Pharmaceutical formulations and methods for the treatment of metabolic and liver disorders

Abstract

Formulations of small molecule GIP / GLP-1 dual receptor agonists and their use are disclosed herein.

Description

Technical Field

[0001] Reference to Sequence Listing This application is filed together with a sequence listing in electronic format. The sequence listing is provided as a file entitled VIKNG.024WO.xml created on July 17, 2023, which is 51,632 bytes in size. The information in the electronic format of the sequence listing is hereby incorporated by reference in its entirety into this specification.

[0002] The present disclosure generally relates to the fields of chemistry and medicine. More specifically, the present disclosure relates to pharmaceutical formulations for the treatment of metabolic disorders and fatty liver diseases.

Background Art

[0003] The 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 minutes of oral nutrient intake and facilitate the rapid processing of orally ingested nutrients. Both peptides share common actions on pancreatic β-cells that act via structurally distinct 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 via direct actions on adipose tissue. In contrast, GLP-1 exerts glycemic effects via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety, and sustained GLP-1 receptor activation is associated with weight loss in both preclinical and clinical studies.

[0004] Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and the most common cause of chronic liver disease. NAFLD can progress to liver inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma. GIP / GLP-1 dual receptor agonists have been developed to treat 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 tolerability at high doses was limited by gastrointestinal adverse events. Dose limitations associated with gastrointestinal adverse events can prevent dosing to the desired effective dose, can impair patient compliance with treatment, and can limit the effectiveness of the treatment regimen. Therefore, there is a need for GIP / GLP1 dual agonist compounds that can be used to treat fatty liver disease and other diseases and disorders. In addition, there is a need for suitable pharmaceutical formulations for such dual agonist compounds.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

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Summary of the Invention

Means for Solving the Problems

[0007] A pharmaceutical composition is disclosed herein, a part of which comprises a compound having the structure of Formula I:

[0008]

Chemical Formula

[0009] or a pharmaceutically acceptable salt thereof, wherein: Aib is 2 - aminoisobutyric acid; J 1 、J 2 、and J 3 each instance is independently an amino acid selected from Aib, naturally occurring amino acids, and non - natural amino acids; U 1 is -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 -; U 2 is -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8- and; J 4 、J 5 、J 6 、J 7 、J 8 、J 9 、J 10 、and J 11 each instance of which is independently a naturally occurring amino acid or a non-natural 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 is selected from the group consisting of -C(=O)(OZ 1 ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, wherein the heteroaryl is independently selected from 1 to 2 Rs selected from halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 、C 3~10 cycloalkyl, C 6~10 aryl, a 5- to 10-membered heteroaryl, and a 5- to 10-membered heterocyclyl and is optionally substituted with; 7 ; R 2 is selected from the group consisting of -C(=O)(OZ 2 ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, wherein the heteroaryl is independently selected from 1 to 2 Rs selected from halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 、C 3~10 cycloalkyl, C 6~10 aryl, a 5- to 10-membered heteroaryl, and a 5- to 10-membered heterocyclyl and is optionally substituted with; 7 ; each R 7 is halogen, C 1~6 alkyl, haloC1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 Independently selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; X and Y are each, -OR 4 , NR 5 R 6 , C 1~6 Alkyl and halo C 1~6 Independently selected from the group consisting of alkyl; Each R 4 is hydrogen, C 1~6 Alkyl, halo C 1~6 Alkyl, C 6~10 Aryl and C 7~11 Arylalkyl; independently selected from the group consisting of; Each R 5 is independently hydrogen or C 1~6 Alkyl; Each R 6 is independently hydrogen or C 1~6 Alkyl; Z 1 and Z 2 are each hydrogen, C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Aryl; independently selected from the group consisting of.

[0010] In some embodiments, the pharmaceutical composition does not contain the compound:

[0011]

Chemical formula

[0012] Does not contain.

[0013] Some embodiments are J 1 , J 2 , and J3 Each instance of is independently included as an amino acid selected from Aib and naturally occurring amino acids. Some embodiments are J 1 , J 2 , and J 3 Each instance of is independently included as an amino acid selected from Aib, A, F, N, R, and Q. Some embodiments include J 1 of the compound of Formula I as Aib or F. Some embodiments include J 1 of the compound of Formula I as F. Some embodiments include J 2 of the compound of Formula I as N or Q. Some embodiments include J 2 of the compound of Formula I as N. Some embodiments include J 3 of the compound of Formula I as A or R. Some embodiments include J 3 of the compound of Formula I as R. Some embodiments include J 4 , J 5 , J 6 , and J 7 Each instance of is independently included as an amino acid selected from A, I, K, R, Q, S, T, and V. Some embodiments include J 4 of the compound of Formula I as K or R. Some embodiments include J 4 of the compound of Formula I as R. Some embodiments include J 5 of the compound of Formula I as I, T, or V. Some embodiments include J 5 of the compound of Formula I as T or V. Some embodiments include J 6 of the compound of Formula I as A or S. Some embodiments include J 6 of the compound of Formula I as S. Some embodiments include J 7 of the compound of Formula I as Q. Some embodiments include J 8 , J 9 , J 10 , and J 11 Each instance of is independently included as an amino acid selected from A, I, and Q. Some embodiments include J 8 of the compound of Formula I as I or Q. Some embodiments include J 9includes it as I or Q. Some embodiments, J of the compound of formula I 10 includes it as Q. Some embodiments, J of the compound of formula I 11 includes it as Q.

[0014] Some embodiments are J of the compound of formula I 1 is selected from Aib or F; J of the compound of formula I 2 is selected from Q or N; J of the compound of formula I 3 is selected from A or R; U of the compound of formula I 1 is selected from -K-V-A-, -K-I-A-Q-, -K-T-A-Q-, -K-T-S-Q-, -K-V-A-Q-, -R-I-A-Q-, or does not exist; U of the compound of formula I 2 is selected from -Q-, -I-A-Q-Q-, or does not exist includes a pharmaceutical composition.

[0015] Some embodiments include each instance of n1, n2, n3, and n4 of the compound of formula I as zero. Some embodiments include each instance of n4, n6, n7, and n8 of the compound of formula I as zero. Some embodiments include each instance of n4, n6, n7, and n8 of the compound of formula I as zero. Some embodiments, Z of the compound of formula I 1 and Z 2 include at least one of them as hydrogen.

[0016] Some embodiments are of formula I-a:

[0017]

Chemical formula

[0018] includes a compound having the structure of, or a pharmaceutical composition having a pharmaceutically acceptable salt thereof.

[0019] Some embodiments are hydrogen, C 1~6Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Z selected from the group consisting of aryl 1 and includes; X and Y are each, -OR 4 is. Some embodiments, the Z of the compound of formula I-a 1 comprises hydrogen, each R of the compound of formula I-a 4 is independently hydrogen or C 7~11 is arylalkyl. Some embodiments, each R of the compound of formula I-a 4 comprises hydrogen. Some embodiments, the Z of the compound of formula I-a 1 comprises hydrogen and each R of the compound of formula I-a 4 comprises hydrogen.

[0020] Some embodiments, formula I-b:

[0021]

Chemical formula

[0022] a compound having the structure of, or a pharmaceutical composition having a pharmaceutically acceptable salt thereof.

[0023] Some embodiments, hydrogen, C 6~10 aryl and C 7~11 each R of the compound of formula I-b, independently selected from the group consisting of arylalkyl 4 comprises. Some embodiments, each R of the compound of formula I-b 4 comprises hydrogen.

[0024] Some embodiments, a compound selected from the following:

[0025]

Chemical formula

[0026] [Chemistry]

[0027] [Chemistry]

[0028] or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

[0029] Some embodiments include a compound having the structure of Formula II:

[0030] [Chemistry]

[0031] or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of -C(=O)(OZ 1 ), -P(=O)(X)(Y), and one or two R 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, optionally substituted with one or two R 7 selected independently therefrom, and one or two heteroatoms selected from N, O, and S, contained in a 5- to 10-membered heteroaryl; R 2 is selected from the group consisting of -C(=O)(OZ 2 ), -P(=O)(X)(Y), and one or two R 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, optionally substituted with one or two R 7selected from the group consisting of 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, optionally substituted; each R 7 is independently selected from the group consisting of halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; X and Y are each independently selected from the group consisting of -OR 4 , NR 5 R 6 C 1~6 alkyl, and haloC 1~6 alkyl; each R 4 is independently selected from the group consisting of hydrogen, C 1~6 alkyl, haloC 1~6 alkyl, C 6~10 aryloxy, and C 6~10 arylalkoxy; each R 5 is independently hydrogen or C 1~6 alkyl; each R 6 is independently hydrogen or C 1~6 alkyl; Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl, and C 6~10 aryl, provided that at least one of Z and Z 1 is not hydrogen. 2

[0032] Some embodiments are of formula II-a:

[0033] ​ [Chemical formula]

[0034] It includes a compound having the structure of, or a pharmaceutical composition having a pharmaceutically acceptable salt thereof.

[0035] Some embodiments include Z selected from the group consisting of hydrogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl and C 6~10 aryl; X and Y are each -OR 1 Some embodiments include Z selected from the group consisting of hydrogen, haloC 4 alkoxy and C 1~6 alkoxy; each R 1~6 is independently selected from the group consisting of hydrogen, C 1 aryloxy and C 4 arylalkoxy. Some embodiments include Z 6~10 as hydrogen and each R 6~10 independently as hydrogen or C 1 arylalkoxy. Some embodiments include each R 4 as hydrogen. Some embodiments include Z 6~10 as hydrogen and each R 4 as hydrogen. 1 as hydrogen and each R 4 as hydrogen.

[0036] Some embodiments include a compound having the structure of formula III-b:

[0037] [Chemical formula]

[0038] It includes a compound having the structure of, or a pharmaceutical composition having a pharmaceutically acceptable salt thereof.

[0039] Some embodiments include hydrogen, C 1~6Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Z selected from the group consisting of aryl 2 and; X and Y are each, -OR 4 is. Some embodiments are hydrogen, halo C 1~6 Alkoxy and C 1~6 Z selected from the group consisting of alkoxy 2 and; each R 4 is independently selected from hydrogen, C 6~10 Aryloxy and C 6~10 Arylalkoxy. Some embodiments are Z 2 as hydrogen and each R 4 as hydrogen or C 6~10 Arylalkoxy. Some embodiments are each R 4 as hydrogen. Some embodiments are Z 2 as hydrogen and each R 4 as hydrogen.

[0040] Some embodiments are of formula II-c:

[0041]

Chemical formula

[0042] A compound having the structure of, or a pharmaceutical composition having a pharmaceutically acceptable salt thereof.

[0043] Some embodiments are each of X and Y as -OR 4 and. Some embodiments are hydrogen, C 6~10 Aryloxy and C 6~10 Each R independently selected from the group consisting of arylalkoxy 4 and. Some embodiments are each R 4 as hydrogen.

[0044] A compound having a structure selected from the group consisting of:

[0045]

Chemical formula

[0046]

Chemical formula

[0047]

Chemical formula

[0048]

Chemical formula

[0049] and a pharmaceutical composition having a pharmaceutically acceptable salt thereof.

[0050] Some embodiments include a chiral carbon having an "S" configuration and represented by " * ". Some embodiments include a chiral carbon having an "R" configuration and represented by " * ".

[0051] Some embodiments include a pharmaceutical composition comprising a compound of formula I or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0052] Some embodiments disclosed herein include a pharmaceutical composition for administration to a subject in need thereof, wherein the pharmaceutical composition comprises: one or more non-aqueous solvents or solubilizing enhancers constituting less than 20% by mass of the pharmaceutical composition; and a therapeutically effective dose of a compound having the structure of formula I or II, or a pharmaceutically acceptable salt thereof.

[0053] Some embodiments disclosed herein include pharmaceutical compositions in which one or more non-aqueous solvents or solubilizing enhancers constitute less than 10% by weight of the composition.

[0054] Some embodiments disclosed herein include pharmaceutical compositions in which one or more non-aqueous solvents or solubilizing enhancers constitute less than 5% by weight of the composition.

[0055] Some embodiments disclosed herein include pharmaceutical compositions in which one or more non-aqueous solvents or solubilizing enhancers include propylene glycol.

[0056] Some embodiments disclosed herein include pharmaceutical compositions in which propylene glycol is present in a mass percentage of about 10% or less.

[0057] Some embodiments disclosed herein include pharmaceutical compositions in which propylene glycol is present in a mass percentage of about 2% or less.

[0058] Some embodiments disclosed herein include pharmaceutical compositions in which propylene glycol is present in a mass percentage of about 0.1% to about 2%.

[0059] Some embodiments disclosed herein include pharmaceutical compositions in which propylene glycol is present in a mass percentage of about 0.4% to about 1.5%.

[0060] Some embodiments disclosed herein include pharmaceutical compositions in which one or more non-aqueous solvents or solubilizing enhancers include polysorbate.

[0061] Some embodiments disclosed herein include pharmaceutical compositions in which polysorbate is present in a mass percentage of approximately 0.001% to approximately 0.1%.

[0062] Some embodiments disclosed herein include pharmaceutical compositions in which polysorbate is present at a mass percentage of from approximately 0.003% to approximately 0.05%.

[0063] Some embodiments disclosed herein include pharmaceutical compositions in which the polysorbate is polysorbate 80.

[0064] Some embodiments disclosed herein include pharmaceutical compositions in which the polysorbate is polysorbate 20.

[0065] Some embodiments disclosed herein include pharmaceutical compositions in which one or more non-aqueous solvents or solubilizing enhancers include glycerol.

[0066] Some embodiments disclosed herein include pharmaceutical compositions in which glycerol is present at a mass percentage of from approximately 0.5% to approximately 5%.

[0067] Some embodiments disclosed herein include pharmaceutical compositions in which one or more non-aqueous solvents or solubilizing enhancers include metacresol.

[0068] Some embodiments disclosed herein include pharmaceutical compositions in which metacresol is present at a mass percentage of from approximately 0.1% to approximately 1%.

[0069] Some embodiments disclosed herein include pharmaceutical compositions in which one or more non-aqueous solvents or solubilizing enhancers include phenol.

[0070] Some embodiments disclosed herein include pharmaceutical compositions in which phenol is present at a mass percentage of from approximately 0.1% to approximately 1%.

[0071] Some embodiments disclosed herein include pharmaceutical compositions in which phenol is present at a mass percentage of from approximately 0.1% to approximately 0.6%.

[0072] Some embodiments disclosed herein include pharmaceutical compositions comprising from approximately 0.1% to approximately 5% by weight of propylene glycol and from approximately 0.1% to approximately 1% by weight of phenol.

[0073] Some embodiments disclosed herein include pharmaceutical compositions comprising from approximately 0.001% to approximately 0.01% by weight of polysorbate 80.

