GIP / GLP1 co-agonist compounds

Abstract

The present invention relates to GIP / GLP1 co-agonist compounds. The present invention relates to compounds having activity against both the human glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP-1) receptor. The invention also relates to compounds having an extended duration of action on each of these receptors. In addition, the present invention relates to compounds that can be administered orally. The compounds are useful in the treatment of type 2 diabetes mellitus ("T2DM"). In addition, the compounds are useful in the treatment of obesity.

Description

This application is a divisional application of Chinese patent application 201980049095.7 “GIP / GLP1 co-agonist compounds” filed on July 22, 2019. Technical Field

[0001] The present invention relates to compounds that are active at both human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. The present invention also relates to compounds that have an extended duration of action at each of these receptors. In addition, the present invention relates to compounds that can be administered orally. The compounds can be used to treat type 2 diabetes ("T2DM"). In addition, the compounds can be used to treat obesity. Background Art

[0002] In the past few decades, the prevalence of diabetes has continued to rise. T2DM is the most common form of diabetes, accounting for about 90% of all diabetes. T2DM is characterized by high blood sugar levels, which are mainly related to insulin resistance. The current standard of care for T2DM includes diet and exercise, oral medications and injectable glucose-lowering drug treatment (including incretin-based therapy, such as GLP-1 receptor agonists). There are currently multiple GLP-1 receptor agonists available for the treatment of T2DM, although the current commercially available GLP-1 receptor agonists are generally limited in dosage due to gastrointestinal side effects (such as nausea and vomiting). For available GLP-1 receptor agonists, subcutaneous injection is a typical route of administration. When oral medications and incretin-based therapy are not adequately treated, insulin therapy is considered. Although there is progress in the treatment available today, many T2DM patients fail to reach their blood sugar control goals. Uncontrolled diabetes leads to several conditions related to the increased morbidity and mortality of patients. It is necessary to enable more T2DM patients to reach their blood sugar treatment goals.

[0003] Obesity is a complex medical condition that results in excessive accumulation of adipose tissue masses. Obesity is a global public health problem today, associated with undesirable health outcomes and morbidity. Expected treatments for obese patients seek to reduce overweight, improve obesity-related complications, and maintain long-term weight loss. Available obesity treatments are particularly unsatisfactory for severely obese patients. Alternative treatment options are needed to cause therapeutic weight loss in patients who need such treatment.

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

[0005] There is a need for a T2DM treatment that can provide effective glucose control to most patients who need such treatment. There is also a need for a T2D treatment that can provide effective glucose control and has a favorable side effect spectrum. Alternative treatment options are needed to provide therapeutic weight loss for patients who need such treatment. For patients who need to treat severe obesity, alternative treatment options are needed.

[0006] Compounds having agonist activity at both the GIP and GLP-1 receptors and suitable for oral administration are desired. Compounds having prolonged duration of action at each of the GIP and GLP-1 receptors are needed to allow less frequent dosing. Summary of the invention

[0007] Therefore, the present invention provides compounds of formula I: R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 (SEQ ID NO: 3) in: R1 is a modification of the N-terminal amino group, wherein the modification is selected from Ac and absent; X1 is selected from the group consisting of Y, H, D-Tyr, F, desH and desY, X2 is selected from Aib, αMeP, A, P and D-Ala; or X1 and X2 combine to form desH-ψ[NHCO]-Aib; X3 is selected from E, N, Aad and cTA; X6 is selected from the group consisting of F, αMeF and αMeF(2F); X 10 Selected from A, L, H, 3Pal, 4Pal, V, Y, E, αMeF, αMeF(2F), I, αMeY, Q, D-His, D-Tyr, cTA and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X11 Selected from S, αMeS and D-Ser; X 12 Selected from I, S, D-Ile and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 13 Selected from Nle, Aib, L, αMeL and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 14 Selected from L and K, wherein K is conjugated to C 16 -C 22 a fatty acid, wherein the fatty acid is optionally conjugated to the K via a linker; X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 17 Selected from K, Q, I and conjugated to C 16 -C 22 an amino acid to a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker; X 19 Selected from Q, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 20 Selected from Aib, Q, H, R, K, αMeK and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 21 Selected from H, Aad, D, Aib, T, A, E, I and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 22 Selected from F and αMeF; X 23 Selected from I, L, A, G, F, H, E, V and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 24Selected from S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 25 is selected from Y and αMeY; X 26 Selected from L, αMeL and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 27 Selected from L, I and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 28 Selected from E, A, S, D-Glu and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 29 Selected from Aib, G, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 30 Selected from C, G, G-R2 and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H; X 31 Not present or selected from PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 6), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X34 -R2 (SEQ ID NO: 7), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 8) and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 9); in: X 32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 34 Selected from G, C, and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; X 35 A or K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; X 36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 38is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 39 Selected from C, S, and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; X 40 is selected from C and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; q is selected from 14, 15, 16, 17, 18, 19 and 20; and R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent; or a pharmaceutically acceptable salt thereof; If X 30 is G-R2, then X 31 does not exist; Where X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40 No more than one of may be a fatty acid containing substituent; and Where X 30 , X 34 , X 39 and X 40 No more than one of can be C; and If X 30 , X 34 , X 39 and X 40 If one of them is C, then X 10 , X 12, X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40 None of them contain fatty acid substituents.

[0008] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein q is 16. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 31 is selected from SEQ ID NO: 5 and SEQ ID NO: 8. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X conjugated to a fatty acid 17 The amino acid is a natural amino acid. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 17 Selected from K, Q and I.

[0009] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein K is conjugated to C 16 -C 22 A fatty acid, wherein the fatty acid is optionally conjugated to the K via a linker.

[0010] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 14 or X 17 Selected from K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 14-CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(Trx)-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(Trx)-(γ-Glu)-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)-(εK)-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)2-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2) 16 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2) 14 -CO2H and KDab-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-Dab-(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2) 18 -CO2H.

[0011] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 14 or X 17 Selected from K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 14 -CO2H and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 18 -CO2H.

[0012] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 14 or X 17 Selected from K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 14 -CO2H. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 14 or X 17 Selected from K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 14 or X 17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H, wherein a is 2, b is 1, and q is selected from 18 and 20. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 14 or X 17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H, wherein a is 2, b is 1 and q is 18. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 14 or X 17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H, wherein a is 2, b is 1 and q is 20.

[0013] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X1 and X2 do not combine to form desH-ψ[NHCO]-Aib (hereinafter referred to as "compound of formula II").

[0014] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: X 17 is conjugated to C 16 -C 22 an amino acid containing a fatty acid, wherein the fatty acid is conjugated to the amino acid optionally via a linker; and X 30 Selected from G-R2 and G; If X 30 is G, then X 31 Selected from PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), wherein X 32 It is S, X 33 It's S and X 34 is G (SEQ ID NO: 297), and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), wherein X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X 38 It is P and X 39 is S (SEQ ID NO: 298) (hereinafter referred to as "the compound of Formula III").

[0015] In one embodiment, it is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein X 17 The amino acid is conjugated to the fatty acid via a linker (hereinafter referred to as "Formula IIIa" compound).

[0016] In one embodiment, it is a compound of formula III and IIIa or a pharmaceutically acceptable salt thereof, wherein: X 10 Selected from A, L, H, 3Pal, 4Pal, V, Y, E, αMeF, αMeF(2F), I, αMeY, Q, D-His, D-Tyr and cTA; X12 Selected from I, S and D-Ile; X 13 Selected from Nle, Aib, L and αMeL; X 14 Selected from L and K; X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK and R; X 19 Selected from Q and A; X 20 Selected from Aib, Q, H, R, K and αMeK; X 21 Selected from H, Aad, D, Aib, T, A, E and I; X 23 Selected from I, L, A, G, F, H, E and V; X 24 Selected from S, Aad, D-Glu, E, Aib, H, V, A, Q, D and P; X 26 Selected from L and αMeL; X 27 Selected from L and I; X 28 Selected from E, A, S and D-Glu; X 29 Selected from Aib, G and A; X 30 Selected from G and G-R2; If X 30 is G; then X 31 Selected from PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), wherein X 32 It is S, X 33 It's S and X 34 G (SEQ ID NO: 297) and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), wherein X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X38 It is P and X 39 is S (SEQ ID NO: 298) (hereinafter referred to as "the compound of Formula IIIb").

[0017] In one embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein the linker comprises 1 to 2 amino acids, and in further embodiments of these specific compounds of formula III, IIIa and IIIb, it is those wherein the linker amino acids are independently selected from Glu and γ-Glu. In another embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein the linker comprises one or two (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties, and in further embodiments of these specific compounds of formula III, IIIa and IIIb, it is wherein the linker is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b , wherein a is selected from 1 or 2; and b is selected from those of 1 or 2.

[0018] In one embodiment, it is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein X 17 is conjugated to C 16 -C 22 An amino acid to a fatty acid, wherein the amino acid is K and wherein the fatty acid is conjugated to the amino acid, optionally via a linker.

[0019] In one embodiment, it is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein: R1 does not exist; X1 and X2 do not combine to form desH-ψ[NHCO]-Aib; X 17 is conjugated to C 16 -C 22 K of a fatty acid, wherein the fatty acid is conjugated to the amino acid optionally via a linker.

[0020] In one embodiment, it is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein: X1 is Y; X2 is Aib; X3 is E; X 10 Selected from A, L, H, 3Pal, 4Pal, V and Y; X 11 It is S; X 12 It's I; X14 It is L; X 16 Selected from K, E, Orn, Dab and Dap; X 17 is conjugated to C 16 -C 22 K of a fatty acid, wherein the fatty acid is optionally conjugated to the amino acid via a linker; X 19 It is Q; X 20 It is Aib; X 21 Selected from H, Aad, D, Aib, T, A and E; X 22 It is F; X 23 It's I; X 24 Selected from S, Aad, D-Glu and E; X 26 is L; and X 28 Selected from E and A.

[0021] In one embodiment, it is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein: X1 is Y; X2 is Aib; X3 is E; X6 is αMeF(2F); X 10 Selected from Y, 4-PaI and V; X 11 It is S; X 12 It's I; X 13 Selected from L, Aib and αMeL; X 14 It is L; X 16 Selected from E, K and Orn; X 17 is conjugated to C 16 -C 22 K of a fatty acid, wherein the fatty acid is optionally conjugated to the amino acid via a linker; X 19 It is Q; X 20 It's Aib X 21 Selected from E, A and T; X 22 It is F; X 23 It's I; X 24 It is D-Glu; X 25 is selected from Y and αMeY; X 26 It is L; X 27 It's I; X 28 It is E; X 29 It is G; X 30 is G; and X 31 It is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), wherein X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X 38 It is P, X 39 It is S (SEQ ID NO: 298).

[0022] In one embodiment, it is a compound of formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein R2 is absent.

[0023] In one embodiment, it is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein R2 is NH2.

[0024] In one embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 13 It's αMeL.

[0025] In one embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 25 It is Y and X 13 It's αMeL.

[0026] In one embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 17 is K conjugated to a fatty acid via a linker attached to the ε-amino group of the K side chain, wherein the fatty acid and linker have the following formula: (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H, wherein a is 1 or 2; b is 1 or 2; and q is selected from 14 to 20.

[0027] In one embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 16 It's Orn, X 13 is αMeL and X 25 is Y. In one embodiment, it is a compound of Formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 16 It is E, X 13 is αMeL and X 25 is Y. In one embodiment, it is a compound of Formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 16 It is E, X 13 It is αMeL, X 10 It is Y and X 25 In one embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 16 It's Orn, X 13 It is αMeL, X 10 It is 4Pal and X 25 is Y. In one embodiment, it is a compound of Formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 16 It's Orn, X 13 It is αMeL, X 10 It's V and X 25 is Y. In one embodiment, it is a compound of Formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 16 It is E, X 13 It is αMeL, X 25 It is Y and X 17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H, wherein a is 2; b is 1; and q is selected from 14 to 20. In one embodiment, it is a compound of formula III, IIIa and IIIb or a pharmaceutically acceptable salt thereof, wherein X 16 It is E, X 13 It is αMeL, X10 It is Y and X 25 is Y, and X 17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H, wherein a is 2; b is 1; and q is selected from 16 to 20.

[0028] In one embodiment, it is a compound of formula I, the compound is selected from SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 10, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 12, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 13, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, it is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein X1 is selected from Y, F, and D-Tyr; X6 is F; and X 13 Selected from Aib, L and αMeL.

