Triazole derivatives and their use as PDE4 activators

A method of lowering excessive intracellular cyclic AMP signaling comprising administering to a patient signalling, comprising administering to a patient in need thereof an effective amount of a compound of Formula 1:

• wherein
• R1 is selected from H, (C1-4)alkyl and (C1-4)alkyloxy, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros;
• R2 and R6 are independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros;
• R3, R4 and R5 are independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkylsulfonyl, C(O)-NR16R17, C(O)-OR16, S(O)2-NR16R17, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros;
• R7, R8, R10 and R11 are independently selected from H and F;
• R9 is selected from H, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkylsulfonyl, C(O)-NR16R17, C(O)-OR16, S(O)2-NR16R17, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros;
• R12, R13, R14 and R15 are independently selected from H and (C1-4)alkyl;
• each R16 and R17, when present, is independently selected from H and (C1-4)alkyl;
• or a pharmaceutically acceptable salt thereof, wherein the patient has a disease selected from the group consisting of:
• a. pituitary adenoma, Cushing's disease, polycystic kidney disease or polycystic liver disease;
• b. hyperthyroidism, Jansens's metaphyseal chondrodysplasia, hyperparathyroidism, or familial male-limited precocious puberty;
• c. McCune-Albright syndrome;
• d. cholera, whooping cough, anthrax, or tuberculosis;
• e. HIV, AIDS, or Common Variable Immunodeficiency (CVID);
• f. melanoma, pancreatic cancer, leukaemia, prostate cancer, adrenocortical tumours, testicular cancer, primary pigmented nodular adrenocortical diseases (PPNAD), or Carney Complex;
• g. autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD);
• h. maturity onset diabetes of young type 5 (MODY5);
• or
• i. cardiac hypertrophy.

A method of activating long isoforms of PDE4 comprising administering to a subject an effective amount of a compound of Formula 2:

• wherein
• R1 is H, (C1-6)alkyl and (C3-7)cycloalkyl, the (C1-6)alkyl and (C3-7)cycloalkyl groups being optionally substituted with 1 to 3 substituents selected from OH, (C1-4)alkyloxy, (C1-4)alkyl-sulfonyl, C(O)-NR16R17, C(O)-OR16, S(O)2-NR16R17, CN and halogen;
• R2 and R6 are independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros;
• R3, R4 and R5 are independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkylsulfonyl, C(O)-NR16R17, C(O)-OR16, S(O)2-NR16R17, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros;
• R7, R8, R10 and R11 are independently selected from H and F;
• R9 is selected from H, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkylsulfonyl, C(O)-NR16R17, C(O)-OR16, S(O)2-NR16R17, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros;
• R12, R13, R14 and R15 are independently selected from H and (C1-4)alkyl;
• each R16 and R17, when present, is independently selected from H and (C1-4)alkyl;
• or a pharmaceutically acceptable salt thereof.