GIP/GLP1 Co-Agonist Compounds

The present invention relates to compounds having activity at both the human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. The present invention also relates to compounds having an extended duration of action at each of these receptors. Furthermore, the present invention relates to compounds that may be administered orally. Compounds may be useful in the treatment of type 2 diabetes mellitus (“T2DM”). Also, the compounds may be useful in the treatment of obesity.

Over the past several decades, the prevalence of diabetes has continued to rise.

T2DM is the most common form of diabetes accounting for approximately 90% of all diabetes. T2DM is characterized by high blood glucose levels associated mainly with insulin resistance. The current standard of care for T2DM includes diet and exercise, treatment with oral medications, and injectable glucose lowering drugs, including incretin-based therapies, such as GLP-1 receptor agonists. A variety of GLP-1 receptor agonists are currently available for treatment of T2DM, although currently marketed GLP-1 receptor agonists are generally dose-limited by gastrointestinal side effects such as nausea and vomiting.

Subcutaneous injection is the typical route of administration for the available GLP-1 receptor agonists. When treatment with oral medications and incretin-based therapies are insufficient, insulin treatment is considered. Despite the advances in treatment available today, many patients with T2DM are unable to reach their glycemic control goals. Uncontrolled diabetes leads to several conditions associated with increased morbidity and mortality of patients. There is a need for a treatment to enable more patients with T2DM to reach their glycemic treatment goal.

Obesity is a complex medical disorder resulting in excessive accumulation of adipose tissue mass. Today obesity is a global public health concern that is associated with undesired health outcomes and morbidities. Desired treatments for patients with obesity strive to reduce excess body weight, improve obesity-related co-morbidities, and maintain long-term weight reduction. Available treatments for obesity are particularly unsatisfactory for patients with severe obesity. There is a need for alternative treatment options to induce therapeutic weight loss in patients in need of such treatment.

WO2016/111971 describes peptides stated to have GLP-1 and GIP activity.

WO20 13/164483 also discloses compounds stated to have GLP-1 and GIP activity.

There is a need for T2DM treatments capable of providing effective glucose control for a larger portion of the patients in need of such treatment. There is a further need for T2D treatments capable of providing effective glucose control and with a favorable side effect profile. There is a need for alternate treatment options to provide therapeutic weight loss in a patient in need of such treatment. There is a need for an alternate treatment option for a patient in need of treatment for severe obesity.

There is a desire for compounds having agonist activity at the GIP and GLP-1 receptors that are suitable for oral administration. Compounds with extended duration of action at each of the GIP and GLP-1 receptors are desirable to allow for less frequent dosing of the compound.

Accordingly, the present invention provides a compound of Formula I:

R1X1X2X3GTX6TSDX10X11X12X13X14DX16X17AX19X20X21X22X23X24X25X26X27 X28X29X30X31 (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, 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);

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, aMeS, and D-Ser;

X12 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;

X13 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;

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, Orn, Dab, Dap, S, T, H, Aib, aMeK, 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 Mb, Q, H, R, K, aMeK, 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 aMeF;

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 aMeY;

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-(γOGlu)-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:

X32 is 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)q-CO2H];

X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-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.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein q is 16. In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X31 is selected from the group consisting of SEQ ID NO:5 and SEQ ID NO:8. In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the Xn amino acid that is conjugated to a fatty acid is a natural amino acid. In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X17 is selected from the group consisting of K, Q and I.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X14 or X17 is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)14-CO2H, K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)18-CO2H,K(2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-(Trx)-CO-(CH2)18-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(Trx)-(γ-Glu)-CO-(CH2)18-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-GlU)-CO-(CH2)18-CO2H, K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(εK)-CO-(CH2)18-CO2H, K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)2-CO-(CH2)18-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)18-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2)16-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2)14-CO2H, and KDab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Dab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO-(CH2)18-CO2H.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X14 or X17 is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H,K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)14-CO2H, and K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)18-CO2H.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X14 or X17 is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H, K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H, and K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)14-CO2H. In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xu or X17 is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H and K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H. In an embodiment is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein X14 or X17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein a is 2, b is 1, and q is selected from the group consisting of 18 and 20. In an embodiment is a compound of

Formula I, or pharmaceutically acceptable salt thereof, wherein X14 or X17 is K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein a is 2, b is 1 and q is 18. In an embodiment is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein X14 or X17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein, a is 2, b is 1, and q is 20.

In an embodiment is a Formula I compound, or pharmaceutically acceptable salt thereof, wherein X1 and X2 do not combine to form desH- Ψ[NHCO]-Aib (hereafter a “Formula II” compound).

In an embodiment is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein:

X17 is an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; and

X30 is selected from the group consisting of G-R2 and G;

wherein if X30 is G, then X31 is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO:4), wherein X32 is S, X33 is S and X34 is G (SEQ ID NO:297), and PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P and X39 is S (SEQ ID NO:298) (hereafter a “Formula III” compound).

In an embodiment is a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein the X17 amino acid is conjugated to the fatty acid via a linker (hereafter a “Formula IIIa” compound).

In an embodiment is a compound of Formula III and IIIa, or a pharmaceutically acceptable salt thereof, wherein:

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, and cTA;

X12 is selected from the group consisting of I, S, and D-Ile;

X13 is selected from the group consisting of Nle, Aib, L, and αMeL;

X14 is selected from the group consisting of L and K;

X16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R;

X19 is selected from the group consisting of Q, and A;

X20 is selected from the group consisting of Aib, Q, H, R, K, and aMeK;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I;

X23 is selected from the group consisting of I, L, A, G, F, H, E, and V;

X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P;

X26 is selected from the group consisting of L, and αMeL;

X27 is selected from the group consisting of L, and I;

X28 is selected from the group consisting of E, A, S, and D-Glu;

X29 is selected from the group consisting of Aib, G, and A;

X30 is selected from the group consisting of G and G-R2;

wherein if X30 is G; then X31 is selected from the group consisting of PX32X33X34-R2

(SEQ ID NO: 4), wherein X32 is S, X33 is S and X34 is G (SEQ ID NO:297) and

PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P and X39 is S (SEQ ID NO:298) (hereafter a “Formula IIIb” compound).

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

In an embodiment is a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein X17 is an amino acid conjugated to a C16-C22 fatty acid, wherein the amino acid is K and wherein said fatty acid is optionally conjugated to said amino acid via a linker.

In an embodiment is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:

R1 is absent;

X1 and X2 do not combine to form desH-Ψ[NHCO]-Aib;

X17 is K conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker.

In an embodiment is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:

X1 is Y;

X2 is Aib;

X3 is E;

X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y;

X11 is S;

X12 is I;

X14 is L;

X16 is selected from the group consisting of K, E, Orn, Dab, and Dap;

X17 is K conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker;

X19 is Q;

X20 is Aib;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E;

X22 is F;

X23 is I;

X24 is selected from the group consisting of S, Aad, D-Glu, and E;

X26 is L; and

X28 is selected from the group consisting of E and A.

In an embodiment is a compound of Formula III, or pharmaceutically acceptable salt thereof, wherein:

X1 is Y;

X2 is Aib;

X3 is E;

X6 is αMeF(2F);

X10 is selected from the group consisting of Y, 4-Pal, and V;

X11 is S;

X12 is I;

X13 is selected from the group consisting of L, Aib, and αMeL;

X14 is L;

X16 is selected from the group consisting of E, K, and Orn;

X17 is K conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker;

X19 is Q;

X20 is Aib

X21 is selected from the group consisting of E, A, and T;

X22 is F;

X23 is I;

X24 is D-Glu:

X25 is selected from the group consisting of Y and αMeY;

X26 is L;

X27 is I;

X28 is E;

X29 is G;

X30 is G; and

X31 is PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P, X39 is S (SEQ ID NO:298).