[0030] In one embodiment, it is a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R1 is absent; X1 is selected from Y, F and D-Tyr; X6 is F; X 13 is selected from Aib, L and αMeL; X2 is Aib; X3 is E; X 10 It is Y; X 11 Yes S; X 12 is I; X 14 Yes L; X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK and R; X 17 is conjugated to C 16 -C 22 an amino acid containing a fatty acid, wherein the fatty acid is conjugated to the amino acid optionally via a linker; X 19 It is Q; X 20 Selected from Aib, Q, H and K; X 21Selected from H, D, T, A and E; X 22 It is F;X 23 is I; X 24 Selected from D-Glu and E; X 26 Yes L; X 27 is I; X 28 Selected from E, A, S and D-Glu; X 29 Selected from Aib, G and A; X 30 Selected from C, G and G-R2; X 31 Not present or selected from PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 6); wherein: X 32 Yes S; X 33 Yes S; X 34 Selected from G and C; X 35 Yes A; X 36 It is P; X 37 It is P; X 38 It is P; X 39 selected from C and S; and X 40 It is C.

[0031] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X1 is selected from Y, F and D-Tyr; X6 is F; and X 13 Selected from Aib, L and αMeL; X 28 It is A; X 29 It is G; X 30 It is G; X 31 It is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5); X34 is G; and X 39 YesS 。

[0032] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X1 is selected from Y and D-Tyr; and X 13 It's αMeL.

[0033] In one embodiment, it is a compound of formula I selected from SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, and SEQ ID NO: 308, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 303, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 304, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 305, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 306, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 307, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of formula I, the compound is SEQ ID NO: 308, or a pharmaceutically acceptable salt thereof. In one embodiment, it is a compound of Formula I, which is SEQ ID NO: 386, or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: X 10 Selected from A, L, H, 3Pal, 4Pal, V, Y, αMeF, αMeF(2F), I, αMeY, Q, D-His, E, cTA and D-Tyr; X 12 Selected from I, D-Ile and S; X 13 Selected from Nle, Aib, L and αMeL; X 14 It is L; X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK and R; X 17 Selected from K, Q and I; X19 Selected from Q and A; X 20 Selected from Aib, Q, H, R, K and αMeK; X 21 Selected from H, Aad, D, Aib, T, A, E and I; X 23 Selected from I, L, A, G, F, H, E and V; X 24 Selected from S, Aad, D-Glu, E, Aib, H, V, A, Q, D and P; X 26 Selected from L and αMeL; X 27 Selected from L and I; X 28 Selected from E, A, S and D-Glu; and X 29 is selected from the group consisting of Aib, G and A (hereinafter referred to as "the compound of Formula IV").

[0035] In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein X 39 is C. In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein X 40 It is C.

[0036] In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein X 30 , X 34 , X 39 and X 40 One and only one of is C. In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein X 30 , X 34 , X 39 and X 40 In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein C is modified using a time-delay technology, wherein the time-delay technology is XTEN. In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein C is modified using a time-delay technology, wherein the time-delay technology is (Glu) m Biotin, wherein m is 0, 1, 2 or 3. In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein: X1 is Y; X2 is Aib; X3 is E; X 10Selected from A, L, H, 3Pal, 4Pal, V and Y; X 11 It is S; X 12 It's I; X 16 Selected from K, E, Orn, Dab and Dap; X 19 It is Q; X 20 Selected from Aib and K; X 21 Selected from H, Aad, D, Aib, T, A and E; X 22 It is F; X 23 It's I; X 24 Selected from S, Aad, D-Glu and E; X 26 is L; and X 28 Selected from E and A; or a pharmaceutically acceptable salt thereof.

[0037] In one embodiment, it is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein X1 is Y; X2 is Aib; X3 is E; X 10 Selected from A, L, H, 3Pal, 4Pal, V and Y; X 11 It is S; X 12 It's I; X 16 Selected from K, E, Orn, Dab and Dap; X 20 It is Aib; X 21 Selected from H, Aad, D, Aib, T, A and E; X 22 It is F; X 24 Selected from S, Aad, D-Glu and E; X 27 is I; and X 28 Selected from E and A.

[0038] In one embodiment, it is a compound of formula I or a pharmaceutical salt thereof, wherein: X 14 It is L; X17 Selected from K, Q and I; X 30 is selected from G-R2 and G; and q is selected from 16, 18 and 20; If X 30 is G, then X 31 Selected from: PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), wherein: X 32 It is S, X 33 It is S, X 34 G and R2 are absent (SEQ ID NO: 299) or X 32 It is S, X 33 It is S, X 34 is G and R2 is NH2 (SEQ ID NO: 300); and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), wherein: X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X 38 It is P, X 39 S and R2 are absent (SEQ ID NO: 301) or X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X 38 It is P, X 39 is S and R2 is NH2 (SEQ ID NO: 302); and Where X 10 , X 12 , X 13 , X 14 , X 16 , X 19 , X 20, X 21 , X 23 , X 24 , X 26 , X 27 , X 28 and X 29 One of them is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2)qCO2H (hereinafter referred to as "the compound of Formula V").

[0039] In one embodiment, it is a compound of formula V or a pharmaceutically acceptable salt thereof, wherein: X1 is Y; X2 is Aib; X3 is E; X 10 Selected from A, L, H, 3Pal, 4Pal, V, Y, E, cTA and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 11 It is S; X 12 Selected from I, D-Ile and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 16 Selected from K, E, Orn, Dab, Dap and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 17 Selected from K and I; X 19 Selected from Q and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 20 Selected from Aib and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 21 Selected from H, Aad, D, Aib, T, A, E and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 22 It is F; X 24Selected from S, Aad, D-Glu, E and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 26 Selected from L and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 27 selected from L and I; and X 28 Selected from E, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H.

[0040] In one embodiment, it is a compound of formula V or a pharmaceutically acceptable salt thereof, wherein X 20 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H, wherein q is 16 or 18. In one embodiment, it is a compound of formula V or a pharmaceutically acceptable salt thereof, wherein X 31 It is SEQ ID NO:301 or SEQ ID NO:302.

[0041] One embodiment provides a method for treating a condition selected from T2DM, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof. One embodiment provides a method for providing therapeutic weight loss, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof. In one embodiment, the condition is NAFLD. In one embodiment, the condition is NASH.

[0042] 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 therapy for a condition selected from 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.

[0043] The compound of formula I or its pharmaceutically acceptable salt can be used to treat a variety of symptoms or conditions. For example, certain embodiments provide a method for treating T2DM in a patient, including administering an effective amount of a compound of formula I or its pharmaceutically acceptable salt to an object in need of such treatment. In one embodiment, it is a method for treating obesity in a patient, including administering an effective amount of a compound of formula I or its pharmaceutically acceptable salt to an object in need of such treatment. In one embodiment, the method is to induce non-therapeutic weight loss in an object, including administering an effective amount of a compound of formula I or its pharmaceutically acceptable salt to an object in need of such treatment.

[0044] In certain embodiments, the present invention provides a method for treating metabolic syndrome in a patient, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the method is to treat NASH, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0045] Also provided herein are compounds of the invention for use in combination with one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporters, SGLT-2 inhibitors, growth differentiation factor 15 regulators ("GDF15"), peptide tyrosine tyrosine regulators ("PYY"), modified insulins, amylin, dual amylin calcitonin receptor agonists, and oxytocin agonists ("OXM"). In one embodiment, the compounds of the invention are provided in a fixed dose combination with one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporters, SGLT-2 inhibitors, GDF15, PYY, modified insulins, amylin, dual amylin calcitonin receptor agonists, and OXM. In one embodiment, it is a compound of the invention for simultaneous, separate and sequential use in combination with one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, SGLT-2 inhibitors, GDF15, PYY, modified insulin, amylin, dual amylin calcitonin receptor agonists and OXM. In one embodiment, it is a compound of the invention for simultaneous, separate and sequential use in combination with one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters and SGLT-2 inhibitors to treat a condition selected from T2DM and obesity.

[0046] In other embodiments, the compound or its pharmaceutically acceptable salt can be used to improve bone strength in a subject in need. The compounds of the present invention or its pharmaceutically acceptable salt can be used to treat other conditions, such as Parkinson's disease or Alzheimer's disease. Incretins and incretin analogs that are active on one or more of GIP, GLP-1 and / or glucagon receptors have been described as having potential therapeutic value for a variety of other diseases or conditions, including, for example, obesity, NAFLD and NASH, dyslipidemia, metabolic syndrome, bone-related disorders, Alzheimer's disease and Parkinson's disease. See, e.g., 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 (January 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), ADA2017Poster 1139-P; Ding, KH, Impact of glucose-dependent insulinotropicpeptide 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 agonistin the APP / PS1 transgenic mouse model of Alzheimer'sdisease, BRAIN RES.1678,64-74(2018); TDMüller et al., The New Biology and Pharmacology of Glucagon, PHYSIOL.REV.97:721-766 (2017); Finan, B. et al., Unimolecular Dual IncretinsMaximize Metabolic Benefits in Rodents, Monkeys, and Humans, SCI.TRANSL.MED., 5:209 (October 2013);. C. Insulin, incretins and other growth factors aspotential novel treatments for Alzheimer's and Parkinson's diseases, BIOCHEM.SOC.TRANS.42(2):593-0 (April 2014).

[0047] Another embodiment provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition selected from T2DM, obesity, NAFLD, NASH, dyslipidemia, and metabolic syndrome. In one embodiment, the medicament is used to treat T2DM. In one embodiment, the medicament is used to treat obesity. In one embodiment, the medicament is used to treat NAFLD. In one embodiment, the medicament is used to treat NASH.

[0048] Another embodiment provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and at least one selected from a carrier, a diluent, and an excipient.

[0049] In one embodiment, it is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, at least one penetration enhancer and at least one protease inhibitor. In one embodiment, it is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, at least one penetration enhancer, and at least one selected from a carrier, a diluent and an excipient.

[0050] In one embodiment, it is a pharmaceutical composition, which includes a compound of formula I or a pharmaceutically acceptable salt thereof, a penetration enhancer, a protease inhibitor, and at least one selected from a carrier, a diluent, and an excipient. In one embodiment, it is a pharmaceutical composition, which includes a compound of formula I or a pharmaceutically acceptable salt thereof and a penetration enhancer. In one embodiment, it is a pharmaceutical composition, which includes a compound of the present invention or a pharmaceutically acceptable salt thereof and a penetration enhancer. In one embodiment, the penetration enhancer is selected from sodium decanoate ("C10"), sodium taurodeoxycholate ("NaTDC"), lauroylcarnitine ("LC"), dodecyl maltoside ("C12-maltoside"), dodecyl phosphatidylcholine ("DPC"), sodium N-[8-(2-hydroxybenzoyl)amino] caprylate ("SNAC") and rhamnolipid. In one embodiment, the penetration enhancer is selected from C10 and LC. In one embodiment, the protease inhibitor is selected from soybean trypsin inhibitor ("SBTI"), soybean trypsin-chymotrypsin inhibitor ("SBTCI"), ecotin, sunflower trypsin inhibitor ("SFTI"), leupeptin, citric acid, ethylenediaminetetraacetic acid ("EDTA"), sodium glycocholate, and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride ("AEBSF"). In one embodiment, the protease inhibitor is selected from SBTI, SBTCI, and SFTI. In one embodiment, the protease inhibitor is SBTI.

[0051] As used herein, the term "treating" or "to treat" includes inhibiting, slowing, halting or reversing the progression or severity of a symptom, condition or disorder.

[0052] Certain compounds of the present invention are generally effective over a wide dosage range. For example, a dosage for once-weekly parenteral administration may be in the range of 0.05 mg to about 30 mg per person per week.

[0053] The compounds of the present invention include novel amino acid sequences having affinity for respective GLP-1 and GIP receptors, which have desired potency at each of these receptors. GLP-1 is a 36 amino acid peptide, the major biologically active fragment of which is a 30-amino acid C-terminal amidated peptide (GLP-1 7-36 )(SEQ ID NO:2) is produced.

[0054] GIP is a 42 amino acid peptide (SEQ ID NO: 1) which, like GLP-1, is also known as an incretin and plays a physiological role in glucose homeostasis by stimulating the secretion of insulin from pancreatic β cells in the presence of glucose.

[0055] The compounds provide the desired potency for each of the GIP and GLP-1 receptors. In one embodiment, the compounds are suitable for oral administration. In one embodiment, the compounds have the desired GIP and GLP receptors through extended time action (time action). In one embodiment, the compounds have the desired GIP and GLP receptor activity, wherein the GIP agonist potency is 2.5 to 5 times the potency of the GLP1 receptor, as measured by the casein cAMP assay described below, wherein the potency is normalized relative to native GIP and GLP on the day the assay is performed. In one embodiment, the compounds have the desired GIP and GLP receptor activity, wherein the GIP agonist potency is 2.5 to 10 times the potency of the GLP1 receptor, as measured by the casein cAMP assay, wherein the potency is normalized relative to native GIP and GLP on the day the assay is performed.

