about 10mg / kg body weight. Therefore, for people administered to 70kg, dosage range will be about 0.88mg / day to about 8000mg / day, about 1.8mg / day or less to about 7000mg / day or more, about 3.6mg / day to about 6000mg / day, about 5.3mg / day to about 5000mg / day or about 11mg / day to about 3000mg / day. Of course, the amount of active compound administered will depend on the object and disease state treated, the severity of the pain, the mode of administration and schedule and the judgment of the prescribing physician.

[0383] The administration of the compounds disclosed herein or their pharmaceutically acceptable salts can be carried out via any acceptable mode of administration for medicaments of similar utility, including but not limited to oral administration, subcutaneous administration, intravenous administration, intranasal administration, topical administration, transdermal administration, intraperitoneal administration, intramuscular administration, intrapulmonary administration, vaginal administration, rectal or intraocular administration. Oral and parenteral administration are generally used to treat the indications of the objects of the preferred embodiments.

[0384] The compounds useful as described above can be formulated into pharmaceutical compositions for treating these conditions. Standard pharmaceutical preparation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), which are incorporated by reference in their entirety. Therefore, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereomers, tautomers, polymorphs and solvates thereof) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.

[0385] In addition to the selected compounds useful as described above, some embodiments also include compositions comprising a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except in the case where any conventional media or agents are incompatible with the active ingredient, it is considered to be used in therapeutic compositions. In addition, various adjuvants commonly used in the art, for example, may be included. Considerations regarding the inclusion of various components in pharmaceutical compositions are described in, for example, Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which are incorporated herein by reference in their entirety.

[0386] Some examples of substances that can be used as pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline and phosphate buffered solutions.

[0387] The choice of a pharmaceutically acceptable carrier for use in conjunction with a subject compound is essentially determined by the manner in which the compound is to be administered.

[0388] Compositions as described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" is a composition comprising a compound of an amount suitable for being administered to an animal (preferably a mammalian subject) in a single dose according to good medical practice. However, the preparation of a single or unit dosage form does not mean that the dosage form is administered once a day or once per course of treatment. It is expected that such dosage forms are administered once, twice, three times or more a day, and can be administered as an infusion within a period of time (e.g., about 30 minutes to about 2-6 hours), or as a continuous infusion, and can be given more than once in a course of treatment, although single administration is not particularly excluded. Those skilled in the art will recognize that the preparation does not specifically consider the entire course of treatment, and such a decision is left to the technical staff of the therapeutic field rather than the preparation.

[0389] As described above, useful compositions can be any of various suitable forms for various routes of administration, such as oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intracapsular, intraarterial, intravenous, intramuscular, subcutaneous or other parenteral routes of administration. In some embodiments, the composition can be in a form suitable for subcutaneous administration. It will be appreciated by those skilled in the art that oral and nasal compositions include compositions administered by inhalation and prepared using available methods. Depending on the specific route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating materials. Optional pharmaceutically active substances may be included that do not substantially interfere with the inhibitory activity of the compound. The amount of the carrier used in conjunction with the compound is sufficient to provide the material for the actual amount of the compound used for administration per unit dose. Techniques and compositions for preparing dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0390] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet grinding, enteric coating, sugar coating, film coating or multiple compression, including suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, flow inducers and melting agents (melting agent). Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstructed by non-effervescent granules and effervescent preparations reconstructed by effervescent granules, which include suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0391] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders, such as starch, gelatin and sucrose; disintegrants, such as starch, alginic acid and cross-linked sodium carboxymethylcellulose; lubricants, such as magnesium stearate, stearic acid and talc. Glidants, such as silicon dioxide, can be used to improve the flow characteristics of the powder mixture. Colorants, such as FD&C dyes, may be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, mint and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents disclosed above. The choice of carrier components depends on secondary considerations, such as taste, cost and storage stability, which are not critical and can be easily made by those skilled in the art.

[0392] Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also include one or more components, such as sweeteners, flavoring agents, and coloring agents disclosed above.

[0393] Such compositions may also be coated by conventional methods, typically using pH or time-dependent coatings, so that the subject compound is released in the gastrointestinal tract near the desired local application or at different times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, acrylic resin coatings, waxes, and shellac.

[0394] The compositions described herein may optionally contain other pharmaceutically active substances.

[0395] Other compositions for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms. Such compositions generally include soluble filler materials, such as sucrose, sorbitol and mannitol; and binders, such as one or more of gum arabic, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavorings disclosed above may also be included.

[0396] Liquid compositions (which are configured for topical ophthalmic use) are formulated so that they can be topically applied to the eye. Comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. In the case where comfort cannot be maximized, liquids should be formulated so that liquids for topical ophthalmic use are tolerable to the patient. In addition, ophthalmologically acceptable liquids should be packaged for single use, or contain preservatives to prevent contamination from multiple uses.

[0397] For ophthalmic applications, physiological saline solution is usually used as the main vehicle to prepare solutions or medicines. It is preferred that the ophthalmic solution is maintained at a comfortable pH with an appropriate buffer system. The preparation may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0398] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate, and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water.

[0399] Tonicity adjusting agents may be added as required or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerol or any other suitable ophthalmologically acceptable tonicity adjusting agent.

[0400] Various buffers and means for adjusting pH can be used, as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH will be between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. Acids or bases can be used as needed to adjust the pH of these preparations.

[0401] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0402] Other excipient components that may be included in ophthalmic formulations are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents may be used in place of or in combination with it.

[0403] For topical use, creams, ointments, gels, solutions or suspensions, etc. containing the compounds disclosed herein are used. Topical formulations can generally be composed of pharmaceutical carriers, co-solvents, emulsifiers, penetration enhancers, preservative systems, and emollients.

[0404] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to reach the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl and citric acid. In various embodiments, the pH range of the final composition is 2 to 8, or preferably 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium phosphate or potassium phosphate, citric acid, tartaric acid, gelatin and carbohydrates, such as dextrose, mannitol and dextran. Other acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to obtain a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol and chlorobutanol.

[0405] Compositions for intravenous administration can be provided to a caregiver in the form of one or more solids, which are reconstituted in water with a suitable diluent (e.g., sterile water, saline or dextrose) shortly before administration. In other embodiments, the composition is provided in a solution prepared for parenteral administration. In other embodiments, the composition is provided in a solution further diluted before administration. In embodiments including the combination of a compound as described herein and another medicament, the combination can be provided to a caregiver as a mixture, or the caregiver can mix two medicaments before administration, or two medicaments can be administered separately.

[0406] The actual dosage of the active compounds described herein depends on the specific compound and the condition to be treated; selection of the appropriate dosage is well within the knowledge of those skilled in the art.

