# US 8,785,463 B2 · GPR 119 agonists

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- Number: US 8,785,463 B2
- Document ID: US8785463B2
- Status: Granted
- Kind: B2
- Application number: 13/824,552
- Filed: 2011-10-05
- Published: 2013-09-26
- Granted: 2014-07-22
- Earliest claimed: 2010-10-08
- Assignees: Cadila Healthcare Limited
- Applicants: Harikishore Pingali; Pandurang Zaware
- Inventors: Harikishore Pingali; Pandurang Zaware
- Web page: https://patentgrep.com/patent/US8785463B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 239/52: Two oxygen atoms
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to novel GPR 119 agonists of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

## Claims

### Claim 1

A compound of formula (I),
its tautomeric form, its stereoisomer, and pharmaceutically acceptable salt thereof
wherein
R1 represents H or an optionally substituted group selected from a member of the group consisting of linear or branched (C1-C6)-alkyl, haloalkyl, (C1-C6)alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, alkylsulfonyl, and arylsulfonyl groups, or a group represented by (CH2)mCO2R4, (CH2)mCOR4 or (CH2)mCONH2 wherein each R4 independently represents H or a group selected from a member of the group consisting of linear or branched (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl;
and m is an integer of 0 to 3;
R2 represents H, cyano, nitro, formyl, linear or branched (C1-C6) alkyl, or (C1-C6) alkoxyl;
R3 represents an optionally substituted group selected from a member of the group consisting of linear or branched (C1-C6)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroaralkyl or a group represented by C(O)OR5, C(O)R5, and SO2R5 wherein each R5 independently represents H or an optionally substituted group selected from a member of the group consisting of linear or branched (C1-C6)alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hererocyclylalkyl, heteroaryl, and heteroaralkyl groups; n represents an integer from 0 to 3; and
“A” represents
wherein p represents an integer from 1 to 3; and X represents O or S.

### Claim 2 (depends on 1)

The compound of claim 1
wherein R1 is selected from a member of the group consisting of linear or branched (C1-C6) alkyl, haloalkyl, (C1-C6)alkenyl, cycloalkyl, aralkyl alkylsulfonyl, and arylsulfonyl groups, or a group represented by (CH2)mCO2R4, (CH2)mCOR4 or (CH2)mCONH2 wherein each R4 independently represents H or a group selected from a member of the group consisting of linear or branched (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl and heteroaryl; and m=is an integer from 0 to 3.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R1 is selected from a member of the group consisting of linear or branched (C1-C6) alkyl, haloalkyl, (C1-C6) alkenyl, aralkyl alkylsulfonyl, and arylsulfonyl groups or a group represented by (CH2)mCO2R4, (CH2)mCOR4 or (CH2)mCONH2 wherein each R4 independently represents a group selected from a member of the group consisting of linear or branched (C1-C6)-alkyl and aryl groups, m=is an integer from 0 to 3.

### Claim 4 (depends on 1)

The compound of claim 1 wherein R2 is selected from a member of the group consisting of H, nitro, linear or branched (C1-C6)-alkyl, and (C1-C6) alkoxyl groups.

### Claim 5 (depends on 1)

The compound of claim 1 wherein each of R1, R3, R4 and R5 are independently hydroxyl, oxo, halo, thio, nitro, amino, cyano, formyl, or a substituted or unsubstituted group selected from a member of the group consisting of amidino, alkyl, haloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid, ester, amide, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, arylthio, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxylamino, sulfenyl derivatives, sulfonyl derivatives, and sulfonic acid.