[0056] As used herein, the term "amino acid" means both naturally occurring amino acids and non-natural amino acids. Amino acids are typically described using the standard single letter code (e.g., L = leucine) as well as α-methyl substituted residues of natural amino acids (e.g., α-methylleucine, or αMeL, and α-methyllysine, or αMeK) and certain other non-natural amino acids (such as α-aminoisobutyric acid, or "Aib", "4Pal", "Orn", etc.). The structures of these amino acids are presented below:

[0057] As used herein, "Orn" means ornithine. As used herein, "4Pal" means 3-(4-pyridyl)-L-alanine. As used herein, "αMeF(2F)" means α-methyl 2-F-phenylalanine. As used herein, "αMeY", "αMeK" and "αMeL" each mean α-methyl-tyrosine, α-methyl-lysine and α-methyl-leucine. As used herein, "e" and "D-Glu" mean D-glutamic acid. As used herein, "D-His" and "h" each mean D-histidine. As used herein, "D-Tyr" and "y" each mean D-tyrosine. As used herein, "D-Ser" and "s" mean D-serine. As used herein, "D-Ala" and "a" each mean D-alanine. As used herein, "αMeF(2F)" means α-methyl-F(2F) and α-methyl-Phe(2F). As used herein, "αMeF" means α-methyl-F and α-methyl-Phe. As used herein, "αMeY" means α-methyl-Tyr. As used herein, "αMeK" means α-methyl-Lys. As used herein, "αMeL" means α-methyl-Leu. As used herein, "αMeS" means α-methyl-serine and α-methyl-Ser. As used herein, "αMeP" means α-methyl-proline and α-methyl-Pro. As used herein, "desH" means desHis. As used herein, "desY" means desTyr.

[0058] When X1 is DesH and X2 is Aib, DesH and Aib may combine to form a group as exemplified above, DesH-ψ[NHCO]-Aib.

[0059] As used herein, the term "conjugated to C 16 -C 22 "Amino acid conjugated to a fatty acid" refers to any natural or unnatural amino acid having a functional group conjugated to the fatty acid by means of a covalent bond to the fatty acid or, preferably, by means of a linker, by chemical modification. Examples of such functional groups include amino, carboxyl, chloro, bromo, iodo, azido, alkynyl, alkenyl, and thiol. Examples of natural amino acids including such functional groups include K (amino), C (thiol), E (carboxyl), and D (carboxyl). In one embodiment, the conjugated amino acid is K.

[0060] As described above, in one embodiment, compounds of Formula I, II, III, IV and V are compounds of the invention wherein the fatty acid moiety is conjugated via a linker or a direct bond. In one embodiment, the compounds of the invention include a fatty acid moiety conjugated to K at position 14 or 17, preferably via a linker. In one embodiment, the conjugation is an acylation. In one embodiment, the conjugation is conjugated to the ε-amino group of the K side chain. In one embodiment, the compounds of the invention include a fatty acid moiety conjugated to K at position 17 via a linker.

[0061] In one embodiment, the compounds of the invention include a fatty acid moiety that is directly conjugated to a natural or unnatural amino acid having a functional group available for conjugation without a linker. In certain preferred embodiments, the conjugated amino acid is selected from K, C, E, and D. In particularly preferred embodiments, the conjugated amino acid is K. In such embodiments, the conjugation is to the ε-amino group of the K side chain.

[0062] In one embodiment, the linker comprises one to four amino acids, amino polyethylene glycol carboxylates, or mixtures thereof. In one embodiment, the amino polyethylene glycol carboxylates have the formula: H-{NH-CH2-CH2-[O-CH2-CH2]pO-(CH2)z-CO}r-OH, wherein p is any integer from 1 to 12, z is any integer from 1 to 20, and r is 1 or 2.

[0063] In one embodiment, it is a compound of formula I comprising an amino acid conjugated to a fatty acid via a linker, wherein the linker is one to two amino acids selected from Glu and γ-Glu. In one embodiment, the linker is one to two (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. The compounds of the present invention utilize C-terminal groups chemically conjugated to the functional groups of amino acids by direct bonds or by linkers. 16 -C 22 In one embodiment, the fatty acid moiety is conjugated to the lysine via a linker between the lysine at position 17 and the fatty acid. In one embodiment, the fatty acid moiety is conjugated to the lysine via a linker between the lysine at position 20 and the fatty acid. In one embodiment, the fatty acid chain is any single C 16 -C 22 fatty acid.

[0064] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the fatty acid is conjugated with a linker, and the linker comprises one or more (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties in combination with zero or one to four amino acids. In one embodiment, the linker may comprise one to four Glu or γ-Glu amino acid residues. In one embodiment, the linker may comprise 1 or 2 Glu or γ-Glu amino acid residues. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, comprising a fatty acid conjugated via a linker, wherein the linker comprises 1 or 2 γ-Glu amino acid residues. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, comprising a fatty acid conjugated via a linker, wherein the linker may comprise one to four amino acid residues (e.g., Glu and γ-Glu amino acids) for use in combination with up to 36 (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. Specifically, in one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, comprising a fatty acid conjugated via a linker, wherein the linker constitutes a combination of one to four Glu and γ-Glu amino acids and one to four (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, comprising a fatty acid conjugated via a linker, wherein the linker comprises a combination of one or two γ-Glu amino acids and one or two (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, comprising a fatty acid conjugated via a linker, wherein the linker and fatty acid components have the following formula: (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein a is 1 or 2, b is 1 or 2 and q is 16 or 18. In one embodiment, a is 2, b is 1 and q is 18; and the structure is: In one embodiment, a is 1, b is 2, and q is 18; and the structure is: In one embodiment, a is 1, b is 1 and q is 18; and the structure is:

[0065] The term "C 16 -C 22"Fatty acid" as used herein means a carboxylic acid having between 16 and 22 carbon atoms. In one embodiment, a C 16 -C 22 The fatty acid may be a saturated diacid. In one embodiment, the fatty acid is C 20 -C 22 In one embodiment, q is selected from the group consisting of 14, 16, 18 and 20. In one embodiment, q is selected from the group consisting of 18 and 20. In one embodiment, q is 18. In one embodiment, q is 20.

[0066] In one embodiment, specific saturated C 16 -C 22 Fatty acids include, but are not limited to, hexadecanedioic acid (C 16 Diacid), heptadecanedioic acid (C 17 Octadecanedioic acid (C 18 Diacid), nonadecanedioic acid (C 19 diacid), eicosanedioic acid (C 20 Diacid), heneicosane dioic acid (C 21 Docosanoic acid (C 22 diacids), including branched and substituted derivatives thereof.

[0067] In one embodiment, C 16 -C 22 The fatty acids are selected from saturated C 18 Diacid, saturated C 19 Diacid, saturated C 20 Diacids and their branched and substituted derivatives. In one embodiment, C 16 -C 22 The fatty acid is selected from stearic acid, arachidic acid and eicosandioic acid. 16 -C 22 The fatty acid is arachidic acid.

[0068] As shown in the chemical structures of Examples 1-5 below, in one embodiment, the linker-fatty acid moiety is attached to the epsilon-amino group of the lysine side chain.

[0069] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X39 and X 40 In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40 None of them is a substituent containing a fatty acid; and X 30 , X 34 , X 39 , and X 40 In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40 None of them contain fatty acid substituents.

[0070] As used herein, "delayed delivery technology" means peptide delayed delivery technology, such as recombinant human serum albumin ("rHSA"); peptide conjugated to a pharmaceutically acceptable polymer, such as a polymerized amino acid sequence ("XTEN"), an unsulfated heparin-like carbohydrate polymer ("HEP"), hydroxyethyl starch ("HES"), a llama heavy chain antibody fragment ("VHH"); PEGylation; Fc conjugation; bovine serum albumin ("BSA") (Sleep, D. Epert Opin Drug Del (2015) 12, 793-812; Podust VN et al., J Control. Release, 2015; ePUB; Hey, T. et al. in: R. Kontermann (ed.), Therapeutic Proteins: Strategies to Modulate their Plasma Half-Lives, Wiley-VCH VerlagGmbh&Co.KGaA, Weinheim, Germany, 2012, pp. 117-140; DeAngelis, PL, Drug Dev Delivery (2013) January, 12 / 31 / 2012. In one embodiment, the time-delay technique is applied using a linker group. In one embodiment, the time-delay technique is applied using 0, 1, 2 or 3 amino acids as a linker.

[0071] In one embodiment, it is free of fatty acids (ie, wherein X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40Compounds of Formula I or pharmaceutically acceptable salts thereof that are not compounds containing fatty acid substituents) or time-delay technology can be administered to patients in need thereof via transdermal or infusion administration methods. Further, compounds of Formula I or pharmaceutically acceptable salts thereof that do not have fatty acids can be further modified using peptide time-delay technology, such as recombinant human serum albumin ("rHSA"); peptides are conjugated to pharmaceutically acceptable polymers, such as polymerized amino acid sequences ("XTEN"), unsulfated heparin-like carbohydrate polymers ("HEP"), and hydroxyethyl starch ("HES"). In one embodiment, a cysteine ​​amino acid in a compound of Formula I or pharmaceutically acceptable salt thereof that does not have fatty acids is used to apply time-delay technology using procedures known to those skilled in the art. In one embodiment, the time-delay technology is applied to an amino acid in a compound of Formula I or pharmaceutically acceptable salt thereof that does not have fatty acids. In one embodiment in which the time-delay technology is applied to a compound of Formula I or pharmaceutically acceptable salt thereof that does not have fatty acids, X 17 is selected from I, K and Q. In one embodiment in which the time-delay technique is applied to a compound of Formula I or a pharmaceutically acceptable salt thereof without a fatty acid, X 30 is C. In one embodiment where the time-delay technique is applied to a compound of Formula I or a pharmaceutically acceptable salt thereof without a fatty acid, X 34 is C. In one embodiment where the time-delay technique is applied to a compound of Formula I or a pharmaceutically acceptable salt thereof without a fatty acid, X 39 is C. In one embodiment where the time-delay technique is applied to a compound of Formula I or a pharmaceutically acceptable salt thereof without a fatty acid, X 40 It is C.

[0072] When used herein with reference to one or more of the GIP or GLP-1 receptors, the terms "activity," "activate[s]," "activat[ing]," and the like refer to the ability of a compound, or a pharmaceutically acceptable salt thereof, to bind to and induce a response at the receptor as measured using assays known in the art, such as the in vitro assays described below.

[0073] The affinity of the compounds of the present invention or their pharmaceutically acceptable salts for each of the GIP and GLP1 receptors can be measured using techniques known in the art for measuring receptor binding levels, including, for example, the techniques described in the Examples below, and is generally expressed as a Ki value. The activity of the compounds of the present invention for each receptor can also be measured using techniques known in the art, including, for example, the in vitro activity assays described below, and is generally expressed as an EC 50The value is the concentration of compound that causes a half-maximal simulation in a dose-response curve.

[0074] In one embodiment, the pharmaceutical composition of the compound of formula I is suitable for administration by parenteral route (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). Some pharmaceutical compositions and methods for preparing the same are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (DB Troy ed., 21st ed., Lippincott, Williams & Wilkins, 2006). In addition to the anatomical and physiological characteristics of the gastrointestinal tract, the physiochemical properties of peptides may also provide challenges to the effective oral delivery of peptides. In one embodiment, the pharmaceutical composition for oral administration comprises the compound of the present invention and a penetration enhancer. In one embodiment, the pharmaceutical composition for oral administration comprises a compound of formula I or a pharmaceutically acceptable salt thereof, a penetration enhancer and a protease inhibitor. In one embodiment, the pharmaceutical composition for oral administration comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a penetration enhancer.

[0075] The monolithic and multi-particulate dosage forms of the compounds of the present invention are contemplated. In one embodiment, the compound of formula I is provided in the form of a monolithic composition. The monolithic composition is intended to release all components at a single location. The multi-particulate composition is intended to achieve rapid delivery from the stomach to the intestine and allow the composition components to be distributed over a larger surface of the small intestine. Monolithic and multi-particulate dosage compositions require the compound to be released simultaneously with a functional excipient. In one embodiment, the monolithic composition of the compound of formula I or a pharmaceutically acceptable salt thereof is formulated as an enteric capsule, an enteric coated capsule or an enteric coated tablet. Such a multi-particulate composition can be formulated as an enteric coated mini-tablet, or an enteric coated granule, wherein the coating is generally intact in the low pH of the stomach and dissolves at a higher pH of the intestine. Two types of coated mini-tablets or coated granules can be formulated so as to be delivered to the proximal small intestine by dissolving above pH 5.5 or to the distal small intestine by dissolving above pH 7-7.2. If distal small intestine delivery is desired, a coating system for distal small intestine release may also be applied to the monolithic capsule or tablet.Mini-tablets can be filled into standard uncoated capsules.