[0407] If desired, the compounds and compositions described herein may be present in a package or dispenser device containing one or more unit dosage forms containing the active ingredient. Such packages or devices may, for example, include metal or plastic foil, such as blister packs or glass, and rubber stoppers, such as in vials. The package or dispenser device may be accompanied by instructions for administration. The compounds and compositions described herein are formulated in a compatible pharmaceutical carrier, and may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0408] The amount of the compound in the preparation can vary within the full range used by those skilled in the art. Typically, based on weight percentage (wt%), the preparation will contain about 0.01-99.99wt% of the compound of the present technology based on the total preparation, and the remainder is one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80wt%. Representative pharmaceutical preparations are described below. Example

[0409] General Procedure

[0410] It will be apparent to those skilled in the art that methods for preparing precursors and functional groups associated with the compounds claimed herein are generally described in the literature. In these reactions, variants may also be used, which are known to those of ordinary skill in the art but are not mentioned in more detail. In view of the literature and this disclosure, those skilled in the art are fully capable of preparing any compound.

[0411] It should be appreciated that those skilled in the art of organic chemistry can easily perform operations without further guidance, that is, it is entirely within the scope and practice of those skilled in the art to perform these operations. These include reducing carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions (electrophilic and nucleophilic), etherifications, esterifications and saponifications, etc. These operations are discussed in standard textbooks, for example, March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein in their entirety by reference), etc. Unless otherwise noted, all intermediate compounds of the present invention are used without further purification.

[0412] Those skilled in the art will readily appreciate that when other functional groups in the molecule are masked or protected, it is best to carry out certain reactions to avoid any undesirable side reactions and / or increase the yield of the reaction. Those skilled in the art typically utilize blocking groups to achieve such increased yields or to avoid undesirable reactions. These reactions are present in the literature and are also within the scope of those skilled in the art. Many examples of these operations can be found in, for example, T.Greene and P.Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), which are incorporated herein by reference in their entirety.

[0413] The following example schemes are provided to guide the reader and represent preferred methods for preparing the compounds exemplified herein. These methods are not restrictive, and other approaches can obviously be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. Those skilled in the art are fully capable of preparing these compounds by providing those methods of the literature and the present disclosure. The compound numbers used in the synthetic schemes described below are only used for those specific schemes and should not be interpreted as being the same numbering in other parts of the application or being confused with the same numbering.

[0414] The trademarks used herein are examples only and reflect the illustrative material used in connection with the present invention. One skilled in the art will recognize that variations in batches, manufacturing processes, etc., can be expected. Therefore, the examples and the trademarks used therein are non-limiting, and they are not intended to be limiting, but are merely illustrative of how one skilled in the art might choose to perform one or more embodiments of the present invention.

[0415] The following abbreviations have the designated meanings:

[0416] λz=lambda z (apparent elimination rate constant)

[0417] AUC = area under the plasma concentration versus time curve

[0418] AUC last = AUC from time 0 to the last quantifiable concentration

[0419] AUC inf = AUC extrapolated from time 0 to infinity

[0420] Aib = aminoisobutyric acid

[0421] BLQ = below limit of quantitation

[0422] Bn=Benzyl

[0423] Boc=tert-butyloxycarbonyl

[0424] Bu=Butyl

[0425] C max = maximum observed concentration at T max Appears when

[0426] CL / F = systemic clearance after extravascular administration

[0427] CV% = coefficient of variation in percent

[0428] DMF = dimethylformamide

[0429] EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0430] Et=ethyl

[0431] HATU = tetramethyluranium hexafluorophosphate azabenzotriazolyl

[0432] HBTU = benzotriazolyl tetramethyluranium hexafluorophosphate

[0433] HMDS = Hexamethyldisilazane

[0434] HPLC = High Performance Liquid Chromatography

[0435] LC-MS / MS = Liquid chromatography tandem mass spectrometry

[0436] LLOQ = Lower limit of quantitation

[0437] Me = methyl

[0438] N = number of samples with values

[0439] NaHMDS = sodium hexamethyldisilazide

[0440] NMR = Nuclear Magnetic Resonance

[0441] PCC = Pyridinium Chlorochromate

[0442] PEG = Polyethylene glycol

[0443] Ph = Phenyl

[0444] PK = Pharmacokinetics

[0445] PO = oral administration

[0446] R 2 = regression correlation coefficient

[0447] T max =C appears max Time

[0448] t 1 / 2 = Half-life

[0449] tBu=tert-butyl

[0450] TFA = trifluoroacetic acid

[0451] THF = Tetrahydrofuran

[0452] TMS = trimethylsilyl

[0453] V z / F = volume of distribution after extravascular administration

[0454] The following example schemes are provided to guide the reader and collectively represent example methods for preparing the compounds provided herein. In addition, other methods for preparing the compounds described herein will be apparent to those of ordinary skill in the art based on the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0455] Example 1

[0456] Synthesis of Intermediate 1 (INT1)

[0457] Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with one equivalent of NaHMDS to prepare the ylide, which is immediately reacted with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol in a Wittig reaction. The resulting bromoolefin is hydrogenated and treated with dibenzyl phosphite in a weak base to form the phosphonate. Hydrolysis of the carboxylic acid methyl ester provides the desired INT 1 with a terminal carboxylic acid and dibenzyl phosphonate.

[0458]

[0459] Synthesis of Intermediate 2 (INT2)

[0460] Coupling of docosanoic acid with benzyl alcohol using EDC·HCl and DMAP in THF gave INT2 as the monobenzyl ester.

[0461]

[0462] Synthesis of Intermediate 3 (INT3)

[0463] Tert-butyl 4-hydroxybutyrate undergoes Swern oxidation to give the aldehyde. The aldehyde is condensed with (R)-1-amino-2-methoxy-1-phenylethane to form an imine. The lithium salt of diethyl phosphite is added in THF to generate an α-aminophosphonate, which undergoes hydrogenolysis to cleave the N-alkyl group and provide INT 3 with a free primary amine, tert-butyl ester, and diethyl phosphonate. The optical purity of INT 3 was confirmed to be at least 96% by 1HNMR by Mosher amide analysis.

[0464]

[0465] Synthesis of Intermediate 4 (INT4)

[0466] INT 1 was coupled with 1-tert-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4.

[0467]

[0468] Synthesis of Intermediate 5 (INT5)

[0469] INT 2 was coupled with INT 3 in the presence of HATU and triethylamine in DMF to prepare a new amide bond. Cleavage of the ethyl phosphonate with TMS-Br gave the free phosphonic acid. Re-esterification of the benzyl ester with a large excess of N,N'-diisopropylcarbamide afforded the corresponding dibenzyl phosphonate. Cleavage of the tert-butyl ester with TFA afforded INT 5.

[0470]

[0471] Synthesis of Intermediate 6 (INT6)

[0472] INT 1 was coupled with INT 3 in the presence of HATU and triethylamine in DMF to provide a new amide bond. Cleavage of the benzyl and ethyl phosphonates with TMS-Br produced the free phosphonic acids of both. Re-esterification of the benzyl ester with a large excess of N,N'-diisopropylcarbamide afforded the corresponding tetrabenzyl diphosphonate. Cleavage of the tert-butyl ester with TFA gave INT 6.

[0473]

[0474] Example 2

[0475] Synthesis of the common peptide backbone

[0476] A 39 amino acid peptide backbone was constructed using solid phase peptide synthesis techniques using imide, HATU or HBTU activation for the synthesis of amide bonds on Rink resin. Reagent selection varied depending on the identity of the amino acid being attached. The R group of lysine-19 was extended with 2 PEG2 amide linkers. The entire backbone was synthesized on the resin and then INT 4, INT 5 or INT 6 was coupled to the amino terminus of the lysine-bound linker.

