Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-9315519-B2
Application number	US-201314434765-A
Country	US
Kind code	B2
Filing date	Oct 11, 2013
Priority date	Oct 12, 2012
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

The present invention provides compounds of Formula (I): or stereoisomers, pharmaceutically acceptable salts thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of factor XIa and/or plasma kallikrein which may be used as medicaments.

First claim

What is claimed is:

1. A compound according to formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
ring A is heterocycle comprising carbon atoms and NR 2 ;
L is selected from a bond, —CHR 7 —, —CHR 7 CHR 7 —, —CR 7 ═CR 7 —, and —C≡C—;
ring B is phenyl or 5- to 6-membered heterocycle containing carbon atoms and 1-3 heteroatoms selected from the group consisting of N, NR 6 , O, and S(O) p , wherein said phenyl or heterocycle is substituted with 0-3 R 5 ;
---- is an optional bond;
R 1 , at each occurrence, is H
R 2 is selected from —C(═NH)NH 2 and C(═NOR 6 )NH 2 ;
R 3 is selected from C 1-6 alkyl substituted with 1-3 R 3a , C 3-10 carbocycle substituted with 1-3 R 3a , and 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said heterocycle is substituted with 1-3 R 3a ;
R 3a , at each occurrence, is selected from H, halogen, C 1-4 alkyl, —OH, C 1-4 alkoxy, —CN, —NH 2 , —NH(C 1-4 alkyl), —CO 2 H, —CH 2 CO 2 H, —CO 2 (C 1-4 alkyl), —CO 2 —C 1-4 alkylene-O(C alkyl), —CO 2 —C 1-4 alkylene-N(C 1-4 alkyl) 2 , —CONH 2 , —CONH(C 1-6 alkyl), —CON(C 1-4 alkyl) 2 , —CONHCO 2 C 1-4 alkyl, —NHCOC 1-4 alkyl, —NHCO 2 (C 1-4 alkyl), SO 2 R 6 , SO 2 NR 6 R 6 , SO 2 NHC(O)R 6 , NHSO 2 NR 6 , NHSO 2 R 6 , R c , —CONHR c , and —CO 2 R c ;
R 4 , at each occurrence, is selected from H, F, and C 1-4 alkyl;
R 5 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, OH, CN, NH 2 , —N(C 1-4 alkyl) 2 , NO 2 , —OCO(C 1-4 alkyl), —O—C 1-4 alkylene-O(C 1-4 alkyl), —O—C 1-4 alkylene-N(C 1-4 alkyl) 2 , —CO 2 H, —CO 2 (C 1-4 alkyl), —(CH 2 ) n CONH 2 , SO 2 R 6 , SO 2 NR 6 R 6 , SO 2 NHC(O)R 6 , NHSO 2 NR 6 , NHSO 2 R 6 , —(CH 2 ) n —C 3-10 carbocycle and —(CH 2 ) n -5- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said carbocycle or heterocycle is substituted with 1-3 R b ;
R 6 , at each occurrence, is selected from H and C 1-4 alkyl;
R 7 , at each occurrence, is selected from H, halo, OH, and C 1-4 alkyl;
R a , at each occurrence, is selected from H, C 1-4 alkyl, CO(C 1-4 alkyl), COCF 3 , CO 2 (C 1-4 alkyl), —CONH 2 , —CONH—C 1-4 alkylene-CO 2 (C 1-4 alkyl), C 1-4 alkylene-CO 2 (C 1-4 alkyl), R c , CO 2 R c , and CONHR c ;
R b , at each occurrence, is selected from H, CN, ═O, OH, halogen, C 1-4 alkyl, C 1-4 alkoxy, OCF 3 , NH 2 , NO 2 , N(C 1-4 alkyl) 2 , CO(C 1-4 alkyl), CO(C 1-4 haloalkyl), CO 2 (C 1-4 alkyl), CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —NHCO 2 (C 1-4 alkyl), SO 2 R 6 , SO 2 NR 6 R 6 , SO 2 NHC(O)R 6 , NHSO 2 NR 6 , NHSO 2 R 6 , —R c , COR c , CO 2 R c , and CONHR c ; optionally, R b and R b together with the carbon atom to which they are both attached form a 5-6 membered heterocyclic ring;
R c , at each occurrence, is selected from —(CH 2 ) n —C 3-6 cycloalkyl, —(CH 2 ) n -phenyl, and —(CH 2 ) n -5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), 0, and S(O) p ; wherein each ring moiety is substituted with 0-2 R d ;
R d , at each occurrence, is selected from ═O, F, —OH, C 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkoxy, and —NHCO(C 1-4 alkyl), and heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and
p, at each occurrence, is selected from 0, 1, and 2.