[0074] Some embodiments disclosed herein include pharmaceutical compositions comprising a therapeutically effective dose of lactose and a compound having the structure of Formula II or a pharmaceutically acceptable salt thereof:

[0075]

Chemical formula

[0076] Wherein: R 1 is independently selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y), and one or two R 1~6 independently selected from alkyl, haloalkyl, haloalkoxy, -OR 1~6 alkyl, haloalkyl, haloalkoxy, -OR 1~6 alkoxy, -OR 5 , cycloalkyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, optionally substituted with one or two R 3~10 independently selected from N, O, and S containing one or two heteroatoms, and is selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with one or two R 6~10 independently selected from N, O, and S containing one or two heteroatoms, and is selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with one or two R 7 independently selected from N, O, and S containing one or two heteroatoms, and is selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with one or two R R 2 is independently selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y), and one or two R 1~6 independently selected from alkyl, haloalkyl, haloalkoxy, -OR 1~6 alkyl, haloalkyl, haloalkoxy, -OR 1~6 alkoxy, -OR 5 , cycloalkyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, optionally substituted with one or two R 3~10 independently selected from N, O, and S containing one or two heteroatoms, and is selected from the group consisting of 5- to 10-membered heteroaryl optionally substituted with one or two R 6~10One or two Rs independently selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl 7 Selected from the group consisting of 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O, and S, optionally substituted; Each R 7 Is independently selected from halogen, C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; X and Y are each independently selected from -OR 4 NR 5 R 6 C 1~6 Alkyl and halo C 1~6 Alkyl; Each R 4 Is independently selected from hydrogen, C 1~6 Alkyl, halo C 1~6 Alkyl, C 6~10 Aryl, and C 6~10 Arylalkyl; Each R 5 Is independently hydrogen or C 1~6 Alkyl; Each R 6 Is independently hydrogen or C 1~6 Alkyl; Z 1 And Z 2 Are each independently selected from hydrogen, C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, and C 6~10 Aryl, provided that Here, at least one of Z 1 And Z 2 Is not hydrogen.

[0077] Some embodiments disclosed herein include pharmaceutical compositions in which lactose is present as lactose monohydrate at a mass percentage of approximately 2% to approximately 10%. Some embodiments include " * " which indicates a chiral carbon having an "S" configuration. Some embodiments include " * " which indicates a chiral carbon having an "R" configuration. Some embodiments include a pharmaceutically acceptable aqueous carrier. Some embodiments include the aqueous carrier as water or physiological saline. Some embodiments include pharmaceutical compositions containing a buffer. In some embodiments, the buffer includes 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 of the foregoing. Some embodiments include a buffer containing sodium citrate. Some embodiments include a buffer containing disodium phosphate. Some embodiments include a buffer containing L-histidine. Some embodiments include a buffer containing methionine.

[0078] Some embodiments include a pharmaceutical composition having a pH of from about 2 to 12. Some embodiments include a pharmaceutical composition having a pH of from about 5.0 to 7.5. Some embodiments include a pharmaceutical composition having a pH of about 6.0. Some embodiments include a pharmaceutical composition configured for subcutaneous administration. Some embodiments include a pharmaceutical composition that is liquid.

[0079] Some embodiments disclosed herein are Z 1 is hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, halo C 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl and C 6~10 selected from the group consisting of aryl; each of X and Y is -OR 4 and a pharmaceutical composition thereof.

[0080] Some embodiments disclosed herein are Z 1 is hydrogen, halo C 1~6 alkoxy and C 1~6 selected from the group consisting of alkoxy; each R 4 is independently hydrogen, C 6~10 aryl and C 6~10 and a pharmaceutical composition selected from the group consisting of arylalkyl.

[0081] Some embodiments disclosed herein are Z 1 is hydrogen, and each R 4 is independently hydrogen or C 6~10 and a pharmaceutical composition which is arylalkyl.

[0082] Some embodiments disclosed herein include a pharmaceutical composition wherein each R 4 is hydrogen.

[0083] Some embodiments disclosed herein are such that the compound has a structure consisting of:

[0084]

Chemical formula

[0085] It includes a pharmaceutical composition having the compound or any pharmaceutically acceptable salt thereof.

[0086] Some embodiments disclosed herein include a pharmaceutical composition in which " * " represents a chiral carbon having an "S" configuration.

[0087] Some embodiments disclosed herein include a pharmaceutical composition in which " * " represents a chiral carbon having an "R" configuration.

[0088] Some embodiments disclosed herein include a pharmaceutical composition comprising a pharmaceutically acceptable aqueous carrier.

[0089] Some embodiments disclosed herein include a pharmaceutical composition in which the aqueous carrier is water or physiological saline.

[0090] Some embodiments disclosed herein include a pharmaceutical composition comprising a buffer solution.

[0091] Some embodiments disclosed herein include pharmaceutical compositions in which 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 of the foregoing.

[0092] Some embodiments disclosed herein include pharmaceutical compositions in which the buffer comprises sodium citrate.

[0093] Some embodiments disclosed herein include pharmaceutical compositions in which the buffer comprises disodium phosphate.

[0094] Some embodiments disclosed herein include pharmaceutical compositions in which the buffer comprises L-histidine.

[0095] Some embodiments disclosed herein include pharmaceutical compositions in which the buffer comprises methionine.

[0096] Some embodiments disclosed herein include pharmaceutical compositions having a pH of from about 2 to 12.

[0097] Some embodiments disclosed herein include pharmaceutical compositions having a pH of from about 5.0 to 7.5.

[0098] Some embodiments disclosed herein include pharmaceutical compositions having a pH of approximately 6.0.

[0099] Some embodiments disclosed herein include pharmaceutical compositions configured for subcutaneous administration.

[0100] Some embodiments disclosed herein include pharmaceutical compositions in a liquid form.

[0101] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 0.47% by weight of propylene glycol, approximately 0.18% by weight of phenol, approximately 0.037% by weight of disodium phosphate anhydrous, and approximately 1.5% by weight of a compound of Formula I or II.

[0102] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 4.9% by weight of sorbitol, approximately 0.12% by weight of L - histidine, approximately 0.09% by weight of methionine, approximately 1.5% by weight of a compound of Formula I or II, and approximately 0.04% by weight of polysorbate 20.

[0103] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 0.94% by weight of propylene glycol, approximately 0.36% by weight of phenol, approximately 0.074% by weight of disodium phosphate anhydrous, approximately 1.5% by weight of a compound of Formula I or II, and approximately 0.005% by weight of polysorbate 80.

[0104] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 0.8% by weight of sodium chloride, approximately 0.193% by weight of sodium citrate dihydrate, approximately 0.01% by weight of polysorbate 80, approximately 1.5% by weight of a compound of Formula I or II, and approximately 0.018% by weight of EDTA.2Na.

[0105] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 5.802% by weight of trehalose dihydrate, approximately 0.005% by weight of polysorbate 80, approximately 0.0072% by weight of methionine, approximately 0.108% by weight of sodium citrate dihydrate, approximately 1.5% by weight of a compound of formula I or II, and approximately 1.5% by weight of mannitol.

[0106] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 1.21% by weight of glycerol, approximately 0.441% by weight of sodium citrate dihydrate, approximately 0.102% by weight of magnesium chloride hexahydrate, approximately 1.5% by weight of a compound of formula I or II, and approximately 0.0039% by weight of zinc oxide.

[0107] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 0.3% by weight of metacresol, approximately 0.441% by weight of sodium citrate dihydrate, approximately 1.5% by weight of a compound of formula I or II, and approximately 4.54% by weight of mannitol.

[0108] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 4.9% by weight of lactose monohydrate, approximately 0.113% by weight of disodium hydrogen phosphate anhydrous, and approximately 1.5% by weight of a compound of formula I or II.

[0109] Some embodiments disclosed herein include pharmaceutical compositions comprising approximately 1.40% by weight of propylene glycol, approximately 0.55% by weight of phenol, approximately 1.5% by weight of a compound of formula I or II, approximately 0.113% by weight of disodium hydrogen phosphate anhydrous, and approximately 0.005% by weight of polysorbate 80.

[0110] Some embodiments disclosed herein include a pharmaceutical composition comprising one or more of propylene glycol, phenol, metacresol, 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.

[0111] Some embodiments disclosed herein include a method of preventing, treating, or alleviating one or more fatty liver diseases in a subject, the method comprising administering the pharmaceutical composition to a subject in need thereof.

[0112] Some embodiments disclosed herein include a method wherein the fatty liver disease is selected from the group consisting of steatosis, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease.

[0113] Some embodiments disclosed herein include a method wherein the administration of the pharmaceutical composition results in the prevention, treatment, or alleviation of fibrosis, fibrotic conditions, or fibrotic symptoms.

[0114] Some embodiments disclosed herein include a method wherein the administration of the pharmaceutical composition results in a reduction in the amount of extracellular matrix proteins present in one or more tissues of the subject.

[0115] Some embodiments disclosed herein include a method wherein the administration of the pharmaceutical composition results in a reduction in the amount of collagen present in one or more tissues of the subject.

[0116] Some embodiments disclosed herein include a method wherein the administration of the pharmaceutical composition results in a reduction in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

[0117] Some embodiments disclosed herein include a method of preventing, treating, or alleviating one or more diseases or disorders in a subject, comprising administering a pharmaceutical composition to a subject in need thereof, wherein the disease or disorder is liver fibrosis, kidney fibrosis, bile duct fibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

[0118] Some embodiments disclosed herein include a method wherein the disease or disorder is non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis.

[0119] Some embodiments disclosed herein include a pharmaceutical formulation wherein the therapeutically effective dosage is from about 1.0 mg / kg.

[0120] Some embodiments disclosed herein include a method wherein the route of administration is subcutaneous.

Brief Description of the Drawings

[0121]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0122] In some embodiments, the pharmaceutical formulation is provided for administration to a subject in need thereof. Various embodiments of these pharmaceutical formulations include a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a pharmaceutically acceptable diluent, and any combination of the foregoing. Some embodiments of the pharmaceutical formulation include a therapeutically effective dose of a compound, or a pharmaceutically acceptable salt thereof, as described elsewhere herein. Some embodiments of the pharmaceutical formulation are administered for the prevention, treatment, or alleviation of one or more fatty liver diseases in a subject.

[0123] Compound In some embodiments, the pharmaceutical formulation includes a compound that is a non-cyclic functionalized peptide that acts as a GIP / GLP-1 dual receptor agonist. Various embodiments of these compounds include compounds having the structure of formula (I) as described herein, or a pharmaceutically acceptable salt thereof. The structure of formula (I) is the following structure and mixtures thereof:

[0124]

Chemical formula

[0125] including all stereoisomers and racemic mixtures, including pharmaceutically acceptable salts thereof. In the formulas (I) and compounds described herein, "H-" represents hydrogen on the N-terminal amine, and "-NH2" represents the amino that forms the C-terminal amide.

[0126] In some embodiments of the compound of formula (I): Aib is 2-aminoisobutyric acid; J 1 、J 2 、and J 3 each instance of is independently an amino acid selected from Aib, naturally occurring amino acids, and non-natural amino acids.

[0127] In some embodiments of the compound of formula (I): U 1 is -(J 4 )n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 - and; U 2 is -(J 8 ) n5 -(J 9 ) n6 -(J 10 ) n7 -(J 11 ) n8 - and; J 4 , J 5 , J 6 , J 7 , J 8 , J 9 , J 10 , and J 11 each instance of which is independently a naturally occurring amino acid or a non-natural 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 is selected from the group consisting of -C(=O)(OZ 1 ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with 1 to 2 R 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, a 5- to 10-membered heteroaryl, and a 5- to 10-membered heterocyclyl independently selected; 7 and is optionally substituted; R 2 is selected from the group consisting of -C(=O)(OZ 2 ), -P(=O)(X)(Y), and a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with halogen, C1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 One or two Rs independently selected from aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl 7 Optionally substituted; Each R 7 Is halogen, C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 Independently selected from the group consisting of aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl; X and Y are each, -OR 4 , NR 5 R 6 , C 1~6 Alkyl and halo C 1~6 Independently selected from the group consisting of; Each R 4 Is hydrogen, C 1~6 Alkyl, halo C 1~6 Alkyl, C 6~10 Aryl and C 7~11 Independently selected from the group consisting of arylalkyl; Each R 5 Is independently hydrogen or C 1~6 Alkyl; Each R 6 Is independently hydrogen or C 1~6 Alkyl; Z 1 And Z 2 Are each hydrogen, C 1~6 Alkyl, halo C 1~6 Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Independently selected from the group consisting of aryl.

[0128] In some embodiments, the compound is not the following:

[0129] [Chemical formula]

[0130] In some embodiments of the compound of formula (I), each instance of J 1 , J 2 , and J 3 is independently an amino acid selected from Aib and naturally occurring amino acids.

[0131] In some embodiments of the compound of formula (I), each instance of J 1 , J 2 , and J 3 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 is R.

[0132] In some embodiments of the compound of formula (I), each instance of J 4 , J 5 , J 6 , and J 7 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 6is S. In some embodiments, J 7 is Q.

[0133] In some embodiments of the compound of formula (I), J 8 , J 9 , J 10 , and J 11 each instance of is an amino acid selected independently from A, I, and Q. In some embodiments, J 8 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 is Q.

[0134] In some embodiments of the compound of formula (I), J 1 is selected from Aib or F; J 2 is selected from Q or N; J 3 is selected from A or R; U 1 is selected from -K-V-A-, -K-I-A-Q-, -K-T-A-Q-, -K-T-S-Q-, -K-V-A-Q-, -R-I-A-Q-, or does not exist; U 2 is selected from -Q-, -I-A-Q-Q-, or does not exist.

[0135] In some embodiments of the compound 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.

[0136] In some embodiments of the compound of formula (I), Z 1 and Z 2 at least one of is not hydrogen.

[0137] As some embodiments of the compound of formula (I), formula (I-a):

[0138] [Chemical formula]

[0139] Compounds having the structure of or pharmaceutically acceptable salts thereof are included.

[0140] In some embodiments of the compounds of formula (I-a) or pharmaceutically acceptable salts thereof, Z 1 is hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, halo C 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl and C 6~10 aryl; X and Y are each -OR 4 respectively.

[0141] In some embodiments of the compounds of formula (I-a) or pharmaceutically acceptable salts thereof, Z 1 is hydrogen, and each R 4 is independently hydrogen or C 7~11 arylalkyl.

[0142] In some embodiments of the compounds of formula (I-a) or pharmaceutically acceptable salts thereof, each R 4 is hydrogen.

[0143] In some embodiments of the compounds of formula (I-a) or pharmaceutically acceptable salts thereof, Z 1 is hydrogen, and each R 4 is hydrogen.

[0144] Some embodiments of the compounds of formula (I) are of formula (I-b):

[0145] [Chemical formula]

[0146] Compounds having the structure of or pharmaceutically acceptable salts thereof are included.

[0147] In some embodiments of the compound of formula (I-b) or a pharmaceutically acceptable salt thereof, each R 4 is independently selected from the group consisting of hydrogen, C 6~10 aryl, and C 7~11 arylalkyl.

[0148] In some embodiments of the compound of formula (I-b) or a pharmaceutically acceptable salt thereof, each R 4 is hydrogen.

[0149] Some embodiments include compounds having a structure selected from the group consisting of:

[0150]

Chemical formula

[0151]

Chemical formula

[0152]

Chemical formula

[0153]

Chemical formula

[0154] or a pharmaceutically acceptable salt thereof.

[0155] Other embodiments of the pharmaceutical formulations described herein include compounds having the 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:

[0156]

Chemical formula

[0157] In some embodiments of the compound of formula II: R 1 is independently selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y), and one or two Rs independently selected from halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, and is selected from the group consisting of 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O, and S optionally substituted with one or two Rs 7 ; R 2 is independently selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y), and one or two Rs independently selected from halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, -OR 5 , C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, and is selected from the group consisting of 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O, and S optionally substituted with one or two Rs 7 ; Each R 7 can be independently selected from the group consisting of halogen, C 1~6 alkyl, haloC 1~6 alkyl, haloC 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; X and Y are each independently -OR 4 , NR 5 R 6 , C 1~6 alkyl, and haloC 1~6can be independently selected from the group consisting of alkyl; each R 4 is hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, C 6~10 aryl and C 6~10 can be independently selected from the group consisting of arylalkyl; each R 5 is independently hydrogen or C 1~6 alkyl may be; each R 6 is independently hydrogen or C 1~6 alkyl may be; Z 1 and Z 2 are each hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, halo C 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl and C 6~10 aryl can be independently selected from the group, provided that however, Z 1 and Z 2 at least one of which is the condition that it is not hydrogen.