[0477]

[0478] Example 3

[0479] Synthesis of compound 4

[0480] The peptide backbone was coupled to INT 4 to give the resin-bound protected compound 4. Cleavage of the resin, the protecting groups on the peptide chain and the benzyl ester of INT 4 with TFA provided compound 4, which was purified by HPLC.

[0481]

[0482] Example 4

[0483] Synthesis of compound 8

[0484] The peptide backbone was coupled to INT 5 to give the resin-bound protected compound 8. Cleavage of the resin, the protecting groups on the peptide chain and the benzyl ester of INT 4 with TFA provided compound 8, which was purified by HPLC.

[0485]

[0486] Example 5

[0487] Synthesis of compound 12

[0488] The peptide backbone was coupled with INT 6 to give the resin-bound protected compound 12. Cleavage of the resin, the protecting groups on the peptide chain and the benzyl ester of INT 4 with TFA provided compound 12, which was purified by HPLC.

[0489]

[0490] Example 6

[0491] Synthesis of peptide backbone

[0492] Using Fmoc solid phase peptide synthesis technology, the peptide backbone of each 39 amino acids is constructed using imide, HATU or HBTU activation for synthesizing amide bonds on Rink resin. Reagent selection varies according to the identity of the amino acid connected. Lysine at lysine-16, lysine-19 or lysine-20 is protected with a Dde protecting group. After the complete backbone is completed, the aminoalkyl side chain of lysine-16, lysine-19 or lysine-20 is extended with two PEG2 amide linkers, and then the isoglutamic acid residue is connected. Specifically, the Dde group on the lysine is cleaved. Then, the deprotected amino group on the lysine is coupled with the PEG2 group protected by Boc with the following structure:

[0493]

[0494] After the Boc group is removed, the second PEG2 is added. Finally, after the Boc group of the second PEG2 is removed, Fmoc-protected isoglutamate is coupled to the second PEG2. The Fmoc group is then removed.

[0495] After the synthesis of the entire main chain and side chain on lysine-16, lysine-19 or lysine-20, it is coupled to INT-1. Thus, before coupling with INT-1, the following intermediates are obtained.

[0496] The aminoalkyl side chain of lysine-16 was extended as described above to prepare peptides 14BB and 15BB.

[0497]

[0498]

[0499] The aminoalkyl side chain of the side chain of lysine-20 was extended to produce peptides 16BB, 17BB, 18BB, 19BB, 20BB and 21BB.

[0500]

[0501]

[0502]

[0503]

[0504] The side chain of lysine-19 was extended to produce peptide 22BB.

[0505]

[0506] Example 7

[0507] Synthesis of compound 15

[0508] Peptide 15BB was coupled to INT-1 to obtain resin-bound protected compound 15. Coupling with INT-1 was achieved by coupling INT-1 to the NH2 group of isoglutamic acid of lysine-16 in peptide 15BB using amide coupling conditions. The resin, the protecting groups on the peptide chain, and the benzyl ester were cleaved with TFA to obtain compound 15, which was then purified by reverse phase HPLC. The purity was 95.0% by RP-HPLC. The peptide content was 96.0%, and satisfactory amino acid analysis results were obtained. LCMS analysis showed a molecular weight of 4849.4 g / mol.

[0509]

[0510] Example 8

[0511] Synthesis of compound 14

[0512] Compound 14 was prepared in a manner similar to the preparation of compound 15 from peptide 14BB and INT-1.

[0513]

[0514] Example 9

[0515] Synthesis of compound 16

[0516] Compound 16 was prepared in a manner similar to the preparation of compound 15 from peptide 16BB and INT-1.

[0517]

[0518] Example 10

[0519] Synthesis of compound 17

[0520] Compound 17 was prepared in a manner similar to the preparation of compound 15 from peptide 17BB and INT-1.

[0521]

[0522] Embodiment 11

[0523] Synthesis of compound 18

[0524] Compound 18 was prepared in a manner similar to the preparation of compound 15 from peptide 18BB and INT-1.

[0525]

[0526] Example 12

[0527] Synthesis of compound 19

[0528] Compound 19 was prepared in a manner similar to the preparation of compound 15 from peptide 19BB and INT-1.

[0529]

[0530] Example 13

[0531] Synthesis of compound 20

[0532] Compound 20 was prepared in a manner similar to the preparation of compound 15 from peptide 20BB and INT-1.

[0533]

[0534] Embodiment 14

[0535] Synthesis of compound 21

[0536] Compound 21 was prepared in a manner similar to the preparation of compound 15 from peptide 21BB and INT-1.

[0537]

[0538] Embodiment 15

[0539] Synthesis of compound 22

[0540] Compound 22 was prepared in a manner similar to the preparation of compound 15 from peptide 22BB and INT-1.

[0541]

[0542] Example 16

[0543] Synthesis of compound 23

[0544] Compound 23 was prepared in a manner similar to the preparation of compound 15 from peptide 23BB and INT-1.

[0545]

[0546] Embodiment 17

[0547] Synthesis of compound 24

[0548] Compound 24 was prepared in a manner similar to the preparation of compound 15 from peptide 24BB and INT-1.

[0549]

[0550] Embodiment 18

[0551] Synthesis of compound 25

[0552] Compound 25 was prepared in a manner similar to the preparation of compound 15 from a peptide backbone similar to that described herein and INT-1.

[0553]

[0554] Embodiment 19

[0555] In vitro GLP-1 and GIP binding activity

[0556] use Binding assay and Epics Therapeutics cell lines Binding data for tirzepatide, compound 4, compound 8, and compound 12 were obtained for two human recombinant G protein-coupled receptors, GLP-1 and GIP. The agonist activity of the test compound is expressed as the reference agonist at its IC 100 The activity percentages at the concentrations are shown in Table 1.

[0557] Table 1

[0558]

[0559] Embodiment 20

[0560] Biological effects of compounds in mice

[0561] NASH was induced in mice by feeding mice Gubra amylin NASH (GAN) diet, as described in Boland et al. World J Gastroenterol. 2019, 25 (33): 4904-4920. One week before the first dose of the compound was administered, the mice were weighed and randomized, and their food intake was measured. The mice were randomly assigned to dosing groups, with 12 mice in each group. The designated dose groups were: tirpoide (10 mg / kg); compound 4 (10 mg / kg); compound 8 (10 mg / kg); compound 12 (10 mg / kg); one group was treated with vehicle simulation only as a control. Compound dose adjustment (nmol / kg): 0.6 (day 0), 1.2 (day 1), 2.4 (day 2), 4.8 (day 3), 4.8 (day 4), 12 (day 5), 30.0 (starting from day 6).

[0562] After two weeks, the animals were sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), plasma total triglycerides and plasma total cholesterol were measured, and terminal necropsy of each liver was performed to determine the relative liver weight as a percentage of body weight, analyze the full range of liver biochemistry (including liver total triglycerides, plasma insulin and liver total cholesterol) and histological evaluation of galectin-3 and α-smooth muscle actin.

