Macrocycles as factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-9453029-B2
Application number	US-201514733996-A
Country	US
Kind code	B2
Filing date	Jun 9, 2015
Priority date	Feb 11, 2010
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The present invention provides compounds of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently a C 3-10 carbocycle or a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ;
ring B is imidazolyl;
ring C is phenyl;
L 1 is independently selected from the group consisting of: a bond, —CHR 5 —, —CHR 5 CHR 5 —, —CR 5 ═CR 5 —, —C≡C—, —OCH 2 —, —CHR 5 NH—, —CH 2 O—, —SCH 2 —, —SO 2 CH 2 —, —CH 2 NH—, and —CR 5 R 5 —;
L is independently selected from the group consisting of: —C 1-6 alkylene-(C 3-8 carbocycle)-C 0-4 alkylene-, and —C 1-6 alkylene-(5- to 6-membered heterocycle)-C 0-4 alkylene-; wherein said heterocycle comprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ; wherein said alkylene is substituted with 0-2 R 7 and optionally one or more of the carbon atoms of said alkylene may be replaced by O, S, NH, N(C 1-4 alkyl), CO, CONH, NHCO, OCONH, NHCO 2 , SO 2 NH, NHSO 2 , CON(C 1-4 alkyl), or N(C 1-4 alkyl)CO; wherein said carbocycle and heterocycle are substituted with 0-2 R 7a ;
Y is independently selected from the group consisting of: CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , O, S, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —OCON(C 1-4 alkyl)-, —NHCONH—, —SO 2 NH—, —NHCO 2 —, and —NHSO 2 —;
R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, OH, C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , CN, NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 (C 1-4 alkyl), —CO(C 1-4 alkyl), —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CH 2 NHCO 2 (C 1-4 alkyl), —OCH 2 CO 2 H, —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHSO 2 (C 1-4 alkyl), —SO 2 NH 2 , —C(═NH)NH 2 , and phenyl substituted with 0-2 R a ;
R 2 is independently a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 2a ;
R 2a is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, —CH 2 OH, C 1-4 alkoxy, OH, CF 3 , OCF 3 , CN, NH 2 , CO 2 H, CO 2 (C 1-4 alkyl), COC 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —SO 2 (C 1-4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), and —SO 2 N(C 1-4 alkyl) 2 ;
R 3 is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —CH 2 CO 2 H, and C 3-6 cycloalkyl;
R 4 is independently selected from the group consisting of: H, and C 1-4 alkyl;
R 5 is, independently at each occurrence, selected from the group consisting of: H, halogen, OH, and C 1-4 alkyl;
R 6 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4 alkyl), —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H, —CH 2 CO 2 (C 1-4 alkyl), —(CH 2 ) 2 CO 2 (C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), —CH 2 NH 2 , —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4 alkyl), —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4 alkyl), —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHSO 2 (C 1-4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4 alkyl), —C(O)NH(CH 2 ) 2 O(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —CH 2 CONH 2 , and

R 7 and R 7a are, independently at each occurrence, selected from the group consisting of: halogen, OH, NH 2 , CH 2 NH 2 , CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 1-4 alkoxy, CH 2 OH, CH 2 O(C 1-4 alkyl), CH 2 O(CH 2 ) 1-4 O(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), CH 2 CO 2 H, CH 2 CO 2 (C 1-4 alkyl), CONH 2 , CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , —OCO(C 1-4 alkyl), —CON(C 1-4 alkyl)(CH 2 ) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, —(CO) 0-1 (CH 2 ) 0-1 —C 3-6 carbocycle, and —(CO) 0-1 (CH 2 ) 0-1 -(4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ; wherein said carbocycle and heterocycle are substituted with 0-2 R 8 ;
R 8 is, independently at each occurrence, selected from the group consisting of: halogen, OH, CHF 2 , CF 3 , C 1-4 alkoxy, CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), CONH 2 , and C 1-4 alkyl;
R 9 is a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), O, and S(O) p ;
R a is, independently at each occurrence, selected from the group consisting of: halogen, OH, CF 3 , C 1-4 alkoxy, and C 1-4 alkyl;
p is, independently at each occurrence, selected from the group consisting of: 0, 1, and 2.

2. The compound of claim 1 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently a 6-membered carbocycle, a 9- to 10-membered carbocycle, or a 5- to 10-membered heterocycle comprising: carbon atoms and 1-3 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ;
ring B is imidazolyl; and
ring C is phenyl.

3. The compound of claim 2 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
ring A is independently selected from the group consisting of: benzene, cyclohexane, indane, tetrahydronaphthalene, naphthalene, dihydroisoxazole, isoxazole, pyrazole, imidazole, triazole, piperidine, indazole, indole, benzimidazole, quinoline, isoquinoline, tetrahydroquinoline, and tetrahydroisoquinoline;

4. The compound of claim 1 , 2 , or 3 , a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
L 1 is independently selected from the group consisting of: a bond, —CH 2 CH 2 —, —CH═CH—, —C(Me)=CH—, —C═C—, and —CH 2 NH—;
L is independently selected from the group consisting of: —(CH 2 ) 1-2 -(phenylene)-(CH 2 ) 0-3 —, —CH 2 O(CH 2 ) 1-4 -(phenylene)-(CH 2 ) 0-3 —, —(CH 2 ) 1-2 -(phenylene)-CONH(CH 2 ) 0-2 —, —(CH 2 ) 1-2 -phenylene-CON(C 1-4 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 1-2 -(pyridinylene)-(CH 2 ) 0-3 , —CH 2 -pyrimidinylene-(CH 2 ) 0-3 —,

wherein each ring moiety is substituted with 0-2 R 7a ;
Y is independently selected from the group consisting of: CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , O, S, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—;
R 1 is, independently at each occurrence, selected from: halogen, CN, OH, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CO(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —C(═NH)NH 2 , —C(O)NH 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4 alkyl), and —SO 2 NH 2 ,
R 3 is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , and —CH 2 CO 2 H; and
R 6 is, independently at each occurren

Assignees

• Bristol Myers Squibb Co

Inventors

• Quan Mimi L
• Decicco Carl P
• Corte James R
• Wang Cailan

Classifications

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D487/18

  Bridged systems · CPC title

• C07D471/18

  Bridged systems · CPC title

• C07D487/06 Primary

  Peri-condensed systems · CPC title

• C07D487/16

  Peri-condensed systems · CPC title