Azepinoindole derivatives as pharmaceutical agents

A method of reducing plasma cholesterol or triglyceride levels, or of treating, or ameliorating one or more symptoms of a disease or disorder in which nuclear receptor activity is implicated, wherein the disease or disorder is selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease, coronary heart disease, cerebrovascular disorder, intermittent claudication, atherosclerotic cardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity, hyperglycemia, cholestasis and obesity, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

• or a pharmaceutically acceptable derivative selected from the group consisting of salts, esters, enolether, enolesters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, and hydrates thereof;
• wherein:
• R1 is —C(J)OR14, —C(J)SR14 and —C(J)N(R15)R16;
• J is O, S or NR17;
• R2 is hydrogen, halo or optionally substituted alkyl;
• R3 is —C(O)R9;
• R4, R5, R6 and R7 are together selected from a), b), c), d), e) or f) below:
• a) R4 and R5 are each independently selected from hydrogen or halo;
• and R6 and R7 are each independently selected from a group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21—OC(J)R10,
• —R21—N(R25)C(J)R10, and —R21—SC(J)R10;
• or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted cycloalkenyl ring, optionally substituted alkylidene, optionally substituted cycloalkylidene, optionally substituted heterocyclylidene, optionally substituted aralkylidene or an optionally substituted heteroaralkylidene;
• b) R4 and R5 are each independently selected from a group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21—N(R25)C(J)R10 and —R21—SC(J)R10;
• or R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, an optionally substituted cycloalkenyl ring, an optionally substituted alkylidene, optionally substituted cycloalkylidene, optionally substituted heterocyclylidene, optionally substituted aralkylidene or an optionally substituted heteroaralkylidene;
• and R6 and R7 is are each independently selected from hydrogen or halo;
• or
• c) R4 and R6 are each independently selected from hydrogen or halo;
• and R5 and R7 are each independently selected from a group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21—OC(J)R10,
• —R21—N(R25)C(J)R10 and —R21—SC(J)R10;
• d) R4 is hydrogen or halo;
• R5 is selected from a group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21—OC(J)R10, —R21—N(R25)C(J)R10 and —R21—SC(J)R10;
• and R6 and R7 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21OC(J)R10, —R21—N(R25)C(J)R10 and —R21—SC(J)R10;
• or
• R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted cycloalkenyl ring, optionally substituted alkylidene, optionally substituted cycloalkylidene, optionally substituted heterocyclylidene, optionally substituted aralkylidene or an optionally substituted heteroaralkylidene;
• e) R4 and R5 are each independently selected from a group consisting of hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21OC(J)R10, —R21—N(R25)C(J)R10 and —R21—SC(J)R10;
• or R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted cycloalkenyl ring, optionally substituted alkylidene, optionally substituted cycloalkylidene, optionally substituted heterocyclylidene, optionally substituted aralkylidene or an optionally substituted heteroaralkylidene;
• R6 is hydrogen or halo;
• and R7 is selected from a group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21—OC(J)R10,
• —R21—N(R25)C(J)R10 and —R21—SC(J)R10;
• f) R4 and R5 are each independently selected from a group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21—OC(J)R10, —R21—N(R25)C(J)R10 and —R21—SC(J)R10;
• or R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, an optionally substituted cycloalkenyl ring, an optionally substituted alkylidene, optionally substituted cycloalkylidene, optionally substituted heterocyclylidene, optionally substituted aralkylidene or an optionally substituted heteroaralkylidene;
• and R6 and R7 are each independently selected from a group consisting of halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —C(J)R10, —R21—OC(J)R10,
• —R21—N(R25)C(J)R10, and —R21—SC(J)R10;
• or R6 and R7, together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted cycloalkenyl ring, optionally substituted alkylidene, optionally substituted cycloalkylidene, optionally substituted heterocyclylidene, optionally substituted aralkylidene or an optionally substituted heteroaralkylidene;
• R8a, R8b, R8c and R8d are each independently selected from the group consisting of hydrogen, halo, pseudohalo, azido, amidino, guanidino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —R21—OR22,
• —R21—SR22, —R2l—N(R23)(R24), —R21—C(J)R22, —R21, —C(J)OR22, —R21—C(J)SR22, —R21—C(J)N(R23)(R24),—R21—N(R25)S(O)2R26 and —R21—S(O)2N(R23)(R24);
• R9 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
• each R10 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR11, —SR11 and —N(R12)(R13);
• each RH is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• R12 and R13 are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;
• or R12 and R13, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
• each R14 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR18, —SR18 and —N(R19)(R20);
• R15 and R16 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —OR18, —SR18 and —N(R19)(R20);
• or R15 and R16, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;
• R17 is hydrogen, optionally substituted alkyl, optionally substituted substituted alkenyl or optionally substituted alkynyl;
• each R18 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
• R19 and R20 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;
• or
• R19 and R20, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
• each R21 is independently a direct bond or an alkylene;
• each R22 independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —R21—OR32, —R21—SR32, —R21—N(R33)(R34);
• —R21—C(J)R32, R21—C(J)OR32, —R21C(J)SR32 and-R21—C(J)N(R33)(R34);
• each R23 and R24 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, —R21—OR32, —R21—SR32,
• —R21—N(R33)(R34), —R21—C(J)R32, —R21—C(J)OR32, —R21—C(J)SR32, and
• —R21 —C(J)N(R33)(R34);
• or R23 and R24, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
• each R25 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• each R26 is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• each R32 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• and
• R33 and R34 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl;
• or
• R33 and R34, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
• and at least one additional active agent(s) selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, melinamide, probucol, raloxifene, nicotinic acid, niacinamide, β-sitosterol, cholestyramine, colestipol, clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemfibrozil, vitamin B6, vitamin B12, vitamin C, vitamin E, chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glimepiride, glipizide, metformin, ciglitazone, pioglitazone, troglitazone, rosiglitazone, dehydroepiandrosterone, acarbose, miglitol, voglibose, pramlintide, amylin, insulin, phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, sibutramine, orlistat, neuropeptide Y, enterostatin, cholecytokinin, bombesin, galanin or gamma amino butyric acid (GABA), and aspirin.