[0076] As used herein, the term "penetration enhancer" means a penetration enhancer that enhances the oral absorption of the compounds of the present invention. As used herein, a penetration enhancer means a penetration enhancer such as sodium decanoate, sodium taurodeoxycholate, lauroylcarnitine, dodecyl maltoside, dodecyl phosphatidylcholine, SNAC, rhamnolipids, and penetration enhancers reported in the literature, such as permeability inhibitors of phosphatase, PIP-250 and PIP-640 (see Pharmaceutics. 2019 Jan; 11(1):41, (see Biomaterials. 2012; 33:3464-3474), ZOT (zona occludens toxin), ΔG (fragment of ZOT) (see Int. J. Pharm. 2009; 365, 121-130). In one embodiment, the penetration enhancer is selected from sodium decanoate, sodium taurodeoxycholate, and lauroylcarnitine. In one embodiment, the penetration enhancer is selected from C10, LC, and NaTDC. In one embodiment, the penetration enhancer is C10.

[0077] As used herein, the term "protease inhibitor" means a protease inhibitor that can be selected from protein-based, peptide-based, and small molecule-based. Protease inhibitors are well known and can include, for example, soybean trypsin inhibitor ("SBTI"), soybean trypsin-chymotrypsin inhibitor ("SBTCI"), colicin, sunflower trypsin inhibitor ("SFTI"), leupeptin, citric acid, ethylenediaminetetraacetic acid ("EDTA"), sodium glycocholate, and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride ("AEBSF"). In one embodiment, the protease inhibitor is selected from SBTI, SBTCI, and SFTI. In one embodiment, the protease inhibitor is SBTI.

[0078] In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is a potent GIPR / GLP-1R dual agonist, which is a partial agonist of GLP-1R, such as cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 S] (GTPγS) binding assay; and partial agonist of GLP-1R, as demonstrated by β-arrestin-2 recruitment assay. In one embodiment, it is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is a GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 Stimulation of GLP-1R-induced Gα in the [S](GTPγS) binding assay s In one embodiment, it is in the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35Compounds that exhibit a partial agonism of 75% or less in the [S](GTPyS) binding assay and a partial agonism of 35% or less in the GLP-CHO cell β-arrestin recruitment assay.

[0079] In one embodiment, it is a method for treating diabetes, comprising administering an effective amount of a compound that is active in the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 S] (GTPγS) binding assay; and an effective amount of a compound that is a GIP agonist. In one embodiment, the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 A compound that exhibits partial agonism in a [S](GTPγS) binding assay is co-administered with a compound having GIP agonist activity. In one embodiment, within one week before or after administration of a compound having GIP agonist activity, a GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 S] (GTPγS) binding assay shows a partial agonist compound as an active agent. In one embodiment, the method for treating diabetes comprises administering an effective amount of a compound that exhibits 35% or less in a GLP-CHO cell β-arrestin recruitment assay; and administering an effective amount of a compound that exhibits 35% or less in a GLP-1RHEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 S](GTPγS) binding assays showed partial agonism of 75% or less.

[0080] The compounds of the present invention can react with any of a variety of inorganic acids and organic acids / bases to form pharmaceutically acceptable acid / base addition salts. Pharmaceutically acceptable salts and common preparation methods thereof are well known in the art (see, e.g., P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011)). Pharmaceutically acceptable salts of the present invention include, but are not limited to, sodium salts, trifluoroacetates, hydrochlorides, ammonium salts and acetates. In one embodiment, pharmaceutically acceptable salts are selected from sodium salts, hydrochlorides and acetates.

[0081] The present invention also encompasses novel intermediates and methods for synthesizing the compounds of the invention or their pharmaceutically acceptable salts. The intermediates and compounds of the present invention can be prepared by a variety of procedures known in the art. In particular, the following examples describe methods utilizing chemical synthesis. The specific synthetic steps of each described approach can be combined in different ways to prepare the compounds of the invention. Reagents and starting materials are readily available to those skilled in the art.

[0082] As used herein, the term "effective amount" refers to the amount or dosage of a compound of the present invention or a pharmaceutically acceptable salt thereof, which, after being administered to a patient in single or multiple doses, provides the desired effect to a patient under diagnosis or treatment. The effective amount can be determined by a person skilled in the art using known techniques and by observing the results obtained under similar circumstances. When determining the effective amount for a subject, a variety of factors are considered, including (but not limited to): the species of mammal; its size, age, and general health; the specific disease or condition involved; the extent or severity of the disease or condition; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosage regimen; the use of concomitant drugs; and other relevant circumstances.

