# US 2013/0158004 A1 · Azetidine Derivatives

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- Number: US 2013/0158004 A1
- Document ID: US20130158004A1
- Status: Published application
- Kind: A1
- Application number: 13/714,511
- Filed: 2012-12-14
- Published: 2013-06-20
- Earliest claimed: 2011-12-19
- Assignees: Boehringer Ingelheim International GmbH
- Inventors: Martin FLECK; Bernd NOSSE; Niklas HEINE; Gerald Juergen ROTH
- Web page: https://patentgrep.com/patent/US20130158004A1

## CPC

- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 407/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Azetidine derivatives of which the following is exemplary and their use in the treatment of obesity, diabetes or dyslipidemia.

## Claims

### Claim 1

A compound of the formula I
wherein
Ar1 is selected from the group Ar1-G1 consisting of:
6- to 10-membered aryl and 5- to 10-membered heteroaryl, which may each be substituted with one or more substituents R1,
wherein two substituents R1 linked to adjacent C-atoms of Ar1 together may form a C3-5-alkylene bridge in which 1, 2 or 3 CH2-groups may be replaced independently of each other by O, C(═O), S, S(═O), S(═O)2, NH or N(C1-4-alkyl)-, wherein the alkylene bridge may optionally be substituted by one or two F atoms or one or two C1-3-alkyl groups; and
R1 is selected from the group R1-G1 consisting of:
H, F, Cl, Br, I, CN, OH, —NO2, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-10-carbocyclyl, C3-10-carbocyclyl-C1-3-alkyl, C1-6-alkyl-O—, C3-6-alkenyl-O—, C3-6-alkynyl-O—, C3-10-carbocyclyl-O—, C3-10-carbocyclyl-C1-3-alkyl-O—, C1-6-alkyl-S—, C1-6-alkyl-S(═O)—, C1-6-alkyl-S(═O)2—, C3-10-carbocyclyl-S—, C3-10-carbocyclyl-C—1-3-alkyl-S—, C1-4-alkyl-C(═O)—, C3-10-carbocyclyl-C(═O)—, RN1RN2N—, RN1RN2N—C2-3-alkyl-O—, RN1RN2N—C(═O)—, RN1RN2N—S(═O)2—, C1-6-alkyl-C(═O)—NRN1—, C1-6-alkyl-S(═O)2—NRN1—, C1-6-alkyl-C(═O)—NRN1—C1-3-alkyl-, HO—C(═O)—, C1-6-alkyl-O—C(═O)—, heterocyclyl, heterocyclyl-O—, heterocyclyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl-O—, heterocyclyl-C(═O)—, aryl, aryl-C1-3-alkyl, aryl-O—, aryl-C1-3-alkyl-O—, heteroaryl, heteroaryl-C1-3-alkyl, heteroaryl-O— and heteroaryl-C1-3-alkyl-O—,
wherein in each carbocyclyl and heterocyclyl a CH2-group may optionally be replaced by —C(═O)— or —C(═CRN22)—, and
wherein each carbocyclyl and heterocyclyl may be optionally substituted with one or more C1-4-alkyl, which may be optionally substituted with one or more substituents RC, and
wherein each alkyl, carbocyclyl and heterocyclyl may be optionally substituted with one or more substituents RC, and
wherein each heterocyclyl may be optionally substituted with aryl or heteroaryl, and
wherein each aryl and heteroaryl group may be optionally substituted with one or more substituents R2,
RC is selected from the group RC-G1 consisting of:
F, Cl, Br, CN, OH, C1-4-alkyl-O—, C3-7-cycloalkyl-O—, C3-7-cycloalkyl-C1-3-alkyl-O—, H2N—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, C1-4-alkyl-C(═O)—, C1-4-alkyl-S(═O)2—, HO—C(═O)— and C1-4-alkyl-O—C(═O)—, wherein each alkyl or cycloalkyl may be optionally substituted with one or more substituents selected from F and OH, and
RN1 is selected from the group RN1-G1 consisting of:
H, C1-6-alkyl, C3-10-carbocyclyl, C3-10-carbocyclyl-C1-3-alkyl, C3-6-alkenyl, C3-6-alkynyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl,
wherein each carbocyclyl and heterocyclyl may be optionally substituted with one or more C1-4-alkyl, and
wherein in each carbocyclyl and heterocyclyl a CH2-group may optionally be replaced by —C(═O)—, and
wherein each alkyl, carbocyclyl and heterocyclyl may be optionally substituted with one or more substituents RC, and
wherein each aryl and heteroaryl group may be optionally substituted with one or more substituents R2,
