GIP / GLP1 coagonist compounds

Abstract

To provide compounds which have agonist activity at both the human glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor, are suitable for oral administration, and may be useful in treatment of type 2 diabetes mellitus.SOLUTION: The present invention provides a compound in which a specific modification is applied to a peptide having a specific amino acid sequence, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a human glucose-dependent insulinotropic polypeptide (GIP) receptor and and glucagon-like peptide-1 (GLP-1) receptor activity. The present invention also provides compounds that have long-lasting effects at each of these receptors. The present invention further relates to compounds which can be administered orally. These compounds are These compounds may be useful in the treatment of type 2 diabetes mellitus ("T2DM"). It may be useful in treatment. [Background technology]

[0002] The prevalence of diabetes has been increasing for the past several decades. T2DM accounts for approximately 90% of all diabetes cases. % of all diabetes mellitus patients. T2DM is primarily associated with insulin resistance. T2DM is characterized by high blood sugar levels. The current standard treatment for T2DM is dietary restriction and exercise. , oral medications, and incretin-based therapies such as GLP-1 receptor agonists. There are currently various types of treatment for T2DM. GLP-1 receptor agonists are available, but the currently marketed GLP-1 receptor Agonists are generally dose-limiting due to gastrointestinal side effects such as nausea and vomiting. Subcutaneous injection is the most common route of administration for available GLP-1 receptor agonists. If oral and incretin-based therapies are insufficient, insulin therapy may be considered. Despite the advances in treatments available today, many T2DM patients still experience glycemic control. Failure to achieve control goals. Uncontrolled diabetes increases patient morbidity and mortality. This leads to various diseases related to increased blood sugar levels. There is a need for treatment that can

[0003] Obesity is a complex medical disorder that leads to the excessive accumulation of adipose tissue mass. Today, obesity is It is a global public health concern associated with adverse health outcomes and morbidity. The preferred treatment for patients with obesity involves reducing excess body weight, reducing obesity-related comorbidities, and The aim of the study is to improve obesity by reducing the risk of developing obesity, and to maintain weight loss in the long term. To induce therapeutic weight loss in patients who need treatment, Alternative treatment options are needed to treat

[0004] WO 2016 / 111971 describes a compound that is said to have GLP-1 and GIP activity. WO 2013 / 164483 also describes peptides that inhibit GLP-1 and and compounds that are said to have GIP activity. Summary of the Invention

[0005] There are currently no T2DM treatments that can provide effective glucose control to the majority of patients who need treatment. What is needed is a method for treating glucose intolerance and other conditions that can provide effective glucose control and have a favorable side effect profile. There is a need for additional T2D treatments that offer therapeutic weight loss to patients in need of treatment. There is a need for alternative treatment options to provide a better treatment for patients needing treatment for severe obesity. There is a need for alternative treatment options for

[0006] Compounds suitable for oral administration that have agonistic activity at the GIP and GLP-1 receptors are It is desirable to be able to reduce the frequency of administration of the compound, thereby improving the GIP and GLP-1 receptors. Compounds that have a long duration of action in each of these regimes are desirable.

[0007] Thus, the present invention provides a compound of formula I: R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX1 9X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 (array No. 3) or a pharma- ceutically acceptable salt thereof, wherein R1 is a modification of the N-terminal amino group, the modification being selected from the group consisting of Ac and absence , X1 is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY. , X2 is selected from the group consisting of Aib, αMeP, A, P, and D-Ala; and X1 and X2 combine to form desH-ψ[NHCO]-Aib, X3 is selected from the group consisting of E, N, Aad, and cTA; X6 is selected from the group consisting of F, αMeF, and αMeF(2F); X 10 are 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)q COH; X 11is selected from the group consisting of S, αMeS, and D-Ser; X 12 are I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)- from the group consisting of 2-(γ-Glu)-CO-(CH2)qCO2H Selected, X 13 Nle, Aib, L, αMeL, and K(2-[2-(2-amino-ethoxy) 2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 14 is selected from the group consisting of L and K, where K is C 16 -C 22 Binds to fatty acids wherein the fatty acid is optionally linked to the K via a linker; X 16 K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R, and and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Gl u) -CO-(CH2)qCO2H; X 17 are K, Q, I, and C 16 -C 22 A group of amino acids that bind to fatty acids wherein said fatty acid is optionally linked to said amino acid via a linker; X 19 Q, A, and K (2-[2-(2-amino-ethoxy)-ethoxy]-a cetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 20 Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino- Ethoxy]-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X21 H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2-A 2-(γ-Glu)-CO-(CH2)qC OH; X 22 is selected from the group consisting of F and αMeF; X 23 are I, L, A, G, F, H, E, V, and K (2-[2-(2-amino- 2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 24 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 the group consisting of Y and αMeY; X 26 L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy ]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H R, X 27 are L, I, and K (2-[2-(2-amino-ethoxy)-ethoxy]-amino cetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 28 are E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy) -ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H is selected from X 29 Aib, G, A, and K (2-[2-(2-amino-ethoxy)-ethoxy] Selected from the group consisting of: 2-(γ-Glu)-CO-(CH2)qCO2H And, X 30 are C, G, G-R2 and K(2-[2-(2-amino-ethoxy)-ethoxy] [gamma-Glu]-CO-(CH2)q-CO2H Selected, X 31 is absent or PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X3 3X 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-(CH)q-CO 2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 8), and and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Gly u)-CO-(CH2)q-CO2H]X 32 X33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 - R2 (SEQ ID NO: 9), (In the formula, X 32 is S, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-a Cetyl) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 33 is S, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-a Cetyl) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 34 are G, C, and K [(2-[2-(2-amino-ethoxy)-ethoxy] -Acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H] And, X 35 A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-a Cetyl) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 36 is P, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-a Cetyl) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 37 is P, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-a Cetyl) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) 2-(γ-Glu)-CO-(CH2)q-CO2H], X 39 are C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy] -Acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H] And, X 40 C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetate (γ-Glu)-CO-(CH)q-COH] ), q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; R2 is a modification of the C-terminus (wherein the modification is NH2 or absent); X 30 If G-R2, then X 31 is absent, 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 One of them contains fatty acids. The substituents may include X 30 , X 34 , X 39 , and X40 Of these, at most one is C, X 30 , X 34 , X 39 , and X 40 If any of is C, then X 10 , X 12 , X1 3. X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X2 7. X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X3 7. X 38 , X 39 , and X 40 None of the substituents contain fatty acids. Provided is a compound of formula I, or a pharma- ceutically acceptable salt thereof:

[0008] One embodiment is a compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein q is 16. In one embodiment, X 31 is selected from the group consisting of SEQ ID NO:5 and SEQ ID NO:8; I, or a pharma- ceutically acceptable salt thereof. In one embodiment, X 17 The compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein the amino acid is a naturally occurring amino acid. In one embodiment, X is a salt. 17 is selected from the group consisting of K, Q and I; or a pharma- ceutically acceptable salt thereof.

[0009] In one embodiment, K is C 16 -C22 The fatty acid is linked to a linker. Optionally linked to said K is a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0010] In one embodiment, X 14 or X 17 K(2-[2-(2-amino-ethoxy)- Toxo[acetyl]-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]-a Cetyl) 2- (γ-Glu)-CO-(CH2) 14 -CO2H,K(2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 18 -COH,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 -CO 2H,K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(εK)- (γ-Glu)-CO-(CH2) 18 -CO2H,K(2-[2-(2-amino-ethoxy) oxy)-ethoxy]-acetyl)-(εK)-(εK)-CO-(CH2) 18 -CO2 H, K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2- (γ-Gl u) 2-CO-(CH2) 18-CO2H,K(2-[2-(2-amino-ethoxy)- Ethoxy]-acetyl)2-CO-(CH2) 18 -CO2H,K(2-[2-(2-A (amino-ethoxy)-ethoxy]-acetyl) 2- (εK)-CO-(CH2) 16 -CO 2H,K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl )2 -(εK) -CO-(CH 2)14 -CO2H, and KDab-(2-[2-(2-amino-ethoxy) 2-[2-(2-amino-ethoxy)-ethoxy]-acetyl]-Dab-(2-[2-(2-amino-ethoxy)- Toxo[acetyl]-CO-(CH2) 18 -COH; A compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0011] In one embodiment, X 14 or X 17 K(2-[2-(2-amino-ethoxy)- Toxo[acetyl]-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]-a Cetyl) 2- (γ-Glu)-CO-(CH2) 14 -CO2H, and K(2-[2- (2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2) 18 -CO2 H, or a pharma- ceutically acceptable salt thereof. .

[0012] In one embodiment, X 14 or X 17 K(2-[2-(2-amino-ethoxy)- Toxo[acetyl]-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, X is a compound of formula I, or a pharma- ceutically acceptable salt thereof. 14 or X 17 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)1 6-CO2H, or a pharma- ceutically acceptable salt thereof. In one embodiment, X is a salt. 14 or X 17 K(2-[2-(2-amino-ethoxy) oxy)-ethoxy]-acetyl a -(γ-Glu) b -CO-(CH2) q -CO2H wherein a is 2, b is 1, and q is selected from the group consisting of 18 and 20. or a pharma- ceutically acceptable salt thereof. One embodiment is a compound of formula I, 14 or X 17K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H (wherein a is 2 and b is 1) and q is 18, or a pharma- ceutically acceptable salt thereof. In one embodiment, X 14 or X 17 K(2-[2-(2-amino-ethoxy)-ethoxy] xy]-acetyl) a -(γ-Glu) b -CO-(CH2) q -CO2H (wherein a is 2, b is 1 and q is 20), or a pharma- ceutical composition thereof. are acceptable salts.

[0013] In one embodiment, X1 and X2 form desH-ψ[NHCO]-Aib A compound of formula I (hereinafter "compound of formula II"), or a pharma- ceutically acceptable derivative thereof, which does not bind to It is a useful salt.

[0014] In one embodiment, X 17 But, C 16 -C 22 an amino acid bound to a fatty acid, said fatty acid comprising a linker; and optionally linked to said amino acid via X 30 is selected from the group consisting of G-R2 and G; X 30 If G, then X 31 PX 32 X 33 X 34 -R2 (SEQ ID NO: 4) (wherein X 32 is S and X 33 is S and X 34 is G (SEQ ID NO: 297), and PX 32 X33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) (wherein X 32 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P, X 37 is P and X 38 is P and X 39 is S (SEQ ID NO: 298) Selected from the group: A compound of formula I (hereinafter "compound of formula III"), or a pharma- ceutically acceptable salt thereof. do.

[0015] In one embodiment, the X 17 Formula II, in which the amino acid is linked to the fatty acid via a linker I (hereinafter, compound of formula IIIa), or a pharma- ceutically acceptable salt thereof. .

[0016] In one embodiment, X 10 is A, L, H, 3Pal, 4Pal, V, Y, E, αMeF, αMeF(2F ), I, αMeY, Q, D-His, D-Tyr, and cTA. , X 12 is selected from the group consisting of I, S, and D-Ile; X 13 is selected from the group consisting of Nle, Aib, L, and αMeL; X 14 is selected from the group consisting of L, and K; X 16 K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R, X 19is selected from the group consisting of Q, and A; X 20 is selected from the group consisting of Aib, Q, H, R, K, and αMeK; X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I; X 23 is selected from the group consisting of I, L, A, G, F, H, E, and V; X 24 from S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P. is selected from the group consisting of X 26 is selected from the group consisting of L, and αMeL; X 27 is selected from the group consisting of L, and I; X 28 is selected from the group consisting of E, A, S, and D-Glu; X 29 is selected from the group consisting of Aib, G, and A; X 30 is selected from the group consisting of G and G-R2; X 30 If G, then X 31 PX 32 X 33 X 34 -R2 (SEQ ID NO: 4) , X 32 is S and X 33 is 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 is S and X 33 is S and X 34 is G and X 35 is A and X 36 P and X37 is P and X 38 is P and X 39 is S (SEQ ID NO: 298) Selected from the group consisting of: Compounds of formula III and formula IIIa (hereinafter "formula IIIb" compounds), or pharmaceutical compositions thereof are physically acceptable salts.

[0017] In one embodiment, the linker is a compound represented by Formula III, Formula IIIa, and A compound of formula IIIb, or a pharma- ceutically acceptable salt thereof, Further specific embodiments of the compounds of formula Ia and IIIb include those in which the linker amino acid is Glu. and γ-Glu. The anchor is one or two (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl Compounds of formula III, IIIa and IIIb containing a phenyl) moiety, or pharma- ceutical acceptable salts thereof. and specific further compounds of formula III, formula IIIa and formula IIIb are acceptable salts thereof. In another embodiment, the linker is (2-[2-(2-amino-ethoxy)-ethoxy]-amino Cetyl) a -(γ-Glu) b wherein a is selected from the group consisting of 1 or 2. , b is a compound selected from the group consisting of 1 or 2).

[0018] In one embodiment, X 17 But, C 16 -C 22 It is an amino acid bound to a fatty acid (see above). wherein the amino acid is K, and the fatty acid is optionally linked to the amino acid via a linker, III, or a pharma- ceutically acceptable salt thereof.

[0019] In one embodiment, R1 is absent, X1 and X2 do not combine to form desH-ψ[NHCO]-Aib, X 17 But, C 16 -C 22 K is a linker that binds to a fatty acid. a compound of formula III, or a pharma- ceutically acceptable salt thereof, It is a possible salt.

[0020] In one embodiment, X1 is Y, X2 is Aib, X3 is E, X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y; X 11 But S, X 12 But, I, X 14 is L, X 16 is selected from the group consisting of K, E, Orn, Dab, and Dap; X 17 But, C 16 -C 22 K bound to a fatty acid, wherein the fatty acid is a linker. is optionally attached to said amino acid via X 19 But Q, X 20 But, Aib, X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E; X 22 But F, X 23 But, I, X 24 is selected from the group consisting of S, Aad, D-Glu, and E; X 26 is L, X 28is selected from the group consisting of E and A; A compound of formula III, or a pharma- ceutically acceptable salt thereof.

[0021] In one embodiment, X1 is Y, X2 is Aib, X3 is E, X6 is αMeF(2F), X 10 is selected from the group consisting of Y, 4-PaI, and V; X 11 But S, X 12 But, I, X 13 is selected from the group consisting of L, Aib, and αMeL; X 14 is L, X 16 is selected from the group consisting of E, K, and Orn; X 17 But, C 16 -C 22 K bound to a fatty acid, wherein the fatty acid is a linker. is optionally attached to said amino acid via X 19 But Q, X 20 But, Aib, X 21 is selected from the group consisting of E, A, and T; X 22 But F, X 23 But, I, X 24 is D-Glu, X 25 is selected from the group consisting of Y and αMeY; X 26 is L, X 27 But, I, X 28 But E, X 29 But G, X 30 But G, X 31 But, PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO:5 )(wherein, X 32 is S and X 33 is S and X 34 is G and X 35 is A , X 36 is P and X 37 is P and X 38 is P and X 39 is S (sequence number No. 298) A compound of formula III, or a pharma- ceutically acceptable salt thereof.

[0022] One embodiment is a compound of formula III, IIIa, and IIIb, wherein R2 is absent. or a pharma- ceutically acceptable salt thereof.

[0023] One embodiment is the compound of formula III, formula IIIa, and formula IIIb, wherein R2 is NH2. or a pharma- ceutically acceptable salt thereof.

