IP Library › Granted Patent US 8,524,704

Granted Patent B2

US 8,524,704 · App. 12/535,453 · Granted Sep 3, 2013

Azepinoindole derivatives as pharmaceutical agents

Inventors: Brett Busch (San Diego, CA); Brenton T. Flatt (Poway, CA); Xiao-Hui Gu (Rockville, MD); Richard Martin (San Diego, CA); Raju Mohan (Encinitas, CA); Tie-Lin Wang (San Diego, CA); Jason H. Wu (San Diego, CA)

Assignee: Exelixis, Inc.

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Quick Facts

Patent No.: US 8,524,704
App. No.: 12/535,453
Granted: Sep 3, 2013
Kind: B2

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Abstract

Compounds, compositions and methods for modulating the activity of receptors are provided. In particular, compounds and compositions are provided for modulating the activity of receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder directly or indirectly related to the activity of the receptors.

Claims (142)

1. A composition comprising 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:

R 1 is —C(J)OR 14 , —C(J)SR 14 and —C(J)N(R 15 )R 16 ;

J is O, S or NR 17 ;

R 2 is hydrogen, halo or optionally substituted alkyl;

R 3 is —C(O)R 9 ;

R 4 , R 5 , R 6 and R 7 are together selected from a), b), c), d), e) or f) below:

a) R 4 and R 5 are each independently selected from hydrogen or halo; and R 6 and R 7 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)R 10 , —R 21 —OC(J)R 10 ,

—R 21 —N(R 25 )C(J)R 10 , and —R 21 —SC(J)R 10 ; or R 6 and R 7 , 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) R 4 and R 5 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)R 10 , —R 21 —OC(J)R 10 ; —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or R 4 and R 5 , 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 R 6 and R 7 is are each independently selected from hydrogen or halo; or

c) R 4 and R 6 are each independently selected from hydrogen or halo; and R 5 and R 7 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)R 10 , —R 21 —OC(J)R 10 ,

—R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ;

d) R 4 is hydrogen or halo; R 5 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)R 10 , —R 21 —OC(J)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; and R 6 and R 7 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)R 10 , —R 21 —OC(J)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or

R 6 and R 7 , 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) R 4 and R 5 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)R 10 , —R 21 —OC(J)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or R 4 and R 5 , 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; R 6 is hydrogen or halo; and R 7 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)R 10 , —R 21 —OC(J)R 10 ,

—R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ;

f) R 4 and R 5 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)R 10 , —R 21 —OC(J)R 10 ; —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or R 4 and R 5 , 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 R 6 and R 7 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)R 10 , R 21 —OC(J)R 10 ,

R 8a ; R 8b ; R 8c and R 8d are each independently selected from the group consisting of hydrogen, halo, pseudohalo, cyano, 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, —R 21 —OR 22 ,

—R 21 —SR 22 , —R 21 —N(R 23 )(R 24 ); —R 21 —C(J)R 22 , —R 21 —C(J)OR 22 , —R 21 —C(J)SR 22 , —R 21 —C(J) N(R 23 )(R 24 ), —R 21 —N(R 25 )S(O) 2 R 26 and —R 21 —S(O) 2 N(R 23 )(R 24 );

R 9 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

each R 10 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, —OR 11 , —SR 11 and —N(R 12 )(R 13 );

each R H 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;

R 12 and R 13 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 R 12 and R 13 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

each R 14 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, —OR 18 , —SR 18 and —N(R 19 )(R 20 );

R 15 and R 16 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, —OR 18 , —SR 18 and —N(R 19 )(R 20 );

or R 15 and R 16 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

R 17 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

each R 18 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;

R 19 and R 20 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

R 19 and R 20 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

each R 21 is independently a direct bond or an alkylene;

each R 22 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, —R 21 —OR 32 , —R 21 —SR 32 , —R 21 —N(R 33 )(R 34 ),

—R 21 —C(J)R 32 , —R 21 —C(J)OR 32 , —R 21 —C(J)SR 32 and —R 21 —C(J)N(R 33 )(R 34 );

each R 23 and R 24 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, —R 21 —OR 32 , —R 21 —SR 32 ,

—R 21 —N(R 33 )(R 34 ) , —R 21 —C(J)R 32 , —R 21 —C(J)OR 32 , —R 21 —C(J)SR 32 , and

—R 21 —C(J)N(R 33 )(R 34 );

or R 23 and R 24 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

each R 25 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 R 26 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 R 32 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

R 33 and R 34 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

R 33 and R 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl,

said composition further comprising 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 B 6 , vitamin B 12 , 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.

