# US 8,569,340 B2 · AMPK-activating piperidinyloxypyiridine carboxamide and sulfonamide compounds and methods for using the same

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,569,340 B2
- Document ID: US8569340B2
- Status: Granted
- Kind: B2
- Application number: 13/348,380
- Filed: 2012-01-11
- Published: 2012-05-10
- Granted: 2013-10-29
- Earliest claimed: 2007-11-16
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Hui Hong; Xiang Xu; Jiaxin Yu; Rajinder Singh; Ihab S. Darwish; Sambaiah Thota
- Inventors: Hui Hong; Xiang Xu; Jiaxin Yu; Rajinder Singh; Ihab S. Darwish; Sambaiah Thota
- Web page: https://patentgrep.com/patent/US8569340B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/06: Antihyperlipidemics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- 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 211/46: having a hydrogen atom as the second substituent in position 4
- C07D 211/58: attached in position 4
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are carboxamide, sulfonamide and amine compounds, as well as pharmaceutical compositions and methods of use. One embodiment is a compound having the structure in which R1, R2, R4, E, T, n 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
the piperidinyloxy group and the -E- group are disposed about the central pyridine in a para or meta relationship to one another;
E is —C(O)— or —S(O)2—;
R1 is H, —(C1-C4 alkyl) or —C(O)O—(C1-C4 alkyl);
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 or 2;
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 on the same carbon optionally combine to form oxo;
x is 0, 1, 2 or 3;
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 or 3;
Q and G are each independently a bond, —CH2—, —C(O)—, —CH(CH3)— or —S(O)2—;
v is 0, 1, 2 or 3;
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; and
R17 is phenyl, pyridyl, pyrimidinyl or imidazolyl, each 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,
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(NR9)NR9—, —N9SO2—, —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) and —C(O)O—(C1-C4 alkyl).

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is H.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein G is —CH2— or —CH(CH3)—.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein G is —C(O)— or —S(O)2—.

### Claim 5 (depends on 1)

A compound according to claim 1, having the structural formula
in which R27 is 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 R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl).

### Claim 6 (depends on 1)

A compound according to claim 1, having the structural formula
in which R27 is 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 R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl).

### Claim 7 (depends on 1)

A compound according to claim 1, having the structural formula
in which R27 is 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 R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl).

### Claim 8 (depends on 1)

A compound according to claim 1, having the structural formula
in which R27 is 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 R29 is —H, —(C1-C4 alkyl) or —CO—O—(C1-C4 alkyl).

### Claim 9 (depends on 1)

A compound according to claim 1, having the structural formula

### Claim 10 (depends on 1)

A compound according to claim 1, having the structural formula
in which R25 is selected from halo, cyano, —(C1-C3 haloalkyl), —O—(C1-C2 haloalkyl), —(C1-C3 alkyl), —O—(C1-C2 alkyl), —C(O)—(C0-C2 alkyl), —C(O)O—(C0-C2 alkyl), —C(O)N(C0-C2 alkyl)(C0-C4 alkyl) and NO2.

### Claim 11 (depends on 1)

A compound according to claim 1, having the structural formula
in which Q is —C(O)— or —S(O)2—.

### Claim 12 (depends on 1)

A compound according to claim 1, having the structural formula

### Claim 13 (depends on 1)

A compound according to claim 1, having the structural formula

### Claim 14 (depends on 12)

The compound according to claim 12, wherein x is 0 and v is 0.

### Claim 15 (depends on 12)

The compound according to claim 12, wherein x is 0, v is 0 and w is 0.

### Claim 16 (depends on 12)

The compound according to claim 12, wherein x is 0, v is 0, w is 0, and Q is a bond or —CH2—.

### Claim 17 (depends on 16)

The compound according to claim 16; wherein G is —CH2—.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein E is —C(O)—.

### Claim 19 (depends on 1)

The compound according to claim 1 wherein R17 is pyridyl, or phenyl 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 20 (depends on 12)

The compound according to claim 12 wherein each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl) and —(C1-C2 haloalkyl).

### Claim 21 (depends on 1)

The compound according to claim 1, having the structure
wherein Q is —CH2— or a single bond and R17 is selected from
and
in which R25 is selected from halo, cyano, —(C1-C3 haloalkyl), —O—(C1-C2 haloalkyl), —(C1-C3 alkyl), —O—(C1-C2 alkyl), —C(O)—(C0-C2 alkyl), —C(O)O—(C0-C2 alkyl), —C(O)N(C0-C2 alkyl)(C0-C4 alkyl) and NO2.

### Claim 22 (depends on 21)

The compound according to claim 21, wherein x is 0, v is 0 and w is 0.

### Claim 23 (depends on 16)

The compound according to claim 16; wherein y is 0, or y is not 0 and at least one R5 is halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2.

### Claim 24 (depends on 12)

The compound according to claim 12 wherein each R7, R8 and R10 is independently selected from H, —(C1-C2 alkyl) and —(C1-C2 haloalkyl).

### Claim 25 (depends on 1)

The compound according to claim 1, wherein y is 0, or y is not 0 and at least one R5 is halo, cyano, —(C1-C4 haloalkyl), —O—(C1-C4 haloalkyl), —(C1-C4 alkyl), —O—(C1-C4 alkyl), —C(O)—(C0-C4 alkyl), —C(O)O—(C0-C4 alkyl), —C(O)N(C0-C4 alkyl)(C0-C4 alkyl), NO2.

### Claim 26 (depends on 1)

A compound according to claim 1, wherein the compound is
5-(1-(4-cyanophenyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)picolinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4-yloxy)picolinamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-5-(1-(4-cyanophenyl)piperidin-4-yloxy)picolinamide;
methyl 4-((4-(5-(1-(4-cyanophenyl)piperidin-4-yloxy)picolinamido)piperidin-1-yl)methyl)benzoate;
methyl 4-((4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamido)piperidin-1-yl)methyl)benzoate;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-4-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamide;
N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)isonicotinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)isonicotinamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)isonicotinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-4-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(4-fluorobenzyl)piperidin-4-yl)-4-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamide;
N-(1-phenethylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-benzylpiperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(4-(dimethylamino)benzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(4-morpholinobenzyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
N-(1-(pyrimidin-5-ylmethyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)-N-(1-((1-trityl-1H-imidazol-4-yl)methyl)piperidin-4-yl)picolinamide;
N-(1-((1H-imidazol-4-yl)methyl)piperidin-4-yl)-5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide;
methyl 4-((4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamido)piperidin-1-yl)methyl)benzoate;
4-((4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)nicotinamido)piperidin-1-yl)methyl)benzoic acid;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide;
N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-cyanophenyl)piperidin-4-yloxy)pyridine-3-sulfonamide;
6-(1-(4-cyanobenzyl)piperidin-4-yloxy)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)pyridin-3-sulfonamide;
N-(1-(4-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide;
N-(1-(3-cyanobenzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide;
N-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide;
N-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide; or
N-(1-(4-fluorobenzoyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyridine-3-sulfonamide.

### Claim 27 (depends on 1)

A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent or excipient; and a compound according to claim 1.