Compositions and methods for the treatment of metabolic and liver disorders

Abstract

Disclosed herein are small molecule GIP / GLP-1 dual receptor agonist compositions, pharmaceutical compositions, their uses and preparations.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 139,676, filed January 20, 2021, which is incorporated by reference in its entirety.

[0002] The present disclosure generally relates to the field of treatments for metabolic disorders and fatty liver disease. More specifically, the present disclosure relates to the field of small molecule drugs for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD). [Background technology]

[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 ingestion of nutrients, facilitating rapid disposal of orally ingested nutrients. Both peptides share common actions on islet β-cells acting through 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 through direct actions on adipose tissue. In contrast, GLP-1 exerts glucoregulatory effects through 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] Nonalcoholic fatty liver disease (NAFLD) is the 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, nonalcoholic 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 may prevent dosing to a desired effective dose, impair patient compliance to treatment, and limit the effectiveness of treatment regimens. Thus, there is a need for novel GIP / GLP1 dual agonist compounds that can be used to treat fatty liver disease and other diseases and disorders. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO 87 / 05297, Johnston et al., published September 11, 1987 [Non-patent literature]

[0006] [Non-Patent Document 1] Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon", J. Biol. Chem. 2010 285: pp. 11039-11044 [Non-Patent Document 2] Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th ed., Pergamon Press [Non-Patent Document 3] Protective Groups in Organic Chemistry (edited by JFW McOmie, Plenum Press, 1973) [Non-Patent Document 4] PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd edition) Wiley, New York (1999) [Non-Patent Document 5] R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989 [Non-Patent Document 6] L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995. [Non-Patent Document 7] Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley, and Sons, 1991) [Non-Patent Document 8] Rodd's Chemistry of Carbon Compounds, vols. 1-5 [Non-Patent Document 9] Supplementals (Elsevier Science Publishers, 1989) [Non-Patent Document 10] Organic Reactions, volumes 1-40 (John Wiley, and Sons, 1991) [Non-Patent Document 11] March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th edition, 2001) [Non-Patent Document 12] Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) [Non-Patent Document 13] Remington's The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins (2005) [Non-Patent Document 14] Modern Pharmaceutics, 4th ed., Chapters 9 and 10 (Banker & Rhodes, 2002) [Non-Patent Document 15] Lieberman et al., Pharmaceutical Dosage Forms; Tablets (1989) [Non-Patent Document 16] Ansel, Introduction to Pharmaceutical Dosage Forms 8th edition (2004) [Non-Patent Document 17] Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 pp. 238-311 [Non-Patent Document 18] Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 pp. 287-332 [Non-Patent Document 19] March Advanced Organic Chemistry (Wiley) [Non-Patent Document 20] Care and Sundberg, Advanced Organic Chemistry [Non-Patent Document 21] T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th ed., John Wiley & Sons (2007) [Non-Patent Document 22] Boland et al., World J Gastroenterol, 2019, 25(33):4904-4920 [Non-Patent Document 23] Lau, J. et al., J. Med. Chem. 2015, 58, 7370-7380 Summary of the Invention [Means for solving the problem]

[0007] Some embodiments disclosed herein include compounds of formula I:

[0008] [ka]

[0009] or a pharma- ceutically acceptable salt thereof, wherein R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with Each R 7 is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 may be independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; X and Y are each -OR 4 , N.R. 5 R 6 , C 1~6 Alkyl and haloC 1~6 alkyl; Each R 4 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, C 6~10 Aryloxy and C 6~10 arylalkoxy; Each R 5 are independently hydrogen or C 1~6 may be alkyl; Each R 6 are independently hydrogen or C 1~6 may be alkyl; Z 1 and Z 2 are 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; However, Z 1 and Z 2 At least one of these must not be hydrogen.

[0010] Other embodiments disclosed herein include pharmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein and a pharma- ceutically acceptable excipient.

[0011] Other embodiments disclosed herein include a method for preventing, treating or ameliorating one or more fatty liver diseases in a subject by administering to the subject in need thereof a compound disclosed herein, or a pharmacologic acceptable salt thereof.Fatty liver diseases include, but are not limited to, steatosis, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD).

[0012] Other embodiments disclosed herein include a method for preventing, treating, or ameliorating one or more diseases or disorders in a subject by administering to a subject in need thereof a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.In some embodiments, the disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.In some embodiments, the disease or disorder is metabolic disorder or metabolic syndrome.In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In some embodiments, compounds are provided that are non-macrocyclic functionalized peptides that act as GIP / GLP-1 dual receptor agonists. Various embodiments of these compounds include compounds having the structure of Formula I, as described above, or a pharma- ceutically acceptable salt thereof. The structure of Formula I encompasses all stereoisomers and racemic mixtures, including the following structures and mixtures thereof:

[0014] [ka]

[0015] In some embodiments of the compounds of formula I: R 1 is -C(=O)(OZ 1 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with R 2 is -C(=O)(OZ 2 ), -P(=O)(X)(Y), and halogens, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, -OR 5 , C 3~10 Cycloalkyl, C 6~10 1 to 2 R independently selected from aryl, 5 to 10 membered heteroaryl, and 5 to 10 membered heterocyclyl; 7 5-10 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S, optionally substituted with Each R 7is a halogen, C 1~6 Alkyl, haloC 1~6 Alkyl, haloC 1~6 Alkoxy, C 1~6 Alkoxy, C 3~10 Cycloalkyl, C 6~10 may be independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl; X and Y are each -OR 4 , N.R. 5 R 6 , C 1~6 Alkyl and haloC 1~6 alkyl; Each R 4 is hydrogen, C 1~6 Alkyl, haloC 1~6 Alkyl, C 6~10 Aryloxy and C 6~10 arylalkoxy; Each R 5 are independently hydrogen or C 1~6 may be alkyl; Each R 6 are independently hydrogen or C 1~6 may be alkyl; Z 1 and Z 2 are 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; However, Z 1 and Z 2 At least one of these must not be hydrogen.

[0016] Some embodiments of the compounds of formula I include those of formula Ia:

[0017] [ka]

[0018] or a pharma- ceutically acceptable salt thereof.

[0019] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is 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 selected from -OR 4 It is.

[0020] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is hydrogen, haloC 1~6 Alkoxy and C 1~6 alkoxy; each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 Arylalkoxy can be independently selected from the group consisting of arylalkoxy.

[0021] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is hydrogen, and each R 4 are independently hydrogen or C 6~10 It may be an arylalkoxy.

[0022] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen.