2. The composition of claim 1 wherein R 9 is optionally substituted heterocyclyl or optionally substituted aryl.

3. The composition of claim 2 wherein:

R 4 , R 5 and R 6 are hydrogen,

R 7 is optionally substituted alkyl, substituted alkenyl, or optionally substituted alkynyl.

4. The composition of claim 2 , wherein R 4 and R 5 are independently selected from hydrogen or halo; and R 6 and R 7 are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

5. The composition of claim 4 wherein R 4 and R 5 are hydrogen and R 6 and R 7 are both optionally substituted alkyl.

6. The composition of claim 5 wherein R 8b is —N(R 23 )(R 24 ) or —N(R 25 )S(O) 2 R 26 ;

where R 23 and R 24 are each independently hydrogen, optionally substituted alkyl, optionally substituted aralkyl, —C(J)R 32 , —C(J)N(R 33 )(R 34 ) or —C(J)OR 32 ;

R 33 and R 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

7. The composition of claim 2 wherein R 8a is —N(R 23 )(R 24 ) where R 23 and R 24 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl; or

R 23 and R 24 are each independently hydrogen, optionally substituted alkyl, optionally substituted aralkyl, —C(J)R 32 , —C(J)N(R 33 )(R 34 ), or —C(J)OR 32 , where

R 25 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;

R 26 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;

R 32 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

R 33 and 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

8. The composition of claim 2 wherein R 8a is —OR 22 where R 22 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or —R 21 —OR 32 ;

R 21 is a direct bond or an alkylene; and

9. The composition of claim 1 further comprising a pharmaceutically acceptable carrier or excipient.

10. 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):

R 1 is —C(J)OR 14 , —C(J)SR 14 and —C(J)N(R 15 )R 16 ;

J is O, S or NR 17 ;

R 2 is hydrogen, halo or optionally substituted alkyl;

R 3 is —C(O)R 9 ;

R 4 , R 5 , R 6 and R 7 are together selected from a), b), c), d), e) or f) below:

b) R 4 and R 5 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)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or R 4 and R 5 , 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 R 6 and R 7 is are each independently selected from hydrogen or halo; or

—R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ;

d) R 4 is hydrogen or halo; R 5 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)R 10 , —R 21 —OC(J)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; and R 6 and R 7 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)R 10 , —R 21 OC(J)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or

e) R 4 and R 5 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)R 10 , —R 21 OC(J)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or R 4 and R 5 , 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; R 6 is hydrogen or halo; and R 7 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)R 10 , —R 21 —OC(J)R 10 ,

—R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ;

f) R 4 and R 5 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)R 10 , —R 21 —OC(J)R 10 , —R 21 —N(R 25 )C(J)R 10 and —R 21 —SC(J)R 10 ; or R 4 and R 5 , 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 R 6 and R 7 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)R 10 , —R 21 —OC(J)R 10 ,

R 8a , R 8b , R 8c and R 8d 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, —R 21 —OR 22 ,

—R 21 —SR 22 , —R 2l —N(R 23 )(R 24 ), —R 21 —C(J)R 22 , —R 21 , —C(J)OR 22 , —R 21 —C(J)SR 22 , —R 21 —C(J)N(R 23 )(R 24 ),—R 21 —N(R 25 )S(O) 2 R 26 and —R 21 —S(O) 2 N(R 23 )(R 24 );

or R 15 and R 16 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring;

R 17 is hydrogen, optionally substituted alkyl, optionally substituted substituted alkenyl or optionally substituted alkynyl;

R 19 and R 20 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

each R 21 is independently a direct bond or an alkylene;

—R 21 —C(J)R 32 , R 21 —C(J)OR 32 , —R 21 C(J)SR 32 and-R 21 —C(J)N(R 33 )(R 34 );

—R 21 —N(R 33 )(R 34 ), —R 21 —C(J)R 32 , —R 21 —C(J)OR 32 , —R 21 —C(J)SR 32 , and

—R 21 —C(J)N(R 33 )(R 34 );

or R 23 and R 24 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

R 33 and R 34 , 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 B 6 , vitamin B 12 , 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.

