US 7,622,585 B2Granted

Phenylglycinamide derivatives useful as anticoagulants

AssigneeBristol-Myers Squibb Company

InventorsXiaojun Zhang, Eldon Scott Priestley, Alexandra A. Nirschl, Yan Zou

Life of this patent

Estimating the term…

Abstract

The present invention relates generally to phenylglycinamide derivatives that inhibit serine proteases. In particular it0 is directed to novel phenylglycinamide derivatives, and analogues thereof, which are useful as selective inhibitors of serine protease enzymes of the coagulation cascade; for example thrombin, factor VIIa, factor Xa, factor XIa, factor IXa, and/or plasma kallikrein. In particular, it relates to compounds that are factor VIIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.

Claims23

Dependent claims

A compound of Formula (I):

or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from:
R1 is, independently at each occurrence, H, F, Cl, Br, I, C1-5 alkyl substituted with 0-1 OH, C1-5 haloalkyl, C2-5 alkenyl, C2-5 alkynyl, —O—C1-5 alkyl, —O—C1-5 haloalkyl, —S—C1-5 alkyl, or C3-6 cycloalkyl;
R2 and R3 are, independently at each occurrence, H, F, Cl, Br, I, ORa, SRa, OCF3, CN, NO2, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —NRcC(O)ORa, —NRcC(O)NRcRd, —SO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, C3-10 carbocycle substituted with 0-3 Rf, or a 5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
R4 is, independently at each occurrence, H, F, Cl, Br, I, ORa, SRa, OCF3, CN, NO2, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —NRcC(O)ORa, —NRcC(O)NRcRd, —SO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, C3-10 carbocycle substituted with 0-3 Rf, or a 5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle are substituted with 0-3 Rf;
alternatively, R2 and R3 may combine to form a 5- to 7-membered carbocycle or heterocycle comprising:
carbon atoms and 0-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said carbocycle and heterocycle are substituted with 0-3 Rf;
alternatively, R3 and R4 may combine to form a 5- to 7-membered carbocycle or heterocycle comprising:
carbon atoms and 0-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said carbocycle and heterocycle are substituted with 0-3 Rf;
W is NH or O;
Z is
substituted with 0-2 R6 ;
R6 is, independently at each occurrence, F, Cl, Br, I, CN, OH, CF3, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy;
X1 and X2 are, independently at each occurrence, H or NH2;
ring A is a 4- to 8-membered heterocycle comprising:
the nitrogen atom shown in the ring, carbon atoms and 0-1 additional heteroatom selected from N, NRc, O, and S(O)p, 0-1 carbonyl, and 0-2 double bonds, wherein said heterocycle is substituted with 0-2 R7;
R7 is, independently at each occurrence, ORa, F, Cl, Br, I, CN, NO2, —OCF3, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —SO2NRcRd, —NRcSO2Ri, —SO2NHC(O)Ra, —C(O)NHSO2Ra, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, tetrazole, —(CH2)r-phenyl substituted with 0-3 Rf, or a —(CH2)r-5- to 6-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
R8 is H, CN, —CO2Ra, —C(O)NRcRd, tetrazolyl, or C1-4 alkyl substituted with 0-2 R8a;
R8a is, independently at each occurrence, ═O, ORa, F, Cl, Br, I, CN, NO2, —OCF3, —NRbRc, —C(O)Ra, —CO2Ra, —OC(O)Ra, —OC(O)NRcRd, —NRdC(O)Ra, —C(O)NRcRd, —NRcC(O)NRcRd, NRcC(O)ORa, —SO2NRcRd, —NRcSO2Ri, —NRcSO2NRcRd, —SO2NHC(O)Ra, —C(O)NHSO2Ra, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, tetrazole, C3-6 cycloalkyl substituted with 0-3 Rf, phenyl substituted with 0-3 Rf, or 5- to 6-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
R9 is phenyl substituted with 0-3 R10, naphthyl substituted with 0-3 R10, or a 5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R11;
R10 is, independently at each occurrence, F, Cl, Br, I, —(CH2)r—ORa, SRa, OCF3, SCF3, CN, NO2, —B(OH)2, —(CH2)r—NRbRc, —C(O)Ra, —(CH2)r—CO2Ra, —(CH2)r—NRcCO2Ra, —NRdC(O)Ra, —(CH2)r—C(O)NRcRd, —NRcC(O)NRcRd, —SO2NRcRd, —OSO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rf, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle are substituted with 0-3 Rf;
