Gip/glp1 co-agonist compounds

A compound, or a pharmaceutically acceptable salt thereof, of the formula:

• R1X1X2X3GTX6TSDX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27X28X29X30X31 (SEQ ID NO:3) wherein:
• R1 is a modification of the N-terminal amino group wherein the modification is selected from the group consisting of Ac and absent;
• X1 is selected from the group consisting of Y, F, D-Tyr, 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 F;
• X10 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;
• X11 is selected from the group consisting of S, αMeS, and D-Ser;
• X12 is selected from the group consisting of I, S, D-I1e, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H;
• X13 is selected from the group consisting of Aib, L, and αMeL:
• X14 is selected from the group consisting of L and K, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker;
• X16 is selected from the group consisting of K, E, Om, Dab, Dap, S, T, H, Aib, αMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H;
• X17 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker;
• X19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H;
• X20 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;
• X21 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;
• X22 is selected from the group consisting of F and αMeF:
• X23 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;
• X24 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;
• X25 is selected from the group consisting of Y and αMeY;
• X26 is selected from the group consisting of L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H;
• X27 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;
• X29 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;
• X30 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;
• X31 is absent or is selected from the group consisting of PX32X33X34—R2 (SEQ ID NO:4), PX32X33X34X35X36X37X38X39—R2 (SEQ ID NO:5), PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H]X32X33X34-R2 (SEQ ID NO:7), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H]X32X33X34X35X36X37X38X39-R2 (SEQ ID NO:8), and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H]X32X33X34X35X36X37X38X39X40—R2 (SEQ ID NO:9);
• wherein:
• X32is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H];
• X33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H];
• X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)qCO2H];
• X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H];
• X36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H];
• X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H];
• X38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H];
• X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO—(CH2)q—CO2H];
• X40 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;
• and
• R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent;
• or a pharmaceutically acceptable salt thereof;
• wherein if X30 is G-R2, then X31 is absent;
• wherein no more than one of X10, X12, X13, X14, X16, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 may be a substituent that contains a fatty acid;
• and
• wherein no more than one of X30, X34, X39, and X40 may be C;
• and
• wherein if one of X30, X34, X39, and X40 is C, then none of X10, X12, X13, X14, X16, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 is a substituent that contains a fatty acid.