GIP / GLP1 coagonist compounds

Abstract

This invention provides compounds suitable for oral administration that exhibit agonist activity at GIP and GLP-1 receptors. [Solution] The present invention provides compounds that are active in both the human glucose-dependent insulin-stimulating polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. The present invention also relates to compounds that have a sustained action over a long period of time in each of these receptors. Furthermore, the present invention also relates to compounds that can be administered orally. These compounds may be useful in the treatment of type 2 diabetes mellitus ("T2DM"). These compounds may be useful in the treatment of obesity.

Description

[Technical Field]

[0001] This invention relates to compounds that are active in both the human glucose-dependent insulin-stimulating polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. The invention also relates to compounds that exert a prolonged effect on each of these receptors. Furthermore, the invention relates to compounds that can be administered orally. These compounds may be useful in the treatment of type 2 diabetes mellitus ("T2DM"). These compounds may also be useful in the treatment of obesity. [Background technology]

[0002] Over the past several decades, the prevalence of diabetes has continued to rise. T2DM is the most common form of diabetes, accounting for approximately 90% of all diabetes cases. T2DM is characterized by hyperglycemia, primarily associated with insulin resistance. Current standard treatments for T2DM include dietary restrictions and exercise, oral medications, and injectable hypoglycemic agents, including incretin-based therapies such as GLP-1 receptor agonists. While various GLP-1 receptor agonists are currently available for the treatment of T2DM, currently marketed GLP-1 receptor agonists are generally limited in dosage due to gastrointestinal side effects such as nausea and vomiting. Subcutaneous injection is the most common route of administration for available GLP-1 receptor agonists. If oral medications and incretin-based therapies are insufficient, insulin therapy is considered. Despite the advances in treatment available today, many T2DM patients still fail to achieve their glycemic control targets. When diabetes is left uncontrolled, it can lead to various diseases that contribute to increased morbidity and mortality in patients. Treatment is needed to enable more T2DM patients to achieve their blood glucose treatment goals.

[0003] Obesity is a complex medical disorder that leads to the excessive accumulation of adipose tissue. Today, obesity is a global public health concern associated with undesirable health outcomes and morbidity. Desired treatments for patients with obesity aim to reduce excess weight, improve obesity-related comorbidities, and maintain long-term weight loss. Available treatments for obesity are particularly inadequate for patients with severe obesity. Alternative treatment options are needed to induce therapeutic weight loss in patients requiring such treatment.

[0004] WO2016 / 111971 describes peptides that are said to possess GLP-1 and GIP activity. WO2013 / 164483 also discloses compounds that are said to possess GLP-1 and GIP activity.

[0005] There is a need for T2DM treatments that can provide effective glucose control to a larger proportion of patients requiring such treatment. There is a further need for T2D treatments that can provide effective glucose control and have a favorable side effect profile. There is a need for alternative treatment options to provide therapeutic weight loss to patients requiring treatment. There is a need for alternative treatment options for patients requiring treatment for severe obesity.

[0006] Compounds suitable for oral administration that exhibit agonist activity at GIP and GLP-1 receptors are desired. Compounds that exert long-lasting effects at both GIP and GLP-1 receptors are desirable, as this would reduce the frequency of compound administration. Compounds possessing two acylation modifications in combination with their amino acid sequences are desirable to provide GLP-1 and GIP activity from a single compound. [Overview of the Initiative]

[0007] Therefore, the compound of formula I X1X2EGTX6TSDX 10 X 11 X 12 X 13 LDX 16 X17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30 (Array number 505) (wherein X1 is selected from the group consisting of Y and R1Y, R1 is the Ac modification of the N-terminal amino group, X2 is Aib, X6 is selected from the group consisting of αMeF and αMeF(2F), X 10 is selected from the group consisting of 4Pal, Y, αMeF, αMeF(2F), αMeL, αMeV, Ac4c, Ac5c, Ac6c, Bip, (1Nal), 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ1, X 11 is selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tle, X 12 is selected from the group consisting of I and KZ1, [[ID=四十]]X 13 is selected from the group consisting of αMeL and αMeF, X 16 is Orn, X 17 is selected from the group consisting of Q, I, and KZ1, X 20 is selected from the group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c, X 21 is selected from the group consisting of E, KZ1, G, Orn, and 4Pal, X 22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, (1Nal), 2Nal, αMeF(2F), ChA, Bzt, and αMeF, X 24 Note: Some amino acid abbreviations are enclosed in parentheses in the translation for clarity as they might be less common or need to be distinguished in the context. Also, the original text seems to be a chemical or biological sequence-related description with specific symbols and notations, and the translation attempts to maintain the integrity of the information as accurately as possible.However, selected from the group consisting of D-Glu, E, G, and KZ1, X 25 However, selected from the group consisting of Y, αMeY, αMeF, and KZ1, X 28 However, selected from the group consisting of E, Orn, and KZ1, X 30 However, it is selected from the group consisting of G, Orn, KZ1, K(Z1)R6, OrnR2, and GR2. R2, X 31 , X 31 SSG (Sequence ID 5), X 31 SSG-R3 (Sequence ID 6), X 31 SSG 35 PPPX 39 (Sequence ID 7), X 31 SSG 35 PPPX 39 R3 (Sequence ID 8), X 31 SSG 35 PPPX 39 X 40 (Sequence ID 9), X 31 SSG 35 PPPX 39 X 40 Selected from the group consisting of R3 (SEQ ID NO: 10) and modifications of the c-terminal group, the modification is NH2. R6 is PSSG (sequence number 506), PSSG-R3 (sequence number 507), PSSGX 35 PPPX 39 (Sequence ID 508), PSSGX 35 PPPX 39 R3 (Sequence ID 509), PSSGX 35 PPPX 39 X 40 (Sequence ID 510), PSSGX 35 PPPX 39 X 40 Selected from the group consisting of R3 (SEQ ID NO: 511) and modifications of the c-terminal group, the modification is NH2. X 31 However, selected from the group consisting of P and KZ1, X 35 However, selected from the group consisting of A and Orn, X39 However, selected from the group consisting of S and Orn, X 40 However, it is a KZ1, R3 is a modification of the C-terminal group, and the modification is NH2. X 10 , X 12 , X 17 , X 21 , X 24 , X 25 , X 28 , X 30 , X 31 , and X 40 Of these, two and only two are KZ1 or K(Z1)R6. Z1 is selected from the group consisting of R5 and -R4R5. R4 is the linker, R5 is a fatty acid), or The pharmaceutically acceptable salt is provided. Compounds of formula II: X1X2EGTX6TSDX 10 X 11 X 12 X 13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30 (Sequence No. 4) (In the formula, X1 is selected from the group consisting of Y and R1Y. R1 is the Ac modification of the N-terminal amino group. X2 is Aib, X6 is selected from the group consisting of αMeF and αMeF(2F), X 10 However, selected from the group consisting of 4Pal, Y, αMeF, αMeF(2F), αMeL, αMeV, Ac4c, Ac5c, Ac6c, Bip, 1Nal, 2Nal, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ1, X11 is selected from the group consisting of Ac5c, S, αMeS, Aib, G, Dap, and Tle, X 12 is selected from the group consisting of I and KZ1, X 13 is selected from the group consisting of αMeL and αMeF, X 16 is Orn, X 17 is selected from the group consisting of Q, I, and KZ1, X 20 is selected from the group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c, X 21 is selected from the group consisting of E, KZ1, G, Orn, and 4Pal, X 22 is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, 1Nal, 2Nal, αMeF(2F), ChA, Bzt, and αMeF, X 24 is selected from the group consisting of D-Glu, E, G, and KZ1, X 25 is selected from the group consisting of Y, αMeY, αMeF, and KZ1, X 28 is selected from the group consisting of E, Orn, and KZ1, X 30 is selected from the group consisting of G, Orn, KZ1, and GR2, R2 is X 31 SSG (SEQ ID NO: ⑤), X 31 SSG-R3 (SEQ ID NO: ⑥), X 31 SSGX 35 PPPX 39 (SEQ ID NO: ⑦), X 31 SSGX 35 PPPX 39 R3 (SEQ ID NO: ⑧), X 31 SSGX 35 PPPX 39 X 40 (SEQ ID NO: ⑨), X 31 SSGX 35 PPPX39 X 40 Selected from the group consisting of R3 (SEQ ID NO: 10) and modifications of the c-terminal group, the modification is NH2. X 31 However, selected from the group consisting of P and KZ1, X 35 However, selected from the group consisting of A and Orn, X 39 However, selected from the group consisting of S and Orn, X 40 However, it is a KZ1, R3 is a modification of the C-terminal group, and the modification is NH2. X 10 , X 12 , X 17 , X 21 , X 24 , X 25 , X 28 , X 30 , X 31 , and X 40 Of these, two and only two are KZ1. Z1 is selected from the group consisting of R5 and -R4R5. R4 is the linker, R5 is a fatty acid), or The pharmaceutically acceptable salt is provided.