In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein R2 is absent.

In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein R2 is NH2.

In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X13 is αMeL.

In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X25 is Y and X13 is αMeL.

In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X17 is K conjugated to a fatty acid via a linker to the epsilon-amino group of the K side-chain wherein said fatty acid and linker have the following formula:

(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein a is 1 or 2; b is 1 or 2; and q is selected from the group consisting of 14 to 20.

In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X16 is Orn, X13 is αMeL, and X25 is Y. In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X16 is E, X13 is αMeL, and X25 is Y. In an embodiment, is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X16 is E, X13 is αMeL, X10 is Y, and X25 is αMeY. In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X16 is Orn, X13 is αMeL, X10 is 4Pal, and X25 is Y. In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X16 is Orn, X13 is αMeL, X10 is V, and X25 is Y. In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X16 is E, X13 is αMeL, X25 is Y, and X17 is K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein a is 2; b is 1; and q is selected from the group consisting of 14 to 20. In an embodiment is a compound of Formula III, IIIa and IIIb, or a pharmaceutically acceptable salt thereof, wherein X16 is E, X13 is αMeL, X10 is Y, and X25 is Y and and X17 is K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein a is 2; b is 1; and q is selected from the group consisting of 16 to 20.

In an embodiment is a compound of Formula I selected from the group consisting of SEQ ID NO: 10, SEQ ID NO:ll, SEQ ID NO:12, SEQ ID NO:13, and SEQ ID NO:14, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO: 10, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO: 12, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO: 13, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO: 14, or a pharmaceutically acceptable salt thereof.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Xi is selected from the group consisting of Y, F, and D-Tyr; X6 is F; and X13 is selected from the group consisting of Aib, L, and αMeL.

In an embodiment, is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ri is absent; X1 is selected from the group consisting of Y, F, and D- Tyr; X6 is F; X13 is selected from the group consisting of Aib, L, and αMeL; X2 is Aib; X3 is E; X10 is Y; X11 is S; X12 is I; X14 is L; X16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R; X17 is 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 Q; X20 is selected from the group consisting of Aib, Q, H, and K; X21 is selected from the group consisting of H, D, T, A, and E; X22 is F; X23 is I; X24 is selected from the group consisting of D-Glu and E; X26 is L; X27 is I; X28 is selected from the group consisting of E, A, S, and D-Glu; X29 is selected from the group consisting of Aib, G, and A; X30 is selected from the group consisting of C, G, and G-R2; X31 is absent or is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO:4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), and PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6); wherein: X32is S; X33 is S; X34 is selected from the group consisting of G and C; X35 is A; X36 is P; X37 is P; X38 is P;

X39 is selected from the group consisting of C and S; and X40 is C.

In an embodiment, is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from the group consisting of Y, F, and D-Tyr; X6 is F; and X13 is selected from the group consisting of Aib, L, and αMeL; X28 is A; X29 G; X30 is G; X3 is PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5); X34 is G; and X39 is S.

In an embodiment, is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X1 is selected from the group consisting of Y and D-Tyr; and X13 αMeL.

In an embodiment is a compound of Formula I selected from the group consisting of SEQ ID NO:303, SEQ ID NO:304, SEQ ID NQ:305, SEQ ID NO:306, SEQ ID NO: 307, and SEQ ID NO:308, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO:303, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO:304, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO:305, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO:306, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO:307, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NO:308, or a pharmaceutically acceptable salt thereof. In an embodiment is a compound of Formula I that is SEQ ID NG:386, or a pharmaceutically acceptable salt thereof.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein:

X10 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;

X12 is selected from the group consisting of I, D-Ile, and S;

X13 is selected from the group consisting of Me, Aib, L, and αMeL;

X14 is L;

X16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R;

X17 is selected from the group consisting of K, Q, and I;

X19 is selected from the group consisting of Q and A;

X20 is selected from the group consisting of Aib, Q, H, R, K, and αMeK;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I;

X23 is selected from the group consisting of I, L, A, G, F, H, E, and V;

X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P;

X26 is selected from the group consisting of L and αMeL;

X27 is selected from the group consisting of L and I;

X28 is selected from the group consisting of E, A, S, and D-Glu; and

X29 is selected from the group consisting of Aib, G, and A (hereafter a “Formula IV” compound).

In an embodiment of is a compound of Formula IV, or a pharmaceutically acceptable salt thereof wherein X39 is C. In an embodiment is a compound of Formula IV, or a pharmaceutically acceptable salt thereof wherein X40 is C.

In an embodiment is a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein one, and only one, of X30, X34, X39, and X40 is C. In an embodiment is a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein one, and only one, of X30, X34, X39, and X40 is C modified using time-extension technology. In an embodiment is a compound of Formula IV, or pharmaceutically acceptable salt thereof, wherein C is modified using time-extension technology wherein the time-extension technology is XTEN. In an embodiment is a compound of Formula IV, or pharmaceutically acceptable salt thereof, wherein C is modified using time-extension technology wherein the time-extension technology is a (Glu)m biotin wherein m is 0, 1 , 2, or 3. In an embodiment is a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein:

X1 is Y;

X2 is Aib;

X3 is E;

X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y;

X11 is S;

X12 is I;

X16 is selected from the group consisting of K, E, Orn, Dab, and Dap;

X19 is Q;

X20 is selected from the group consisting of Aib and K;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E;

X22 is F;

X23 is I;

X24 is selected from the group consisting of S, Aad, D-Glu, and E;

X26 is L; and

X28 is selected from the group consisting of E and A;

or a pharmaceutically acceptable salt thereof.

In an embodiment is a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein

X1 is Y;

X2 is Aib;

X3 is E;

X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y;

X11 is S;

X12 is I;

X16 is selected from the group consisting of K, E, Orn, Dab, and Dap;

X20 is Aib;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E;

X22 is F;

X24 is selected from the group consisting of S, Aad, D-Glu, and E;

X27 is I; and

X28 is selected from the group consisting of E and A.

In an embodiment is a compound of Formula I, or a pharmaceutical salt thereof, wherein:

X14 is L;

X17 is selected from the group consisting of K, Q, and I;

X30 is selected from the group consisting of G-R2 and G; and

q is selected from the group consisting of 16, 18, and 20;

wherein if X30 is G, then X31 is selected from the group consisting of:

PX32X33X34-R2 (SEQ ID NO:4), wherein:

X32 is S, X33 is S, X34 is G and R2 is absent (SEQ ID NO:299) or X32 is S, X33 is S, X34 is G and R2 is NH2 (SEQ ID NO:300);

and

PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein:

X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P, X39 is S and R2 is absent (SEQ ID NO:301) or

X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P, X39 is S and R2 is NH2 (SEQ ID NO:302); and

wherein one of X10, X12, X13 , X14, X16, X19, X20, X21, X23, X24, X26, X27, X28, and X29 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO)-(CH2)qCO2H (hereafter a “Formula V” compound).

In an embodiment is a compound of Formula V, or a pharmaceutically acceptable salt thereof, wherein:

X1 is Y;

X2 is Aib;

X3 is E;

X10 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-(y-Glu)-CO)-(CH2)qCO2H;

X11 is S;

X12 is selected from the group consisting of I, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X16 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;

X17 is selected from the group consisting of K and I;

X19 is selected from the group consisting of Q and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X20 is selected from the group consisting of Aib 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, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X22 is F;

X24 is selected from the group consisting of S, Aad, D-Glu, E, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO)-(CH2)qCO2H;

X26 is selected from the group consisting of L and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X27 is selected from the group consisting of L and I; and

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,

In an embodiment is a compound of Formula V, or a pharmaceutically acceptable salt thereof, wherein X20 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO)-(CH2)qCO2H, wherein q is 16 or 18. In an embodiment is a compound of Formula V, or a pharmaceutically acceptable salt thereof, wherein X31 is SEQ ID NO:301 or SEQ ID NO:302.