[0158] Some embodiments of the compound of formula II include formula II-a:

[0159]

Chemical formula

[0160] Compounds having the structure of, or pharmaceutically acceptable salts thereof.

[0161] In some embodiments of the compound of formula II-a or pharmaceutically acceptable salts thereof; Z 1 is hydrogen, C 1~6 alkyl, halo C 1~6 alkyl, halo C 1~6 alkoxy, C 1~6 alkoxy, C 3~10 cycloalkyl and C 6~10selected from aryl; X and Y are each -OR 4 is.

[0162] In some embodiments of the compounds of formula II-a or pharmaceutically acceptable salts thereof; Z 1 is hydrogen, haloC 1~6 alkoxy and C 1~6 alkoxy; each R 4 is hydrogen, C 6~10 aryl and C 6~10 arylalkyl can be independently selected.

[0163] In some embodiments of the compounds of formula II-a or pharmaceutically acceptable salts thereof; Z 1 is hydrogen, and each R 4 is independently hydrogen or C 6~10 arylalkyl may be.

[0164] In some embodiments of the compounds of formula II-a or pharmaceutically acceptable salts thereof; each R 4 is hydrogen.

[0165] In some embodiments of the compounds of formula II-a or pharmaceutically acceptable salts thereof; Z 1 is hydrogen, and each R 4 is hydrogen.

[0166] Some embodiments of the compounds of formula II include those of formula II-b:

[0167]

Chemical formula

[0168] Compounds having the structure of or pharmaceutically acceptable salts thereof are included.

[0169] In some embodiments of the compounds of formula II-b or pharmaceutically acceptable salts thereof; Z 2 is hydrogen, C 1~6 alkyl, haloC 1~6Alkyl, halo C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl and C 6~10 Selected from aryl; X and Y are each -OR 4 is.

[0170] In some embodiments of the compounds of formula II-b or their pharmaceutically acceptable salts; Z 2 is hydrogen, halo C 1~6 Alkoxy and C 1~6 Selected from alkoxy; each R 4 is hydrogen, C 6~10 Aryl and C 6~10 Can be independently selected from arylalkyl.

[0171] In some embodiments of the compounds of formula II-b or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R 4 Can be independently hydrogen or C 6~10 May be arylalkyl.

[0172] In some embodiments of the compounds of formula II-b or their pharmaceutically acceptable salts; each R 4 is hydrogen.

[0173] In some embodiments of the compounds of formula II-b or their pharmaceutically acceptable salts; Z 2 is hydrogen, and each R 4 is hydrogen.

[0174] Some embodiments of the compounds of formula II include formula II-c:

[0175]

Chemical formula

[0176] Compounds having the structure of, or their pharmaceutically acceptable salts.

[0177] In some embodiments of the compounds of formula II-c or their pharmaceutically acceptable salts; X and Y are each -OR 4 wherein.

[0178] In some embodiments of the compounds of formula II-c or their pharmaceutically acceptable salts; each R 4 is independently selected from hydrogen, C 6~10 aryl and C 6~10 arylalkyl.

[0179] In some embodiments of the compounds of formula II-c or their pharmaceutically acceptable salts; each R 4 is hydrogen.

[0180] Some embodiments include:

[0181]

Chemical formula

[0182]

Chemical formula

[0183]

Chemical formula

[0184]

Chemical formula

[0185] Compounds having a structure selected from the group consisting of, and their pharmaceutically acceptable salts.

[0186] Some embodiments include " * " compounds in which the chiral carbon has the "S" configuration.

[0187] Some embodiments include " *Examples of compounds in which "」" represents a chiral carbon having an "R" configuration are given.

[0188] 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 indicated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Further, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms, including any polymorphic forms, are included within the scope of the compounds disclosed herein. In addition, some of the compounds disclosed herein can form solvates (i.e., hydrates) with water or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0189] One skilled in the art will recognize that some of the structures described herein can be resonance forms or tautomers of compounds that can be significantly represented by other chemical structures, even kinetically; one skilled in the art will recognize that such structures can only represent a very small portion of a sample of such compounds. Such compounds are considered to be within the scope of the structures shown, but such resonance forms or tautomers are not represented herein.

[0190] Formulations Some embodiments include a pharmaceutical formulation comprising a compound of formula I or II (e.g., compound 4). In some embodiments, the pharmaceutical formulation comprises one or more non-aqueous solvents or solubilizing enhancers. In some embodiments, the pharmaceutical formulation further comprises an aqueous carrier and may be suitable for subcutaneous injection. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers comprise one or more of propylene glycol, phenol, metacresol, glycerol, polysorbate 80, or polysorbate 20. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers are non-aqueous solvents (e.g., propylene glycol, phenol, metacresol, or glycerol). In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers are solubilizing enhancers (e.g., propylene glycol, phenol, polysorbate 80, or polysorbate 20).

[0191] In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers include propylene glycol. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers include phenol. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers are glycerol. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers include polysorbate 80. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers include polysorbate 20. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers include metacresol. In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers are present in the formulation at 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%, 0.049%, 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%, 0.75%, 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%, 10%, 20%, 30%, 33%, 35%, 37%, 39%, and 40%, or are present in a mass percentage that includes and / or spans the ranges below these values. In some embodiments, one or more non-aqueous solvents or solubilizing enhancers constitute less than 10% by mass of the formulation. In some embodiments, one or more non-aqueous solvents or solubilizing enhancers constitute less than 5% by mass of the formulation. In some embodiments, one or more non-aqueous solvents or solubilizing enhancers are present in the formulation at a mass percentage of from about 0.1% to 2.0% by mass. In some embodiments, one or more non-aqueous solvents or solubilizing enhancers are present in the formulation at a mass percentage of from about 0.001% to 5.0% by mass. In some embodiments, one or more non-aqueous solvents or solubilizing enhancers are present in the formulation at a mass percentage of from about 0.01% to 0.1% by mass. In some embodiments, one or more non-aqueous solvents or solubilizing enhancers are present in the formulation at a mass percentage of from about 0.01% to 0.5% by mass.

[0192] In some embodiments, the amount of the compound of Formula I or II (e.g., Compound 4) in the pharmaceutical formulation has a mass percentage of 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%, 1.35%, 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 mass percentage within and / or spanning the ranges including the foregoing values. In some embodiments, the amount of the compound of Formula I or II (e.g., Compound 4) in the pharmaceutical formulation ranges from approximately 0.05% to about 0.5% by mass. In some embodiments, the amount of the compound of Formula I or II (e.g., Compound 4) in the pharmaceutical formulation is approximately 1.5% by mass. In some embodiments, the amount of the compound of Formula I or II (e.g., Compound 4) in the pharmaceutical formulation is approximately 0.2% by mass.

[0193] In some embodiments, the one or more non-aqueous solvents or solubilizing enhancers include propylene glycol. In various embodiments, the amount of propylene glycol in the pharmaceutical formulation is 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 has a mass percentage within a range that includes and / or spans between the aforementioned values. In some embodiments, propylene glycol is present at a mass percentage of about 10% or less. In some embodiments, propylene glycol is present at a mass percentage of about 2% or less. In some embodiments, propylene glycol is present at a mass percentage of about 0.1% to about 2%. In some embodiments, propylene glycol is present at a mass percentage of about 0.1% to about 0.5%. In some embodiments, propylene glycol is present at a mass percentage of about 0.4% to about 1.5%.In some embodiments, the amount of propylene glycol in the pharmaceutical formulation is approximately 1.40% by weight. In some embodiments, propylene glycol is present at a weight percentage of from about 0.9% to about 1%. In some embodiments, the amount of propylene glycol in the pharmaceutical formulation is approximately 0.94% by weight.

[0194] In some embodiments, one or more non-aqueous solvents or solubilizing agents include phenol. In various embodiments, the amount of phenol in the pharmaceutical formulation is 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 has a weight percentage within a range including and / or spanning the foregoing values. In some embodiments, phenol is present at a weight percentage of from approximately 0.1% to approximately 1%. In some embodiments, phenol is present at a weight percentage of from approximately 0.1% to approximately 0.6%. In some embodiments, phenol is present at a weight percentage of from about 0.1% to about 0.5%. In some embodiments, the amount of phenol in the pharmaceutical formulation is approximately 0.55% by weight. In some embodiments, phenol is present at a weight percentage of from about 0.3% to about 0.4%. In some embodiments, the amount of phenol in the pharmaceutical formulation is approximately 0.36% by weight.

[0195] In some embodiments, one or more non-aqueous solvents or solubilizing enhancers include metacresol. In various embodiments, the amount of metacresol in the pharmaceutical formulation has a mass percentage of 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 mass percentage below the range including and / or spanning the aforementioned values. In some embodiments, metacresol is present at a mass percentage of from approximately 0.1% to approximately 1%. In some embodiments, metacresol is present at a mass percentage of from approximately 0.01% to approximately 0.05%. In some embodiments, metacresol is present at a mass percentage of approximately 0.3%. In some embodiments, metacresol is present at a mass percentage of approximately 0.02%.

[0196] In some embodiments, one or more non-aqueous solvents or solubilizing enhancers include glycerol. In various embodiments, the amount of glycerol in the pharmaceutical formulation has a mass percentage of about: 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 a mass percentage below the range including and / or spanning the aforementioned values. In some embodiments, glycerol is present at a mass percentage of from approximately 0.5% to approximately 5%. In some embodiments, glycerol is present at a mass percentage of from approximately 0.01% to approximately 0.05%. In some embodiments, glycerol is present at a mass percentage of approximately 1.2% (e.g., 1.21%). In some embodiments, glycerol is present at a mass percentage of approximately 0.02%.

[0197] In some embodiments, the one or more non-aqueous solvents or dissolution enhancers include polysorbate. In various embodiments, the amount of polysorbate in the pharmaceutical formulation is 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%, 0.049%, 0.050%, 0.060%, 0.070%, 0.080%, 0.090%, 0.10%, or has a mass percentage below a range including and / or spanning the aforementioned values. In some embodiments, the amount of polysorbate in the pharmaceutical formulation is approximately 0.005% by mass of the formulation. In other embodiments, the amount of polysorbate in the pharmaceutical formulation is between approximately 0.005% and 0.01% by mass of the formulation. In some embodiments, polysorbate is present at a mass percentage of from approximately 0.001% to approximately 0.1%. In some embodiments, polysorbate is present at a mass percentage of from approximately 0.003% to approximately 0.05%. In some embodiments, polysorbate is present at a mass percentage of from approximately 0.0003% to approximately 0.005%. In some embodiments, polysorbate is present at a mass percentage of from approximately 0.004% to approximately 0.006%. In some embodiments, polysorbate is present at a mass percentage of approximately 0.005%.

[0198] In some embodiments, the polysorbate is polysorbate 80. In some embodiments, polysorbate 80 is present at a mass percentage of approximately 0.005%. In some embodiments, polysorbate 80 is present at a mass percentage of approximately 0.01%. In some embodiments, the polysorbate is polysorbate 20. In some embodiments, polysorbate 20 is present at a mass percentage of approximately 0.04%.

[0199] In some embodiments, the pharmaceutical preparation can contain one or more of propylene glycol, phenol, metacresol, 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.

[0200] In some embodiments, the pharmaceutical preparation can contain propylene glycol, phenol, disodium phosphate anhydrous, polysorbate 80, and a compound of formula I or II (e.g., compound 4). For example, the pharmaceutical preparation can contain approximately 1.40% by mass of propylene glycol, 0.55% by mass of phenol, 1.5% by mass of the compound of formula I or II (e.g., compound 4), 0.113% by mass of disodium phosphate anhydrous, and 0.005% by mass of polysorbate 80. In another example, the pharmaceutical preparation can contain approximately 0.94% by mass of propylene glycol, 0.36% by mass of phenol, 0.074% by mass of disodium phosphate anhydrous, 1.5% by mass of the compound of formula I or II (e.g., compound 4), and 0.005% by mass of polysorbate 80. In some embodiments, the pharmaceutical preparation can contain approximately 0.9% to approximately 1% by mass of propylene glycol, approximately 0.3% to approximately 0.4% by mass of phenol, approximately 0.004% to approximately 0.006% by mass of polysorbate 80, and approximately 1 mg / ml to approximately 5 mg / ml (e.g., approximately 1 mg / ml to approximately 2 mg / ml) of compound 4.

[0201] In some embodiments, the pharmaceutical formulation can contain glycerol, zinc oxide, magnesium chloride hexahydrate, sodium citrate dihydrate, and a compound of Formula I or II (e.g., Compound 4). For example, the pharmaceutical formulation can contain approximately 1.21% by weight of glycerol, 0.441% by weight of sodium citrate dihydrate, 0.102% by weight of magnesium chloride hexahydrate, 1.5% by weight of a compound of Formula I or II (e.g., Compound 4), and 0.0039% by weight of zinc oxide.

[0202] In some embodiments, the pharmaceutical formulation can contain one or more of metacresol, mannitol, sodium citrate dihydrate, and a compound of Formula I or II (e.g., Compound 4). For example, the pharmaceutical formulation can contain approximately 0.3% by weight of metacresol, 0.441% by weight of sodium citrate dihydrate, 1.5% by weight of a compound of Formula I or II (e.g., Compound 4), and 4.54% by weight of mannitol.

[0203] In some embodiments, the pharmaceutical formulation can contain one or more of disodium hydrogen phosphate anhydrous, lactose monohydrate, and a compound of Formula I or II (e.g., Compound 4). For example, the pharmaceutical formulation can contain approximately 4.9% by weight of lactose monohydrate, 0.113% by weight of disodium hydrogen phosphate anhydrous, and 1.5% by weight of a compound of Formula I or II (e.g., Compound 4).

[0204] In some embodiments, the pharmaceutical formulation can contain one or more of mannitol, methionine, trehalose dihydrate, sodium citrate dihydrate, polysorbate 80, and a compound of Formula I or II (e.g., Compound 4). For example, the pharmaceutical formulation can contain approximately 5.802% by weight of trehalose dihydrate, 0.005% by weight of polysorbate 80, 0.0072% by weight of methionine, 0.108% by weight of sodium citrate dihydrate, 1.5% by weight of a compound of Formula I or II (e.g., Compound 4), and 1.5% by weight of mannitol.

[0205] In some embodiments, the pharmaceutical preparation can contain one or more of sodium chloride, sodium citrate dihydrate, polysorbate 80, EDTA·2Na, and the compound of formula I or II (e.g., compound 4). For example, the pharmaceutical preparation can contain approximately 0.8% by mass of sodium chloride, 0.193% by mass of sodium citrate dihydrate, 0.01% by mass of polysorbate 80, 1.5% by mass of the compound of formula I or II (e.g., compound 4), and 0.018% by mass of EDTA·2Na.

[0206] In some embodiments, the pharmaceutical preparation can contain one or more of L-histidine, methionine, sorbitol, polysorbate 20, and the compound of formula I or II (e.g., compound 4). For example, the pharmaceutical preparation can contain approximately 4.9% by mass of sorbitol, 0.12% by mass of L-histidine, 0.09% by mass of methionine, 1.5% by mass of the compound of formula I or II (e.g., compound 4), and 0.04% by mass of polysorbate 20.

[0207] In some embodiments, the pharmaceutical preparation can contain one or more of propylene glycol, phenol, disodium hydrogen phosphate anhydrous, and the compound of formula I or II (e.g., compound 4). For example, the pharmaceutical preparation can contain approximately 0.47% by mass of propylene glycol, 0.18% by mass of phenol, 0.037% by mass of disodium hydrogen phosphate anhydrous, and 1.5% by mass of the compound of formula I or II (e.g., compound 4).