[0024] In one embodiment, X 13 is αMeL; or a pharma- ceutically acceptable salt thereof.

[0025] In one embodiment, X 25 is Y and X 13 Formula III, IIIa and IIIb are and IIIb, or a pharma- ceutically acceptable salt thereof.

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

[0027] In one embodiment, X 16 is Orn, and X 13 is αMeL, and X 25 is Y, Compounds of formula III, IIIa and IIIb, or pharma- ceutically acceptable salts thereof In one embodiment, X 16 is E and X 13 is αMeL, and X 25 is Y, III, Formula IIIa and Formula IIIb, or a pharma- ceutically acceptable salt thereof. In one embodiment, X 16 is E and X 13 is αMeL, and X 10 is Y and X2 5 is αMeY, In one embodiment, X is a commercially available salt thereof. 16 is Orn, and X 13 is αMeL X 10 is 4Pal, and X 25 is Y; b, or a pharma- ceutically acceptable salt thereof. 16 Orn Yes, X 13is αMeL, and X 10 is V and X 25 is Y; Compounds of formula IIa and IIIb, or pharma- ceutically acceptable salts thereof. X 16 is E and X 13 is αMeL, and X 25 is Y and X 17 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 14 to 20) or a compound of formula III, IIIa, or IIIb, and pharma- ceutically acceptable salts thereof. 16 is E and X 13 αMeL and X 10 is Y and X 25 is Y and X 17 K(2-[2-(2-amino- Ethoxy)-ethoxy]-acetyl a -(γ-Glu) b -CO-(CH2) q -CO 2H (wherein a is 2, b is 1, and q is selected from the group consisting of 16 to 20). or a pharma- ceutically acceptable salt thereof. It is a salt.

[0028] One embodiment includes SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14. A compound of formula I selected from the group consisting of: One embodiment is a compound of formula I, which is SEQ ID NO: 10, or a pharma- ceutically acceptable salt thereof. One embodiment is a compound of formula I, which is SEQ ID NO: 11, or a pharma- ceutically acceptable form thereof. One embodiment is a compound of formula I, which is SEQ ID NO: 12, or a pharma- ceutically acceptable salt thereof. One embodiment is a compound of formula I, which is SEQ ID NO: 13, or a pharma- ceutically acceptable salt thereof. One embodiment is a compound of formula I, which is SEQ ID NO: 14, or a pharmacopoeitic salt thereof. are acceptable salts.

[0029] One embodiment is a compound in which X1 is selected from the group consisting of Y, F, and D-Tyr, and X6 is F. Yes, X 13 is selected from the group consisting of Aib, L, and αMeL; or a pharma- ceutically acceptable salt thereof.

[0030] One embodiment is where R1 is absent and X1 is selected from the group consisting of Y, F, and D-Tyr. is selected, X6 is F, and X 13 is selected from the group consisting of Aib, L, and αMeL , X2 is Aib, X3 is E, and X 10 is Y and X 11 is S and X 12 is I and X 14 is L and X 16 K, E, Orn, Dab, Dap, S, T, H , Aib, αMeK, and R; X 17 But, C 16 -C 22 fat an amino acid linked to an acid, wherein the fatty acid is linked to the amino acid via a linker; Optionally bonded), X 19 is Q and X 20 consists of Aib, Q, H, and K selected from the group, X 21 is selected from the group consisting of H, D, T, A, and E; 22 but F and X 23 is I and X 24 is selected from the group consisting of D-Glu and E, 26 is L and X 27 is I and X 28 is the group consisting of E, A, S, and D-Glu Selected from X 29 is selected from the group consisting of Aib, G, and A; 30 is C, G and G-R2, 31 is absent or PX 32 X 33 X3 4-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) 32 is S and X 33 is S Yes, X 34 is selected from the group consisting of G and C; 35 is A and X 36 is P X 37 is P and X 38 is P and X 39 is selected from the group consisting of C and S , X 40 is C), a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0031] One embodiment is a compound in which X1 is selected from the group consisting of Y, F, and D-Tyr, and X6 is F. Yes, X 13 is selected from the group consisting of Aib, L, and αMeL; 28 is A , X 29 is G and X 30 is G and X 31 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 - R2 (SEQ ID NO: 5), 34 is G and X 39 is S, A compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0032] One embodiment is a compound in which X is selected from the group consisting of Y and D-Tyr; 13 αMeL or a pharma- ceutically acceptable salt thereof.

[0033] In one embodiment, the sequences of SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:305, SEQ ID NO:306, A compound of formula I selected from the group consisting of SEQ ID NO: 307, and SEQ ID NO: 308, or and pharma- ceutically acceptable salts thereof. One embodiment is a compound of formula I, which is SEQ ID NO: 303: or a pharma- ceutically acceptable salt thereof. One embodiment is a compound of formula I, which is SEQ ID NO: 304. One embodiment is a compound of the formula SEQ ID NO: 305, or a pharma- ceutically acceptable salt thereof. I or a pharma- ceutically acceptable salt thereof. One embodiment is SEQ ID NO: 306. or a pharma- ceutically acceptable salt thereof. One embodiment is a compound of formula I, represented by SEQ ID NO: 307 or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound of formula I is 308, or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound of formula I is The compound of formula I, which is column number 386, or a pharma- ceutically acceptable salt thereof.

[0034] In one embodiment, X 10 is A, L, H, 3Pal, 4Pal, V, Y, αMeF, αMeF(2F), I, αMeY, Q, D-His, E, cTA, and D-Tyr. , X 12 is selected from the group consisting of I, D-Ile, and S; X 13 is selected from the group consisting of Nle, Aib, L, and αMeL; X 14 is L, X 16 K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R, X 17 is selected from the group consisting of K, Q, and I; X 19 is selected from the group consisting of Q and A; X 20 is selected from the group consisting of Aib, Q, H, R, K, and αMeK; X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I; X 23 is selected from the group consisting of I, L, A, G, F, H, E, and V; X 24 from S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P. is selected from the group consisting of X 26 is selected from the group consisting of L and αMeL; X 27 is selected from the group consisting of L and I; X 28 is selected from the group consisting of E, A, S, and D-Glu; X 29is selected from the group consisting of Aib, G, and A; A compound of formula I (hereinafter "compound of formula IV"), or a pharma- ceutically acceptable salt thereof. .

[0035] In one embodiment, X 39 is C, or a pharma- ceutically acceptable salt thereof. In one embodiment, X 40 is C, or a pharma- ceutically acceptable salt thereof. It is a useful salt.

[0036] In one embodiment, X 30 , X 34 , X 39 , and X 40 One of them, and only one of them, is C. In one embodiment, X is a compound of formula IV, or a pharma- ceutically acceptable salt thereof. 30 , X 34 , X 39 , and X 40 One of the 100,0 ... C, or a pharma- ceutically acceptable salt thereof. and C is modified with a time extension technology, said time extension technology being XTEN; In one embodiment, C is a compound that is The time extension technique is modified using (Glu) m Biotin (where m is 0, 1, 2, or or 3), or a pharma- ceutically acceptable salt thereof. In the embodiment, X1 is Y, X2 is Aib, X3 is E, X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y; X 11 But S, X 12 But, I, X 16 is selected from the group consisting of K, E, Orn, Dab, and Dap; X 19 But Q, X 20 is selected from the group consisting of Aib and K; X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E; X 22 But F, X 23 But, I, X 24 is selected from the group consisting of S, Aad, D-Glu, and E; X 26 is L, X 28 is selected from the group consisting of E and A; A compound of formula IV, or a pharma- ceutically acceptable salt thereof.

[0037] In one embodiment, X1 is Y, X2 is Aib, X3 is E, X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y; X 11 But S, X 12 But, I, X 16 is selected from the group consisting of K, E, Orn, Dab, and Dap; X 20 But, Aib, X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E; X 22 But F, X 24 is selected from the group consisting of S, Aad, D-Glu, and E; X 27But, I, X 28 is selected from the group consisting of E and A; A compound of formula IV, or a pharma- ceutically acceptable salt thereof.

[0038] In one embodiment, X 14 is L, X 17 is selected from the group consisting of K, Q, and I; X 30 is selected from the group consisting of G-R2 and G; q is selected from the group consisting of 16, 18, and 20; X 30 If G, then X 31 but PX 32 X 33 X 34 -R2 (SEQ ID NO: 4) (wherein X 32 is S and X 33 is S Yes, X 34 is G and R2 is absent (SEQ ID NO: 299), or X 32 is S X 33 is S and 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), X 32 is S and X 33 is S and X 34 is G and X 35 is A and X 36 teeth P and X 37 is P and X 38 is P and X 39 is S and R2 is absent (SEQ ID NO: 301), or X 32 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P and X 37 is P and X 38 is P and X 39 is S and R2 is NH2 (SEQ ID NO: 302)) 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 Either K(2-[2-(2-amino-

[0223] 2-γGlu-CO-(CH2)qCO2H, A compound of formula I (hereinafter "compound of formula V"), or a pharma- ceutically acceptable salt thereof.

[0039] In one embodiment, X1 is Y, X2 is Aib, X3 is E, X 10 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 But S, X 12 I, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy] Selected from the group consisting of: 2-(γ-Glu)-CO-(CH2)qCO2H And, X 16 K, E, Orn, Dab, Dap, and K(2-[2-(2-amino- 2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 17 is selected from the group consisting of K and I; X 19 Q, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl (γ-Glu)-CO-(CH)qCOH; X 20 Aib and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetate (γ-Glu)-CO—(CH)qCOH; X 21 H, Aad, D, Aib, T, A, E, and K(2-[2-(2-amino -ethoxy]-ethoxy]-acetyl 2- (γ-Glu)-CO-(CH2)qCO2 H, X 22 But F, X 24 S, Aad, D-Glu, E, and K(2-[2-(2-amino-ethoxy) (Ci)-ethoxy]-acetyl 2- (γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 26 However, L and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl ) 2- (γ-Glu)-CO-(CH2)qCO2H; X 27 is selected from the group consisting of L and I; X 28E, A, and K (2-[2-(2-amino-ethoxy)-ethoxy]-a cetyl)2-(γ-Glu)-CO—(CH2)qCO2H, A compound of formula V, or a pharma- ceutically acceptable salt thereof.

[0040] In one embodiment, X 20 K(2-[2-(2-amino-ethoxy)-ethoxy]-a Cetyl) 2- (γ-Glu)-CO-(CH2)qCO2H, where q is 16 or is 18), or a pharma- ceutically acceptable salt thereof. , X 31 is SEQ ID NO: 301 or SEQ ID NO: 302, or a pharmaceutical composition thereof. are physically acceptable salts.

[0041] One embodiment is a method for administering a compound of formula I, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. and administering an effective amount of the compound to treat T2DM, obesity, and non-alcoholic fatty liver disease (NAFLD). ), nonalcoholic steatohepatitis (NASH), dyslipidemia, and metabolic syndrome In one embodiment, a compound of formula I is provided, administering to a subject in need thereof an effective amount of the compound, or a pharma- ceutical acceptable salt thereof. In one embodiment, the condition is NAFLD. In one embodiment, the condition is NASH.

[0042] One embodiment is a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in therapy. In one embodiment, the present invention provides a method for treating T2DM, obesity, NAFLD, NASH, dyslipidemia, and and metabolic syndrome. In one embodiment, a compound of formula I is provided, or a pharma- ceutically acceptable salt thereof, 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 compounds of formula I, or pharma- ceutically acceptable salts thereof, are useful in the treatment of a variety of conditions or diseases. For example, in certain embodiments, a method for treating T2DM in a patient may include administering administering to a subject in need of such treatment a compound of formula I, or a pharma- ceutically acceptable derivative thereof. In one embodiment, the method comprises administering to a subject in need of treatment an effective amount of a salt. The method of claim 1, further comprising administering to a patient suffering from obesity an effective amount of a compound of formula I, or a pharma- ceutically acceptable salt thereof. In one embodiment, the method comprises administering to a subject in need of treatment a compound of formula I A non-therapeutic weight loss treatment comprising administering an effective amount of a compound, or a pharma- ceutically acceptable salt thereof. This is a method of inducing a reduction in a target.

[0044] In certain embodiments, the present invention provides a method for administering to a subject in need of treatment a compound of formula I, or The present invention relates to a method for treating a patient suffering from metabolic syndrome, the method comprising administering an effective amount of a pharma- ceutical acceptable salt thereof to said patient. In one embodiment, a method of treating a subject in need of treatment is provided, comprising administering to the subject a compound of formula I The present invention relates to a method for treating NASH, the method comprising administering to a patient a therapeutically effective amount of be.

[0045] Further provided herein are metformin, thiazolidinedione, sulfonyluria. Dextrose, dipeptidyl peptidase 4 inhibitor, sodium glucose cotransporter, SGLT-2 inhibitors, growth differentiation factor 15 modulators ("GDF15"), peptide tyrosine tyrosine Prolactin-modulators ("PYY"), modified insulin, amylin, dual amylin calcitonin tonin receptor agonists, and oxyntomodulin agonists ("OXM"), Selected one or more drugs will be administered to treat T2DM, obesity, NAFLD, NASH, and dyslipidemia. and metabolic syndrome. In one embodiment, the compounds of the present invention are intended for simultaneous, separate or sequential use. The drugs are metformin, thiazolidinediones, sulfonylureas, and dipeptidyl peptidases. 4 inhibitors, sodium glucose cotransporter, SGLT-2 inhibitors, GDF15, PYY, Modified insulin, amylin, dual amylin-calcitonin receptor agonist, and O XM. In the form, the compounds of the present invention include metformin, thiazolidinedione, sulfonylurea , dipeptidyl peptidase 4 inhibitor, sodium glucose cotransporter, SGLT-2 inhibitor Inhibitors, GDF15, PYY, modified insulin, amylin, dual amylin calcitonin and one or more agents selected from the group consisting of receptor agonists, OXM, and OXM. For simultaneous, separate or sequential use to treat a condition selected from the group consisting of obesity. In one embodiment, the compound of the present invention is a compound for the treatment of Zindione, sulfonylurea, dipeptidyl peptidase 4 inhibitor, sodium glucose and SGLT-2 inhibitors, and obesity. It is a compound for use in.

[0046] In another embodiment, the compound, or a pharma- ceutically acceptable salt thereof, is administered to a subject in need thereof. The compounds of the present invention, or pharma- ceutically acceptable salts thereof, may be useful in improving bone strength in rats. Such salts may be useful in treating other diseases, such as Parkinson's disease or Alzheimer's disease. Insulin with activity at one or more of the GIP, GLP-1, and / or glucagon receptors Cretin and incretin analogs are involved in obesity, NAFLD, NASH, dyslipidemia, and metastases. Other conditions include osteoporotic syndrome, bone-related diseases, Alzheimer's disease, and Parkinson's disease. It has been described as potentially having therapeutic value for many diseases or conditions. For example, “Jall S.,et.al,Monomeric GLP-1 / GIP / gluca gon triagonism corrects obesity,hepatost eatosis,and dyslipidemia in female mice, Mol Metab.6(5):440-446 (March 2017); Car bone LJ, et. al., Incretin-based therapy es for the treatment of non-alcoholic fa tty liver disease: A systematic review d meta-analysis.J.Gastroenterol.Hepatol. , 31(1):23-31 (Jan. 2016); B. Finan,et.a l,Reappraisal of GIP Pharmacology for Me tabolic Diseases.Trends Mol.Med.,22(5):3 59-76 (May 2016);Choi,I.Y.,etal.,Potent body weight loss and efficacy in a NASH animal model by a novel long-acting GLP- 1 / Glucagon / GIP triple-agonist(HM15211),A DA 2017 Poster 1139-P;Ding, K.H.,Impact of glucose-dependent insulinotropic pept ide on age-induced bone loss,J.Bone Mine r.Res., 23(4):536-43 (2008);Tai,J.et.al, Neuroprotective effects of a triple GLP- 1 / GIP / glucagon receptor agonist in the A PP / PS1 transgenic mouse model of Alzheim er’s disease,Brain Res.1678,64-74(2018); T.D.Muller et al.,The New Biology and Ph armacology of Glucagon, Physiol.Rev.97:7 21-766(2017);Finan,B.et.al,Unimolecular Dual Incretins Maximize Metabolic Benefi ts in Rodents,Monkeys,and Humans,Sci.Tra nsl.Med.,5:209(October 2013);Holscher C, Insulin, incretins and other growth factors rs as potential novel treatments for Alz heimer's and Parkinson's diseases.Bioche m.Soc.Trans.42(2):593-0(Apr.2014)".

