# US 9,518,000 B2 · Bicyclo [2.2.1] acid GPR120 modulators

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- Number: US 9,518,000 B2
- Document ID: US9518000B2
- Status: Granted
- Kind: B2
- Application number: 14/774,289
- Filed: 2014-03-13
- Published: 2016-01-21
- Granted: 2016-12-13
- Earliest claimed: 2013-03-14
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Yan Shi; Peter T. W. Cheng; Ying Wang; Shung C. Wu; Hao Zhang
- Web page: https://patentgrep.com/patent/US9518000B2

## CPC

- C07C 59/13: containing rings
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/381: having five-membered rings
- A61K 31/397: having four-membered rings, e.g. azetidine
- A61K 31/415: 1,2-Diazoles
- A61K 31/4245: Oxadiazoles
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- 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 5/50: for increasing or potentiating the activity of insulin
- 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 9/12: Antihypertensives
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- C07C 43/192: containing halogen
- C07C 43/196: containing hydroxy or O-metal groups
- C07C 47/277: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 59/215: containing singly bound oxygen containing groups
- C07C 59/72: containing six-membered aromatic rings and other rings
- C07C 62/34: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 69/675: of saturated hydroxy-carboxylic acids
- C07C 69/708: Ethers
- C07C 69/732: of unsaturated hydroxy carboxylic acids
- C07C 69/734: Ethers
- C07C 69/736: the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
- C07C 69/757: having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] in the acid moiety
- C07C 69/76: Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C 205/34: having nitro groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
- C07C 235/26: the carbon skeleton being saturated and containing rings
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07C 311/51: Y being a hydrogen or a carbon atom
- C07C 323/19: with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/38: One sulfur atom
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 307/79: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 333/16: by oxygen atoms
- C07D 333/28: Halogen atoms
- C07D 333/56: Radicals substituted by oxygen atoms
- C07C 2601/02: with a three-membered ring
- C07C 2602/08: the other ring being five-membered, e.g. indane
- C07C 2602/42: the bicyclo ring system containing seven carbon atoms
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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 provides compounds of Formula (I): (I) or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR120 G protein-coupled receptor modulators which may be used as medicaments.

## Claims

### Claim 1

A compound of Formula (I):
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
L1 is independently L4-O or O-L4;
L2 is independently a hydrocarbon linker substituted with 0-2 Rc, a hydrocarbon-heteroatom linker substituted with 0-2 Rc, or —(CH2)1-2—(C3-4 cycloalkyl substituted with 0-2 Rc)—(CH2)0-1—; wherein said hydrocarbon linker has one to six carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to four carbon atoms and one group selected from O, —CO—, S, —SO—, —SO2—, NH, N(C1-4 alkyl), —CONH—, and —NHCO—;
L4 is independently a bond or a hydrocarbon linker; wherein said hydrocarbon linker has one to four carbon atoms and may be straight or branched;
R1 is independently selected from: C6-10 carbocycle and a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NRb, O, and S(O)p; wherein said carbocycle and heterocycle are substituted with 0-4 R3 and 0-1 R4;
R2 independently selected from: OH, CO2H, CO2(C1-4 alkyl), CONReRf, and —CONHSO2Rf;
R3, at each occurrence, is independently selected from: halogen, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 haloalkoxy, C1-4 haloalkylthio, and NO2;
R4 is independently -L3-R5;
L3 is independently selected from: a bond, O, and C(═O);
R5 is independently selected from: phenyl and a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NRb, O, and S(O)p; wherein each ring moiety is substituted with 0-2 Ra;
Ra, at each occurrence, is independently selected from: halogen, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl;
Rb, at each occurrence, is independently selected from: H, C1-4 alkyl, and —(CH2)0-2-(phenyl substituted with 0-3 Rd);
Rc, at each occurrence, is independently selected from: ═O, halogen, OH, C1-4 alkyl, C1-4 haloalkyl, and C1-4 alkoxy;
Rd, at each occurrence, is independently selected from: halogen, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl;
Re, at each occurrence, is independently selected from: H and C1-4 alkyl;
Rf, at each occurrence, is independently selected from: H, C1-4 alkyl, —(CH2)0-2-phenyl, and C3-6 cycloalkyl substituted with 1-2 OH;
Re and Rf may be combined with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclic ring comprising carbon atoms and 1 additional heteroatom selected from N, NRb, O, and S; wherein said heterocycle is substituted with and 0-1 OH; and
p is, independently at each occurrence, selected from 0, 1, and 2.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein:
L1 is independently L4-O;
L2 is independently a hydrocarbon linker substituted with 0-1 Rc,
a hydrocarbon-heteroatom linker substituted with 0-1 Rc, or —(CH2)1-2—(C3-4 cycloalkyl substituted with 0-1 Rc)—(CH2)0-1—; wherein said hydrocarbon linker has one to six carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to four carbon atoms and one group selected from O and S;
R1 is independently selected from: phenyl, indanyl, naphthyl, and a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NRb, O, and S(O)p; wherein each ring moiety substituted with 0-4 R3 and 0-1 R4; and
R4 is independently selected from: thienyl, oxadiazolyl, and -L3-phenyl; wherein each ring moiety is substituted with 0-2 Ra.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein the compound is of Formula (II):
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
L2 is independently a hydrocarbon linker a hydrocarbon-heteroatom linker, or —(CH2)1-2-(cyclopropyl substituted with 0-1 Rc)—(CH2)0-1—; wherein said hydrocarbon linker has one to five carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to three carbon atoms and one O;
L4 is independently selected from: a bond, CH2 and CH(C1-4 alkyl);
R1 is independently selected from:
and a ring moiety substituted with 0-2 R3 and selected from the group consisting of thienyl, isoxazolyl, pyrimidinyl, indanyl, naphthyl, benzothiophenyl, and
R3, at each occurrence, is independently selected from: NO2, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 haloalkoxy, and C1-4 haloalkylthio;
R4 is independently selected from: thienyl, oxadiazolyl, and -L3-phenyl; wherein each ring moiety is substituted with 0-2 Ra;
L3 is independently selected from: a bond, O, and C(═O);
Ra, at each occurrence, is independently selected from: halogen and C1-4 alkyl; and
Rb is independently phenyl substituted with 0-2 halo.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein:
L2 is independently selected from: CH2OCH2, OCH2CH2, CH2CH2CH2, CH2CH(C1-2 alkyl)CH2, CH2CH2CH(C1-2 alkyl), CH2CH═CH, and
R1-L4- is independently selected from:
R3, at each occurrence, is independently selected from: halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 haloalkoxy, and C1-4 haloalkylthio;
R4 is independently selected from: thienyl and -L3-(phenyl substituted with 0-2 halo); and
L3 is independently selected from: a bond, O, and C(═O).

### Claim 5 (depends on 1)

A compound according to claim 1, wherein:
L2 is independently selected from the group consisting of CH2OCH2, OCH2CH2, CH2CH2CH2, CH2CH(Me)CH2, CH2CH2CH(Me), CH2CH═CH, and
and
R1-L4- is independently selected from:

### Claim 6 (depends on 1)

A compound according to claim 1, wherein:
L2 is independently selected from: OCH2CH2, CH2CH2CH2, and
and
R1-L4- is independently selected from:

### Claim 7 (depends on 1)

A compound according to claim 1, wherein:
R1-L4- is independently selected from:

### Claim 8 (depends on 1)

A compound according to claim 1, wherein the compound is selected from the exemplified Examples 1 to 100 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.