| 主权项 |
1. A method for treating a disease or disorder selected from the group consisting of type II diabetes, atherosclerosis, obesity, non-alcoholic fatty liver disease, diseases and disorders linked to elevated ceramide levels in a subject, diseases and disorders in which cell proliferation is deficient or desired in a subject, disorders of aging, disorders of mitochondrial function, muscular dystrophic states, neurological disorders associated with reduced mitochondrial function, oxidative stress or both, hypoxic states, angina pectoris, coronary ischemia and organ damage secondary to coronary vessel occlusion, intermittent claudication, multi-infarct dementia, myocardial infarction, stroke, high altitude sickness and heart failure, including congestive heart failure ischemia, ischemic reperfusion injury, myocardial ischemia or infarction, cerebrovascular accidents, operative ischemia, traumatic hemorrhage, resuscitation injury, spinal cord trauma, inflammatory diseases, Down's syndrome, Hallervorden-Spatz disease, Huntingtons chorea, Wilson's disease, diabetic angiopathy, uveitis, chronic obstructive pulmonary disease (COPD), asthma, neoplasia, Crohn's disease, inflammatory bowel disease, pancreatitis and age-related disorders, or for activating the AMPK pathway, up-regulating ceramidase activity, reducing triglyceride levels, increasing insulin sensitivity, increasing metabolic efficiency, increasing fiber oxidative capacity, increasing endurance, increasing aerobic workload, reducing oxidative stress, reducing free radical damage, reducing organ inflammation, mimicking the effects of exercise, retarding cellular responses associated with the activation of the ceramide-mediated signal transduction pathway, reducing the effect of aging on the skin, treating radiation and dermatitis in the skin in a subject, the method comprising administering to the subject an effective amount of a compound having the structural formulaor a pharmaceutically acceptable salt- or N-oxide thereof, wherein
R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl); G is —CH2—, —C(O)—, —S(O)2—, —CH(CH3)—, —C(CH3)2—, —O—, —C(O)—NH—, —C(O)—NH—CH2—, —CH2CH2—, a single bond, —OCH2—, CH2CH2O—, —CH(COOMe)- or —CH(COOEt)-; R17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —N3, —SF5, —NO2 and —CN; each R3 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN; w is 0, 1, 2 or 3; each R4 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R4 on the same carbon optionally combine to form oxo, and two R4 on different carbons optionally combine to form a —(C0-C4 alkylene)- bridge; x is 0, 1, 2, 3 or 4; J is absent, —C(O)—, —NR13—, —NR13C(O)— or —C(O)NR13—, in which R13 is selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl); the ring system denoted by “B” is absent, arylene, heteroarylenewherein each of Y1 and Y2 is N, C or CH, provided that at least one of Y1 and Y2 is N; p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6, orwherein Y1 is N or C and Y2 is N, C or CH, provided that at least one of Y1 and Y2 is N, the ring system denoted by “C” is an arylene or a heteroarylene, p is 0, 1, 2, 3 or 4, q is 1, 2, 3 or 4, and the sum of p and q is 1, 2, 3, 4, 5 or 6;
Q is a single bond, —CH2—, —CH2O—, —OCH2CH2—, —CH2CH2—, —O—, —CHF—, —CH(CH3)—, —C(CH3)2—, —CH(OH)—, —CH(COOMe)-, —CH(COOEt)-, —C(O)— or —S(O)2—; the ring system denoted by “A” is heteroaryl or aryl; each R5 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-L-R7, —(C0-C6 alkyl)-NR8R9, —(C0-C6 alkyl)-OR10, —(C0-C6 alkyl)-C(O)R10, —(C0-C6 alkyl)-S(O)0-2R10, -halogen, —N3, —SF5, —NO2 and —CN; and y is 0, 1, 2, 3 or 4; in which
each L is independently selected from —NR9C(O)O—, —OC(O)NR9—, —NR9C(O)—NR9—, —NR9C(O)S—, —SC(O)NR9—, —NR9C(O)—, —C(O)—NR9—, —NR9C(S)O—, —OC(S)NR9—, —NR9C(S)—NR9—, —NR9C(S)S—, —SC(S)NR9—, —NR9C(S)—, —C(S)NR9—, —SC(O)NR9—, —NR9C(S)—, —S(O)0-2—, —C(O)O, —OC(O)—, —C(S)O—, —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—, —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9— and —NR9SO2NR9—,each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl), —(C1-C2 haloalkyl), —(C0-C2 alkyl)-L-(C0-C2 alkyl), —(C0-C2 alkyl)-NR9(C0-C2 alkyl), —(C0-C2 alkyl)-O—(C0-C2 alkyl), —(C0-C2 alkyl)-C(O)—(C0-C2 alkyl) and —(C0-C2 alkyl)-S(O)0-2—(C0-C2 alkyl), andeach R9 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl). |