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

An embodiment provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy. An embodiment provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in therapy to treat a condition selected from the group consisting of T2DM, obesity, NAFLD, NASH, dyslipidemia and metabolic syndrome. In an embodiment, the condition is T2DM. In an embodiment, the condition is obesity. In an embodiment, the condition is NAFLD. In an embodiment, the condition is NASH. In an embodiment, the condition is metabolic syndrome.

The compounds of Formula I, or a pharmaceutically acceptable salt thereof, may be useful in the treatment of a variety of symptoms or disorders. For example, certain embodiments, provide a method for treatment of T2DM in a patient comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In an embodiment, is a method for treatment of obesity in a patient comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In an embodiment, the method is inducing non-therapeutic weight loss in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

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

Also provided herein is a compound of the present invention for use in simultaneous, separate and sequential combinations with one or more agents selected from metformin, a thiazolidinedione, a sulfonylurea, a dipeptidyl peptidase 4 inhibitor, a sodium glucose co-transporter, a SGLT-2 inhibitor, a growth differentiation factor 15 modulator (“GDF15”), a peptide tyrosine tyrosine modulator (“PYY”), a modified insulin, amylin, a dual amylin calcitonin receptor agonist, and oxyntomoduiin agonist (“OXM”) in the treatment of a

condition selected from the group consisting of T2DM, obesity, NAFLD, NASH, dyslipidemia and metabolic syndrome. In an embodiment, a compound of the present invention is provided in a fixed dose combination with one or more agents selected from metformin, a thiazolidinedione, a sulfonylurea, a dipeptidyl peptidase 4 inhibitor, a sodium glucose co-transporter, a SGLT-2 inhibitorGDF15, PYY, a modified insulin, amylin, a dual amylin calcitonin receptor agonist, and OXM In an embodiment is a compound of the present invention for use in simultaneous, separate and sequential combinations with one or more agents selected from metformin, a thiazolidinedione, a sulfonylurea, a dipeptidyl peptidase 4 inhibitor, a sodium glucose co-transporter, a SGLT-2 inhibitor, GDF15, PYY, a modified insulin, amylin, a dual amylin calcitonin receptor agonist, and OXM in the treatment of a condition selected from the group consisting of T2DM and obesity. In an embodiment is a compound of the present invention for use in simultaneous, separate and sequential combinations with one or more agents selected from metformin, a thiazolidinedione, a sulfonylurea, a dipeptidyl peptidase 4 inhibitor, a sodium glucose co-transporter, and a SGLT-2 inhibitor in the treatment of a condition selected from the group consisting of T2DM and obesity.

In other embodiments, the compounds, or a pharmaceutically acceptable salt thereof, may be useful to improve bone strength in subjects in need thereof. The compounds of the present invention, or a pharmaceutically acceptable salt thereof, may be useful in the treatment of other disorders such as Parkinson’s disease or Alzheimer’s disease. Incretins and incretin analogs having activity at one or more of the GIP, GLP-1 and/or glucagon receptors have been described as having the potential to have therapeutic value in a number of other diseases or conditions, including for example obesity, NAFLD and NASH, dyslipidemia, metabolic syndrome, bone related disorders, Alzheimer’s disease, and Parkinson’s disease. See, e.g., Jail S., et. al, Monomeric GLP-1 /GIP /glucagon triagonism corrects obesity, hepatosteatosis, and dyslipidemia in female mice , MOL. METAB. 6(5):440-446 (March 2017); Carbone L.J., et. al., Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis. J. GASTROENTEROL. HEPATOL., 31(1):23-31 (Jan. 2016); B. Finan, et. al, Reappraisal of GIP Pharmacology for Metabolic Diseases.

TRENDS MOL. MED., 22(5):359-76 (May 2016); Choi, I.Y., et al., Potent body weight loss and efficacy in a NASH animal model by a novel long-acting GLP-1/Glucagon/GIP triple-agonist (HM15211), ADA 2017 Poster 1139-P; Ding, K.H., Impact of glucose-dependent insulinotropic peptide on age-induced bone loss, J. BONE MINER. RES., 23(4):536-43 (2008); Tai, J. et. al, Neuroprotective effects of a triple GLP-1/GIP /glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer ’s disease, BRAIN RES. 1678, 64-74 (2018); T.D. Müller et al., The New Biology and Pharmacology of Glucagon, PHYSIOL. REV. 97: 721-766 (2017); Finan, B. et. al, Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans, SCI. TRANSL. MED., 5:209 (October 2013); Holscher C, Insulin, incretins and other growth factors as potential novel treatments for Alzheimer's and Parkinson's diseases. BIOCHEM. Soc. TRANS. 42(2):593-0 (Apr. 2014).

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

Another embodiment provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one selected from the group consisting of a carrier, diluent, and excipient.

In an embodiment is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, at least one permeation enhancer and at least one protease inhibitor. In an embodiment, is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, at least one permeation enhancer, and at least one selected from the group consisting of carrier, diluent, and excipient.

In an embodiment is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, a permeation enhancer, a protease inhibitor, and at least one selected from the group consisting of carrier, diluent, and excipient. In an embodiment is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a permeation enhancer. In an embodiment is a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a permeation enhancer. In an embodiment the permeation enhancer is selected from the group consisting of sodium decanoate (“C10”), sodium taurodeoxycholate (“NaTDC”), lauroyl carnitine (“LC”), dodecyl maltoside (“C12-maltoside”), dodecyl phosphatidylcholine (“DPC”), sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (“SNAC”) and a Rhamnolipid. In an embodiment the permeation enhancer is selected from the group consisting of C10 and LC. In an embodiment a 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”). In an embodiment, a protease inhibitor is selected from the group consisting of SBTI, SBTCI, and SFTI. In an embodiment, a protease inhibitor is SBTI.

As used herein, the term “treating” or “to treat” includes restraining, slowing, stopping, or reversing the progression or severity of a symptom, condition, or disorder.

Certain compounds of the present invention are generally effective over a wide dosage range. For example, dosages for once weekly parenteral dosing may fall within the range of 0.05 mg to about 30 mg per person per week.

The compounds of the present invention include novel amino acid sequences having affinity for the respective GLP-1 and GIP receptors, with desired potency at each of these receptors. GLP-1 is a 36 amino acid peptide, the major biologically active fragment of which is produced as a 30-amino acid, C-terminal amidated peptide (GLP-17-36) (SEQ ID NO:2).

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

The compounds provide desired potency at each of the GIP and GLP-1 receptors. In an embodiment, compounds are suitable for oral administration. In an embodiment, compounds have desirable GIP and GLP receptor extended time action. In an embodiment, compounds have desirable GIP and GLP receptor activity wherein the GIP agonist potency is from 2.5 to 5 times the GLP1 receptor potency as measured by the casein cAMP assay described herein below, wherein the potency is normalized against native GIP and GLP on the day the assay is run. In an embodiment, compounds have desirable GIP and GLP receptor activity wherein the GIP agonist potency is from 2.5 to 10 times the GLP1 receptor potency as measured by the casein cAMP assay, wherein the potency is normalized against native GIP and GLP on the day the assay is run.

