Factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-10093683-B2
Application number	US-201515305421-A
Country	US
Kind code	B2
Filing date	Apr 21, 2015
Priority date	Apr 22, 2014
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

The present invention provides a compound of Formula (I)

and pharmaceutical compositions comprising one or more compounds of Formula (I), and methods for using the compounds of Formula (I) for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.

First claim

What is claimed is:

1. A compound of Formula I:

wherein X is absent, CH 2 , CH 2 O, O or NH;
Y 1 is CR 3 or N,
Y 2 is CR 3 or N,
Y 3 is CR 3 or N,
Y 4 is CR 3 or N,
with the proviso that three of Y 1 , Y 2 , Y 3 and Y 4 are not simultaneously N, and all four of Y 1 , Y 2 , Y 3 and Y 4 are not simultaneously N;
Z is S, SO, SO 2 or C═O;
L is NHC(═O);
M is phenyl, wherein said phenyl group is optionally substituted with one to three substituents independently selected from halo, cyano, hydroxy, oxo, C 1-6 alkyl or NR 6 R 7 ;
R 1a is hydrogen, halo, cyano, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, C 1-4 alkyl-C 3-6 cycloalkyl, C 1-4 alkyl-aryl, C 1-4 alkyl-heteroaryl or C 1-4 alkyl-heterocyclyl, wherein said alkyl groups are optionally substituted with one to three substituents independently selected from halo, hydroxy, methoxy, SR 4 , SOR 4 , SO 2 R 4 , C(═O)R 9 , C(═O)NHR 9 , C(═O)NHCH 2 R 9 , C(═O)NHSO 2 R 9 or NHC(═O)R 4 , and said cycloalkyl, aryl, heteraryl and heterocyclyl groups are optionally substituted with one to three groups independently selected from halo, hydroxy, oxo, cyano, C 1-4 alkyl, C 2-4 alkenyl-OR 4 , OR 4 , C(═O)NR 6 R 7 , NHC(═O)R 4 , NHC(═O)R 9 , NHC(═O)OR 9 , C(═O)R 9 , R 9 , OR 9 , NHSO 2 R 4 , SO 2 R 4 or NR 6 R 7 ;
R 1b is hydrogen, halo, cyano, hydroxy or C 1-4 alkyl, wherein said alkyl is optionally substituted with one to three groups independently selected from halo or hydroxy;
or R 1a and R 1b can be taken together with the atom between them to form a C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl ring system wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl ring systems are optionally substituted with one to three groups independently selected from halo, hydroxy or aryl;
R 2 is hydrogen, halo, cyano, OR 4 , R 4 , R 9 , C(═O)OR 4 , C 1-3 alkyl-C(═O)OR 5 , NR 4 R 7 , NR 6 R 9 , NHC(═O)R 4 , NHC(═O)OR 4 , NHC(═O)O—C 1-3 alkyl-OR 5 , NHC(═O)O(C 1-3 alkyl)R 9 , NHC(═O)O(R 4 )C(═O)OH, C 1-3 alkyl-NHC(═O)OR 5 , NHC(═O)NR 6 R 7 , NH(C═NH)NR 6 R 7 , C(═O)NR 6 R 7 , CH 2 C(═O)NR 6 R 7 , C(CH 3 )(NR 6 R 7 )C(═O)R 4 , NHC(═O)NH—C 1-3 alkyl-R 9 , SO 2 R 4 , NHSO 2 R 4 , NHSO 2 R 9 , SO 2 NR 6 R 7 , P(═O)(OCH 2 CH 3 ) 2 , P(═O)(OH) 2 ; or B(OH) 2 ;
each R 3 is independently hydrogen, R 4 , C 3-6 cycloalkyl, halo, cyano or OR 4 , wherein said alkyl and cycloalkyl groups are optionally substituted with one to three groups independently selected from halo or hydroxy;
each R 4 is independently hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with one to three halo or hydroxy;
each R 5 is independently hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with one to three halo;
each R 6 is independently hydrogen or C 1-6 alkyl;
each R 7 is independently hydrogen or C 1-6 alkyl;
each R 8 is independently hydrogen, halo or methyl;
each R 9 is independently aryl, heteroaryl, heterocyclyl or C 3-8 cycloalkyl, wherein said aryl, heteroaryl, heterocyclyl and cycloalkyl groups are optionally substituted with one to three substituents independently selected from the group consisting of halo, cyano, oxo, cyclopropyl, R 4 , OR 4 , C(═O)OR 4 or NR 6 R 7 ;
n is an integer from zero to three;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein X is O; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein R 1a is C 1-4 alkyl-aryl and R 1b is hydrogen; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 wherein R 1a is CH 2 -phenyl and R 1b is hydrogen; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein R 2 is NHC(═O)OR 4 ; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 3 is halo; or a pharmaceutically acceptable salt thereof.

7. A compound selected from:
methyl (4-(((S)-1-((S)-6-chloro-2-oxo-1,2-dihydrospiro[pyrido[2,3-d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-chloro-2-oxo-1,2-dihydrospiro[pyrido[2,3-d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-oxo-1-((R)-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((S)-6-chloro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-chloro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((2S)-1-(6′-chloro-2′-oxo-1′,2′-dihydrospiro[azepane-3,4′-benzo[d][1,3]oxazin]-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
(S)-methyl (4-((1-(6′-chloro-2′-oxo-1′,2′-dihydrospiro[azetidine-3,4′-benzo[d][1,3]oxazin]-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-chloro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((S)-6-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-methoxy-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-oxo-1-((R)-2-oxo-6-(trifluoromethyl)-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-chloro-5,7-difluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-chloro-8-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((2S)-1-(6-chloro-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((S)-6-methyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-methyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-pyrrolidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-methyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-5-fluoro-6-methyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((S)-1-((R)-6-cyclopropyl-5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,3′-piperidin]-1′-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((2S)-1-(6′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[pyrrolidine-3,4′-quinolin]-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carbamate;
methyl (4-(((2S)-1-(6′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[pyrrolidine-3,4′-quinazolin]-1-yl)-1-oxo-3-phenylpropan-2-yl)carbamoyl)phenyl)carba

Assignees

• Merck Sharp & Dohme

Inventors

• Lim Yeon-Hee
• Guo Zhuyan
• Ali Amjad
• Edmondson Scott D
• Liu Weiguo
• Gallo-Etienne Gioconda V
• Wu Heping
• Gao Ying-Duo
• Stamford Andrew W
• Yu Younong
• Kevin Nancy J
• Anand Rajan
• Sha Deyou
• Neelamkavil Santhosh F
• Hussain Zahid
• Kumar Puneet
• Moningka Remond
• Duffy Joseph L
• Xu Jiayi
• Jiang Yu
• Chakrabarti Anjan
• Sone Hiroki

Classifications

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D498/20 Primary

  Spiro-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title