[0023] In some embodiments of the compounds of formula Ia or pharma- ceutically acceptable salts thereof; Z 1 is hydrogen, and each R 4 is hydrogen.

[0024] Some embodiments of the compounds of formula I include those of formula Ib:

[0025] [ka]

[0026] or a pharma- ceutically acceptable salt thereof.

[0027] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is 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 selected from -OR 4 It is.

[0028] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is hydrogen, haloC 1~6 Alkoxy and C 1~6 alkoxy; each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 Arylalkoxy can be independently selected from the group consisting of arylalkoxy.

[0029] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is hydrogen, and each R 4 are independently hydrogen or C 6~10 It may be an arylalkoxy.

[0030] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen.

[0031] In some embodiments of the compounds of formula Ib or pharma- ceutically acceptable salts thereof; Z 2 is hydrogen, and each R 4 is hydrogen.

[0032] Some embodiments of the compounds of formula I include those of formula Ic:

[0033] [ka]

[0034] or a pharma- ceutically acceptable salt thereof.

[0035] In some embodiments of the compounds of formula Ic or pharma- ceutically acceptable salts thereof; X and Y are each -OR 4 It is.

[0036] In some embodiments of the compounds of formula Ic or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen, C 6~10 Aryloxy and C 6~10 Arylalkoxy can be independently selected from the group consisting of arylalkoxy.

[0037] In some embodiments of the compounds of formula Ic or pharma- ceutically acceptable salts thereof, each R 4 is hydrogen.

[0038] In some embodiments:

[0039] [ka]

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] and pharma- ceutically acceptable salts thereof.

[0044] In some embodiments, * " exhibits a chiral carbon having the "S" configuration.

[0045] In some embodiments, * " exhibits a chiral carbon having the "R" configuration.

[0046] 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. Separation of individual isomers or selective synthesis of individual isomers is achieved by application of various methods well known to practitioners in the art. Unless otherwise indicated, all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein, including any polymorphic forms. 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 in the scope of the compounds disclosed herein.

[0047] The skilled artisan will recognize that some structures depicted herein may be resonance forms or tautomers of compounds that may be significantly, even kinetically, represented by other chemical structures; the skilled artisan will recognize that such structures may only represent a very small proportion of the samples of such compounds. Although such compounds are believed to be within the scope of the depicted structures, such resonance forms or tautomers are not represented herein.

[0048] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, those in this section prevail unless otherwise stated.

[0049] "Solvate" refers to the compound formed by the interaction of a solvent with a compound described herein, or a salt thereof. Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0050] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a compound, which are not biologically or otherwise undesirable for use in a pharmaceutical product. In many cases, the compounds herein can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987, which is incorporated herein by reference in its entirety.

[0051] As used herein, "C" refers to a set of integers where "a" and "b" are integers. a From C b " or "C a~b " refers to the number of carbon atoms in the specified group. That is, the group can contain from "a" to "b" carbon atoms, inclusive. Thus, for example, "C1 to C4 alkyl" or "C 1~4An "alkyl" group is any alkyl group having one to four carbons, i.e., CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 Refers to C-.

[0052] The term "halogen" or "halo" as used herein means any one of the radioactive 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.

[0053] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (wherever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "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 encompasses the occurrence of the term "alkyl" even when no numerical range is specified). The alkyl group can be a medium-sized alkyl having 1 to 9 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compound can be a "C 1~4 By way of example only, "C 1~4"Alkyl" indicates that there are 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 in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0054] As used herein, "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 12 carbon atoms in the chain in which one or more hydrogens are replaced with halogens. Examples of haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CF 2 CF 3 and other groups that would be considered equivalent to any one of the preceding examples in light of ordinary skill in the art and the teachings provided herein.

[0055] As used herein, "alkoxy" refers to a group of the formula -OR where R is alkyl as defined above, including, but not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. 1~9 Refers to "alkoxy".

[0056] As used herein, "polyethylene glycol" refers to a compound of the formula

[0057] [ka]

[0058] where n is an integer greater than 1 and R is hydrogen or alkyl. The number of repeating units "n" can be indicated by a number of members. Thus, for example, "2- to 5-membered polyethylene glycol" refers to n being an integer 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.

[0059] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms in the chain backbone, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. Heteroalkyl groups can have 1 to 20 carbon atoms, although this definition also encompasses occurrences of the term "heteroalkyl" when no numerical range is specified. Heteroalkyl groups can be medium size heteroalkyls having 1 to 9 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls having 1 to 4 carbon atoms. In various embodiments, heteroalkyls can have 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl groups of the compounds are defined as "C 1~4 A heteroalkyl group may be designated as "heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1~4 "Heteroalkyl" means that the heteroalkyl chain has 1 to 4 carbon atoms and, additionally, one or more heteroatoms in the backbone of the chain.

[0060] 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 which share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0061] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) that contains only carbon in the ring backbone. When aryl is a ring system, every ring in the system is aromatic. An aryl group can have from 6 to 18 carbon atoms, although 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 defined as "C 6~10 Aryl, C 6 Or C 10 The aryl group may be designated as "aryl" or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0062] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl as defined above, including, but not limited to, phenyloxy. 6~10 aryloxy" or "C 6~10 "Arylthio" etc.

[0063] "Aralkyl" or "arylalkyl" refers to an aryl group connected as a substituent through an alkylene group, such as, but not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl, "C 7~14 In some cases, the alkylene group can be a lower alkylene group (i.e., C 1~4 alkylene group).

[0064] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) that contains one or more heteroatoms in the ring backbone, i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. When heteroaryl is a ring system, every ring in the system is aromatic. Heteroaryl groups can have 5 to 18 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heteroaryl" when no numerical range is specified. In some embodiments, heteroaryl groups have 5 to 10 ring members, or 5 to 7 ring members. Heteroaryl groups can be designated as "5-membered to 7-membered heteroaryl," "5-membered to 10-membered heteroaryl," or similar designations. 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.

[0065] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group connected as a substituent via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group can be a lower alkylene group (i.e., C 1~4 alkylene group).

[0066] As used herein, "carbocyclyl" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. Carbocyclyl groups can have 3 to 20 carbon atoms, although this definition also encompasses occurrences of the term "carbocyclyl" when no numerical range is specified. Carbocyclyl groups may be medium-sized carbocyclyls having 3 to 10 carbon atoms. Carbocyclyl groups can also be carbocyclyls having 3 to 6 carbon atoms. Carbocyclyl groups are defined as "C 3~6 Carbocyclyl may be designated as "carbocyclyl" or a similar designation. Examples of carbocyclyl 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.