R11 is, independently at each occurrence, ═O, F, Cl, Br, I, —(CH2)r—ORa, SRa, OCF3, SCF3, CN, NO2, —B(OH)2, —(CH2)rNRbRc, —C(O)Ra, —(CH2)rCO2Ra, —(CH2)r—NRcCO2Ra, —NRdC(O)Ra, —(CH2)r—C(O)NRcRd, —NRcC(O)NRcRd, —SO2NRcRd, —OSO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, or C2-6 alkynyl substituted with 0-2 Re, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rf, —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle are substituted with 0-3 Rf;
Ra is, independently at each occurrence, H, C1-6 alkyl substituted with 0-4 Rh, —(CH2)r—C3-7 carbocycle substituted with 0-4 Rf, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heteroaryl is substituted with 0-4 Rf;
Rb is, independently at each occurrence, H, C1-6 alkyl, —(CH2)n-phenyl, (C1-6 alkyl)C(O)—, (C3-6 cycloalkyl)-C0-4 alkyl-C(O)—, (C6-10 aryl)-(C0-4 alkyl)-C(O)—, (5- to 10-membered heteroaryl)-C0-4 alkyl-C(O)—, (C1-6 alkyl)-NHC(O)—, (C1-6 alkyl)2—NHC(O)—, (C6-10 aryl)-C0-4 alkyl-NHC(O)—, (5- to 10-membered heteroaryl)-C0-4 alkyl-NHC(O)—, (C1-6 alkyl)-SO2—, (C6-10 aryl)-C0-4 alkyl-SO2—, or (5- to 10-membered heteroaryl)-C0-4 alkyl-SO2—, wherein said phenyl, aryl and heteroaryl are substituted with 0-2 Rf;
Rc is, independently at each occurrence, H, C1-6 alkyl substituted with 0-3 Rh, —(CH2)n—C3-7 cycloalkyl substituted with 0-3 Rh, or —(CH2)n-phenyl substituted with 0-3 Rh;
alternatively, Rb and Rc, when attached to the same nitrogen atom, may be taken together with the nitrogen atom to form a 4- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein heterocycle are substituted with 0-3 Rf;
Rd is, independently at each occurrence, H, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rf, or a —(CH2)r-5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
alternatively, Rc and Rd, when attached to the same nitrogen atom, may be taken together with the nitrogen atom to form a 4- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein heterocycle are substituted with 0-3 Rf;
Re is, independently at each occurrence, ═O, ORa, F, Cl, Br, I, CN, NO2, —SRa, —OCF3, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —OC(O)Ra, —NRdC(O)ORa, —NRdC(O)NRcRd, —OC(O)NRcRd, —SO2NRcRd, —NC(O)ORa, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C3-10 carbocycle substituted with 0-3 Rf, or a 5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
Rf is, independently at each occurrence, ═O, ORg, F, Cl, Br, I, CN, NO2, —SRg, —OCF3, —NRcRc, —C(O)Rg, —CO2Rg, —NRcC(O)Rg, —C(O)NRcRc, —OC(O)Rg, —NRcC(O)ORg, —NRcC(O)NRcRc, —OC(O)NRcRc, —SO2NRcRc, —NRcSO2NRcRc, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle substituted with 0-3 Rh, or a 5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, and substituted with 0-3 Rh;
Rg is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
Rh is, independently at each occurrence, ═O, —(CH2)rORg, F, Cl, Br, I, CN, NO2, —OCF3, —NRgRg, —C(O)Rg, —CO2Rg, —NRgC(O)Rg, —C(O)NRgRg, —SO2NRgRg, —NRgSO2NRgRg, —NRgSO2—C1-4 alkyl, —NRgSO2CF3, —NRgSO2-phenyl, —SO2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (C1-6 alkyl)C(O)—, (C3-6 cycloalkyl)-C0-4 alkyl-C(O)—, (C6-10 aryl)-(C0-4 alkyl)-C(O)—, (5-10 membered heteroaryl)-C0-4 alkyl-C(O)—, (C1-6 alkyl)-NHC(O)—, (C1-6 alkyl)2—NHC(O)—, (C6-10 aryl)-C0-4 alkyl-NHC(O)—, (5-10 membered heteroaryl)-C0-4 alkyl-NHC(O)—, (C1-6 alkyl)-SO2—, (C6-10 aryl)-C0-4 alkyl-SO2—, (5-10 membered heteroaryl)-C0-4 alkyl-SO2—, —(CH2)r C3-10 carbocycle, or a —(CH2)r-5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p;
Ri is, independently at each occurrence, H, C1-6 alkyl substituted with 0-3 Rh, C3-6 cycloalkyl substituted with 0-3 Rh, —(CH2)n-phenyl substituted with 0-3 Rh, —(CH2)r-5- to 10 -membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rh;
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.