[0047] In another embodiment, the compounds of the present invention, or pharma- ceutical acceptable salts, are administered to treat T2DM, obesity, , NAFLD, NASH, dyslipidemia, and metabolic syndrome A method for use in the manufacture of a medicament for treating a selected condition is provided. In one embodiment, the medicament is for the treatment of T2DM. In one embodiment, the medicament is for the treatment of obesity. In one embodiment, the medicament is for the treatment of NAFLD. Thus, the agent is for the treatment of NASH.

[0048] Another embodiment is a compound of formula I, or a pharma- ceutically acceptable salt thereof, in combination with a carrier, diluent, and at least one selected from the group consisting of an excipient. .

[0049] One embodiment is a combination of a compound of formula I, or a pharma- ceutically acceptable salt thereof, and at least one A pharmaceutical composition comprising a penetration enhancer and at least one protease inhibitor. The embodiment includes a compound of formula I, or a pharma- ceutically acceptable salt thereof, and at least one penetration enhancer. and at least one selected from the group consisting of a carrier, a diluent, and an excipient. and (iii).

[0050] One embodiment is a combination of a compound of formula I, or a pharma- ceutically acceptable salt thereof, a penetration enhancer, and a prodrug. a protease inhibitor and at least one selected from the group consisting of a carrier, a diluent, and an excipient; and a pharmaceutical composition comprising the compound of formula I or a pharmaceutical In one embodiment, the compound of the present invention is a pharmaceutical composition comprising a compound of the present invention, a therapeutically acceptable salt thereof, and a penetration enhancer. In one embodiment, the pharmaceutical composition comprises the compound, or a pharma- ceutical acceptable salt thereof, and a permeation enhancer. In some embodiments, the penetration enhancer is sodium decanoate ("C10"), taurodeoxycholine, Sodium Tetrahydrofuran ("NaTDC"), Lauroyl Carnitine ("LC"), Dodecyl Maltate Toside ("C12-maltoside"), dodecylphosphatidylcholine ("DPC"), N -Sodium [8-(2-hydroxybenzoyl)amino]caprylate ("SNAC") In one embodiment, the penetration enhancer is selected from the group consisting of: In one embodiment, the protease inhibitor is selected from the group consisting of C10 and LC. soybean trypsin inhibitor ("SBTI"), soybean trypsin-chymotrypsin inhibitor ( "SBTCI"), ecotin, sunflower trypsin inhibitor ("SFTI"), leupeptin Citric Acid, Ethylenediaminetetraacetic Acid ("EDTA"), Sodium Glycocholate, From 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride ("AEBSF") In one embodiment, the protease inhibitor is selected from the group consisting of SBTI, SBT In one embodiment, the protease inhibitor is selected from the group consisting of: The harmful agent is SBTI.

[0051] As used herein, "treating" or "treating The term "to treat" includes the progression or severity of a symptom, condition, or disorder. This includes limiting, slowing, stopping, or reversing the speed.

[0052] The specific compounds of the present invention are generally effective over a wide dosage range. Dosage for parenteral administration once a week ranges from 0.05 mg to approximately 30 mg per person per week. It may be within a range.

[0053] The compound of the present invention has affinity for both GLP-1 and GIP receptors, and GLP-1 contains a 36 amino acid sequence that has the desired potency at each of the receptors. It is an acid peptide, the main biologically active fragment of which is a 30 amino acid C-terminal amidated Peptide (GLP-1 7-36 ) (SEQ ID NO:2).

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

[0055] These compounds provide the desired potency at each of the GIP and GLP-1 receptors. In one embodiment, the compound is suitable for oral administration. In one embodiment, the compound is It has a desirable long-lasting effect on the GIP and GLP receptors. In embodiments, the compounds have desirable activity at the GIP and GLP receptors and are GI P agonist potency is measured by the casein cAMP assay described below. The potency was 2.5-5 times higher than that of the LP1 receptor, and the potency was determined by measuring the natural GI In one embodiment, the compound is standardized against GIP and GLP. The desired activity at the LP receptor and GIP agonist potency are as follows: 2.5- to 10-fold higher than GLP1 receptor potency as measured by in vivo cAMP assay. Potencies are normalized to native GIP and GLP on the same day that the assay is performed.

[0056] As used herein, the term "amino acid" refers to naturally occurring amino acids, and The term refers to both natural and unnatural amino acids. Amino acids are usually designated by their standard one-letter codes (e.g. , L=leucine), and alpha-methyl substituted residues of natural amino acids (e.g., α-methyl α-methyl-lysine, or αMeL, and α-methyl-lysine, or αMeK, Aminoisobutyric acid, or other specific It is demonstrated using unnatural amino acids, the structures of which are shown below.

[0057] [ka]

[0058] [ka]

[0059] As used herein, "Orn" means ornithine. By "4Pal" is meant 3-(4-pyridyl)-L-alanine. When used in this document, "αMeF(2F)" refers to alpha-methyl 2-F-phenylalanine. As used herein, "αMeY", "αMeK", and "αMe "L" stands for alpha-methyl tyrosine, alpha-methyl lysine, and alpha-methyl As used herein, "e" and "D-Glu" refer to D -glutamic acid. As used herein, "D-His" and "h" refer to and D-histidine, respectively. As used herein, "D-Tyr" and "D-Ser" and "y" each mean D-tyrosine. " and "s" refer to D-serine. As used herein, "D-Ala" and "a" each mean D-alanine. eF(2F)" is a methyl-F(2F) and alpha-methyl-Phe(2 As used herein, "αMeF" refers to alpha-methyl-F and and alpha-methyl-Phe. As used herein, "αMeY" means , alpha-methyl-Tyr. As used herein, "αMeK" means As used herein, "αMeL" means alpha-methyl-Lys. As used herein, "αMeS" means aryl-methyl-Leu. As used herein, alpha-methyl-serine and alpha-methyl-Ser are In this case, "αMeP" refers to alpha-methyl-proline and alpha-methyl-Pro As used herein, "desH" means desHis. As used herein, "desY" means desTyr.

[0060] When X1 is DesH and X2 is Aib, DesH and Aib are combined to form the above A group such as that illustrated in DesH-ψ[NHCO]-Aib can be formed.

[0061] As used herein, "C 16 -C 22 The term "amino acid bound to a fatty acid" is chemically modified via a covalent bond to a fatty acid or, preferably, via a linker. It refers to any natural or unnatural amino acid that has a functional group attached to a fatty acid. Examples of the group include an amino group, a carboxyl group, a chloro group, a bromo group, an iodo group, and an azide group. Examples of functional groups that may be included include alkynyl groups, alkenyl groups, and thiol groups. Examples of natural amino acids include K (amino), C (thiol), E (carboxyl), and and D (carboxyl). In one embodiment, the linked amino acid is K. be.

[0062] As noted above, embodiments of the compounds of Formula I, Formula II, Formula III, Formula IV, and Formula V include fatty acids. The compounds of the invention are those in which the fatty acid moiety is attached via a linker or a direct bond. In an embodiment, the compounds of the invention are preferably linked to the 14- or 17-position via a linker. In one embodiment, the linkage is an acylation. In one embodiment, the bond is to the ε-amino group of the K side chain. One embodiment comprises a fatty acid moiety attached to the K at position 17 via a linker.

[0063] In one embodiment, the compounds of the invention are available for conjugation directly without a linker. The fatty acid moiety is linked to a natural or unnatural amino acid having a specific functional group. In a preferred embodiment, the binding amino acid is selected from the group consisting of K, C, E, and D. In a particularly preferred embodiment, the binding amino acid is K. In this form, the attachment is to the ε-amino group of the K side chain.

[0064] In one embodiment, the linker is 1 to 4 amino acids, aminopolyethyleneglycol. In one embodiment, the aminopoly Ethylene glycol carboxylate has the formula: H-{NH-CH2-CH2-[O-CH2-CH2]pO-(CH2)z-CO} r-OH, where p is any integer from 1 to 12 and z is any integer from 1 to 20. where r is either 1 or 2.

[0065] One embodiment is an amino acid linked to a fatty acid via a linker, the linker being G The compound of formula I, which contains 1 to 2 amino acids selected from the group consisting of γ-Glu and γ-Glu. In one embodiment, the linker is one to two (2-[2-(2-amino The compounds of the present invention are directly bonded or is chemically bonded to the functional group of an amino acid by one of the linkers 16 -C 22 fat In one embodiment, the fatty acid moiety utilizes a linker between the lysine and the fatty acid. In one embodiment, the fatty acid moiety is linked to lysine at position 17 via a fatty acid moiety. In one embodiment, the fatty acid is linked to a lysine at position 20 via a linker between the fatty acid. The chain can be any single chain C 16 -C 22 It is a fatty acid.

[0066] In one embodiment, the fatty acids are linked by a linker, the linker being one or more (2- [2-(2-amino-ethoxy)-ethoxy]-acetyl) moiety and 0 or 1 to and 4 amino acids, or a pharma- ceutically acceptable salt thereof. In an embodiment, the linker comprises 1 to 4 Glu or γ-Glu amino acid residues. In one embodiment, the linker comprises one or two Glu or γ-Glu amino acids. In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, The salt comprises a fatty acid linked via a linker, the linker comprising one or two γ- In one embodiment, the compound of formula I or a pharma- ceutically acceptable salt thereof comprises a Glu amino acid residue. Possible salts include fatty acids linked via a linker, the linker having up to 36 (2 -[2-(2-amino-ethoxy)-ethoxy]-acetyl) moiety. The amino acid sequence may include 1 to 4 amino acid residues (e.g., Glu and γ-Glu amino acids) that are Specifically, one embodiment includes a fatty acid linked via a linker, the linker being 1-4 Glu and γ-Glu amino acids and 1-4 (2-[2-(2-amino Compounds of formula I consisting of a combination of (( ... or a pharma- ceutically acceptable salt thereof. One embodiment is a lipid linked via a linker. and the linker comprises one or two γ-Glu amino acids and one or two (2 -[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties. , a compound of formula I, or a pharma- ceutically acceptable salt thereof. and a fatty acid bonded to the linker, the linker and the fatty acid moiety having the formula: or a pharma- ceutically acceptable salt thereof: (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu) b-CO-(CH2)q-CO2H (wherein a is 1 or 2 and 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 its structure is as follows:

[0067] [ka]

[0068] In one embodiment, a is 1, b is 2, q is 18, and the structure is It is.

[0069] [ka]

[0070] In one embodiment, a is 1, b is 1, q is 18, and the structure is: It is.

[0071] [ka]

[0072] As used herein, "C 16 -C 22 The term "fatty acid" refers to a group of fatty acids with 16 to 22 amino acids. In one embodiment, the term "carboxylic acid" is used herein to refer to a carboxylic acid having carbon atoms. C 16 -C 22 The fatty acid may be a saturated dibasic acid. In one embodiment, the fatty acid is C 20 -C 22 is 。 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: In an embodiment, q is 18. In one embodiment, q is 20.

[0073] In one embodiment, the compounds disclosed herein and specific saturated C 16 -C 22 Fatty acids include hexadecanedioic acid (C 16 diacid), heptadecanedioic acid (C 17 diacid), octadecanedioic acid (C 18 diacid), nonadecanedioic acid (C 19 diacid), eicosane Diacid (C 20 diacid), heneicosanedioic acid (C 21 diacid), docosanedioic acid (C 22 Diacid)( including branched and substituted derivatives thereof.

[0074] In one embodiment, C 16 -C 22 Fatty acids are saturated C 18 Diacid, saturated C 19 diacid, saturated Japanese C 20 In one embodiment, the compound is selected from the group consisting of diacids, and branched and substituted derivatives thereof. In terms of form, C 16 -C 22 The fatty acids are stearic acid, arachidonic acid, and eicosapentaenoic acid. In one embodiment, the compound is selected from the group consisting of C 16 -C 22 Fatty acids are It is quidonic acid.

[0075] As shown in the chemical structures of Examples 1 to 5 below, in one embodiment, the above-mentioned linker-lipid The fatty acid moiety is linked to the ε-amino group of the lysine side chain.

[0076] In one embodiment, X30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 and X 40 wherein none of the groups is C, or a fatty acid-containing substituent, In one embodiment, X is a compound represented by the formula: 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 However, none of the substituents contain fatty acids, and X 30 , X3 4. X 39 , and X 40 wherein none of the formula I is C, or a pharma- ceutically acceptable salt thereof. In one embodiment, X is an acceptable salt thereof. 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23、 X 24 , X26 , 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 wherein none of the substituents contains a fatty acid; It is a useful salt.

[0077] As used herein, "time extension technology" refers to peptide time extension technology. For example, recombinant human serum albumin ("rHSA"), a polymeric sequence of amino acids ("XT"), Peptide conjugation to a pharma- ceutical acceptable polymer such as PEG-1000 (EN) or a non-sulfated heparin-like carbohydrate. Hydroxyethyl starch ("HES"), llama heavy chain antibody These include VHH fragments ("VHH"), PEGylation, Fc binding, and bovine serum albumin ("BSA"). (Sleep, D. Epert Opin Drug Del (2015) 12, 793-812;Podust VN et.al.J Control.Releas e,2015;ePUB;Hey,T.et.al.in:R.Kontermann( Ed.), Therapeutic Proteins: Strategies to Modulate their Plasma Half-Lives,Wiley-V CH Verlag Gmbh&Co.KGaA, Weinheim, Germany, 2012,pp117-140;DeAngelis,PL,Drug Dev Del ivery (2013) January, 12 / 31 / 2012). In one embodiment, the time extension technique is applied using a linker group. is applied with 0, 1, 2 or 3 amino acids as linkers.