[0067] "(Carbocyclyl)alkyl" refers to a carbocyclyl group connected as a substituent via an alkylene group, including, but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. 4-10 (carbocyclyl)alkyl." In some cases, the alkylene group is a lower alkylene group.

[0068] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0069] As used herein, "cycloalkenyl" means a carbocyclyl ring or ring system having at least one double bond, where none of the rings in the ring system are aromatic. An example is cyclohexenyl.

[0070] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged, or spiro-connected fashion. 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 the non-aromatic or aromatic ring in the ring system. Heterocyclyl groups can have from 3 to 20 ring members (i.e., the number of atoms that make up the ring backbone, including carbon atoms and heteroatoms), although this definition also encompasses occurrences of the term "heterocyclyl" when no numerical range is specified. Heterocyclyl groups may be medium-sized heterocyclyls having from 3 to 10 ring members. Heterocyclyl groups can also be heterocyclyls having from 3 to 6 ring members. Heterocyclyl groups can be designated as "3- to 6-membered heterocyclyl" or similar designations.

[0071] In various embodiments, the heterocyclyl contains 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclyl contains 1 to 4 nitrogen atoms, 1 to 3 nitrogen atoms, 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In preferred 6-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 to up to 3 O, N, or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatoms are selected from 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidionyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathiyl, 1,4-oxathiinyl, 1,4-oxathiyl, 2H-1,2-oxazinyl, trioxadiyl, 1H-1,2-oxazin ... nyl, 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.

[0072] "(Heterocyclyl)alkyl" is a heterocyclyl group connected as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0073] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 carbocyclyl, aryl, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl and acryl.

[0074] An "O-carboxy" group refers to a "-OC(=O)R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 It is selected from carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0075] A "C-carboxy" group refers to a "-C(=O)OR" group, where R is hydrogen, C(=O)O, or C(=O)O, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 It is selected from carbocyclyl, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0076] A "cyano" group refers to a "-CN" group.

[0077] A "cyanato" group refers to a "-OCN" group.

[0078] An "isocyanato" group refers to a "-NCO" group.

[0079] A "thiocyanato" group refers to a "-SCN" group.

[0080] An "isothiocyanato" group refers to a "-NCS" group.

[0081] A "sulfinyl" group refers to a "-S(=O)R" group, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0082] The "sulfonyl" group is defined as -SO 2 R” group, where R is hydrogen, C as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0083] The "S-sulfonamide" group is defined as "-SO 2 NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0084] An “N-sulfonamide” group is defined as “-N(R A )SO2 R B " group, where R A and R b each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0085] The "O-carbamyl" group is "-OC(=O)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0086] The "N-carbamyl" group is defined as "-N(R A )OC(=O)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0087] The "O-thiocarbamyl" group is "-OC(=S)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0088] The "N-thiocarbamyl" group is defined as "-N(R A )OC(=S)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0089] A "C-amide" group is defined as "-C(=O)NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0090] An "N-amide" group is defined as "-N(R A )C(=O)R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0091] The "amino" group is "-NR A R B " group, where R A and R B each independently represents hydrogen, C as defined herein 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0092] An "aminoalkyl" group refers to an amino group connected via an alkylene group.

[0093] An "alkoxyalkyl" group is an alkoxy group connected via an alkylene group, e.g., "C 2~8 "Alkoxyalkyl" and the like.

[0094] As used herein, "natural amino acid side chain" refers to a side chain substituent of a naturally occurring amino acid. Naturally occurring amino acids have a substituent attached to the α-carbon. Naturally occurring amino acids include arginine, lysine, aspartic acid, glutamic acid, glutamine, asparagine, histidine, serine, threonine, tyrosine, cysteine, methionine, tryptophan, alanine, isoleucine, leucine, phenylalanine, valine, proline, and glycine.

[0095] As used herein, "unnatural amino acid side chain" refers to the side chain substituents of a non-naturally occurring amino acid. Unnatural amino acids include β-amino acids (β 3 and β 2), homo-amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids and N-methyl amino acids. Illustrative unnatural amino acids are available from Sigma-Aldridge, listed under "Unnatural Amino Acids & Derivatives." See also Travis S. Young and Peter G. Schultz, "Beyond the Canonical 20 Amino Acids: Expanding the Genetic Lexicon," J. Biol. Chem. 2010 285: 11039-11044, which is incorporated by reference in its entirety.

[0096] 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 deemed "substituted", the group can independently be any of the following: C 1 ~C 6 Alkyl, C 1 ~C 6 Alkenyl, C 1 ~C 6 Alkynyl, C 1 ~C 6 Heteroalkyl, C 3 ~C 7 Carbocyclyl (Halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C 6 (optionally substituted with haloalkoxy), C 3 ~C 7 -Carbocyclyl-C 1 ~C 6 -Alkyl (halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C6 haloalkoxy), 5- to 10-membered heterocyclyl (halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C 6 haloalkoxy), 5- to 10-membered heterocyclyl-C 1 ~C 6 -Alkyl (halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C 6 aryl (halo, optionally substituted with haloalkoxy); 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C 6 aryl (C 1 ~C 6 )Alkyl(Halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C 6 haloalkoxy), 5- to 10-membered heteroaryl (halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C 6 haloalkoxy), 5- to 10-membered heteroaryl (C 1 ~C 6)Alkyl(Halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl and C 1 ~C 6 (optionally substituted with haloalkoxy), halo, cyano, hydroxy, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkoxy(C 1 ~C 6 ) alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo (C 1 ~C 6 ) alkyl (e.g., -CF 3 ), Haro(C 1 ~C 6 ) alkoxy (e.g., -OCF 3 ), C 1 ~C 6 Alkylthio, arylthio, amino, amino(C 1 ~C 6 ) alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," that group may be substituted with the above-mentioned substituents.

[0097] In some embodiments, the substituted groups are individually and independently selected from the group C 1 ~C 4 Substituted with one or more substituents selected from alkyl, amino, hydroxy and halogen.

[0098] It should be understood that certain group naming conventions can include either mono or di groups, depending on the context. For example, if a substituent requires two points of attachment to the remainder of the molecule, the substituent is understood to be a di group. For example, a substituent that is identified as an alkyl requiring two points of attachment is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -. Other group naming conventions clearly indicate that the group is a di-group, such as "alkylene" or "alkenylene."