2. The compound of claim 1 having formula (II):

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
ring A is 4- to 12-membered monocyclic, bicyclic heterocycle comprising carbon atoms and NR 2 , wherein said heterocycle may be a spiro;
L is selected from a bond, —CHR 7 —, and —CHR 7 CHR 7 —;
R 1 , at each occurrence, is H;
R 2 is selected from —C(═NH)NH 2 and C(═NOR 6 )NH 2 ;
R 3 is selected from C 3-10 carbocycle substituted with 1-3 R 3a , and 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ;

wherein said heterocycle is substituted with 1-3 R 3a ;
R 3a , at each occurrence, is selected from H, halogen, C 1-4 alkyl, —OH, C 1-4 alkoxy, —CN, —NH 2 , —NH(C 1-4 alkyl), —CO 2 H, CO 2 (C 1-4 alkyl), and —NHCO 2 (C 1-4 alkyl);
R 4 , at each occurrence, is selected from H, F, and C 1-4 alkyl;
R 5 is selected from H, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, —(CH 2 ) n —C 3-10 carbocycle and —(CH 2 ) n -5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said carbocycle or heterocycle is substituted with 1-3 R b ;
R 6 , at each occurrence, is selected from H and C 1-4 alkyl;
R 7 , at each occurrence, is selected from H and C 1-4 alkyl;
R a is selected from H, C 1-4 alkyl, CO(C 1-4 alkyl), COCF 3 , CO 2 (C 1-4 alkyl), and —CONH 2 ;
R b is selected from H, ═O, OH, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, OCF 3 , NH 2 , N(C 1-4 alkyl) 2 , CO(C 1-4 alkyl), CO(C 1-4 haloalkyl), CO 2 (C 1-4 alkyl), CONH 2 , —CONH(C 1-4 alkyl), and —CON(C 1-4 alkyl) 2 , SO 2 (C 1-4 alkyl), SO 2 NH(C 1-4 alkyl), NHSO 2 NR 6 , NHSO 2 (C 1-4 alkyl), and R c ; optionally, R b and R b together with the carbon atom to which they are both attached form a 4-6 membered heterocyclic ring.

3. The compound of claim 2 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
R 5 is selected from H, halogen, phenyl, and —(CH 2 ) n -5- to 10-membered heterocycle or heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR a , O, and S(O) p ; wherein said phenyl or heterocycle is substituted with 1-3 R b .

4. The compound of claim 3 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
R 5 is selected from H, F,

W is selected from CR b R b , O, S(O) p , and NR a ;
R a is selected from H, C 1-4 alkyl, CO(C 1-4 alkyl), and COCF 3 ;
R b is selected from H, ═O, OH, halogen, C 1-4 alkyl, C 1-4 alkoxy, OCF 3 , NH 2 , N(C 1-4 alkyl) 2 , CO(C 1-4 alkyl), CO(C 1-4 haloalkyl), CO 2 (C 1-4 alkyl), CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , phenyl, pyridyl; optionally, R b and R b together with the carbon atom to which they are both attached form a 4-6 membered heterocyclic ring;
q, at each occurrence, is selected from 0, 1, and 2; and
r, at each occurrence, is selected from 0, 1, and 2.

5. The compound of claim 4 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
R 5 is

selected from

6. The compound of claim 5 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:

is selected from

7. The compound of claim 2 or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
ring A is selected from

Assignees

• Bristol Myers Squibb Co

Inventors

• Pinto Donald J P
• Clark Charles G
• Orwat Michael J
• Smith Ii Leon M
• Ewing William R

Classifications

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D217/26

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title