[0008] The Z1 -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2) 12-CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 12 -CO2H, -(εK)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(7-(4-carboxyphenoxy)heptanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(8-(4-carboxyphenoxy)octanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(11-(4-carboxyphenoxy)undecanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)2-CO-(CH2) 12 -CO2H, -PEG3-(γ-Glu)-CO-(CH2) 12 -CO2H, -PEG4-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(11-(4-carboxyphenoxy)undecanoyl, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 14 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Ahx-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-(γ-Glu)-CO-(CH2) 12 -CO2H, -Ahx-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -Aoc-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Ahx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -Ahx-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -Aoc-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG4-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG3-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-Aoc-CO-(CH2) 12 -CO2H, -PEG6-(γ-Glu)-CO-(CH2) 12 -CO2H, -PEG5-(γ-Glu)-CO-(CH2) 12 -CO2H, -PEG6-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG5-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-Trx-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-Trx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Trx-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Trx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)2-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)2-(10-(4-carboxyphenoxy)decanoyl), -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, and A peptide of formula I, or a pharmaceutically acceptable salt thereof, is provided, selected from the group consisting of -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl).

[0009] The Z1 -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 10-CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 12 -CO2H, -(εK)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(7-(4-carboxyphenoxy)heptanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(8-(4-carboxyphenoxy)octanoyl), and A peptide of formula I, or a pharmaceutically acceptable salt thereof, is provided, selected from the group consisting of -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl).

[0010] The Z1 -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2) 10 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-CO-(CH2) 14 -CH3, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 12 -CO2H, -(εK)-(εK)-(γ-Glu)-CO-(CH2) 12 -CO2H, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH2) 12 -CO2H, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(7-(4-carboxyphenoxy)heptanoyl), -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(8-(4-carboxyphenoxy)octanoyl), and A peptide of formula I, or a pharmaceutically acceptable salt thereof, is provided, selected from the group consisting of -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl).

[0011] R5 -CO-(CH2) 12 -CO2H, -CO-(CH2) 10-CO2H, -(10-(4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), -(4-(4-tert-butylphenyl)butanoyl), -CO-(CH2) 14 -CH3, -CO-(CH2) 12 -CH3, -CO-(CH2) 10 -CH3, -(7-(4-carboxyphenoxy)heptanoyl), -(8-(4-carboxyphenoxy)octanoyl), (11-(4-carboxyphenoxy)undecanoyl), -(12-(4-carboxyphenoxy)dodecanoyl), and CO-(CH2) 14 A compound of formula I, or a pharmaceutically acceptable salt thereof, is provided, selected from the group consisting of -CO2H.

[0012] R5 -CO-(CH2) 12 -CO2H, -CO-(CH2) 10 -CO2H, -(10-(4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), -(4-(4-tert-butylphenyl)butanoyl), -CO-(CH2) 14 -CH3, -CO-(CH2) 12 -CH3, -CO-(CH2) 10 Compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, selected from the group consisting of -CH3, -(7-(4-carboxyphenoxy)heptanoyl), and -(8-(4-carboxyphenoxy)octanoyl).

[0013] R4 -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)2)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Trx-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-Trx-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-Aoc-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Aoc-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Ahx-(γ-Glu)-, -PEG3-(γ-Glu)-, -PEG4-(γ-Glu)-, -PEG5-(γ-Glu)-, -PEG6-(γ-Glu)-, -Ahx-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-, -Aoc-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-, -(εK)-(γ-Glu)-, -(εK)-(γ-Glu)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-, -(εK)-(εK)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)2-, and A compound of formula I, or a pharmaceutically acceptable salt thereof, is provided, selected from the group consisting of (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-.

[0014] R4 -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-(γ-Glu)-, -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-, -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-, -(εK)-(γ-Glu)-, -(εK)-(γ-Glu)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-, -(εK)-(εK)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-, and A compound of formula I, or a pharmaceutically acceptable salt thereof, is provided, selected from the group consisting of -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).

[0015] X 17 and X 31 However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1. 17 and X 24 However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1. 17 and X 21 However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1. 17 and X 28 However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1. 17 and X 40 However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1. 21 and X 40 However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1. 21 and X 28 However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1. 24 and X 28However, compounds of formula I, or pharmaceutically acceptable salts thereof, are provided, each being KZ1.

[0016] A compound of formula I or a pharmaceutically acceptable salt thereof, (wherein X1 is Y, X6 is αMeF(2F), X 10 However, selected from the group consisting of 4Pal, Y, and KZ1, X 11 However, selected from the group consisting of S, αMeS, and Aib, X 12 However, I is X 13 However, it is αMeL, and X 16 However, it is Orn, and X 17 However, selected from the group consisting of I and KZ1, X 20 However, Aib and X 21 However, selected from the group consisting of KZ1 and E, X 22 However, selected from the group consisting of F and αMeF, X 24 However, selected from the group consisting of D-Glu and KZ1, X 25 However, it is αMeY, and X 28 However, selected from the group consisting of E and KZ1, X 30 However, a group consisting of G and GR2 is selected, and R2 is X 31 SSG 35 PPPX 39 (Sequence ID 7), X 31 SSG 35 PPPX 39 R3 (sequence number 8), and X 31 SSG 35 PPPX 39 X 40 Selected from the group consisting of (SEQ ID NO: 9) and modifications of the c-terminal group, wherein the modification is NH2 and X 31 However, selected from the group consisting of P and KZ1, X 35 However, selected from the group consisting of A and Orn, X 39 However, selected from the group consisting of S and Orn, X 40 However, selected from the group consisting of KZ1, R3 is a modification of the C-terminal group, the modification is NH2, and X 10 , X 17 , X 21 , X 24 , X 28, and X 31 A group consisting of (one and only one of which is KZ1, where Z1 is -R4R5, where R4 is a linker, and R5 is a fatty acid) is provided, or a pharmaceutically acceptable salt thereof.

[0017] The compound, Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H)SSGAPPPS-NH2, Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))SSGAPPPS-NH2, Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))SSGAPPPS-NH2, Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))SSGAPPPS-NH2, and Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 A compound of formula I, or a pharmaceutically acceptable salt thereof, is provided, selected from the group consisting of -CH3)SSGAPPPS-NH2.

[0018] In one embodiment, the R4 linker is one to two amino acids selected from the group consisting of εK and γ-Glu. In one embodiment, the R4 linker contains one to three (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. In one embodiment, the R5 fatty acid moiety is conjugated to lysine via an R4 linker between lysine and the R5 fatty acid.

[0019] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the R4 linker comprises 0 to 4 amino acids and 0 to 3 (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. In one embodiment, the R4 linker comprises 1 to 3 amino acids independently selected from the group consisting of εK and γ-Glu. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the R4 linker comprises 1 to 2 amino acids independently selected from the group consisting of εK and γ-Glu. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof comprises two Z1 fatty acid moieties, where each R5 fatty acid of the Z1 moieties is conjugated to a different lysine of the peptide via the R4 linker, and the R4 linker comprises 0 to 2 γ-Glu amino acid residues. In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two Z1 fatty acid moieties, where each R5 fatty acid of Z1 is conjugated to a different lysine of the peptide via an R4 linker, and R4 comprises 1 to 3 amino acids and 1 to 3 (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties, where each R5 fatty acid of Z1 is conjugated to a different lysine of the peptide via an R4 linker, and R4 comprises 1 to 3 εK and

number

[0020] In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties, wherein the R5 fatty acids of Z1 are conjugated via R4 linkers, and the R4 linkers have the following formula: -(εK) a1 -(γ-Glu) a2 -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a3 -(εK) b1 -(γ-Glu) b2 -, In the formula, a1 is selected from the group consisting of 0, 1, and 2, a2 ​​is selected from the group consisting of 0, 1, and 2, a3 is selected from the group consisting of 0, 1, 2, and 3, b1 is 0 or 1, and b2 is 0 or 1. In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties, the R5 fatty acids of Z1 are conjugated via R4 linkers, and Z1 is of formula: -(εK) a1 -(γ-Glu) a2 -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a3 -(εK) b1 -(γ-Glu) b2 -CO-(CH2) q It contains -CO2H, where a1 is selected from the group consisting of 0, 1, and 2, a2 ​​is selected from the group consisting of 0, 1, and 2, a3 is selected from the group consisting of 0, 1, 2, and 3, b1 is 0 or 1, b2 is 0 or 1, and q is selected from the group consisting of 10, 12, 14, and 16.