[0099] When two R groups are described as "together with the atoms to which they are attached" forming a ring (e.g., a carbocyclyl ring, a heterocyclyl ring, an aryl ring, or a heteroaryl ring), the collective unit of the atoms and the two R groups is meant to be the recited ring. The ring is not otherwise limited by the definition of each R group when taken individually. For example, the following substructures exist:

[0100] [ka]

[0101] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 together with the nitrogen to which they are attached form a heterocyclyl, R 1 and R 2 It is meant that may be selected from hydrogen or alkyl, or alternatively, the substructure may be the structure:

[0102] [ka]

[0103] where Ring A is the nitrogen-containing heterocyclyl ring as shown.

[0104] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," the collective unit of the atoms, intervening bonds, and two R groups is meant to be the recited ring. For example, the following substructure exists:

[0105] [ka]

[0106] R 1 and R 2 is defined as being selected from the group consisting of hydrogen and alkyl, or R 1 and R 2 When together with the atom to which they are attached form an aryl or carbocyclyl, R 1 and R 2 It is meant that may be selected from hydrogen or alkyl, or alternatively, the substructure may be the structure:

[0107] [ka]

[0108] where A is an aryl ring or a carbocyclyl containing the double bond as shown.

[0109] Whenever a substituent is depicted as a digroup (i.e., having two points of attachment to the remainder of the molecule), it is to be understood that the substituent may be attached in any orientation unless otherwise indicated. Thus, for example, -AE- or

[0110] [ka]

[0111] Substituents depicted as include those where A is oriented such that it is attached at the leftmost attachment point of the molecule, and those where A is attached at the rightmost attachment point of the molecule.

[0112] The term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats and mice, but also includes many other species.

[0113] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes 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. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants as commonly used in the art may be included. Considerations for the inclusion of various ingredients 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.

[0114] "Subject", as used herein, means a human or non-human mammal, e.g., a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0115] An "effective amount" or "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent that is effective to alleviate to some extent one or more of the symptoms of a disease or condition or to reduce the likelihood of its occurrence, as well as to cure the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated; however, even after a cure is obtained, certain long-term or permanent effects may exist (such as extensive tissue damage).

[0116] "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 no longer exhibits symptoms of the disease or condition, but who is susceptible or otherwise at risk for a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering a treatment to a subject who is already suffering from a disease or condition.

[0117] Method of preparation The compounds disclosed herein can be synthesized by the methods described below or by modification of these methods. The manner of modifying the methodology includes, among others, temperature, solvent, reagents, etc., known to those skilled in the art. In general, during any of the processes for the preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. JFW McOmie, Plenum Press, 1973); and PGM Green, TW 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 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, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 19955, both of which are hereby incorporated by reference in their entirety. The routes shown and described herein are exemplary only and are in no way intended or to be construed as limiting the scope of the claims in any manner. Those skilled in the art will recognize modifications of the disclosed syntheses and may undertake alternative routes based on the disclosures herein; all such modifications and alternative routes are within the scope of the claims.

[0118] In the schemes below, protecting groups for the oxygen atoms are selected for their compatibility with the synthetic steps required, and for compatibility of the installation and deprotection steps with the overall synthetic scheme (PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999)).

[0119] If the compounds of the present technology contain one or more chiral centers, these 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 that are well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0120] 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 sources 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 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.

[0121] In one embodiment, the methods disclosed herein can include constructing a 39-amino acid peptide scaffold using solid phase peptide synthesis techniques to provide intermediate (II). The peptide scaffold comprises two PEGyl groups. 2 The method further comprises the step of: 2 The method comprises an amide coupling reaction between the amine of the amide and a suitably substituted carboxylic acid (III) to provide a resin-bound intermediate (IV). In one embodiment, the method involves hydrolysis of intermediate (IV) under acidic conditions followed by purification to obtain the final product (I). (Scheme 1).

[0122] [ka]

[0123] The above example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds encompassed herein. Additionally, 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.

[0124] Administration and Pharmaceutical Compositions The compound is administered in a therapeutically effective dosage.Although human dosage level has not yet been optimized for the compounds described herein, generally, the daily dosage can be about 0.0125mg / kg to about 120mg / kg or more of body weight, about 0.025mg / kg or less to about 70mg / kg of body weight, about 0.05mg / kg to about 50mg / kg of body weight, or about 0.075mg / kg to about 10mg / kg of body weight.Thus, for administration to a 70kg human, the dosage range is about 0.08mg per day to about 8000mg per day, about 1.8mg per day or less to about 7000mg per day or more, about 3.6mg per day to about 6000mg per day, about 5.3mg per day to about 5000mg per day, or about 11mg per day to about 3000mg per day. The amount of active compound administered will, of course, be dependent on the subject and the disease condition being treated, the severity of the affliction, the manner and schedule of administration, and the judgment of the prescribing physician.

[0125] Administration of the compounds disclosed herein or their pharma- ceutically acceptable salts may be via any of the accepted modes of administration for agents serving similar utilities, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or intraocular. Oral and parenteral administration are the norm in treating the indications that are the subject of the preferred embodiments.

[0126] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treating 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 by reference in its entirety.Thus, some embodiments include pharmaceutical compositions that include: (a) a safe and therapeutically effective amount of a compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs and solvates) or its pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0127] In addition to the selected compounds useful as described above, some embodiments include compositions containing pharma- ceutically acceptable carriers. The term "pharma- ceutically acceptable carriers" or "pharma- ceutically acceptable excipients" includes 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 pharma- ceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants as commonly used in the art may be included. Considerations for the inclusion of various ingredients 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.

[0128] Some examples of substances which can serve as pharma- ceutically acceptable carriers or components thereof are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and 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; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0129] The choice of a pharma- ceutically acceptable carrier to be used in conjunction with a subject compound is basically determined by the way the compound is to be administered.

[0130] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound that is suitable for administration to an animal, preferably a mammalian subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of treatment. Such dosage forms are contemplated to be administered once, twice, three or more times per day, can be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be given more than once during a course of treatment, although single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate an entire course of treatment, and such a decision is left to the skilled artisan of treatment rather than formulation.

[0131] The compositions useful as described above 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 compositions may be in a form suitable for subcutaneous administration. The skilled artisan will recognize that oral and nasal compositions include compositions administered by inhalation and made 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, surface active agents, and encapsulating materials. 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 a practical amount of material 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, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker & Rhodes ed., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0132] 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, flavorings, flow inducers, and melting agents, and may be compressed, tablet powder, enteric coated, sugar coated, film coated, or multiple 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, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavoring agents.