As used herein the term “amino acid” means both naturally occurring amino acids and unnatural amino acids. The amino acids are typically depicted using standard one letter codes (e.g., L = leucine), as well as alpha-methyl substituted residues of natural amino acids (e.g., α-methyl leucine, or αMeL and α-methyl lysine, or αMeK) and certain other unnatural amino acids, such as alpha amino isobutyric acid, or “Aib,” “4Pal,” “Orn,” and the like. The structures of these amino acids appear below:

As used herein “Orn” means ornithine. As used herein “4Pal” means 3-(4-Pyridyl)-L- alanine. As used herein “αMeF(2F)” means alpha-methyl 2-F-phenylalanine. As used herein “αMeY,” αaMeK,” and “αMeL” mean alpha methyl tyrosine, alpha methyl lysine, and alpha methyl leucine, respectively. As used herein, “e” and “D-Glu” mean D-glutamic acid. As used herein “D-His” and “h” each mean D-histidine. As used herein “D-Tyr”and “y” each means D-tyrosine. As used herein “D-Ser” and “s” means means D-serine. As used herein “D-Ala” and “a” each means D-alanine. As used herein, “αMeF(2F)” means alpha-methyl- F(2F) and alpha-methyl -Phe(2F). As used herein, “aMeF”, means alpha-m ethyl -F and alpha- methyl-Phe. As used herein, “αMeY”, means alpha-methyl -Tyr. As used herein “αMeK”, means alpha-methyl-Lys. As used herein, “αMeL”, means alpha-methyl-Leu. As used herein, “αMeS”, means alpha-methyl-serine and alpha-methyl-Ser. As used herein “αMeP”, means alpha-methyl-proline and alpha-methyl-Pro. As used herein, “desH”, means desHis. As used herein, “desY”, means desTyr.

When X1 is DesH and X2 is Aib, and the DesH and Aib can combine to form a group as illustrated above, DesH-Ψ[NHCO]-Aib.

When used herein, the terra “amino acid conjugated to a C16-C22 fatty acid” refers to any natural or unnatural amino acid with a functional group that has been chemically modified to conjugate to a fatty acid by way of a covalent bond to the fatty acid or, preferably, by way of a linker. Examples of such functional groups include amino, carboxyl, chloro, bromo, iodo, azido, alkynyl, alkenyl, and thiol groups. Examples of natural amino acids which include such functional groups include K (amino), C (thiol), E (carboxyl) and D (carboxyl). In an embodiment the conjugated amino acid is K.

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

In an embodiment, compounds of the present invention include a fatty acid moiety conjugated directly, without a linker, to a natural or unnatural amino acid with a functional group available for conjugation. In certain preferred embodiments the conjugated amino acid is selected from the group consisting of K, C, E and D. In particularly preferred embodiments the conjugated amino acid is K. In such embodiments, the conjugation is to the epsilon-amino group of the K side-chain.

In an embodiment, the linker comprises one to four amino acids, an amino polyethylene glycol carboxylate, or mixtures thereof. In an embodiment, the amino polyethylene glycol carboxylate has the following formula:

H-{NH-CH2-CH2-[O-CH2-CH2]p-O-(CH2)z-CO}r-OH, wherein p is any integer from

1 to 12, z is any integer from 1 to 20, and r is 1 or 2.

In an embodiment is a compound of Formula I which comprises an amino acid conjugated to a fatty acid via a linker, wherein the linker is one to two amino acids selected from the group consisting of Glu and In an embodiment the linker is one to two (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. The compounds of the present invention utilize a C16-C22 fatty acid chemically conjugated to the functional group of an amino acid either by a direct bond or by a linker. In an embodiment, the fatty acid moiety is conjugated to a lysine at position 17 via a linker between the lysine and the fatty acid. In an embodiment, the fatty acid moiety is conjugated to a lysine at position 20 via a linker between the lysine and fatty acid. In an embodiment, the fatty acid chain is any single chain C16-C22 fatty acid.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the fatty acid is conjugated with a linker, and the linker comprises one or more (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties, in combination with zero or one to four amino acids. In an embodiment, the linker may comprise one to four Glu or γ-Glu amino acid residues. In an embodiment, the linker may comprise 1 or 2 Glu or γ-Glu amino acid residues. In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises a fatty acid conjugated via a linker wherein, the linker comprises either 1 or 2 γ-Glu amino acid residues. In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, comprises a fatty acid conjugated via a linker wherein the linker may comprise one to four amino acid residues (such as, for example Glu and γ-Glu amino acids) used in combination with up to 36 (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. Specifically, in an embodiment is a Formula I compound, or a pharmaceutically acceptable salt thereof, which comprises a fatty acid conjugated via a linker wherein, the linker constitutes combinations of one to four Glu and γ-Glu amino acids and one to four (2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. In an embodiment is a Formula I compound, or a pharmaceutically acceptable salt thereof, which comprises a fatty acid conjugated via a linker wherein the linker is comprised of combinations of one or two g-Glu amino acids and one or two (2- [2-(2-Amino-ethoxy)-ethoxy] -acetyl) moieties. In an embodiment is a Formula I compound, or a pharmaceutically acceptable salt thereof, which comprises a fatty acid conjugated via a linker wherein the linker and fatty acid components have the following formula:

(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b-CO-(CH2)q-CO2H, wherein a is 1 or 2, b is 1 or 2 and q is 16 or 18. In an embodiment, a is 2, b is 1 and q is 18; and the structure is:

In an embodiment, a is 1, b is 2 and q is 18; and the structure is:

In an embodiment a is 1, b is 1, and q is 18; and the structure is:

The term “C16-C22 fatty acid as used herein means a carboxylic acid with between 16 and 22 carbon atoms. In an embodiment, the C16-C22 fatty acid suitable for use herein can be

a saturated diacid. In an embodiment, the fatty acid is C20-C22. In an embodiment q is

selected from the group consisting of 14, 16, 18, and 20. In an embodiment q is selected

from 18 and 20. In an embodiment q is 18. In an embodiment q is 20.

In an embodiment, specific saturated C16-C22 fatty acids that are suitable for the

compounds and uses thereof disclosed herein include, but are not limited to, hexadecanedioic acid (C16 diacid), heptadecanedioic acid (C17 diacid), octadecanedioic acid (C18 diacid), nonadecanedioic acid (C19 diacid), eicosanedioic acid (C20 diacid), heneicosanedioic acid

(C21 diacid), docosanedioic acid (C22 diacid), including branched and substituted derivatives thereof.

In an embodiment, the C16-C22 fatty acid is selected from the group consisting of a

saturated Cix diacid, a saturated C19 diacid, a saturated C20 diacid, and branched and

substituted derivatives thereof. In an embodiment, the C16-C22 fatty acid is selected from the group consisting of stearic acid, arachadic acid and eicosanedioic acid. In an embodiment, the C16-C22 fatty acid is arachadic acid.

As shown in the chemical structures of Examples 1-5 below, in an embodiment the linker-fatty acid moieties described above link to the epsilon-amino group of the lysine side-chain.

In an embodiment, is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein none of X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 is C or is a substituent that contains a fatty acid. In an embodiment, is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein 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; and none of X30, X34, X39, and X40 is C. In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein 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.