[0083] As used herein, the term "subject in need" refers to a mammal, preferably a human, suffering from a disease or condition requiring treatment or therapy, including, for example, those listed in the preceding paragraphs. 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. DETAILED DESCRIPTION The present invention also relates to the following embodiments: 1. A compound of the formula: R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28X 29 X 30 X 31 (SEQ ID NO: 3), wherein: R1 is a modification of the N-terminal amino group, wherein the modification is selected from Ac and absent; X1 is selected from the group consisting of Y, H, D-Tyr, F, desH and desY; X2 is selected from Aib, αMeP, A, P and D-Ala ； or X1 and X2 combine to form desH-ψ[NHCO]-Aib; X3 is selected from E, N, Aad and cTA; X6 is selected from the group consisting of F, αMeF and αMeF(2F); X 10 Selected from A, L, H, 3Pal, 4Pal, V, Y, E, αMeF, αMeF(2F), I, αMeY, Q, D-His, D-Tyr, cTA and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 11 Selected from S, αMeS and D-Ser; X 12 Selected from I, S, D-Ile and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 13 Selected from Nle, Aib, L, αMeL and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 14 Selected from L and K, wherein K is conjugated to C 16 -C 22 a fatty acid, wherein the fatty acid is optionally conjugated to the K via a linker; X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 17 Selected from K, Q, I and conjugated to C 16 -C 22 an amino acid to a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker; X 19Selected from Q, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 20 Selected from Aib, Q, H, R, K, αMeK and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 21 Selected from H, Aad, D, Aib, T, A, E, I and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 22 Selected from F and αMeF; X 23 Selected from I, L, A, G, F, H, E, V and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 24 Selected from S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 25 is selected from Y and αMeY; X 26 Selected from L, αMeL and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 27 Selected from L, I and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 28 Selected from E, A, S, D-Glu and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 29 Selected from Aib, G, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 30 Selected from C, G, G-R2 and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H; X 31 Not present or selected from PX32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 6), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 -R2 (SEQ ID NO: 7), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 8) and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 9); wherein: X 32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 34 Selected from G, C and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; X 35 A or K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; X 36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]; X 39 Selected from C, S and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; X 40 is selected from C and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)q-CO2H]; q is selected from 14, 15, 16, 17, 18, 19 and 20; and R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent; or a pharmaceutically acceptable salt thereof; If X 30 is G-R2, then X 31 does not exist; Where X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40 No more than one of may be a fatty acid containing substituent; and Where X 30 , X 34 , X 39 and X 40 No more than one of can be C; and If X 30 , X 34 , X 39 and X 40 If one of them is C, then X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40 None of them contain fatty acid substituents. 2. The compound or pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein X1 and X2 do not combine to form desH-ψ[NHCO]-Aib. 3. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1 or Embodiment 2, wherein X 17 is conjugated to C 16 -C 22 Amino acids of fatty acids. 4. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 3, wherein: X1 is Y; X2 is Aib; X3 is E; X 10 Selected from A, L, H, 3Pal, 4Pal, V and Y; X 11 It is S; X 12 It's I; X 14 It is L; X 16 Selected from K, E, Orn, Dab and Dap; X 17 is conjugated to C 16 -C 22 K of a fatty acid, wherein the fatty acid is conjugated to K via a linker; X 19 It is Q; X 20 It is Aib; X 21 Selected from H, Aad, D, Aib, T, A and E; X 22 It is F; X 23 It's I; X 24 Selected from S, Aad, D-Glu and E; X 26 It is L; X 27 selected from L and I; and X 28 Selected from E and A. 5. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 4, wherein: X 30 It's G and X 31 It is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), wherein X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X 38 It is P and X 39 It is S (SEQ ID NO: 298). 6. A compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 1, 2 or 5, wherein X17 It's K. 7. The compound of embodiment 4 or a pharmaceutically acceptable salt thereof, wherein the linker comprises one to two amino acids. 8. The compound of embodiment 7 or a pharmaceutically acceptable salt thereof, wherein the linker comprises one to two (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. 9. The compound or pharmaceutically acceptable salt thereof as described in embodiment 8, wherein the linker comprises one to two amino acids independently selected from Glu and γ-Glu. 10. The compound of embodiment 9 or a pharmaceutically acceptable salt thereof, wherein the linker has the following formula: {(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b, wherein a is 1 or 2; and b is 1 or 2. 11. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 10, wherein X 17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H, wherein: a is 1 or 2; b is 1 or 2; and q is selected from 14 to 20. 12. The compound of embodiment 11 or a pharmaceutically acceptable salt thereof, wherein a is 1. 13. A compound as described in embodiment 11 or a pharmaceutically acceptable salt thereof, wherein a is 2. 14. The compound of any one of embodiments 11 to 13, or a pharmaceutically acceptable salt thereof, wherein b is 1. 15. A compound as described in any one of embodiments 11 to 13, or a pharmaceutically acceptable salt thereof, wherein b is 2. 16. A compound as described in any one of embodiments 11 to 15, or a pharmaceutically acceptable salt thereof, wherein q is 18. 17. The compound of any one of embodiments 11 to 15, or a pharmaceutically acceptable salt thereof, wherein q is 16. 18. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 11, wherein X 17 It is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H. 19. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 18, wherein X 27 It's I. 20. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 18, wherein X 27 It's L. 21. A compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, wherein: R1 does not exist; X1 is Y; X2 is Aib; X3 is E; X6 is αMeF(2F); X 10 Selected from Y, 4-PaI and V; X 11 It is S; X 12 It's I; X 13 Selected from L, Aib and αMeL; X 14 It is L; X 16 Selected from E, K and Orn; X 17 It is K; X 19 It is Q; X 20 It's Aib X 21 Selected from E, A and T; X 22 It is F; X 23 It's I; X 24 It is D-Glu; X 26 It is L; X 27 It's I; X 28 It is E; X 29 It is G; X 30 is G; and X 31 It is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), wherein X 32 It is S, X 33 It is S, X 34 It is G, X35 It is A, X 36 It is P, X 37 It is P, X 38 It is P and X 39 It is S (SEQ ID NO: 298). 22. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 21, wherein X 25 It is Y. 23. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 22, wherein X 13 It's αMeL. 24. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 23, wherein X 16 It's Orn. 25. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 23, wherein X 16 It's E. 26. A compound as described in any one of embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein X 10 It is Y. 27. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 25, wherein X 10 It's V. 28. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 25, wherein X 10 It's 4Pal. 29. The compound or pharmaceutically acceptable salt thereof according to embodiment 11, wherein X 13 is αMeL; a is 2; b is 1; q is 16; and X 25 It is Y. 30. The compound according to embodiment 11 or a pharmaceutically acceptable salt thereof, wherein X 13 is αMeL; a is 2; b is 1; q is 18; and X 25 It is Y. 31. The compound or pharmaceutically acceptable salt thereof according to embodiment 11, wherein X 13 is αMeL; a is 2; b is 1; q is 14; and X 25 It is Y. 32. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 24, wherein X 10 is Y; and X 16 It's Orn. 33. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 23, wherein X 10 is Y; and X16 It's E. 34. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 23, wherein X 10 is 4Pal; and X 16 It's Orn. 35. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 23, wherein X 10 is V; and X 16 It's Orn. 36. The compound of embodiment 1, wherein the compound is selected from SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof. 37. The compound of embodiment 36, wherein the compound is SEQ ID NO: 13, or a pharmaceutically acceptable salt thereof. 38. The compound of embodiment 36, wherein the compound is SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof. 39. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof in: X 10 Selected from A, L, H, 3Pal, 4Pal, V, Y, αMeF, αMeF(2F), I, αMeY, Q, D-His, E, cTA and D-Tyr; X 12 Selected from I, D-Ile and S; X 13 Selected from Nle, Aib, L and αMeL; X 14 It is L; X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK and R; X 17 Selected from K, Q and I; X 19 Selected from Q and A; X 20 Selected from Aib, Q, H, R, K and αMeK; X 21 Selected from H, Aad, D, Aib, T, A, E and I; X 23 Selected from I, L, A, G, F, H, E and V; X 24Selected from S, Aad, D-Glu, E, Aib, H, V, A, Q, D and P; X 26 Selected from L and αMeL; X 27 Selected from L and I; X 28 Selected from E, A, S and D-Glu; and X 29 Selected from Aib, G and A. 40. The compound of embodiment 39 or a pharmaceutically acceptable salt thereof, wherein: X1 is Y; X2 is Aib; X3 is E; X 10 Selected from A, L, H, 3Pal, 4Pal, V and Y; X 11 It is S; X 12 It's I; X 16 Selected from K, E, Orn, Dab and Dap; X 19 It is Q; X 20 Selected from Aib and K; X 21 Selected from H, Aad, D, Aib, T, A and E; X 22 It is F; X 23 It's I; X 24 Selected from S, Aad, D-Glu and E; X 26 is L; and X 28 Selected from E and A. 41. A compound or a pharmaceutically acceptable salt thereof as described in any one of Embodiments 39 or 40, wherein X 30 , X 34 and X 39 One of them is C. 42. The compound of embodiment 41 or a pharmaceutically acceptable salt thereof, wherein the compound is modified using time-delay technology. 43. A compound as described in any one of embodiments 39 to 42, or a pharmaceutically acceptable salt thereof, wherein q is 18. 44. A compound as described in any one of embodiments 39 to 42, or a pharmaceutically acceptable salt thereof, wherein q is 16. 45. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 39 to 44, wherein X 27 It's L. 46. ​​A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 39 to 45, wherein X 31 It is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2. 47. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 39 to 45, wherein X 31 Does not exist. 48. A compound as described in embodiment 47 or a pharmaceutically acceptable salt thereof, wherein R2 is NH2. 49. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof in: X 14 It is L; X 17 Selected from K, Q and I; X 30 is selected from G-R2 and G; and q is selected from 16, 18 and 20; If X 30 is G, then X 31 Selected from: PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), wherein: X 32 It is S, X 33 It is S, X 34 G and R2 are absent (SEQ ID NO: 299) or X 32 It is S, X 33 It is S, X 34 is G and R2 is NH2 (SEQ ID NO: 300); and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), wherein: X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X 38 It is P, X 39 S and R2 are absent (SEQ ID NO: 301) or X 32 It is S, X 33 It is S, X 34 It is G, X 35 It is A, X 36 It is P, X 37 It is P, X 38 It is P, X 39 is S and R2 is NH2 (SEQ ID NO: 302); and Where X 10 , X 12 , X 13 , X 14 , X 16 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 and X 29 One of them is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2)qCO2H. 50. The compound of embodiment 49 or a pharmaceutically acceptable salt thereof, wherein: X1 is Y; X2 is Aib; X3 is E; X 10 Selected from A, L, H, 3Pal, 4Pal, V, Y, E, cTA and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 11 It is S; X 12 Selected from I, D-Ile and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 14Selected from L and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 16 Selected from K, E, Orn, Dab, Dap and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 17 Selected from K and I; X 19 Selected from Q and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 20 Selected from Aib and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 21 Selected from H, Aad, D, Aib, T, A, E and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H; X 22 It is F; X 23 It's I; X 24 Selected from S, Aad, D--Glu, E and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 26 Selected from L and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 27 Selected from L and I; X 28 Selected from E, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2-(γ-Glu)-CO-(CH2)qCO2H; X 30 is G; and X 31 Selected from PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X 33 X 34 X 35 X 36 X37 X 38 X 39 -R2 (SEQ ID NO: 5), X 32 It is S; X 33 It is S; X 34 It is G; X 35 It is A; X 36 It is P; X 37 It is P; X 38 is P; and X 39 It’s S. 51. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 49 to 50, wherein X 20 It is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H. 52. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 49 to 51, wherein PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 is selected from the group consisting of PSSGAPPPS (SEQ ID NO: 301) and PSSGAPPPS-NH2 (SEQ ID NO: 302). 53. A compound as described in any one of embodiments 49 to 52, or a pharmaceutically acceptable salt thereof, wherein q is 18. 54. A compound as described in any one of embodiments 49 to 52, or a pharmaceutically acceptable salt thereof, wherein q is 16. 55. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof in: X1 is selected from the group consisting of Y, F, D-Tyr and desY, X6 is F; and X 13 Selected from Aib, L, and αMeL. 56. A compound as described in embodiment 55 or a pharmaceutically acceptable salt thereof, wherein R1 does not exist; X2 is Aib; X3 is E; X10 It is Y; X 11 It is S; X 12 It's I; X 14 It is L; X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK and RX 17 is conjugated to C 16 -C 22 an amino acid to a fatty acid, wherein the fatty acid is conjugated to the amino acid, optionally via a linker; X 19 It is Q; X 20 Selected from Aib, Q, H and K; X 21 Selected from H, D, T, A and E; X 22 It is F; X 23 It's I; X 24 Selected from D-Glu and E; X 26 It is L; X 27 It's I; X 28 Selected from E, A, S and D-Glu; X 29 Selected from Aib, G and A; X 30 Selected from C, G and G-R2; X 31 Not present or selected from PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) and PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 6); wherein: X 32 It is S; X 33 It is S; X 34 Selected from G and C; X 35 It is A; X 36 It is P; X 37 It is P; X 38 It is P; X 39 selected from C and S; and X 40 It is C. 57. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 55 to 56, wherein X 17 It is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H. 58. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 55 to 57, wherein PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 is selected from the group consisting of PSSGAPPPS (SEQ ID NO: 301) and PSSGAPPPS-NH2 (SEQ ID NO: 302). 59. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 55 to 58, wherein X 28 It is A; X 29 G; X 30 It is G; X 31 It is PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) X 34 is G; and X 39 It’s S. 60. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 55 to 59, wherein X1 is selected from Y and D-Tyr; and X 13 It's αMeL. 61. A compound as described in any one of embodiments 55 to 60, or a pharmaceutically acceptable salt thereof, wherein q is 16. 62. A compound as described in any one of embodiments 55 to 60, or a pharmaceutically acceptable salt thereof, wherein q is 18. 63. A compound or a pharmaceutically acceptable salt thereof as described in embodiment 1, wherein the compound is selected from SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO: 392. 64. The compound of embodiment 63 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO: 305. 65. The compound of embodiment 63 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO: 307. 66. The compound of embodiment 63 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO: 308. 67. The compound of embodiment 63 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO: 392. 68. A compound as described in any one of embodiments 1 to 67, or a pharmaceutically acceptable salt thereof, wherein the compound is a partial agonist of GLP-1R. 69. A compound or a pharmaceutically acceptable salt thereof as described in embodiment 68, wherein the compound is expressed in GIPR and GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 Stimulation of GLP-1R-induced Gα in the [S](GTPγS) binding assay s activation. 70. The compound of any one of embodiments 68 or 69, or a pharmaceutically acceptable salt thereof, wherein the compound is a partial agonist of GLP-1R for a β-arrestin-2 recruitment assay. 71. A method for treating a condition selected from type 2 diabetes, obesity, NAFLD, non-alcoholic steatohepatitis, dyslipidemia and metabolic syndrome, comprising administering to a patient in need thereof an effective amount of a compound as described in any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof. 72. A method for treating obesity, comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1 to 70 or a pharmaceutically acceptable salt thereof. 73. A method for providing therapeutic weight loss, comprising administering to a subject in need thereof an effective amount of a compound as described in any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof. 74. A method for treating type 2 diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 70 or a pharmaceutically acceptable salt thereof. 75. A pharmaceutical composition comprising a compound as described in any one of Embodiments 1 to 70 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient. 76. The pharmaceutical composition of embodiment 75, wherein the composition is administered as a subcutaneous injection. 77. The pharmaceutical composition of embodiment 75, wherein the composition is administered orally. 78. The pharmaceutical composition of embodiment 77, wherein the composition comprises a penetration enhancer and at least one pharmaceutically acceptable carrier, diluent or excipient. 79. A pharmaceutical composition as described in embodiment 78, wherein the penetration enhancer is selected from sodium decanoate ("C10"), sodium taurodeoxycholate ("NaTDC"), lauroylcarnitine ("LC"), dodecyl maltoside ("C12-maltoside"), dodecylphosphatidylcholine ("DPC"), sodium taurodeoxycholate ("NaTDC") and rhamnolipid. 80. The pharmaceutical composition of embodiment 79, wherein the penetration enhancer is selected from C10 and LC. 81. The pharmaceutical composition of embodiment 80, wherein the penetration enhancer is C10. 82. The pharmaceutical composition of any one of embodiments 77 to 81, wherein the composition comprises a penetration enhancer and a protease inhibitor, and at least one pharmaceutically acceptable carrier, diluent, or excipient. 83. The pharmaceutical composition of embodiment 82, wherein the protease inhibitor is selected from soybean trypsin inhibitor ("SBTI"), soybean trypsin-chymotrypsin inhibitor ("SBTCI"), colicin, sunflower trypsin inhibitor ("SFTI"), leupeptin, citric acid, ethylenediaminetetraacetic acid ("EDTA"), sodium glycocholate and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride ("AEBSF"). 84. The pharmaceutical composition of embodiment 83, wherein the protease inhibitor is selected from SBTI, SBTICI and SFTI. 85. The pharmaceutical composition of embodiment 84, wherein the protease inhibitor is SBTI. 86. The pharmaceutical composition of any one of embodiments 77 to 85, wherein the composition is a monolithic formulation. 87. The pharmaceutical composition of any one of embodiments 77 to 85, wherein the composition is a multiparticulate formulation. 88. The pharmaceutical composition of any one of embodiments 77 to 85, wherein the composition is a capsule or a tablet. 89. The pharmaceutical composition of embodiment 86, wherein the composition is an enteric-coated capsule or tablet. 90. A compound as described in any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof, for use as a medicament. 91. A compound as described in any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof, for use in treating a disease selected from type 2 diabetes, obesity, NAFLD, NASH, dyslipidemia and metabolic syndrome. 92. A compound as described in any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof, for use in treating type 2 diabetes. 93. Use of a compound as described in any one of embodiments 1 to 70, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition selected from type 2 diabetes, obesity, NAFLD, NASH, dyslipidemia and metabolic syndrome. 94. Use of a compound as described in any one of embodiments 1 to 70 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating type 2 diabetes. 95. A method for treating diabetes, comprising administering an effective amount of guanosine 5'-(γ-thio) triphosphate-[ 35 Compounds that exhibit partial agonism of 75% or less in a [S](GTPyS) binding assay, and effective amounts of compounds that are GIP agonists. 96. The method of embodiment 95, wherein the diabetes is type 2 diabetes. 97. A method as described in any one of embodiments 95 or 96, wherein in the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 Compounds that exhibited partial agonism of 75% or less in the [S](GTPyS) binding assay were co-administered with compounds having GIP agonist activity. 98. A method as described in any one of embodiments 95 to 97, wherein in the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[35 Compounds that exhibited 75% or less partial agonism in the [S](GTPyS) binding assay were co-administered with compounds that exhibited 35% or less in the GLP-CHO cell [beta]-arrestin recruitment assay. 99. A method as described in any one of embodiments 95 to 98, wherein in the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 Compounds showing partial agonism in the [S](GTPyS) binding assay are administered as active ingredients within one week before or after administration of compounds having GIP agonist activity. 100. The method of any one of embodiments 95 to 98, wherein in the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 Compounds showing partial agonism in the [S](GTPγS) binding assay were administered as active ingredients within one week before or after administration of compounds having GIP agonism and showing 35% or less in the GLP-CHO cell β-arrestin recruitment assay.

[0084] The present invention is further illustrated by the following examples, which should not be construed as limiting.

[0085] Peptide synthesis Example 1 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2 (SEQ ID NO: 10).

[0086] The structure of SEQ ID NO: 10 is shown below, using standard single letter amino acid code, with the exception of residues Aib2, αMeF(2F)6, αMeL13, K17, Aib20, D-Glu24, and Ser39, where the structure of these amino acid residues has been expanded: The peptide backbone of Example 1 was synthesized on a Symphony X peptide synthesizer (Gyros Protein Technologies. Tucson, AZ) using fluorenylmethoxycarbonyl (Fmoc) / tert-butyl (t-Bu) chemistry.

[0087] The resin consisted of 1% DVB cross-linked polystyrene with a degree of substitution of 0.3-0.4 meq / g (Fmoc-Rink-MBHA low loading resin, 100-200 mesh, EMD Millipore). Standard side chain protecting groups were used. Fmoc-Lys(Mtt)-OH was used for lysine at position 17 and Boc-Tyr(tBu)-OH was used for tyrosine at position 1. The Fmoc group was removed using 20% ​​piperidine in DMF before each coupling step (2×7 min). All standard amino acid couplings were performed using equimolar ratios of Fmoc amino acids (0.3 mM), diisopropylcarbodiimide (0.9 mM) and Oxyma (0.9 mM) at a 9-fold molar excess over theoretical peptide loading for 1 hour (to give primary amines) and 3 hours (to give secondary amines). The exception was coupling with Cα-methylated amino acids, which was performed for 3 hours. After completion of the peptide backbone synthesis, the resin was washed extensively 6 times with DCM to remove residual DMF. The Mtt protecting group on lysine at position 17 was selectively removed from the peptide resin using two treatments (2 x 40 min treatments) of 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM.

