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Macrocycles with hetrocyclic P2' groups as factor XIA inhibitors

A compound, heterocyclic group technology, applied in the field of novel macrocyclic compounds and their analogs, can solve problems such as limiting oral availability and intestinal permeability

Active Publication Date: 2016-09-28
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is well known in the art that such functional groups can limit intestinal permeability and thus oral availability

Method used

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  • Macrocycles with hetrocyclic P2' groups as factor XIA inhibitors
  • Macrocycles with hetrocyclic P2' groups as factor XIA inhibitors
  • Macrocycles with hetrocyclic P2' groups as factor XIA inhibitors

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Experimental program
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Embodiment approach

[0810] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0811] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0812] In another embodiment, the present invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof .

[0813] In another embodiment, the present invention provides methods for preparing compounds of the present invention.

[0814] In another embodiment, the present invention provides in...

Embodiment 30G

[1523] Example 30G. Preparation of (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 2,6 ] Octadeca-1(18),2(6),4,14,16-pentaen-8-one

[1524] 4N HCl (3.88 mL, 15.5 mmol) in dioxane was added to N-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7 ,15-Tetraazatricyclo[12.3.1.0 2,6 ]octadec-1(18),2(6),4,14,16-penten-13-yl]carbamate tert-butyl ester (2.25 g, 5.2 mmol) in MeOH (10 mL). The reaction mixture was stirred at rt for 2h. Cool the reaction mixture in an ice bath and add 7N NH in MeOH 3 (13.3 mL, 93.0 mmol). After 5min, use CH 2 Cl 2 (80 mL) the reaction mixture was diluted and the solid formed was filtered. The filtrate was concentrated to give (9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0 2,6 ] Octadeca-1(18),2(6),4,14,16-penten-8-one (1.3 g, 3.88 mmol, 75% yield). MS(ESI)m / z:336.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.33(s,1H),8.71(d,J=5.0Hz,1H),7.94(t,J=58Hz,1H),7.85(s,1H),7.40(s,1H),7.32(d ...

Embodiment 45

[1721] Preparation of (9R,13S)-13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl) -3,9-Dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0 2,6 ] Octadeca-1(18),2(6),4,14,16-pentaen-8-one

[1722]

[1723] In a similar manner to the procedure described in Example 314, (9R,13S)- 13-(4-{5-chloro-2-[(pyrimidin-2-yl)amino]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-3,9-dimethyl Base-3,4,7,15-tetraazatricyclo[12.3.1.0 2 ,6 ] Octadeca-1(18),2(6),4,14,16-penten-8-one bistrifluoroacetate (2.75 mg, 19% yield). MS(ESI)m / z:582.5(M+H) + . 1 H NMR (400MHz, CD 3 OD)δ9.12(s,1H),8.74(d,J=5.1Hz,1H),8.46-8.42(m,3H),7.73(s,1H),7.66(d,J=2.6Hz,1H) ,7.54-7.48(m,2H),7.43(dd,J=8.9,2.5Hz,1H),6.85(t,J=5.0Hz,1H),6.79(s,1H),6.06(dd,J=12.7 ,4.3Hz,1H),4.05(s,3H),2.78-2.67(m,1H),2.42-2.31(m,1H),2.16-2.02(m,2H),1.69-1.44(m,2H), 1.02 (d, J=6.8Hz, 3H), 0.80-0.63 (m, 1H). Analytical HPLC (Method A): RT = 8.33 min, 97.9% purity; Factor XIa Ki = 2,000 nM.

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Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts 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.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Applications 61 / 933,942, filed January 31, 2014, and 62 / 058,293, filed October 1, 2014, which are incorporated in their entirety this application. technical field [0003] The present invention generally relates to novel macrocyclic compounds and analogs thereof which are inhibitors of Factor XIa or dual inhibitors of Factor XIa and plasma kallikrein, compositions containing said compounds and their use, for example, in the treatment or A method of preventing a thromboembolic disorder or treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Background technique [0004] Although anticoagulants (such as warfarin, ), heparin, low molecular weight heparin (LMWH) and synthetic pentasaccharides) and antiplatelet agents (such as aspirin and clopidogrel, ), but thromboembolic disorders rem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08C07D487/08A61K31/529A61P7/00
CPCC07D487/08C07D471/08C07D471/18A61P11/00A61P13/12A61P27/00A61P43/00A61P7/00A61P7/02A61P9/00A61P9/10C07D403/06C07D403/14A61K31/4192A61P27/02A61K31/513
Inventor J·R·科尔特I·德卢卡方天安杨武王裕丰A·K·迪尔格K·B·帕比塞蒂W·R·尤因朱晔恒R·R·韦克斯勒D·J·P·品托M·J·奥瓦特利昂·M·史密斯二世
Owner BRISTOL MYERS SQUIBB CO
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