[0078] One embodiment is fatty acid-free (i.e., X 10 , X 12 , X 13 , X 14 , X1 6. X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X2 9. X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X3 9, and X 40 wherein none of the substituents contains a fatty acid), a compound of formula I, or A pharma- ceutically acceptable salt or a compound that is administered transdermally or via injection to a patient in need thereof. Further, the compound of formula I, which is free of fatty acids, or a pharma- ceutical acceptable salt thereof, is a time-extending technique. Possible salts include, for example, recombinant human serum albumin ("rHSA"), a polymer of amino acids. peptide conjugation to a pharma- ceutical acceptable polymer, such as an XTEN sequence; Valine-like carbohydrate polymers ("HEP"), and hydroxyethyl starch ("HE In one embodiment, the peptide may be further modified using peptide time-extension techniques such as A cysteine ​​amino acid in a compound of formula I, free of fatty acids, or a pharma- ceutically acceptable salt thereof. In one embodiment, the time extension technique is applied using procedures known to those skilled in the art. The interphase extension technique comprises the step of administering to the subject a compound of formula I, or a pharma- ceutically acceptable salt thereof, free of fatty acids. In one embodiment, the time extension technique is applied to a fatty acid-free amino acid of formula I or a pharma- ceutical acceptable salt thereof, 17 But from I, K and Q In one embodiment, the time extension technique is selected from the group consisting of the fatty acid-free compounds of formula I. or a pharma- ceutically acceptable salt thereof, 30 is C. In one embodiment, In the present invention, the time extension technology is a fatty acid-free compound of formula I, or a pharma- ceutically acceptable salt thereof. applies to X 34 is C. In one embodiment, the time extension technique is a fatty acid-free, Applies to compounds of formula I, or a pharma- ceutically acceptable salt thereof, 39 is C. In one embodiment, the time extension technology comprises a fatty acid-free compound of formula I, or a pharma- ceutically acceptable salt thereof. Applies to possible salts, X 40 is C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] As used herein with reference to one or more GIP or GLP-1 receptors, The terms "activity", "activation" and the like refer to the in vitro assays described below. The activity of the compound, or a pharma- ceutically acceptable salt thereof, as measured using assays known to those skilled in the art. , binding ability, and ability to induce a response at the receptor.

[0080] The compounds of the present invention, or pharma- ceutically acceptable salts thereof, have the following properties: The affinity for each of the receptors can be measured, for example, by the measurement techniques described in the Examples below. using techniques known in the art to measure receptor binding levels, typically expressed as Ki values. The activity of the compounds of the invention at each receptor can be further measured, for example, by using techniques known to those of skill in the art, including the in vitro activity assays described below. Generally, EC 50 It is expressed as a value that corresponds to the half-maximal dose-response curve. is the concentration of the compound that causes the simulation.

[0081] In one embodiment, the pharmaceutical compositions of the compounds of formula I are suitable for administration by a parenteral route. In one embodiment, the compound of formula Pharmaceutical compositions of the compounds of formula I are suitable for oral administration (e.g., tablets, capsules). Several pharmaceutical compositions and methods for their preparation are well known in the art. For example, Remington: The Science and Practice o f Pharmacy(DBTroy,Editor,21st Edition, (See Lippincott, Williams & Wilkins, 2006.) Gastrointestinal In addition to the anatomical and physiological characteristics of the peptide, the physiochemical properties of the peptide determine its efficacy. In one embodiment, the pharmaceutical composition for oral administration is In one embodiment, the pharmaceutical composition for oral administration comprises the compound of formula (I) and a penetration enhancer. a compound of formula I, or a pharma- ceutically acceptable salt thereof; a permeation enhancer; and a protease inhibitor. In one embodiment, the pharmaceutical composition for oral administration comprises a compound of formula I, or and a penetration enhancer.

[0082] The compounds of the present invention are contemplated in monolithic and multiparticulate dosage forms. In the present invention, the compound of formula I is provided as a monolithic composition. The multiparticulate composition is intended to release the entire composition at a single location. The present invention is intended to achieve rapid delivery of the composition and distribute the composition components over a large surface area of ​​the small intestine. In monolithic and multiparticulate dosage compositions, simultaneous release of compound and functional excipients is possible. In one embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, The nolitic composition may be contained in an enteric capsule, an enteric coated capsule, or an enteric coated tablet. Such multiparticulate compositions are formulated as granules, with the coating generally remaining intact in the low pH of the stomach. Yes, enteric-coated minitablets or enteric-coated granules, which dissolve in the high pH of the intestine. Two types of coated minitablets or coated granules have a pH above 5.5. For delivery to the proximal small intestine, where it dissolves at pH 7-7.2 or for delivery to the distal small intestine, where it dissolves at pH 7-7.2 or above If distal small intestinal delivery is desired, the drug may be formulated as a monolithic capsule or The tablet can also be coated with a coating system for distal small intestinal release. may be filled into standard uncoated capsules.

[0083] As used herein, the term "penetration enhancer" refers to an agent that enhances the oral absorption of the compounds of the present invention. As used herein, a penetration enhancer refers to a penetration enhancer that enhances the absorption of decane. Sodium taurodeoxycholate, sodium lauroyl carnitine, dodecyl malate Rutosides, dodecylphosphatidylcholine, SNAC, rhamnolipids, and e.g. Permeant inhibitor of phosphatase,PIP-25 0 and PIP-640. aceutics.2019 Jan;11(1):41 ​​(see Biomateria ls.2012;33:3464-3474),ZOT(zonula occlude ns toxin),ΔG(fragment of ZOT)(see below Int.J. In one embodiment, the penetration enhancer The accelerators are sodium decanoate, sodium taurodeoxycholate, and sodium lauroyl phosphate. In one embodiment, the penetration enhancer is selected from the group consisting of C10, LC In one embodiment, the penetration enhancer is selected from the group consisting of C1 The value is 0.

[0084] As used herein, the term "protease inhibitor" refers to a protein-based protease inhibitors, which may be selected from the group consisting of peptide-based, and small molecule-based Protease inhibitors are well known and include soybean trypsin inhibitor ("SBTI"). , soybean trypsin-chymotrypsin inhibitor ("SBTCI"), ecotin, sunflower SFTIs, leupeptin, citric acid, ethylenediaminetetraacetic acid (" EDTA), sodium glycocholate, and 4-(2-aminoethyl)benzenesulfonyl ether. In one embodiment, sulfonyl fluoride hydrochloride ("AEBSF") and the like may be used. The protease inhibitor is selected from the group consisting of SBTI, SBTCI, and SFTI. In one embodiment, the protease inhibitor is an SBTI.

[0085] In one embodiment, the compound is a cell membrane guanosine 5'-(γ-thio)triphosphate-[ 35 S]( It is a partial agonist at the GLP-1R as shown by a GTPγS binding assay. on the GLP-1R as shown by β-arrestin-2 recruitment assay. is a partial agonist, is a potent GIPR / GLP-1R dual agonist, I, or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound is 1R of HEK293 cell membrane guanosine 5'-(γ-thio)triphosphate-[ 35 S](GTP GLP-1R-activated Gα in a γS binding assay s The compound of formula I stimulates or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound is a GLP-1R HE K293 cell membrane guanosine 5'-(γ-thio)triphosphate-[ 35 S](GTPγS) binding Compounds that show 75% or less partial agonism in the GLP-CHO assay Showed partial agonism of 35% or less in a cellular β-arrestin recruitment assay It is a compound.

[0086] In one embodiment, the method comprises isolating GLP-1R from HEK293 cell membrane guanosine 5'-(γ-thio ) triphosphate-[ 35 Compounds showing 75% or less partial agonism in the [S] binding assay were included. and administering an effective amount of a compound that is a GIP agonist. In one embodiment, the present invention relates to a method for treating a disease. 5'-(γ-thio)triphosphate-[ 35S](GTPγS) binding assay Compounds that exhibit GIP agonism are co-administered with compounds that have GIP agonist activity. In an embodiment, the HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate (TG) of GLP-1R is phosphoric acid-[ 35 Compounds that exhibit partial agonism in the [S](GTPγS) binding assay within one week before or after administration of a compound having GIP agonist activity as an active agent. In one embodiment, the method for treating diabetes includes administering to a GLP-CHO cell Compounds that demonstrate ≤35% partial agonism in the β-arrestin recruitment assay and the administration of an effective amount of guanosine 5'-(γ-thiol) to the HEK293 cell membrane of GLP-1R. O) Triphosphate-[ 35 S](GTPγS) binding assay with partial agonism of 75% or less The method includes administering an effective amount of a compound that exhibits the following:

[0087] The compounds of the present invention react with a number of inorganic and organic acids / bases to produce pharma- ceutically acceptable salts. Pharmaceutically acceptable salts and methods for preparing them may be used. General methods are well known in the art (see, for example, P. Stahl, et al. al.Handbook of Pharmaceutical Salts:Prop erties,Selection and Use,2nd Revised Edi The pharma- ceutically acceptable salts of the present invention are These include sodium, trifluoroacetate, hydrochloride, ammonium, and acetate salts. In one embodiment, the pharma- ceutically acceptable salt is, but is not limited to, sodium salt. The compound is selected from the group consisting of the hydrochloride, hydrochloride, and acetate salts.

[0088] The present invention also relates to novel compounds useful in the synthesis of the compounds of the present invention, or pharma- ceutically acceptable salts thereof. The intermediates and compounds of the present invention are also known in the art. It can be prepared by a variety of known procedures. In particular, in the following examples, the process is carried out using chemical synthesis. The specific synthetic steps for each route described are described in detail below. The reagents and starting materials may be combined in different ways to prepare the compounds. are readily available to those

[0089] As used herein, the term "effective amount" refers to a dose or doses administered to a patient. The compounds of the invention, or compounds thereof, which, when administered, provide a desired effect in a patient being diagnosed or treated. The effective amount refers to the amount or dosage of a pharma- ceutically acceptable salt of the compound of the formula (I). One skilled in the art can determine this by observing results obtained under similar circumstances. In determining an effective amount, the species, size, age, and general health of the mammal involved, the specific disease or disorder, the extent, involvement or severity of the disease or disorder, response, the particular compound administered, the mode of administration, the bioavailability characteristics of the administered formulation, the selection including, but not limited to, the medication regimen chosen, the use of concomitant medications, and other relevant circumstances. No, many factors are taken into consideration.

[0090] As used herein, the term "subject in need thereof" refers to a subject in need of treatment or therapy. The term "human mammal" refers to a mammal, preferably a human, having a disease or condition requiring the treatment of a disease or condition, such as the above-mentioned As used herein, "EDTA" refers to ethylenediaminetetraacetate. As used herein, "DMSO" means dimethyl sulfoxide. As used herein, "CPM" means counts per minute. As used herein, "IBMX" means 3-isobutyl-1-methyl As used herein, "LC / MS" means liquid chromatography / mass spectrometry. As used herein, "HTRF" means homogeneous high temperature radiofrequency (HTRF) / mass spectrometry. As used herein, "BSA" refers to bovine serum albumin. It means Min.

[0091] The present invention will be further illustrated by the following examples, which are not intended to limit the invention. is not to be interpreted as a EXAMPLES

[0092] 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)-YLIEGGPS SGAPPPS-NH2 (sequence number 10).

[0093] The structure of SEQ ID NO:10 is shown below using the standard one-letter amino acid code, where: , the amino acid residues Aib2, αMeF(2F)6, and αMeL1 have expanded structures. 3, K17, Aib20, D-Glu24, and Ser39 are exceptions.

[0094] [ka]

[0095] The peptide backbone of Example 1 is fluorenylmethyloxycarbonyl (Fmoc) / tert-butyl ether. Using t-butyl (t-Bu) chemistry, the peptide synthesizer Symphony X (Gyr os Protein Technologies, Tucson, AZ) .

[0096] The resin was 1% DVB cross-linked polystyrene (Fmoc- Rink-MBHA Low Loading Resin, 100-200 Mesh, EMD Millipore). Standard side chain protecting groups were used. Fmoc-Lys( Mtt)-OH is used for lysine at position 17, and Boc-Tyr(tBu)-OH) is used for lysine at position 1 Each coupling step (7 min x 2) was preceded by DMF The Fmoc group is removed using 20% ​​piperidine in 100% methanol. All the tags were prepared using Fmoc amino acids (0.3 mM), diisopropylcarbodiimide (0.9 Equimolar ratios of 0.1 mM DMSO (0.01 mM) and Oxyma (0.9 mM) were used to theoretically load The reaction is carried out at a 9-fold molar excess over the primary amine for 1 hour and the secondary amine for 3 hours. , and coupling to Cα-methylated amino acids for 3 h. After chain synthesis is complete, the resin is washed extensively six times with DCM to remove residual DMF. The Mtt protecting group of lysine at position 7 was removed by cleavage in DCM with 30% hexafluoroisopropanol (O akwood Chemicals) twice (40 min treatment x 2), and peptide It is selectively removed from the resin.

[0097] Subsequent attachment of the fatty acid linker moiety is accomplished by the use of 2-[2-(2-Fmoc-amino-ethoxy )-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fm oc-Glutamic acid α-t-butyl ester (Fmoc-Glu-OtBu, Ark P harm, Inc.), and mono-OtBu-eicosanedioic acid (WuXi AppTe c) in a 3-fold excess of the reagent (AA:PyAOP :DIPEA=1:1:1mol / mol) was used for each coupling of 1 hour duration. can be.

[0098] Once synthesis is complete, wash the peptide resin with DCM and air dry thoroughly. , and incubated at room temperature for 2 h in 10 mL of cleavage cocktail (trifluoroacetic acid:water:triisopropyl The resin was filtered off and treated with 2 mL of anhydrous TFA. The combined filtrate was treated with a 5-fold excess of cold diethyl ether (-20°C) to obtain The crude peptide is precipitated. The peptide / ether suspension is then stirred at 3500 rpm for 2 min. The mixture was centrifuged for 10 min to form a solid pellet, the supernatant was decanted, and the solid pellet was further washed with ether. Triturate twice and dry in vacuum. The crude peptide is purified by elution with 20% acetonitrile / 20% acetic acid / 6 0% water and run on Luna 5 μm phenyl-hexanes with a linear gradient of 100% acetonitrile Xyl preparative column (21 x 250 mm, Phenomenex), and 0.1% TF A / water buffer system (30-50% acetonitrile 60 min) was used for RP-HPL The purity of the peptides was assessed using analytical RP-HPLC and the pools were purified by The purity of the main pool of compound 1 was found to be 98.0%. The final major product pool was then lyophilized, resulting in lyophilized peptide TFA. A salt was formed. The molecular weight was determined by LC-MS (observed: M+3=1657.2 , Calculated: M+3=1657.0).

[0099] 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)-YLIEG GPSSGAPPPS-NH2 (SEQ ID NO:11)

[0100] The structure of SEQ ID NO:11 is shown below using the standard one-letter amino acid code, where: , the amino acid residues Aib2, αMeF(2F)6, and αMeL1 have expanded structures. 3, with the exception of Orn16, K17, Aib20, D-Glu24, and Ser39 .

[0101] [ka]

[0102] A compound according to SEQ ID NO:11 is prepared essentially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3=1642.6, calculated: M+3= 1642.8).

[0103] 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)-YLIEG GPSSGAPPPS-NH2 (SEQ ID NO:12)

[0104] The structure of SEQ ID NO:12 is shown below using the standard one-letter amino acid code, where: , the amino acid residues Aib2, αMeF(2F)6, and αMeL1 have expanded structures. 3, with the exception of Orn16, K17, Aib20, D-Glu24, and Ser39 .

[0105] [ka]

[0106] A compound according to SEQ ID NO:12 is prepared essentially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3=1651.8, calculated: M+3= 1652.2).

[0107] Example 4 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-O rn-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)

[0108] The structure of SEQ ID NO:13 is shown below using the standard one-letter amino acid code, where: , the structure of amino acid residues is extended to residues Aib2, αMeF(2F)6, 4Pal1 0, αMeL13, Orn16, K17, Aib20, D-Glu24, αMeY25, and Ser39 are exceptions.

[0109] [ka]

[0110] A compound according to SEQ ID NO:13 is prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3=1642.5, calculated: M+3= 1642.1).

