Macrocycles as factor XIa inhibitors

Patent metadata

Field	Value
Publication number	US-9802939-B2
Application number	US-201414578846-A
Country	US
Kind code	B2
Filing date	Dec 22, 2014
Priority date	Feb 11, 2010
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

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 (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:

is independently selected from the group consisting of:

L 1 is independently selected from the group consisting of: a bond, —CHR 5 CHR 5 —, —CR 5 ═CHR 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 3-8 alkylene and C 3-8 alkenylene; wherein said alkylene and alkenylene are substituted with 0-2 R 7 and optionally one or two of the carbon atoms of said alkylene and alkenylene may be replaced by O, CO, S, NH, N(C 1-4 alkyl), CONH—, NHCO, OCONH, SO 2 NH, or CON(C 1-4 alkyl);
Y is independently selected from the group consisting of: CH 2 , CO, 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)), —N(C 1-4 alkyl)CH 2 —, —N(CO 2 (C 1-4 alkyl))CH 2 —, —N(CH 2 CO 2 (C 1-4 alkyl))CH 2 —, —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —OCON(C 1-4 alkyl)-, —NHCONH—, and —SO 2 NH—;
alternatively, L-Y is —C 3-6 alkylene-CH═N—;
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, C 1-4 haloalkyl, OH, 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), —OCH 2 CO 2 H, —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4 alkyl), —SO 2 NH 2 , and —C(═NH)NH 2 ;
R 2 is independently a 5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, 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 , CN, NH 2 , CO 2 H, CO 2 (C 1-4 alkyl), COC 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), and —CON(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 , —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(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4 alkyl), —CONH(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 , —NHCO 2 (CH 2 ) 2 N(C 1-4 alkyl) 2 , —NHCOCF 3 , and —NHCO 2 (CH 2 ) 0-1 R 9 ;
R 7 is, independently at each occurrence, selected from the group consisting of: halogen, OH, C 1-4 haloalkyl, C 1-4 alkoxy, CH 2 OH, CH 2 O(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), CO 2 (CH 2 ) 2 O(C 1-4 alkyl)), CO 2 CH 2 CF 3 , CO 2 (CH 2 ) 2 SO 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), —CH 2 NH(CH 2 ) 2 O(C 1-4 alkyl), —CO 2 (CH 2 ) 2 N(C 1-4 alkyl) 2 , —CONH(CH 2 ) 2 O(C 1-4 alkyl), —CONH(CH 2 ) 2 N(C 1-4 alkyl) 2 , —CON(C 1-4 alkyl)(CH 2 ) 2 O(C 1-4 alkyl), —CONH(CH 2 ) 2 N(C 1-4 alkyl) 2 , —CON(C 1-4 alkyl)(CH 2 ) 2 N(C 1-4 alkyl) 2 , —CONH(C 1-4 alkoxy), —CONHBn, —CONH(OBn), —(CH 2 ) 1-3 Ph, C 1-4 alkyl, and —(CH 2 ) 0-1 —(CO) 0-1 -(W) 0-1 -(CH 2 ) 0-2 -(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 heterocycle is 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, 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 ;
W is independently selected from the group consisting of: O and NH; and
p is, independently at each occurrence, selected from the group consisting of: 0, 1, and 2.

