# US 8,273,772 B2 · Heteroaryl compounds as P2Y1 receptor inhibitors

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- Number: US 8,273,772 B2
- Document ID: US8273772B2
- Status: Granted
- Kind: B2
- Application number: 12/619,702
- Filed: 2009-11-17
- Published: 2010-04-15
- Granted: 2012-09-25
- Earliest claimed: 2005-01-19
- Assignees: Bristol-Myers Squibb Company
- Inventors: James C. Sutton; Zulan Pi; Rejean Ruel; Alexandre L'Heureux; Carl Thibeault; Patrick Y. S. Lam
- Web page: https://patentgrep.com/patent/US8273772B2

## CPC

- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- 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 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 213/80: in position 3
- C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides novel heteroaryl compounds and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y1 receptor activity.

## Claims

### Claim 1

A compound of Formula (II):
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
ring A is
R1c is independently C1-6 alkyl substituted with 0-2 Ra, C2-6 alkenyl substituted with 0-2 Ra, C2-6 alkynyl substituted with 0-2 Ra, Br, CN, CF3, —CF2CF3, —C(NH2)═N(OH), C(O)Rc, —CH(═NOH), —C(O)ORc, NR12R13, —C(O)NR12R13, —CON(Me)(CH2)2OH, —S(O)pNR12R13, —(CH2)r—C3-6 cycloalkyl substituted with 0-2 Rb, —(CH2)r-adamantyl substituted with 0-2 Rb, —(CH2)r-phenyl substituted with 0-4 Rb, or —(CH2)r-naphthyl substituted with 0-4 Rb;
R5 is phenyl substituted with 1-4 R5a;
R5a is, independently at each occurrence, F, Cl, Br, I, —(CRiRi)r—ORc, SRc, CN, CF3, —CF2CF3, OCF3, —OCF2CF2H, —OCF2CF3, —NR12R13, —C(O)Rc, —C(O)ORc, —C(O)NR12R13, —NR14C(O)Rd, —S(O)pNR12R13, —S(O)Rd, —S(O)2Rd, —Si(Me)3, Si(C1-4 alkyl)3, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-4 alkyl-C(O)—, C1-4 alkyl-O—C(O)—, C1-4 alkyl-C(O)NH—, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, or —(CRfRf)r—C3-10 carbocycle substituted with 0-3 Re;
alternatively, two R5a groups attached to two adjacent carbon atoms, together with the carbon atoms to which they are attached, form a 5- to 7-membered carbocyclic ring, wherein said carbocyclic ring is substituted with 0-3 Re;
R7 is H, Br, CN, NH2, NMe2, or —NH(4-OMe-Ph);
R8 is H, Br, CN, NMe2, or —N(Me)(4-OMe-Ph);
R11 is, independently at each occurrence, H, —COPh, —COBn, —SO2Me, —SO2Ph, —SO2Bn, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NR12R13, C1-4 alkyl substituted with 0-2 Ra, —(CH2)r—C3-6 cycloalkyl substituted with 0-2 Rb, —(CH2)r-phenyl substituted with 0-3 Rb, or —CHMe-phenyl substituted with 0-3 Rb;
R12 is, independently at each occurrence, H, C1-6 alkyl substituted with 1-5 fluorine, —(CRfRf)rC(O)NRfRf, C1-6 alkyl, —(CH2)r—C3-6 cycloalkyl, or —(CH2)n-phenyl; wherein said alkyl and phenyl are substituted with 0-2 Rg;
R13 is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
R14 is, independently at each occurrence, H, C1-6 alkyl, C2-6 alkenyl, or —(CH2)r-phenyl carbocycle substituted with 0-3 Rg;
Ra is, independently at each occurrence, H, F, OCF3, CF3, —(CRfRf)rORc, —(CRfRf)rSRc, CN, —(CRfRf)rNR12R13, —(CRfRf)rC(O)Rc, —(CRfRf)rC(O)ORc, —(CRfRf)rC(O)NR12R13, —(CRfRf)rNR14C(O)Rd, —(CRfRf)rS(O)pNR12R13, —(CRfRf)rS(O)Rd, —(CRfRf)rS(O)2Rd, C1-4 alkyl substituted with 1-5 fluorine, or —(CH2)r—C3-10 carbocycle substituted with 0-3 Re;
Rb is, independently at each occurrence, C1-6 alkyl substituted with 0-2 Ra, C2-6 alkenyl substituted with 0-2 Ra, C2-6 alkynyl substituted with 0-2 Ra, F, Cl, Br, CF3, —OCF3, —(CH2)r—ORc, —(CH2)r—C(O)ORc, —(CRfRf)rNR12R13, —(CH2)r—C(O)NR12R13, CN, —OCH2C(Me)2CH2NMe2, NO2, —SO2Me, OBn, —(CH2)r—C3-6 cycloalkyl, —(CH2)r-phenyl substituted with 0-2 Re, or —(CH2)r-naphthyl substituted with 0-3 Re;
Rd is, independently at each occurrence, CF3, OH, C1-4 alkoxy, C1-6 alkyl, or —(CH2)r—C3-10 carbocycle substituted with 0-2 Re;