[0111] 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)

[0112] The structure of SEQ ID NO:14 is shown below using the standard one letter amino acid code, where: , the amino acid residues Aib2, αMeF(2F)6, and αMeL1 have expanded structures. 3, Orn16, K17, Aib20, D-Glu24, αMeY25, and Ser3 Number 9 is an exception.

[0113] [ka]

[0114] A compound according to SEQ ID NO:14 is prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3=1626.1, calculated: M+3= 1626.1).

[0115] Examples 6 to 287 The compounds according to Example 6 (SEQ ID NO: 15) to Example 287 (SEQ ID NO: 296) are Prepared substantially as described in the procedure of Example 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

[0116] Example 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)

[0117] The structure of SEQ ID NO:303 is shown below using the standard one-letter amino acid code: The amino acid residues Aib2, K17, Aib20, and S er39 is an exception.

[0118] [ka]

[0119] The compound according to SEQ ID NO:303 was prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3 = 1602.5, calculated: M+ 3=1602.8).

[0120] Example 289 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-amino- Ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2) 18 -CO 2H) AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 30 4) The structure of SEQ ID NO:304 is shown below using the standard one letter amino acid code, where: , the structure of the amino acid residues is extended residues Aib2, αMeL13, K17, Aib2 Exceptions are 0 and Ser39.

[0121] [ka]

[0122] The compound according to SEQ ID NO:304 was prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3 = 1626.8, calculated: M+ 3=1626.8).

[0123] Example 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 the standard one-letter amino acid code: The amino acid residues D-Tyr1, Aib2, αMeL13, Exceptions are K17, Aib20, and Ser39.

[0124] [ka]

[0125] The compound according to SEQ ID NO: 305 is prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3 = 1626.6, calculated: M+3 =1626.8).

[0126] Example 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)-YLIAGGPS SGAPPPS-NH2 (SEQ ID NO: 306)

[0127] The structure of SEQ ID NO:306 is shown below using the standard one-letter amino acid code: The amino acid residues D-Tyr1, Aib2, αMeL13, Exceptions are Orn16, K17, Aib20, D-Glu24, and Ser39.

[0128] [ka]

[0129] The compound according to SEQ ID NO: 306 is prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3 = 1602.4, calculated: M+3 =1602.8).

[0130] Example 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)

[0131] The structure of SEQ ID NO:307 is shown below using the standard one-letter amino acid code: The amino acid residues D-Tyr1, Aib2, αMeL13, Exceptions are K17, Aib20, αMeY25, and Ser39.

[0132] [ka]

[0133] The compound according to SEQ ID NO:307 is prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3 = 1631.3, calculated: M+3 =1631.5).

[0134] Example 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-LIAGGPSSGA PPPS-NH2 (SEQ ID NO: 308)

[0135] The structure of SEQ ID NO:308 is shown below using the standard one-letter amino acid code: The amino acid residues D-Tyr1, Aib2, αMeL13, Exceptions are Orn16, K17, Aib20, αMeY25, and Ser39.

[0136] [ka]

[0137] The compound according to SEQ ID NO:308 is prepared substantially as described in the procedure of Example 1. The molecular weight is determined by LC-MS (measured: M+3 = 1626.5, calculated: M+3 =1626.8).

[0138] Example 294 to Example 381 Compounds according to Example 294 (SEQ ID NO: 309) to Example 381 (SEQ ID NO: 396) The material is prepared substantially as described in the procedure of Example 1. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0139] Binding assays Glucagon (also called Gcg) is manufactured by Eli Lilly and Company. The standard sample prepared was GLP-1, 7-36-NH2 (also called GLP-1). , CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 100 μM aliquots in 100% DMSO. GIP1-42 (referred to as GIP ) was synthesized by peptide synthesis and HPLC chromatography as described above. Prepared at Y Research Laboratories (>80% purity, 100% 100 μM aliquots in DMSO). 125 I] radiolabeled Gcg, GLP-1, Or GIP, 125 I]-lactoperoxidase or Perk Obtained from Elmer (Boston, MA).

[0140] Stably transformed cell lines were constructed by subcloning the receptor cDNA into the pcDNA3 expression plasmid. Cloned and cloned into human embryonic kidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese hamster ovary (CHO) (hGIPR) cells, and then Geneticin (hGLP-1R and hGIPR) or hygromycin B (hGcgR ) is prepared by selecting

[0141] Two methods are used to prepare crude cell membranes.

[0142] Method 1 : Tris HCl (pH 7.5) 50 mM, and Roche Complete Frozen cell pellets were incubated in a hypotonic buffer containing te™ protease inhibitors (containing EDTA). Thaw the pellets on ice. Using an r-Elvehjem homogenizer, vortex the cell suspension 25 times. The nate is centrifuged at 1100 x g for 10 minutes at 4°C. The supernatant is collected and stored on ice. Meanwhile, the pellet is resuspended in homogenization buffer and rehomogenized as above. The filtrate is centrifuged at 1100 x g for 10 minutes. The second supernatant is combined with the first supernatant and Centrifuge at 5000 x g for 1 hour at 4°C. The resulting membrane pellet is diluted with protease inhibitor The cells were resuspended in homogenization buffer containing approximately 1-3 mg / mL of the agent, and flash frozen in liquid nitrogen. Store in aliquots in a -80°C freezer until use.

[0143] Method 2 : Tris HCl (pH 7.5) 50 mM, MgCl2 1 mM, Roch e Complete™ protease inhibitors (EDTA-free), and DNAs Frozen cell pellets were incubated in a hypotonic buffer containing 25 units / ml of eI (Invitrogen). Thaw the samples on ice. Using a Lvehjem homogenizer, vortex the cell suspension 20-25 times. The lysate is centrifuged at 1800 x g for 15 minutes at 4°C. The supernatant is collected and stored on ice. Meanwhile, the pellet was resuspended in homogenization buffer (DNAse I-free) and resuspended as described above. Homogenize. Centrifuge the homogenate at 1800 x g for 15 minutes. Combine with the first supernatant and centrifuge for an additional 15 minutes at 1800 x g. The entire supernatant is then The resulting membrane pellet was centrifuged at 25,000 x g for 30 min at 37 °C. Resuspend the sample in homogenization buffer (free of DNAse I) containing approximately 1-3 mg / mL of the inhibitor and use. Store in aliquots in a -80°C freezer until use.

[0144] Connection determination method The equilibrium binding dissociation constants (K d )teeth,[ 125 I]S Due to the high propanol content of the stock material, the results of the homologous competitive binding analysis rather than saturation binding were not consistent. The K determined for the receptor preparation d The values ​​were as follows: hGcgR( 3.9 nM), hGLP-1R (1.2 nM) and hGIPR (0.14 nM).

[0145] [ 125 I]-glucagon binding Scintillation with wheat germ agglutinin (WGA) beads (Perkin Elmer) The human Gcg receptor binding assay is performed using a selective proximity assay (SPA) format. The binding buffer was 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonyl HEPES (pH 7.4), 2.5 mM CaCl2, 1 mM MgCl2, 0 0.1% (w / v) bacitracin (Research Products), 0.003 % (w / v) of polyoxyethylene sorbitan monolaurate (TWEEN® -20), and EDTA-free Roche Complete™ Protease Inhibitor The peptide and Gcg are thawed and serially diluted 3-fold in 100% DMSO. (10-point concentration-response curve). Then, add 45 μL of assay binding buffer or unlabeled G Containing a cg control (non-specific binding or NSB, 1 μM final), Corning Add 5 μL of serially diluted compounds or DMS to a 3632 clear bottom assay plate. Next, transfer 50 μL [ 125 I]-Gcg (0.15 nM final), 50 μL of human GcgR membrane (1.5 µg / well), and 50 µL of WGA SPA beads (80–1 Add 50 μg / well of platelets using a Biotek Multiflo dispenser. Seal the plate, mix on a plate shaker (setting 6) for 1 minute, and incubate at room temperature for 12 hours. After bating and leaving the cells, the PerkinElmer Trilux MicroBeta (registered trademark) was used. The plate is read in a (trademark) scintillation counter. The response curve indicates the peptides tested. The final assay concentration range of the dopamine receptor antagonist is typically 1150 nM to 0.058 nM, with the control Gcg at 10 00nM~0.05nM.

[0146] [ 125 I]-GLP-1 binding The human GLP-1 receptor binding assay was performed using a SPA format with WGA beads. The binding buffer is 25 mM HEPES (pH 7.4), 2.5 mM CaCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% ( w / v) TWEEN®-20, and EDTA-free Roche Comple Contains te™ protease inhibitors. Thaw peptides and GLP-1 and mix at 100% Serially dilute 3-fold in DMSO (10-point concentration-response curve). Then, add 45 μL of Se binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, 0.25 µL) M final) into a Corning® 3632 clear bottom assay plate. Transfer 5 μL of serially diluted compound or DMSO to the 125 I]-G LP-1 (0.15 nM final), 50 μL of human GLP-1R membrane (0.5 μg / well) , and 50 μL of WGA SPA beads (100–150 μg / well) in Biote Add with Multiflo dispenser. Seal plate and place on plate shaker. Mix for 1 minute on the plate (setting 6), incubate at room temperature for 5-12 hours, then rinse with water. KinElmer Trilux MicroBeta® Scintillation Counter The final assay concentration range of peptides tested in the response curve is , usually 1150nM-0.058nM, and the control GLP-1 is 250nM-0.013nM It is.

[0147] [ 125 I]-GIP bond The human GIP receptor binding assay uses an SPA format with WGA beads. The binding buffer is 25 mM HEPES (pH 7.4), 2.5 mM Ca Cl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) TWEEN®-20 and Roche Complete without EDTA (trademark) containing protease inhibitors. Thaw peptides and GIP and resuspend in 100% DMSO Serially dilute 3-fold in 10-point concentration-response curve. Then, add 45 μL of assay solution. Binding buffer or unlabeled GIP control (nonspecific binding or NSB, 0.25 µM final) Add 5 μL of Transfer serially diluted compounds or DMSO. Next, add 50 μL 125 I]-GIP(0. 0.75–0.15 nM final), 50 µL of human GIPR membrane (3 µg / well), and 5 Add 100 μL of WGA SPA beads (100–150 μg / well) to a Biotek Multiplate reader. Add with tiflo dispenser. Seal plate and place on plate shaker for 1 min. Mix (setting 6) and incubate at room temperature for 2.5-12 hours, then add Perkin in an Elmer Trilux MicroBeta® scintillation counter. Read the plate. The final assay concentration range of peptides tested in the response curve is typically 1150nM~0.058nM or 115nM~0.0058nM, and the control GIP was 2 50nM~0.013nM.

[0148] Binding assay data analysis The CPM raw data of the concentration curves of peptides, Gcg, GLP-1, or GIP were The M value indicates nonspecific binding (excessive unlabeled Gcg, GLP-1, or GIP). Subtract the binding (if the binding is positive) and divide by the total binding signal corrected for non-specific binding. The inhibition rate is calculated by 4 parameters (curve maximum, curve minimum, IC 50 , Hill Slope) Nonlinear regression routine (Genedata Screener, version 12.0 4, Genedata AG, Basal, Switzerland) The affinity constant (K i ) is the formula K i =IC 50 / (1+D / K d ) based on absolute I C 50where D is the concentration of radioligand used in the experiment, I C 50 is the concentration that causes 50% inhibition of binding, and K d is the equilibrium binding of the radioligand is the dissociation constant (see above). K i Values ​​are reported as geometric means, with errors expressed as standard errors of the mean (S The mean mean ± SEM values ​​are expressed as mean ± SEM, where n is the number of independent replicates (determined by assays performed on different days) and The geometric mean is calculated as follows: Geometric mean = 10 (arithmetic mean of Log Ki values)

[0149] Ki ratios for each receptor and species (Ki of native control peptide / Ki of test compound) The Ki ratio is a rapid estimation of the apparent affinity of a peptide relative to a native control peptide. A Ki ratio < 1 is an indicator of the binding of the test peptide to the receptor more strongly than the native peptide. A lower affinity (higher Ki value) indicates that the test has a higher affinity for the compound. The peptide has a higher affinity (lower Ki value) for the receptor than the native peptide. This indicates that:

[0150] n=1 / x means that out of the total number of replicates (x), only one value is used to represent the average. SEM is calculated only when there are n=2 or more non-matching results. are expressed as geometric means, with standard error of the mean (SEM) and number of replicates (n) in parentheses. show.

[0151] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9]

[0152] Functional activity (using BSA) HEK-293 clones expressing hGLP-1R, hGcgR, and hGIP-R Determine functional activity in cell lines. 1X GlutaM in 20 μl assay volume. AX™ Addition (L-alanyl-L-glutamine dipeptide, Gibco® ), 0.25% FBS (dialyzed fetal bovine serum), 0.05% Fraction VB SA (bovine serum albumin), 250 μM 3-isobutyl-1-methylxanthine (I BMX), and 20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonyl in DMEM (Gibco Cat. No. 31053) supplemented with heparin-containing acetic acid (HEPES). Peptides (20-point CRC, 2.75x Labcyte Echo direct dilution) were used to Treat cell lines overexpressing each receptor.

[0153] After 60 min of incubation at room temperature, the increase in intracellular cAMP was measured using homogeneous time-resolved fluorescent assays. Using the CisBio cAMP Dynamic 2 light (HTRF) assay kit The cAMP-d2 conjugate in the cell lysis buffer was then added, and the Also in the cell lysis buffer was the antibody anti-cAMP-Eu 3+ -Adding cryptate The resulting competitive assay detects intracellular cAMP levels by: Incubate at room temperature for at least 60 min, then measure at 320 nm and 665 nm. and detection using an instrument emitting at 620 nm. Envision units (665 nm m / 620 nm emission*10,000) is inversely proportional to the amount of cAMP present, Convert this to nM cAMP per well using a standard curve.

[0154] The amount of cAMP (nM) produced in each well was determined by human GLP-1(7-36)NH2 The maximum observed for either human Gcg, human GIP(1-42)NH2 Convert to percent response. Maximum fit to a four-parameter logistic equation. Relative EC5 values ​​were calculated by nonlinear regression analysis using percent response versus concentration of added peptide. Find the 0 value.

[0155] Human GLP-1(7-36)NH2 at human GLP-1R, human Gc at human GcgR g, and the EC of human GIP(1-42)NH2 at human GIP-R. 50 Verdict: Peptide The concentration range is 448 pM to 99.5 nM. Human GLP-1R, human GcgR, and Example EC in human GIP-R 50 Judgment: Peptide concentration range is 51.5fM to 11.4 μM.