RN2 is selected from the group RN2-G1 consisting of: H and C1-6-alkyl, and
Ar2 is selected from the group Ar2-G1 consisting of:
phenylene and a 5- or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, or S, wherein all of the before mentioned groups may be optionally substituted with one or more substituents R2, and
R2 is selected from the group R2-G1 consisting of:
F, Cl, Br, CN, OH, C1-4-alkyl-, C1-4-alkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)2—, H2N—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, C1-4-alkyl-C(═O)—NH— and heterocyclyl,
wherein each alkyl may be optionally substituted with one or more F-atoms and/or with a substituent selected from OH, C1-3-alkyl-O— and CN; and
wherein two substituents R2 attached to an aryl or heteroaryl group may be linked to each other and form a C2-5-alkylene bridging group in which 1 or 2-CH2-groups may be replaced by a group independently of each other selected from O, S, NH and N(C1-4-alkyl)-, wherein the C2-5-alkylene bridging group is optionally be substituted by 1 or 2 C1-3-alkyl groups;
L is selected from the group L-G1 consisting of:
a C1-4-alkylene group that is optionally substituted by one or two CH3;
X is selected from the group X-G1 consisting of: O and S;
R is selected from the group R-G1 consisting of: H and C1-3-alkyl; and
T is selected from the group T-G1 consisting of:
C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C3-10-carbocyclyl, C3-10-carbocyclyl-C1-3-alkyl, C1-6-alkyl-O—, C3-10-carbocyclyl-O—, C3-10-carbocyclyl-C1-3-alkyl-O—, C1-6-alkyl-S—, C3-10-carbocyclyl-S—, C3-10-carbocyclyl-C1-3-alkyl-S—, C1-4-alkyl-C(═O)—, C1-4-alkyl-S(═O)2—, RN1RN2—N—, RN1RN2—N—C1-3-alkyl-, RN1RN2—N—CO—, C1-4-alkyl-C(═O)—RN2N—C1-3-alkyl, heterocyclyl, aryl and heteroaryl,
wherein in each carbocyclyl and heterocyclyl a CH2-group may optionally be replaced by —C(═O)—, and
wherein each carbocyclyl and heterocyclyl may be optionally substituted with one or more C1-4-alkyl, which may be optionally substituted with one or more substituents RC, and
wherein each alkyl, carbocyclyl and heterocyclyl may be optionally substituted with one or more substituents RC, and
wherein each alkyl may optionally be substituted with a heteroaryl group; and
wherein each aryl and heteroaryl group may be optionally substituted with one or more substituents R2;
or a tautomer or pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein
X is O, and
R is H or CH3.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein Ar1 is selected from a group consisting of:
phenyl, pyridinyl, pyrimidinyl, benzoxazolyl, benzoisoxalyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl and oxazolopyrimidinyl,
wherein the above-mentioned phenyl, pyridinyl and pyrimidinyl are each substituted with one to three groups independently selected from R1, and/or
wherein two adjacent carbon atoms of a phenyl group may be linked to each other via a —O—CH2—O—, —O—CF2—O—, —O—CH2—CH2—O—, —O—CH2—CH2—CH2—CH2—, —O—CH2—CH2—CH2—C(CH3)2—, —O—CH2—CH2—CH2—O— or —O—CH2—C(CH3)2—CH2—O— bridge, and
wherein the above-mentioned benzoxazolyl, benzoisoxalyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl and oxazolopyrimidinyl groups are each optionally substituted with Cl, CH3 or phenyl.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein R1 is selected from the group consisting of:
H, F, Cl, Br, CN, OH, C1-4-alkyl, C2-4-alkenyl, C3-7-cycloalkyl, C3-7-cycloalkyl-CH2—, C1-4-alkyl-O—, C3-7-cycloalkyl-O—, C3-7-cycloalkyl-C1-3-alkyl-O—, C1-4-alkyl-S(═O)2, RN1RN2N—, HO—C(═O)—, C1-4-alkyl-O—C(═O)—, phenyl, phenyl-O—, phenyl-CH2—O—, pyridinyl,
wherein each alkyl, cycloalkyl and heterocyclyl may be optionally substituted with one to three substituents independently selected from the group consisting of F and CN, and