As used herein “time-extension technology” means a peptide time-extension technology for example, recombinant human serum albumin (“rHSA”), peptide conjugation to a pharmaceutically acceptable polymer, such as polymeric sequence of amino acids (“XTEN”), unsulfated heparin-like carbohydrate polymer (“HEP”), hydroxyl ethyl starch (“HES”), llama heavy-chain antibody fragments (“VHH”), pegylation, Fc conjugation, bovine serum albumin (“BSA”) (Sleep, D. Epert Opin Drug Del (2015) 12, 793-812; Podust VN et.al. J Control. Release, 2015; ePUB; Hey, T. et. al. in: R. Kontermann (Ed.), Therapeutic Proteins: Strategies to Modulate their Plasma Half-Lives, Wiley-VCH Verlag Gmbh & Co. KGaA, Weinheim, Germany, 2012, ppl 17-140; DeAngelis, PL, Drug Dev Delivery (2013) January, 12/31/2012. In an embodiment time-extension technology is applied using a linker group. In an embodiment, the time-extension technology is applied using 0, 1, 2, or 3 amino acids as linker.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, without a fatty acid (i.e., a compound where 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) or time-extension technology may be administered to a patient in need thereof via transdermal or infusion methods of administration. Further, a compound of Formula I, or a pharmaceutically acceptable salt thereof, without a fatty acid may be further modified using a peptide time-extension technology for example, recombinant human serum albumin (“rHSA”), peptide conjugation to a pharmaceutically acceptable polymer, such as polymeric sequence of amino acids (“XTEN”), unsulfated heparin-like carbohydrate polymer (“HEP”), and hydroxyl ethyl starch (“HES”). In an embodiment, a time-extension technology is applied using a cysteine amino acid in a Formula I compound, or a pharmaceutically acceptable salt thereof, without a fatty acid, using procedures known to the skilled artisan. In an embodiment, a time-extension technology is applied to one amino acid in a Formula I compound, or a pharmaceutically acceptable salt thereof, without a fatty acid. In an embodiment, wherein a time-extension technology is applied to a Formula I compound, or a pharmaceutically acceptable salt thereof, without a fatty acid, X17 is selected from the group consisting of I, K and Q. In an embodiment wherein a time-extension technology is applied to a Formula I compound, or a pharmaceutically acceptable salt thereof, without a fatty acid, X30 is C. In an embodiment wherein a time-extension technology is applied to a Formula I compound, or a pharmaceutically acceptable salt thereof, without a fatty acid, X34 is C. In an embodiment wherein a time-extension technology is applied to a Formula I compound, or a pharmaceutically acceptable salt thereof, without a fatty acid, X39 is C. In an embodiment wherein a time-extension technology is applied to a Formula I compound, or a pharmaceutically acceptable salt thereof, without a fatty acid, X40 is C.

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

The affinity of compounds, or a pharmaceutically acceptable salt thereof, of the present invention for each of the GIP and GLP-1 receptors may be measured using techniques known for measuring receptor binding levels in the art, including, for example those described in the examples below, and is commonly expressed as a Ki value. The activity of the compounds of the present invention at each of the receptors may also be measured using techniques known in the art, including for example the in vitro activity assays described below, and is commonly expressed as an EC50 value, which is the concentration of compound causing half-maximal simulation in a dose response curve.

In an embodiment, a pharmaceutical composition of a compound of Formula I is suitable for administration by a parenteral route (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal). In an embodiment, a pharmaceutical composition of a compound of Formula I is suitable for oral administration (e.g., tablet, capsule). Some pharmaceutical compositions and processes for preparing same are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21 st Edition, Lippincott, Williams & Wilkins, 2006). Physiochemical properties of a peptide in addition to anatomical and physiological features of the gastrointestinal tract may provide challenges to efficient oral delivery of a peptide. In an embodiment a pharmaceutical composition for oral administration comprises of a compound of this invention, and a permeation enhancer. In an embodiment, a pharmaceutical composition for oral administration comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, a permeation enharncer, and a protease inhibitor. In an embodiment, a pharmaceutical composition for oral administration comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a permeation enharncer,

Monolithic and multi-particulate dosage forms for compounds of the present invention are contemplated. In an embodiment, a compound of Formula I is provided as a monolithic composition. A monolithic composition is intended for release of all components in a single location. A multi-particuate composition is intended to achieve fast transit from the stomach to the intestine and allow for distribution of composition components over large surface of small intestine. Concurrent release of a compound and functional excipients is desired for monolithic and multi-particulate dosage compositions. In an embodiment a monolithic composition of a compound of Formula I, or a pharmaceutically acceptable salt thereof, is formulated as an enteric capsule, enteric coated capsule or an enteric coated tablet. Such multi-particulate composition may be formulated as an enteric coated minitablets, or enteric coated granules where the coating is generally intact in the stomach at low pH and dissolves at the higher pH of the intestine. Two types of coated minitablets or coated granules may be formulated for either delivery to proximal small intestine by dissolution above pH 5.5 or to distal small intestine by dissolution above pH 7-7.2. A coating system for distal small intestinal release can also be applied to monolithic capsules or tablets if distal small intestinal delivery is desired. Minitablets may be filled into a standard uncoated capsule.

As used herein the term “permeation enhancer” means permeation enhancer that enhances oral absorption of a compound of this invention. As used herein, permeation enhancer means permeation enhancers, such as sodium decanoate, sodium taurodeoxycholate, lauroyl carnitine, dodecyl maltoside, dodecyl phosphatidylcholine,

SNAC, a Rhamnolipid, and permeation enhancers reported in the literature, such as for example, Permeant inhibitor of phosphatase, PIP-250 and PIP-640. See, Pharmaceutics.

2019 Jan; 11(1): 41, (See Biomaterials. 2012; 33: 3464-3474), ZOT (zonula occludens toxin), ΔG (fragment of ZOT) (See Int. J. Pharm. 2009; 365, 121-130). In an embodiment, a permeation enhancer is selected from the group consisting of sodium decanoate, sodium taurodeoxycholate, and lauroyl carnitine. In an embodiment, a permeation enhancer is selected from the group consisting of C10, LC, and NaTDC. In an embodiment a permeation enhancer is C10.

As used herein the term “protease inhibitor” means a protease inhibitor that may be selected from the group consisting of protein based, peptide based, and small molecule based. Protease inhibitors are well known and may include, for example, soybean trypsin inhibitor (“SBTI”), soybean trypsin-chymotrypsin inhibitor (“SBTCI”), ecotin, sunflower trypsin inhibitor (“SFTI”), leupeptin, citric acid, ethylenediaminetetraacetic acid (“EDTA”), sodium glycocholate and 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (“AEBSF”). In

an embodiment a protease inhibitor is selected from the group consisting of SBTI, SBTCI and SFTI. In an embodiment, a protease inhibitor is SBTI.

In an embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a potent GIPR/GLP-1R dual agonist that is a partial agonist on the GLP-1R as demonstrated by a Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay, and a partial agonist on the GLP-1R as demonstarted by a f-arrcstin-2 recruitment assay. In an embodiment is a compound of Formula I, or pharmaceutically acceptable salt thereof, wherein the compound stimulates GLP-1R induced activation of Gas in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay. In an embodiment, is a compound showing partial agonism of 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay, and 35% or less in the GLP-CHO Cell β-Arrestin.Recruitment Assay.

In an embodiment is a method for treating diabetes comprising administering an effective amount of a compound showing partial agonism of 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay, and an effective amount of a compound that is a GIP agonist. In an embodiment, the compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay is co-administered with a compound having GIP agonist activity. In an embodiment, the compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay is administered as an active agent within one week before or after a compound having GIP agonist activity. In an embodiment, a method for treating diabetes comprises administering an effective amount of a compound showing 35% or less in the GLP-CHO Cell b-Arrestin.Recruitment Assay and administering an effective amount of a compound showing partial agonism of 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay.

Compounds of the present invention may react with any of a number of inorganic and organic acids/bases to form pharmaceutically acceptable aci d/base addition salts.

Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. (See, e.g., P. Stahl, etal. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2nd Revised Edition (Wiley-VCH, 2011)). Pharmaceutically acceptable salts of the present invention include, but are not limited to, sodium, trifluoroacetate, hydrochloride, ammonium, and acetate salts. In an embodiment, a pharmaceutically acceptable salt of is selected from the group consisting of sodium, hydrochloride, and acetate salts.

The present invention also encompasses novel intermediates and processes useful for the synthesis of compounds of the present invention, or a pharmaceutically acceptable salt thereof. The intermediates and compounds of the present invention may be prepared by a variety of procedures known in the art. In particular, the Examples below describe a process using chemical synthesis. The specifi c synthetic steps for each of the routes described may be combined in different ways to prepare compounds of the present invention. The reagents and starting materials are readily available to one of ordinary skill in the art.