[0208] The pharmaceutical preparation can include at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is aqueous. In some embodiments, the pharmaceutically acceptable carrier includes physiological saline or sterile water.

[0209] In some embodiments, the pharmaceutically acceptable carrier is present in the formulation in a mass percentage of 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 more than a range including and / or spanning the aforementioned values. In some embodiments, the pharmaceutically acceptable carrier is present in the formulation in a mass percentage of about 20% to 99%. In some embodiments, the pharmaceutically acceptable carrier is present in the formulation in a mass percentage of about 90% to 98%. In some embodiments, the pharmaceutically acceptable carrier is present in the formulation in a mass percentage of about 94% to 98%.

[0210] In some embodiments, the mass ratio of the aqueous pharmaceutically acceptable carrier (e.g., water) to the non-aqueous solvent or solubilizing enhancer is 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 less than a range including and / or spanning the aforementioned values. In some embodiments, the mass ratio of the aqueous pharmaceutically acceptable carrier (e.g., water) to the non-aqueous solvent or solubilizing enhancer is from 10:1 to 50:1.

[0211] 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 of the foregoing. In some embodiments, the pharmaceutically acceptable carrier comprises a pH buffer.

[0212] In some embodiments, the pharmaceutical formulation comprises propylene glycol and a pH buffering compound. In some embodiments, the pH buffering solution comprises tartrate. In some embodiments, the pH buffering solution comprises disodium phosphate. In some embodiments, the pH buffering solution comprises tartrate. In some embodiments, the pH buffering solution comprises citrate (e.g., sodium citrate). In some embodiments, the pH buffering solution comprises acetate. In some embodiments, the pH buffering compound comprises 2-(N-morpholino)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 mass percentage of about 10% or less, and the pH buffering compound is present in the formulation at a mass percentage of about 5% or less. In some embodiments, propylene glycol is present in the formulation at a mass percentage of about 0.2% to 1.5%. In some embodiments, propylene glycol is present in the formulation at a mass percentage of about 0.1% to 2.0%. In some embodiments, propylene glycol is present in the formulation at a mass percentage of about 0.4% to 1.4%. In some embodiments, the pH buffering compound is present in the formulation at a mass percentage of about 0.01% to 5.0%. In some embodiments, the pH buffering compound is present in the formulation at a mass percentage of about 0.01% to 1.0%. In some embodiments, the pH buffering compound is present in the formulation at a mass percentage of about 0.03% to 1.0%. In some embodiments, the pH of the formulation is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or a range including and / or spanning the aforementioned values. In some embodiments, the formulation has a pH of about 3 to 7. In some embodiments, the formulation has a pH of about 4 to 6.8. In some embodiments, the formulation has a pH of about 5 to 6.8.

[0213] The pharmaceutical preparation contains a therapeutically effective dosage or amount. As used herein, the term "therapeutically effective dosage" or "therapeutically effective amount" depends on the subject being treated and the disease state, the severity of the affliction, the mode and schedule of administration, and the judgment of the prescribing physician. In some embodiments, the therapeutically effective dosage may be a daily dosage of from about 0.0125 mg / kg to about 120 mg / kg or more of body weight, from about 0.025 mg / kg or less to about 70 mg / kg of body weight, from about 0.05 mg / kg to about 50 mg / kg, or from about 0.075 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg human, the dosage range is from about 0.88 mg per day to about 8000 mg per day, from about 1.8 mg or less per day to about 7000 mg or more per day, from about 3.6 mg per day to about 6000 mg per day, from about 5.3 mg per day to about 5000 mg per day, or from about 11 mg per day to about 3000 mg per day. In some embodiments, the therapeutically effective dosage is in the range of 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, 100v, 200 mg / kg, 500 mg / kg, or including and / or spanning the aforementioned values. In some embodiments, the therapeutically effective dosage is from about 0.01 mg / kg to about 5 mg / kg. In some embodiments, the therapeutically effective dosage is from about 0.05 mg / kg to about 1 mg / kg. In some embodiments, the therapeutically effective dosage is from about 0.15 mg / kg to about 0.25 mg / kg.

[0214] The pharmaceutical preparation can be administered by routes of administration including, but not limited to, enteral, intravenous, oral, intra-articular, intramuscular, subcutaneous, intraperitoneal, epidural, intranasal, topical, intralung, intravaginal, rectal, transdermal, and transmucosal. In some embodiments, the route of administration is selected from the group consisting of enteral, intravenous, oral, intra-articular, 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.

[0215] The pharmaceutical preparation can be provided in a dosage form. In some embodiments, the dosage form is selected from a solid form and a 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 a solid form. In some embodiments, the dosage form is a 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 an 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 in the range between any two of these values. In some embodiments, the dilution ratio is from 10 to 20 (e.g., 15).

[0216] 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 agents, and absorption delaying agents, among others. 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 carboxymethyl cellulose, 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, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifying and surfactant agents such as Tween; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; tabletting agents; stabilizers; antioxidants; preservatives such as benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenyl mercury, and phenyl mercury nitrate; tonicity adjusting agents such as sodium chloride, potassium chloride, mannitol, and glycerin; vehicles such as polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamer, carboxymethyl cellulose, and hydroxyethyl cellulose; and pyrogen-free water. In some embodiments, the pharmaceutically acceptable excipient is selected based on the route of administration and can include solid or liquid fillers, diluents, hydrotropes, surface active agents, and encapsulating substances. For example, in the case of intravenous administration, excipients can include gelatin; carbohydrates such as dextrose, mannitol, and dextran; and antioxidants such as sodium bisulfite, sodium acetone 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.

[0217] In some embodiments, the pharmaceutical formulation is administered to a mammalian subject.

[0218] In some embodiments, the pharmaceutical formulation is administered to a human subject.

[0219] Definitions Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. In the event of multiple definitions for a term herein, the definition provided in this section shall control unless otherwise specified.

[0220] "Solvate" refers to a compound formed by the interaction of a solvent with a compound or a salt thereof described herein. Suitable solvates include hydrates and are pharmaceutically acceptable solvates.

[0221] The term "pharmaceutically acceptable salt" refers to salts which retain the biological effectiveness and properties of the compound and which are not biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds herein can form salts with acids and / or bases due to the presence of amino and / or carboxyl groups or similar groups. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Examples of organic acids from which the 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, etc. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts. Examples of organic bases from which the 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, etc., specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine, etc. Many such salts are known in the art as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated herein by reference in its entirety).

[0222] As used herein, "C" where "a" and "b" are integers a from C b to C a~b " or "C 1~4The term "alkyl" refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0223] As used herein, the term "halogen" or "halo" means any one of the radioactively stable atoms in column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0224] As used herein, "alkyl" refers to a straight-chain or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group can have from 1 to 20 carbon atoms (and whenever it appears herein, a numerical range such as "from 1 to 20" refers to each integer within the given range; e.g., "from 1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" when no numerical range is specified). The alkyl group may be a medium-sized alkyl having from 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl having from 1 to 4 carbon atoms. The alkyl group of the compound may be designated as "C 1~4 alkyl" or a similar name. By way of example only, "C 1~4 alkyl" indicates that there are from 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0225] As used herein, "haloalkyl" refers to a straight or branched alkyl group having from 1 to 12 carbon atoms in the chain, wherein one or more hydrogens are replaced by halogen. Examples of haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that are considered equivalent to any one of the foregoing examples in light of the ordinary techniques in the art and the teachings provided herein.

[0226] As used herein, "alkoxy" refers to a group of the formula -OR, where R is alkyl as defined above, for example, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, including "C" 1~9 alkoxy.

[0227] As used herein, "polyethylene glycol" refers to the formula

[0228]

Chemical formula

[0229] wherein n is an integer greater than 1 and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by referring to a number of members. Thus, for example, "2-member to 5-member polyethylene glycol" refers to an integer n selected from 2 to 5. In some embodiments, R is selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

[0230] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms in the backbone, i.e., an element other than carbon, including but not limited to nitrogen, oxygen, and sulfur. A heteroalkyl group can have from 1 to 20 carbon atoms, but this definition also encompasses occurrences of the term "heteroalkyl" when no numerical range is specified. A heteroalkyl group can be a medium-sized heteroalkyl having from 1 to 9 carbon atoms. A heteroalkyl group can also be a lower heteroalkyl having from 1 to 4 carbon atoms. In various embodiments, a heteroalkyl can have from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of the compound can be designated as "C 1~4 heteroalkyl" or a similar name. A heteroalkyl group can contain one or more heteroatoms. By way of example only, "C 1~4 heteroalkyl" indicates that there are from 1 to 4 carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0231] The term "aromatic" refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0232] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon in the ring backbone. When an aryl is a ring system, every ring in the system is aromatic. An aryl group can have from 6 to 18 carbon atoms, but this definition also encompasses occurrences of the term "aryl" when no numerical range is specified. In some embodiments, an aryl group has from 6 to 10 carbon atoms. An aryl group is "C 6~10 aryl", "C6 or C10 "Aryl", or can be designated by a similar name. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl and anthracenyl.

[0233] As used herein, "aryloxy" and "arylthio" are RO- and RS- where R is an aryl as defined above, for example, including, but not limited to, phenyloxy, "C 6~10 aryloxy" or "C 6~10 arylthio", etc.

[0234] "Aralkyl" or "arylalkyl" is an aryl group connected via an alkylene group as a substituent, for example, including, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl and naphthylalkyl, "C 7~14 aralkyl", etc. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 alkylene group).

[0235] 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, every ring in the system is aromatic. A heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also encompasses the occurrence of the term "heteroaryl" when no numerical range is specified. In some embodiments, the heteroaryl group has 5 to 10 ring members, or 5 to 7 ring members. The heteroaryl group can be designated as "5- to 7-membered heteroaryl", "5- to 10-membered heteroaryl", or a similar name. In various embodiments, heteroaryl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, heteroaryl 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. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.

[0236] "Heteroalkyl" or "heteroarylalkyl" is a heteroaryl group connected via an alkylene group as a substituent. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1~4 alkylene group).

[0237] As used herein, "carbocyclic" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system skeleton. When the carbocyclic is a ring system, two or more rings may be joined together in a fused, bridged, or spiro-connected manner. The carbocyclic can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, examples of carbocyclic include cycloalkyl, cycloalkenyl, and cycloalkynyl. The carbocyclic group can have from 3 to 20 carbon atoms, but this definition also includes the occurrence of the term "carbocyclic" when no numerical range is specified. The carbocyclic group may be a medium-sized carbocyclic having from 3 to 10 carbon atoms. The carbocyclic group can also be a carbocyclic having from 3 to 6 carbon atoms. The carbocyclic group can be designated as "C 3~6 carbocyclic" or a similar name. Examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclic [2.2.2] octanyl, adamantyl, and spiro [4.4] nonanyl.

[0238] "(Carbocyclic)alkyl" refers to a carbocyclic group connected via an alkylene group as a substituent, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc., but is not limited thereto. "C 4-10 (Carbocyclic)alkyl", etc. In some cases, the alkylene group is a lower alkylidene group.

[0239] As used herein, "cycloalkyl" means a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0240] As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, where the rings in the ring system are not aromatic. An example is cyclohexenyl.

[0241] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring skeleton. Heterocyclyls may be joined together in a fused, bridged, or spiro-connected manner. Heterocyclyls 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 either a non-aromatic ring or an aromatic ring in the ring system. A heterocyclyl group can have from 3 to 20 ring members (i.e., the number of atoms constituting the ring skeleton, including carbon atoms and heteroatoms), but this definition also includes the occurrence of the term "heterocyclyl" when no numerical range is specified. A heterocyclyl group can be a medium-sized heterocyclyl having from 3 to 10 ring members. A heterocyclyl group can also be a heterocyclyl having from 3 to 6 ring members. A heterocyclyl group can be designated as "3- to 6-membered heterocyclyl" or a similar name.

[0242] In various embodiments, the heterocyclyl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclyl contains from 1 to 4 nitrogen atoms, from 1 to 3 nitrogen atoms, from 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 a preferred 6-membered monocyclic heterocyclyl, the heteroatom is selected from up to 3 O, N or S, and in a preferred 5-membered monocyclic heterocyclyl, the heteroatom is selected from 1 or 2 heteroatoms selected from O, N or S. Examples of the heterocyclyl ring 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-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0243] "(Heterocyclyl)alkyl" is a heterocyclyl group connected via an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0244] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acrylyl.

[0245] The "O-carboxy" group refers to the "-OC(=O)R" group, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 selected from carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0246] The "C-carboxy" group refers to the "-C(=O)OR" group, where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 selected from carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0247] The "cyano" group refers to the "-CN" group.

[0248] The "cyanato" group refers to the "-OCN" group.

[0249] The "isocyanate" group refers to the "-NCO" group.

[0250] The "thiocyanate" group refers to the "-SCN" group.

[0251] The "isothiocyanate" group refers to the "-NCS" group.

[0252] The "sulfinyl" group refers to the "-S(=O)R" group, where R is hydrogen, C alkyl as defined herein, 1~6 C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0253] The "sulfonyl" group refers to the "-SO2R" group, where R is hydrogen, C alkyl as defined herein, 1~6 C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0254] The "S-sulfonamide" group refers to the "-SO2NR A R B " group, where R A and R B are each independently hydrogen, C alkyl as defined herein, 1~6 C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected therefrom.

[0255] The "N-sulfonamide" group refers to the "-N(R A )SO2R B " group, where RA and R b each independently is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0256] The "O-carbamyl" group refers to the "-OC(=O)NR A R B " group, where R A and R B each independently is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0257] The "N-carbamyl" group refers to the "-N(R A )OC(=O)R B " group, where R A and R B each independently is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0258] The "O-thiocarbamyl" group refers to the "-OC(=S)NR A R B " group, where R A and R B each independently is selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6Alkynyl, C 3~7 Carbocyclic, C 6~10 Selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0259] The "N-thiocarbamyl" group refers to the "-N(R A )OC(=S)R B " group, where R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected as defined herein.

[0260] The "C-amide" group refers to the "-C(=O)NR A R B " group, where R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected as defined herein.

[0261] The "N-amide" group refers to the "-N(R A )C(=O)R B " group, where R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected as defined herein.

[0262] The "amino" group refers to the "-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, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic selected as defined herein.

[0263] The "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0264] The "alkoxyalkyl" group refers to an alkoxy group connected via an alkylene group, such as "C 2~8 alkoxyalkyl", etc.

[0265] As used herein, a substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", the group is independently C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), 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-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,It is meant to be substituted with one or more substituents selected from C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanate, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo(=O). When a group is described as "optionally substituted", the group may always be substituted with the above substituents.,

[0266] In some embodiments, the substituted group is individually and independently substituted with one or more substituents selected from C1-C4 alkyl, amino, hydroxy and halogen.,

[0267] Certain group naming conventions should be understood to be able to include either a mono group or a di group depending on the context. For example, when a substituent requires two attachment points to the rest of the molecule, the substituent is understood to be a di group. For example, substituents identified as alkyl that require two attachment points include di groups such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other group naming conventions clearly indicate that the group is a di group such as "alkylene" or "alkenylene".

[0268] When two R groups are stated to "together with the atoms to which they are attached" form a ring (e.g., a carbocyclic ring, a heterocyclic ring, an aryl ring or a heteroaryl ring), the set unit of the atoms and the two R groups is meant to be the ring listed. The ring, when taken individually, is not otherwise limited by the definition of each R group. For example, the following substructures exist:

[0269]

Chemical formula

[0270] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R2 When they combine with the nitrogen to which they are attached to form a heterocyclyl, R 1 and R 2 are meant to be selectable from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0271]

Chem.