[0156] [Table 4]

[0157] cAMP pharmacological function assay in the presence of casein One additional set of cAMP assays for human GLP-1 receptor (GLP-1R), gastric inhibition HEK293 cells expressing the peptide receptor (GIPR) and glucagon receptor (GcgR) The pharmacological activity of the hGLP1R / GIPR peptide was determined by the expression of the human GLP-1 receptor ( GLP-1R), gastric inhibitory peptide receptor (GIPR), or GLP-2 receptor (GLP -2R) in a 20 μl assay volume. , 0.1% casein (Sigma catalog no. C4765), 250 μM IBMX, 1 x GlutaMAX™ (Gibco Cat. No. 35050), and 20 mM DME supplemented with HEPES (HyClone catalog number SH30237.01) The cell lines were overexpressed (2 After incubation at room temperature for 60 minutes, the increase in intracellular cAMP was measured. Add the CisBio cAMP Dynamic 2 HTRF Assay Kit (62A M4PEJ) was used to quantitatively determine the amount of cAMP-d2 conjugate (20 μl). Add the lysis buffer containing cAMP and the antibody anti-cAMP-Eu3+-cryptate (20 μl). After incubation at room temperature for 1 hour, the HTRF signal was detected by Env Detection was performed using a plate reader (PerkinElmer) 620 Fluorescence emission was measured at 620 nm and 665 nm, and the ratio of 620 nm and 665 nm was calculated. Compound dosing was then converted to nM cAMP per well using a cAMP standard curve. Dose-response curves were plotted with minimum (buffer only) and maximum (maximum concentration of each control ligand) values. Four-parameter plotted as a percentage of normalized stimulation and fitted with a variable slope. The parameters were analyzed using nonlinear regression (Genedata Screener 13). EC50 is the concentration of a compound that produces a half-maximal simulation of a dose-response curve. Percentage of maximum response vs. added, fitted to a four-parameter logistic equation. Calculate the relative EC by nonlinear regression analysis using the peptide concentrations. 50 Find the value.

[0158] Casein (serum acetate) was used as a nonspecific blocker that does not interact with the fatty acid moiety of the analyte molecule. In the presence of α-glutamin, homogeneous time-resolved fluorescence measurements were performed using the examples and Assays are performed to determine the intrinsic potency of the comparator molecules.

[0159] Intracellular cAMP levels are determined by extrapolation using a standard curve. Response curves were aligned to a minimum (buffer only) and a maximum (maximum concentration of each control ligand). Four-parameter regression analysis plotted as a percentage of normalized stimulation and fitted with variable slope. The data is analyzed using nonlinear regression (Genedata Screener 13). EC 50 is the concentration of the compound that produces half-maximal simulation of the dose-response curve. The respective relative EC50 values ​​of the mean calculations are determined from the curve fitting.

[0160] Compound concentration-response curves were plotted against minimum (buffer only) and maximum (each control ligand Plot as percentage of stimulation normalized to maximum concentration (maximum concentration) and fit to variable slope The results were analyzed using a four-parameter nonlinear regression (Genedata Screener 13) EC50 is the compound that simulates the half-maximal dose in the dose-response curve. is the concentration of the compound. EC 50 Summary statistics are calculated as follows: Geometric mean: GM=10^(log 10 The arithmetic mean of EC 50 value). Report the standard error of the mean: SEM=geometric mean×(log 10 Standard deviation conversion of EC 50 (value / square root of number of executions) x 10 log e . Logarithmic transformation uses EC that corresponds to multiplication rather than arithmetic scale. 50 The value is taken into account.

[0161] Test peptide, natural ligands GIP and GLP-1, as baseline (minimum) Buffer only and the highest concentration of each GIP and GLP-1 standard were used as the maximum for calculations. To illustrate, as shown in Example 1, the test pen For the peptides, the assay is performed eight times. and hGLP-1 amide EC50 are examples of geometric mean values ​​from a series of 18 assays. For zero solution, the values ​​are different each day. Therefore, each example uses the geometric mean of these values. This is used to standardize the assays performed in the examples.

[0162] [Table 5-1]

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

Table 5-7

Table 5-8

Table 5-9

Table 5-10

Table 5-11

Table 5-12

Table 5-13

Table 5-14

[0163] As shown by the data in Table 3, the compounds of the examples exhibited the following properties in the presence of 0.1% casein: Stimulates cAMP from human GLP-1R and GIPR.

[0164] IN VIVO research Pharmacokinetics in male CD-1 mice Male CD-1 mice were administered a single subcutaneous dose of 200 nMol / kg, followed by selected The pharmacokinetics of the example was evaluated. Blood samples were collected over 168 hours and the resulting Pharmacokinetic parameters were calculated using individual plasma concentrations. Plasma (K3EDTA) concentration is determined using a qualified LC / MS method that measures the intact mass of the examples. Analogs as internal standards were assayed using immunoaffinity-based precipitation with anti-GIP / GLP1 antibodies. It is extracted 100% from mouse plasma and is combined with various instruments for LC / MS detection. The mean pharmacokinetic parameters are shown in Table 4.

[0165] [Table 6]

[0166] The results of this study for the tested examples are consistent with the extended pharmacokinetic profile. do.

[0167] Pharmacokinetics in male cynomolgus monkeys After a single subcutaneous dose of 50 nMol / kg was administered to male cynomolgus monkeys, Blood samples were collected over a 336-hour period, and the resulting individual Calculate the pharmacokinetic parameters using the plasma concentration of peptide plasma (K3EDTA) Concentrations are determined using a qualified LC / MS method that measures the intact mass of the compound. and analogs as internal standards were used for immunoaffinity-based precipitation with anti-GIP / GLG1 antibodies. The protein is extracted from 100% cynomolgus monkey plasma using a chromatograph. The mean pharmacokinetic parameters are shown in Table 5.

[0168] [Table 7]

[0169] Pharmacokinetics in male Sprague-Dawley rats after subcutaneous or intrajejunal administration Male Sprague-Dawley rats were given a single dose of 50 nMol / kg (dissolved in PBS, pH 7.4). The drug was administered subcutaneously (SC) twice a day or at 1 μmol / kg (250 mM sodium decanoate) ("C10") and 12 mg / mL soybean trypsin inhibitor (SBTI) The pharmacokinetics of selected examples are evaluated after a single intrajejunal (IJ) dose. Blood Samples were collected over a period of 168 hours after SC administration or over a period of 72 hours after IJ administration. The individual plasma concentrations are used to calculate the pharmacokinetic parameters. Plasma (K3EDTA) concentrations are determined using a qualified LC / MS method to measure The examples are tested using analog peptides as internal standards. Each test peptide and analog is extracted using immunoaffinity-based precipitation with The mean pharmacokinetic parameters of the examples are shown in Tables 6 and 7.

[0170] [Table 8]

[0171] [Table 9]

[0172] As shown by the results in Table 7, these examples are consistent with exposure following intrajejunal administration. The jejunal exposure in this assay is consistent with the examples given for oral formulations and administration. This confirms that there is a possibility that

[0173] In Vivo Effects on Insulin Secretion in Male Wistar Rats Femoral artery and femoral vein cannulae (Envigo, Indianapolis, IN) Male Wistar rats (280-320 g) were placed in a plastic bag with a filter top. Rats were housed singly in carbonate cages at 21°C and maintained on a 12:12-h light:dark cycle. The rats were kept in a dark room (lights on at 6:00 a.m.) and had free access to food and deionized water. The subjects were randomly assigned to groups based on their weight, and 16 hours before glucose administration, they received 0.04, 0.1, or 0.3 , 1, 3, and 10 nmol / kg, 1.5 ml / kg, subcutaneously, and then The animals were fasted. The animals were weighed and anesthetized with sodium pentobarbital administered intraperitoneally. The blood sample at time 0 was collected in an EDTA tube. The blood samples were collected and glucose was then administered intravenously (0.5 mg / kg, 5 ml / kg). The samples were analyzed using glucose titers at 2, 4, 6, 10, 20 and 30 minutes after intravenous glucose administration. Plasma glucose levels were collected for clinical chemistry. Plasma insulin was determined using an electrochemiluminescence assay (Meso S Glucose and insulin are determined using the ELISA kit (California, Gaithersburg, MD). The insulin AUC is investigated compared to vehicle control with n=5 animals / group. Results are expressed as (SEM) (N).

[0174] [Table 10]

[0175] The data provided in Table 8 demonstrate that insulin secretion increases in a dose-dependent manner. It shows.

[0176] [Table 11]

[0177] The data provided in Table 9 demonstrate that insulin secretion increases in a dose-dependent manner. It shows.

[0178] Study of diet-induced obesity in C57 / B16 mice C57 / Bl6 diet-induced obese (DIO) male mice weighing 41–50 g (Taconic Animals were kept on a 12-h light / dark photoperiod (10:10, 12 ... Individually housed in a temperature-controlled (24°C) facility with lights off at 00AM and on at 10PM After 2 weeks of acclimation to the facility, mice were randomly assigned to a 10-kg / kg / day, 10-day, 15-day, and 20-day, 10-day, and 20-day, 15 ... Randomly divide animals into treatment groups (n=6 / group) so that each group has a similar starting mean body weight .

[0179] Vehicle (40 mM Tris-HCl at pH 8.0), or 0.03 nmol / k Treat mice with one of several peptides at doses ranging from 1000g to 10 nmol / kg. Ad libitum-fed DIO mice were incubated 30–90 min before the onset of the dark cycle (QD) every day for 14 days. Treatments will be administered subcutaneously to the mice. Body weight and food intake will be monitored daily during the course of the study.

[0180] All data are expressed as the mean ± SEM of 5–6 rats per group. Statistical analysis was assessed by one-way ANOVA followed by Dunnett's multiple comparison test, with differences in treatment groups. Groups were compared to the vehicle group or to each other. Significant differences of p<0.05 were noted. It was determined.

[0181]

number

[0182] In each study, the "0" dose group represented vehicle-treated mice. Data are expressed as the mean ± SEM of 5–6 mice per group. The mean mean was evaluated using one-way ANOVA and then Dunnett's multiple comparison test, with the treatment group set at "0" Compare with the dose (vehicle). *Significant difference of p<0.05 is confirmed. The change in body weight 15 days after treatment with 100 mg / kg of ... "Percent change" refers to the difference in body weight on day 15 between the test group and the vehicle group. The weight loss rate from day 1 to day 15 was recorded for animals administered the vehicle. The changes were approximately less than 1% in each study. Delta and % change data from vehicle were For all examples, all doses tested were statistically significantly different from the control (p<0. 05).

[0183] [Table 12]

[0184] As shown by the data provided in Table 10 above, the examples tested in the assay The compound reduces body weight in a dose-dependent manner in the studies described.

[0185] Proteolytic stability assay Proteolytic stability assays are useful for evaluating the oral delivery potential of peptides. The stability of the peptides is compared in 1% rat small intestinal fluid (rSIF). To assess the activity of the peptides, the amount of intact peptides in the peptide samples was measured at 0, 3, 15, and 30 min. The amount of intact peptide in the peptide sample is measured by incubation with 90% porcine small intestinal fluid (pSIF) for 0 min, Proteolytic stability is assessed by measurements at 30, 45, and 60 minutes. Sample preparation when using rat small intestinal fluid (rSIF):

[0186] Prepare peptides at 0.4 mg / mL in 50 mM Tris (pH 8.0). Add small intestinal juice at a ratio of 1% (v / v). Incubate the mixture at 37°C and 150 rpm. From each sample, 30 μL was removed and incubated at 4°C for 3 min, 15 min, and 4 min before adding rSIF. At each time point, TF in 50% ACN was placed in a new tube. Quench the reaction with 1% TFA in 50% ACN at 1:1. The samples were diluted 100-fold using 50 mM Tris, pH 8 (1:1) and analyzed by mass spectrometry (M Prepare for analysis using S).

[0187] Sample preparation when using porcine small intestinal fluid (pSIF): Dilute the peptide to a concentration of 0.4 mg / mL in 90% porcine small intestinal fluid. After mixing, add 20 μL The mixture is then incubated at 37°C for 1 h at 4°C for 2 h at 4°C. Incubate at 150 rpm. Remove 20 μL from each sample and incubate for 30, 45, or 60 minutes. and 60 minutes into a new tube. The reaction is quenched with 1% TFA in 50% ACN 1:1 at 20 °C. Centrifuge at 1,000 x g for 20 minutes at 4°C. Add dilution buffer (10% TFA in 50% ACN) The supernatant was diluted 100-fold with 50 mM Tris (pH 8) at 1:1 ratio and analyzed by mass spectrometry. Prepare for analysis using MS.

[0188] MS conditions: Liquid chromatography separation on a Waters Acquity UPLC 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 (300 Å, 1.7 μm, A 1 mm x 50 mm tube was used at 40°C. The gradient was 5% B between 0-1.5 and 1.5-1 5%-90% of B between .8, 90%-95% of B between 1.8-3.0, 3.0-3. 95%-95% of B between 5, 95%-5% of B between 3.5-4.0, 4.0-5.0 The MS analysis was performed using a Waters Xevo G2-XS QT Data were collected in the range of 50–2000 m / z in positive and sensitivity modes. The MSe continuum is used to acquire the data. Data analysis is performed using MassLynx.

[0189] [Table 13]

[0190] The proteolytic peptide results provided in Table 11 show that the peptide of Example 4 is and may be suitable for oral delivery.

[0191] [Table 14]

[0192] The proteolytic peptide results provided in Table 12 are consistent with those of both Examples 4 and 5. These results suggest that this peptide may be suitable for oral formulation and delivery.

[0193] In Vivo research The purpose of this study is to determine the relative clinical immunogenic potential of compounds. method: CD8+ T cell-depleted peripheral blood mononuclear cells from a cohort of 10 healthy donors were prepared. , carboxyfluorescein diacetate succinimidyl ester (CFSE, In Vitrogen) 2.0 mL of medium control, keyhole limpet Hemocyanin ("KLH") (0.33 μM), anti-chemokine receptor type 4 ("CD4 +") (0.33 μM), and the compounds of Examples 1, 2, and 3 (10 μM) were used. Test samples in triplicate. Incubate the cultures 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 FlowJo (registered trademark) software (FlowJo, LLC, Tre The data was analyzed using eStar.

[0194] Results and Discussion All donors showed positive T cell responses to KLH (100%). An analysis of the frequency and strength of D4+ T cell responses is shown in Table 13.

[0195] [Table 15]

[0196] These data are from Examples 1, 2, 3, 4, 288, 289, 301, 303 and 3 Sixteen compounds had a low frequency of positive CD4+ T cell responses (CDI>2.5), with a small number of positive The donor showed a low response intensity (CDI<6), which was related to CD4+ T cells. This indicates a low risk of immunogenicity using the assay.

[0197] GLP-1R HEK293 cell membrane [ 35 S]GTPγS binding assay The GLP-1 receptor activates the GTP-bound Gα S Increase GLP-1R-induced Gα S Stimulates activation Potency of peptides prepared using purified membranes from HEK293 cells expressing human GLP-1R The assay is performed similarly to that previously described. (Bueno et al.,J.Biol.Chem.,(2016)291,107 00 and Willard et al.,Mol.Pharmacol.(201 2) 82, 1066). Test peptides were solubilized in DMSO and diluted with 20 mM HEPES. (pH 7.4) containing 5 μg membrane, 50 mM NaCl, 5 mM MgCl2, 4 0 μg / ml saponin, 0.1% BSA, and 500 pm 35 S-labeled GTPγ The reaction was incubated at room temperature for 30 min in reaction buffer containing rabbit anti-Gα S Polychrome Nonidet containing monoclonal antibody and 0.5 mg of anti-rabbit polyvinyl toluene beads The mixture was then allowed to develop for 30 minutes. The mixture was centrifuged at 80 x g for 10 min using a MicroBeta TriLux device. Count for 1 minute per well. Peptide concentration-response curves were generated using a 4-parameter logistic regression. Fit the model and EC 50 Calculate the potency as: The minimum and maximum conjugates of the receptor Data on % stimulation were obtained using DMSO and GLP-1(7-36) as controls. Standardization of the assay data (Campbell et al., Assay Guidance Manual 2017). GIPR-induced Gα S Samples that stimulate activation The potency of the peptides is reported in Table 14. The assay results showed that GLP-1R induced Gα S With respect to activation, peptides that are partial agonists for the GLP-1R are identified.