[0088] The subsequent attachment of the fatty acid-linker moiety was accomplished by coupling 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fmoc-glutamic acid α-tert-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.), mono-OtBu-eicosanedioic acid (WuXi AppTec, Shanghai, China). A 3-fold excess of reagents (AA:PyAOP:DIPEA=1:1:1 mol / mol) was used for each coupling that was 1 hour long.

[0089] After completing the synthesis, the peptide resin was washed with DCM and then thoroughly air-dried. The dried resin was treated with 10mL cleavage mixture (trifluoroacetic acid: water: triisopropylsilane, 95:2.5:2.5v / v) at room temperature for 2 hours. The resin was filtered out, washed twice (each time with 2mL pure TFA), and the combined filtrate was treated with 5 times of volume excess cold ether (-20°C) to precipitate the crude peptide. The peptide / ether suspension was then centrifuged at 3500rpm for 2 minutes to form a solid pellet, the supernatant was decanted, and the solid pellet was ground twice more with ether and vacuum dried. The crude peptide was dissolved in 20% acetonitrile / 20% acetic acid / 60% water, and purified by RP-HPLC on a Luna 5μm Phenyl-Hexyl preparative column (21×250mm, Phenomenex), using a linear gradient of 100% acetonitrile and 0.1% TFA / water buffer system (30-50% acetonitrile, within 60 minutes). Peptide purity was assessed using analytical RP-HPLC and the pooling criteria was >95%. The main pool of compound 1 was found to be 98.0% pure. The final main product pool was then lyophilized to yield the lyophilized peptide TFA salt. The molecular weight was determined by LC-MS (observed: M+3=1657.2; calculated M+3=1657.0).

[0090] Example 2 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2 (SEQ ID NO: 11) The structure of SEQ ID NO: 11 is shown below, using standard single letter amino acid code, with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20 D-Glu24, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 11 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1642.6; calculated M+3 = 1642.8).

[0091] Example 3 Example 3 is a compound represented by the following description: Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2 (SEQ ID NO: 12) The structure of SEQ ID NO: 12 is shown below, using standard single letter amino acid code, with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 12 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1651.8; calculated M+3 = 1652.2).

[0092] Example 4 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH2 (SEQ ID NO: 13) The structure of SEQ ID NO: 13 is shown below, using standard single letter amino acid code, with the exception of residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24αMeY25, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 13 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1642.5; calculated M+3 = 1642.1).

[0093] Example 5 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16-CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH2 (SEQ ID NO: 14) The structure of SEQ ID NO: 14 is shown below, using standard single letter amino acid code, with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 14 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1626.1; calculated M+3 = 1626.1).

[0094] Example 6 to Example 287 The compounds according to Example 6 (SEQ ID NO: 15) to Example 287 (SEQ ID NO: 296) were prepared substantially as described in the procedure of Example 1.

[0095] N / I means not included.

[0096] Embodiment 288 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 303) The structure of SEQ ID NO:303 is shown below, using standard single letter amino acid numbering, with the exception of residues Aib2, K17, Aib20, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 303 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1602.5; calculated M+3 = 1602.8).

[0097] Embodiment 289 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 304) The structure of SEQ ID NO:304 is shown below, using standard single letter amino acid numbering, with the exception of residues Aib2, αMeL13, K17, Aib20, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 304 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1626.8; calculated M+3 = 1626.8).

[0098] Embodiment 290 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 305) The structure of SEQ ID NO:305 is shown below, using standard single letter amino acid numbering, with the exception of residues D-Tyr1, Aib2, αMeL13, K17, Aib20, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 305 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1626.6; calculated M+3 = 1626.8).

[0099] Embodiment 291 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-AFI-(D-Glu)-YLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 306) The structure of SEQ ID NO: 306 is shown below, using the standard single letter amino acid number, with the exception of residues D-Tyr1, Aib2, αMeL13, Orn16, K17, Aib20, D-Glu24 and Ser39 (where the structure of these amino acid residues has been expanded): The compound according to SEQ ID NO: 306 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1602.4; calculated M+3 = 1602.8).

[0100] Embodiment 292 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH2 (SEQ ID NO: 307) The structure of SEQ ID NO:307 is shown below, using standard single letter amino acid numbering, with the exception of residues D-Tyr1, Aib2, αMeL13, K17, Aib20, αMeY25, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 307 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1631.3; calculated M+3 = 1631.5).

[0101] Embodiment 293 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH2 (SEQ ID NO: 308) The structure of SEQ ID NO:308 is shown below, using standard single letter amino acid numbering, with the exception of residues D-Tyrl, Aib2, αMeL13, Orn16, K17, Aib20, αMeY25, and Ser39, where the structure of these amino acid residues has been expanded: The compound according to SEQ ID NO: 308 was prepared essentially as described in the procedure of Example 1. The molecular weight was determined by LC-MS (observed: M+3 = 1626.5; calculated M+3 = 1626.8).

[0102] Example 294 to Example 381 The compounds according to Example 294 (SEQ ID NO: 309) to Example 381 (SEQ ID NO: 396) were prepared substantially as described in the procedure of Example 1.

[0103] N / I means not included.

[0104] Binding assay Glucagon (referred to as Gcg) was a reference standard prepared by Eli Lilly and Company. GLP-1, 7-36-NH2 (referred to as GLP-1) was obtained from CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 μM aliquots in 100% DMSO). GIP 1-42 (referred to as GIP) was prepared as described above at Lilly Research Laboratories using peptide synthesis and HPLC chromatography (>80% purity, 100 μM aliquots in 100% DMSO). 125 I]-Lactoperoxidase preparation [ 125 I] Radiolabeled Gcg, GLP-1 or GIP.

[0105] Stably transfected cell lines were prepared by subcloning the receptor cDNAs into pcDNA3 expression plasmids 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).

[0106] Two methods were used to prepare crude cell membranes.

[0107] Method 1 Frozen cell pellets were lysed on ice in 50 mM Tris HCl pH 7.5 and Roche Complete TM The 25-stroke The cell suspension was broken up using a glass Potter-Elvehjem homogenizer with a pestle. The homogenate was centrifuged at 1100 × g for 10 minutes at 4°C. The supernatant was collected and stored on ice while the pellet was resuspended in homogenization buffer and rehomogenized as described above. The homogenate was centrifuged at 1100 × g for 10 minutes. The second supernatant was combined with the first supernatant and centrifuged at 35000 × g for 1 hour at 4°C. The resulting membrane pellet was resuspended in homogenization buffer containing about 1 to 3 mg / mL protease inhibitors, snap frozen in liquid nitrogen, and stored as aliquots in a -80°C freezer until use.

[0108] Method 2 : Frozen cell pellets were lysed on ice in 50 mM Tris HCl pH 7.5, 1 mM MgCl2, Roche Complete TM The cells were then resuspended in a hypotonic buffer containing EDTA-free protease inhibitors and 25 units / ml of DNase I (Invitrogen). The cell suspension was broken up using a glass Potter-Elvehjem homogenizer with a pestle. The homogenate was centrifuged at 1800 × g for 15 minutes at 4°C. The supernatant was collected and stored on ice while the pellet was resuspended in homogenization buffer (without DNase I) and rehomogenized as described above. The homogenate was centrifuged at 1800 × g for 15 minutes. The second supernatant was combined with the first supernatant and centrifuged at 1800 × g for another 15 minutes. The total supernatant was then centrifuged at 25000 × g for 30 minutes at 4°C. The resulting membrane pellet was resuspended in homogenization buffer (without DNase I) containing approximately 1 to 3 mg / mL protease inhibitors and stored as aliquots in a -80°C freezer until use.

[0109] Combined determination method due to [ 125 I] The stock material contained high levels of propanol, so homologous competition binding assays were used rather than saturation binding to determine the equilibrium binding dissociation constants (K) for various receptor / radioligand interactions. d ). K determined for receptor preparations d Values ​​are as follows: hGcgR (3.9 nM), hGLP-1R (1.2 nM), and hGIPR (0.14 nM).

[0110] [ 125 I]-glucagon binding 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-piperazineethanesulfonic 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. and Roche Complete EDTA-free TM Protease inhibitors. Peptides and Gcg were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5 μL of serially diluted compound or DMSO was transferred to a 45 μL assay binding buffer or unlabeled Gcg control (nonspecific binding or NSB, final 1 μM). 3632 clear bottom assay plate. Then, 50 μL [ 125 I]-Gcg (final 0.15 nM), 50 μL human GcgR membrane (1.5 μg / well) and 50 μL WGA SPA beads (80 to 150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute and after a 12 hour incubation / sedimentation time at room temperature, the beads were washed with a PerkinElmer Trilux Scintillation counter reading.The final assay concentration range for the peptides tested in the response curve was typically 1150 nM to 0.058 nM and for the control Gcg, 1000 nM to 0.05 nM.

[0111] [ 125 I]-GLP-1 binding The human GLP-1 receptor binding assay was performed using the SPA format with WGA beads. The binding buffer contained 25 mM HEPES, pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) and Roche Complete EDTA-free TM Protease inhibitors. Peptides and GLP-1 were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5 μL of serially diluted compound or DMSO was transferred to a 45 μL assay binding buffer or unlabeled GLP-1 control (nonspecific binding or NSB, final 0.25 μM). 3632 clear bottom assay plate. Then, 50 μL [ 125 I]-GLP-1 (final 0.15 nM), 50 μL human GLP-1R membrane (0.5 μg / well and 50 μL WGA SPA beads (100-150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute and after a 5-12 hour incubation / sedimentation time at room temperature, the beads were washed with a PerkinElmer Trilux Scintillation counter reading.The final assay concentration range for the peptides tested in the response curve was typically 1150 nM to 0.058 nM and for the control GLP-1, 250 nM to 0.013 nM.

[0112] [125I]-GIP binding Human GIP receptor binding assay was performed using the SPA format with WGA beads. The binding buffer contained 25 mM HEPES, pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) and Roche Complete EDTA-free TM Protease inhibitors. Peptides and GIP were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Next, 5 μL of serially diluted compound or DMSO was transferred to a 45 μL assay binding buffer or unlabeled GIP control (nonspecific binding or NSB, final 0.25 μM). 3632 clear bottom assay plate. Then, 50 μL [ 125 I]-GIP (final 0.075-0.15 nM), 50 μL human GIPR membrane (3 μg / well) and 50 μL WGA SPA beads (100-150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute and after 2.5 to 12 hours incubation / sedimentation time at room temperature, the beads were precipitated with a PerkinElmer Trilux Scintillation counter reading.The final assay concentration range for the peptides tested in the response curve was typically 1150 nM to 0.058 nM or 115 nM to 0.0058 nM, and for the control GIP, 250 nM to 0.013 nM.

[0113] Binding assay data analysis The CPM raw data of the concentration curves of peptide, Gcg, GLP-1 or GIP were converted to percent inhibition by subtracting nonspecific binding (binding in the presence of excess unlabeled Gcg, GLP-1 or GIP, respectively) from the individual CPM values ​​and dividing by the total binding signal (also corrected by subtracting nonspecific binding). 50 Data were analyzed using the nonlinear regression routine (Genedata Screener, version 12.0.4, Genedata AG, Basal, Switzerland). Based on the equation K i =IC 50 / (1+D / K d ), by absolute IC 50 The affinity constant (K i ), where D is the concentration of the radioligand used in the experiment, IC 50 is the concentration that causes 50% inhibition of binding, and K d K is the equilibrium binding dissociation constant of the radioligand (described above). i Values ​​are reported as geometric means, with errors expressed as standard error of the mean (SEM), and n equal to the number of independent replicates (determined in assays performed on different days). The geometric mean was calculated as follows: Geometric mean = 10 (Log Ki值的算术平均值)) Calculate the Ki ratio for each receptor and each species (Ki of the natural control peptide / Ki of the test compound). The Ki ratio is a quick indication of the apparent affinity of the peptide compared to the natural control peptide. A Ki ratio <1 indicates that the test peptide has a lower affinity (higher Ki value) for the receptor compared to the natural peptide, while a Ki ratio >1 indicates that the test peptide has a higher affinity (lower Ki value) for the receptor compared to the natural peptide.

[0114] n=1 / x means that only one value out of the total number of replicates (x) is used to represent the mean. SEM was calculated only when n=2 or more, when there were unqualified results. Means are presented as geometric means, which indicate the standard error of the mean (SEM) and the number of replicates (n) in parentheses.

[0115] Table 1. In vitro binding affinity (K) of the molecules of the examples and comparative examples to human GLP-1R, GcgR and GIPR i )

[0116] Functional activity (using BSA) Functional activity was determined in HEK-293 clonal cell lines expressing hGLP-1R, hGcgR, and hGIP-R. Cell lines overexpressing each receptor were treated with peptide (20-point CRC, 2.75x Labcyte Echo direct dilution) in a 20 μl assay volume in DMEM (Gibco Cat. No. 31053) supplemented with 1X GlutaMAX TM Supplement (L-alanyl-L-glutamine dipeptide ), 0.25% FBS (fetal bovine serum), 0.05% fraction V BSA (bovine serum albumin), 250 μM 3-isobutyl-1-methylxanthine (IBMX) and 20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES).