[0272] wherein ring A is a heterocyclyl ring containing the nitrogen shown.

[0273] Similarly, when it is stated that two "adjacent" R groups "together with the atoms to which they are attached" form a ring, the atoms, intervening bonds, and the set unit of the two R groups are meant to be the rings listed. For example, the following substructures exist:

[0274]

Chem.

[0275] R 1 and R 2 are defined as being selected from the group consisting of hydrogen and alkyl, or when R 1 and R 2 combine with the atoms to which they are attached to form an aryl or carbocyclyl, R 1 and R 2 are meant to be selectable from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0276]

Chem.

[0277] wherein A is an aryl ring or a carbocyclyl containing the double bond shown.

[0278] When a substituent is depicted as a di-group (i.e., having two attachment points to the rest of the molecule), it should always be understood that the substituent may be attached in an arrangement in any orientation, unless otherwise indicated. Thus, for example, substituents depicted as -AE- or

[0279]

Chemical formula

[0280] include substituents where A is attached in a direction such that it is the leftmost attachment point of the molecule and where A is attached at the rightmost attachment point of the molecule.

[0281] The term "mammal" is used in its ordinary biological sense. Thus, it includes, without limitation, specifically, primates including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, and mice, but also many other species.

[0282] "Subject", as used herein, means a human or non-human mammal, such as a dog, cat, mouse, rat, female cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, and any other vertebrate or invertebrate animal.

[0283] "Effective amount" or "therapeutically effective amount", as used herein, refers to the amount of a therapeutic agent that is effective to alleviate to some extent one or more symptoms of a disease or disorder or to reduce the likelihood of its manifestation and that includes curing the disease or disorder. "Curing" means that the symptoms of the disease or disorder are eliminated; however, even after a cure is obtained, certain long-term or permanent effects may exist (such as extensive tissue damage, etc.).

[0284] "To treat", "treatment" or "treating", as used herein, refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition but is susceptible to or at risk of a particular disease or condition, such that the treatment reduces the likelihood that the subject will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who already has a disease or condition.

[0285] Method of preparation The compounds disclosed in this specification can be synthesized by the methods described below or by modifications of these methods. Ways of modifying the methodology include, inter alia, temperatures, solvents, reagents and the like known to those skilled in the art. Generally, during any of the processes for the preparation of the compounds disclosed in this specification, it may be necessary and / or desirable to protect any sensitive or reactive groups on any of the molecules involved. This can be achieved by means of conventional protecting groups, for example those described in Protective Groups in Organic Chemistry (edited by J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd edition) Wiley, New York (1999), both of which are hereby incorporated by reference in their entirety. The protecting groups can be removed at a convenient subsequent stage using methods known from the art. Synthetic chemical transformations useful in synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both of which are hereby incorporated by reference in their entirety. The pathways shown and described herein are illustrative only and are not intended or should be construed in any way as limiting the scope of the claims. Those skilled in the art can recognize modifications of the disclosed syntheses and can devise alternative pathways based on the disclosure herein; all such modifications and alternative pathways are within the scope of the claims.

[0286] In the following schemes, the protecting groups for the oxygen atoms are selected for their compatibility with the required synthetic steps and for the compatibility of the introduction and deprotection steps with the overall synthetic scheme (P.G.M. Green, T.W. Wutts, Protecting Groups in Organic Synthesis (3rd Edition) Wiley, New York (1999)).

[0287] If the compounds of the present technology contain one or more chiral centers, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or d(l) stereoisomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present technology unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0288] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be prepared by the procedures described in standard reference texts 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) or obvious modifications thereof.

[0289] Preparation of the compound of formula (I) Scheme 1 illustrates one method for making the compound of formula (I). The method can include the step of providing a resin-bound peptide by constructing a peptide backbone using solid-phase peptide synthesis techniques. The side chain of the central lysine containing the Dde group can then be extended with a linker containing two PEG2 amide linkers and an isoglutamic acid (or related analog) linker to provide intermediate (A). The method includes the step of providing a resin-bound intermediate (C) by a coupling reaction between the isoglutamic acid (or related analog) amine of intermediate (A) and intermediate (B). In formulas (A)-(C), R 1 ' and R2 ' is the protected version of the R 1 group and R 2 group. In one embodiment, the method involves removing the resin and the protecting group by subjecting intermediate (C) to hydrolysis under acidic conditions, followed by purification to obtain the final product (I). The peptide skeletons disclosed herein can be synthesized by solid-phase peptide synthesis techniques described in Methods in Molecular Biology, 298, Peptide Synthesis and Applications, (edited by J. Howl, Humana Press, 2005); and Amino Acids, Peptides and Proteins in Organic Chemistry, Volume 3, Building Blocks, Catalysts and Coupling Chemistry, (edited by A. B. Hughs, Wiley-VCH, 2011), or obvious modifications thereof, both of which are hereby incorporated by reference in their entirety herein.

[0290]

Chemical formula

[0291] Preparation of the compound of formula II In one embodiment, the method disclosed herein can include providing intermediate (A') by constructing a 39-amino acid peptide skeleton using solid-phase peptide synthesis techniques. The peptide skeleton contains two PEG2 amide linkers. The method involves providing a resin-bound intermediate (C') by an amide coupling reaction between the amine of the terminal PEG2 amide of intermediate (A') and a carboxylic acid (B') appropriately substituted. In one embodiment, the method involves subjecting intermediate (C') to hydrolysis under acidic conditions followed by purification to obtain the final product (formula II). (Scheme 2).

[0292]

Chemical formula

[0293] The pharmaceutical formulations disclosed herein can be prepared using standard pharmaceutical formulation techniques, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, each of which is hereby incorporated by reference in its entirety. In some embodiments, the pharmaceutical formulations can be prepared as unit dosage forms. Techniques and compositions for preparing unit dosage forms are described in Modern Pharmaceutics, 4th Edition, 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 hereby incorporated by reference in its entirety.

[0294] The above scheme examples are provided for the reader's guidance and collectively represent exemplary methods for making the compounds encompassed herein. Further, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0295] Methods of Treatment The pharmaceutical formulations disclosed herein comprise a compound that can act effectively as a GIP / GLP1 dual receptor agonist or a tautomer thereof and / or a pharmaceutically acceptable salt thereof. The pharmaceutical formulations further comprise one or more pharmaceutically acceptable carriers and one or more pharmaceutically acceptable diluents.

[0296] Some embodiments provide a method of preventing, treating, or alleviating one or more fatty liver diseases in a subject. In some embodiments, the method comprises administering to a subject in need thereof one or more of the pharmaceutical formulations disclosed herein.

[0297] Some embodiments provide a method of preventing, treating, or alleviating obesity, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. In some embodiments, the method comprises administering to a subject in need thereof one or more of the pharmaceutical formulations disclosed herein.

[0298] In some embodiments, administering one or more of the pharmaceutical formulations disclosed herein results in the prevention, treatment, or alleviation of fibrosis, fibrotic conditions, or fibrotic symptoms.

[0299] In some embodiments, the pharmaceutical formulations described herein can be used to treat a host with a condition resulting from fibrosis or inflammation and specifically including those associated with myofibroblast differentiation. Exemplary conditions include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic, and genetic chronic diseases), kidney fibrosis (e.g., resulting from chronic inflammation, infection, or type II diabetes), lung fibrosis (idiopathic, or environmental insult 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 (e.g., resulting from alcohol abuse and chronic inflammatory diseases of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders), cardiac fibrosis (resulting from infection, inflammation, and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, non-alcoholic fatty liver disease, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemia-reperfusion injury-related fibrosis, fibrosis by injection, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.

[0300] In some embodiments, a method of administering one or more of the pharmaceutical formulations disclosed herein results in a reduction in the amount of extracellular matrix protein present in one or more tissues of the subject.

[0301] In some embodiments, a method of administering one or more of the pharmaceutical formulations disclosed herein results in a reduction in the amount of collagen present in one or more tissues of the subject.

[0302] In some embodiments, a method of administering one or more of the pharmaceutical formulations disclosed herein results in a reduction in the amount of type I, type Ia, or type III collagen present in one or more tissues of the subject.

[0303] Some embodiments provide a method for preventing, treating, or alleviating one or more of liver fibrosis, kidney fibrosis, bile duct fibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis in a subject. In some embodiments, the method comprises administering one or more of the pharmaceutical formulations disclosed herein to a subject in need thereof.

[0304] Some embodiments provide a method for preventing, treating, or alleviating one or more of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, or primary biliary cirrhosis in a subject. In some embodiments, the method comprises administering one or more of the pharmaceutical formulations disclosed herein to a subject in need thereof.

[0305] Some embodiments provide a method for preventing, treating, or alleviating one or more metabolic disorders or metabolic syndrome. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 true diabetes, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. In some embodiments, the method comprises administering one or more of the pharmaceutical formulations disclosed herein to a subject in need thereof.

[0306] In some embodiments, administering one or more of the pharmaceutical formulations disclosed herein results in activation of the glucose-dependent insulinotropic polypeptide (GIP) receptor. In some embodiments, administering one or more of the pharmaceutical formulations disclosed herein results in activation of the glucagon-like peptide-1 (GLP-1) receptor. In some embodiments, administering one or more of the pharmaceutical formulations disclosed herein results in activation of the GIP receptor and the GLP-1 receptor.

[0307] Some embodiments include co - administering the pharmaceutical formulations and / or compounds or pharmaceutically acceptable salts thereof described herein, together with additional pharmaceuticals. By "co - administering", it is meant that two or more agents can be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is achieved by combining the agents in a single dosage form. In another embodiment, the agents are administered sequentially. In one embodiment, the agents are administered via the same route, for example, orally. In another embodiment, the agents are administered via different routes, for example, one is administered subcutaneously, another is administered orally, and another is administered i.v.

[0308] To further illustrate this invention, the following examples are given. The examples, of course, should not be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the knowledge 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 the present disclosure and one of ordinary skill in the art with the skills in the art can prepare and use the invention without using an exhaustive list of examples. The following examples further describe the invention and are used for illustrative purposes only and should not be construed as limiting.

[0309] Administration and Pharmaceutical Compositions Some embodiments provide a pharmaceutical composition comprising at least one therapeutically effective amount of a compound as described elsewhere herein and a pharmaceutically acceptable excipient.

[0310] The compound is administered at a therapeutically effective dose. Human dosage levels have not yet been optimized for the compounds described herein, but generally, the daily dosage may be from about 0.0125 mg / kg to about 120 mg / kg or more of body weight, from about 0.025 mg / kg or less to about 70 mg / kg, from about 0.05 mg / kg to about 50 mg / kg of body weight, or from about 0.075 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg human, the dosage range is from about 0.88 mg per day to about 8000 mg per day, from about 1.8 mg or less per day to about 7000 mg or more per day, from about 3.6 mg per day to about 6000 mg per day, from about 5.3 mg per day to about 5000 mg per day, or from about 11 mg per day to about 3000 mg per day. The amount of the active compound administered will, of course, depend on the subject being treated and the disease state, the severity of the affliction, the mode and schedule of administration, and the judgment of the prescribing physician.

[0311] Administration of the compounds or pharmaceutically acceptable salts thereof disclosed herein may be via any of the acceptable modes of administration for agents useful in a similar manner, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Oral and parenteral administrations are common when treating the indications that are the subject of the preferred embodiments.

[0312] As described above, useful compounds can be formulated into pharmaceutical compositions for use in the treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), which is incorporated herein by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs, and solvates), or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0313] In addition to the selected compounds useful as described above, some embodiments include compositions containing a pharmaceutically acceptable carrier. The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional media or agent is contemplated for therapeutic compositions, except in cases where it is incompatible with the active ingredient. In addition, various adjuvants commonly used in the art may be included. Considerations regarding the inclusion of the various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, which is incorporated herein by reference in its entirety.

[0314] Some examples of substances that can act 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 carboxymethyl cellulose, 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 theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tweens; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents; tabletting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0315] The selection of the pharmaceutically acceptable carrier to be used in conjunction with the subject compound is basically determined by the manner in which the compound is to be administered.

[0316] The compositions described herein are preferably provided in unit dosage form. As used herein, "unit dosage form" is a composition containing an amount of a compound appropriate for administration to an animal, preferably a mammalian subject, in a single dose in accordance with good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is to be administered once a day or once per treatment cycle. Such dosage forms are intended to be administered once, twice, three times, or more times a day and can be administered by infusion over a period of time (e.g., about 30 minutes to about 2 - 6 hours) or by continuous infusion and can be given more than once during a treatment cycle, although single administration is not specifically excluded. One of ordinary skill in the art will recognize that the formulation does not specifically contemplate the entire treatment cycle and that such determinations are left to the practitioner of the treatment rather than the formulation.

[0317] As described above, the useful compositions may be in any of a variety of suitable forms for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, subcutaneous, or other parenteral routes of administration. In some embodiments, the composition may be in a form suitable for subcutaneous administration. Those skilled in the art will recognize that oral and nasal compositions include compositions that are administered by inhalation and prepared using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating substances. Optional pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound may be included. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, which are hereby incorporated by reference in their entirety: Modern Pharmaceutics, 4th Edition, 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).

[0318] A variety of oral dosage forms may be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorants, glidants, and melting agents and may be compressed, powder compressed tablets, enteric coated, sugar coated, film coated, or multi-compressed. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorants.

[0319] Pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well known in the art. Tablets typically include 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 croscarmellose; 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 can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavorings, are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components depends on secondary considerations such as insignificant taste, cost, and storage stability and can be readily made by those skilled in the art.

[0320] Oral compositions also include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for the preparation of 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 can also contain one or more components such as the sweeteners, flavoring agents, and coloring agents disclosed above.

[0321] Such compositions can also be coated by conventional methods, typically with pH- or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract, in the vicinity of the desired local application or at various times to extend the desired action. 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, Eudragit coatings, waxes, and shellac.

[0322] The compositions described herein can optionally contain other active drugs.

[0323] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. They can also include the flow promoters, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above.

[0324] Liquid compositions formulated for topical ophthalmic use are formulated such that they can be topically administered to the eye. Comfort should be maximized to the extent possible, although sometimes formulation considerations (e.g., drug stability) may be required over optimal comfort. If comfort cannot be maximized, the liquid should be formulated such that it is tolerable for the patient for topical ophthalmic use. Additionally, the ophthalmically acceptable liquid should either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0325] For ophthalmic use, solutions or medicaments are often prepared using physiological saline solution as the main vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using a suitable buffer system. The formulation may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0326] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, 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, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0327] Tonicity adjusters can be added if required or convenient. These include, but are not limited to, salts, especially sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0328] As long as the resulting preparation is ophthalmically acceptable, various buffers and means for adjusting the pH can be used. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffer, citrate buffer, phosphate buffer and borate buffer. Acids or bases can be used to adjust the pH of these formulations if required.

[0329] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0330] Other excipient components that can be included in the ophthalmic preparation are chelating agents. A useful chelating agent is disodium edetate, but other chelating agents can also be used instead of or in combination with it.

[0331] For topical use, creams, ointments, gels, solutions, suspensions, etc. containing the compounds disclosed herein are used. Topical formulations can generally be composed of a pharmaceutical carrier, a co-solvent, an emulsifier, a penetration enhancer, a preservative system, and an emollient.