[0563] Hepatic triglyceride (TG) levels are shown in Table 2. The data show that administration of Compound 4, Compound 8, or Compound 12 resulted in lower relative and total hepatic triglycerides compared to administration of telpotide alone or vehicle. Hepatic galectin 3 (Gal-3) levels determined by quantitative histological assessment are shown in Table 2. The data show that administration of Compound 4, Compound 8, or Compound 12 resulted in lower relative and total hepatic galectin 3 compared to administration of telpotide alone or vehicle. Alpha-smooth muscle actin (α-SMA) levels determined by quantitative histological assessment are shown in Table 2. The data show that administration of Compound 4, Compound 8, or Compound 12 resulted in lower relative and total hepatic α-smooth muscle actin compared to administration of telpotide.

[0564] Table 2

[0565]

[0566] Embodiment 21

[0567] HSA regulates GLP-1 and GIP binding activity in vitro

[0568] The binding assays of Example 6 were repeated for compound tirpotide (TRZ), compound 4, and compound 12, wherein the assays were performed in the presence or absence of 2% human serum albumin (HSA). The ratios of compound-receptor binding to 2% HSA and compound-receptor binding to 0% HSA are listed in Table 3. For the GLP-1 receptor and GIP receptor, the HSA ratios of tirpotide were 12.8 and 5.82, respectively. For the GLP-1 receptor and GIP receptor, the HAS ratios of compound 4 were 6.42 and 1.25, respectively. For the GLP-1 receptor and GIP receptor, the HAS ratios of compound 12 were 5.26 and 1.70, respectively. The larger HAS ratios of tirpotide compared to compound 4 and compound 12 indicate that tirpotide has a greater binding affinity for albumin than compound 4 or compound 12.

[0569] Table 3

[0570]

[0571] Example 22 - Formulation

[0572] Nine aqueous formulations suitable for subcutaneous injection were prepared containing Compound 4. The concentrations of the ingredients in each formulation are shown in Table 4 as weight percent.

[0573] Table 4. Preparation composition

[0574]

[0575] *The pH of the formulation was adjusted to approximately 6.0 using 1 N HCl / NaOH.

[0576] WFI: Water for Injection

[0577] General Procedures

[0578] Prepare a 0.2 mg / mL zinc oxide stock solution for the following experiments by adding approximately 1.0 mg zinc oxide to a 5 mL volumetric flask, filling the flask with water and stirring. Prepare a 5.0 mg / mL polysorbate 80 stock solution for the following experiments by adding approximately 5.0 mg polysorbate 80 to a 1 mL volumetric flask, filling the flask with water and stirring. Prepare a 20.0 mg / mL polysorbate 20 stock solution for the following experiments by adding approximately 20.0 mg polysorbate 20 to a 1 mL volumetric flask, filling the flask with water and stirring. Prepare an EDTA2Na2 H2O stock solution for the following experiments by adding approximately 9.0 mg EDTA2Na2 H2O to a 1 mL volumetric flask, filling the flask with water and stirring.

[0579] Preparation of Formulation 1

[0580] To prepare a 5 mL sample of formulation 1, approximately 23.5 mg of propylene glycol, 9.0 mg of phenol, and 1.85 mg of anhydrous disodium phosphate were added to a 5 mL volumetric flask. Approximately 4.0 mL of water was added to the flask to dissolve the added compounds. The pH of the solution was then adjusted to approximately 6.0-7.0 using 1 N NaOH / HCl. Approximately 75.0 mg of compound 4 was added to the solution, and the pH of the solution was then adjusted to approximately 6.0 to 6.3 by adding 40 μL of 1 N NaOH while vortexing or sonicating the solution. Water was then added to the fill line on the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0581] Preparation of Formulation 2

[0582] In order to prepare the sample of 5mL preparation 2, add about 70.0mg of propylene glycol, 27.5mg of phenol, 5.65mg of anhydrous disodium phosphate and 0.25mg of polysorbate 80 stock solution (about 50 μ L) in 5mL volumetric flask.In bottle, add about 4.0mL of water, to dissolve the compound added.Then use 1N NaOH / HCl that the pH of solution is adjusted to about 6.0-7.0.In solution, add about 75.0mg of compound 4, then by adding 40 μL of 1N NaOH that the pH of solution is adjusted to about 6.0 to 6.3 simultaneously vortex or ultrasonic treatment solution.Then add water to the fill line on 5mL volumetric flask, so that the cumulative volume of solution reaches 5mL.

[0583] Preparation of Formulation 3

[0584] To prepare a 5 mL sample of Formulation 3, approximately 60.5 mg of glycerol, 5.1 mg of magnesium chloride hexahydrate, 22.05 mg of sodium citrate dihydrate, and 0.195 mg of zinc oxide stock solution (approximately 1 mL) were added to a 5 mL volumetric flask. Approximately 3.0 mL of water was added to the flask to dissolve the added compounds. The pH of the solution was then adjusted to approximately 6.0-7.0 using 1 N NaOH / HCl. Approximately 75.0 mg of Compound 4 was added to the solution, and the pH of the solution was then adjusted to approximately 6.0 to 6.3 by adding 35 μL of 1 N NaOH while vortexing or sonicating the solution. Water was then added to the fill line on the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0585] Preparation of Formulation 4

[0586] In order to prepare the sample of 5mL preparation 4, add about 15.0mg of meta-cresol, 227mg of mannitol and 22.05mg of sodium citrate dihydrate in 5mL volumetric flask.In bottle, add about 4.0mL of water, to dissolve the compound added.Then use 1N NaOH / HCl that the pH of solution is adjusted to about 6.0-7.0.In solution, add about 75.0mg of compound 4, then by adding 47 μ L 1N NaOH, the pH of solution is adjusted to about 6.0 to 6.3 while vortex or ultrasonic treatment solution.Then add water to the fill line on 5mL volumetric flask, make the cumulative volume of solution reach 5mL.

[0587] Preparation of Formulation 5

[0588] In order to prepare a sample of 5mL preparation 5, about 245mg of lactose monohydrate and 5.65mg of anhydrous disodium phosphate were added to a 5mL volumetric flask. About 4.0mL of water was added to the bottle to dissolve the added compound. Then the pH of the solution was adjusted to about 6.0-7.0 using 1N NaOH / HCl. About 75.0mg of compound 4 was added to the solution, and then the pH of the solution was adjusted to about 6.0 to 6.3 by adding 96 μL 1N NaOH while vortexing or ultrasonicating the solution. Water was then added to the fill line on the 5mL volumetric flask so that the total volume of the solution reached 5mL.

[0589] Preparation of Formulation 6

[0590] In order to prepare the sample of 5mL preparation 6, add about 75.0mg of mannitol, 3.6mg of methionine, 290.1mg of trehalose dihydrate, 0.25mg of polysorbate 80 stock solution (about 50 μ L) and 5.4mg sodium citrate dihydrate in 5mL volumetric flask.In bottle, add about 4.0mL of water, to dissolve the compound added.Then use 1NNaOH / HCl that the pH of solution is adjusted to about 6.0-7.0.In solution, add about 75.0mg of compound 4, then by adding 10 μL 1NNaOH that the pH of solution is adjusted to about 6.0 to 6.3 simultaneously vortex or ultrasonic treatment solution.Then add water to the fill line on 5mL volumetric flask, make the cumulative volume of solution reach 5mL.