49 more elements

A compound selected from the group consisting of:

2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-l -(2-phenylpyrrolidin-1-yl)ethanone;
3-(1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-pyrrohdin-2-yl)benzenesulfonamide;
N-(3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidin-2-yl)phenyl)acetamide;
N-(3-((R)-1-((S)-2-(1-aminoisoquinohn-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidin-2-yl)phenyl)acetamide;
N-(3-((S)-1-((R)-2-(1-aminoisoquinolin-6-ylaminol)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidin-2-yI)phenyl)acetamide;
N-(3-((S) 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidin-2-yl)phenyl)acetamide;
N-(3-((R)-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3,4-dimethoxyphenyl)acetyl)pyrrohdin-2-yl)phenyl)acetamide;
methyl 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-phenylpyrrolidine-3-carboxylate;
1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-phenylpyrrolidine-3-carboxylic acid;
methyl 1-(2-(1-aininoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-(isopropylthio)phenyl)pyrrolidine-3 -carboxylate;
1 -(2-( 1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-(isopropylthio)phenyl)pyrrolidine-3-carboxylic acid;
methyl 1-(2-(1 -aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-sopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
1 -(2-(1 -aminoisoquinolin-6ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-(isopropylsufonyl)phenyl)pyrrolidine-3-carboxylic acid;
methyl 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(3-nitrophenyl)pyrrolidine-3-carboxylate;
1 -(2-( 1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(3-nitrophenyl)pyrrolidine-3-carboxylic acid;
methyl 2-(3-acetamidophenyl)-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylate;
2-(3-acetamidophenyl)-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-cthoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylic acid;
1-(2-(5-amino-2(isopropylsulfonyl)phenyl)pyrrolidin-1-yl)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)ethanone;
methyl 2-(5-amino-2isopropylsulfonyl)phenyl)-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylate;
2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)-1-(2-(2-(isopropylsulfonyl)phenyl)pyrrolidin-1-yl)ethanone;
2-(5 -amino-2-(isopropylsulfonyl)phenyl) 1(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylic acid;
N-(3-(1-(2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3-methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfoflyl)phenyl)acetamide;
methyl 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)-5-nitrophenyl)pyrrolidine-3-carboxylatc;
1-(2-(1-aminoisoquinolin-6-ylarnino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)-5-nitrophenyl)pyrrolidine-3-carboxylic acid;
(cis)-methyl 2-(5-acetamido-2isopropylsulfonyl)phenyl)1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylate;
trans-methyl 2-(5-acetamido-2-(isopropylsulfonyl)phenyl) 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylate;
cis-methyl 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)-5methoxycarbonyl)phenyl)pyrrolidine-3-carboxylate;
trans-methyl 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-isopropylsulfonyl)-5-(methoxycarbonyl)phenyl)pyrrolidine-3-carboxylate;
N-(3-(1-(2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenyl)acetamide;
N-(3-(1-(2-(1-aminoisoquinoliu-6-ylamino)-2-(4-chloro-3-ethoxypheny1)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenyl)acetamide;
N-(3-(1-(2-(1-aminoisoquinolin-6-ylarnino)-2-(3-ethoxy-4-fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfony)phenyl)acetamide;
cis-2-(5-acetamido-2-(isopropylsulfonyl)phenyl)-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylic acid;
trans-2-(5-acetamido-2-(isopropylsulfonyl)phenyl)-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)pyrrolidine-3-carboxylic acid;
cis-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)-5-(metboxycarbonyl)phenyl)pyrrolidine-3-carboxylic acid;
trans-1-(2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetyl)-2-(2isopropylsulfonyl)-5-(methoxycarbonyl)phenyl)pyrrolidine-3-carboxylic acid;