[0332] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as physiological saline or dextrose solution. Suitable excipients can include, but are not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates, such as dextrose, mannitol, and dextran. Further 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 can also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0333] Compositions for intravenous administration can be provided to a caregiver in one or more solid forms that are reconstituted immediately prior to administration with a suitable diluent, such as sterile water, saline, or dextrose in water. In other embodiments, the composition is provided in a solution that is ready for parenteral administration. In yet other embodiments, the composition is provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of the compounds and another agent described herein, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

[0334] The actual dosage of the active compounds described herein will depend on the particular compound and the condition to be treated; the selection of an appropriate dosage is well within the knowledge of a skilled artisan.

[0335] The compounds and compositions described herein can be provided, if desired, in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such pack or device can include, for example, a metal or plastic foil, such as a blister pack, or glass and rubber stoppers in vials, etc. The pack or dispenser device can be accompanied by instructions for administration. The compounds and compositions described herein can be formulated in a pharmaceutically acceptable carrier, and further prepared, placed in an appropriate container, and labeled for treatment of the indicated condition.

[0336] The amount of the compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation contains the compound of the present technology from about 0.01 wt% to 99.99 wt% based on the total formulation on a weight percent (wt%) basis, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1 wt% to 80 wt%. Representative pharmaceutical formulations are described below.

Example

[0337] General procedures It will be apparent to the skilled person that methods for preparing precursors and functional groups related to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to utilize variants that are known per se to the person skilled in the art but not described in more detail. The skilled person provided with the literature and this disclosure is well equipped to prepare any of the compounds.

[0338] It is recognized that the skilled person in the art of organic chemistry can readily carry out the operations without further instruction, i.e., carrying out these operations is well within the scope and practice of the skilled person. These include, for example, reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic, etherification, esterification and saponification, etc. These operations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (which are hereby incorporated by reference in their entirety). All intermediate compounds of the present invention were used without further purification unless otherwise specified.

[0339] Certain reactions are best carried out when other functional groups are masked or protected in the molecule, and thus it will be readily appreciated by the skilled person to avoid any unwanted side reactions and / or increase the yield of the reaction. Often, the skilled person achieves such yield increases or avoids unwanted reactions by using protecting groups. These reactions are found in the literature and are well within the scope of the skilled person. Many examples of these operations can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Edition, John Wiley & Sons (2007), which is hereby incorporated by reference in its entirety.

[0340] The following scheme examples are provided for the reader's guidance and represent preferred methods for making the compounds illustrated herein. These methods are not limiting, and it is clear that other routes may be used to prepare these compounds. Such methods specifically include solid-phase based chemistries including combinatorial chemistry. One of ordinary skill in the art is fully equipped with the ability to prepare these compounds by methods as provided in the literature and this disclosure. The compound numbering used in the synthetic schemes illustrated below is meant for those particular schemes only and should not be construed or confused with the same numbering in other sections of this application.

[0341] The trademarks used herein are for example only and reflect the exemplary materials used at the time of the invention. One of ordinary skill in the art will recognize that variations in lots, manufacturing processes, etc. are to be expected. Therefore, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but are merely illustrative of how one of ordinary skill in the art can make a selection for carrying out one or more of the embodiments of the invention.

[0342] The following abbreviations have the indicated meanings: λz = lambda (apparent elimination rate constant) AUC = area under the plasma concentration-time curve AUC last = AUC from time 0 to the time of the final quantifiable concentration AUC inf = AUC extrapolated from time 0 to infinity Aib = aminoisobutyric acid BLQ = below the limit of quantification Bn = benzyl Boc = tert-butoxycarbonyl Bu = butyl C max = T max at which the maximum observed concentration occurs CL / F = systemic clearance following extravascular administration CV% = coefficient of variation percentage DMF = Dimethylformamide EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Et = Ethyl HATU = Hexafluorophosphate azabenzotriazole tetramethyl uronium HBTU = Hexafluorophosphate benzotriazole tetramethyl uronium HMDS = Hexamethyldisilazane HPLC = High Performance Liquid Chromatography LC-MS / MS = Liquid Chromatography Tandem Mass Spectrometry LLOQ = Lower Limit of Quantification Me = Methyl N = Number of samples with numerical values NaHMDS = Sodium hexamethyldisilazide NMR = Nuclear Magnetic Resonance PCC = Pyridinium chlorochromate PEG = Polyethylene glycol Ph = Phenyl PK = Pharmacokinetics PO = Oral administration R 2 = Regression correlation coefficient T max = C max Time when t 1 / 2 = Half-life tBu = tert-Butyl TFA = Trifluoroacetic acid THF = Tetrahydrofuran TMS = Trimethylsilyl V z / F = Volume of distribution following extravascular administration

[0343] The following scheme examples are provided for the reader's guidance and collectively represent exemplary methods for making the compounds provided herein. Further, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0344] (Example 1) Synthesis of Intermediate 1 (INT 1) Methyl 7-bromoheptanoate is treated with triphenylphosphine to form the corresponding phosphonium salt. The salt is treated with 1 equivalent of NaHMDS to generate an ylide, which is immediately reacted in a Wittig reaction with the aldehyde from the PCC oxidation of 12-bromo-1-dodecanol. The resulting bromoalkene is hydrogenated and treated with dibenzyl phosphite in a weak base to form a phosphonate ester. Hydrolysis of the methyl carboxylate provides the desired INT 1 with a terminal carboxylic acid and dibenzyl phosphonate.

[0345] [Chemical formula]

[0346] Synthesis of Intermediate 2 (INT 2) Docosanedioic acid is coupled to benzyl alcohol using EDC·HCl and DMAP in THF to obtain INT 2 as a monobenzyl ester.

[0347] [Chemical formula]

[0348] Synthesis of Intermediate 3 (INT 3) t-Butyl 4-hydroxybutanoate undergoes Swern oxidation to give an aldehyde. The aldehyde is condensed with (R)-1-amino-2-methoxy-1-phenylethane to form an imine. Addition of the lithium salt of diethyl phosphite in THF generates an α-aminophosphonate, which upon hydrogenolysis cleaves the N-alkyl group to afford INT 3 having a free primary amine, a t-butyl ester, and a diethyl phosphonate ester. The optical purity of INT 3 was confirmed to be at least 96% by 1H NMR via Mosher amide analysis.

[0349]

Chemical Structure

[0350] Synthesis of Intermediate 4 (INT 4) INT 1 is coupled with the 1-t-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4.

[0351]

Chemical Structure

[0352] Synthesis of Intermediate 5 (INT 5) INT 2 is coupled with INT 3 in the presence of HATU and triethylamine in DMF to prepare a new amide linkage. Cleavage of the ethyl phosphonate ester using TMS-Br gives a free phosphonic acid. Re-esterification using a large excess of the benzyl ester of N,N'-diisopropylcarbodiimide provides the corresponding dibenzyl phosphonate. The t-butyl ester is cleaved using TFA to afford INT 5.

[0353]

Chemical Structure

[0354] Synthesis of Intermediate 6 (INT 6) INT 1 provides a new amide linkage by being coupled with INT 3 in the presence of HATU and triethylamine in DMF. Cleavage of the benzyl and phosphonic acid ethyl ester using TMS-Br gives both free phosphonic acids. Re-esterification using a large excess of the benzyl ester of N,N'-diisopropylcarbamimidic acid provides the corresponding tetrabenzyl diphosphonate ester. The t-butyl ester is cleaved using TFA to give INT 6.

[0355]

Chemical Structure

[0356] (Example 2) Synthesis of the Common Peptide Backbone The 39-amino acid peptide backbone is constructed using solid-phase peptide synthesis techniques with diimide, HATU, or HBTU activation for amide bond synthesis on Rink resin. The reagent selection varies based on the identity of the amino acids being attached. The R-group of lysine-19 was extended with two PEG2 amide linkers. The entire backbone is synthesized on the resin before coupling INT 4, INT 5, or INT 6 to the amino terminus of the lysine-linked linker.

[0357]

Chemical Structure

[0358] (Example 3) Synthesis of Compound 4 The peptide backbone is coupled to INT 4 to obtain the protected Compound 4 attached to the resin. Cleavage of the resin, protecting groups on the peptide chain, and the benzyl ester of INT 4 using TFA provides Compound 4, which is purified via HPLC.

[0359]

Chemical Structure

[0360] (Example 4) Synthesis of Compound 8 The peptide backbone is coupled to INT 5 to obtain the protected Compound 8 bound to the resin. Cleavage of the resin, the protecting groups on the peptide chain, and the benzyl ester of INT 4 using TFA provide Compound 8, which is purified via HPLC.

[0361] [Chemical Structure]

[0362] (Example 5) Synthesis of Compound 12 The peptide backbone is coupled to INT 6 to obtain the protected Compound 12 bound to the resin. Cleavage of the resin, the protecting groups on the peptide chain, and the benzyl ester of INT 4 using TFA provide Compound 12, which is purified via HPLC.

[0363] [Chemical Structure]

[0364] (Example 6) Synthesis of the Peptide Backbone Each 39 - amino - acid peptide backbone was constructed using the Fmoc solid - phase peptide synthesis technique with diimide, HATU, or HBTU activation for amide bond formation on Rink resin. The reagent selection varied based on the identity of the amino acids being coupled. Lysine at Lysine - 16, Lysine - 19, or Lysine - 20 was protected with the Dde protecting group. Upon completion of the full backbone, the aminoalkyl side chains of Lysine - 16, Lysine - 19, or Lysine - 20 were extended with two PEG2 amide linkers, followed by an isoglutamic acid residue. Specifically, the Dde group on lysine was cleaved. The deprotected amino group on lysine was then coupled to the Boc - protected PEG2 group having the following structure:

[0365] [Chemistry]

[0366] After removing the BOC group, the second PEG2 was added. Finally, after removing the second PEG2 BOC group, Fmoc-protected isoglutamate was coupled to the second PEG2. The Fmoc group was then removed.

[0367] After synthesizing the entire backbone and side chain on lysine-16, lysine-19, or lysine-20, it was coupled to INT-1. Thus, the following intermediate was obtained before INT-1 coupling.

[0368] Peptides 14BB and 15BB were prepared by extending the aminoalkyl side chain of lysine-16 as noted above.

[0369] [Chemistry]

[0370] Peptides 16BB, 17BB, 18BB, 19BB, 20BB, and 21BB were prepared by extending the aminoalkyl side chain of the side chain of lysine-20.

[0371] [Chemistry]

[0372] [Chemistry]

[0373] [Chemistry]

[0374] [Chemistry]

[0375] Peptide 22BB was prepared by extending the side chain of lysine-19.

[0376]

Chemical formula

[0377] (Example 7) Synthesis of Compound 15 Peptide 15BB was coupled to INT-1 to obtain resin-bound protected Compound 15. The coupling to INT-1 was achieved using amide coupling conditions to couple INT-1 to the NH2 group of isoglutamic acid of lysine-16 in Peptide 15BB. Cleavage of the resin, protecting groups on the peptide chain, and benzyl ester was performed with TFA to provide Compound 15, which was then purified via reverse-phase HPLC. By RP-HPLC, the purity was 95.0%. The peptide content was 96.0%, giving satisfactory amino acid analysis results. LCMS analysis showed a molecular weight of 4849.4 g / mol.

[0378]

Chemical formula

[0379] (Example 8) Synthesis of Compound 14 Compound 14 was prepared from Peptide 14BB and INT-1 in a manner similar to the preparation of Compound 15.

[0380]

Chemical formula

[0381] (Example 9) Synthesis of Compound 16 Compound 16 was prepared from Peptide 16BB and INT-1 in a manner similar to the preparation of Compound 15.

[0382]

Chemical formula

[0383] (Example 10) Synthesis of Compound 17 Compound 17 was prepared from peptide 17BB and INT-1 in a manner similar to the preparation of Compound 15.

[0384] [Chemical formula]

[0385] (Example 11) Synthesis of Compound 18 Compound 18 was prepared from peptide 18BB and INT-1 in a manner similar to the preparation of Compound 15.

[0386] [Chemical formula]

[0387] (Example 12) Synthesis of Compound 19 Compound 19 was prepared from peptide 19BB and INT-1 in a manner similar to the preparation of Compound 15.

[0388] [Chemical formula]

[0389] (Example 13) Synthesis of Compound 20 Compound 20 was prepared from peptide 20BB and INT-1 in a manner similar to the preparation of Compound 15.

[0390] [Chemical formula]

[0391] (Example 14) Synthesis of Compound 21 Compound 21 was prepared from peptide 21BB and INT-1 in a manner similar to the preparation of compound 15.

[0392]

Chemical Structure

[0393] (Example 15) Synthesis of Compound 22 Compound 22 was prepared from peptide 22BB and INT-1 in a manner similar to the preparation of compound 15.

[0394]

Chemical Structure

[0395] (Example 16) Synthesis of Compound 23 Compound 23 was prepared from peptide 23BB and INT-1 in a manner similar to the preparation of compound 15.

[0396]

Chemical Structure

[0397] (Example 17) Synthesis of Compound 24 Compound 24 was prepared from peptide 24BB and INT-1 in a manner similar to the preparation of compound 15.

[0398]

Chemical Structure

[0399] (Example 18) Synthesis of Compound 25 Compound 25 was prepared from a peptide backbone similar to that described herein and INT-1 in a manner similar to the preparation of compound 15.

[0400]

Chemical Structure

[0401] (Example 19) In vitro GLP-1 and GIP binding activity Using the TagLite® binding assay and Epics Therapeutics cell lines, binding data for tildepagliflozin, 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 compounds is expressed as a percentage of the activity of the reference agonist at its IC 100 concentration as shown in Table 1 (Table 1).

[0402]

Table 1

[0403] (Example 20) Biological effects of the compounds in mice As described by Boland et al., World J Gastroenterol, 2019, 25(33): 4904-4920, NASH was induced in mice by administering the Gubra amylin NASH (GAN) diet. One week prior to the administration of the first dose of the compound, the mice were weighed, randomized, and their food intake was measured. The mice were randomly assigned to treatment groups of 12 mice per group. The assigned dose groups were as follows: tildepagliflozin (10 mg / kg); Compound 4 (10 mg / kg); Compound 8 (10 mg / kg); Compound 12 (10 mg / kg); one group was sham-treated with vehicle only as a control. Compound dose titration (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 (from day 6).

[0404] Two weeks later, the animals were sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol were measured, terminal necropsies of each liver were performed, relative liver weight was determined as a percentage of body weight, total liver biochemistry including total liver triglycerides, plasma insulin and total liver cholesterol was assayed, and histological evaluations of galectin-3 and alpha-smooth muscle actin were likewise performed.

[0405] Liver triglyceride (TG) levels are shown in Table 2. The data indicate that administration of compound 4, compound 8 or compound 12 resulted in lower relative and total liver triglycerides when compared to administration of tildepazide or vehicle alone. Liver galectin-3 (Gal-3) levels as determined by histological quantification are shown in Table 2. The data indicate that administration of compound 4, compound 8 or compound 12 resulted in lower relative and total liver galectin-3 when compared to administration of tildepazide or vehicle alone. Alpha-smooth muscle actin (α-SMA) levels as determined by histological quantification are shown in Table 2. The data indicate that administration of compound 4, compound 8 or compound 12 resulted in lower relative and total liver alpha-smooth muscle actin when compared to administration of tildepazide.

[0406] [Table 2]

[0407] (Example 21) HSA-Modulated In Vitro GLP-1 and GIP Binding Activity The binding assay of Example 6 was repeated for compound tilzegapotide (TRZ), compound 4 and compound 12, and the assay was performed in the presence or absence of 2% human serum albumin (HSA). The ratio of compound-receptor binding using 2% HSA to compound-receptor binding using 0% HSA is listed in Table 3. Tilzegapotide has HSA ratios of 12.8 and 5.82 for the GLP-1 receptor and GIP receptor, respectively. Compound 4 has HSA ratios of 6.42 and 1.25 for the GLP-1 receptor and GIP receptor, respectively. Compound 12 has HSA ratios of 5.26 and 1.70 for the GLP-1 receptor and GIP receptor, respectively. When compared to compound 4 and compound 12, the larger HSA ratio of tilzegapotide indicates that the binding affinity of tilzegapotide for albumin is greater than that of compound 4 or compound 12.