[0591] Preparation of Formulation 7

[0592] In order to prepare the sample of 5mL preparation 7, add about 40.0mg sodium chloride, 0.5mg polysorbate 80 stock solution (about 100 μ L), 0.9mg EDTA2Na2 H2O stock solution (about 100 μ L) and 9.65mg sodium citrate dihydrate in 5mL volumetric flask.In bottle, add about 4.0mL water, to dissolve the compound added.Then use 1NNaOH / HCl that the pH of solution is adjusted to about 6.0-7.0.In solution, add about 75.0mg compound 4, then by adding 48 μL 1NNaOH that the pH of solution is adjusted to about 6.0 to 6.3 vortex or ultrasonic treatment solution simultaneously.Then add water to the fill line on 5mL volumetric flask, make the cumulative volume of solution reach 5mL.

[0593] Preparation of Formulation 8

[0594] To prepare a 5 mL sample of formulation 8, approximately 245 mg of sorbitol in a 70% w / w solution, 2.0 mg of polysorbate 20 stock solution (approximately 100 μL), 4.5 mg of methionine, and 6.0 mg of L-histidine were added to a 5 mL volumetric flask. Approximately 4.0 mL of water was added to the bottle to dissolve the added compounds. The pH of the solution was then adjusted to approximately 6.0-7.0 using 1 N NaOH / HCl. Approximately 75.0 mg of compound 4 was added to the solution, and the pH of the solution was then adjusted to approximately 6.0 to 6.3 by adding 40 μL of 1 N NaOH while vortexing or ultrasonicating the solution. Water was then added to the fill line on the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0595] Preparation of Formulation 9

[0596] In order to prepare the sample of 5mL preparation 9, add about 47.0mg of propylene glycol, 18.0mg of phenol, 0.25mg of polysorbate 80 stock solution (about 50 μ L) and 3.70mg of anhydrous disodium phosphate in 5mL volumetric flask.In bottle, add about 4.0mL of water, to dissolve the compound added.Then use 1N NaOH / HCl that the pH value of solution is adjusted to about 6.0-7.0.In solution, add about 75.0mg of compound 4, then by adding 1N NaOH / HCl that the pH value of solution is adjusted to about 6.0 to 6.3 simultaneously vortex or ultrasonic treatment solution.Then add water to the fill line on 5mL volumetric flask, make the cumulative volume of solution reach 5mL.

[0597] Example 23: Pharmacokinetic studies

[0598] The pharmacokinetic properties of formulations 1 to 8 of Example 22 were compared in a study after a single subcutaneous administration in male cynomolgus monkeys. Unaudited plasma concentrations versus time data received from Fronace Laboratories were analyzed using Phoenix WinNonlin (v8.3, Certara LP, Princeton, NJ). Each formulation was tested at a 0.2 mg / kg dose level and diluted to a concentration of 0.2 mg / mL. Each of the three animals involved in each test group received a dosing volume of 1 mL / kg. Plasma samples were collected from each animal at 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours, 240 hours, 336 hours, and 504 hours after dosing.

[0599] Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.3) noncompartmental analysis functions (linear trapezoidal rule for AUC calculations). Calculations were performed using nominal dose values ​​and sampling times. C was determined by direct evaluation of concentration versus time data. max and the corresponding T max All AUC calculations were performed using the linear trapezoidal rule. When data allowed, the terminal rate constant (lambda z, λz) was determined. The value of λz was calculated from the slope of the regression line of the natural log-transformed concentration versus time, where the data points were randomly distributed around the line and C was used in the regression. max The regression correlation coefficient (R 2 )>0.90, and it was determined that the period (span) of the regression was at least 2.0 times larger than the calculated half-life itself.

[0600] In order to optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. INF The value is calculated as: AUC last +(C last / λz). CL / F value was calculated as dose / AUC INF , Vz / F value was calculated as dose / (AUC INF *λz). If AUC INF If the extrapolated area percentage is > 20%, the AUC is not reported. INF , Vz / F and CL / F values. Terminal half-life (t 1 / 2 ) is calculated as: ln(2) / λz. If the span defining the lambda z line is less than t 1 / 2 If the value is twice that of 1 / 2 The values ​​were removed from the summary statistics. Table 5 below discloses the mean pharmacokinetic data obtained from each experiment for each of Formulations 1-8. Figure 1 The mean concentration of Compound 4 in each study subject over time after administration of Formulations 1-8 is shown. Figure 1 As shown, each of Formulations 1-8 had similar responses and stabilities.

[0601] Table 5

[0602]

[0603] Another study used telpotide (0.2 mg / kg) in 1) vehicle containing 0.1% bovine serum albumin in phosphate buffered saline or 2) 40% propylene glycol and 60% 10 mM pH 6 citrate buffer, yielding half-lives of 66.2 hours and 59.8 hours, respectively. Thus, the half-lives of formulations 1-8 were higher than the telpotide formulations.

[0604] Example 24 - Formulation

[0605] The vehicle was prepared by mixing 1175 mg propylene glycol, 449.92 mg phenol, 174.64 mg anhydrous disodium phosphate and 1.25 ml of a 5 mg / ml polysorbate 80 aqueous solution. The pH of the mixture was adjusted to 6.22 with 1 N HCl, then diluted to 100 mL by adding an appropriate volume of water for injection (WFI). The preparation for subcutaneous administration was prepared by combining the test compound with the vehicle and diluting with sterile water for injection (SWFI) to form a solution having a final concentration of 0.2 mg / ml, as described in Table 6. The weight percentage of the vehicle component in the preparation was 0.94% propylene glycol, 0.36% phenol, 0.074% anhydrous disodium phosphate and 0.005% polysorbate 80 aqueous solution.

[0606] Table 6. Preparation of formulations

[0607] preparation Compound Amount of compound (mg) Volume of vehicle (ml) Volume of SWFI (ml) Final pH 10 4 4.730 16.1712 4.0438 6.19 11 17 4.409 16.0328 4.0082 6.15 12 20 4.579 16.3536 4.0884 6.23 13 25 4.330 16.4952 4.1238 6.19

[0608] Example 25. Pharmacokinetic studies

[0609] In a study after a single subcutaneous administration in male cynomolgus monkeys, the pharmacokinetic properties of formulations 10, 11, 12 and 13 were compared. Unaudited plasma concentrations versus time data were analyzed using Phoenix WinNonlin (v8.3, Certara LP, Princeton, NJ). Each formulation was tested at a 0.2 mg / kg dose level. Each of the three animals involved in each test group received a dosing volume of 1 mL / kg. Plasma samples were collected from each animal before dosing, 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours, 240 hours, 336 hours and 504 hours after dosing.

[0610] Pharmacokinetic analysis of plasma concentration versus time data was performed using Phoenix WinNonlin (v 8.3) non-compartmental analysis functions (linear trapezoidal rule for AUC calculations).