wherein each phenyl and pyridinyl group may be optionally substituted with one F or —OCH3.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein Ar2 is selected from the group consisting of:
phenylene and pyridylene, wherein all of the before mentioned groups may be optionally substituted with one to three substituents R2,
wherein R2 is F, Cl, C1-2-alkyl-, C1-2-alkyl-O—, C1-3-alkyl-C(═O)—NH or HO—CH2—C(═O)—NH—.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein L is a linear C1-2-alkylene group that is optionally substituted with one CH3.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein T is selected from the group consisting of:
C1-4-alkyl, C2-4-alkenyl, C3-6-cycloalkyl, C3-7-cycloalkenyl, C3-5-cycloalkyl-C1-3-alkyl-, heteroaryl-C1-3-alkyl-, C1-3-alkyl-O—, RT1RT2—N—, C1-3-alkyl-C(═O)—RT2N—C1-3-alkyl-, heterocyclyl, phenyl and heteroaryl,
wherein in each heterocyclyl, a CH2-group may optionally be replaced by —C(═O)—; and
wherein each cycloalkyl and heterocyclyl may be optionally substituted with one or more C1-3-alkyl, which may be optionally substituted with one or more substituents RC; and
wherein each alkyl, cycloalkyl and heterocyclyl may be optionally substituted with one or more F; and
wherein heterocyclyl is defined as hereinbefore and hereinafter, preferably heterocyclyl is selected from the group consisting of
and
wherein heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl; and
wherein each phenyl and heteroaryl group may be optionally substituted with one or more substitutents selected from the group consisting of CH3, CH3—C(═O)—NH— and HO—CH2—C(═O)—NH—; and
wherein RC is selected from the group consisting of F, Cl, CN, OH and C1-3-alkyl-; and
wherein RT1 is selected from the group consisting of H, methyl and ethyl; and
wherein RT2 is H or methyl.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein
Ar1 is selected from the group consisting of phenyl, pyridinyl and pyrimidinyl,
wherein the above-mentioned phenyl and pyridinyl groups are each substituted with one to three groups independently selected from R1, and
wherein the above-mentioned pyrimidinyl groups is substituted with one or two R1, and
wherein two adjacent carbon atoms of a phenyl group may be linked to each other via a —O—CH2—CH2—O—, —O—CH2—CH2—CH2—C(CH3)2—, —O—CH2—CH2—CH2—O—, or —O—CH2—C(CH3)2—CH2—O— bridge;
R1 is selected from the group consisting of F, Cl, Br, CN, CF3, C1-4 alkyl, —O—C1-4 alkyl, cyclopropyl, —O—C3-5 cycloalkyl, —O—CH2-cyclopropyl, and
Ar2 is phenylene;
L is a linear C1-2-alkylene group that is optionally substituted with one CH3;
X is O;
R is H; and
T is selected from the group consisting of: C1-4-alkyl, C2-4-alkenyl, C3-5-cycloalkyl, C5-6-cycloalkenyl, cyclopropyl-CH2—, CH3O—, RT1RT2—N—, CH3—C(═O)—NH—C1-3-alkyl, heterocyclyl, phenyl and heteroaryl,
wherein RT1 is H, CH3 or CH2CH3; and
RT2 is H or CH3; and
wherein each alkyl, cycloalkyl and heterocyclyl may be optionally substituted with one F, CN, CH3, CF3, cyclopropyl, —N(CH3)2, pyridinyl, OH or —OCH3; and
wherein heterocyclyl is selected from the group consisting of:
and
wherein heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, furanyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl; and
wherein each phenyl and heteroaryl group may be optionally substituted with one or two substituents independently selected from CH3, —NH—CO—CH3, —NH—CO—CH2—OH.

### Claim 9 (depends on 1)

A compound according to claim 1, which is:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 11 (depends on 1)

A method for treating obesity, diabetes or dyslipidemia in a patient suffering from one of said conditions which method comprises administering to said patient a therapeutically effective amount of a compound according to claim 1.