[0408] [Table 3]

[0409] (Example 22) Formulations Nine aqueous formulations containing compound 4 suitable for subcutaneous injection were prepared. The concentration of the components in each formulation is specified in Table 4 as percent by mass.

[0410] [Table 4]

[0411] General procedure The 0.2 mg / mL zinc oxide stock solution in the following experiments was prepared by adding approximately 1.0 mg of zinc oxide to a 5 mL volumetric flask, filling the flask with water, and stirring. The 5.0 mg / mL polysorbate 80 stock solution used in the following experiments was prepared by adding approximately 5.0 mg of polysorbate 80 into a 1 mL volumetric flask, filling the flask with water, and stirring. The 20.0 mg / mL polysorbate 20 stock solution in the following experiments was prepared by adding approximately 20.0 mg of polysorbate 20 into a 1 mL volumetric flask, filling the flask with water, and stirring. The EDTA2Na2H2O stock solution in the following experiments was prepared by adding approximately 9.0 mg of EDTA2Na2H2O into a 1 mL volumetric flask, filling the flask with water, and stirring.

[0412] Preparation of Formulation 1 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 disodium hydrogen phosphate anhydrous 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 1N NaOH / HCl. Approximately 75.0 mg of Compound 4 was added to the solution, and then the pH of the solution was adjusted to approximately 6.0 to 6.3 by adding 40 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added up to the fill line of the 5 mL volumetric flask to make the total volume of the solution 5 mL.

[0413] Preparation of Formulation 2 To prepare a 5 mL sample of Formulation 2, approximately 70.0 mg of propylene glycol, 27.5 mg of phenol, 5.65 mg of disodium phosphate anhydrous, and approximately 50 μL of a stock solution of polysorbate 80 (0.25 mg) 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 1N NaOH / HCl. Approximately 75.0 mg of Compound 4 was added to the solution, and then the pH of the solution was adjusted from approximately 6.0 to 6.3 by adding 40 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added to bring the total volume of the solution to 5 mL up to the fill line of the 5 mL volumetric flask.

[0414] Preparation of Formulation 3 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 approximately 1 mL of a stock solution of zinc oxide (0.195 mg) 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 1N NaOH / HCl. Approximately 75.0 mg of Compound 4 was added to the solution, and then the pH of the solution was adjusted from approximately 6.0 to 6.3 by adding 35 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added to bring the total volume of the solution to 5 mL up to the fill line of the 5 mL volumetric flask.

[0415] Preparation of Formulation 4 To prepare a 5 mL sample of Formulation 4, approximately 15.0 mg of metacresol, 227 mg of mannitol, and 22.05 mg of sodium citrate dihydrate 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 1N NaOH / HCl. Approximately 75.0 mg of Compound 4 was added to the solution, and then the pH of the solution was adjusted to approximately 6.0 to 6.3 by adding 47 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added up to the fill line of the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0416] Preparation of Formulation 5 To prepare a 5 mL sample of Formulation 5, approximately 245 mg of lactose monohydrate and 5.65 mg of disodium phosphate anhydrous 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 1N NaOH / HCl. Approximately 75.0 mg of Compound 4 was added to the solution, and then the pH of the solution was adjusted to approximately 6.0 to 6.3 by adding 96 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added up to the fill line of the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0417] Preparation of Formulation 6 To prepare a 5 mL sample of formulation 6, approximately 75.0 mg of mannitol, 3.6 mg of methionine, 290.1 mg of trehalose dihydrate, 0.25 mg of polysorbate 80 stock solution (approximately 50 μL), and 5.4 mg of sodium citrate dihydrate 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 1N NaOH / HCl. Approximately 75.0 mg of compound 4 was added to the solution, and then the pH of the solution was adjusted to approximately 6.0 to 6.3 by adding 10 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added to the fill line of the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0418] Preparation of formulation 7 To prepare a 5 mL sample of formulation 7, approximately 40.0 mg of sodium chloride, 0.5 mg of polysorbate 80 stock solution (approximately 100 μL), 0.9 mg of EDTA2Na2H2O stock solution (approximately 100 μL), and 9.65 mg of sodium citrate dihydrate 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 1N NaOH / HCl. Approximately 75.0 mg of compound 4 was added to the solution, and then the pH of the solution was adjusted to approximately 6.0 to 6.3 by adding 48 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added to the fill line of the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0419] Preparation of formulation 8 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 flask to dissolve the added compounds. The pH of the solution was then adjusted to approximately 6.0 - 7.0 using 1N NaOH / HCl. Approximately 75.0 mg of compound 4 was added to the solution, and then the pH of the solution was adjusted to approximately 6.0 to 6.3 by adding 40 μL of 1N NaOH while vortexing or sonicating the solution. Water was then added to the fill line of the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0420] Preparation of formulation 9 To prepare a 5 mL sample of formulation 9, approximately 47.0 mg of propylene glycol, 18.0 mg of phenol, 0.25 mg of polysorbate 80 stock solution (approximately 50 μL), and 3.70 mg of disodium phosphate anhydrous 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 1N NaOH / HCl. Approximately 75.0 mg of compound 4 was added to the solution, and then the pH of the solution was adjusted to approximately 6.0 to 6.3 by adding 1N NaOH / HCl while vortexing or sonicating the solution. Water was then added to the fill line of the 5 mL volumetric flask to bring the total volume of the solution to 5 mL.

[0421] (Example 23) Pharmacokinetic study The pharmacokinetic properties of Formulations 1 to 8 from Example 22 were compared in a study following a single subcutaneous dose administration in male cynomolgus monkeys. Uncensored plasma concentration-time data were analyzed as received from Frontage Laboratories using Phoenix WinNonlin (v 8.3, Certara L.P., Princeton, NJ). Each formulation was tested at a dose level of 0.2 mg / kg and diluted to a concentration of 0.2 mg / mL. Each of the three animals involved in each test group received a dose volume of 1 mL / kg. Plasma samples were collected from each animal at pre-dose, 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 post-dose.

[0422] Pharmacokinetic analysis was performed on the plasma concentration-time data using the Phoenix WinNonlin (v 8.3) non-compartmental analysis function (linear trapezoidal method for AUC calculation). Nominal dose values and sample collection times were used for the calculation. C max and the corresponding T max values were determined by direct determination of the concentration-time data. All AUC calculations were performed using the linear trapezoidal method. When the data permitted, the terminal rate constant (lambda z, λz) was determined. The value of λz was calculated by the slope of the regression line of the natural logarithm-transformed concentration-time, where the data points were randomly distributed around the line and at least three data points after C max were used in the regression, and the correlation coefficient (R 2 ) was > 0.90 and the period (span) over which the regression was determined was at least 2.0 times longer than the calculated half-life itself.

[0423] To optimize the reliability of the identified terminal phase (λz), the data points used to define λz were manually selected. AUC INF values were calculated as follows: AUC last +(C last / λz). The CL / F value was calculated as dose / AUC INF and the Vz / F value was calculated as dose / (AUC INF* calculated as AUC(λz). If the percentage of the extrapolated area for AUC INF was > 20%, the AUC INF , Vz / F, and CL / F values were not reported. The terminal half-life (t 1 / 2 ) was calculated as follows: ln(2) / λz. If the span for defining the lambda z line was less than twice t 1 / 2 , the t 1 / 2 value was marked with an asterisk ( * ) and removed from the summary statistics. Table 5 below discloses the mean pharmacokinetic data obtained from each experiment using each of Formulations 1 - 8. Figure 1 shows the mean concentration of the compound of Compound 4 in each study subject over time of administration of Formulations 1 - 8. As shown in Figure 1, each of Formulations 1 - 8 had similar responses and stabilities.

[0424]

Table 5

[0425] Another study using 1) a vehicle of 0.1% bovine serum albumin in phosphate buffered saline aqueous solution, or 2) tildepazotide (0.2 mg / kg) in 40% propylene glycol and 60% 10 mM pH 6 citrate buffer solution obtained half-lives of 66.2 hours and 59.8 hours, respectively. Thus, the half-lives of Formulations 1 - 8 were higher than those of the tildepazotide formulation.

[0426] (Example 24) Formulation A vehicle was prepared by combining 1175 mg of propylene glycol, 449.92 mg of phenol, 174.64 mg of disodium phosphate anhydrous, and 1.25 ml of a 5 mg / ml aqueous polysorbate 80 solution. The pH of the mixture was adjusted to 6.22 with 1N HCl and then diluted to 100 mL by adding an appropriate volume of water for injection (WFI). A formulation for subcutaneous administration was prepared as described in Table 6 by combining the test compound with the vehicle and diluting with sterile water for injection (SWFI) to form a solution with a final concentration of 0.2 mg / ml. The resulting mass percentages of the vehicle components in the formulation were 0.94% propylene glycol, 0.36% phenol, 0.074% disodium phosphate anhydrous, and 0.005% polysorbate 80 in water.

[0427]

Table 6

[0428] (Example 25) Pharmacokinetic Study The pharmacokinetic properties of Formulations 10, 11, 12, and 13 were compared in a study following single subcutaneous dose administration in male cynomolgus monkeys. Uncensored plasma concentration vs. time data were analyzed using Phoenix WinNonlin (v 8.3, Certara L.P., Princeton, NJ). Each formulation was tested at a dose level of 0.2 mg / kg. Each of the three animals involved in each test group received a dose volume of 1 mL / kg. Plasma samples were collected from each animal at pre-dose, 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 post-dose.

[0429] Pharmacokinetic analysis was performed on the plasma concentration vs. time data using the Phoenix WinNonlin (v 8.3) non-compartmental analysis function (linear trapezoidal method for AUC calculation).

[0430] Table 7 below discloses the average pharmacokinetic data obtained from each experiment using each of Formulations 10 - 13. Figure 2 shows the average plasma concentration over time for each of Formulations 10 - 13.

[0431] [Table 7]

[0432] (Example 26) Pharmacokinetic Study A subcutaneous formulation containing 10 mM disodium phosphate anhydrous, 1.4% propylene glycol, 0.5% phenol, and water and either Compound 4, Compound 14, Compound 15, or Compound 17 was prepared. The formulation was administered to cynomolgus monkeys at a dose of 0.2 mg / kg. Plasma concentration - time data were collected and pharmacokinetic values were determined. The results are reported in Table 8.

[0433] [Table 8]

[0434] (Example 27) Stability Study The stability of formulations containing various concentrations of Compound 4 in solution with 0.94% w / v propylene glycol, 0.36% w / v phenol, 0.074% w / v potassium dibasic phosphate anhydrous, and 0.005% w / v polysorbate 80 was evaluated immediately after storage at - 20°C, 5°C, and 25°C / 60% R.H. Storage for up to 3 months demonstrated little reduction in the assay of Compound 4 and increase in impurity content. For example, a formulation containing 2.5 mg / ml of Compound 4 prepared under GMP conditions and stored at 25°C / 60% R.H. for 1 month resulted in a 103% to 102.4% decrease in the Compound 4 assay and a 0.57% to 0.76% increase in total impurities.

[0435] While certain embodiments have been illustrated and described, those of ordinary skill in the art will, after reading the foregoing specification, be able to effect changes, substitutions of equivalents, and other types of modifications to the compounds or salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures thereof of the present technology as described herein. Each aspect and embodiment described above may also include or incorporate variations or aspects as disclosed with respect to any or all of the other aspects and embodiments.

[0436] The present technology should not be limited with respect to the particular aspects described herein which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent ways within the scope of the present technology in addition to those enumerated herein will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that the present technology is not limited to the particular methods, reagents, compounds, compositions, labeled compounds or biological systems which can, of course, vary. Moreover, the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Accordingly, this specification is intended to be considered as illustrative only and the breadth, scope and spirit of the present technology are indicated only by the appended claims, their definitions and any equivalents thereof.

[0437] The embodiments illustratively described herein can be appropriately practiced without any element(s) (singular or plural) or limitation(s) (singular or plural) not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," etc. shall be read in a broad and non-limiting sense. In addition, the terms and expressions used herein are used as descriptive terms and not as limitations, and in the use of such terms and expressions, there is no intention to exclude any equivalents of the features shown and described or a part thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. In addition, the phrase "consisting essentially of" is understood to include elements as specifically recited, as well as additional elements that do not materially affect the basic and novel features of the claimed technology. The phrase "consisting of" excludes any element not specified.

[0438] In addition, when a feature or aspect of the present disclosure is described with respect to a Markush group, those skilled in the art will recognize that the present disclosure thereby also describes the feature or aspect with respect to any individual member of the Markush group or a subgroup of its members. Each of the narrower species and subgeneric classifications that fall within the broad disclosure also forms part of the present technology. This includes a comprehensive description of the technology with any provisos or negative limitations that exclude any object from the genus concept, regardless of whether the deleted material is specifically recited herein.

[0439] All publications, patent applications, issued patents, and other documents (e.g., academic journals, articles, and / or textbooks) referred to in this specification are incorporated herein by reference as if each individual publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded to the extent they are inconsistent with the definitions in this disclosure.

[0440] Other embodiments are described in the following claims, together with the full scope of equivalents to which such claims are entitled.

[0441] The present invention has been shown and described with reference to preferred embodiments and various alternative embodiments in particular, but it will be understood by those skilled in the relevant art that various changes in form and detail may be made therein without departing from the spirit and scope of the present invention.

[0442] All references, issued patents, and patent applications enumerated in the body of this specification are hereby incorporated by reference in their entirety for all purposes.

[0443] The present invention has been described with reference to embodiments and examples, but it should be understood that numerous and various modifications can be made without departing from the spirit of the present invention. Accordingly, the present invention is limited only by the following claims.

Claims

1. A pharmaceutical composition comprising: One or more non-aqueous solvents or solubilizing agents constituting less than 20% by mass of the pharmaceutical composition; and Formula I: 【Chemical 1】 A compound having the structure or a pharmaceutically acceptable salt thereof [Wherein: Aib is 2-aminoisobutyric acid; J 1 、 J 2 、 and J 3 Each instance of, and J is independently an amino acid selected from Aib, a naturally occurring amino acid, and a non-natural amino acid; U 1 is -(J 4 ) n1 -(J 5 ) n2 -(J 6 ) n3 -(J 7 ) n4 -; U 2 is -(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 of is, independently, a naturally occurring amino acid or a non-natural 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 is selected from the group consisting of -C(=O)(OZ 1 ), -P(=O)(X)(Y), and 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, and the heteroaryl is halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, -OR 5 , C 3～10 cycloalkyl, C 6～10 aryl, 1 to 2 Rs independently selected from 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl 7 and is optionally substituted with; R 2 is selected from the group consisting of -C(=O)(OZ 2 ), -P(=O)(X)(Y), and 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms selected from N, O, and S, wherein the heteroaryl is independently selected from halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, -OR 5 , C 3～10 cycloalkyl, C 6～10 aryl, 1 to 2 Rs independently selected from 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl 7 and is optionally substituted by; Each R 7 is independently selected from the group consisting of halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; X and Y are each independently selected from the group consisting of -OR 4 , NR 5 R 6 , C 1～6 alkyl and halo C 1～6 alkyl; Each R 4 is independently selected from the group consisting of hydrogen, C 1～6 alkyl, halo C 1～6 alkyl, C 6～10 aryl and C 7～11 arylalkyl; Each R 5 is independently hydrogen or C 1～6 alkyl; Each R 6 is independently hydrogen or C 1～6 alkyl; Z 1 and Z 2 each independently selected from the group consisting of hydrogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 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: [Chemical 2] 。

3. J 1 、 J 2 、 and J 3 wherein each instance of J is independently an amino acid selected from Aib and naturally occurring amino acids, the pharmaceutical composition according to claim 1.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

24. J of the compound of formula I 1 is selected from Aib or F; J of the compound of formula I 2 is selected from Q or N; J of the compound of formula I 3 is selected from A or R; U of the compound of formula I 1 is selected from -K-V-A-, -K-I-A-Q-, -K-T-A-Q-, -K-T-S-Q-, -K-V-A-Q-, -R-I-A-Q- or does not exist; U of the compound of formula I 2 is selected from -Q-, -I-A-Q-Q- or is absent The pharmaceutical composition according to any one of claims 1 to 4.

