Five-membered heterocycles useful as serine protease inhibitors

Patent metadata

Field	Value
Publication number	US-9617224-B2
Application number	US-201514722434-A
Country	US
Kind code	B2
Filing date	May 27, 2015
Priority date	Jun 15, 2004
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V):

or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R 3 , R 4 , R 6 , R 11 , X 1 , X 2 , and X 3 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.

First claim

What is claimed is:

1. A compound of Formula (V):

or its stereoisomers, tautomers, a pharmaceutically acceptable salts, or solvates thereof, wherein:
A is C 3-8 cycloalkyl substituted with 0-1 R 1 and 0-3 R 2 —
X 1 , X 2 , and X 3 are independently CR 3 , CR 4 , CR 4 R 5 , N, NR 3 , NR 6 or C(O);
provided that

is a triazole
Z is —C(R 11 )(R 12 )—, or —C(R 11 )(R 12 )—(CH 2 )— L is —C(O)NR 10 — R 1 is, independently at each occurrence, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —C(═NH)NH 2 , —C(O)NR 8 R 9 , —S(O) p NR 8 R 9 , —(CH 2 ) r NR 7 R 8 , —(CH 2 ) r NR 7 C(O)OR a , —CH 2 NH 2 , CH 2 NH(C 1-3 alkyl), —CH 2 N(C 1-3 alkyl) 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 NH(C 1-3 alkyl), —CH 2 CH 2 N(C 1-3 alkyl) 2 , —CH(C 1-4 alkyl)NH 2 , —C(C 1-4 alkyl) 2 NH 2 , —C(═NR 8a )NR 7 R 8 , —NHC(═NR 8a )NR 7 R 8 , ═NR 8 , —NR 8 CR 8 (═NR 8a ), F, Cl, Br, I, OCF 3 , CF 3 , —(CH 2 ) r OR a , —(CH 2 ) r SR a , CN, 1-NH 2 -1-cyclopropyl, or C 1-6 alkyl substituted with 0-1 R 1a ; R 1a is H, —C(═NR 8a )NR 7 R 8 , —NHC(═NR 8a )NR 7 R 8 , —NR 8 CH(═NR 8a ), —NR 7 R 8 , —C(O)NR 8 R 9 , F, OCF 3 , CF 3 , OR a , SR a , CN, —NR 9 SO 2 NR 8 R 9 , —NR 8 SO 2 R c , —S(O) p —C 1-4 alkyl, —S(O) p -phenyl, or —(CF 2 ) r CF 3 ; R 2 is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , OR a ,
SR a , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR 7 R 8 , —C(O)NR 7 R 8 , —NR 7 C(O)R b , —S(O) 2 NR 8 R 9 , —NR 8 S(O) 2 R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R 2a , C 2-6 alkenyl substituted with 0-2 R 2a , C 2-6 alkynyl substituted with 0-2 R 2a , —(CH 2 ) r —C 3-10 carbocycle substituted with 0-3 R 2b , or —(CH 2 ) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 2b ;
R 2a is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR 8 , CN, OCF 3 , CF 3 , OR a , SR a , —NR 7 R 8 , —C(O)NR 8 R 9 , —NR 7 C(O)R b , —S(O) p NR 8 R 9 , —NR 8 SO 2 R c , —S(O)R c , or —S(O) 2 R c ;
R 2b is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR 8 , CN, NO 2 , OR a , SR a , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR 7 R 8 , —C(O)NR 7 R 8 , —NR 7 C(O)R b , —S(O) 2 NR 8 R 9 , —S(O) 2 R c , —NR 8 SO 2 NR 8 R 9 , —NR 8 SO 2 R c , —(CF 2 ) r CF 3 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, or C 1-4 haloalkoxy;
alternately, when R 1 and R 2 groups are substituted on adjacent ring atoms, they can be taken together with the ring atoms to which they are attached to form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-4 heteroatoms selected from N, O, and S(O) p , wherein said carbocycle or heterocycle is substituted with 0-2 R 2b ;
R 3 is, independently at each

occurrence, —(CH 2 ) r C(O)NR 8 R 9 , —(CH 2 ) r C(O)NR 8 (CH 2 ) s CO 2 R 3b , —(CH 2 ) r CO 2 R 3b , —(CH 2 ) r —C 3-10 carbocycle substituted with 0-3 R 3a and 0-1 R 3d , or —(CH 2 ) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 3a and 0-1 R 3d ;
R 3a is, independently at each occurrence, ═O, F, Cl, Br, I, OCF 3 , CF 3 , NO 2 , CN, —(CH 2 ) r OR 3b , —(CH 2 ) r SR 3b , —(CH 2 ) r NR 7 R 8 , C(═NR 8a )NR 8 R 9 , —NHC(═NR 8a )NR 7 R 8 , —NR 8 CR 8 (═NR 8a ), —(CH 2 ) r NR 8 C(O)R 3b , ═NR 8 , —(CH 2 ) r NR 8 C(O)R 3b , —(CH 2 ) r NR 8 C(O) 2 R 3b , —(CH 2 ) r S(O) p NR 8 R 9 , —(CH 2 ) r NR 8 S(O) p R 3c , —S(O) p R 3c , —S(O) p R 3c , —C(O)—C 1-4