[0021] In one embodiment, a1 is 1, a2 is 0, a3 is 2, b1 is 0, b2 is 1, q is 12, and the structure is as follows: -(εK)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H.

[0022] In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties, wherein the R5 fatty acids of Z1 are conjugated via R4 linkers, and the R4 linker and R5 fatty acid component have the following formula: [ka] In the formula, q2 is selected from the group consisting of 7, 8, 10, 11, and 12.

[0023] In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties, wherein the R5 fatty acids of Z1 are conjugated via an R4 linker, and the R5 fatty acids are selected from the group consisting of -(7-(4-carboxyphenoxy)heptanoyl) and -(8-(4-carboxyphenoxy)octanoyl). In another embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties conjugated via an R4 linker, wherein the R5 fatty acids are selected from the group consisting of -(10-(4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), and -(4-(4-tert-butylphenyl)butanoyl).

[0024] In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties conjugated via an R4 linker, and the R5 fatty acid is -CO-(CH2) 14 -CH3, -CO-(CH2) 12 -CH3 and -CO-(CH2) 10 Selected from the group consisting of -CH3.

[0025] In one embodiment, the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises two of the same Z1 fatty acid moieties conjugated via an R4 linker, and the R5 fatty acid is -CO-(CH2) 12 -CO2H and -CO-(CH2) 10Selected from the group consisting of -CO2H. In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, each comprising two of the same Z1 fatty acid moieties conjugated via an R4 linker, wherein the R5 fatty acid is -CO-(CH2) 10 -CH3 and -CO-(CH2) 12 Selected from the group consisting of -CH3.

[0026] In one embodiment, the R5 fatty acid is -CO-(CH2) 12 -CO2H, -CO-(CH2) 10 -CO2H, -(10-(4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), -(4-(4-tert-butylphenyl)butanoyl), -CO-(CH2) 14 -CH3, -CO-(CH2) 12 -CH3, -CO-(CH2) 10 Selected from the group consisting of -CH3, -(7-(4-carboxyphenoxy)heptanoyl), and -(8-(4-carboxyphenoxy)octanoyl).

[0027] One embodiment provides a method for treating a condition selected from the group consisting of T2DM, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome, comprising administering an effective dose of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need. One embodiment provides a method for providing therapeutic weight loss, comprising administering an effective dose of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need. In one embodiment, the condition is NAFLD. In one embodiment, the condition is NASH.

[0028] One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from the group consisting of T2DM, obesity, NAFLD, NASH, dyslipidemia, and metabolic syndrome. In one embodiment, the condition is T2DM. In one embodiment, the condition is obesity. In one embodiment, the condition is NAFLD. In one embodiment, the condition is NASH. In one embodiment, the condition is metabolic syndrome.

[0029] Compounds of formula I, or pharmaceutically acceptable salts thereof, may be useful in treating a variety of symptoms or disorders. For example, in certain embodiments, a method is provided for treating T2DM in a patient, comprising administering an effective amount of compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject requiring such treatment. One embodiment is a method for treating an obese patient, comprising administering an effective amount of compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject requiring such treatment. In one embodiment, the method is an induction of non-therapeutic weight loss in a subject, comprising administering an effective amount of compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject requiring such treatment.

[0030] In certain embodiments, the present invention provides a method for treating metabolic syndrome in a patient, comprising administering an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject requiring such treatment. One embodiment is a treatment for NASH, comprising administering an effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, to a subject requiring treatment.

[0031] Also provided herein are compounds of the present invention for simultaneous, individual, and sequential use in combination with one or more agents selected from metformin, thiazolidinediones, sulfonylurea, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporters, SGLT-2 inhibitors, growth differentiation factor 15 modulators ("GDF15"), peptide tyrosine tyrosine modulators ("PYY"), modified insulin, amylin, dual amylin calcitonin receptor agonists, and oxytomodulin agonists ("OXM") in the treatment of conditions selected from the group consisting of T2DM, obesity, NAFLD, NASH, dyslipidemia, and metabolic syndrome. In one embodiment, the compounds of this specification are provided in combination of a certain dose with one or more agents selected from metformin, thiazolidinediones, sulfonylurea, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporters, SGLT-2 inhibitors, GDF15, PYY, modified insulin, amylin, dual amylin calcitonin receptor agonists, and OXM. In one embodiment, the compounds of the present invention are compounds for simultaneous, individual, or sequential use of one or more agents selected from metformin, thiazolidinediones, sulfonylurea, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporters, SGLT-2 inhibitors, GDF15, PYY, modified insulin, amylin, dual amylin calcitonin receptor agonists, and OXM to treat a condition selected from the group consisting of T2DM and obesity. In one embodiment, the compounds of the present invention are compounds for the simultaneous, individual, or sequential use of one or more agents selected from metformin, thiazolidinediones, sulfonylurea, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporters, and SGLT-2 inhibitors to treat a condition selected from the group consisting of T2DM and obesity.

[0032] In other embodiments, the compounds, or pharmaceutically acceptable salts thereof, may be useful in improving bone strength in a target area of ​​interest. The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be useful in treating other diseases, such as Parkinson's disease or Alzheimer's disease. Incretins and incretin analogs having activity at one or more of the GIP, GLP-1, and / or glucagon receptors have been described as potentially having therapeutic value for many other diseases or conditions, including obesity, NAFLD, NASH, dyslipidemia, metabolic syndrome, bone-related diseases, Alzheimer's disease, and Parkinson's disease. For example, Jall S., et. al, Monomeric GLP-1 / GIP / glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice, MOL.METAB.6(5):440-446 (March 2017), Carbone LJ, et. al., Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis.J.GASTROENTEROL.HEPATOL.,31(1):23-31(Jan.2016), B.Finan,et.al,Reappraisal of GIP Pharmacology for Metabolic Diseases.TRENDS MOL.MED.,22(5):359-76(May 2016),Choi,IY,et al.,Potent body weight loss and efficacy in a NASH animal model by a novel long-acting GLP-1 / Glucagon / GIP triple-agonist(HM15211), ADA 2017 Poster 1139-P, Ding, KH, Impact of glucose-dependent insulinotropic peptide on age-induced bone loss, J.BONE MINER.RES.,23(4):536-43(2008), Tai,J.et.al,Neuroprotective effects of a triple GLP-1 / GIP / glucagon receptor agonist in the APP / PS1 transgenic mouse model of Alzheimer's disease,BRAIN RES.1678,64-74(2018), TDMuller et al.,The New Biology and Pharmacology of Glucagon,PHYSIOL.REV.97:721-766(2017), Finan,B.et.al,Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents,Monkeys,and Humans,SCI.TRANSL.MED.,5:209(October 2013), Holscher C,Insulin, incretins and other growth factors as potential novel treatments for Alzheimer's and Parkinson's diseases. Please refer to BIOCHEM.SOC.TRANS.42(2):593-0 (Apr.2014).

[0033] Another embodiment provides the use of the compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for treating a condition selected from the group consisting of T2DM, obesity, NAFLD, NASH, dyslipidemia, and metabolic syndrome. In one embodiment, the drug is for the treatment of T2DM. In one embodiment, the drug is for the treatment of obesity. In one embodiment, the drug is for the treatment of NAFLD. In one embodiment, the drug is for the treatment of NASH.

[0034] Another embodiment provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of carriers, diluents, and excipients.

[0035] As used herein, the terms “treating” or “to treat” include limiting, slowing, stopping, or reversing the progression or severity of a symptom, condition, or disorder.

[0036] The specific compounds provided herein are generally effective over a wide range of dosages. For example, a once-weekly parenteral dose may range from 0.05 mg to approximately 30 mg per person per week. The compounds provided herein are available orally and can be administered using oral formulation techniques. Oral formulations can be formulated for regular administration, such as once daily.

[0037] The compounds of the present invention contain novel amino acid sequences that have affinity for GLP-1 and GIP receptors, respectively, and exhibit desired efficacy in each of these receptors. GLP-1 is a 36-amino acid peptide, and its main bioactive fragment is a 30-amino acid C-terminally amidated peptide (GLP-1 7-36 It is generated as (sequence number 2).

[0038] GIP, also known as an incretin like GLP-1, is a 42-amino acid peptide (SEQ ID NO: 1) that plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in the presence of glucose.