11. The method of claim 10 wherein said nuclear receptor is farnesoid X receptor.

12. The method of claim 11 , wherein said at least one additional active agent is administered simultaneously with, prior to, or after administration of the compound.

13. The method of claim 11 , wherein the disease or disorder is selected from hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, arthereosclerosis, atherosclerotic disease, atherosclerotic cardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity, hyperglycemia, cholestasis and obesity.

14. The method of claim 13 wherein said at least one additional active agent is selected from phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, sibutramine, orlistat, neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, galanin or gamma amino butyric acid (GABA) simultaneously with, prior to, or after administration of the compound.

15. The method of claim 10 , wherein the disease or disorder is selected from the group consisting of atherosclerosis, atherosclerotic disease, and atherosclerotic cardiovascular disease.

16. The method of claim 10 , wherein the disease or disorder is selected from the group consisting of Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity and hyperglycemia.

17. The method of 16 , wherein said at least one additional active agent is selected from chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glimepiride, glipizide, metformin, ciglitazone, pioglitazone, troglitazone, rosiglitazone; dehydroepiandrosterone; acarbose, miglitol, voglibose, pramlintide, amylin, or insulin, administered simultaneously with, prior to, or after administration of said compound or pharmaceutically acceptable derivative thereof selected from the group consisting of salts, esters, enolether, enolesters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, and hydrates thereof.

18. The method of claim 10 wherein R 9 is optionally substituted heterocyclyl or optionally substituted aryl.

19. The method of claim 18 wherein:

R 4 , R 5 and R 6 are hydrogen,

R 7 is optionally substituted alkyl, substituted alkenyl, or optionally substituted alkynyl.

20. The method of claim 18 , wherein R 4 and R 5 are independently selected from hydrogen or halo; and R 6 and R 7 are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl.

21. The method of claim 20 wherein R 4 and R 5 are hydrogen and R 6 and R 7 are both optionally substituted alkyl.

22. The method of claim 21 wherein R 8b is —N(R 23 )(R 24 ) or —N(R 25 )S(O) 2 R 26 ;

where R 23 and R 24 are each independently hydrogen, optionally substituted alkyl, optionally substituted aralkyl, —C(J)R 32 , —C(J)N(R 33 )(R 34 ) or —C(J)OR 32 ;

R 33 and R 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

23. The method of claim 18 wherein R 8a is —N(R 23 )(R 24 ) where R 23 and R 24 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl; or

R 23 and R 24 are each independently hydrogen, optionally substituted alkyl, optionally substituted aralkyl, —C(J)R 32 , —C(J)N(R 33 )(R 34 ), or —C(J)OR 32 where

R 33 and R 34 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.

24. The method of claim 18 wherein R 8a is —OR 22 where R 22 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or —R 21 —OR 32 ;

R 21 is a direct bond or an alkylene; and

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 9, 2016

From: EXELIXIS, INC.

To: AKARNA THERAPEUTICS, LTD.

Reel/Frame 039385/0932 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 27, 2011

From: BUSCH, BRETT B.; FLATT, BRENTON T.; GU, XIAO-HUI; MARTIN, RICHARD; MOHAN, RAJU; WANG, TIE-LIN; WU, JASON H.

To: EXELIXIS, INC.

Reel/Frame 025708/0472 →

Continuity (4)

Continuation 10895431 · Dec 2, 2003

Continuation In Part 10447302 · May 27, 2003

Provisional Application 60383574 · May 24, 2002

Related Publication 20100173824A1 · Jul 8, 2010