alkyl, —(CH 2 ) r CO 2 R 3b , —(CH 2 ) r C(O)NR 8 R 9 , —(CH 2 ) r OC(O)NR 8 R 9 , —NHCOCF 3 , —NHSO 2 CF 3 , —SO 2 NH R 3b , —SO 2 NHCOR 3c , —SO 2 NHCO 2 R 3c , —CONHSO 2 R 3c , —NHSO 2 R 3c , —CONHOR 3b , C 1-4 haloalkyl, C 1-4 haloalkoxy-, C 1-6 alkyl substituted by R 3d , C 2-6 alkenyl substituted by R 3d , C 2-6 alkynyl substituted by R 3d , C 3-6 cycloalkyl substituted by 0-1 R 3d , —(CH 2 ) r —C 3-10 carbocycle substituted with 0-3 R 3d , or —(CH 2 ) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 3d ;
alternately, when two R 3a groups are located on adjacent atoms, they can be taken together with the atoms to which they are attached to form a C 3-10 carbocycle substituted with 0-2 R 3d or a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 3d ;
R 3b is, independently at each occurrence, H, C 1-6 alkyl substituted with 0-2 R 3d , C 2-6 alkenyl substituted with 0-2 R 3d , C 2-6 alkynyl substituted with 0-2 R 3d , —(CH 2 ) r —C 3-10 carbocycle substituted with 0-3 R 3d , or —(CH 2 ) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 3d ;
R 3c is, independently at each occurrence, C 1-6 alkyl substituted with 0-2 R 3d , C 2-6 alkenyl substituted with 0-2 R 3d , C 2-6 alkynyl substituted with 0-2 R 3d , —(CH 2 ) r —C 3-10 carbocycle substituted with 0-3 R 3d , or —(CH 2 ) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 3d ;
R 3d is, independently at each occurrence, H, ═O, —(CH 2 ) r OR a , F, Cl, Br, CN, NO 2 , —(CH 2 ) r NR 7 R 8 , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR 7 C(O)R b , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 8 R 9 , —NR 8 SO 2 R c , —S(O) p R c , —(CF 2 ) r CF 3 , C 1-6 alkyl substituted with 0-2 R e , C 2-6 alkenyl substituted with 0-2 R e , C 2-6 alkynyl substituted with 0-2 R e , —(CH 2 ) r —C 3-10 carbocycle substituted with 0-3 R d , or —(CH 2 ) r -5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R d ;
R 4 is, independently at each occurrence, H, ═O, F, Cl, Br, I, OCF 3 , CF 3 , OR a , SR a , CN, NO 2 , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR 7 R 8 , —C(O)NR 8 R 9 , —NR 7 C(O)R b , —S(O) p NR 8 R 9 , —NR 8 S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R 4a , C 2-6 alkenyl substituted with 0-2 R 4a , C 2-6 alkynyl substituted with 0-2 R 4a , —(CH 2 ) r —C 3-10 carbocycle substituted with 0-3 R 4b , or —(CH 2 ) r -5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 4b ;
R 4a is, independently at each occurrence, H, F, ═O, C 1-6 alkyl, OR a , SR a , CF 3 , CN, NO 2 , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR 7 R 8 , —C(O)NR 8 R 9 , —NR 7 C(O)R b , —S(O) p NR 8 R 9 , —NR 8 S(O) 2 R c , —S(O)R c , or —S(O) 2 R c ;
R 4b is, independently at each occurrence, H, ═O, ═NR 8 , F, Cl, Br, I, OR a , SR a , CN, NO 2 , CF 3 , —SO 2 R c , —NR 7 R 8 , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR 7 R 8 , —C(O)NR 8 R 9 , —NR 7 C(O)R b , —S(O) p NR 8 R 9 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-4 haloalkyl, or C 1-4 haloalkoxy-;
alternately, R 3 and R 4 groups when located on adjacent atoms, can be taken together to form a C 3-10 carbocycle substituted with 0-2 R 3d or a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 3d ;
R 5 is, independently at each occurrence, H, F, OCF 3 , CF 3 , OR a , SR a , CN, NO 2 , —C(O)R a , —C(O)OR a , —OC(O)R a , —NR 7 R 8 , —C(O)NR 7 R 8 , —NR

Assignees

• Bristol Myers Squibb Co

Inventors

• Hangeland Jon J
• Quan Mimi L
• Smallheer Joanne M
• Bisacchi Gregory S
• Corte James R
• Friends Todd J
• Sun Zhong
• Rossi Karen A
• Cavallaro Cullen L

Classifications

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/06

  Antiarrhythmics · CPC title