[0039] These compounds provide desired efficacy to GIP and GLP-1 receptors, respectively. In one embodiment, the compounds are suitable for oral administration. In one embodiment, the compounds have a desiredly long-lasting effect on GIP and GLP receptors. [Modes for carrying out the invention]

[0040] As used herein, “linker” means the group that conjugates the R5 fatty acid to the lysine of the peptide. As used herein, “fatty acid” means a hydrocarbon having a carboxyl group. As used herein, “Ac” means acetyl modification. In one embodiment, the fatty acid is an albumin-binding group. As used herein, the term “amino acid” means both naturally occurring and non-natural amino acids. Amino acids are usually indicated by a standard single-letter code (e.g., L = leucine), and by the alpha-methyl substitution residues of naturally occurring amino acids (e.g., α-methylleucine, or αMeL and α-methyllysine, or αMeK), as well as by alpha-aminoisobutyric acid, or other specific non-natural amino acids such as “Aib,” “4Pal,” and “Orn.” The structures of non-natural amino acids and other abbreviations are shown below: [ka] [ka] [ka]

[0041] As used herein, "Orn" means ornithine. As used herein, "4Pal" means 3-(4-pyridyl)-L-alanine. As used herein, "αMeF(2F)" means alpha-methyl 2-F-phenylalanine, alpha-methyl-F(2F), and alpha-methyl-Phe(2F). As used herein, "αMeY" means alpha-methyltyrosine, alpha-methyl-Tyr, and alpha-methyl-Y. As used herein, "αMeL" means alpha-methylleucine, alpha-methyl-L, and alpha-methyl-Leu. As used herein, "e" and "D-Glu" mean D-glutamic acid. As used herein, "αMeF" means alpha-methyl-F and alpha-methyl-Phe. As used herein, "αMeS" means alpha-methyl-serine, alpha-methyl-S, and alpha-methyl-Ser. As used herein, "AEEA" means (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl), "AEEA2" means (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2, and "AEEA3" means (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)3.

[0042] As used herein, "Ahx" is 6-aminohexanoyl-, "Aoc" is 8-aminooctanoyl-, "PEG3" is [3-(2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy)-propanoyl]-, and "PEG4" is (3-[2-(2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]- "Propanoyl)-" is "PEG5" is [3-(2-[2-(2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-ethoxy)-propanoyl]-" and "PEG6" is (3-[2-(2-[2-(2-[2-(2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy)-ethoxy]-ethoxy)-ethoxy]-propanoyl)-". "Tle" is tert-leucine.

[0043] As shown in the chemical structures of the following examples, in one embodiment, the linker fatty acid moiety (-R5R4) is bonded to the epsilon-amino group of the lysine side chain.

[0044] Where used herein in reference to one or more GIP or GLP-1 receptors, terms such as “activity” and “activation” refer to the binding capacity and response-inducing capacity at the receptor of a compound, or a pharmaceutically acceptable salt thereof, as measured by assays known to those skilled in the art, such as the in vitro assays described below.

[0045] The affinity of the compound of the present invention, or a pharmaceutically acceptable salt thereof, to the GIP receptor and the GLP-1 receptor, respectively, can be measured using receptor binding level measurement techniques known in the art, generally expressed as Ki values, including, for example, the measurement techniques described in the following examples. The activity of the compound of the present invention at each receptor may further be measured using techniques known to those skilled in the art, including, for example, the in vitro activity assay described below, generally EC 50 This is expressed as a value, which is the concentration of the compound that causes a simulation of the maximum half dose in the dose-response curve.

[0046] In one embodiment, the pharmaceutical composition of the compound of formula I is suitable for parenteral administration (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal). In one embodiment, the pharmaceutical composition of the compound of formula I is suitable for oral administration (e.g., tablets, capsules). Several pharmaceutical compositions and processes for their preparation are well known in the art. (See, for example, Remington: The Science and Practice of Pharmacy (DB Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006).

[0047] The compounds provided herein can react with several inorganic and organic acids / bases to form pharmaceutically acceptable acid / base addition salts. Pharmaceutically acceptable salts and general methods for preparing them are well known in the art (see, for example, P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011)). The pharmaceutically acceptable salts of the present invention include, but are not limited to, sodium, trifluoroacetic acid, its hydrochloride, ammonium, and acetate. In one embodiment, the pharmaceutically acceptable salt is selected from the group consisting of sodium, its hydrochloride, and acetate.

[0048] The present invention also encompasses novel intermediates and processes useful for the synthesis of the compounds of the present invention or their pharmaceutically acceptable salts. The intermediates and compounds of the present invention can be prepared by various procedures known in the art. In particular, the following examples describe processes using chemical synthesis. The specific synthesis steps for each of the described routes may be combined in different ways to prepare the compounds of the present invention. The reagents and starting materials are readily available to those skilled in the art.

[0049] As used herein, the term “effective dose” means the amount or dose of the compound provided in the present invention, or a pharmaceutically acceptable salt thereof, that, when administered to a patient once or multiple times, provides the desired effect to a patient undergoing diagnosis or treatment. The effective dose can be determined by those skilled in the art by using known art and by observing results obtained under similar circumstances. In determining the effective dose for a subject, a number of factors are taken into consideration, including but not limited to the species, size, age, and overall health of the mammal, the specific disease or disorder involved, the degree or involvement or severity of the disease or disorder, the individual patient’s response, the specific compound administered, the mode of administration, the bioavailability characteristics of the administered formulation, the chosen administration regimen, the use of concomitant medications, and other relevant circumstances.

[0050] As used herein, the term “subjects requiring it” means mammals, preferably humans, that have a disease or condition requiring treatment or therapy, including, for example, those listed in the paragraph above. As used herein, “EDTA” means ethylenediaminetetraacetic acid. As used herein, “DMSO” means dimethyl sulfoxide. As used herein, “CPM” means counts per minute. As used herein, “IBMX” means 3-isobutyl-1-methylxanthine. As used herein, “LC / MS” means liquid chromatography / mass spectrometry. As used herein, “HTRF” means homogeneous time-resolved fluorescence. As used herein, “BSA” means bovine serum albumin. [Examples]

[0051] The present invention will be further illustrated by the following embodiments, but these embodiments should not be construed as limiting the present invention.

[0052] Peptide synthesis Example 1 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H)SSGAPPPS-NH2 (Sequence ID 11). The structure of Sequence ID No. 11 is shown below using standard single-letter amino acid codes, with the exception of residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, K31, and Ser39, whose structures are extended. [ka]

[0053] The peptide backbone of Example 1 was synthesized using fluorenylmethyloxycarbonyl (Fmoc) / tert-butyl (t-Bu) chemistry in a Symphony multiplex peptide synthesizer (Gyros Protein Technologies, Tucson, AZ).

[0054] The resin consists of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) with a substitution amount of 0.35 mmol / g. Standard side-chain protecting groups were used. Fmoc-Lys(Mtt)-OH was used on lysine residues at positions 17 and 31, and Boc-Tyr(tBu)-OH) was used on the tyrosine residue at position 1. Prior to each coupling step (2 x 7 minutes), the Fmoc group was removed using 20% ​​piperidine in DMF. All standard amino acid couplings were performed for 1 hour using equimolar ratios of Fmoc amino acids (0.3 mM in DMF), diisopropylcarbodiimide (0.9 mM in DMF), and oxima (0.9 mM in DMF) in theoretically 9-fold molar excess relative to the peptide loading. The exception is coupling to Ca-methylated amino acids, which is coupled for 3 hours. After the synthesis of the peptide backbone is complete, the resin is thoroughly washed with DCM to remove residual DMF. The Mtt protecting groups on the lysine residues at positions 17 and 31 are selectively removed from the peptide resin using 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM (treated for 3 × 1 hour), and the resin is thoroughly washed with DCM and DMF.

[0055] Subsequent attachment of the linker moiety is achieved by stepwise coupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.) and Fmoc-glutamic acid at-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.) following the above procedure for standard coupling and deprotection reactions. After the final removal of the Fmoc protecting group, mono-OtBu-tetradecanediic acid (WuXi AppTec, Shanghai, China) is coupled overnight using a 4-fold excess of fatty acid, diisopropylcarbodiimide, and oxima (1:1:1 mol / mol / mol) in 1:1 DCM / DMF. Once the synthesis is complete, the peptide-resin is washed with DCM and then completely dried under vacuum.