[0117] After incubation at room temperature for 60 minutes, the resulting increase in intracellular cAMP was quantitatively determined using the CisBio cAMP Dynamic 2 Homogeneous Time-Resolved Fluorescence (HTRF) Assay Kit. Intracellular cAMP levels were determined by adding cAMP-d2 conjugate in cell lysis buffer followed by the antibody anti-cAMP-Eu also in cell lysis buffer. 3+ -cryptate. The resulting competitive assay was incubated at room temperature for at least 60 minutes and then detected using an instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665 nm / 620 m*10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP / well using a cAMP standard curve.

[0118] The amount of cAMP produced in each well (nM) was converted to a percentage of the maximum response observed in the presence of human GLP-1(7-36)NH2, human Gcg, or human GIP(1-42)NH2. 50 Values ​​were derived by nonlinear regression analysis using percent maximal response vs. concentration of added peptide, fit with a four parameter logistic equation.

[0119] Determination of the ECs of human GLP-1(7-36)NH2 for human GLP-1R, human Gcg for human GcgR, and human GIP(1-42)NH2 for human GIP-R 50 : The peptide concentration range is 448 pM to 99.5 nM. Determination of EC of human GLP-1R, human GcgR and human GIP-R examples 50 : The peptide concentration ranged from 51.5 fM to 11.4 μM.

[0120] Table 2. Functional cAMP potency (EC) of the peptides of Examples and Comparative Examples (hGcg, hGIP amide and hGLP-1 amide) in the presence of FBS 50 )

[0121] cAMP pharmacological functional assay in the presence of casein Another set of cAMP assays was performed in HEK293 cells expressing human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), glucagon receptor (GcgR). The pharmacological activity of hGLP1R / GIPR peptides was determined in Hek293 cells stably expressing human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), or GLP-2 receptor (GLP-2R). Cell lines (20 μl) overexpressing each receptor were treated with test peptides in a 20 μl assay volume in DMEM (Gibco catalog number 31053) supplemented with 0.1% casein (Sigma catalog number C4765), 250 μM IBMX, 1X GlutaMAXTM (Gibco catalog number 35050), and 20 mM HEPES (HyClone catalog number SH30237.01). After incubation at room temperature for 60 minutes, the intracellular cAMP increase caused was quantitatively determined using the CisBio cAMP Dynamic 2HTRF assay kit (62AM4PEJ). Lysis buffer containing cAMP-d2 conjugate (20 μl) and antibody anti-cAMP-Eu3+-cryptate (20 μl) was then added to determine cAMP levels. After incubation at room temperature for 1 hour, the HTRF signal was detected using an Envision 2104 plate reader (PerkinElmer). Fluorescence emission at 620 nm and at 665 nm was measured, and the ratio between 620 nm and 665 nm was calculated, and then converted to nM cAMP / well using a cAMP standard curve. The dose response curve of the compound was plotted as a percentage of stimulation standardized to the minimum (buffer only) and maximum (maximum concentration of each control ligand), and analyzed using a four-parameter nonlinear regression fit (Genedata Screener 13) with a variable slope. EC50 is the concentration of compound that induces half-maximal simulation in a dose-response curve. 50 Values ​​were derived by nonlinear regression analysis using percent maximal response vs. concentration of added peptide, fit with a four parameter logistic equation.

[0122] Homogeneous time-resolved fluorescence was used to determine the intrinsic activity of the Example and Comparative Example molecules in the presence of casein (but not serum albumin) as a non-specific blocker that does not interact with the fatty acid portion of the analyzed molecules.

[0123] Intracellular cAMP levels were determined by extrapolation using standard curves. Compound dose response curves were plotted as percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) and analyzed using a four-parameter nonlinear regression fit with variable slope (Genedata Screener 13). EC 50 is the compound concentration that induces half-maximal simulation in the dose-response curve. 50 Values ​​were determined by curve fitting.

[0124] Compound concentration response curves were plotted as percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) and analyzed using a four-parameter nonlinear regression fit with variable slope (GenedataScreener 13). 50 is the concentration of compound that elicits half-maximal simulation in a dose-response curve.

[0125] EC 50 Summary statistics are calculated as follows: Geometric mean: GM=10^(log 10 Converted EC 50 arithmetic mean of the values).

[0126] The standard error of the mean is reported as follows: SEM = geometric mean × (log 10 Converted EC 50 standard deviation of the values / square root of the number of runs)×log e 10.

[0127] Logarithmic transformation shows EC 50 The values ​​are on a multiplicative scale rather than an arithmetic scale.

[0128] The assay was run daily with the test peptides and the native ligands GIP and GLP-1, buffer alone as baseline (minimum), and the highest concentration of the corresponding GIP and GLP-1 standards as maximum for calculations. For illustration purposes, the test peptides were tested in 8 runs of the assay as described in Example 1. For the avoidance of doubt, the hGIP amide and hGLP-1 amide EC values ​​in Table 3 are 50 is an illustrative geometric mean from a series of 18 assay values, and the values ​​vary from day to day (compared to zero buffer). Therefore, each example will use the geometric mean of these values ​​to standardize the example assay runs.

[0129] Table 3. Functional activation of hGLP-1R, hGIPR, and hGcgR in the presence of 0.1% casein

[0130] As demonstrated by the data in Table 3, the Example compounds stimulated cAMP production by human GLP-1R and GIPR in the presence of 0.1% casein.

[0131] In vivo studies Pharmacokinetics in male CD-1 mice The pharmacokinetics of selected examples were evaluated after a single subcutaneous administration of 200 nMol / kg to male CD-1 mice. Blood samples were collected over 168 hours and the resulting individual plasma concentrations were used to calculate pharmacokinetic parameters. Plasma (K3 EDTA) concentrations were determined using a qualified LC / MS method that measured the intact mass of the examples. Each example and analog was extracted from 100% mouse plasma using an immunoaffinity-based precipitation method using an anti-GIP / GLP1 antibody as an internal standard. Each instrument was combined for LC / MS detection. The average pharmacokinetic parameters are shown in Table 4.

[0132] Table 4. Mean pharmacokinetic parameters of peptides after a single subcutaneous administration of 200 nMol / kg to male CD-1 mice (N=2 / time point, non-continuous sampling) Abbreviation: T 1 / 2 = half-life, T max = time to reach maximum concentration, C max = maximum plasma concentration, AUCINF_D_obs = AUCinf divided by dose, CL / F = clearance / bioavailability. Note: Data are mean values, where n = 2 / time point / group.

[0133] The results of this study for the Examples tested were consistent with a prolonged pharmacokinetic profile.

[0134] Pharmacokinetics in Male Cynomolgus Monkeys The pharmacokinetics of the selected embodiments were evaluated after a single subcutaneous administration of 50nMol / kg to male cynomolgus macaques. Blood samples were collected over 336 hours, and pharmacokinetic parameters were calculated using the resulting individual plasma concentrations. The peptide plasma (K3 EDTA) concentration was determined using a qualified LC / MS method that measures the intact mass of the compound. Various peptides and analogs were extracted from 100% cynomolgus macaque plasma using an anti-GIP / GLG1 antibody as an internal standard using an immunoaffinity-based precipitation method. Each instrument was combined for LC / MS detection. The average pharmacokinetic parameters are shown in Table 5.

[0135] Table 5. Mean pharmacokinetic parameters of peptides following a single subcutaneous administration of 50 nMol / kg to male cynomolgus monkeys Abbreviation: T 1 / 2 = half-life, T max = time to reach maximum concentration, C max= maximum plasma concentration, AUCINF_D_obs = AUCinf divided by dose, CL / F = clearance / bioavailability. Note: Data are mean values, with n=2 / group. As seen in Table 5, the results of this study for the tested example peptides are consistent with a prolonged pharmacokinetic profile.

[0136] Pharmacokinetics after subcutaneous or intrajejunal administration in male Sprague Dawley rats The pharmacokinetics of selected examples were evaluated after a single subcutaneous (SC) administration of 50 nMol / kg (dissolved in PBS, pH 7.4) or a single intrajejunal (IJ) administration of 1 μmol / kg (mixed with 250 mM sodium decanoate ("C10") and 12 mg / mL soybean trypsin inhibitor (SBTI)) to male Sprague Dawley rats. Blood samples were collected over 168 hours after SC administration and 72 hours after IJ administration. Pharmacokinetic parameters were calculated using individual plasma concentrations. Plasma (K3 EDTA) concentrations were determined using a qualified LC / MS method that measured the intact mass of the examples. Each example was tested with a similar peptide as an internal standard. Each test peptide and analog was extracted using an immunoaffinity-based precipitation method using an anti-GIP / GLP1 antibody. The average pharmacokinetic parameters for the examples are shown in Tables 6 and 7.

[0137] Table 6. Mean (+ / -SD) pharmacokinetic parameters of peptides following a single subcutaneous administration of 50 nMol / kg to male Sprague Dawley rats Abbreviation: T 1 / 2 = half-life, T max = time to reach maximum concentration, C max = maximum plasma concentration, AUCINF_D_obs = AUCinf divided by dose, CL / F = clearance / bioavailability. Note: Data are mean values, where n = 3 / group (Table 6).

[0138] As seen in Table 6, the results obtained in this study using these example peptides are consistent with a prolonged pharmacokinetic profile.

[0139] Table 7. Mean (+ / -SD) pharmacokinetic parameters of peptides following a single intrajejunal administration of 1 μmol / kg to male Sprague Dawley rats The data are mean values, where n=3 / group and n=6 / group (Table 7).

[0140] These Examples were consistent with exposure following intrajejunal administration as illustrated by the results in Table 7. The intrajejunal exposure in this assay supports that the Examples are amenable to oral formulation and administration.

[0141] In vivo effects on insulin secretion in male Wistar rats Male Wistar rats (Envigo, Indianapolis, IN) (280-320 grams) with femoral artery and femoral vein cannulae were housed in polycarbonate cages with filter tops. Rats were maintained at 21 ° C with a 12:12 hour light-dark cycle (lights on at 6:00 am) and were free to receive food and deionized water. Rats were randomly divided into groups according to body weight and administered 1.5 ml / kg subcutaneously with a dosage of 0.04, 0.1, 0.3, 1, 3 and 10 nmol / kg, glucose was administered after 16 hours, followed by fasting. Animals were weighed and anesthetized via intraperitoneal administration of sodium pentobarbital (65 mg / kg, 30 mg / ml). Blood samples were placed in EDTA tubes when collecting 0, followed by intravenous administration of glucose (0.5 mg / kg, 5 ml / kg). Blood samples were collected at 2, 4, 6, 10, 20 and 30 minutes after intravenous administration of glucose to obtain glucose and insulin levels. Plasma glucose levels were determined using a clinical chemistry analyzer. Plasma insulin was determined using an electrochemiluminescence assay (Meso Scale, Gaithersburg, MD). Glucose and insulin AUC were examined compared to vehicle controls, with n=5 animals / group. Results are presented (SEM) (N).

[0142] Table 8: Effects of Example Compounds on Insulin Secretion During Intravenous Glucose Tolerance Test

[0143] Table 8 presents data demonstrating a dose-dependent increase in insulin secretion.

[0144] Table 9: ivGTT insulin secretion shown in the following data:

[0145] Table 9 presents data demonstrating a dose-dependent increase in insulin secretion.

[0146] Studies in diet-induced obese C57 / B16 mice Diet-induced obese (DIO) C57 / Bl6 male mice weighing 41-50 g were used (Taconic, Germantown, NY). Animals were individually housed in a temperature-controlled (24°C) facility with a 12-hour light / dark photoperiod (lights off at 10:00 a.m. and lights on at 10:00 p.m.) with free access to food and water. After acclimation to the facility for 2 weeks, mice were randomly assigned to treatment groups (n=6 / group) based on body weight so that each group had a similar starting average body weight.

[0147] Mice were treated with vehicle (40 mM Tris-HCl, pH 8.0) or several peptides ranging from 0.03 nmol / kg to 10 nmol / kg. Treatments were administered subcutaneously (QD) to ad libitum fed DIO mice 30-90 minutes before the onset of the dark cycle each day for 14 days. During the study, body weight and food intake were monitored daily.

[0148] All data are expressed as mean ± SEM of 5-6 mice per group. Statistical analysis was assessed by one-way ANOVA followed by Dunnett's multiple comparison test to compare treatment groups with the vehicle group or with each other. Significant differences were determined as p < 0.05.