Re is, independently at each occurrence, H, ═O, —(CH2)r—ORf, F, Cl, Br, I, CN, NO2, —(CH2)r—NR12R13, —C(O)Rf, —(CH2)r—C(O)ORf, —NR14C(O)Rf, —(CH2)r—C(O)NR12R13, —SO2NR12R13, —NR14SO2NR12R13, —NR14SO2—C1-4 alkyl, —NR14SO2CF3, —NR14SO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, Si(C1-4 alkyl)3, C1-8 alkyl substituted with 0-2 Rg, C2-8 alkenyl substituted with 0-2 Rg, C2-8 alkynyl substituted with 0-2 Rg, —(CH2)r—C3-8 cycloalkyl substituted with 0-2 Rg, or —(CH2)r—C6-10 aryl substituted with 0-2 Rg;
alternatively, two Re groups, together with the atoms to which they are attached, form a 5- to 7-membered carbocyclic ring, wherein said carbocyclic ring is substituted with 0-2 Rg;
Rf is, independently at each occurrence, H, F, C1-6 alkyl, or —(CH2)n-phenyl;
Rg is, independently at each occurrence, H, ═O, ORf, F, Cl, Br, I, CN, NO2, —NRfRf, —C(O)Rf, —C(O)ORf, —NRfC(O)Rf, —C(O)NRfRf, —SO2NRfRf, —NRfSO2NRfRf, —NRfSO2—C1-4 alkyl, —NRfSO2CF3, —NRfSO2-phenyl, —S(O)2CF3, —S(O)p—C1-4 alkyl, —S(O )p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
Ri is, independently at each occurrence, H or C1-6 alkyl;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4;
p, at each occurrence, is selected from 0, 1, and 2; and
r, at each occurrence, is selected from 0, 1, 2, 3, and 4.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein:
R1c is independently C1-6 alkyl substituted with 0-2 Ra, C2-6 alkenyl substituted with 0-2 Ra, C2-6 alkynyl substituted with 0-2 Ra, Br, CF3, C(O)Rc, —C(O)ORc, NR12R13, —C(O)NR12R13, —(CH2)r—C3-6 cycloalkyl substituted with 0-2 Rb, —(CH2)r-adamantyl substituted with 0-2 Rb, —(CH2)r-phenyl substituted with 0-3 Rb, or —(CH2)r-naphthyl substituted with 0-3 Rb;
Ra is, independently at each occurrence, —O(CH2)2OMe, —C(O)ORc, —(CRfRf)rNR12R13, —(CRfRf)rC(O)NR12R13, C1-4 alkyl substituted with 1-5 fluorine, SPh, phenoxy substituted with 0-2 Re, or benzoxy substituted with 0-2 Re;
Rb is, independently at each occurrence, C1-6 alkyl, C1-4 alkoxyl, F, Cl, CF3, —OCF3, OH, —CH2OH, CN, —(CRfRf)rNR12R13, —CH2NMe2, NO2, —SO2Me, —(CH2)r—C3-6 cycloalkyl, CH(Ph)2, —(CH2)r-phenyl substituted with 0-2 Re, or —(CH2)r-naphthyl substituted with 0-3 Re; and
Re is, independently at each occurrence, C1-6 alkyl, F, Cl, CN, or Bn.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein the compound is of Formula (IIb):
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R1c is H, i-Pr, t-Bu, neopentyl, cyclopropyl, 1-Ph-cyclopropyl, cyclobutyl, cycopentyl, cyclohexyl, 4-NHBn-cyclohexyl, 4-N(Me)Bn-cyclohexyl, —CH2OBn, —CH2O(CH2)2OMe, CO2H, CO2Et, —C(Me)2(CH2)2CO2Me, —CH2N(Me)Bn, —(CH2)3N(Me)Bn, —C(Me)2(CH2)3N(Me)Bn, —CON(Me)Bn, —C(Me)2CH2CON(Me)Bn, —C(Me)2(CH2)2CON(Me)Bn, Ph, phenethyl, 3-Me-Ph, 4-Me-Ph, 4-t-Bu-Ph, 3-OH-Ph, 2-OMe-Ph, 4-OMe-Ph, 4-F-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-CF3-Ph, 3-OCF3-Ph, 4-OCF3-Ph, 4-CN-Ph, 3-NMe2-Ph, 4-NMe2-Ph, 2-CH2NMe2-Ph, 3-CH2NMe2-Ph, 4-CH2NMe2-Ph, 4-NO2-Ph, 4-Ph-Ph, 3,5-diCl-Ph, 4-F-Bn, 4-OMe-Bn, 4-NMe2-Bn, naphth-2-yl, or
R5 is 2-t-Bu-Ph, 2-Br-Ph, 2-CO2Me-Ph, or 3-CO2Et-Ph.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein the compound is the following formula:
or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein:
R1c is H, i-Pr, t-Bu, neopentyl, —CH2O(CH2)2OMe, —C(Me)2(CH2)2CO2Me, —(CH2)3N(Me)(Bn, —C(Me)2(CH2)3N(Me)Bn, —C(Me)2CH2CON(Me)Bn, —C(Me)2(CH2)2CON(Me)Bn, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Ph, 3-Me-Ph, 4-Me-Ph, 4-t-Bu-Ph, 2-OMe-Ph, 4-OMe-Ph, 4-F-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-CF3-Ph, 3-OCF3-Ph, 4-OCF3-Ph, 4-CN-Ph, 3-NMe2-Ph, 4-NMe2-Ph, 3-CH2NMe2-Ph, 4-CH2NMe2-Ph, 4-NO2-Ph, 3,5-diCl-Ph, 4-Ph-Ph, 4-F-Bn, —CH2OBn, 4-OMe-Bn, 4-NMe2-Bn, phenethyl, 1-Ph-cyclopropyl, —CON(Me)Bn,
naphth-2-yl, or

### Claim 5 (depends on 1)

A compound according to claim 1, wherein the compound is selected from the group consisting of:
or a stereoisomer or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

### Claim 7 (depends on 2)

A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2.

### Claim 8 (depends on 3)

A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3.

### Claim 9 (depends on 4)

A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.

### Claim 10 (depends on 5)

A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 5.