cis-methyl 1-(2-(1-arninoisoquino-6-ylamino)-2-(3-ethoxy-4-fluoropheny)acetyl)- 2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
cis-methyl 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3-ethoxyphenyl)acetyl)- 2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
cis-methyl 1-(2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)pheny)pyrrolidine-3-carboxylate;
N-(3((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyt)acetyl)pyrrolidin-2-yl)-4-isopropylsulfonyl)phenyl)acetamide;
N-(3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrroIidin-2-yl)-4-(isopropylsufonyl)phenyI)acetamide;
N-(3-((S)-1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylacetamide;
N-(3-((S)-1-((5)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenyl)acetamide;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyi)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenycarbamate;
methyl 3-1-(R)-2-(1aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfony)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yI)-4-isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-isopropylsulfonyl)phenylearbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-isopropylsulfonyl)phenyIcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
N-(3-((R)-1-((R)-2(1-aminoisoquinolin-6-ylamino)-2-phenylacetyl)pyrrolidin-2-yl)- 4-(isopropylsuifonyl)phenyl)acetamide;
N-(3((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-phenylacetyl)pyrrolidin-2-yl)- 4-(isopropylsulfonyl)phenyl)acetamide;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinohn-6-ylamino)-2-(4-fluoro-3- methoxypheny)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenycarbamate;
methyl 3((R)-1((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
(2R, 3S)-methyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-methyl 1-((R)-2-(1-aminoisoquinolin-6-ylarnino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2S, 3R)-methyl 1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3 -ethoxy-4- isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3carboxylate;
(2R, 3S)-methyl 2(-acetarnido-2-(isopropylsulfonyl)phenyl)-1-((R)-2-(1- aminoisoquinolin-6-ylamino)-2-(5ethoxy-2-fluorophenyl)acetyl)pyrrolidine-3-carboxylate;
(2R, 3S)-methyl 2-(5-acetamido-2-isopropylsulfonyl)phenyl)-1-((S)-2-(1- arninoisoquinolin-6-ylamino)-2-(5 -ethoxy-2-fluorophenyl)acetyl)pyrrolidine-3-carboxylate;
(2S, 3R)-methyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)-2-(2isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfony)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4- methoxyphenyl)acetyl)pyrrolidin-2-yI)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6ylamino)-2-(2-fluoro-5- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-5- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropyisulfonyl)phenylcarbamate;
methyl 3-((R)-1((R)-2-(aminoisoquinolin-6-ylamino)-2-(2-fluoro-5- methylphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-5- methylphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
(2S, 3R)-1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
methyl 3((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsuifonyl)phenylcarbamate;
methyl 3((R)-1-((S)-2-(1-aminoisoquinohn-6-ylamino)-2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfony)phenylcarbamate;
(S)-2-(1aminoisoquinolin-6-ylamino)-2(5-ethoxy-2-fluorophenyl)-1((R)-2-(2- (isopropylsulfonyl)phenyl)pyrrolidin-1-yl)ethanone;
(R)-2-(1-aminoisoquinolin-6-ylamino)-2(5-ethoxy-2-fluorophenyl)-1-((R)-2-(2- (isopropylsulfonyl)phenyl)pyrrolidin-1-yl)ethanone;
(2S, 3R)-methyl 1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)-2-(2-(isopropylsulfonyl)-5-(methoxycarbonyl)phenyl)-pyrrolidine-3- carboxylate;
(2S, 3R)-methyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)-2-(2-(isopropylsulfonyl)-5-(methoxycarbonyl)phenyl)-pyrrolidine-3- carboxylate;
(R)-1-((R)-2-(5-amino-2-(isopropylsulfonyl)phenyl)pyrrolidin-1-yl)-2-( 1- aminoisoquinolin-6-ylamino)-2(5-ethoxy-2-fluorophenyl)ethanone;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-phenylacetyl)pyrrolidin-2- yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-phenylacetyl)pyrrolidin-2- yl)-4-(isopropylsulfonyl)phenylcarbamate;