[0611] Table 7 below discloses the mean pharmacokinetic data obtained from each experiment for each of Formulations 10-13. Figure 2 Mean plasma concentrations over time are shown for each of Formulations 10-13.

[0612] Table 7

[0613]

[0614] Example 26 - Pharmacokinetic Studies

[0615] Subcutaneous formulations were prepared containing 10 mM dehydrated disodium phosphate, 1.4% propylene glycol, 0.5% phenol and water and compound 4, compound 14, compound 15 or compound 17. The formulations were administered to cynomolgus monkeys at a dose of 0.2 mg / kg. Plasma concentrations were collected versus time data and pharmacokinetic values ​​were determined. The results are reported in Table 8.

[0616] Table 8

[0617]

[0618] Example 27 - Stability Study

[0619] When stored at -20°C, 5°C and 25°C / 60% RH, the stability of formulations containing different concentrations of compound 4 solutions was evaluated, and the compound 4 solution contained 0.94% w / v propylene glycol, 0.36% w / v phenol, 0.074% w / v anhydrous disodium phosphate (anhydrous dibasic sodium phosphate) and 0.005% w / v polysorbate 80. Storage for up to three months showed that the content of compound 4 was almost not reduced, and the impurity content was almost not increased. For example, a formulation prepared under GMP conditions and containing 2.5 mg / ml compound 4 was stored at 25°C / 60% RH for one month, resulting in a decrease in compound 4 content from 103% to 102.4%, and an increase in total impurities from 0.57% to 0.76%.

[0620] Although some embodiments have been illustrated and described, those of ordinary skill in the art, after reading the foregoing description, may make changes, substitutions of equivalents or other types of changes to the compounds of the present technology described herein or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures. Each aspect and embodiment described above may also include or incorporate such changes or aspects disclosed with respect to any or all other aspects and embodiments.

[0621] The present technology is also not limited to the specific aspects described herein, which are intended to be a single description of the individual aspects of the present technology. Without departing from the spirit and scope of the present technology, many modifications and changes can be made to the present technology, which will be obvious to those skilled in the art. In addition to those methods listed herein, functionally equivalent methods within the scope of the present technology will be obvious to those skilled in the art from the previous description. Such modifications and changes are intended to fall within the scope of the appended claims. It should be understood that the present technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds or biological systems, which can certainly be changed. It should also be understood that the terms used herein are only used for the purpose of describing specific aspects and are not intended to be restrictive. Therefore, this specification is intended to be considered as merely exemplary, and the breadth, scope and spirit of the present technology are indicated only by the appended claims, the definitions therein and any equivalents thereof.

[0622] The embodiments illustratively described herein may be appropriately practiced in the absence of any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. should be understood broadly and not restrictively. In addition, the terms and expressions used herein have been used as descriptive and not restrictive terms, and when such terms and expressions are used, it is not intended to exclude any equivalents of the features shown and described or portions thereof, but it should be recognized that various modifications may be made within the scope of the claimed technology. In addition, the phrase "essentially consisting of..." will be understood to include those elements specifically enumerated and those additional elements that do not substantially affect the basic and novel features of the claimed technology. The phrase "consisting of..." excludes any element that is not specified.

[0623] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also forms part of the present technology. This includes the general description of the present technology with any subject proviso or negative limitation removed from the genus, regardless of whether the excised material is specifically enumerated herein.

[0624] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) mentioned in this specification are incorporated herein by reference, as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated herein by reference in its entirety. Definitions contained in text incorporated by reference will be excluded to the extent they conflict with definitions in this disclosure.

[0625] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0626] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternative embodiments, it will be understood by those skilled in the relevant art that various changes in form and details may be made therein without departing from the spirit and scope of the invention.

[0627] All references, issued patents, and patent applications cited within the subject matter of this specification are hereby incorporated by reference in their entirety for all purposes.

[0628] Although the present invention has been described with reference to embodiments and examples, it should be understood that many and various modifications can be made without departing from the spirit of the present invention. Therefore, the present invention is limited only by the appended claims.

Claims

1. A pharmaceutical composition comprising: one or more non-aqueous solvents or solubility enhancers comprising less than 20% by weight of the pharmaceutical composition; and A compound having the structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein: Aib is 2-aminoisobutyric acid; J 1 , J 2 and J 3 Each instance in which is independently an amino acid selected from Aib, naturally occurring amino acids, and unnatural amino acids; U 1 For -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 -; U 2 For -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 -; J 4 , J 5 , J 6 , J 7 , J 8 , J 9 , J 10 and J 11 Each instance in is independently a naturally occurring amino acid or an unnatural amino acid; Each of n1, n2, n3, n4, n5, n6, n7 and n8 is independently 0 or 1, provided that the sum of n1+n2+n3+n4+n5+n6+n7+n8 is 4; R 1 Selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl; Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryl and C 7-11 Arylalkyl; Each R 5 are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 Alkyl; and Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl.

2. The pharmaceutical composition according to claim 1, wherein the compound is not:

3. The pharmaceutical composition according to claim 1, wherein J 1 , J 2 and J 3 Each instance in which is independently an amino acid selected from Aib and naturally occurring amino acids.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein J 1 , J 2 and J 3 Each instance in is independently an amino acid selected from Aib, A, F, N, R and Q.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein J in the compound of formula I is 1 Is Aib or F.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein J in the compound of formula I is 1 For F.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein J in the compound of formula I is 2 N or Q.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein J in the compound of formula I is 2 is N.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein J in the compound of formula I is 3 A or R.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein J in the compound of formula I is 3 For R.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein J of the compound of formula I is 4 , J 5 , J 6 and J 7 Each instance in is independently an amino acid selected from A, I, K, R, Q, S, T, and V.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein J in the compound of formula I is 4 K or R.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein J in the compound of formula I is 4 For R.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein J in the compound of formula I is 5 I, T or V.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein J in the compound of formula I is 5 It is T or V.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein J in the compound of formula I is 6 A or S.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein J in the compound of formula I is 6 For S.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein J in the compound of formula I is 7 For Q.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein J of the compound of formula I is 8 , J 9 , J 10 and J 11 Each instance in is independently an amino acid selected from A, I and Q.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein J in the compound of formula I is 8 I or Q.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein J in the compound of formula I is 9 I or Q.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein J in the compound of formula I is 10 For Q.

23. The pharmaceutical composition according to any one of claims 1 to 22, wherein J in the compound of formula I is 11 For Q.

24. The pharmaceutical composition according to any one of claims 1 to 4, wherein In the compound of formula I, J 1 Selected from Aib or F; In the compound of formula I, J 2 Select from Q or N; In the compound of formula I, J 3 Selected from A or R; U in the compound of formula I 1 is selected from -KVA-, -KIAQ-, -KTAQ-, -KTSQ-, -KVAQ-, -RIAQ-, or is absent; and U in the compound of formula I 2 Selected from -Q-, -IAQQ-, or absent.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein each instance of n1, n2, n3 and n4 of the compound of Formula I is zero.

26. The pharmaceutical composition of any one of claims 1 to 24, wherein each instance of n4, n6, n7 and n8 of the compound of Formula I is zero.