### Claim 6 (depends on 1)

The compound of claim 1 selected from a member of the group consisting of
(Z)-tert-Butyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl-4-((6-(4-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(4-((6-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)-3-(methylsulfonyl)thiazolidine-2,4-dione;
(Z)-Ethyl-4-((5-methyl-6-(3-((3-methyl-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(3-((5-Methyl-6-((1-(methylsulfonyl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-acetylpiperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(4-((6-((1-(3-iso-Propyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-tert-Butyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(4-((6-((1-(3-iso-Propyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-Methyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Benzyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Ethyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-iso-Butyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-iso-Propyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(4-((5-Methyl-6-((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-tert-Butyl 2-(((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate;
(Z)-tert-Butyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Ethyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Methyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-iso-Butyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl 2-(((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)methyl)pyrrolidine-1-carboxylate;
(Z)-tert-Butyl-4-((6-(4-((3-(methylsulfonyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(3-((6-((1-(3-Isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-Benzylpiperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((5-Methyl-6-((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-Benzyl-4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Benzyl-4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl 4-((6-(4-((3-ethyl-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Methyl 4-((6-(3-((3-isopropyl-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Isobutyl 4-((6-((3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Isobutyl-4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Methyl-4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Methyl-4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(4-((6-((1-Benzylpiperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(4-((6-((1-Benzylpiperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-Benzylpiperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-tert-Butyl 4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2-methoxyphenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(4-((6-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(Pyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(4-((6-((1-(Pyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-tert-Butyl 4-((6-(3-((2,4-dioxo-3-(2-oxopropyl)thiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl-4-((6-(3-((3-(2-ethoxy-2-oxoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl-4-((6-(4-((2,4-dioxo-3-(2-oxopropyl)thiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(3-((6-((1-(5-Chloropyrimidin-2-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(5-Bromopyridin-2-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(3R,4S)-tert-Butyl 4-((6-(3-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)-3-fluoropiperidine-1-carboxylate;
(Z)-Benzyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Ethyl-4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Ethyl-4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Isobutyl-4-((6-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-Isobutyl 4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-5-(3-((6-((1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-ione;
(Z)-6-(4-((6-(3-((2,4-Dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidin-1-yl)nicotinonitrile;
(Z)-tert-Butyl-4-((6-(3-((3-benzyl-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl-4-((6-(3-((3-allyl-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl-4-((6-(3-((3-(2-bromoethyl)-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-tert-Butyl-4-((6-(3-((3-ethyl-2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)-5-methylpyrimidin-4-yl)oxy)piperidine-1-carboxylate;
(Z)-3-Ethyl-5-(3-((6-((1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(5-Ethylpyrimidin-2-yl) piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)-3-(2-oxopropyl)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(isopropylsulfonyl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-acetylpiperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(4-((6-((1-acetylpiperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)-5-ethylpyrimidin-4-yl)oxy)benzylidene)-3-methylthiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)-5-ethylpyrimidin-4-yl)oxy)benzylidene)-3-(2-oxopropyl)thiazol dine-2,4-dione;
(Z)-3-isopropyl-5-(3-((6-((1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)oxy)-5-methylpyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-6-(4-((6-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)pyrimidin-4-yl)oxy)piperidin-1-yl)nicotinonitrile;
(Z)-5-(3-((6-((1-(methyl sulfonyl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(3-((6-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(4-((6-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-3-(methylsulfonyl)-5-(4-((6-((1-(methylsulfonyl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione;
(Z)-5-(4-((6-((1-(5-bromopyridin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione; and
(Z)-5-(3-((6-((1-(5-bromopyridin-2-yl)piperidin-4-yl)oxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

### Claim 8 (depends on 1)

A method for lowering glucose levels, comprising administering the compound of claim 1 to a mammal in need thereof.

### Claim 9 (depends on 1)

A method for treating obesity, comprising administering the compound of claim 1 to a mammal in need thereof.

### Claim 10 (depends on 1)

A method for treating diabetes comprising administering a compound of claim 1 to a mammal in need thereof.

### Claim 11 (depends on 1, 7)

A pharmaceutical composition of claim 7 wherein the compound of claim 1 is present in an effective amount to modulate a GPR-119 receptor.

### Claim 12 (depends on 1)

A process for preparing a compound of claim 1 wherein R1, R2, R3, X, A and n are as defined in claim comprising
reacting a compound of formula (VI),
with a compound of formula (VII)
to obtain a compound of formula (Ia);
and
reacting a compound of formula (Ia) with R1-L, wherein L represents a suitable leaving group selected from a member of the group consisting of halogen, mesylate, tosylate, and triflate to yield a compound of formula (I)