(R)-1-((S)-2-amino-2-(isopropylsulfonyl)phenyl)pyrrolidin-1-yl)-2-(1- aminoisoquinolin-6-ylamino)-2-(ethoxy-2-fluorophenyl)ethanone;
methyl 3-((R)-1-((R)-2-(aminoisoquinolin-6-yloxy)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yI)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5 -ethyl-2- ftuorophenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethyl-2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3((R)-1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-(S))-2-(1-aminoisoquinolin-6-ylamino)-2-(fluoro-4,5- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
(2R, 3S)-methyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3carboxylate;
(2R, 3S)-methyl 1-((R)-2-(1-aminoisoquinolin-6-ylainino)-2-(5-ethoxy-2- fluorophenyl)acetyl)-2(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-yloxy)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfony)phenylcarbamate;
(2R, 3S)-methyl 1-((5)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)-2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-methyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyi)-2-(isopropylsulfonyl)pheny)pyrrolidine-3-carboxylate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2,4-difluoro-5- methylphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfony)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-ammnoisoquinolin-6-ylamino)-2-(2,4-difluoro-5- methylphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4- isopropoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-ethoxy-2,4- difluorophenyl)acetyl)pyrrolidin-2-yI)-4-(isopropylsulfonyt)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2,4-difluoro-5- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5 -ethoxy-2- fluorophenyl)acetyl)-2-(2-(isopropylsulfonyl)-5-(metboxycarbonyl)phenyl)-pyrrolidine-3- carboxylic acid;
methyl 3-((S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3ethoxy-4- isopropoxyphenyl)acetyl)pyyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((S)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- isopropoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5ethoxy-2- fluorophenyl)acetyl)pyrrolidin-2-yI)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)2-(2,4-difluoro-5- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(2,4-difluoro-5- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
ethyl 3-((R)-1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acety)pyrroIidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
ethyl 3(R)-1-((S)-2(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfony)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3(R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3,4- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)2-(1-aminoisoquinolin-6-ylamino)-2-(3,4- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
(R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4-isopropoxyphenyl)- 1-((2R, 4R)- 4-hydroxy-2-phenylpyrrolidin-1-yl)ethanone;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5dimethoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-fluoro-4,5- dimethoxyphenyl)acetyl)-2-(ethylsulfony1)phenyl)pyrrolidine-3-carboxylic acid;
methyl 3((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-5-ethyl-2- fluorophenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2(5-ethyl-2-fluoro-3- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3((R)-1((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-3- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-chloro-2- fluorophenyl)acetyl)pyrrolidin-2-yI)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methoxy-4- methylphenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(2-fluoro-5-methoxy-4- methylphenyl)acetyl)pyrrolidin-2-yl)-4ethylsulfonyl)phenylcarbamate;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-chloro-2- fluorophenyl)acetyl)-2-(2-(ethylsuifonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-chloro-2- fluorophenyl)acetyl)-2-(2ethylsulfonyl)phenyl)pyrrolidine-3carboxylate;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-ethyl-2-fluoro-3- methoxyphenyl)acetyl)-2-(2ethylsulfonyl)phenyl)pyrrolidine-3carboxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethyl-2-fluoro-3- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-chloro-2- fluorophenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5 -ethyl-2-fluoro-3- methoxyphenyl)acetyl)-2-(2-)ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-(1,1,2,2- tetrafluoroethoxy)phenyl)acetyl)pyrrolidin-2-yl)-4-(ethylsulfonyl)phenylcarbamate;