[0056] The dried resin was treated with 10 mL of a cutting cocktail (trifluoroacetic acid:water:triisopropylsilane, 95:2.5:2.5 v / v) at room temperature for 2 hours. The resin was filtered off, washed twice with 2 mL of anhydrous T'FA, and the combined filtrate was treated with a 5-fold excess of cold diethyl ether (-20°C) to precipitate the crude peptide. The peptide / ether suspension was then centrifuged at 3500 rpm for 2 minutes to form a solid pellet, the supernatant was drained, the solid pellet was further pulverized twice with ether, and dried in vacuum. The crude peptide was solubilized in 20 mL of 20% acetonitrile / 20% acetic acid / 60% water and purified by RP-HPLC on a SymmetryPrep 7 μm C18 preparative column (19 x 300 mm, Waters) with a linear gradient of 100% acetonitrile and a 0.1% TFA / water buffer system (35-55% acetonitrile in 60 minutes). The purity of the peptide was evaluated using analytical RP-HPLC, with a pooling standard exceeding 95%. The main pool purity of Example 1 was found to be 96.0%. The final main product pool was subsequently lyophilized, resulting in the production of lyophilized peptide TFA salts. The molecular weight was determined by LC-MS (measured: M+3 = 1853.9, calculated: M+3 = 1854.1).

[0057] Example 2 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))SSGAPPPS-NH2(SEQ ID NO: 12) The structure of Sequence ID No. 12 is shown below using standard single-letter amino acid codes, with the exception of the amino acid residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, K31, and Ser39, whose structures are extended: [ka]

[0058] The compound according to Sequence ID No. 12 is prepared substantially as described by the procedure of Example 1, except that tert-butyl 4-(9-carboxy-nonyloxy)benzoate (WuXi AppTec, Shanghai, China) was used in the final coupling step. The molecular weight is determined by LC-MS (measured: M+3=1887.1, calculated: M+3=1887.4).

[0059] Example 3 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))SSGAPPPS-NH2(SEQ ID NO: 13) The structure of Sequence ID No. 13 is shown below using standard single-letter amino acid codes, with the exception of the amino acid residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, K31, and Ser39, whose structures are extended: [ka]

[0060] The compound according to Sequence ID No. 13 is prepared substantially as described by the procedure of Example 1, except that 4-(4-iodophenyl)butyric acid (WuXi AppTec, Shanghai, China) was used in the final coupling step. The molecular weight is determined by LC-MS (measured: M+3=1875.1, calculated: M+3=1875.2).

[0061] Example 4 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))SSGAPPPS-NH2(SEQ ID NO: 14) The structure of Sequence ID No. 14 is shown below using standard single-letter amino acid codes, with the exception of the amino acid residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, K31, and Ser39, whose structures are extended: [ka]

[0062] The compound according to Sequence ID No. 14 is prepared substantially as described by the procedure of Example 1, except that 4-(4-tert-butylphenyl)butyrate (WuXi AppTec, Shanghai, China) was used in the final coupling step. The molecular weight is determined by LC-MS (measured: M+3 = 1828.3, calculated: M+3 = 1828.7).

[0063] Example 5 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3)SSGAPPPS-NH2 (Sequence ID 15). The structure of Sequence ID No. 15 is shown below using standard single-letter amino acid codes, with the exception of the amino acid residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, K31, and Ser39, whose structures are extended: [ka]

[0064] The compound according to Sequence ID No. 15 is prepared substantially as described by the procedure of Example 1, except that lauric acid (Sigma Aldrich) is used in the final coupling step. The molecular weight is determined by LC-MS (measured: M+3 = 1815.1, calculated: M+3 = 1815.4).

[0065] Examples 6 to 211 The compounds according to Examples 6 (SEQ ID NO: 16) to 494 (SEQ ID NO: 504) are prepared substantially according to the procedure described in Example 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

[0066] Binding assay Glucagon (referred to as Gcg) is a standard sample prepared by Eli Lilly and Company. GLP-1,7-36-NH2 (referred to as GLP-1) is obtained from CPC Scientific (Sunnyvale, CA, purity 97.2%, 100 μM aliquot in 100% DMSO). GIP1-42 (referred to as GIP) is prepared at Lilly Research Laboratories using peptide synthesis and HPLC chromatography as described above (purity > 80%, a 100 μM aliquot in 100% DMSO). 125 I] The radiolabeled Gcg, GLP-1, or GIP is 125 I] prepared using lactoperoxidase and obtained from Perkin Elmer (Boston, MA). Stably transfected cell lines are prepared by subcloning the receptor cDNA into the pcDNA3 expression plasmid and transfecting into human embryonic kidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese hamster ovary (CHO) (hGIPR) cells, followed by selection with Geneticin (hGLP-1R and hGIPR) or hygromycin B (hGcgR).

[0067] Two methods are used to prepare crude cell membranes.

[0068] Method 1: Thaw the frozen cell pellet on ice in a hypotonic buffer containing 50 mM Tris HCl at pH 7.5 and Roche Complete® protease inhibitor including EDTA. Stir the cell suspension 25 times using a glass Potter-Elvehjem homogenizer equipped with a Teflon® inner tube. Centrifuge the homogenate at 1100 × g for 10 minutes at 4°C. Collect the supernatant and store it on ice, while resuspending the pellet in homogenizing buffer and rehomogenizing as described above. Centrifuge the homogenate at 1100 × g for 10 minutes. Combine the second supernatant with the first supernatant and centrifuge at 35000 × g at 4°C for 1 hour. Resuspend the resulting membrane pellet in homogenizing buffer containing approximately 1–3 mg / mL of protease inhibitor, rapidly freeze in liquid nitrogen, and store as aliquots in a freezer at -80°C until use.

[0069] Method 2: Thaw the frozen cell pellet on ice in a hypotonic buffer containing 50 mM Tris HCl (pH 7.5), 1 mM MgCl2, Roche Complete® EDTA-free protease inhibitor, and 25 units / ml DNAse I (Invitrogen). Stir the cell suspension 20-25 times using a glass Potter-Elvehjem homogenizer with a Teflon® inner tube. Centrifuge the homogenate at 1800×g for 15 minutes at 4°C. Collect the supernatant and store it on ice, while resuspending the pellet in homogenization buffer (without DNAse I) and rehomogenizing as described above. Centrifuge the homogenate at 1800×g for 15 minutes. Combine the second supernatant with the first supernatant and centrifuge again at 1800×g for 15 minutes. Then centrifuge the entire supernatant at 25000×g for 30 minutes at 4°C. The resulting membrane pellet is resuspended in a homogenized buffer (without DNAse I) containing approximately 1-3 mg / mL of protease inhibitor, and stored as aliquots in a freezer at -80°C until use.

[0070] Connection determination method Equilibrium binding dissociation constants (K) of various receptor / radioligand interactions d )teeth,[ 125 I] Due to the high propanol content of the stock material, the determination is made by homologous competitive binding analysis rather than saturation binding. K was determined for the receptor preparation. d The values ​​were as follows: hGcgR (3.9 nM), hGLP-1R (1.2 nM), and hGIPR (0.14 nM).

[0071] [ 125 I]-glucagon bond A human Gcg receptor binding assay was performed using a scintillation proximity assay (SPA) format with wheat germ agglutinin (WGA) beads (Perkin Elmer). The binding buffer contained 25 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin (Research Products), 0.003% (w / v) polyoxyethylene sorbitan monolaurate (TWEEN®-20), and an EDTA-free Roche Complete® protease inhibitor. The peptide and Gcg were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, transfer 5 μL of serially diluted compound or DMSO to a Corning® 3632 bottom-clear assay plate containing 45 μL of assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, 1 μM final). Then, add 50 μL of [ 125Add 115 nM-Gcg (0.15 nM final), 50 μL of human GcgR membrane (1.5 μg / well), and 50 μL of WGA SPA beads (80–150 μg / well) using a Biotek Multiflo dispenser. Seal the plate, mix on a plate shaker for 1 minute (setting 6), and incubate / stand at room temperature for 12 hours, then read the plate using a PerkinElmer Trilux MicroBeta® scintillation counter. The final assay concentration range of the peptides tested in the response curve is typically 1150 nM–0.058 nM, compared to 1000 nM–0.05 nM for the control Gcg.

[0072] [ 125 I]-GLP-1 binding The human GLP-1 receptor binding assay is performed using an SPA format with WGA beads. The binding buffer contains 25 mM HEPES, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) TWEEN®-20, and EDTA-free Roche Complete® protease inhibitor at pH 7.4. The peptide and GLP-1 are thawed and serially diluted 3-fold with 100% DMSO (10-point concentration response curve). Next, 5 μL of the serially diluted compound or DMSO is transferred to a Corning® 3632 bottom-clear assay plate containing 45 μL of assay binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, 0.25 μM final). Next, 50 μL of [ 125Add 115 nM-GLP-1 (0.15 nM final), 50 μL of human GLP-1R membrane (0.5 μg / well), and 50 μL of WGA SPA beads (100-150 μg / well) using a Biotek Multiflo dispenser. Seal the plate, mix on a plate shaker for 1 minute (setting 6), and incubate / stand at room temperature for 5-12 hours, then read the plate using a PerkinElmer Trilux MicroBeta® scintillation counter. The final assay concentration range of the peptides tested in the response curve is typically 1150 nM-0.058 nM, compared to 250 nM-0.013 nM for control GLP-1.