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

29. The compound has the structure of Formula I-a: 【Chemical 3】 The pharmaceutical composition according to any one of claims 1 to 28, having the structure or a pharmaceutically acceptable salt thereof.

30. Z 1 is selected from the group consisting of hydrogen, C 1～6 alkyl, halo C 1～6 alkyl, halo C 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl and C 6～10 aryl; and each of X and Y is -OR 4 The pharmaceutical composition according to claim 29, wherein

31. Z of the compound of formula I-a 1 is hydrogen, and each R of the compound of formula I-a 4 is independently hydrogen or C 7～11 arylalkyl, the pharmaceutical composition according to claim 30.

32. Each R of the compound of formula I-a 4 The pharmaceutical composition according to any one of claims 30 or 31, wherein is hydrogen.

33. Z of the compound of formula I-a 1 is hydrogen, and each R of the compound of formula I-a 4 is hydrogen, the pharmaceutical composition according to claim 30.

34. The compound has the structure of Formula I-b: 【Chemical Formula 4】 The pharmaceutical composition according to any one of claims 1 to 28, having the structure or a pharmaceutically acceptable salt thereof.

35. Each R of the compound of formula I-b 4 is independently selected from the group consisting of hydrogen, C 6～10 aryl and C 7～11 The pharmaceutical composition according to claim 34, wherein the arylalkyl is selected.

36. Each R of the compound of formula I-b 4 The pharmaceutical composition according to claim 35, wherein is hydrogen.

37. 【Fig. 5A】 【Chemical Formula 5B】 【Chemical Formula 5C】 【Chemical Formula 5D】 The pharmaceutical composition according to claim 1, having a structure selected from the group consisting of and pharmaceutically acceptable salts thereof.

38. The compound has the structure of Formula II: [Chemical Formula 6] The pharmaceutical composition according to claim 1, having the structure or a pharmaceutically acceptable salt thereof [Wherein: R 1 is selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y), and one or two Rs independently selected from halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, -OR 5 , C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, and is optionally substituted with one or two heteroatoms selected from N, O, and S contained in a 5- to 10-membered heteroaryl selected from the group consisting of; 7 ​ R 2 is selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y), and one or two Rs independently selected from halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, -OR 5 , C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, and is selected from the group consisting of 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O, and S, optionally substituted by one or two Rs 7 ; Each R 7 is independently selected from the group consisting of halogen, C 1～6 alkyl, halo C 1～6 alkyl, halo C 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl; X and Y are each, independently selected from the group consisting of -OR 4 , NR 5 R 6 , C 1～6 alkyl and halo C 1～6 alkyl; Each R 4 is independently selected from the group consisting of hydrogen, C 1～6 alkyl, halo C 1～6 alkyl, C 6～10 aryloxy and C 6～10 arylalkoxy; Each R 5 is independently hydrogen or C 1～6 alkyl; Each R 6 is independently hydrogen or C 1～6 alkyl; Z 1 and Z 2 each is independently selected from the group consisting of hydrogen, C 1～6 alkyl, halo C 1～6 alkyl, halo C 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl and C 6～10 aryl, and is independently selected from the group consisting of Here, Z 1 and Z 2 at least one of which is not hydrogen.

39. Formula II-a: [Chemical Formula 7] The pharmaceutical composition according to claim 38, having the structure or a pharmaceutically acceptable salt thereof.

40. Z 1 is selected from the group consisting of hydrogen, C 1～6 alkyl, halo C 1～6 alkyl, halo C 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl and C 6～10 aryl; each of X and Y is -OR 4 The pharmaceutical composition according to claim 39, wherein

41. Z 1 is selected from the group consisting of hydrogen, halo C 1～6 alkoxy and C 1～6 alkoxy; each R 4 is independently selected from the group consisting of hydrogen, C 6～10 aryloxy and C 6～10 aryalkoxy, the pharmaceutical composition according to claim 39 or 40.

42. Z 1 is hydrogen, and each R 4 is independently hydrogen or C 6～10 arylalkoxy, the pharmaceutical composition according to any one of claims 39 to 41.

43. Each R 4 The pharmaceutical composition according to any one of claims 39 to 42, wherein 4 is hydrogen.

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

45. Formula II-b: [Chemical Formula 8] The pharmaceutical composition according to claim 38, having the structure of or a pharmaceutically acceptable salt thereof.

46. Z 2 is selected from the group consisting of hydrogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl and C 6～10 aryl; and each of X and Y is -OR 4 The pharmaceutical composition according to claim 45, wherein

47. Z 2 is selected from the group consisting of hydrogen, halo C 1～6 alkoxy and C 1～6 alkoxy; each R 4 is independently selected from the group consisting of hydrogen, C 6～10 aryloxy and C 6～10 arylalkoxy, the pharmaceutical composition according to claim 45 or 46.

48. Z 2 is hydrogen, and each R 4 is hydrogen or C 6～10 arylalkoxy, the pharmaceutical composition according to any one of claims 45 to 47.

49. Each R 4 The pharmaceutical composition according to any one of claims 45 to 48, wherein R is hydrogen.

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

51. Formula II-c: 【Chemical Formula 9】 The pharmaceutical composition according to claim 38, having the structure of or a pharmaceutically acceptable salt thereof.

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

53. Each R 4 is independently selected from the group consisting of hydrogen, C 6～10 aryloxy and C 6～10 arylalkoxy, the pharmaceutical composition according to claim 51 or 52.

54. Each R 4 The pharmaceutical composition according to any one of claims 51 to 53, wherein each R is hydrogen.

55. 【Fig. 10A】 【Chemical Formula 10B】 【Chemical 10C】 【Chemical 10D】 The pharmaceutical composition according to claim 38, having a structure selected from the group consisting of and pharmaceutically acceptable salts thereof.

56. " * ", which represents a chiral carbon having an "S" configuration, the pharmaceutical composition according to any one of claims 38 to 55.

57. " * ", which represents a chiral carbon having an "R" configuration, the pharmaceutical composition according to any one of claims 38 to 55.

58. The pharmaceutical composition according to any one of claims 1 to 57, wherein one or more non-aqueous solvents or solubilizing agents constitute less than 10% by mass of the composition.

59. The pharmaceutical composition according to any one of claims 1 to 57, wherein one or more non-aqueous solvents or solubilizing agents constitute less than 5% by mass of the composition.

60. The pharmaceutical composition according to any one of claims 1 to 59, wherein one or more non-aqueous solvents or solubilizing agents contain propylene glycol.

61. The pharmaceutical composition according to claim 60, wherein propylene glycol is present in a mass percentage of about 10% or less.

62. The pharmaceutical composition according to claim 60, wherein propylene glycol is present in a mass percentage of about 2% or less.

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

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

65. The pharmaceutical composition according to any one of claims 1 to 64, wherein one or more non-aqueous solvents or solubilizing agents contain polysorbate.

66. The pharmaceutical composition according to claim 65, wherein polysorbate is present in a mass percentage of approximately 0.001% to approximately 0.1%.

67. The pharmaceutical composition according to claim 65, wherein polysorbate is present in a mass percentage of approximately 0.003% to approximately 0.05%.

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

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

70. The pharmaceutical composition according to any one of claims 1 to 69, wherein one or more non-aqueous solvents or solubilizing agents contain glycerol.

71. The pharmaceutical composition according to claim 70, wherein glycerol is present in a mass percentage of approximately 0.5% to approximately 5%.

72. The pharmaceutical composition according to any one of claims 1 to 71, wherein one or more non-aqueous solvents or solubilizing enhancers contain metacresol.

73. The pharmaceutical composition according to claim 72, wherein metacresol is present in a mass percentage of approximately 0.1% to approximately 1%.

74. The pharmaceutical composition according to any one of claims 1 to 73, wherein one or more non-aqueous solvents or solubilizing enhancers contain phenol.

75. The pharmaceutical composition according to claim 74, wherein phenol is present in a mass percentage of approximately 0.1% to approximately 1%.

76. The pharmaceutical composition according to claim 74, wherein phenol is present in a mass percentage of approximately 0.1% to approximately 0.6%.

77. The pharmaceutical composition according to any one of claims 1 to 76, comprising approximately 0.1% to approximately 5% by mass of propylene glycol and approximately 0.1% to approximately 1% by mass of phenol.

78. The pharmaceutical composition according to claim 77, comprising approximately 0.001% to approximately 0.01% by mass 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: 【Chemical 11】 [wherein: R 1 is selected from -C(=O)(OZ 1 ), -P(=O)(X)(Y), and one or two Rs independently selected from halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, -OR 5 , C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, and a 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O and S optionally substituted by one or two Rs 7 selected from the group consisting of; R 2 is selected from -C(=O)(OZ 2 ), -P(=O)(X)(Y), and one or two Rs independently selected from halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, -OR 5 , C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl; and is selected from a group consisting of 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O and S, optionally substituted by one or two Rs 7 ; Each R 7 is independently selected from the group consisting of halogen, C 1～6 alkyl, haloC 1～6 alkyl, haloC 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl, C 6～10 aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl; X and Y are each, -OR 4 , NR 5 R 6 , C 1～6 alkyl and halo C 1～6 alkyl, and are independently selected from the group consisting of; Each R 4 is independently selected from the group consisting of hydrogen, C 1～6 alkyl, halo C 1～6 alkyl, C 6～10 aryl and C 6～10 arylalkyl; Each R 5 is independently hydrogen or C 1～6 alkyl; Each R 6 is independently hydrogen or C 1～6 alkyl; Z 1 and Z 2 each is independently selected from the group consisting of hydrogen, C 1～6 alkyl, halo C 1～6 alkyl, halo C 1～6 alkoxy, C 1～6 alkoxy, C 3～10 cycloalkyl and C 6～10 aryl, and is independently selected from the group consisting of Here, Z 1 and Z 2 at least one of which is not hydrogen.

80. The pharmaceutical composition according to claim 79, wherein lactose is present in a mass percentage of approximately 2% to approximately 10% as lactose monohydrate.

81. " * ", which represents a chiral carbon having an "S" configuration, the pharmaceutical composition according to any one of claims 1 to 80.

82. " * ", which represents a chiral carbon having an "R" configuration, the pharmaceutical composition according to any one of claims 1 to 80.

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

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

85. The pharmaceutical composition according to any one of claims 1 to 84, comprising a buffer solution.

86. The pharmaceutical composition according to claim 85, wherein the buffer solution 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 of the foregoing.

87. The pharmaceutical composition according to claim 85, wherein the buffer solution comprises sodium citrate.

88. The pharmaceutical composition according to claim 85, wherein the buffer solution comprises disodium phosphate.

89. The pharmaceutical composition according to claim 85, wherein the buffer solution comprises L-histidine.

90. The pharmaceutical composition according to claim 85, wherein the buffer solution comprises methionine.

91. The pharmaceutical composition according to any one of claims 1 to 90, having a pH of about 2 to 12.

92. The pharmaceutical composition according to any one of claims 1 to 90, having a pH of about 5.0 to 7.

5.

93. The pharmaceutical composition according to any one of claims 1 to 90, having a pH of approximately 6.

0.

94. The pharmaceutical composition according to any one of claims 1 to 93, configured for subcutaneous administration.

95. The pharmaceutical composition according to any one of claims 1 to 94, in liquid form.

96. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 0.47% by mass of propylene glycol, approximately 0.18% by mass of phenol, approximately 0.037% by mass of disodium phosphate anhydrous, and approximately 1.5% by mass of a compound of formula I or II.

97. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 4.9% by mass of sorbitol, approximately 0.12% by mass of L-histidine, approximately 0.09% by mass of methionine, approximately 1.5% by mass of a compound of formula I or II, and approximately 0.04% by mass of polysorbate 20.

98. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 0.94% by mass of propylene glycol, approximately 0.36% by mass of phenol, approximately 0.074% by mass of disodium phosphate anhydrous, approximately 1.5% by mass of a compound of formula I or II, and approximately 0.005% by mass of polysorbate 80.

99. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 0.8% by mass of sodium chloride, approximately 0.193% by mass of sodium citrate dihydrate, approximately 0.01% by mass of polysorbate 80, approximately 1.5% by mass of a compound of formula I or II, and approximately 0.018% by mass of EDTA.2Na.

100. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 5.802% by mass of trehalose dihydrate, approximately 0.005% by mass of polysorbate 80, approximately 0.0072% by mass of methionine, approximately 0.108% by mass of sodium citrate dihydrate, approximately 1.5% by mass of a compound of formula I or II, and approximately 1.5% by mass of mannitol.

101. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 1.21% by mass of glycerol, approximately 0.441% by mass of sodium citrate dihydrate, approximately 0.102% by mass of magnesium chloride hexahydrate, approximately 1.5% by mass of a compound of formula I or II, and approximately 0.0039% by mass of zinc oxide.

102. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 0.3% by mass of metacresol, approximately 0.441% by mass of sodium citrate dihydrate, approximately 1.5% by mass of a compound of formula I or II, and approximately 4.54% by mass of mannitol.

103. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 4.9% by mass of lactose monohydrate, approximately 0.113% by mass of disodium phosphate anhydrous, and approximately 1.5% by mass of a compound of formula I or II.

104. The pharmaceutical composition according to any one of claims 1 to 95, comprising approximately 1.40% by mass of propylene glycol, approximately 0.55% by mass of phenol, approximately 1.5% by mass of a compound of formula I or II, approximately 0.113% by mass of disodium phosphate anhydrous, and approximately 0.005% by mass of polysorbate 80.

105. The pharmaceutical composition according to any one of claims 1 to 95, comprising one or more of propylene glycol, phenol, metacresol, 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 alleviating one or more fatty liver diseases in a subject, comprising the step of administering the pharmaceutical composition according to any one of claims 1 to 105 to a subject in need thereof.

107. The method according to claim 106, wherein the fatty liver disease is selected from the group consisting of steatosis, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.

108. The method according to claim 106 or 107, wherein the administration of the pharmaceutical composition results in the prevention, treatment or alleviation of fibrosis, fibrotic conditions or fibrotic symptoms.

109. The method according to any one of claims 106 to 108, wherein the administration of the pharmaceutical composition results in a reduction in the amount of extracellular matrix proteins present in one or more tissues of the subject.

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

111. The method according to claim 110, wherein the administration of the pharmaceutical composition results in a reduction 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 alleviating one or more diseases or disorders in a subject, comprising the step of administering the pharmaceutical composition according to any one of claims 1 to 106 to a subject in need thereof, wherein the disease or disorder is liver fibrosis, kidney fibrosis, bile duct fibrosis, pancreatic fibrosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

113. The method according to claim 112, wherein the disease or disorder is non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis or primary biliary cirrhosis.

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

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