Difluorolactam compositions for ep4-mediated osteo related diseases and conditions

A method of treating osteoporosis, bone fracture, bone loss, or increasing bone density comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (Ia)

• or a pharmaceutically acceptable salt thereof, wherein:
• L1 is
• a) C3-C7alkylene, C3-C7alkenylene, or C3-C7alkynylene, wherein the C3-C7alkylene, C3-C7alkenylene, or C3-C7alkynylene are each optionally substituted with 1, 2, 3, or 4 fluoro substituents;
• b) —(CH2)t-G-(CH2)p—;
• wherein t is 0, 1, or 2, p is 0, 1, 2, or 3, and t+p=0, 1, 2, 3, or 4;
• or
• c) —(CH2)n-G1-(CH2)p—, —(CH2)n-G2-(CH2)p—, —(CH2)n—C≡C-G2-, or —(CH2)n—C(R13)═C(R3)-G2-, wherein n is 1, 2, 3, 4, or 5, p is 0, 1, 2, or 3, and n+p=1, 2, 3, 4, 5, or 6;
• G is
• G1 is O, C(O), S, S(O), S(O)2, or NR8;
• wherein R8 is H, C1-C4 alkyl, or C1-C4alkylcarbonyl;
• G2 is
• wherein G2 is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C1-C4alkyl, C1-C3haloalkyl, cyano, halogen, C1-C3alkoxy, and C1-C3haloalkoxy;
• R1 is COOR10, CONR10R11, CH2OR10, SO3R10, SO2NR10R11, PO(OR10)2, or tetrazol-5-yl;
• R10 is H, C1-C4 alkyl, or aryl;
• R11 is H, C1-C4 alkyl, COR12, OR10, or SO2R12;
• R12 is C1-C4 alkyl;
• R13, at each occurrence, is independently H or C1-C4alkyl;
• L4 is —C(R2)2—C(R3)2—, —C(R2)═C(R3)—, —C≡C—, or
• wherein R2 and R3 are each H, CH3, fluoro, or choro;
• L2 is —CH2— or a bond;
• R4 and R5 are each independently H, F, CF3, or C1-C4 alkyl;
• or R4 and R5 together with the carbon to which they are attached form a C3-C5cycloalkyl,
• R6 is aryl, heteroaryl, C3-C10alkyl, C3-C10alkenyl, C3-C10alkynyl, C3-C10haloalkyl, C3-C10haloalkenyl, C3-C10haloalkynyl, or L3-R7;
• wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C4alkyl, C1-C3haloalkyl, cyano, halogen, C1-C3alkoxy, C1-C3haloalkoxy;
• and —C1-C3alkylene-C1-C3alkoxy;
• and wherein the C3-C10alkyl, C3-C10alkenyl, C3-C10alkynyl, C3-C10haloalkyl, C3-C10haloalkenyl, and C3-C10haloalkynyl are optionally substituted with a substituent selected from the group consisting of COOR10′, CONR10′R11′, CH2OR10′, SO3R10′, SO2NR10′R11′, PO(OR10′)2, and tetrazol-5-yl;
• R10′ is H, C1-C4 alkyl, or aryl;
• R11′ is H, C1-C4 alkyl, COR12′, OR10′, or SO2R12′;
• R12′ is C1-C4 alkyl;
• L3 is C1-C6alkylene, C2-C6alkenylene, C2-C6alkynylene, —(CH2)m-G3-(CH2)q—, —(CH2)m-G4-(CH2)q—, or -G5-C≡C—;
• wherein the C1-C6alkylene, C2-C6alkenylene, and C2-C6alkynylene are optionally substituted with 1, 2, 3, or 4 fluoro substituents;
• and wherein m and q are each independently 0, 1, 2, or 3 and m+q=0, 1, 2, 3, or 4;
• G3 is O, C(O), S, S(O), S(O)2, or NR9;
• wherein R9 is H, C1-C4 alkyl, or C1-C4alkylcarbonyl;
• G4 is
• wherein G4 is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C1-C4alkyl, C1-C3haloalkyl, cyano, halogen, C1-C3alkoxy, and C1-C3haloalkoxy;
• G5 is
• wherein G5 is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C1-C4alkyl, C1-C3haloalkyl, cyano, halogen, C1-C3alkoxy, and C1-C3haloalkoxy;
• R7 is C3-C8cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• wherein R7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C1-C4alkyl, C1-C3haloalkyl, cyano, halogen, C1-C3alkoxy, C1-C3haloalkoxy, and —C1-C3alkylene-C1-C3alkoxy;
• r is 0 or 1;
• and
• s is 0 or 1.