methyl 3-((R)-1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3- (difluoromethoxy)phenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenyl-carbamate;
methyl 3-((R)-1-((R)-2-(3,4-bis(difluoromethoxy)phenyl)-2-(1-aminoisoquinolin-6- ylamino)acetyl)pyrrolidin-2-yI)-4-(isopropylsulfonyl)phenyl-carbamate;
(2R, 3S)ethyl 1((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2- fluorophenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(5-ethoxy-2-fluoro-4- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
methyl 3-((R)-1-((R)-2-(1-aminoisoquinolin-6-yloxy)-2-(3 4- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquinolin-6-yloxy)-2-(3, 4- dimethoxyphenyl)acetyl)-pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((R)-2-(1-aminoisoquiuolin-6-yloxy)2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenylcarbamate;
methyl 3-((R)-1-((S)-2-(1-aminoisoquino-6-yloxy)-2-(2-fluoro-4,5- dimethoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsalfonyl)phenylcarbamate;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- ethoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- ethoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylarnino)-2-(3-ethoxy-4- fluorophenyl)acetyl)-2-(ethylsulfonyl)phenyI)pyrrolidine-3-carboxyIate;
(2R, 3S)-ethyl 1-((R)-2-(1-arninoisoquinolin-6-ylamino)-2-(3-ethoxy-4- fluorophenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-2-((R)-2-(1-aminoisoquinolim6-ylamino)-2-(4-chloro-3- ethoxyphenyl)acetyl)-2-(ethysulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-fluoro-3- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3-ethoxy-4- fluorophenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- rnethoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- methoxyphenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- rnethoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine3-carhoxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine3-carboxylate;
(2S, 3R)-ethyl 1-((S)-2-(1-aminoisoquinolin-6-ylarnino)-2-(4chloro-3- methoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)pheny)pyrrolidine-3-carboxylate;
(2S, 3R)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(isopropysulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-ethyl 1((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- methoxyphenyl)acetyl)-2-(2-(isopropylsulfony)phenyl)pyrrolidine3-carboxylate;
(2R, 3S)-ethyl 1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- rnethoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3R)-ethyl 2(R)-2-(1-aminoisoquinolin-6-yiarnino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(cyclopropylsulfonyl)phenyl)pyrrolidine-3-carboxylate;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2S, 3R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3methoxyphenyl)acetyl)-2-(2-(isopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-chloro-3- methoxyphenyl)acetyl)-2-(2-(isopropylsulfonyI)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2-(cyclopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- rnethoxyphenyl)acetyl)-2-(2-(cyclopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2S, 3S) ((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- rnethoxyphenyl)acetyl-2-(2-(cyclopropylsulfonyl)pheny)pyrrolidine-3-carboxylic acid;
(2S, 3R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)-2-(2cyclopropylsulfonyl)phenyl)pyrrolidine-3-carboxylic acid;
(2R, 3S)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(3 -ethoxy-4- fluorophenyl)acetyl)-2-(2-(ethylsulfonyl)phenyl)-N,N-dimethylpyrrolidine-3-carboxamide;
3-(3-((R)-1-((R)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)pyrrolidin-2-yI)-4-(isopropylsulfonyl)phenyl) 1,1-dimethylurea;
and
3(3-((R)-1-((S)-2-(1-aminoisoquinolin-6-ylamino)-2-(4-fluoro-3- methoxyphenyl)acetyl)pyrrolidin-2-yl)-4-(isopropylsulfonyl)phenyl)-1,1dimethylurea;
or a stereoisomer a tautomer, or a pharmaceutically acceptable salt thereof.