When used herein, the term “effective amount” refers to the amount or dose of a compound of the present invention, or a pharmaceutically acceptable salt thereof, which, upon single or multiple dose admini stration to the patient, provides the desired effect in the patient under diagnosis or treatment. An effective amount can be determined by a person of skill in the art using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for a subject, a number of factors are considered, including, but not limited to: the species of mammal; its size, age, and general health, the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

When used herein, the term “subject in need thereof’ refers to a mammal, preferably a human, with a disease or condition requiring treatment or therapy, including for example those listed in the preceding paragraphs. As used herein “EDTA” means

ethylenediaminetetraacetic acid. As used herein “DMSO” means dimethyl sulfoxide. As used herein “CPM” means counts per minute. As used herein “IBMX” means 3-isobutyl-1- methylxanthine. As used herein “LC/MS” means liquid chromatography/mass spectrometry.

As used herein “HTRF” means homogeneous time-resolved fluorescence. As used herein “BSA” mean bovine serum albumin.

The invention is further illustrated by the following examples, which are not to be construed as limiting.

PEPTIDE SYNTHESIS

Example 1

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

The structure of SEQ ID NO: 10 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, αMeL13, K17, Aib20,

D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:

The peptide backbone of Example 1 is synthesized using

Fluorenylmethyloxycarbonyi (Fmoc)/tert-Butyi (t-Bu) chemistry on a Symphony X peptide synthesizer (Gyros Protein Technologies. Tucson, AZ).

The resin consists of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHA Low Loading resin, 100-200 mesh, EMD Millipore) at a substitution of 0.3-0.4 meq/g. Standard side-chain protecting groups were used. Fmoc-Lys(Mtt)-OH is used for the lysine at position 17 and Boc-Tyr(tBu)-OH) was used for the tyrosine at position 1. Fmoc groups are removed prior to each coupling step (2 × 7 minutes) using 20% piperidine in DMF. All standard amino acid couplings are performed for 1 hour to a primary amine and 3 hour to a secondary amine, using an equal molar ratio of Fmoc amino acid (0.3 mM), diisopropylcarbodiimide (0.9 mM) and Oxyma (0.9 mM), at a 9-fold molar excess over the theoretical peptide loading.

Exceptions are couplings to C α-methylated amino acids, which are coupled for 3 hours.

After completion of the synthesis of the peptide backbone, the resin is thoroughly washed with DCM for 6 times to remove residual DMF. The Mtt protecting group on the lysine at position 17 is selectively removed from the peptide resin using two treatments of 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM (2 × 40-minute treatment).

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

After the synthesis is complete, the peptide resin is washed with DCM, and then thoroughly air-dried. The dry resin is treated with 10 mL of cleavage cocktail (trifluoroacetic acid: water: triisopropyl silane, 95:2.5:2.5 v/v) for 2 hours at room temperature. The resin is filtered off, washed twice each with 2 mL of neat TFA, and the combined filtrates are treated with 5-fold excess volume of cold diethyl ether (-20°C) to precipitate the crude peptide. The peptide/ether suspension is then centrifuged at 3500 rpm for 2 min to form a solid pellet, the supernatant is decanted, and the solid pellet is triturated with ether two additional times and dried in vacuo. The crude peptide is solubilized in 20% aeetonitrile/20% Acetic

acid/60% water and purified by RP- HPLC on a Luna 5 μm Phenyl-Hexyl preparative column (21 × 250 mm, Phenomenex) with linear gradients of 100% acetonitrile and 0.1% TF A/water buffer system (30-50% acetonitrile in 60 min). The purity of peptide is assessed using analytical RP-HPLC and pooling criteria is >95%. The main pool purity of compound 1 is found to be 98.0%. Subsequent lyophilization of the final main product pool yielded the

lyophilized peptide TFA salt. The molecular weight is determined by LC- MS (obsd: M+3 =1657.2; Calc M+3 =1657.0).

Example 2

Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2)16-CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2

(SEQ ID NO:11)

The structure of SEQ ID NO: 11 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20 D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO: 11 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC- MS (obsd: M+3 =1642.6: Calc M+3 =1642.8).

Example 3

Example 3 is a compound represented by the following description:

Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2

(SEQ ID NO: 12)

The structure of SEQ ID NO: 12 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been

expanded:

The compound according to SEQ ID NO: 12 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by EC- MS (ohsd: M+3 =1651.8; Calc M+3 =1652.2).

Example 4

Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH2 (SEQ ID NO: 13)

The structure of SEQ ID NO: 13 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24 αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO: 13 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC- MS (obsd: M+3 -1642.5; Calc M+3 -1642,1).

Example 5

Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H)AQ-Aib-EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH2 (SEQ ID NO: 14)

The structure of SEQ ID NO: 14 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, αMeLl3, Orn16, K17, Aib20, D-Glu24,αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO: 14 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by EC- MS (obsd: M+3 =1626.1: Calc M+3 =1626.1).

Example 6 through Example 287

The compounds according to Examples 6 (SEQ ID NO: 15) through Example 287 (SEQ ID NO:296) are prepared substantially as described by the procedures of Example 1 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)

The structure of SEQ ID NO:303 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO:303 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC- MS (obsd: M+3 =1602.5; Calc M+3 =1602.8).

Example 289

Y-Aib-EGTFTSDYSI-αMeL -LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)- CO-(CH2)18-CO2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO:304)

The structure of SEQ ID NO:304 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO:304 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC- MS (obsd: M+3 -1626.8; Calc M+3 -1626,8).

Example 290

(D-Tyr)-Aib-EGTFTSDYSI-αMeL -LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y- Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2 (SEQ ID NO:305)

The structure of SEQ ID NO:305 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyr1, Aib2, αMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO:305 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC- MS (obsd: M+3 =1626.6; Calc M+3 =1626.8).

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)-YLIAGGPSSGAPPPS-NH2 (SEQ ID

NO:306)

The structure of SEQ ID NO:306 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyrl, Aib2, αMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO:306 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by EC- MS (obsd: M+3 =1602.4; Calc M+3 =1602.8).

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)

The structure of SEQ ID NO:307 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyr1, Aib2, αMeL13, K17, Aib20, αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO:307 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC- MS (obsd: M+3 =1631.3; Calc M+3 =1631.5).

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-aMeY-LIAGGPSSGAPPPS-NH2

(SEQ ID NO:308)

The structure of SEQ ID NO:308 is depicted below using the standard single letter

amino acid codes with the exception of residues D-Tyrl, Aib2, αMeL13, Orn16, K17, Aib20, αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

The compound according to SEQ ID NO:308 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC- MS (obsd: M+3 =1626.5; Calc M+3 =1626.8).

WE CLAIM:

1. A compound of the formula:

R1X1X2X3GTX6TSDX10X11X12 X13 X14DX16X17AX19X20X21X22X23X24X25X26X27 X28X29X30X31 (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, 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);

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-(y-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-Ile, and K(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X13 is selected from the group consisting of Me, Aib, L, αMeL, and K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

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, Orn, Dab, Dap, S, T, H, Aib, aMeK, 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-(y-Glu)-CO-(CH2)qCO2H;

X20 is selected from the group consisting of Aib, Q, H, R, K, aMeK, 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 aMeF;

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 aMeY;

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:

X32 is S or K [(2-[2-(2-ami no-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];

X34is selected from the group consisting of G, C, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H];

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-ami no-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO- (CH2)q-CO2H];

X37 is P or K [(2-[2-(2-ami no-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO- (CH2)q-CO2H];

X38IS P or K [(2-[2-(2-ami no-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.

2. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 1 wherein X1 and X2 do not combine to form desH-Ψ[NHCO]-Aib.

3. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 1 or Claim 2 wherein X17 is an amino acid conjugated to a C16-C22 fatty acid.

4. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 3 wherein:

X1 is Y;

X2 is Aib;

X3 is E;

X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y;

X11 is S;

X12 is I;

X14 is L;

X16 is selected from the group consisting of K, E, Orn, Dab, and Dap;

X17 is K conjugated to a C16-C22 fatty acid wherein said fatty acid is conjugated to K via a linker;

X19 is Q;

X20 is Aib;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E;

X22 is F;

X23 is I;

X24 is selected from the group consisting of S, Aad, D-Glu, and E;

X26 is L;

X27 is selected from the group consisting of L and I; and

X28 is selected from the group consisting of E and A.

5. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 4 wherein:

X30 is G and X3 is PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P and X39 is S (SEQ ID NO:298).

6. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1, 2 or 5 wherein X17 is K.

7. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 4 wherein the linker comprises one to two amino acids.

8. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 7 wherein the linker comprises from one to two (2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl) moieties.

9. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 8 wherein the linker comprises one to two amino acids independently selected from the group consisting of Glu and γ-Glu.

10. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 9 wherein the linker has the following formula:

{(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(γ-Glu)b, wherein a is 1 or 2; and b is 1 or 2.

11. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 10 wherein X17 is K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(γ- Glu)b-CO-(CH2)q-CO2H, wherein: a is 1 or 2; b is 1 or 2; and q is selected from the group consisting of 14 to 20.

12. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 11 wherein a is 1.

13. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 11 wherein a is 2.

14. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 11 to 13 wherein b is 1.

15. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 11 to 13 wherein b is 2.

16. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 11 to 15 wherein q is 18.

17. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 11 to 15 wherein q is 16.

18. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 11 wherein X17 is K(2-[2-(2-amino-ethoxy)-ethoxy] -acetyl)2-(γ-Glu)- CO-(CH2)q-CO2H.

19. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 18 wherein X27 is I.

20. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 18 wherein X27 is L.

21. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 19 wherein;

R1 is absent;

X1 is Y;

X2 is Aib;

X3 is E;

X6 is αMeF(2F);

X10 is selected from the group consisting of Y, 4-Pal, and V;

X11 is S,

X12 is I;

X13 is selected from the group consisting of L, Aib, and αMeL;

X14 is L;

X16 is selected from the group consisting of E, K, and Orn;

X17 is K;

X19 is Q;

X20 is Aib

X21 is selected from the group consisting of E, A, and T;

X22 is F,

X23 is I;

X24 is D-Glu;

X26 is L;

X27 is I;

X28 is E;

X29 is G;

X30 is G; and

X31 is P X32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5). wherein X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P and X39 is S (SEQ ID NO:298).

22. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 21 wherein X25 is Y.

23. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 22 wherein X13 is αMeL.

24. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 23 wherein X16 is Orn.

25. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 23 wherein X16 is E.

26. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 25 wherein X10 is Y.

27. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 25 wherein X10 is V.

28. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 25 wherein X10 is 4Pal.

29. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 11 wherein X13 is αMeL; a is 2; b is 1; q is 16; and X25 is Y.

30. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 11 wherein X13 is αMeL; a is 2; b is 1; q is 18; and X25 is Y.

31. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 11 wherein X13 is αMeL; a is 2; b is 1; q is 14; and X25 is Y.

32. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 24 wherein X10 is Y; and X16 is Orn.

33. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 23 wherein X10 is Y; and X16 is E.

34. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 23 wherein X10 is 4Pal; and X16 is Orn.

35. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of claims 1 to 23 wherein X10 is V; and X16 is Orn.

36. A compound as claimed by Claim 1 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, or a pharmaceutically acceptable salt thereof.

37. A compound as claimed by Claim 36 wherein the compound is SEQ ID NO: 13, or a pharmaceutically acceptable salt thereof.

38. A compound as claimed by Claim 36 wherein the compound is SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof.

39. A compound, or a pharmaceutically acceptable salt thereof as claimed by Claim 1 wherein:

X10 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;

X12 is selected from the group consisting of I, D-Ile, and S;

X13 is selected from the group consisting of Me, Aib, L, and αMeL;

X14 is L;

X16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, aMeK, and R;

X17 is selected from the group consisting of K, Q, and I;

X19 is selected from the group consisting of Q and A;

X20 is selected from the group consisting of Aib, Q, H, R, K, and αMeK;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, and I;

X23 is selected from the group consisting of I, L, A, G, F, H, E, and V;

X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, and P;

X26 is selected from the group consisting of L and αMeL;

X27 is selected from the group consisting of L and I;

X28 is selected from the group consisting of E, A, S, and D-Glu; and

X29 is selected from the group consisting of Aib, G, and A.

40. A compound, or a pharmaceutically acceptable salt thereof as claimed by Claim 39 wherein:

X1 is Y;

X2 is Aib;

X3 is E;

X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, and Y;

X11 is S;

X12 is I;

X16 is selected from the group consisting of K, E, Orn, Dab, and Dap;

X19 is Q;

X20 is selected from the group consisting of Aib and K;

X21 is selected from the group consisting of H, Aad, D, Aib, T, A, and E;

X22 is F;

X23 is I;

X24 is selected from the group consisting of S, Aad, D-Glu, and E;

X26 is L; and

X28 is selected from the group consisting of E and A.

41. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 39 or 40 wherein one of X30, X34, and X39 is C.

42. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 41 wherein the compound is modified using time-extension technology.

43. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 39 to 42 wherein q is 18.

44. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 39 to 42 wherein q is 16.

45. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 39 to 44 wherein X27 is L.

46. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 39 to 45 wherein X3 is PX32X33X34X35X36X37X38X39-R2.

47. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 39 to 45 wherein X3 is absent.

48. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 47 wherein R2 is NH2.

49. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 1 wherein:

X14 is L;

X17 is selected from the group consisting of K, Q, and I;

X30 is selected from the group consisting of G-R2 and G; and

q is selected from the group consisting of 16, 18, and 20;

wherein if X30 is G, then X31 is selected from the group consisting of:

PX32X33X34-R2 (SEQ ID NO:4), wherein:

X32 is S, X33 is S, X34 is G and R2 is absent (SEQ ID NO:299) or X32 is S, X33 is S, X34 is G and R2 is NH2 (SEQ ID NO:300);

and

PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), wherein:

X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P, X39 is S and R2 is absent (SEQ ID NO:301) or

X32 is S, X33 is S, X34 is G, X35 is A, X36 is P, X37 is P, X38 is P, X39 is S and R2 is NH2 (SEQ ID NO:302); and

wherein one of X10, X12, X13, X14, X16, X19, X20, X21, X23, X24, X26, X27, X28, and X29 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-YGlu-CO-(CH2)qCO2H.

A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 49 wherein:

X1 is Y;

X2 is Aib;

X3 is E;

X10 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;

X11 is S;

X12 is selected from the group consisting of I, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X14 is selected from the group consisting of L and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X16 is selected from the group consisting of K, E, Om, Dab, Dap, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X17 is selected from the group consisting of K and I;

X19 is selected from the group consisting of Q and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X20 is selected from the group consisting of Aib 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, and K(2-[2- (2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X22 is F;

X23 is I;

X24 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;

X26 is selected from the group consisting of L, and K(2-[2-(2-amino-ethoxy)- ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H;

X27 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;

X30 is G; and

X31 is selected from the group consisting of PX32X33X34-R2 (SEQ ID NO:4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 5),

X32 is S;

X33 is S;

X34 is G;

X35 is A;

X36 is P;

X37 is P;

X38 is P; and

X39 is S.

51. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 49 to 50 wherein X20 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ- Glu)-CO-(CH2)q-CO2H.

52. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 49 to 51 wherein PX32X33X34X35X36X37X38X39-R2 is selected from the group consisting of PSSGAPPPS (SEQ ID NO:301) and PSSGAPPPS-NH2 (SEQ ID NO:302).

53. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 49 to 52 wherein q is 18.

54. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 49 to 52 wherein q is 16.

55. A compound, or a pharmaceutically acceptable salt thereof, as claimed by Claim 1 wherein :

X1 is selected from the group consisting of Y, F, D-Tyr, and desY,

X6 is F; and

X13 is selected from the group consisting of Aib, L, and αMeL.

56. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim 55 wherein

R1 is absent;

X2 is Aib;

X3 is E;

X10 is Y;

X11 is S;

X12 is I;

X14 is L;

X16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R

X17 is 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 Q;

X20 is selected from the group consisting of Aib, Q, H, and K;

X21 is selected from the group consisting of H, D, T, A, and E;

X22 is F;

X23 is I;

X24 is selected from the group consisting of D-Glu and E;

X26 is L;

X27 is I;

X28 is selected from the group consisting of E, A, S, and D-Glu;

X29 is selected from the group consisting of Aib, G, and A;

X30 is selected from the group consisting of C, G, and G-R2;

X31 is absent or is selected from the group consisting of PX37X33X34-R2 (SEQ ID NO:4), PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5), and PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO:6); wherein:

X32 is S;

X33 is S;

X34 is selected from the group consisting of G and C;

X35 is A;

X36 is P;

X37 is P;

X38 is P;

X39 is selected from the group consisting of C and S; and

X40 is C.

57. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 55 to 56 wherein X17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ- Glu)-CO-(CH2)q-CO2H.

58. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 55 to 57 wherein PX32X33X34X35X36X37X38X39 -R2 is selected from the group consisting of PSSGAPPPS (SEQ ID NO:301) and PSSGAPPPS-NH2 (SEQ ID NO:302).

59. A compound, or pharmaceutically acceptable salt thereof, as claimed by any one of Claims 55 to 58 wherein

X28 is A;

X29 G;

X30 is G;

X31 is PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO:5)

X34 is G; and

X39 is S.

60. A compound, or pharmaceutically acceptable salt thereof, as claimed by any one of Claims 55 to 59 wherein

X1 is selected from the group consisting of Y and D-Tyr; and X13 is αMeL.

61. A compound, or pharmaceutically acceptable salt thereof, as claimed by any one of Claims 55 to 60 wherein q is 16.

62. A compound, or pharmaceutically acceptable salt thereof, as claimed by any one of Claims 55 to 60 wherein q is 18.

63. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim 1 w'herein 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 NQ:308, and SEQ ID NO:392.

64. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim 63 wherien the compound is SEQ ID NO:305.

65. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim 63 wherien the compound is SEQ ID NO:307.

66. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim 63 wherien the compound is SEQ ID NO:308.

67. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim 63 wherien the compound is SEQ ID NO:392.

68. A compound, or pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 67 wherein the compound is a partial agonist on the GLP-1R.

69. A compound, or pharmaceutically acceptable salt thereof, as claimed by Claim 68 wherein the compound stimulates GLP-1R induced activation of Gas in the GIPR and GLP-1RHEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPγS) Binding Assay.

70. A compound, or pharmaceutically acceptable salt thereof, as claimed by any one of Claims 68 or 69 w'herein the compound is a partial agonist on the GLP-1R with respect to the f-arrcstin-2 recruitment assay.

71. A method for treating a condition selected from the group consisting of type 2 diabetes mellitus, obesity, NAFLD, nonalcoholic steatohepatitis, dyslipidemia, and metabolic syndrome, comprising administering to a patient in need thereof, an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70.

72. A method for treating obesity, comprising administering to a patient in need thereof, an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70.

73. A method for providing therapeutic weight loss, comprising administering to a subject in need thereof, an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70.

74. A method for treating type 2 diabetes mellitus comprising administering to a subject in need thereof, an effective amount of the compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70.

75. A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70 and at least one pharmaceutically acceptable carrier, diluent, or excipient.

76. A pharmaceutical composition as claimed by Claim 75 wherein the composition is administered as a subcutaneous injection.

77. A pharmaceutical composition as claimed by Claim 75 wherein the composition is administered orally.

78. A pharmaceutical composition as claimed by Claim 77 wherein the composition comprises a permeation enhancer and at least one pharmaceutically acceptable carrier, diluent, or excipient.

79. A pharmaceutical composition as claimed by Claim 78 wherein the permeation enhancer is selected from the group consisting of sodium decanoate (“C10”), sodium taurodeoxycholate (“NaTDC”), lauroyl carnitine (“LC”), dodecyl maltoside (“C12-maltoside”), dodecyl phosphatidylcholine (“DPC”), sodium taurodeoxycholate (“NaTDC”), and a Rhamnolipid.

80. A pharmaceutical composition as claimed by Claim 79 wherein the permeation enhancer is selected from the group consisting of C10 and LC.

81. A pharmaceutical composition as claimed by Claim 80 wherein the permeation enhancer is C10.

82. A pharmaceutical composition as claimed by any one of Claims 77 to 81 wherein the composition comprises a permeation enhancer and a protease inhibitor, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

83. A pharmaceutical composition as claimed by Claim 82 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. A pharmaceutical composition a claimed by Claim 83 wherein the protease inhibitor is selected from the group consisting of SBTI, SBTICI, and SFTI.

85. A pharmaceutical composition as claimed by Claim 84 wherein the protease inhibitor is SBTI

86. A pharmaceutical composition as claimed by any one of Claims 77 to 85 wherein the composition is a monolithic formulation.

87. A pharmaceutical composition as claimed by any one of Claims 77 to 85 wherein the composition is a multiparticulate formulation.

88. A pharmaceutical composition as claimed by any one of Claims 77 to 85 wherein the composition is a capsule or tablet.

89. A pharmaceutical composition as claimed by Claim 86 wherein the composition is an enteric capsule or tablet.

90. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70 for use as a medicament.

91. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70 for use in treating a disease selected from the group consisting of treating type 2 diabetes mellitus, obesity, NAFLD, NASH, dyslipidemia and metabolic syndrome.

92. A compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70 for use in treating treating type 2 diabetes mellitus.

93. The use of a compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70 in the manufacture of a medicament for treating a condition selected from the group consisting of type 2 diabetes mellitus, obesity, NAFLD, NASH, dyslipidemia and metabolic syndrome.

94. The use of a compound, or a pharmaceutically acceptable salt thereof, as claimed by any one of Claims 1 to 70 in the manufacture of a medicament for treating type 2 diabetes mellitus.

95. A method for treating diabetes comprising administering an effective amount of a compound showing partial agonism of 75% or less in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPyS) Binding Assay, and an effective amount of a compound that is a GIP agonist.

96. A method as claimed by Claim 95 wherein the diabetes is type 2 diabetes.

97. A method as claimed by any one of Claims 95 or 96 wherein a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma- thio) Triphosphate-[35S] (GTPyS) Binding Assay is co-administered with a compound having GIP agonist activity.

98. A method as claimed by any one of Claims 95 to 97 wherein a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma- thio) Triphosphate-[35S] (GTPyS) Binding Assay is co-administered with a compound of a compound showing 35% or less in the GLP-CHO Cell β- Arrestin. Recruitment Assay.

99. A method as claimed by any one of Claims 95 to 98 wherein a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma- thio) Triphosphate-[35S] (GTPyS) Binding Assay is administered as an active agent within one week before or after a compound having GIP agonist activity.

100. A method as claimed by any one of Claims 95 to 98 wherein a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma- thio) Triphosphate-[35S] (GTPyS) Binding Assay is administered as an active agent within one week before or after a compound having GIP agonism and showing showing 35% or less in the GLP-CHO Cell β-Arrestin. Recruitment Assay.