[0198] GLP-1R CHO cell β-arrestin recruitment assay Activated G protein-coupled receptors bind to the β-arrestin family of signaling proteins. GLP-1R-induced arrestin recruitment mechanism The efficacy of peptides against the target peptides was evaluated using the Enzyme Fragment analysis in PathHunter. t Complementation method is used to determine essentially as described (von Degenfeld et al.,FASEB J.,2007(14): 3819-26 and Hamdouchi et al., J. Med Chem .,2016 59(24):10891-10916). Pro-Link tagged human CHO-K1 expressing GLP-1R and enzyme acceptor tagged β-arrestin-2 Cells are available from DiscoveRx and can be prepared as frozen cells for the assay. Test peptides were dissolved in DMSO and dispensed using an Echo acoustic dispenser (Lab Serial dilutions are performed using a 0.1% w / v phosphate buffered saline (Cyte). PathHunter cell assay buffer (Disco) containing zein (Sigma) veRx). 100 nl of peptide was added to 10 μl of assay medium in a 384-well plate. Dispense into culture medium and then add 10 μl of cells in assay medium to obtain 5,000 cells per well. Incubate the plate at 37°C / 5% CO2 for 90 minutes. Then, add 10 μl of PathHunter detection reagent (DiscoveRx) and plate Incubate the plate for 60 min at room temperature. Measure the luminescence signal. Peptide concentration-response curve was fitted to a four-parameter logistic model to obtain EC 50 Calculate the potency at . DMSO and GLP-1(7-36) were used as minimum and maximum controls. Normalize the data to % stimulation (Campbell et al., Assay Guidance ce Manual 2017). GLP-1R-induced β-arrestin recruitment The potency of the sample peptides to stimulate is reported in Table 14. The assay results showed that Regarding GLP-1R partial agonist peptidase 1 (PTA), Chid is identified.

[0199] [Table 16-1] [Table 16-2] [Table 16-3] [Table 17-1] [Table 17-2] [Table 17-3]

[0200] Compositions for oral administration The peptide is dissolved in Tris buffer (pH 8.0, 50 mM). E") Prepare C10 in Tris buffer (pH 8.0, 50 mM) as follows: LC, DPC, C12-maltoside and rhamnolipid were dissolved in phosphate buffered saline. Dissolve in buffered saline ("PBS") (1X, pH 7.2). The final concentration of peptide was 300 μM and the final concentration of PE was 300 μM. The final concentration of protease inhibitors was 100 mM (5% w / v for rhamnolipids). The concentration is 1% (v / v).

[0201] In rat small intestinal fluid, 1% (v / v) with or without peptidase inhibitors or 5 The peptides were incubated at 37°C in 0% (v / v) porcine small intestinal fluid. At this time, samples were removed and quenched with 1% TFA in 50% ACN / water to determine enzyme activity. The intact peptides at different time points were detected by ultraviolet (UV) detection or LC-MS. Analyze by high performance liquid chromatography (HPLC) with MS / MS and mix with the enzyme solution. The amount of peptide was normalized to the amount of peptide before the addition. Studies that have demonstrated this are reported in Table 15.

[0202] [Table 18]

[0203] According to the results in Table 15, the oral formulation composition of the peptide of Example 4 was administered with PE and PI. This demonstrates that the compound can be prepared without using any of the above.

[0204] Oral formulation composition Examples of formulation compositions of the peptides of the invention are provided in Table 16. The compositions are in no way limited by the examples provided.

[0205] [Table 19]

[0206] The efficacy of the formulated composition on peptide exposure was assessed via intrajejunal (IJ) administration of the liquid formulation. To prepare a liquid formulation for IJ administration in rats, peptide, C10 or Dissolve and mix NaTDC and SBTI in 50 mM Tris buffer pH 8.0. For LC / citric acid formulations, dissolve LC and citric acid in water to the desired final concentration. The formulation composition is provided in Table 16. may be administered as an oral composition.

[0207] Enteric Capsules Enteric capsule compositions may be desirable for certain peptides of the invention, e.g. For example, the enteric composition may be prepared using the methods shown in Table 17. and filling the mixture into an enteric coated capsule.

[0208] The enteric compositions in Table 17 were prepared by adding half the amount of sodium decanoate listed in a mortar. As shown in Table 17, SBTI (Examples 382 to 385) or SFTI (Example 386 and Example 387), and peptides (peptides of Examples 1 to 4) Add the remaining half of the sodium decanoate. Using a pestle and spatula, mix the mixture. Mix gently. If necessary, use a pestle to mix further to ensure a uniform mixture. The capsules are made by weighing out the required amount of the mixture separately, filling the capsules, and then sealing the capsules. It can be filled manually by tightly closing the capsule cap on the body.

[0209] Dissolution testing of the single capsules is completed using known methods. The composition may be formulated as a therapeutically effective oral composition.

[0210] [Table 20]

[0211] Amino acid sequence SEQ ID NO:1 GIP (human) YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNI TQ SEQ ID NO:2 GLP-1(7-36)(human) HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 SEQ ID NO:3 R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX1 9X 20 X 21 X 22X 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 38 X3 9-R2 SEQ ID NO:9 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu )-CO-(CH2)q-CO2H]X 32 X33 X 34 X 35 X 36 X 37 X 38 X3 9X 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)-YLIEGGPSS GAPPPS-NH2 SEQ ID NO:11 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)-YLIEG GPSSGAPPPS-NH2 SEQ ID NO:12 Example 3 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)-YLIEG GPSSGAPPPS-NH2 SEQ ID NO:13 Example 4 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-O rn-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 Sequence number 300 PSSG-NH2 SEQ ID NO:301 PSSGAPPPS SEQ ID NO:302 PSSGAPPPS-NH2

[0212] The present invention may include the following aspects. [1] 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 28 X 29 X 30 X 31 (SEQ ID NO:3): [In the formula, R1 is a modification of the N-terminal amino group, where the modification is selected from the group consisting of Ac and absence; X1 is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY; X2 is selected from the group consisting of Aib, αMeP, A, P, and D-Ala; or X1 and X2 combine to form desH-ψ[NHCO]-Aib, X3 is selected from the group consisting of E, N, Aad, and cTA; X6 is selected from the group consisting of F, αMeF, and αMeF(2F); X 10 is selected from the group consisting of 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 is selected from the group consisting of S, αMeS, and D-Ser; X 12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 13 is selected from the group consisting of Nle, Aib, L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 14 is selected from the group consisting of L and K, where K is C 16 -C 22 Binding to a fatty acid, said fatty acid being optionally bound to said K via a linker; X 16 is selected from the group consisting of 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 17are K, Q, I, and C 16 -C 22 an amino acid linked to a fatty acid, said fatty acid optionally linked to said amino acid via a linker; X 19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 20 is selected from the group consisting of Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 21 is selected from the group consisting of 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 is selected from the group consisting of F and αMeF; X 23 is selected from the group consisting of 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 is selected from the group consisting of 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 the group consisting of Y and αMeY; X 26 is selected from the group consisting of L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 30 is selected from the group consisting of C, G, G-R2 and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q-CO2H; X 31 is absent or 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 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) (In the formula, 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 is selected from the group consisting of G, C, and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q-CO2H]; X 35 is 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-(CH)-COH], X 39is selected from the group consisting of C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH)q-COH]; X 40 is selected from the group consisting of C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q-CO2H] q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; R2 is a modification of the C-terminus (where the modification is NH2 or absent)] or a pharma- ceutically acceptable salt thereof, X 30 If G-R2, then X 31 is absent, 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 may be a fatty acid-containing substituent; X 30 , X 34 , X 39 , and X 40 may be C; X 30 , X 34 , X 39 , and X 40 If any of is C, then X10 , 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 the substituents contain fatty acids. The compound, or a pharma- ceutically acceptable salt thereof. [2] The compound according to [1] above, wherein X1 and X2 do not bond to form desH-ψ[NHCO]-Aib, or a pharma- ceutically acceptable salt thereof. [3]X 17 C 16 -C 22 The compound according to the above [1] or [2], which is an amino acid that binds to a fatty acid, or a pharma- ceutically acceptable salt thereof. [4] X1 is Y, X2 is Aib, X3 is E, X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y; X 11 But S, X 12 But, I, X 14 is L, X 16 is selected from the group consisting of K, E, Orn, Dab, and Dap; X 17 But, C 16 -C 22a K bound to a fatty acid, wherein the fatty acid is bound to K via a linker; X 19 But Q, X 20 But, Aib, X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E; X 22 But F, X 23 But, I, X 24 is selected from the group consisting of S, Aad, D-Glu, and E; X 26 is L, X 27 is selected from the group consisting of L and I; X 28 is selected from the group consisting of E and A; The compound according to any one of the above [1] to [3], or a pharma- ceutically acceptable salt thereof. [5]X 30 is G and X 31 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) (wherein X 32 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P and X 37 is P and X 38 is P and X 39 is S (SEQ ID NO: 298)); The compound according to any one of the above [1] to [4], or a pharma- ceutically acceptable salt thereof. [6]X 17 The compound according to the above [1], [2], or [5], or a pharma- ceutically acceptable salt thereof, wherein [7] The compound according to [4] above, or a pharma- ceutically acceptable salt thereof, wherein the linker comprises 1 to 2 amino acids. [8] The compound according to [7] above, wherein the linker comprises 1 to 2 (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties, or a pharma- ceutically acceptable salt thereof. [9] The compound according to [8] above, or a pharma- ceutically acceptable salt thereof, wherein the linker comprises 1 to 2 amino acids independently selected from the group consisting of Glu and γ-Glu.

[10] The linker has the following formula: {(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b, where a is 1 or 2 and b is 1 or 2. The compound according to the above [9], or a pharma- ceutically acceptable salt thereof, having the formula:

[11] X 17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO-(CH2)q-CO2H (wherein a is 1 or 2, b is 1 or 2, and q is selected from the group consisting of 14 to 20), or a pharma- ceutically acceptable salt thereof.

[12] The compound according to

[11] above, wherein a is 1, or a pharma- ceutically acceptable salt thereof.

[13] The compound according to

[11] above, wherein a is 2, or a pharma- ceutically acceptable salt thereof.

[14] The compound according to any one of the above

[11] to

[13] , wherein b is 1, or a pharma- ceutically acceptable salt thereof.

[15] The compound according to any one of the above

[11] to

[13] , or a pharma- ceutically acceptable salt thereof, wherein b is 2.

[16] The compound according to any one of the above

[11] to

[15] , or a pharma- ceutically acceptable salt thereof, wherein q is 18.

[17] The compound according to any one of the above

[11] to

[15] , or a pharma- ceutically acceptable salt thereof, wherein q is 16.

[18] X 17The compound according to any one of the above [1] to

[11] , wherein K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q-CO2H, or a pharma- ceutically acceptable salt thereof.

[19] X 27 The compound according to any one of the above [1] to

[18] , or a pharma- ceutically acceptable salt thereof, wherein

[20] X 27 is L, or a pharma- ceutically acceptable salt thereof.

[21] R1 is absent, X1 is Y, X2 is Aib, X3 is E, X6 is αMeF(2F), X 10 is selected from the group consisting of Y, 4-PaI, and V; X 11 But S, X 12 But, I, X 13 is selected from the group consisting of L, Aib, and αMeL; X 14 is L, X 16 is selected from the group consisting of E, K, and Orn; X 17 is K, X 19 But Q, X 20 But, Aib, X 21 is selected from the group consisting of E, A, and T; X 22 But F, X 23 But, I, X 24 is D-Glu, X 26 is L, X 27 But, I, X 28But E, X 29 But G, X 30 But G, X 31 But, PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5) (wherein X 32 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P and X 37 is P and X 38 is P and X 39 is S (SEQ ID NO: 298) The compound according to any one of the above [1] to

[19] , or a pharma- ceutically acceptable salt thereof.

[22] X 25 is Y, or a pharma- ceutically acceptable salt thereof.

[23] X 13 The compound according to any one of the above [1] to

[22] , or a pharma- ceutically acceptable salt thereof, wherein is αMeL.

[24] X 16 The compound according to any one of the above [1] to

[23] , or a pharma- ceutically acceptable salt thereof, wherein is Orn.

[25] X 16 The compound according to any one of the above [1] to

[23] , or a pharma- ceutically acceptable salt thereof, wherein

[26] X 10 is Y, or a pharma- ceutically acceptable salt thereof.

[27] X 10 The compound according to any one of the above [1] to

[25] , or a pharma- ceutically acceptable salt thereof, wherein

[28] X 10The compound according to any one of the above [1] to

[25] , or a pharma- ceutically acceptable salt thereof, wherein is 4Pal.

[29] X 13 is αMeL, a is 2, b is 1, q is 16, and X 25 The compound according to the above

[11] , or a pharma- ceutically acceptable salt thereof, wherein

[30] X 13 is αMeL, a is 2, b is 1, q is 18, and X 25 The compound according to the above

[11] , or a pharma- ceutically acceptable salt thereof, wherein

[31] X 13 is αMeL, a is 2, b is 1, q is 14, and X 25 The compound according to the above

[11] , or a pharma- ceutically acceptable salt thereof, wherein

[32] X 10 is Y and X 16 The compound according to any one of the above [1] to

[24] , or a pharma- ceutically acceptable salt thereof, wherein is Orn.

[33] X 10 is Y and X 16 The compound according to any one of the above [1] to

[23] , or a pharma- ceutically acceptable salt thereof, wherein

[34] X 10 is 4Pal, and X 16 The compound according to any one of the above [1] to

[23] , or a pharma- ceutically acceptable salt thereof, wherein is Orn.

[35] X 10 is V and X 16 The compound according to any one of the above [1] to

[23] , or a pharma- ceutically acceptable salt thereof, wherein is Orn.

[36] The compound according to [1] above, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14.

[37] The compound according to

[36] above, wherein the compound is SEQ ID NO: 13, or a pharma- ceutically acceptable salt thereof.

[38] The compound according to

[36] above, wherein the compound is SEQ ID NO: 11, or a pharma- ceutically acceptable salt thereof.

[39] X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, αMeF, αMeF(2F), I, αMeY, Q, D-His, E, cTA, and D-Tyr; X 12 is selected from the group consisting of I, D-Ile, and S; X 13 is selected from the group consisting of Nle, Aib, L, and αMeL; X 14 is L, X 16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R; X 17 is selected from the group consisting of K, Q, and I; X 19 is selected from the group consisting of Q and A; X 20 is selected from the group consisting of Aib, Q, H, R, K, and αMeK; X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I; X 23 is selected from the group consisting of I, L, A, G, F, H, E, and V; X 24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P; X 26 is selected from the group consisting of L and αMeL; X 27 is selected from the group consisting of L and I; X 28 is selected from the group consisting of E, A, S, and D-Glu; X 29 is selected from the group consisting of Aib, G, and A; The compound according to the above [1], or a pharma- ceutically acceptable salt thereof.

[40] X1 is Y, X2 is Aib, X3 is E, X 10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y; X 11 But S, X 12 But, I, X 16 is selected from the group consisting of K, E, Orn, Dab, and Dap; X 19 But Q, X 20 is selected from the group consisting of Aib and K; X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E; X 22 But F, X 23 But, I, X 24 is selected from the group consisting of S, Aad, D-Glu, and E; X 26 is L, X 28 is selected from the group consisting of E and A; The compound according to the above

[39] , or a pharma- ceutically acceptable salt thereof.

