Macrocyclic glucagon-like peptide 1 receptor agonists

A compound of the formula:

• wherein -A- is —CRaRbCRaRbCRbRbO—, —OCRbRb CRaRbCRaRb—, —OCRb Rb CRbRbO—, —CRaRbCRbRbOCRbRb—, —CRbRbOCRbRbCRaRb—, —CR bRbOCRbRb—, —CRaRbCRbRbO— or —OCRbRbCRaRb—;
• Ra at each occurrence is independently H, halo, C1-C2 alkyl, OH or C1-C3alkoxy;
• Rb at each occurrence is independently H, halo or C1-C2alkyl;
• is
• wherein a is the point of attachment to linker A;
• b is the point of attachment of linker B;
• X1, X2, X3 and X4 are independently N, CH or CR1, wherein no more than two of X1, X2, X3 and X4 are N and no more than two of X1, X2, X3 and X4 are CR1;
• X5 is N, CH or CR1a, X6, X7 and X8 are independently N, CH or CR1, wherein no more than two of X5, X6, X7 and X8 are N and no more than two of X5, X6, X7 and X8 are CR1a or CR1;
• R1 at each occurrence is independently CN;
• halo;
• C1-C3alkyl optionally substituted with OH;
• C1-C3haloalkyl;
• C1-C3alkoxy;
• C3-C5cycloalkyl;
• —SO2C1-C3alkyl;
• wherein each X9 is independently CH or N and no more than one X9 in the ring is N, each Re is independently selected from:
• H, C1-C3haloalkyl, halo, C3-C5cycloalkyl and C1-C3alkyl optionally substituted with OH, Rh is H, C1-C3haloalkyl, halo, C3-C5cycloalkyl, OH, —NRcRd or C1-C3alkyl optionally substituted with OH;
• 5- or 6-membered heteroaryl or phenyl wherein the heteroaryl or phenyl is optionally substituted with one or two substituents independently selected from:
• C1-C3alkoxy, C3-C5cycloalkyl, —CH2—C3-C5cycloalkyl, —SO2C1-C3alkyl, C4-C5heterocyclyl, —CH2—C4-C5heterocyclyl, halo, C1-C3haloalkyl, C1-C3haloalkoxy, CN, —CONRcRd, —NRcRd or C1-C3alkyl optionally substituted with OH;
• R1a is CN;
• halo;
• C1-C3alkyl optionally substituted with OH;
• C1-C3haloalkyl;
• or C1-C3alkoxy;
• —B- is —CH2O—, —OCH2— or —CH2NH—;
• Y1, Y2 and Y7 are independently N, CH or CR2, wherein no more than one of Y1, Y2 and Y7 is N and no more than two of Y1, Y2 and Y7 is CR2;
• Y3, Y4, Y5 and Y6 are independently N, CH or CR2, wherein no more than two of Y3, Y4, Y5 and Y6 are N and no more than two of Y3, Y4, Y5 and Y6 are CR2;
• R2 at each occurrence is independently halo or methyl;
• Z1, Z2 and Z3 are independently N, CH or CR3, wherein no more than two of Z1, Z2 and Z3 are N and no more than two of Z1, Z2 and Z3 are CR3;
• R3 at each occurrence is independently halo;
• C1-C4alkyl;
• —OC4-C6cycloalkyl optionally substituted with C1-C2alkoxy, OH, C1-C3alkyl or C1-C3haloalkyl;
• —OC4-C6heterocyclyl optionally substituted with C1-C2alkoxy, OH, C1-C3alkyl or C1-C3haloalkyl;
• or C1-C4alkoxy optionally substituted with one or two substituents selected from:
• C1-C2alkoxy, OH, —NRf Rg, —CONRcRd, CN, halo or 5- or 6-membered heteroaryl optionally substituted with C1-C3alkyl;
• R4 is
• R5 is —CO2H,
• Rc and Rd are each independently H or C1-C3alkyl;
• Rf is H or C1-C3alkyl;
• and
• Rg is H, C1-C3alkyl, C1-C3haloalkyl, C3-C5cycloalkyl, C(O)C1-C3alkyl, or C1-C3alkylC3-C5cycloalkyl;
• or a pharmaceutically acceptable salt thereof.