[0149] The "0" dose group represents the vehicle-treated mice during each study. All data are expressed as mean ± SEM of 5-6 mice per group. Statistical analysis was evaluated by one-way ANOVA followed by Dunnett's multiple comparison test to compare the treated groups with the "0" dose (vehicle). *Significant differences were determined as p<0.05. After 15 days, body weight changed after treatment with the example compounds. "Δ relative to vehicle" refers to the difference in body weight on day 15 between the test group and the vehicle group. "Change%" refers to the percent weight loss of the test group between day 1 and day 15. The percent weight loss of animals receiving the vehicle was recorded and was less than about 1% in each study. The Δ and change% data relative to the vehicle for all examples at all tested doses were statistically significantly different from the control (p<0.05).

[0150] Table 10. Effects of GIP / GLP-1 receptor co-agonists on body weight percentage in diet-induced obese mice after 14 days of treatment

[0151] As illustrated by the data provided in Table 10 above, the Example compounds tested in the assay dose-dependently reduced body weight in the studies described.

[0152] Proteolytic stability assay The proteolytic stability assay is used to evaluate the potential for oral delivery of peptides. The stability of the peptides was compared in 1% rat small intestinal fluid (rSIF). The amount of intact peptide in the sample peptides was measured at 0, 3, 15 and 30 minutes to evaluate proteolytic stability. The amount of intact peptide in the sample peptides was measured at 0, 30, 45 and 60 minutes in 90% porcine small intestinal fluid (pSIF) to evaluate proteolytic stability.

[0153] Sample preparation when using rat small intestinal fluid (rSIF): 0.4 mg / mL of peptide was prepared in 50 mM Tris pH 8.0. Rat small intestinal fluid was added at a ratio of 1% (v / v). The mixture was incubated at 37°C and 150 rpm. Thirty microliters of each sample was removed and placed in a new tube, followed by the addition of rSIF at 3, 15, and 60 minutes. At each time point, the reaction was quenched at 1:1 by 1% TFA in 50% ACN. The samples were diluted 100-fold using dilution buffer (1% TFA in 50% ACN: 50 mM Tris pH 8: 1:1) and prepared for analysis using mass spectrometry (MS).

[0154] Sample preparation when using porcine small intestinal fluid (pSIF): The peptide was diluted to a concentration of 0.4 mg / mL in 90% porcine intestinal fluid. After mixing, 20 μL was immediately removed (0 as the pre-incubation time point). The mixture was then incubated at 37°C and 150 rpm. At 30, 45 and 60 minutes, twenty microliters of each sample were removed and placed in a new tube. At each time point (0, 30, 45, 60), the reaction was quenched at 1:1 by 1% TFA in 50% ACN. The sample was centrifuged at 20,000xg for 20 minutes at 4°C. The supernatant was diluted 100 times using dilution buffer (1% TFA in 50% ACN: 50mMTris pH8: 1:1) and prepared for analysis using mass spectrometry (MS).

[0155] MS conditions: Using mobile phases A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile) and an ACQUITY UPLC Protein BEH C4 column ( Liquid chromatography was performed on a Waters Acquity UPLC (1.7 μm, 1 mm×50 mm) at 40°C. The gradient was 5% B during 0-1.5, 5-90% B during 1.5-1.8, 90-95% B during 1.8-3.0, 95-95% B during 3.0-3.5, 95-5% B during 3.5-4.0, and 5-5% B during 4.0-5.0. MS analysis was performed on a Waters Xevo G2-XSQTOF. Data were acquired in positive and sensitivity modes using a MSe continuous spectrum in the range of 50-2000 m / z. Data analysis was performed using MassLynx.

[0156] Table 11. Percentage of each peptide that was not cleaved at different time points using rSIF

[0157] The proteolytic peptide results provided in Table 11 indicate that the peptide of Example 4 may be suitable for oral formulation and delivery.

[0158] Table 12. Percentage of each peptide that was not cleaved at different time points using pSIF

[0159] The proteolytic peptide results provided in Table 12 indicate that the peptides of Examples 4 and 5 are both useful for oral formulation and delivery.

[0160] In vivo studies The purpose of this study was to determine the relative potential of the compounds for clinical immunogenicity.

[0161] method: CD8+T cell-depleted peripheral blood mononuclear cells were prepared from a group of 10 healthy donors and labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE, Invitrogen). Samples were tested in triplicate using 2.0 mL of culture medium control, keyhole limpet hemocyanin ("KLH") (0.33 μM), anti-chemokine receptor type 4 ("CD4+") (0.33 μM), and compounds of Examples 1, 2, and 3 (10 μM). The cultures were incubated at 37° C. with 5% CO2 for 7 days. On day 7, samples were analyzed by flow cytometry using a high throughput sampler (HTS). The data were analyzed using software (FlowJo, LLC, TreeStar).

[0162] Results and discussion All donors generated positive T cell responses to KLH (100%). Analysis of the frequency and magnitude of CD4+ T cell responses to the example compounds is shown in Table 13.

[0163] Table 13: CD4+ T cell responses of example compounds and positive control (KLH) Cell division index ("CDI"): The ratio of dividing CD4+ T cells to the total number of CD4+ T cells in stimulated samples relative to unstimulated samples.

[0164] These data show that the frequency of positive CD+ T cell responses (CDI>2.5) to compounds of Examples 1, 2, 3, 4, 288, 289, 301, 303 and 316 was low, and the intensity of responses of the few positive donors was low (CDI<6), indicating a low immunogenicity risk using the CD4+ T cell assay.

[0165] GLP-1R HEK293 cell membrane [ 35 [S]GTPγS binding assay The GLP-1 receptor is a G-protein coupled receptor that upon ligand-induced receptor activation, activates GTP-bound Gα s Purified membrane preparations from HEK293 cells expressing human GLP-1R were used to determine Gα induced by peptide stimulation of GLP-1R s The assay was performed similarly as previously described (Bueno et al., J. Biol. Chem., (2016) 291, 10700 and Willard et al., Mol. Pharmacol. (2012) 82, 1066). The test peptides were dissolved in DMSO and diluted in reaction buffer at room temperature for 30 minutes, the reaction buffer being 20 mm HEPES pH 7.4, 50 mM NaCl, 5 mM MgCl2, 40 μg / ml saponin, 0.1% BSA and 500 pM 35 5 μg of membrane was contained in S-labeled GTPγS. s The reaction was terminated with 0.2% Nonidet P-40 detergent in 1% polyclonal antibody and 0.5 mg anti-rabbit polyvinyltoluene beads. The mixture was allowed to form for 30 minutes, centrifuged at 80×g for 10 minutes, and counted for 1 minute / well using a MicroBeta TriLux instrument. The peptide concentration response curve was fitted with a four-parameter logistic model to calculate the potency EC 50 Data were normalized for % stimulation using DMSO and GLP-1(7-36) as minimum and maximum controls for the receptor (Campbell et al., Assay Guidance Manual 2017). Sample peptides stimulate GIPR-induced Gα sThe potency of activation is reported in Table 14. The assay identified Gα induced by s Activating peptides that are partial agonists of GLP-1R.

[0166] GLP-1R CHO cell β-arrestin recruitment assay Activated G protein-coupled receptors can interact with the β-arrestin family of signaling proteins. The potency of peptides for GLP-1R induced arrestin recruitment was determined using the PathHunter enzyme fragment complementation method (von Degenfeld et al., FASEB J., 2007 (14): 3819-26 and Hamdouchi et al., J. Med Chem., 2016 59 (24): 10891-10916) essentially as described. CHO-K1 cells expressing Pro-Link-tagged human GLP-1R and enzyme receptor-tagged β-arrestin-2 can be obtained from DiscoveRx and prepared as assay-ready frozen cells. The test peptides were dissolved in DMSO and serially diluted using an Echo ultrasonic dispenser (LabCyte). The assay medium was PathHunter cell assay buffer (DiscoveRx) containing 0.1% w / v hydrolyzed casein (Sigma). 100 nl of peptide was dispensed in 10 μl of assay medium in a 384-well plate, and then 10 μl of cells in assay medium were added to give 5000 cells per well. The plate was incubated in a 37°C / 5% CO2 incubator for 90 minutes, and 10 μl of PathHunter detection reagent (DiscoveRx) was added, and the plate was incubated at room temperature for 60 minutes. The luminescent signal was measured. The peptide concentration response curve was fitted with a four-parameter logistic model to calculate the potency EC 50 . Data were normalized for % stimulation using DMSO and GLP-1 (7-36) as minimum and maximum controls (Campbell et al., Assay Guidance Manual 2017). The potency of the sample peptides to stimulate GLP-1R-induced β-arrestin recruitment is reported in Table 14. The assay results identified peptides that were partial agonists of GLP-1R relative to β-arrestin-2 recruitment.

[0167] Table 14

[0168] Compositions for oral administration The peptide was dissolved in Tris buffer (pH 8.0, 50 mM). The penetration enhancer ("PE") was prepared as follows: C10 was dissolved in Tris buffer (pH 8.0, 50 mM), and LC, DPC, C12-maltoside and rhamnolipid were each dissolved in phosphate buffered saline ("PBS") (1X, pH 7.2). The solutions of peptide, PE and protease inhibitors were mixed to achieve a final peptide concentration of 300 uM, PE of 100 mM (5% w / v for rhamnolipid), and protease inhibitors of 1% (v / v).

[0169] The peptides were incubated in 1% (v / v) rat intestinal fluid or 50% (v / v) porcine intestinal fluid with and without peptidase inhibitors at 37°C. At different time points, samples were taken and subsequently quenched with 1% TFA in 50% ACN / water to terminate enzyme activity. The intact peptides were analyzed at different time points by high performance liquid chromatography (HPLC) or LC-MS / MS equipped with an ultraviolet (UV) detector and standardized to the amount of peptide before mixing with the enzyme solution. The studies using the peptides of Example 2 and the peptides of Example 4 are reported in Table 15.

[0170] Table 15.

[0171] The results in Table 15 demonstrate that the oral formulation composition of the peptide of Example 4 can be prepared using PE and no PI.

[0172] Oral preparation composition Examples of formulation compositions of the peptides of the present invention are provided in Table 16. The formulation compositions of the peptides of the present invention are by no means limited to the examples provided.

[0173] Table 16

[0174] The formulation composition is assessed to use the liquid formulation via the influence of peptide exposure in rats administered intrajejunal (IJ). In order to prepare the liquid formulation used for rat IJ administration, peptide, C10 or NaTDC and SBTI are dissolved in 50mM Tris buffer pH 8.0 and mixed to obtain the final desired concentration. For LC / citric acid formulations, LC and citric acid are dissolved in water and mixed with the peptide dissolved in the Tris buffer. The formulation composition provided in Table 16 can be used as an oral composition.

[0175] Enteric-coated capsules Certain peptides of the invention may require an enteric capsule composition and may be prepared using, for example, the methods given in Table 17. Enteric compositions may be prepared by blending the ingredients together and filling the blend into an enteric capsule.

[0176] The enteric compositions of Table 17 were prepared by adding half of the amount of sodium caprate to a mortar. SBTI (for Examples 382-385) or SFTI (for Examples 386 and 387) and peptides (peptides of Examples 1 to 4) as shown in Table 17. The remaining half of the sodium caprate was added. The mixture was gently blended together using a pestle and spatula. If necessary, additional mixing was performed using a pestle to obtain a uniform blend. The capsules can be filled manually by weighing the desired amount of blend individually, filling in the capsules and securely closing the capsule caps to the capsule bodies.

[0177] Dissolution testing of a single capsule was performed using known methods. The peptides of the present invention can be formulated as an enteric-coated oral composition. Table 17: Composition of individual enteric-coated capsules for formulation Amino acid sequence SEQ ID NO: 1 GIP(people) YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ SEQ ID NO: 2 GLP-1(7-36)(Human) HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 SEQ ID NO: 3 R1X1 X2 X3GT X6TSD X 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 SEQ ID NO: 4 PX 32 X 33 X 34 -R2 SEQ ID NO: 5 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 SEQ ID NO: 6 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 SEQ ID NO: 7 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 -R2 SEQ ID NO: 8 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 37 X 39 -R2 SEQ ID NO: 9 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 SEQ ID NO: 10 Example 1 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2 SEQ ID NO: 11 Example 2 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Om-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2 SEQ ID NO: 12 Example 3 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Om-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2 SEQ ID NO: 13 Example 4 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Om-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH2 SEQ ID NO: 14 Example 5 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD-Orn-K((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 16 -CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS-NH2 SEQ ID NO: 297 PSSG-R2 SEQ ID NO:298 PSSGAPPPS-R2 SEQ ID NO:299 PSSG SEQ ID NO:300 PSSG-NH2 SEQ ID NO:301 PSSGAPPPS SEQ ID NO:302 PSSGAPPPS-NH2。

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308 and SEQ ID NO:

392.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO:

305.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO:

307.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO:

308.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is SEQ ID NO:

392.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient.

7. Use of a compound as claimed in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition selected from type 2 diabetes, obesity, NAFLD, NASH, dyslipidemia and metabolic syndrome.

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating type 2 diabetes.

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