[41] X 30 , X 34 , and X 39 or a pharma- ceutically acceptable salt thereof. The compound according to any one of the above

[39] or

[40] , wherein one of is C.

[42] The compound according to

[41] above, or a pharma- ceutically acceptable salt thereof, wherein the compound is modified using a time extension technique.

[43] The compound according to any one of the above

[39] to

[42] , wherein q is 18, or a pharma- ceutically acceptable salt thereof.

[44] The compound according to any one of the above

[39] to

[42] , wherein q is 16, or a pharma- ceutically acceptable salt thereof.

[45] X 27is L, or a pharma- ceutically acceptable salt thereof.

[46] X 31 But, PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2, or a pharma- ceutically acceptable salt thereof.

[47] X 31 The compound according to any one of the above

[39] to

[45] , or a pharma- ceutically acceptable salt thereof, wherein

[48] ​​The compound according to

[47] above, or a pharma- ceutically acceptable salt thereof, wherein R2 is NH2.

[49] X 14 is L, X 17 is selected from the group consisting of K, Q, and I; X 30 is selected from the group consisting of G-R2 and G; q is selected from the group consisting of 16, 18, and 20; X 30 If G, then X 31 teeth, PX 32 X 33 X 34 -R2 (SEQ ID NO: 4) (wherein X 32 is S and X 33 is S and X 34 is G and R2 is absent (SEQ ID NO: 299), or X 32 is S and X 33 is S and 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 X32 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P and X 37 is P and X 38 is P and X 39 is S and R2 is absent (SEQ ID NO: 301), or X 32 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P and X 37 is P and X 38 is P and X 39 is S and R2 is NH2 (SEQ ID NO: 302); is selected from the group consisting of 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 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO—(CH2)qCO2H; The compound according to the above [1], or a pharma- ceutically acceptable salt thereof.

[50] X1 is Y, X2 is Aib, X3 is E, X 10 is selected from the group consisting of 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 But S, X 12is selected from the group consisting of I, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 14 is selected from the group consisting of L and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 16 is selected from the group consisting of K, E, Orn, Dab, Dap, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 17 is selected from the group consisting of K and I; X 19 is selected from the group consisting of Q, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 20 is selected from the group consisting of Aib and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 22 But F, X 23 But, I, X 24 is selected from the group consisting of S, Aad, D-Glu, E, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 26 is selected from the group consisting of L and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 27 is selected from the group consisting of L and I; X28 is selected from the group consisting of E, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)-2-(γ-Glu)-CO—(CH2)qCO2H; X 30 But G, X 31 But, PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), 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 is S and X 33 is S and X 34 is G and X 35 is A and X 36 is P and X 37 is P and X 38 is P and X 39 is S; The compound according to the above

[49] , or a pharma- ceutically acceptable salt thereof.

[51] X 20 The compound according to any one of the above

[49] to

[50] , wherein K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q-CO2H, or a pharma- ceutically acceptable salt thereof.

[52] PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 The compound according to any one of the above

[49] to

[51] , or a pharma- ceutically acceptable salt thereof, wherein -R2 is selected from the group consisting of PSSGAPPPS (sequence number 301) and PSSGAPPPS-NH2 (sequence number 302).

[53] The compound according to any one of the above

[49] to

[52] , wherein q is 18, or a pharma- ceutically acceptable salt thereof.

[54] The compound according to any one of the above

[49] to

[52] , wherein q is 16, or a pharma- ceutically acceptable salt thereof.

[55] X1 is selected from the group consisting of Y, F, D-Tyr, and desY; X6 is F, X 13 is selected from the group consisting of Aib, L, and αMeL; The compound according to the above [1], or a pharma- ceutically acceptable salt thereof.

[56] R1 is absent, X2 is Aib, X3 is E, X 10 is Y, X 11 But S, X 12 But, I, X 14 is L, X 16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R; X 17 But, C 16 -C 22 an amino acid bound to a fatty acid, said fatty acid optionally being bound to said amino acid via a linker; X 19 But Q, X 20 is selected from the group consisting of Aib, Q, H, and K; X 21 is selected from the group consisting of H, D, T, A, and E; X 22 But F, X 23 But, I, X 24 is selected from the group consisting of D-Glu and E; X 26 is L, X 27 But, I, X 28 is selected from the group consisting of E, A, S, and D-Glu; X 29 is selected from the group consisting of Aib, G, and A; X 30 is selected from the group consisting of C, G, and G-R2; X 31 but, Are absent, or 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) (In the formula, X 32 is S and X 33 is S and X 34 is selected from the group consisting of G and C; 35 is A and X 36 is P and X 37 is P and X 38 is P and X 39 is selected from the group consisting of C and S; X 40 is C) Selected from the group consisting of: The compound according to the above

[55] , or a pharma- ceutically acceptable salt thereof.

[57] X 17 The compound according to any one of the above

[55] to

[56] , wherein K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q-CO2H, or a pharma- ceutically acceptable salt thereof.

[58] PX 32 X 33 X 34 X35 X 36 X 37 X 38 X 39 The compound according to any one of the above

[55] to

[57] , or a pharma- ceutically acceptable salt thereof, wherein -R2 is selected from the group consisting of PSSGAPPPS (sequence number 301) and PSSGAPPPS-NH2 (sequence number 302).

[59] X 28 But A, X 29 But G, X 30 But G, X 31 But, PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO:5), X 34 But G, X 39 But, S. The compound according to any one of the above

[55] to

[58] , or a pharma- ceutically acceptable salt thereof.

[60] X1 is selected from the group consisting of Y and D-Tyr; 13 The compound according to any one of the above

[55] to

[59] , or a pharma- ceutically acceptable salt thereof, wherein is αMeL.

[61] The compound according to any one of the above

[55] to

[60] , wherein q is 16, or a pharma- ceutically acceptable salt thereof.

[62] The compound according to any one of the above

[55] to

[60] , wherein q is 18, or a pharma- ceutically acceptable salt thereof.

[63] The compound according to [1] above, wherein the compound is selected from the group consisting of 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, or a pharma- ceutically acceptable salt thereof.

[64] The compound according to

[63] above, wherein the compound is SEQ ID NO: 305, or a pharma- ceutically acceptable salt thereof.

[65] The compound according to

[63] above, wherein the compound is SEQ ID NO: 307, or a pharma- ceutically acceptable salt thereof.

[66] The compound according to

[63] above, wherein the compound is SEQ ID NO: 308, or a pharma- ceutically acceptable salt thereof.

[67] The compound according to

[63] above, wherein the compound is SEQ ID NO: 392, or a pharma- ceutically acceptable salt thereof.

[68] The compound according to any one of the above [1] to

[67] , or a pharma- ceutically acceptable salt thereof, wherein the compound is a partial agonist of GLP-1R.

[69] The compound inhibits GIPR and GLP-1R in HEK293 cell membrane guanosine 5'-(γ-thio)triphosphate-[ 35 S] (GTPγS) binding assay, Gα s The compound according to

[68] above, or a pharma- ceutically acceptable salt thereof, which stimulates GLP-1R, inducing activation of

[70] The compound according to

[68] or

[69] above, or a pharma- ceutically acceptable salt thereof, wherein the compound is a partial agonist of GLP-1R in a β-arrestin-2 recruitment assay.

[71] A method for treating a condition selected from the group consisting of type 2 diabetes, obesity, NAFLD, non-alcoholic steatohepatitis, dyslipidemia, and metabolic syndrome, comprising administering to a patient in need thereof an effective amount of the compound described in any one of [1] to

[70] above, or a pharma- ceutically acceptable salt thereof.

[72] A method for treating obesity, comprising administering to a patient in need thereof an effective amount of the compound described in any one of [1] to

[70] above, or a pharma- ceutically acceptable salt thereof.

[73] A method for providing therapeutic weight loss, comprising administering to a patient in need thereof an effective amount of the compound described in any one of [1] to

[70] above, or a pharma- ceutically acceptable salt thereof.

[74] A method for treating type 2 diabetes, comprising administering to a patient in need thereof an effective amount of the compound described in any one of [1] to

[70] above, or a pharma- ceutically acceptable salt thereof.

[75] A pharmaceutical composition comprising the compound according to any one of the above [1] to

[70] or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

[76] The pharmaceutical composition described in

[75] above, wherein the composition is administered as a subcutaneous injection.

[77] The pharmaceutical composition described in

[75] above, wherein the composition is administered orally.

[78] The pharmaceutical composition described in

[77] above, wherein the composition comprises a penetration enhancer and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

[79] The pharmaceutical composition of

[78] above, wherein the penetration enhancer is selected from the group consisting of sodium decanoate ("C10"), sodium taurodeoxycholate ("NaTDC"), lauroylcarnitine ("LC"), dodecyl maltoside ("C12-maltoside"), dodecylphosphatidylcholine ("DPC"), sodium taurodeoxycholate ("NaTDC"), and rhamnolipid.

[80] The pharmaceutical composition described in

[79] above, wherein the penetration enhancer is selected from the group consisting of C10 and LC.

[81] The pharmaceutical composition of

[80] above, wherein the penetration enhancer is C10.

[82] The pharmaceutical composition described in any one of

[77] to

[81] above, wherein the composition comprises a penetration enhancer, a protease inhibitor, and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

[83] The pharmaceutical composition of

[82] above, wherein the protease inhibitor is selected from the group consisting of 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").

[84] The pharmaceutical composition described in

[83] above, wherein the protease inhibitor is selected from the group consisting of SBTI, SBTICI, and SFTI.

[85] The pharmaceutical composition described in

[84] above, wherein the protease inhibitor is SBTI.

[86] The pharmaceutical composition according to any one of the above

[77] to

[85] , wherein the composition is a monolithic formulation.

[87] The pharmaceutical composition according to any one of the above

[77] to

[85] , wherein the composition is a multiparticulate formulation.

[88] The pharmaceutical composition according to any one of the above

[77] to

[85] , wherein the composition is a capsule or a tablet.

[89] The pharmaceutical composition described in

[86] above, wherein the composition is an enteric coated capsule or tablet.

[90] The compound according to any one of the above [1] to

[70] , or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[91] The compound according to any one of the above [1] to

[70] , or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease selected from the group consisting of treatment of type 2 diabetes, obesity, NAFLD, NASH, dyslipidemia, and metabolic syndrome.

[92] The compound according to any one of the above [1] to

[70] , or a pharma- ceutically acceptable salt thereof, for use in treating type 2 diabetes.

[93] Use of the compound according to any one of [1] to

[70] above, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition selected from the group consisting of type 2 diabetes, obesity, NAFLD, NASH, dyslipidemia, and metabolic syndrome.

[94] Use of the compound according to any one of the above [1] to

[70] , or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating type 2 diabetes.

[95] GLP-1R in HEK293 cell membranes is guanosine 5'-(γ-thio)triphosphate-[ 35 A method for treating diabetes comprising administering an effective amount of a compound that exhibits 75% or less partial agonism in a [S] (GTPγS) binding assay and that is a GIP agonist.

[96] The method according to

[95] above, wherein the diabetes is type 2 diabetes.

[97] The GLP-1R in HEK293 cell membranes was found to be guanosine 5'-(γ-thio)triphosphate-[ 35 The method of any one of

[95] or

[96] above, wherein a compound exhibiting partial agonism in a [S] (GTPγS) binding assay is co-administered with a compound having GIP agonist activity.

[98] The GLP-1R in HEK293 cell membranes was found to be guanosine 5'-(γ-thio)triphosphate-[ 35 The method according to any one of the above

[95] to

[97] , wherein a compound exhibiting partial agonism in a [GTPγS] (GTPγS) binding assay is co-administered with a compound exhibiting 35% or less partial agonism in a GLP-CHO cell β-arrestin recruitment assay.

[99] The GLP-1R in HEK293 cell membranes was found to be guanosine 5'-(γ-thio)triphosphate-[ 35 The method according to any one of the above

[95] to

[98] , wherein a compound showing partial agonism in a [S] (GTPγS) binding assay is administered as an active agent within one week before or after a compound having GIP agonist activity.

[0100] The GLP-1R in HEK293 cell membrane guanosine 5'-(γ-thio)triphosphate-[ 35 The method according to any one of the above

[95] to

[98] , wherein a compound exhibiting partial agonism in a [GTPγS] (GTPγS) binding assay is administered as an active agent within one week before or after a compound having GIP agonism and exhibiting 35% or less partial agonism in a GLP-CHO cell β-arrestin recruitment assay.

Claims

1. A compound selected from the group consisting of 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, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein the compound is SEQ ID NO: 305, or a pharma- ceutically acceptable salt thereof.

3. 2. The compound of claim 1, wherein the compound is SEQ ID NO: 307, or a pharma- ceutically acceptable salt thereof.

4. 2. The compound of claim 1, wherein the compound is SEQ ID NO: 308, or a pharma- ceutically acceptable salt thereof.

5. 2. The compound of claim 1, wherein the compound is SEQ ID NO: 392, or a pharma- ceutically acceptable salt thereof.

6. 6. A pharmaceutical composition for use in treating a condition selected from the group consisting of type 2 diabetes, obesity, NAFLD, non-alcoholic steatohepatitis, dyslipidemia, and metabolic syndrome, comprising a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

7. A pharmaceutical composition for use in treating obesity, comprising a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

8. 6. A pharmaceutical composition for use in providing therapeutic weight loss comprising a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

9. A pharmaceutical composition for use in treating type 2 diabetes, comprising a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof.

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

11. The pharmaceutical composition of claim 10, wherein the composition is administered as a subcutaneous injection.

12. The pharmaceutical composition of claim 10, wherein the composition is administered orally.

13. 13. The pharmaceutical composition of claim 12, wherein the composition comprises a penetration enhancer and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

14. 14. The pharmaceutical composition of claim 13, wherein the penetration enhancer is selected from the group consisting of sodium decanoate ("C10"), sodium taurodeoxycholate ("NaTDC"), lauroylcarnitine ("LC"), dodecyl maltoside ("C12-maltoside"), dodecylphosphatidylcholine ("DPC"), sodium taurodeoxycholate ("NaTDC"), and rhamnolipid.

15. 15. The pharmaceutical composition of claim 14, wherein the penetration enhancer is selected from the group consisting of C10 and LC.

16. 16. The pharmaceutical composition of claim 15, wherein the penetration enhancer is C10.

17. 17. The pharmaceutical composition of any one of claims 12 to 16, wherein the composition comprises a penetration enhancer, a protease inhibitor, and at least one pharma- ceutically acceptable carrier, diluent, or excipient.

18. 18. The pharmaceutical composition of claim 17, wherein the protease inhibitor is selected from the group consisting of 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").

19. 20. The pharmaceutical composition of claim 18, wherein the protease inhibitor is selected from the group consisting of SBTI, SBTICI, and SFTI.

20. 20. The pharmaceutical composition of claim 19, wherein the protease inhibitor is SBTI.

21. The pharmaceutical composition according to any one of claims 12 to 20, wherein the composition is a monolithic formulation.

22. The pharmaceutical composition according to any one of claims 12 to 20, wherein the composition is a multiparticulate formulation.

23. The pharmaceutical composition according to any one of claims 12 to 20, wherein the composition is a capsule or a tablet.

24. The pharmaceutical composition according to any one of claims 12 to 20, wherein the composition is an enteric coated capsule or tablet.

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