[0073] [125I]-GIP bond The human GIP receptor binding assay is performed using an SPA format with WGA beads. The binding buffer contains 25 mM HEPES, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) TWEEN®-20, and EDTA-free Roche Complete® protease inhibitor at pH 7.4. The peptide and GIP are thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5 μL of the serially diluted compound or DMSO is transferred to a Corning® 3632 bottom-clear assay plate containing 45 μL of assay binding buffer or unlabeled GIP control (non-specific binding or NSB, 0.25 μM final). Next, 50 μL of [ 125Add 1150-0.058 nM final assay concentration of the tested peptides, 50 μL of human GIPR membrane (3 μg / well), and 50 μL of WGA SPA beads (100-150 μg / well) using a Biotek Multiflo dispenser. Seal the plate, mix on a plate shaker for 1 minute (setting 6), and incubate / stand at room temperature for 2.5-12 hours, then read the plate using a PerkinElmer Trilux MicroBeta® scintillation counter. The final assay concentration range of the peptides tested in the response curve is typically 1150-0.058 nM or 115 nM-0.0058 nM, while the control GIP is 250 nM-0.013 nM.

[0074] Binding assay data analysis The CPM raw data of the concentration curves for peptides, Gcg, GLP-1, or GIP are converted to inhibition rates by subtracting nonspecific binding (binding when unlabeled Gcg, GLP-1, or GIP is present in excess) from each CPM value, and then dividing by the total binding signal, which has been corrected by subtracting nonspecific binding as well. Four parameters are used (curve maximum value, curve minimum value, IC). 50 The data is analyzed using a nonlinear regression routine (Genedata Screener, version 12.0.4, Genedata AG, Basal, Switzerland) with a hill gradient. The affinity constant (K i ) is formula K i =IC 50 / (1+D / K d ) Based on absolute IC 50 The values ​​are calculated, and in the formula, D is the concentration of the radioactive ligand used in the experiment, and IC 50 This is the concentration that causes 50% inhibition of binding, and K d K is the equilibrium binding dissociation constant of the radioactive ligand (as described above). i The value is reported as a geometric mean, the error is expressed as the standard error of the mean (SEM), and n is equal to the number of independent replicas (determined by assays performed on different days). The geometric mean is calculated as follows: Geometric mean = 10 (average of Log Ki values)

[0075] The Ki ratio (Ki of the natural control peptide / Ki of the test compound) is calculated for each receptor and for each type of peptide. The Ki ratio is a rapid indicator of the apparent affinity of a peptide compared to the natural control peptide. A Ki ratio < 1 indicates that the test peptide has lower affinity (higher Ki value) to the receptor than the natural peptide. Conversely, a Ki ratio > 1 indicates that the test peptide has higher affinity (lower Ki value) to the receptor than the natural peptide.

[0076] n=1 / x means that only one value is used to represent the mean from the total number of copies (x). SEM is calculated only if there are n=2 or more non-fitting results. The mean is expressed as a geometric mean, with the standard error of the mean (SEM) and the number of copies (n) shown in parentheses. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0077] functional activity Functional hGIP-R, hGLP-1R, and hGCGR assays Methods: Functional activity is determined using cAMP formation in HEK-293 clone cell lines expressing hGIPR, hGLP-1R, or hGCGR. hGIPR, hGLP-1R, or hGCGR receptor-expressing cells are subjected to 1X GlutaMAX TMThe control polypeptide or one of Examples 1-3 (20-point concentration response curve in DMSO, 2.75-fold Labcyte Echo direct dilution, 384-well plate Corning catalog no. 3570) was treated in 20 μL assay volume (final DMSO concentration was 0.5%) in DMEM (Gibco catalog no. 31053) supplemented with (trademark) (Gibco catalog no. 35050), 0.1% bovine casein (Sigma C4765-10ML), 250 μM IBMX (3-isobutyl-1-methylxanthine, Acros catalog no. 228420010), and 20 mM HEPES (Gibco catalog no. 15630). The experiment was also performed under the same assay conditions with the addition of 1.0% fatty acid-free, globulin-free human serum albumin (Sigma catalog no. A3782).

[0078] After incubation at 37°C for 30 minutes, the increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF assay kit (62AM4PEJ). Briefly, the cAMP-d2 conjugate is added to cell lysis buffer (10 μL), followed by an antibody, anti-cAMP-Eu, also in cell lysis buffer (10 μL). 3+ - Intracellular cAMP levels are detected by adding cryptotate. The resulting competitive assay is incubated at room temperature for at least 60 minutes and then detected using a PerkinElmer Envision® instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665 nm / 620 nm * 10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using the cAMP standard curve. The amount of cAMP generated (nM) in each well is converted to the percentage of the maximum response observed for human GIP(1-42)NH2, hGLP-1(7-36)NH2, or hGCG. Relative EC is determined by nonlinear regression analysis using the maximum response percentage (%) versus added peptide concentration, fitted to a 4-parameter logistic equation. 50 Value and maximum percentage (%) (E maxDerive the following:

[0079] Results: Functional data for hGIP(1-42)NH2, hGLP-1(7-36)NH2, hGCG, and the example compounds are provided in Table 2 (0.1% bovine casein) and Table 3 (0.1% bovine casein, 1.0% human serum albumin) below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12]

[0080] In vivo research Pharmacokinetics in male CD-1 mice The pharmacokinetics of the test peptide are evaluated after a single subcutaneous administration of 200 nMol / kg to male CD-1 mice. Blood samples are collected over 168 hours, and pharmacokinetic parameters are calculated using the resulting individual plasma concentrations. Plasma (K3EDTA) concentrations are determined using a qualified LC / MS method to measure intact clumps of the test peptide. Each test peptide and its analogue as an internal standard are extracted from 100% mouse plasma using immunoaffinity-based precipitation with anti-GIP / GLP1 antibody. Instruments are combined for LC / MS detection. Mean pharmacokinetic parameters are used to determine if the test peptide is consistent with the extended pharmacokinetic profile.

[0081] Insulin secretion in male Wistar rats Male Wistar rats (280-320 grams) with femoral artery and femoral vein cannulas (Envigo, Indianapolis, IN) were housed individually in polycarbonate cages with filter tops. The rats were maintained at 21°C in a 12:12 light-dark cycle (lights turned on at 6:00 AM) and given free access to food and deionized water. Rats were randomized by body weight and administered subcutaneously at doses of 0.04, 0.1, 0.3, 1, 3, and 10 nmol / kg of test peptides at 1.5 ml / kg 16 hours prior to glucose administration, followed by fasting. The animals were weighed and anesthetized by intraperitoneal administration of pentobarbital sodium (65 mg / kg, 30 mg / ml). Blood samples were collected in EDTA tubes at time 0, followed by intravenous glucose administration (0.5 mg / kg, 5 ml / kg). Blood samples are collected to observe glucose and insulin levels at 2, 4, 6, 10, 20, and 30 minutes after intravenous glucose administration. Plasma glucose levels are determined using a clinical chemistry analyzer. Plasma insulin is determined using an electrochemiluminescence assay (Meso Scale, Gaithersburg, MD). Glucose and insulin AUC are investigated compared to a vehicle control with n=5 animals / group. Results are presented as (SEM)(N). The results show the effect of the test peptide on insulin secretion during intravenous glucose tolerance testing. The results show the dose-dependent effect of the test peptide on insulin secretion.

[0082] Diet-induced obesity C57 / B16 mice Male C57 / Bl6 diet-induced obesity (DIO) mice weighing 41-50g (Taconic, Germantown, NY) were used. The animals were individually housed in temperature-controlled facilities (24°C) with a 12-hour light-dark cycle (lights off at 10:00 AM, lights on at 10:00 PM), and were given free access to food and water. After two weeks of acclimatization to the facilities, the mice were randomly divided into treatment groups based on body weight (n=6 / group) so that each group had a similar starting mean body weight.