[0133] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharma- ceutically compatible adjuvants such as inert diluents, e.g., calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders, e.g., starch, gelatin and sucrose; disintegrants, e.g., starch, alginic acid and croscarmellose; lubricants, e.g., magnesium stearate, stearic acid and talc. Glidants, e.g., silicon dioxide, can be used to improve the flow characteristics of powder mixtures. Coloring agents, e.g., FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, e.g., aspartame, saccharin, menthol, peppermint and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically contain one or more solid diluents as disclosed above. The selection of carrier components depends on secondary considerations, such as taste, cost and storage stability, and is not critical and can be easily made by those skilled in the art.

[0134] Oral compositions also include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, flavorings and colorings disclosed above.

[0135] These compositions can also be coated by conventional methods, typically using pH or time dependent coatings, so that the compound of interest is released in the vicinity of the desired local application or at various times in the gastrointestinal tract to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coating, wax and shellac.

[0136] The compositions described herein can optionally include other pharmaceutical actives.

[0137] Other compositions that are useful for achieving systemic delivery of the target compound include sublingual, buccal and nasal dosage forms.These compositions typically comprise soluble filler material, such as sucrose, sorbitol and mannitol; and binder, such as one or more of acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.They can also comprise the glidant, lubricant, sweetener, colorant, antioxidant and flavoring agent disclosed above.

[0138] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered locally to the eye. Comfort should be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. In cases where comfort cannot be maximized, the liquid should be formulated so that the liquid is tolerable to patients for topical ophthalmic use. In addition, ophthalmically acceptable liquids should either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0139] For ophthalmic use, solutions or medicaments are often prepared using physiological saline solution as the primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. The formulations may also contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0140] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0141] Tonicity adjusters can be added where necessary or convenient, including, but not limited to, salts, especially sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0142] Various buffers and means for adjusting pH can be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases can be used to adjust the pH of these formulations when necessary.

[0143] Similarly, ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0144] Another vehicle component that can be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents can be used as appropriate or in conjunction therewith.

[0145] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0146] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. 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, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, 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 pp. 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 pp. 287-332, both of which are incorporated herein by reference in their entireties. Antimicrobial agents may 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.

[0147] Compositions for intravenous administration can be provided to the caregiver in one or more solid forms that are reconstituted with an appropriate diluent, such as sterile water, saline, or dextrose in water, immediately prior to administration. In other embodiments, the compositions are provided in a solution that is ready to be administered parenterally. In yet other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments involving administering a combination of a compound described herein and another agent, 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.

[0148] The actual dose of the active compounds described herein will depend on the particular compound and the condition being treated; selection of the appropriate dose is well within the knowledge of the skilled artisan.

[0149] The compounds and compositions described herein can be present in a pack or dispenser device, if desired, which contains one or more unit dosage forms containing the active ingredient. Such a pack or device can include, for example, metal or plastic foil, such as blister pack, or glass and rubber stopper in vial. The pack or dispenser device can be accompanied by instructions for administration. The compounds and compositions described herein can be formulated in a compatible pharmaceutical carrier, and can be prepared for the treatment of the indicated pathology, placed in a suitable container, and labeled.

[0150] 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 about 0.0199.99wt% of the compound of the present technology based on the total formulation on a weight percent (wt%) basis, and the remainder is one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 180wt%.Representative pharmaceutical formulations are described below.

[0151] Formulation Examples The following are representative pharmaceutical formulations containing a compound of Formula I.

[0152] Formulation Example 1--Tablet Formulation The following ingredients are intimately mixed and compressed into single scored tablets:

[0153] [Table 1]

[0154] Formulation Example 2--Capsule Formulation The following ingredients are intimately mixed and loaded into a hard shell gelatin capsule:

[0155] [Table 2]

[0156] Formulation Example 3--Suspension Formulation The following ingredients are mixed to form a suspension for oral administration:

[0157] [Table 3]

[0158] Formulation Example 4--Injectable Formulation The following ingredients are mixed to form an injectable formulation:

[0159] [Table 4]

[0160] Formulation Example 5--Suppository Formulation Suppositories with a total mass of 2.5 g are prepared by mixing the compound of the present technology with Witepsol® H-15 (triglyceride of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and have the following composition:

[0161] [Table 5]

[0162] Treatment Method The compounds disclosed herein or their tautomers and / or pharma- ceutically acceptable salts can effectively act as GIP / GLP1 dual receptor agonists. Some embodiments provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharma- ceutically acceptable excipient.

[0163] Some embodiments provide a method for preventing, treating or ameliorating one or more fatty liver diseases in a subject.In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0164] Some embodiments provide a method for preventing, treating or ameliorating steatosis, nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0165] In some embodiments, the method of administering one or more of the compounds disclosed herein results in the prevention, treatment, or amelioration of fibrosis, a fibrotic condition, or a fibrotic symptom, hi some embodiments, the method comprises administering one or more of the compounds disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0166] In some embodiments, the compounds and compositions comprising the compounds described herein can be used to treat a host of pathologies, including those resulting from fibrosis or inflammation and specifically associated with myofibroblast differentiation. Exemplary pathologies include progressive liver fibrosis (alcoholic, viral, autoimmune, metabolic and genetic chronic diseases), renal fibrosis (e.g., due to chronic inflammation, infection or type II diabetes), pulmonary fibrosis (idiopathic or due to environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, drugs, etc.), interstitial fibrosis, systemic sclerosis (an autoimmune disease in which many organs become fibrotic), macular degeneration (a fibrotic disease of the eye), pancreatic fibrosis (e.g., due to alcohol abuse and chronic inflammatory diseases of the pancreas), splenic fibrosis ( sickle cell anemia, from other blood disorders), cardiac fibrosis (due to infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, diabetic nephropathy, nonalcoholic steatohepatitis, primary sclerosing cholangitis, corneal fibrosis, liver cirrhosis, fibrotic complications of surgery, chronic allograft vasculopathy and / or chronic rejection in transplanted organs, ischemia-reperfusion injury associated fibrosis, injection fibrosis, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome, and rheumatoid arthritis diseases or disorders.

[0167] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a reduction in the amount of extracellular matrix protein present in one or more tissues of the subject. In some embodiments, the method comprises administering one or more of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0168] In some embodiments, the method of administering one or more of the compounds disclosed herein causes the amount of collagen present in one or more tissues of the subject to be reduced.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein.

[0169] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a reduction in the amount of collagen type I, type Ia or type III present in one or more tissues of the subject.In some embodiments, the method comprises administering one or more of the compounds disclosed herein or their pharma- ceutically acceptable salts.