163 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/328,479Filed 9 Jan 2006 · us provisional application
Priority: 10 Jan 2005
Published: US 2006/0166997 A127 Jul 2006
Granted: 24 Nov 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/00
Drugs for disorders of the cardiovascular system
C07D 207/14
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…

Family

Application60/642,751Us provisional application · filed 10 Jan 2005
US 2006/0166997 A1Pre-grant publication · published 27 Jul 2006
US 7,622,585 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I):

or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:
Y is selected from:
R1 is, independently at each occurrence, H, F, Cl, Br, I, C1-5 alkyl substituted with 0-1 OH, C1-5 haloalkyl, C2-5 alkenyl, C2-5 alkynyl, —O—C1-5 alkyl, —O—C1-5 haloalkyl, —S—C1-5 alkyl, or C3-6 cycloalkyl;
R2 and R3 are, independently at each occurrence, H, F, Cl, Br, I, ORa, SRa, OCF3, CN, NO2, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —NRcC(O)ORa, —NRcC(O)NRcRd, —SO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, C3-10 carbocycle substituted with 0-3 Rf, or a 5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
R4 is, independently at each occurrence, H, F, Cl, Br, I, ORa, SRa, OCF3, CN, NO2, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —NRcC(O)ORa, —NRcC(O)NRcRd, —SO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, C3-10 carbocycle substituted with 0-3 Rf, or a 5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle are substituted with 0-3 Rf;
alternatively, R2 and R3 may combine to form a 5- to 7-membered carbocycle or heterocycle comprising:
carbon atoms and 0-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said carbocycle and heterocycle are substituted with 0-3 Rf;
alternatively, R3 and R4 may combine to form a 5- to 7-membered carbocycle or heterocycle comprising:
carbon atoms and 0-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said carbocycle and heterocycle are substituted with 0-3 Rf;
W is NH or O;
Z is
substituted with 0-2 R6 ;
R6 is, independently at each occurrence, F, Cl, Br, I, CN, OH, CF3, C1-4 alkyl, C1-4 haloalkyl, or C1-4 alkoxy;
X1 and X2 are, independently at each occurrence, H or NH2;
ring A is a 4- to 8-membered heterocycle comprising:
the nitrogen atom shown in the ring, carbon atoms and 0-1 additional heteroatom selected from N, NRc, O, and S(O)p, 0-1 carbonyl, and 0-2 double bonds, wherein said heterocycle is substituted with 0-2 R7;
R7 is, independently at each occurrence, ORa, F, Cl, Br, I, CN, NO2, —OCF3, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —SO2NRcRd, —NRcSO2Ri, —SO2NHC(O)Ra, —C(O)NHSO2Ra, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, tetrazole, —(CH2)r-phenyl substituted with 0-3 Rf, or a —(CH2)r-5- to 6-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
R8 is H, CN, —CO2Ra, —C(O)NRcRd, tetrazolyl, or C1-4 alkyl substituted with 0-2 R8a;
R8a is, independently at each occurrence, ═O, ORa, F, Cl, Br, I, CN, NO2, —OCF3, —NRbRc, —C(O)Ra, —CO2Ra, —OC(O)Ra, —OC(O)NRcRd, —NRdC(O)Ra, —C(O)NRcRd, —NRcC(O)NRcRd, NRcC(O)ORa, —SO2NRcRd, —NRcSO2Ri, —NRcSO2NRcRd, —SO2NHC(O)Ra, —C(O)NHSO2Ra, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, tetrazole, C3-6 cycloalkyl substituted with 0-3 Rf, phenyl substituted with 0-3 Rf, or 5- to 6-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
R9 is phenyl substituted with 0-3 R10, naphthyl substituted with 0-3 R10, or a 5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R11;
R10 is, independently at each occurrence, F, Cl, Br, I, —(CH2)r—ORa, SRa, OCF3, SCF3, CN, NO2, —B(OH)2, —(CH2)r—NRbRc, —C(O)Ra, —(CH2)r—CO2Ra, —(CH2)r—NRcCO2Ra, —NRdC(O)Ra, —(CH2)r—C(O)NRcRd, —NRcC(O)NRcRd, —SO2NRcRd, —OSO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rf, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle are substituted with 0-3 Rf;
R11 is, independently at each occurrence, ═O, F, Cl, Br, I, —(CH2)r—ORa, SRa, OCF3, SCF3, CN, NO2, —B(OH)2, —(CH2)rNRbRc, —C(O)Ra, —(CH2)rCO2Ra, —(CH2)r—NRcCO2Ra, —NRdC(O)Ra, —(CH2)r—C(O)NRcRd, —NRcC(O)NRcRd, —SO2NRcRd, —OSO2NRcRd, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, or C2-6 alkynyl substituted with 0-2 Re, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rf, —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRc, O, and S(O)p, wherein said heterocycle are substituted with 0-3 Rf;