[0083] Mice are treated with either a vehicle (40 mM Tris-HCl at pH 8.0) or a test peptide in a dose range of approximately 0.03 nmol / kg to approximately 10 nmol / kg. The treatment agent is administered subcutaneously to ad libitum DIO mice 30–90 minutes before the start of the dark cycle (QD) daily for 14 days. Body weight and food intake are monitored daily.

[0084] Data are presented as the mean ± SEM of 5-6 rats per group. Statistical analysis is evaluated using one-way ANOVA, followed by Dunnett's multiple comparison test, comparing the treatment group to the vehicle group or comparing them to each other. Significant differences are identified at p<0.05.

number

[0085] amino acid sequence Sequence ID 1 GIP (Human) YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-NH2 Sequence ID 2 Glucagon (human) HSQGTFTSDYSKYLDSRRAQDFVQWLMNT Sequence ID 3 GLP-1(7-36)(human) HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 Sequence ID 4 X1X2EGTX6TSDX 10 X 11 X 12 X13 LDX 16 X 17 AQX 20 X 21 X 22 IX 24 X 25 LIX 28 GX 30 Sequence ID 5 X 31 SSG Sequence ID 6 X 31 SSG-R3 Sequence ID 7 X 31 SSG 35 PPPX 39 Sequence ID 8 X 31 SSG 35 PPPX 39 R3 Sequence ID 9 X 31 SSG 35 PPPX 39 X 40 Sequence ID 10 X 31 SSG 35 PPPX 39 X 40 R3 Sequence ID 11 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 12 -CO2H)SSGAPPPS-NH2 Sequence ID 12 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))SSGAPPPS-NH2 Sequence ID 13 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-iodophenyl)butanoyl))SSGAPPPS-NH2 Sequence ID 14 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))SSGAPPPS-NH2 Sequence ID 15 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 10 -CH3)SSGAPPPS-NH2

Claims

1. Compound: X １ X ２ EGTX ６ TSDX １０ X １１ X １２ X １３ LDX １６ X １７ AQX ２０ X ２１ X ２２ IX ２４ X ２５ LIX ２８ GX ３０ (Sequence ID 505) (In the formula, X １ However, Y and R １ Selected from the group consisting of Y, R １ However, this is an Ac modification of the N-terminal amino group, X ２ However, it is Aib, X ６ However, selected from the group consisting of αMeF and αMeF(2F), X １０ is 4Pal, Y, αMeF, αMeF (2F), αMeL, αMeV, Ac4c, Ac5c, Ac6c, Bip, 1Nal, 2N al, OMeY, hTyr, Nle, V, 4CPhe, ChG, ChA, Bzt, 2FA, 4TAA, 2TA, 3TA, and KZ １ Selected from the group consisting of, X １１ However, selected from the group consisting of S, αMeS, Aib, G, Dap, Ac5c, and Tle, X １２ However, I and KZ １ Selected from the group consisting of, X １３ However, selected from the group consisting of αMeL and αMeF, X １６ However, it is Orn, X １７ However, Q, I, and KZ １ Selected from the group consisting of, X ２０ However, selected from the group consisting of Aib, Orn, 4Pal, αMeF, Ac5c, and Ac6c, X ２１ However, E, KZ １ Selected from the group consisting of G, Orn, and 4Pal, X ２２ However, it is selected from the group consisting of F, 2ClPhe, 3ClPhe, 2FPhe, 3FPhe, 3,5FPhe, 1Naal, 2Naal, αMeF(2F), ChA, Bzt, and αMeF, X ２４ However, D-Glu, E, G, and KZ １ Selected from the group consisting of, X ２５ However, Y, αMeY, αMeF, and KZ １ Selected from the group consisting of, X ２８ However, E, Orn, and KZ １ Selected from the group consisting of, X ３０ However, G, Orn, KZ １ , K(Z １ ) R ６ OrnR ２ , and GR ２ Selected from the group consisting of, R ２ However, X ３１ , X ３１ SSG (Sequence ID 5), X ３１ SSG-R ３ (Sequence No. 6), X ３１ SSGX ３５ PPPX ３９ (Sequence No. 7), X ３１ SSGX ３５ PPPX ３９ R ３ (Sequence No. 8), X ３１ SSGX ３５ PPPX ３９ X ４０ (Sequence No. 9), X ３１ SSGX ３５ PPPX ３９ X ４０ R ３ Selected from the group consisting of (SEQ ID NO: 10) and modifications of the c-terminal group, wherein the modification is NH ２ And, R ６ However, PSSG (Sequence ID 506), PSSG-R ３ (Sequence ID 507), PSGX ３５ PPPX ３９ (Sequence ID 508), PSGX ３５ PPPX ３９ R ３ (Sequence ID 509), PSGX ３５ PPPX ３９ X ４０ (Sequence ID 510), PSGX ３５ PPPX ３９ X ４０ R ３ Selected from the group consisting of (SEQ ID NO: 511) and modifications of the c-terminal group, wherein the modification is NH ２ And, X ３１ However, P and KZ １ Selected from the group consisting of, X ３５ However, selected from the group consisting of A and Orn, X ３９ However, selected from the group consisting of S and Orn, X ４０ However, KZ １ And, R ３ is a modification of the C-terminal group, and the modification is NH ２ and X １０ 、 X １２ 、 X １７ 、 X ２１ 、 X ２４ 、 X ２５ 、 X ２８ 、 X ３０ 、 X ３１ 、 and X ４０ of which, only two, and only two, are KZ １ or K(Z １ )R ６ and Z １ However, R ５ and -R ４ R ５ Selected from the group consisting of, R ４ However, it is a linker, R ５ (but it is a fatty acid), or The pharmaceutically acceptable salt.

2. X ３０ However, G, Orn, KZ １ , and GR ２ Selected from the group consisting of, R ２ However, X ３１ SSG (Sequence ID 5), X ３１ SSG-R ３ (Sequence No. 6), X ３１ SSGX ３５ PPPX ３９ (Sequence No. 7), X ３１ SSGX ３５ PPPX ３９ R ３ (Sequence No. 8), X ３１ SSGX ３５ PPPX ３９ X ４０ (Sequence No. 9), X ３１ SSGX ３５ PPPX ３９ X ４０ R ３ Selected from the group consisting of (SEQ ID NO: 10) and modifications of the c-terminal group, wherein the modification is NH ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Z １ However, -R ４ R ５ A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R ５ However, -CO-(CH ２ ) １２ -CO ２ H, CO-(CH ２ ) １４ -CO ２ H, -CO- (CH ２ ) １０ -CO ２ H, -(10-(4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), -(4-(4-tert-butylphenyl)butanoyl), -CO-(CH ２ ) １４ -CH ３ , -CO-(CH ２ ) １２ -CH ３ , -CO-(CH ２ ) １０ -CH ３ A compound according to any one of claims 1 to 3, selected from the group consisting of -(7-(4-carboxyphenoxy)heptanoyl), -(11-(4-carboxyphenoxy)undecanoyl), -(12-(4-carboxyphenoxy)dodecanoyl), and -(8-(4-carboxyphenoxy)octanoyl), or a pharmaceutically acceptable salt thereof.

5. R ５ but, -CO-(CH ２ ) １２ -CO ２ H, -CO- (CH ２ ) １０ -CO ２ H, -(10-(4-carboxyphenoxy)decanoyl), -(4-(4-iodophenyl)butanoyl), -(4-(4-tert-butylphenyl)butanoyl), -CO-(CH ２ ) １４ -CH ３ , -CO-(CH ２ ) １２ -CH ３ , -CO-(CH ２ ) １０ -CH ３ A compound according to any one of claims 1 to 4, selected from the group consisting of -(7-(4-carboxyphenoxy)heptanoyl) and -(8-(4-carboxyphenoxy)octanoyl), or a pharmaceutically acceptable salt thereof.

6. R ５ but, CO-(CH ２ ) １４ -CO ２ A compound according to any one of claims 1 to 4, selected from the group consisting of H, -(11-(4-carboxyphenoxy)undecanoyl), and -(12-(4-carboxyphenoxy)dodecanoyl), or a pharmaceutically acceptable salt thereof.

7. R ４ However, -(εK) ａ１ -(γ-Glu) ａ２ - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ａ３ - (εK) ｂ１ -(γ-Glu) ｂ２ - and a1 is selected from the group consisting of 0, 1, and 2. a2 is selected from the group consisting of 0, 1, and 2. a3 is selected from the group consisting of 0, 1, 2, and 3. b1 is 0 or 1, A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein b2 is 0 or 1.