[0170] Some embodiments provide a method for preventing, treating or ameliorating one or more of liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic fatty liver disease, nonalcoholic 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 compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0171] Some embodiments provide a method for preventing, treating or ameliorating one or more of non-alcoholic fatty liver disease, 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 compounds disclosed herein to a subject in need thereof.In some embodiments, the method comprises administering one or more of the pharmacologic acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0172] Some embodiments provide a method for preventing, treating or ameliorating one or more metabolic disorders or metabolic syndromes. In some embodiments, the disease or disorder is atherosclerosis, diabetes, hyperglycemic diabetes, type 2 diabetes mellitus, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertension, hypoglycemia, obesity, or Prader-Willi syndrome. In some embodiments, the method comprises administering one or more of the compounds disclosed herein to a subject in need thereof. In some embodiments, the method comprises administering one or more of the pharma- ceutically acceptable salts of the compounds disclosed herein to a subject in need thereof.

[0173] In some embodiments, the method of administering one or more of the compounds disclosed herein results in a compound that activates the glucose-dependent insulinotropic polypeptide (GIP) receptor. In some embodiments, the method of administering one or more of the compounds disclosed herein results in a compound that activates the glucagon-like peptide-1 (GLP-1) receptor. In some embodiments, the method of administering one or more of the compounds disclosed herein results in a compound that activates the GIP receptor and the GLP-1 receptor.

[0174] Some embodiments include co-administration of the compounds, compositions and / or pharmaceutical compositions described herein with additional pharmaceutical agents. By "co-administration" it is meant that two or more pharmaceutical 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 pharmaceutical agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the pharmaceutical agents in a single dosage form. In another embodiment, the pharmaceutical agents are administered sequentially. In one embodiment, the pharmaceutical agents are administered via the same route, e.g., orally. In another embodiment, the pharmaceutical agents are administered via different routes, e.g., one is administered subcutaneously, another is administered orally, and another is administered iv.

[0175] The following examples are included to further illustrate this invention. The examples should not be interpreted as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the knowledge of a person skilled in the art and are considered to fall within the scope of the present invention as described and claimed herein. The reader will recognize that a skilled artisan equipped with this disclosure and the skills in the art can prepare and use the present invention without using the exhaustive examples. The following examples further describe the present invention and are used for illustrative purposes only and should not be interpreted as limiting. EXAMPLES

[0176] General Procedure It is clear to the skilled artisan that the 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 themselves known to those skilled in the art, but are not described in more detail.Given the literature and this disclosure, the skilled artisan is fully equipped to prepare any of the compounds.

[0177] It will be recognized that those skilled in the art of organic chemistry can readily perform the manipulations without further instruction, i.e., it is well within the scope and practice of the skilled artisan to perform these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic, etherification, esterification, and saponification, etc. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry, which are incorporated herein by reference in their entirety. All intermediate compounds of the present invention were used without further purification unless otherwise specified.

[0178] The skilled artisan will readily recognize that certain reactions are best performed when other functional groups are masked or protected in the molecule, thus avoiding any undesired side reactions and / or increasing the yield of the reaction. Often, the skilled artisan will utilize protecting groups to achieve such increased yields or avoid undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Many examples of these manipulations can be found, for example, in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Edition, John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

[0179] The following example schemes are provided for the reader's guidance and represent preferred methods for making the compounds illustrated herein. It is clear that these methods are not limiting and other routes can be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. The skilled artisan is fully equipped to prepare these compounds by the methods as provided in the literature and in this disclosure. The compound numbering used in the synthetic schemes illustrated below is only meaningful for those specific schemes and should not be interpreted or confused with the same numbering in other sections of this application.

[0180] The trademarks used herein are only examples and reflect exemplary materials used at the time of the present invention. A skilled artisan will recognize that variations in lots, manufacturing processes, etc. are expected. Therefore, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but merely illustrative of how a skilled artisan may select to perform one or more of the embodiments of the present invention.

[0181] The following abbreviations have the indicated meanings: Aib = aminoisobutyric acid Bn=benzyl Boc = tert-butoxycarbonyl Bu = butyl DMF = Dimethylformamide EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et = ethyl HATU = Hexafluorophosphate azabenzotriazole tetramethyluranium HBTU = hexafluorophosphate benzotriazole tetramethyluranium HMDS = hexamethyldisilazane HPLC = High Performance Liquid Chromatography Me = methyl NaHMDS = sodium hexamethyldisilazide NMR=nuclear magnetic resonance PCC = pyridinium chlorochromate PEG = polyethylene glycol Ph = phenyl tBu = tert-butyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMS = trimethylsilyl

[0182] The following example schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds provided herein. Additionally, 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.

[0183] 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 one equivalent of NaHMDS to generate the 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 mild base to form the phosphonate. Hydrolysis of the methyl carboxylate provides the desired INT 1 with a terminal carboxylic acid and dibenzyl phosphonate.

[0184] [ka]

[0185] Synthesis of Intermediate 2 (INT 2) The docosanedioic acid is coupled to benzyl alcohol using EDC·HCl and DMAP in THF to give INT 2 as the monobenzyl ester.

[0186] [ka]

[0187] Synthesis of intermediate 3 (INT 3) t-Butyl 4-hydroxybutanoate undergoes Swern oxidation to give the aldehyde. The aldehyde is condensed with (R)-1-amino-2-methoxy-1-phenylethane to form the imine. Addition of the lithium salt of diethyl phosphite in THF generates the α-aminophosphonate, which undergoes hydrogenolysis to cleave the N-alkyl group and provide INT 3 with a free primary amine, t-butyl ester, and phosphonic acid diethyl ester. The optical purity of INT 3 was confirmed to be at least 96% by 1H NMR via Mosher amide analysis.

[0188] [ka]

[0189] Synthesis of intermediate 4 (INT 4) INT 1 is coupled with 1-t-butyl ester of D-glutamic acid in the presence of HATU and triethylamine in DMF to provide INT 4.

[0190] [ka]

[0191] Synthesis of Intermediate 5 (INT 5) INT 2 is coupled with INT 3 in the presence of HATU and triethylamine in DMF to prepare the new amide linkage. Cleavage of the phosphonic acid ethyl ester with TMS-Br gives the free phosphonic acid. Re-esterification with a large excess of the benzyl ester of N,N'-diisopropylcarbamimic acid provides the corresponding dibenzyl phosphonate. The t-butyl ester is cleaved with TFA to provide INT 5.

[0192] [ka]

[0193] Synthesis of intermediate 6 (INT 6) INT 1 is coupled with INT 3 in the presence of HATU and triethylamine in DMF to provide the new amide linkage. Cleavage of the benzyl and phosphonic acid ethyl esters with TMS-Br gives both free phosphonic acids. Re-esterification with a large excess of the benzyl ester of N,N'-diisopropylcarbamimic acid provides the corresponding tetrabenzyl diphosphonate ester. The t-butyl ester is cleaved with TFA to give INT 6.