2. The compound of claim 1 having Formula (IIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

3. The compound of claim 1 having Formula (IIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

4. The compound of claim 1 having Formula (IIe):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

5. The compound of claim 1 , wherein:
L 1 is independently selected from the group consisting of: a bond and —CH═CH— in Formula (II), (IIa), (IIc) or (IIe);
L is independently selected from the group consisting of: —(CH 2 ) 3-6 —, —(CH 2 ) 2-4 CH(C 1-4 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 1-2 —CH═CH—(CH 2 ) 0-3 —, —CH 2 —CH═C(C 1-4 alkyl)-(CH 2 ) 1-2 —, —CH 2 —C(C 1-4 alkyl)=CH—(CH 2 ) 1-2 —, —CH 2 —CH═CH—CH 2 CH(C 1-4 alkyl)-, —CH 2 —CH═CH—CH(C 1-4 alkyl)-(CH 2 ) 0-2 —, —CH 2 —CH═CH—CH 2 C(halo) 2 -, —CH 2 —CH═CH—(CH 2 ) 1-2 CH(CF 3 )—, —CH 2 —CH═CH—CH(OH)CH 2 —, —(CH 2 ) 3 CH(halo)-, —(CH 2 ) 3-4 C(halo) 2 -, —(CH 2 ) 4 CH(CH 2 OH)—, —(CH 2 ) 3-4 CH(C 1-4 alkoxy)-, —(CH 2 ) 4 CH(CH 2 (C 1-4 alkoxy))-, —(CH 2 ) 4 CH(CO 2 H)—, —(CH 2 ) 4 CH(CH 2 CO 2 H)—, —(CH 2 ) 4-5 CH(CO 2 (C 1-4 alkyl))-, —(CH 2 ) 4 CH(CH 2 CO 2 (C 1-4 alkyl))-, —(CH 2 ) 4 CH(CO 2 CH 2 CF 3 )—, —(CH 2 ) 4 CH(CO 2 (CH 2 ) 2 SO 2 (C 1-4 alkyl))-, —(CH 2 ) 4 C(C 1-4 alkyl)(CO 2 (C 1-4 alkyl))-, —(CH 2 ) 4 C(CF 3 )(CO 2 (C 1-4 alkyl))-, —(CH 2 ) 4 CH(CONH 2 ))—, —(CH 2 ) 4 CH(CONH(C 1-4 alkyl))-, —(CH 2 ) 4 CH(CON(C 1-4 alkyl) 2 )-, —(CH 2 ) 3 CH(C 1-4 alkyl)CH(CONH 2 )—, —(CH 2 ) 4 CH(CO 2 (CH 2 ) 2 O(C 1-4 alkyl))-, —(CH 2 ) 4 CH(CH 2 NH(CH 2 ) 2 O(C 1-4 alkyl))-, —(CH 2 ) 4 CH(CONH(C 1-4 alkoxy))-, —(CH 2 ) 4 CH(CONH(OBn))-, —(CH 2 ) 4 CH((CH 2 ) 3 Ph)-, —(CH 2 ) 4 CH(CO 2 (CH 2 ) 2 N(C 1-4 alkyl) 2 )-, —(CH 2 ) 4 CH(CONH(CH 2 ) 2 O(C 1-4 alkyl))-, —(CH 2 ) 4 CH(CONH(CH 2 ) 2 N(C 1-4 alkyl) 2 )-, —(CH 2 ) 4 CH(CON(C 1-4 alkyl)(CH 2 ) 2 O(C 1-4 alkyl))-, —(CH 2 ) 4 CH(CON(C 1-4 alkyl)(CH 2 ) 2 N(C 1-4 alkyl) 2 )-, —(CH 2 ) 4 CH(CH(halo) 2 )-, —(CH 2 ) 4-5 CH(CF 3 )—, —(CH 2 ) 3 C(halo) 2 CH 2 —, —(CH 2 ) 1-3 CH(OH)(CH 2 ) 1-2 —, —CH 2 CH(OH)CH(OH)CH 2 —, —(CH 2 ) 3 CH(OCO(C 1-4 alkyl))CH 2 —, —(CH 2 ) 3 C(O)CH 2 —, —CH 2 O(CH 2 ) 2-4 —, —CH 2 NH(CH 2 ) 2-4 —, —(CH 2 ) 2-3 NH(CH 2 ) 1-2 —, —(CH 2 ) 2-4 N(C 1-4 alkyl)(CH 2 ) 0-2 —, —CH 2 CONH(CH 2 ) 2-4 —, —CH 2 CON(C

Assignees

• Bristol Myers Squibb Co

Inventors

• Corte James R
• Fang Tianan
• Decicco Carl P
• Pinto Donald J P
• Rossi Karen A
• Hu Zilun
• Jeon Yoon
• Quan Mimi L
• Smallheer Joanne M
• Wang Yufeng
• Yang Wu

Classifications

• C07D498/08

  Bridged systems · CPC title

• C07D487/18

  Bridged systems · CPC title

• C07D487/06 Primary

  Peri-condensed systems · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title