Ra is, independently at each occurrence, H, C1-6 alkyl substituted with 0-4 Rh, —(CH2)r—C3-7 carbocycle substituted with 0-4 Rf, or —(CH2)r-5- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heteroaryl is substituted with 0-4 Rf;
Rb is, independently at each occurrence, H, C1-6 alkyl, —(CH2)n-phenyl, (C1-6 alkyl)C(O)—, (C3-6 cycloalkyl)-C0-4 alkyl-C(O)—, (C6-10 aryl)-(C0-4 alkyl)-C(O)—, (5- to 10-membered heteroaryl)-C0-4 alkyl-C(O)—, (C1-6 alkyl)-NHC(O)—, (C1-6 alkyl)2—NHC(O)—, (C6-10 aryl)-C0-4 alkyl-NHC(O)—, (5- to 10-membered heteroaryl)-C0-4 alkyl-NHC(O)—, (C1-6 alkyl)-SO2—, (C6-10 aryl)-C0-4 alkyl-SO2—, or (5- to 10-membered heteroaryl)-C0-4 alkyl-SO2—, wherein said phenyl, aryl and heteroaryl are substituted with 0-2 Rf;
Rc is, independently at each occurrence, H, C1-6 alkyl substituted with 0-3 Rh, —(CH2)n—C3-7 cycloalkyl substituted with 0-3 Rh, or —(CH2)n-phenyl substituted with 0-3 Rh;
alternatively, Rb and Rc, when attached to the same nitrogen atom, may be taken together with the nitrogen atom to form a 4- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein heterocycle are substituted with 0-3 Rf;
Rd is, independently at each occurrence, H, C1-6 alkyl, —(CH2)r—C3-10 carbocycle substituted with 0-3 Rf, or a —(CH2)r-5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
alternatively, Rc and Rd, when attached to the same nitrogen atom, may be taken together with the nitrogen atom to form a 4- to 10-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein heterocycle are substituted with 0-3 Rf;
Re is, independently at each occurrence, ═O, ORa, F, Cl, Br, I, CN, NO2, —SRa, —OCF3, —NRbRc, —C(O)Ra, —CO2Ra, —NRdC(O)Ra, —C(O)NRcRd, —OC(O)Ra, —NRdC(O)ORa, —NRdC(O)NRcRd, —OC(O)NRcRd, —SO2NRcRd, —NC(O)ORa, —NRcSO2NRcRd, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C3-10 carbocycle substituted with 0-3 Rf, or a 5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rf;
Rf is, independently at each occurrence, ═O, ORg, F, Cl, Br, I, CN, NO2, —SRg, —OCF3, —NRcRc, —C(O)Rg, —CO2Rg, —NRcC(O)Rg, —C(O)NRcRc, —OC(O)Rg, —NRcC(O)ORg, —NRcC(O)NRcRc, —OC(O)NRcRc, —SO2NRcRc, —NRcSO2NRcRc, —NRcSO2Ri, —NRcSO2CF3, —SO2CF3, —S(O)pRi, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle substituted with 0-3 Rh, or a 5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, and substituted with 0-3 Rh;
Rg is, independently at each occurrence, H, C1-6 alkyl, or —(CH2)n-phenyl;
Rh is, independently at each occurrence, ═O, —(CH2)rORg, F, Cl, Br, I, CN, NO2, —OCF3, —NRgRg, —C(O)Rg, —CO2Rg, —NRgC(O)Rg, —C(O)NRgRg, —SO2NRgRg, —NRgSO2NRgRg, —NRgSO2—C1-4 alkyl, —NRgSO2CF3, —NRgSO2-phenyl, —SO2CF3, —S(O)p—C1-4 alkyl, —S(O)p-phenyl, —(CF2)rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (C1-6 alkyl)C(O)—, (C3-6 cycloalkyl)-C0-4 alkyl-C(O)—, (C6-10 aryl)-(C0-4 alkyl)-C(O)—, (5-10 membered heteroaryl)-C0-4 alkyl-C(O)—, (C1-6 alkyl)-NHC(O)—, (C1-6 alkyl)2—NHC(O)—, (C6-10 aryl)-C0-4 alkyl-NHC(O)—, (5-10 membered heteroaryl)-C0-4 alkyl-NHC(O)—, (C1-6 alkyl)-SO2—, (C6-10 aryl)-C0-4 alkyl-SO2—, (5-10 membered heteroaryl)-C0-4 alkyl-SO2—, —(CH2)r C3-10 carbocycle, or a —(CH2)r-5- to 12-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p;
Ri is, independently at each occurrence, H, C1-6 alkyl substituted with 0-3 Rh, C3-6 cycloalkyl substituted with 0-3 Rh, —(CH2)n-phenyl substituted with 0-3 Rh, —(CH2)r-5- to 10 -membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NRg, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rh;
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.

49 more elements

Facts

Application

11/328,479Filed 9 Jan 2006 · us provisional application

Priority

10 Jan 2005

Published

US 2006/0166997 A127 Jul 2006

Granted

24 Nov 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/00
Drugs for disorders of the cardiovascular system
C07D 207/14
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…