[0194] [ka]

[0195] Example 2 Synthesis of the common peptide backbone The 39-amino acid peptide backbone is constructed using solid-phase peptide synthesis techniques using diimide, HATU or HBTU activation for amide linkage synthesis on Rink resin. Reagent selection varies based on the identity of the amino acid being connected. The R-group of lysine-19 is linked to two PEG 2 Extended with an amide linker. The entire scaffold is synthesized on resin prior to coupling of INT 4, INT 5 or INT 6 to the amino terminus of the lysine-linked linker.

[0196] [ka]

[0197] Example 3 Synthesis of compound 4 The peptide backbone is coupled to INT 4 to give resin-bound protected compound 4. Cleavage of the resin, the protecting groups on the peptide chain, and the benzyl ester of INT 4 using TFA provides compound 4, which is purified via HPLC.

[0198] [ka]

[0199] Example 4 Synthesis of compound 8 The peptide backbone is coupled to INT 5 to give resin-bound protected compound 8. Cleavage of the resin, the protecting groups on the peptide chain, and the benzyl ester of INT 4 using TFA provides compound 8, which is purified via HPLC.

[0200] [ka]

[0201] Example 5 Synthesis of compound 12 The peptide backbone is coupled to INT 6 to give resin-bound protected compound 12. Cleavage of the resin, the protecting groups on the peptide chain, and the benzyl ester of INT 4 using TFA provides compound 12, which is purified via HPLC.

[0202] [ka]

[0203] Example 6 In vitro GLP-1 and GIP binding activity Binding data for tirzepatide, Compound 4, Compound 8 and Compound 12 were obtained for two human recombinant G protein-coupled receptors, GLP-1 and GIP, using the TagLite® binding assay and Epics Therapeutics cell lines. The agonist activity of the test compounds was measured by their IC as shown in Table 1. 100 The activity is expressed as a percentage of the reference agonist at that concentration.

[0204] [Table 6]

[0205] Example 7 Biological effects of compounds in mice NASH was induced in mice by feeding them the Gubra Amylin NASH (GAN) diet as described in Boland et al., World J Gastroenterol, 2019, 25(33):4904-4920. One week prior to administration of the first dose of compound, mice were weighed and randomized and their food intake was measured. Mice were randomly assigned to dosing groups, with 12 mice per group. The assigned dose groups were: tirzepatide (10 mg / kg); compound 4 (10 mg / kg); compound 8 (10 mg / kg); compound 12 (10 mg / kg); one group was mock-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).

[0206] After 2 weeks, 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 mass was determined as a percentage of body weight, and total liver biochemistry was assayed, including total liver triglycerides, plasma insulin, and total liver cholesterol, as well as histological evaluation of galectin-3 and alpha-smooth muscle actin.

[0207] Liver triglyceride (TG) levels are shown in Table 2 (Table 7). The data show that administration of Compound 4, Compound 8 or Compound 12 resulted in lower relative and total liver triglycerides when compared to administration of tirzepatide or vehicle alone. Liver galectin-3 (Gal-3) levels as determined by histological quantitative assessment are shown in Table 2 (Table 7). The data show that administration of Compound 4, Compound 8 or Compound 12 resulted in lower relative and total liver galectin-3 when compared to administration of tirzepatide or vehicle alone. Alpha-smooth muscle actin (α-SMA) levels as determined by histological quantitative assessment are shown in Table 2 (Table 7). The data show 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 tirzepatide.

[0208] [Table 7]

[0209] Example 8 HSA-modulated in vitro GLP-1 and GIP binding activity The binding assay of Example 6 was repeated for compounds tirzepatide (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 with 2% HSA to compound-receptor binding with 0% HSA is listed in Table 3 (Table 8). Tirzepatide has HSA ratios of 12.8 and 5.82 for GLP-1 receptor and GIP receptor, respectively. Compound 4 has HSA ratios of 6.42 and 1.25 for GLP-1 receptor and GIP receptor, respectively. Compound 12 has HSA ratios of 5.26 and 1.70 for GLP-1 receptor and GIP receptor, respectively. When compared with compound 4 and compound 12, the larger HSA ratio of tirzepatide indicates that the binding affinity of tirzepatide to albumin is greater than that of compound 4 or compound 12.

[0210] [Table 8]

[0211] Example 9 Pharmacokinetics of compounds in monkeys Male cynomolgus monkeys were used to subcutaneously (SC) administer compounds in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline solution.The assigned dose groups were: tirzepatide (0.2mg / kg); Compound 4 (0.2mg / kg); Compound 12 (0.2mg / kg).Samples were obtained 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours, 192 hours, 240 hours and 336 hours after administration of a single dose.

[0212] The mean half-life values ​​are shown in Table 4. The data show that administration of Compound 4 or Compound 12 resulted in significantly greater persistence in the bloodstream compared to administration of tirzepatide. The mean half-life of Compound 4 is nearly two times longer compared to tirzepatide.

[0213] [Table 9]

[0214] In previous studies, a direct correlation between albumin binding affinity and in vivo half-life was observed; compounds with longer half-life exhibited higher albumin binding affinity. (Lau, J. et al., J. Med. Chem. 2015, 58, 7370-7380). As described above, the experiment in Example 8 showed that the binding affinity of tirzepatide to albumin is higher than that of compound 4 or compound 12. In contrast, the pharmacokinetic experiment described in this example determined the half-lives of tirzepatide, compound 4 and compound 12 to be 63.2 hours, 118 hours and 104 hours, respectively. The longer half-life of compound 4 and compound 12 compared to tirzepatide is an unexpected result in view of previous studies. The smaller HSA ratios of Compound 4 and Compound 12 indicate that Compound 4 and Compound 12 are expected to have lower albumin binding affinity and shorter half-life relative to Tirzepatide. The longer half-life for Compound 4 or Compound 12 relative to Tirzepatide is the opposite of the expected result.

[0215] Example 10 Pharmacokinetic studies of formulations The SC dosing experiment described in Example 9 was repeated using different formulations of tirzepatide and Compound 4. Formulation 1 contains the compound in a vehicle of 0.1% bovine serum albumin in phosphate buffered saline solution. Formulation 2 contains the compound in 40% propylene glycol and 60% 10 mM pH 6 citrate buffer solution. Assigned dose groups were administered tirzepatide (0.2 mg / kg) or Compound 4 (0.2 mg / kg) over 21 days.