27. A pharmaceutical composition according to any one of claims 1 to 24, wherein each instance of n5, n6, n7 and n8 of the compound of Formula I is zero.

28. A pharmaceutical composition according to any one of claims 1 to 27, wherein Z of the compound of formula I 1 and Z 2 At least one of them is not hydrogen.

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the compound has the structure of Formula Ia or a pharmaceutically acceptable salt thereof:

30. The pharmaceutical composition according to claim 29, wherein Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

31. The pharmaceutical composition according to claim 30, wherein Z in the compound of formula Ia 1 is hydrogen, and each R in the compound of formula Ia 4 are independently hydrogen or C 7-11 Arylalkyl.

32. The pharmaceutical composition according to any one of claims 30 to 31, wherein each R in the compound of formula Ia 4 For hydrogen.

33. The pharmaceutical composition according to claim 30, wherein Z in the compound of formula Ia 1 is hydrogen, and each R in the compound of formula Ia 4 For hydrogen.

34. A pharmaceutical composition according to any one of claims 1 to 28, wherein the compound has the structure of Formula Ib or a pharmaceutically acceptable salt thereof:

35. The pharmaceutical composition according to claim 34, wherein each R 4 are independently selected from hydrogen, C 6-10 Aryl and C 7-11 Arylalkyl.

36. The pharmaceutical composition according to claim 35, wherein each R 4 For hydrogen.

37. The pharmaceutical composition according to claim 1, having a structure selected from the group consisting of: and pharmaceutically acceptable salts thereof.

38. The pharmaceutical composition according to claim 1, wherein the compound has the structure of Formula II or a pharmaceutically acceptable salt thereof: in: R 1 Selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl; Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryloxy and C 6-10 Arylalkoxy; Each R 5 are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 Alkyl; and Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl, Where Z 1 and Z 2 At least one of them is not hydrogen.

39. The pharmaceutical composition according to claim 38, which has the structure of Formula II-a or a pharmaceutically acceptable salt thereof:

40. The pharmaceutical composition according to claim 39, wherein Z 1 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

41. The pharmaceutical composition according to claim 39 or 40, wherein Z 1 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

42. A pharmaceutical composition according to any one of claims 39-41, wherein Z 1 is hydrogen, and each R 4 are independently hydrogen or C 6-10 Arylalkoxy.

43. A pharmaceutical composition according to any one of claims 39-42, wherein each R 4 For hydrogen.

44. according to the pharmaceutical composition described in any one of claims 93-43, wherein Z 1 is hydrogen, and each R 4 For hydrogen.

45. The pharmaceutical composition according to claim 38, which has the structure of Formula II-b or a pharmaceutically acceptable salt thereof:

46. ​​The pharmaceutical composition according to claim 45, wherein Z 2 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl; and X and Y are each -OR 4 .

47. The pharmaceutical composition according to claim 45 or 46, wherein Z 2 Selected from hydrogen, halogenated C 1-6 Alkoxy and C 1-6 alkoxy; and each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

48. A pharmaceutical composition according to any one of claims 45-47, wherein Z 2 is hydrogen, and each R 4 is hydrogen or C 6-10 Arylalkoxy.

49. A pharmaceutical composition according to any one of claims 45-48, wherein each R 4 For hydrogen.

50. A pharmaceutical composition according to any one of claims 45-49, wherein Z 2 is hydrogen, and each R 4 For hydrogen.

51. The pharmaceutical composition according to claim 38, which has the structure of Formula II-c or a pharmaceutically acceptable salt thereof:

52. The pharmaceutical composition according to claim 51, wherein X and Y are each -OR 4 .

53. The pharmaceutical composition according to claim 51 or 52, wherein each R 4 are independently selected from hydrogen, C 6-10 Aryloxy and C 6-10 Arylalkoxy.

54. A pharmaceutical composition according to any one of claims 51-53, wherein each R 4 For hydrogen.

55. The pharmaceutical composition of claim 38, having a structure selected from the group consisting of: and pharmaceutically acceptable salts thereof.

56. A pharmaceutical composition according to any one of claims 38-55, wherein "*" represents a chiral carbon with an "S" configuration.

57. A pharmaceutical composition according to any one of claims 38-55, wherein "*" represents a chiral carbon with an "R" configuration.

58. The pharmaceutical composition of any one of claims 1-57, wherein the one or more non-aqueous solvents or solubility enhancers comprise less than 10% by weight of the composition.

59. The pharmaceutical composition of any one of claims 1-57, wherein the one or more non-aqueous solvents or solubility enhancers comprise less than 5% by weight of the composition.

60. The pharmaceutical composition of any one of claims 1-59, wherein the one or more non-aqueous solvents or solubility enhancers comprise propylene glycol.

61. The pharmaceutical composition of claim 60, wherein the propylene glycol is present in a weight percentage equal to or less than about 10%.

62. The pharmaceutical composition of claim 60, wherein the propylene glycol is present in a weight percentage equal to or less than about 2%.

63. The pharmaceutical composition of claim 60, wherein the propylene glycol is present in a weight percentage of about 0.1% to about 2%.

64. The pharmaceutical composition of claim 60, wherein the propylene glycol is present in a weight percentage of about 0.4% to about 1.5%.

65. The pharmaceutical composition of any one of claims 1-64, wherein the one or more non-aqueous solvents or solubility enhancers comprise a polysorbate.

66. The pharmaceutical composition of claim 65, wherein the polysorbate is present in an amount of about 0.001% to about 0.1% by weight.

67. The pharmaceutical composition of claim 65, wherein the polysorbate is present in an amount of about 0.003% to about 0.05% by weight.

68. A pharmaceutical composition according to any one of claims 65-67, wherein the polysorbate is polysorbate 20.

69. A pharmaceutical composition according to any one of claims 65-67, wherein the polysorbate is polysorbate 80.

70. The pharmaceutical composition of any one of claims 1-69, wherein the one or more non-aqueous solvents or solubility enhancers comprises glycerol.

71. The pharmaceutical composition of claim 70, wherein the glycerol is present in an amount of about 0.5% to about 5% by weight.

72. The pharmaceutical composition of any one of claims 1-71, wherein the one or more non-aqueous solvents or solubility enhancers comprise m-cresol.

73. The pharmaceutical composition of claim 72, wherein the meta-cresol is present in a weight percent range of about 0.1% to about 1%.

74. The pharmaceutical composition of any one of claims 1-73, wherein the one or more non-aqueous solvents or solubility enhancers comprise phenol.

75. The pharmaceutical composition of claim 74, wherein the phenol is present in an amount of about 0.1% to about 1% by weight.

76. The pharmaceutical composition of claim 74, wherein the phenol is present in an amount of about 0.1% to about 0.6% by weight.

77. The pharmaceutical composition of any one of claims 1-76, comprising about 0.1% to about 5% by weight propylene glycol and about 0.1% to about 1% by weight phenol.

