US 9,315,519 B2 · Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors

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.

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Claims18

Dependent claims

A compound according to formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein:
ring A is heterocycle comprising carbon atoms and NR2;
L is selected from a bond, —CHR7—, —CHR7CHR7—, —CR7═CR7—, 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, NR6, O, and S(O)p, wherein said phenyl or heterocycle is substituted with 0-3 R5;
---- is an optional bond;
R1, at each occurrence, is H
R2 is selected from —C(═NH)NH2 and C(═NOR6)NH2;
R3 is selected from C1-6 alkyl substituted with 1-3 R3a, C3-10 carbocycle substituted with 1-3 R3a, and 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NRa, O, and S(O)p;
wherein said heterocycle is substituted with 1-3 R3a;
R3a, at each occurrence, is selected from H, halogen, C1-4 alkyl, —OH, C1-4 alkoxy, —CN, —NH2, —NH(C1-4 alkyl), —CO2H, —CH2CO2H, —CO2(C1-4 alkyl), —CO2—C1-4 alkylene-O(C alkyl), —CO2—C1-4 alkylene-N(C1-4 alkyl)2, —CONH2, —CONH(C1-6 alkyl), —CON(C1-4 alkyl)2, —CONHCO2C1-4 alkyl, —NHCOC1-4 alkyl, —NHCO2(C1-4 alkyl), SO2R6, SO2NR6R6, SO2NHC(O)R6, NHSO2NR6, NHSO2R6, Rc, —CONHRc, and —CO2Rc;
R4, at each occurrence, is selected from H, F, and C1-4 alkyl;
R5 is selected from H, halogen, C1-4 alkyl, C1-4alkoxy, C1-4haloalkoxy, OH, CN, NH2, —N(C1-4 alkyl)2, NO2, —OCO(C1-4 alkyl), —O—C1-4 alkylene-O(C1-4 alkyl), —O—C1-4 alkylene-N(C1-4 alkyl)2, —CO2H, —CO2(C1-4 alkyl), —(CH2)nCONH2, SO2R6, SO2NR6R6, SO2NHC(O)R6, NHSO2NR6, NHSO2R6, —(CH2)n—C3-10 carbocycle and —(CH2)n-5- to 12-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NRa, O, and S(O)p;
wherein said carbocycle or heterocycle is substituted with 1-3 Rb;
R6, at each occurrence, is selected from H and C1-4 alkyl;
R7, at each occurrence, is selected from H, halo, OH, and C1-4 alkyl;
Ra, at each occurrence, is selected from H, C1-4 alkyl, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), C1-4 alkylene-CO2(C1-4 alkyl), Rc, CO2Rc, and CONHRc;
Rb, at each occurrence, is selected from H, CN, ═O, OH, halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4 alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —NHCO2(C1-4 alkyl), SO2R6, SO2NR6R6, SO2NHC(O)R6, NHSO2NR6, NHSO2R6, —Rc, CORc, CO2Rc, and CONHRc;
optionally, Rb and Rb together with the carbon atom to which they are both attached form a 5-6 membered heterocyclic ring;
Rc, at each occurrence, is selected from —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), 0, and S(O)p;
wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is selected from ═O, F, —OH, C1-4 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, and —NHCO(C1-4 alkyl), and heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 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.

21 more elements

Dependencies are inferred from the claim text.

Description25,797 words

Summary531 words

#The present invention provides novel substituted tetrahydroisoquinoline (THQ) compounds, and their analogues thereof, which are inhibitors of factor XIa or plasma kallikrein, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of thromboembolic disorders.

#Thromboembolic diseases remain the leading cause of death in developed countries despite the availability of anticoagulants such as warfarin (COUMADIN®), heparin, low molecular weight heparins (LMWH), and synthetic pentasaccharides and antiplatelet agents such as aspirin and clopidogrel (PLAVIX®). The oral anticoagulant warfarin, inhibits the post-translational maturation of coagulation factors VII, IX, X and prothrombin, and has proven effective in both venous and arterial thrombosis. However, its usage is limited due to its narrow therapeutic index, slow onset of therapeutic effect, numerous dietary and drug interactions, and a need for monitoring and dose adjustment. Thus discovering and developing safe and efficacious oral anticoagulants for the prevention and treatment of a wide range of thromboembolic disorders has become increasingly important.

#One approach is to inhibit thrombin generation by targeting the inhibition of coagulation factor XIa (FXIa). Factor XIa is a plasma serine protease involved in the regulation of blood coagulation, which is initiated in vivo by the binding of tissue factor (TF) to factor VII (FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa complex activates factor IX (FIX) and factor X (FX) that leads to the production of factor Xa (FXa). The generated FXa catalyzes the transformation of prothrombin into small amounts of thrombin before this pathway is shut down by tissue factor pathway inhibitor (TFPI). The process of coagulation is then further propagated via the feedback activation of Factors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007)). The resulting burst of thrombin converts fibrinogen to fibrin that polymerizes to form the structural framework of a blood clot, and activates platelets, which are a key cellular component of coagulation (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIa plays a key role in propagating this amplification loop and is thus an attractive target for anti-thrombotic therapy.

Detailed description25,266 words

#In one aspect, the present invention provides compounds of Formula (I):

#or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:

#ring A is heterocycle comprising carbon atoms and 1-3 heteroatoms selected from NR2, O, and S(O)p;

Facts

Application

14/434,765Filed 11 Oct 2013 · us provisional application

Priority

12 Oct 2012

Published

US 2015/0259358 A117 Sep 2015

Granted

19 Apr 2016

Term ends

11 Oct 2033

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification8 codes

C07D 513/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
C07D 217/26
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 401/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms

Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors

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Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors

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Abstract

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Claims18

Description25,797 words

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Classification8 codes

Life of this patent

Description25,797 words