[0216] The mean half-life values ​​for the two formulations are shown in Table 5. The data show that administration of compound 4 in formulations 1 and 2 resulted in significantly greater persistence in the bloodstream when compared to administration of tirzepatide in the same formulation. The mean half-life of compound 4 in formulation 1 was nearly twice as long as that of tirzepatide. Formulation 2 resulted in a mean half-life of compound 4 that was twice as long as that of tirzepatide.

[0217] [Table 10]

[0218] The unexpected results described in Example 9 were also observed in this example when the compound was administered in Formulation 1 and Formulation 2. The longer half-life in Formulation 1 and Formulation 2 for Compound 4 relative to tirzepatide is the opposite of the expected results in light of the HSA studies described above.

[0219] Example 11 Compound solubility A 50 mM phosphate buffer was prepared according to the United States Pharmacopeia (USP) guidelines. A 1000 mL solution was prepared by diluting a mass of 27.22 g of potassium phosphate monobasic with water. A volume of 250 mL of potassium phosphate monobasic solution and a volume of 22.4 mL of 1 M NaOH solution were diluted to 1000 mL with water. The pH of the resulting buffer solution was measured to be 6.83. Solubility studies were performed at ambient conditions and were designed to prepare solutions with a maximum concentration of approximately 20 mg / mL. An initial volume of 100 μL of buffer was added to approximately 1-4 mg samples of tirzepatide (TRZ), compound 4, compound 8, and compound 12, followed by swirling or vortex mixing. Additional buffer was added in increments of less than 1 mL up to approximately 200 mL. Quantitative solubility (QNT) was reported in mg / mL. Qualitative solubility (QLT) based on visual observation was described using the USP protocol. The results are listed in Table 6.

[0220] [Table 11]

[0221] Unlike TRZ, compounds 4 and 12 were observed to be completely soluble, with compound 12 being quantitatively more soluble than TRZ.

[0222] Although some embodiments have been illustrated and described, a person of ordinary skill in the art, after reading the foregoing specification, may effect changes, equivalent substitutions, 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 include or incorporate therewith variations or aspects as disclosed with respect to any or all of the other aspects and embodiments.

[0223] The present technology should not be limited in terms of the particular embodiments described herein, which are intended as single illustrations of individual embodiments of the technology. Many modifications and variations of the present technology can be made without departing from the spirit and scope thereof, as will be apparent to those skilled in the art. Functionally equivalent methods 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 should be understood that the present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds, or biological systems, which may of course vary. Moreover, it should be understood that the terminology used herein is for the purpose of describing only particular embodiments, and is not intended to be limiting. Thus, it is intended that the specification be considered as illustrative only, with the breadth, scope, and spirit of the present technology being indicated only by the appended claims, definitions therein, and any equivalents thereof.

[0224] The embodiments illustratively described herein may be suitably practiced without any element(s), limitation(s) not specifically disclosed herein. Thus, for example, the terms "comprise", "include", "contain", etc. shall be read broadly and without limitation. In addition, the terms and expressions used herein are used as descriptive terms and not as limitations, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions 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 the elements as specifically recited, as well as additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0225] In addition, where a feature or aspect of the disclosure is described in terms of a Markush group, one of skill in the art will recognize that the disclosure is also thereby described in terms of any individual member of the Markush group or subgroup of members thereof. Each of the narrower species and subgeneric groupings that fall within the generic disclosure also form part of the technology. This includes the generic description of the technology with any provisos or negative limitations that remove any subject matter from the genus, regardless of whether the omitted material is specifically recited herein.

[0226] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the texts incorporated by reference are excluded to the extent they conflict with definitions in this disclosure.

[0227] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0228] While the present invention has been particularly shown and described with reference to preferred and various alternative embodiments, 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 invention.

[0229] All references, issued patents and patent applications cited within the body of this specification are hereby incorporated by reference in their entirety for all purposes.

[0230] Although the invention has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims

【Request 1】 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof. 【Request 2】 【Chemistry 2】 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof. 【Request 3】 【Chemistry 3】 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof. 【Request 4】 【Chemical 4】 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

5. " * 5. The compound according to claim 1, wherein " designates a chiral carbon having an "S" configuration.

6. " * 5. The compound according to any one of claims 1 to 4, wherein " designates a chiral carbon having an "R" configuration.

7. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharma- ceutically acceptable excipient.

8. 10. A pharmaceutical composition for preventing, treating or ameliorating one or more fatty liver diseases in a subject, comprising a compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof.

9. 9. The pharmaceutical composition of claim 8, wherein the fatty liver disease is selected from the group consisting of steatosis, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.

10. 10. The pharmaceutical composition of claim 8 or 9, wherein administration of the compound results in the prevention, treatment or amelioration of fibrosis, a fibrotic condition or a fibrotic symptom.

11. 11. The pharmaceutical composition of any one of claims 8 to 10, wherein administration of the compound results in a reduction in the amount of extracellular matrix protein present in one or more tissues of the subject.

12. 12. The pharmaceutical composition of any one of claims 8 to 11, wherein administration of the compound results in a reduction in the amount of collagen present in one or more tissues of the subject.

13. 13. The pharmaceutical composition of claim 12, wherein administration of the compound 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.

14. 7. A pharmaceutical composition for preventing, treating or ameliorating one or more diseases or disorders in a subject comprising a compound according to any one of claims 1 to 6, or a pharma- ceutical acceptable salt thereof, wherein the disease or disorder is liver fibrosis, renal fibrosis, biliary fibrosis, pancreatic fibrosis, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis, primary biliary cirrhosis, or idiopathic fibrosis.

15. 15. The pharmaceutical composition of claim 14, 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.

16. 16. The pharmaceutical composition of any one of claims 8 to 15, wherein the compound activates the glucose-dependent insulinotropic polypeptide (GIP) receptor.

17. 16. The pharmaceutical composition of any one of claims 8 to 15, wherein the compound activates the glucagon-like peptide-1 (GLP-1) receptor.

18. 16. The pharmaceutical composition of any one of claims 8 to 15, wherein the compound activates the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor.

19. 19. The pharmaceutical composition of any one of claims 8 to 18, wherein the subject is a mammal.

20. 19. The pharmaceutical composition according to any one of claims 8 to 18, wherein the subject is a human.

21. 21. The pharmaceutical composition of any one of claims 8 to 20, formulated for enteral, intravenous, oral, intraarticular, intramuscular, subcutaneous, intraperitoneal, epidural, transdermal, or transmucosal administration.

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