# US 2014/0194420 A1 · Azabenzimidazole derivative having ampk-activating activity

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- Number: US 2014/0194420 A1
- Document ID: US20140194420A1
- Status: Published application
- Kind: A1
- Application number: 14/233,058
- Filed: 2012-07-13
- Published: 2014-07-10
- Earliest claimed: 2011-07-15
- Assignees: Shionogi & Co., Ltd.
- Inventors: Eiichi Kojima; Keisuke Tonogaki; Nobuyuki Tanaka; Manabu Katou; Akira Ino; Masafumi Iwatsu; Masahiko Fujioka; Yu Hinata; Naoki Ohyabu
- Web page: https://patentgrep.com/patent/US20140194420A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C07D 451/06: Oxygen atoms
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Disclosed is a compound which is useful as an AMPK activator. A compound represented by formula: or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, or substituted or unsubstituted alkyl, R1, R2 and R3 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl or the like, with the proviso that R1, R2 and R3 are not simultaneously hydrogen, X is a single bond, —S—, —O—, —NR5—, —C(═O)— or the like, R5 is hydrogen, or substituted or unsubstituted alkyl, Y is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl or the like.

## Claims

### Claim 1

A compound represented by formula (I):
or a pharmaceutically acceptable salt thereof,
wherein R4 is hydrogen, or substituted or unsubstituted alkyl,
R1, R2 and R3 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino, with the proviso that R1, R2 and R3 are not simultaneously hydrogen,
X is a single bond, —S—, —O—, —NR5—, —C(═O)—, —NR5C(═O)—, —C(═O)NR5—, —NR5—SO2—, —SO2—NR5—, —C(═O)—O— or —O—C(═O)—,
R5 is hydrogen, or substituted or unsubstituted alkyl,
Y is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or
a group represented by formula: —(CR6R7)m-Z,
R6 is each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkyloxy,
R7 is each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkyloxy, or R6 and R7 which are bound to the same carbon atom, together with the carbon atom, may form a substituted or unsubstituted ring,
m is an integer from 1 to 3,
Z is
(1) hydrogen,
(2) cyano,
(3) carboxy,
(4) substituted or unsubstituted alkenyl,
(5) substituted or unsubstituted alkynyl,
(6) substituted or unsubstituted aryl,
(7) substituted or unsubstituted heteroaryl,
(8) substituted or unsubstituted cycloalkyl,
(9) substituted or unsubstituted cycloalkenyl,
(10) substituted or unsubstituted heterocyclyl,
(11) —C(═O)—NR8R9,
(12) —NR10—C(═O)—R11,
(13) —SO2—NR12R13,
(14) —NR14—SO2—R15,
(15) —NR16—C(═O)—NR17R18,
(16) —C(═O)—O—R19,
(17) —P(═O)(—OH)2,
(18) —P(═O)H(—OH),
(19) —P(═O)(—R20)2,
(20) —P(═O)(—OR20)2,
(21) —P(═O)(—OH)(—R20),
(22) —P(═O)(—OH)(—OR20),
(23) —P(═O)(—R20)(—OR20),
(24) —P(═O)(—OH)(—O—(CR21R22)0-4—R23),
(25) —P(═O)(—NR24—CR21R22—COOH)2,
(26) —P(═O)(—NR24—CR21R22—COOR2)2,
(27) —P(═O)(—OH)(—NR24—CR21R22—COOH)2,
(28) —P(═O)(—OH)(—NR24—CR21R22—COOR20),
(29) —P(═O)(—NR24—CR21R22—COOR20)(—O—R20),
(30) —P(═O)(—O—CR21R22—O—C(═O)—R20)2,
(31) —P(═O)(—OH)(—O—CR21R22—O—C(═O)—R20),
(32) —P(═O)(—OH)(—O—(CR21R22)1-4—S(═O)—R20),
(33) —P(═O)(—O—(CR21R22)1-4—S(═O)—R20)2,
(34) —P(═O)(—OH)(—O—(CR21R22)1-4—S—C(═O)—R20),
(35) —P(═O)(—O—(CR21R22)1-4—S—C(═O)—R20)2
or
(36)
R8 and R9 are each independently hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkyloxy, or R8 and R9 taken together with the adjacent nitrogen atom to which they are attached may form a substituted or unsubstituted ring,
R10, R14 and R16 are each independently hydrogen, or substituted or unsubstituted alkyl,
R21 is each independently hydrogen, or substituted or unsubstituted alkyl,
R22 is each independently hydrogen, or substituted or unsubstituted alkyl,
R24 is each independently hydrogen, or substituted or unsubstituted alkyl,
R11 and R15 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
R12, R13, R17, R18 and R19 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
R20 is each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
R23 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
R25 and R26 are each independently —O— or —NH—,
R27 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
with the proviso that a compound wherein R2 is halogen, X is —S—, Y is a group represented by the formula: —(CR6R7)m-Z, m is 3, Z is hydrogen and R1 is substituted or unsubstituted heterocyclyl,
a compound wherein R1 is substituted or unsubstituted heteroaryl, R2 is substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, X is —O— and Y is a group represented by formula: —(CR6R7)m-Z, and
compounds shown below are excluded:

### Claim 2 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino.

### Claim 3 (depends on 2)

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R2 is halogen.

### Claim 4 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

### Claim 5 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino.

### Claim 6 (depends on 5)

The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R1 is substituted or unsubstituted aryl.

### Claim 7 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is —O—.

### Claim 8 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is —S—.

### Claim 9 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is substituted or unsubstituted monocyclic heterocyclyl, or substituted or unsubstituted monocyclic cycloalkyl.

### Claim 10 (depends on 9)

The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein Y is
R28 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, or substituted or unsubstituted amino, and R29 and R30 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted amino.

### Claim 11 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is a group represented by formula: —(CR6R7)m-Z.

### Claim 12 (depends on 11)

The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein m is 1.

### Claim 13 (depends on 11)

The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein either one of R6 and R7 is substituted or unsubstituted alkyl, and another one of R6 and R7 is hydrogen.

### Claim 14 (depends on 11)

The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein Z is carboxy, —C(═O)—NR8R9, or substituted or unsubstituted heteroaryl.

### Claim 15 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

### Claim 16 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

A pharmaceutical composition having an activating effect on adenosine monophosphate-activated protein kinase, wherein the pharmaceutical composition comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 2)

The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted heterocyclylthio, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heteroarylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted acyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino.

### Claim 20 (depends on 1)

A method for treating diabetes, comprising administering the compound according to claim 1 or a pharmaceutically acceptable salt thereof.