# US 8,785,449 B2 · Carboxamide compounds and methods for using the same

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- Number: US 8,785,449 B2
- Document ID: US8785449B2
- Status: Granted
- Kind: B2
- Application number: 13/622,078
- Filed: 2012-09-18
- Published: 2013-01-24
- Granted: 2014-07-22
- Earliest claimed: 2008-04-23
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Jiaxin Yu; Hui Hong; Ihab S. Darwish; Xiang Xu; Rajinder Singh
- Web page: https://patentgrep.com/patent/US8785449B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4725: containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/497: containing further heterocyclic rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/58: attached in position 4
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are carboxamide compounds, as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure in which R1, R2, R3, R4, D, J, Z, T, p, q, w and x are as described herein. In certain embodiments, a compound disclosed herein activates the AMPK pathway, and can be used to treat metabolism-related disorders and conditions.

## Claims

### Claim 1

A compound having the structural formula
or a pharmaceutically acceptable salt or N-oxide thereof, wherein
Y is O or S;
R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl), and
R2 is
in which
each R15 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN and two R15 on the same carbon optionally combine to form oxo;
y is 0, 1, 2, 3 or 4;
R17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
or the C(O)NR1R2 is
in which
f is 0 or 1;
g is 0, 1 or 2;
c is 0, 1, 2, 3 or 4;
R28 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
each R21 is independently selected from each R4 is —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R21 groups combine to form an oxo;
E3 is NH, N substituted by one of the c R21, N substituted by the -G-R28, CH2, CH substituted by one of the c R21, CH substituted by the -G-R28, or C substituted by one of the c R21 and the -G-R28; and
E4 is absent, NH, N substituted by one of the c R21, N substituted by the -G-R28, CH2, CH substituted by one of the c R21, CH substituted by the -G-R28, or C substituted by one of the c R21 and the -G-R28, provided that both of E3 and E4 are not N;
each R3 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN,
w is 0, 1, 2 or 3;
each R4 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R4 groups combine to form an oxo;
x is 0, 1, 2, 3 or 4;
Q is —S(O)2—, L, or (C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16;
the ring denoted by “A” is heteroaryl or aryl;
each R5 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
y is 0, 1, 2, 3 or 4;
in which
each G is independently —S(O)2—, L, or —(C0-C3 alkyl)-, in which each carbon of the —(C0-C3 alkyl)- is optionally and independently substituted with one or two R16,
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—, —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),
each R9 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl), and
each R16 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN, and two R16 on the same carbon optionally combine to form an oxo.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein Y is O.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein Y is S.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein
R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl), and
R2 is

### Claim 5 (depends on 4)

A compound according to claim 4, wherein R1 is H.

### Claim 6 (depends on 4)

A compound according to claim 4, wherein G is —CH2—, —CH(CH3)—, —C(O)—, —S(O)2— or —C(O)—NH—.

### Claim 7 (depends on 6)

A compound according to claim 6, wherein R2 is

### Claim 8 (depends on 1)

A compound according to claim 1, wherein the C(O)NR1R2 is

### Claim 9 (depends on 8)

A compound according to claim 8, wherein c is 0.

### Claim 10 (depends on 8)

A compound according to claim 8, wherein the C(O)NR1R2 is

### Claim 11 (depends on 8)

A compound according to claim 8, wherein G is a single bond, —CH2— or —C(O)—.

### Claim 12 (depends on 1)

A compound according to claim 1, wherein w is 0.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein x is 0.

### Claim 14 (depends on 1)

A compound according to claim 1, wherein w is 0, x is 0, v is 0 and c is 0.

### Claim 15 (depends on 1)

A compound according to claim 1, wherein Q is —CH2—, a single bond, —S(O)2—, —C(O)—, or —CH(CH3)—.

### Claim 16 (depends on 1)

A compound according to claim 1, wherein the ring system denoted by “A” is a monocyclic aryl or heteroaryl.

### Claim 17 (depends on 1)

A compound according to claim 1, having the structural formula

### Claim 18 (depends on 1)

A compound according to claim 1, having the structural formula

### Claim 19 (depends on 1)

A compound according to claim 1, having the structural formula
wherein
Y is O or S;
R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl), and
R2 is
in which R17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
or the C(O)NR1R2 is
in which
f is 0 or 1;
g is 0, 1 or 2;
R28 is monocyclic aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
E3 is NH, N substituted by the -G-R28, CH2, or CH substituted by the -G-R28; and
E4 is absent, NH, N substituted by the -G-R28, CH2, or CH substituted by the -G-R28, provided that both of E3 and E4 are not N;
Q is —CH2—, a single bond, —S(O)2—, —C(O)—, or —CH(CH3)—;
the ring denoted by “A” is monocyclic heteroaryl or aryl;
each R5 is independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN;
y is 0, 1, 2, 3 or 4;
in which
each G is independently —CH2—, —CH(CH3)—, —C(O)—, —S(O)2— or —C(O)—NH—,
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—, —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), and
each R9 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) and —C(O)O—(C1-C4 alkyl).

### Claim 20 (depends on 19)

A compound according to claim 19, wherein
R1 is H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl), and
R2 is
in which R17 is aryl or heteroaryl, optionally substituted with 1, 2 or 3 substituents independently selected from —(C1-C3 alkyl), —(C1-C3 haloalkyl), —(C0-C3 alkyl)-L-R7, —(C0-C3 alkyl)-NR8R9, —(C0-C3 alkyl)-OR10, —(C0-C3 alkyl)-C(O)R10, —(C0-C3 alkyl)-S(O)0-2R10, -halogen, —NO2 and —CN.

### Claim 21 (depends on 20)

A compound according to claim 20, wherein R2 is

### Claim 22 (depends on 19)

A compound according to claim 19, wherein the C(O)NR1R2 is

### Claim 23 (depends on 22)

A compound according to claim 22, wherein the C(O)NR1R2 is

### Claim 24 (depends on 19)

A compound according to claim 19, having the structural formula

### Claim 25 (depends on 1)

A compound according to claim 1, wherein the compound is
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(1-(4-fluorobenzoyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(1-(4-cyanobenzoyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide;
N-(4-isonicotinoylcyclohexyl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamide;
(5-(pyridin-4-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazol-2-yl)methanone;
4-((5-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzamide;
4-((5-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzonitrile;
(5-isonicotinoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazol-2-yl)methanone;
4-(5-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)benzonitrile;
(5-(4-fluorobenzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazol-2-yl)methanone;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-carboxamide; or
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]thiazole-2-carboxamide.

### Claim 26 (depends on 1)

A pharmaceutical composition comprising:
at least one pharmaceutically acceptable carrier, diluent or excipient; and
a compound according to claim 1 or a pharmaceutically acceptable salt or N-oxide thereof.

### Claim 27 (depends on 1)

A method for treating type II diabetes in a subject, the method comprising
administering to the subject an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof.

### Claim 28 (depends on 1)

A method for reducing triglyceride levels in a subject, the method comprising
administering to the subject an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof.

### Claim 29 (depends on 1)

A method for increasing insulin sensitivity of a subject, the method comprising
administering to the subject an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof.

### Claim 30 (depends on 1)

A method for treating atherosclerosis in subject, the method comprising
administering to the subject an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof.

### Claim 31 (depends on 19)

A compound according to claim 19, wherein
R1 is H;
R2 is
G is —CH2— or —C(O)—; and
Q is —CH2— or a single bond.

### Claim 32 (depends on 19)

A compound according to claim 19, wherein
the C(O)NR1R2 is
G is —CH2— or —C(O)—; and
Q is —CH2— or a single bond.