78. The pharmaceutical composition of claim 77, comprising from about 0.001% to about 0.01% by weight of polysorbate 80.

79. A pharmaceutical composition comprising: Lactose; and A therapeutically effective amount of a compound having the structure of Formula II or a pharmaceutically acceptable salt thereof: in: R 1 Selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; R 2 Selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y) and a 5-10 membered heteroaryl group containing 1-2 heteroatoms selected from N, O and S, the heteroaryl group being optionally substituted by 1-2 R 7 Substitution, the R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, -OR 5 , C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; Each R 7 independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl and 5-10 membered heterocyclyl; X and Y are each independently selected from -OR 4 NR 5 R 6 , C 1-6 Alkyl and halogenated C 1-6 alkyl; Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 6-10 Aryl and C 6-10 Arylalkyl; Each R 5 are independently hydrogen or C 1-6 alkyl; Each R 6 are independently hydrogen or C 1-6 Alkyl; and Z 1 and Z 2 are each independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy, C 3-10 Cycloalkyl and C 6-10 Aryl, Where Z 1 and Z 2 At least one of them is not hydrogen.

80. The pharmaceutical composition of claim 79, wherein the lactose is present as lactose monohydrate in a weight percent range of about 2% to about 10%.

81. The pharmaceutical composition of any one of claims 1-80, wherein "*" represents a chiral carbon having an "S" configuration.

82. The pharmaceutical composition of any one of claims 1-80, wherein "*" represents a chiral carbon having an "R" configuration.

83. A pharmaceutical composition according to any one of claims 1-82, comprising a pharmaceutically acceptable aqueous carrier.

84. The pharmaceutical composition of claim 83, wherein the aqueous carrier is water or saline.

85. A pharmaceutical composition according to any one of claims 1-84, wherein the composition comprises a buffer.

86. The pharmaceutical composition of claim 85, wherein the buffer comprises sodium citrate, disodium phosphate, L-histidine, methionine, tartrate, citrate, acetate, 2-(N-morpholino)ethanesulfonic acid (MES), piperazine-N,N'-bis(2-ethanesulfonic acid (PIPES), 3-(N-morpholino)propanesulfonic acid (MOPS), 2-[[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)- 1-piperazineethanesulfonic acid (HEPES), 3-[N-tris(hydroxymethyl)methylamino]-2-hydroxypropanesulfonic acid (TAPSO), N-[tris(hydroxymethyl)methyl]glycine (Tricine), tris(hydroxymethyl)aminomethane (Tris), 2-(bis(2-hydroxyethyl)amino)acetic acid (Bicine), tris(hydroxymethyl)methylamino]propanesulfonic acid (TAPS), N-cyclohexyl-2-aminoethanesulfonic acid (CHES), phosphate, borate or any combination thereof.

87. The pharmaceutical composition of claim 85, wherein the buffer comprises sodium citrate.

88. The pharmaceutical composition of claim 85, wherein the buffer comprises disodium phosphate.

89. The pharmaceutical composition of claim 85, wherein the buffer comprises L-histidine.

90. The pharmaceutical composition of claim 85, wherein the buffer comprises methionine.

91. The pharmaceutical composition of any one of claims 1-90, wherein the pH of the composition is about 2 to 12.

92. The pharmaceutical composition of any one of claims 1-90, wherein the pH of the composition is about 5.0 to 7.

5.

93. The pharmaceutical composition of any one of claims 1-90, wherein the pH of the composition is about 6.

0.

94. A pharmaceutical composition according to any one of claims 1-93, wherein the composition is configured for subcutaneous administration.

95. The pharmaceutical composition of any one of claims 1-94, wherein the composition is in liquid form.

96. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 0.47% propylene glycol, approximately 0.18% phenol, approximately 0.037% anhydrous disodium phosphate, and approximately 1.5% of a compound of Formula I or Formula II.

97. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 4.9% sorbitol, approximately 0.12% L-histidine, approximately 0.09% methionine, approximately 1.5% of a compound of Formula I or Formula II, and approximately 0.04% polysorbate 20.

98. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 0.94% propylene glycol, approximately 0.36% phenol, approximately 0.074% disodium phosphate anhydrous, approximately 1.5% of a compound of Formula I or Formula II, and approximately 0.005% polysorbate 80.

99. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 0.8% sodium chloride, approximately 0.193% sodium citrate dihydrate, approximately 0.01% polysorbate 80, approximately 1.5% of a compound of Formula I or Formula II, and approximately 0.018% EDTA.2Na.

100. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 5.802% trehalose dihydrate, approximately 0.005% polysorbate 80, approximately 0.0072% methionine, approximately 0.108% sodium citrate dihydrate, approximately 1.5% compound of Formula I or Formula II, and approximately 1.5% mannitol.

101. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 1.21% glycerol, approximately 0.441% sodium citrate dihydrate, approximately 0.102% magnesium chloride hexahydrate, approximately 1.5% of a compound of Formula I or Formula II, and approximately 0.0039% zinc oxide.

102. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 0.3% m-cresol, approximately 0.441% sodium citrate dihydrate, approximately 1.5% of a compound of Formula I or Formula II, and approximately 4.54% mannitol.

103. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises about 4.9% lactose monohydrate, about 0.113% disodium phosphate anhydrous, and about 1.5% of a compound of Formula I or Formula II by weight.

104. The pharmaceutical composition of any one of claims 1-95, wherein the pharmaceutical composition comprises, by weight, approximately 1.40% propylene glycol, approximately 0.55% phenol, approximately 1.5% compound of Formula I or Formula II, approximately 0.113% disodium phosphate anhydrous, and approximately 0.005% polysorbate 80.

105. A pharmaceutical composition according to any one of claims 1-95, wherein the pharmaceutical composition comprises one or more of the following: propylene glycol, phenol, m-cresol, disodium phosphate anhydrous, glycerol, mannitol, zinc oxide, magnesium chloride hexahydrate, L-histidine, methionine, sorbitol, sodium chloride, trehalose dihydrate, lactose monohydrate, sodium citrate dihydrate, polysorbate 80, polysorbate 20 and EDTA.2Na.

106. A method for preventing, treating or ameliorating one or more fatty liver diseases in a subject, comprising administering to a subject in need thereof the pharmaceutical composition of any one of claims 1-105.

107. The method of claim 106, wherein the fatty liver disease is selected from steatosis, nonalcoholic steatohepatitis, and nonalcoholic fatty liver disease.

108. The method of claim 106 or 107, wherein the administration of the pharmaceutical composition results in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a fibrotic symptom.

109. The method of any one of claims 106-108, wherein the administration of the pharmaceutical composition results in a decrease in the amount of an extracellular matrix protein present in one or more tissues of the subject.

110. The method of any one of claims 106-109, wherein the administration of the pharmaceutical composition results in a decrease in the amount of collagen present in one or more tissues of the subject.

111. The method of claim 110, wherein the administration of the pharmaceutical composition results in a decrease in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

112. A method for preventing, treating or ameliorating one or more diseases or conditions in a subject, comprising administering to a subject in need thereof a pharmaceutical composition as described in any one of claims 1-106, wherein the disease or condition is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

113. The method of claim 112, wherein the disease or condition is nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, or primary biliary cirrhosis.

114. The method of any one of claims 106-113, wherein the route of administration is subcutaneous.

Images