8. R ４ but, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ - -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu) ２ ) - - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-(γ-Glu)-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Trx-(γ-Glu)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -Trx-(γ-Glu)-, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Aoc-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Aoc-(γ-Glu)-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Ahx-(γ-Glu)-, -PEG3-(γ-Glu)-, -PEG4-(γ-Glu)-, -PEG5-(γ-Glu)-, -PEG6-(γ-Glu)-, -Ahx-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-, -Aoc-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-, -(εK)-(γ-Glu)-, -(εK)-(γ-Glu)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ - -(εK)-(εK)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-, -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-, - (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -, and A compound according to any one of claims 1 to 6, selected from the group consisting of (2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]acetyl)-(γ-Glu)-, or a pharmaceutically acceptable salt thereof.

9. R ４ but, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ - -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-(γ-Glu)-, -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-, -(εK)-(γ-Glu)-, -(εK)-(γ-Glu)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ - -(εK)-(εK)-(γ-Glu)-, -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-, and A compound according to any one of claims 1 to 6, selected from the group consisting of -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-, or a pharmaceutically acceptable salt thereof.

10. Z １ but, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １４ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ - (10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １４ -CH ３ , -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １０ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-CO-(CH ２ ) １４ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -CO-(CH ２ ) １２ -CO ２ H, -(εK)-(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(7-(4-carboxyphenoxy)heptanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(8-(4-carboxyphenoxy)octanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(11-(4-carboxyphenoxy)undecanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -CO-(CH ２ ) １２ -CO ２ H, -PEG3-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -PEG4-(γ-G5)-CO-(CH ２ ) １２ -CO ２ H、 - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(11-(4-carboxyphenoxy)undecanoyl, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １４ -CO ２ H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Ahx-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Aoc-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -Ahx-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -Aoc-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Ahx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Aoc-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -Ahx-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -Aoc-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG4-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG3-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Aoc-CO-(CH ２ ) １２ -CO ２ H, -PEG6-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -PEG5-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -PEG6-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG5-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -Trx-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -Trx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Trx-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Trx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu) ２ -CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu) ２ - (10-(4-carboxyphenoxy)decanoyl), -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, and A compound according to any one of claims 2 and 4 to 9, selected from the group consisting of -(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), or a pharmaceutically acceptable salt thereof.

11. Z １ but, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １４ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ - (10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １４ -CH ３ , -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １０ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-CO-(CH ２ ) １４ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(εK)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -(εK)-(γ-Glu)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -CO-(CH ２ ) １２ -CO ２ H, -(εK)-(εK)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(7-(4-carboxyphenoxy)heptanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(8-(4-carboxyphenoxy)octanoyl), and A compound according to claim 10, or a pharmaceutically acceptable salt thereof, selected from the group consisting of -(2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl).

12. Z １ but, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(11-(4-carboxyphenoxy)undecanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -CO-(CH ２ ) １２ -CO ２ H, -PEG3-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -PEG4-(γ-G5)-CO-(CH ２ ) １２ -CO ２ H、 - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ３ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ , - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(11-(4-carboxyphenoxy)undecanoyl, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １４ -CO ２ H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Ahx-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Aoc-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -Ahx-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -Aoc-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Ahx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Aoc-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -Ahx-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -Aoc-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG4-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG3-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Aoc-CO-(CH ２ ) １２ -CO ２ H, -PEG6-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -PEG5-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H、 -PEG6-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -PEG5-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -Trx-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -Trx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-Trx-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl)-Trx-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu) ２ -CO-(CH ２ ) １２ -CO ２ H, - (2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu) ２ - (10-(4-carboxyphenoxy)decanoyl), -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, -(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl), - (2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H, and A compound according to claim 10, or a pharmaceutically acceptable salt thereof, selected from the group consisting of -(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(2-[2-(2-aminoethoxy)-ethoxy]acetyl)-(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl).

13. X １ However, Y is, X ６ However, it is αMeF(2F), X １０ However, 4Pal, Y, and KZ １ Selected from the group consisting of, X １１ However, selected from the group consisting of S, αMeS, and Aib, X １２ However, it is I, X １３ However, it is αMeL, X １６ However, it is Orn, X １７ However, I and KZ １ Selected from the group consisting of, X ２０ However, it is Aib, X ２１ However, E or KZ １ And, X ２２ However, selected from the group consisting of F and αMeF, X ２４ However, D-Glu and KZ １ Selected from the group consisting of, X ２５ However, it is αMeY, X ２８ However, E and KZ １ Selected from the group consisting of, X ３０ However, G and GR ２ Selected from the group consisting of, R ２ However, X ３１ SSGX ３５ PPPX ３９ (Sequence No. 7), X ３１ SSGX ３５ PPPX ３９ R ３ (Sequence No. 8), and X ３１ SSGX ３５ PPPX ３９ X ４０ Selected from the group consisting of (SEQ ID NO: 9) and modifications of the c-terminal group, wherein the modification is NH ２ And, or a pharmaceutically acceptable salt thereof, the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. X ３０ However, GR ２ And, R ２ However, X ３１ SSGX ３５ PPPX ３９ (Sequence No. 7), X ３１ SSGX ３５ PPPX ３９ R ３ (Sequence No. 8), and X ３１ SSGX ３５ PPPX ３９ X ４０ A compound according to any one of claims 1 to 13, selected from the group consisting of (Sequence ID 9), or a pharmaceutically acceptable salt thereof.

15. X １７ and X ３１ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. X １７ and X ２４ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

17. X １７ and X ２１ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

18. X １７ and X ２８ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

19. X ２１ and X ２８ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

20. X ２４ and X ２８ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

21. X １７ and X ４０ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

22. X ２１ and X ４０ However, each KZ １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

23. The aforementioned compound, Y-Aib-EGT-αMeF(2F)-TSD-4Pa-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H) AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H) SSGAPPPS-NH ２ , Y-Aib-EGT-aMeF(2F)-TSD-4Pa-SI-aMeL-LD-Orn-K((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))SSGAAPPPS-NH ２ , Y-Aib-EGT-aMeF(2F)-TSD-4Pa-SI-aMeL-LD-Orn-K((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl))SSGAAPPPS-NH ２ , Y-Aib-EGT-aMeF(2F)-TSD-4Pa-SI-aMeL-LD-Orn-K((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))SSGAAPPPS-NH ２ , and Y-Aib-EGT-αMeF(2F)-TSD-4Pa-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH3)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ )SSGAPPPS-NH ２ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

24. The aforementioned compound is Y-Aib-EGT-αMeF(2F)-TSD-4Pa-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ )AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １０ -CH ３ )SSGAPPPS-NH ２ The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

25. The aforementioned compound is Y-Aib-EGT-aMeF(2F)-TSD-4Pa-SI-aMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-tert-butylphenyl)butanoyl))SSGAAPPPS-NH ２ The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

26. The aforementioned compound is Y-Aib-EGT-aMeF(2F)-TSD-4Pa-SI-aMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(4-(4-iodophenyl)butanoyl))SSGAAPPPS-NH ２ The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

27. The aforementioned compound is Y-Aib-EGT-aMeF(2F)-TSD-4Pa-SI-aMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGK((2-[2-(2-aminoethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-(10-(4-carboxyphenoxy)decanoyl))SSGAAPPPS-NH ２ The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

28. The aforementioned compound is Y-Aib-EGT-αMeF(2F)-TSD-4Pa-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H) AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) ２ -(γ-Glu)-CO-(CH ２ ) １２ -CO ２ H) SSGAPPPS-NH ２ The compound according to claim 23, or a pharmaceutically acceptable salt thereof.

29. A method for treating a condition selected from the group consisting of type 2 diabetes mellitus, obesity, NAFLD, non-alcoholic steatohepatitis, dyslipidemia, and metabolic syndrome, comprising administering to a patient in need of the treatment an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

30. A method for treating obesity, comprising administering to a patient in need of the treatment an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

31. A method for providing therapeutic weight loss, comprising administering to a subject requiring therapeutic weight loss an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

32. A method for treating type 2 diabetes, comprising administering an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, to a subject in need of the treatment.

33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

34. The pharmaceutical composition according to claim 33, wherein the composition is administered by subcutaneous injection.

35. The pharmaceutical composition according to claim 33, wherein the composition is administered orally.

36. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical agent.

37. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition selected from the group consisting of type 2 diabetes mellitus, obesity, NAFLD, non-alcoholic steatohepatitis, dyslipidemia, and metabolic syndrome.

38. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment of type 2 diabetes.

39. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28, in the manufacture of a drug for treating a condition selected from the group consisting of type 2 diabetes mellitus, obesity, NAFLD, non-alcoholic steatohepatitis, dyslipidemia, and metabolic syndrome.

40. Use of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 28, in the manufacture of a drug for treating type 2 diabetes.

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