US 8,940,720 B2 · Macrocycles as factor XIa inhibitors

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.

A compound having Formula (IIb):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein
L1 is independently selected from the group consisting of:
a bond, —CHR5—, —CHR5CHR5—, —CR5═CR5—, —C≡C—, —OCH2—, —CHR5NH—, —CH2O—, —SCH2—, —SO2CH2—, —CH2NH—, and —CR5R5—;
L is independently selected from the group consisting of:
C3-8 alkylene, C3-8 alkenylene, and C4-8 alkynylene;
wherein said alkylene, alkenylene and alkynylene are substituted with 0-2 R7 and optionally one or more of the carbon atoms of said alkylene and alkenylene may be replaced by O, S, NH, N(C1-4 alkyl), CO, CONH, NHCO, OCONH, NHCO2, —NHCONH—, SO2NH, NHSO2, CON(C1-4 alkyl), or N(C1-4 alkyl)CO;
Y is independently selected from the group consisting of:
CH2, CH(C1-4 alkyl), C(C1-4 alkyl)2, CO, O, S, NH, N(C1-4 alkyl), N(CO2(C1-4 alkyl)), —N(C1-4 alkyl)CH2—, —N(CO2(C1-4 alkyl))CH2—, —N(CH2CO2(C1-4 alkyl))CH2—, —CONH—, —NHCO—, —CONHCH2—, —CON(C1-4 alkyl)CH2—, —OCONH—, —OCON(C1-4 alkyl)—, —NHCONH—, —SO2NH—, —NHCO2—, and —NHSO2—;
alternatively, L-Y is —C3-6 alkylene—CH═N—;
R1 is, independently at each occurrence, selected from the group consisting of:
halogen, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, OH, OCH2F, OCHF2, OCF3, CN, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, CO2(C1-4 alkyl), CO(C1-4 alkyl), —CH2NH2, —CONH2, —CONH(C1-4 alkyl), —OCH2CO2H, —NHCO(C1-4 alkyl), —NHCO2(C1-4 alkyl), —NHSO2(C1-4 alkyl), —SO2NH2, —C(═NH)NH2, and phenyl substituted with 0-2Ra;
R2 is independently a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), O, and S(O)p, wherein said heterocycle is substituted with 0-2 R2a;
R2a is, independently at each occurrence, selected from the group consisting of:
halogen, C1-4 alkyl, —CH2OH, C1-4 alkoxy, OH, CF3, OCF3, CN, NH2, CO2H, CO2(C1-4 alkyl), COC1-4 alkyl, —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —SO2(C1-4 alkyl), —SO2NH2, —SO2NH (C1-4 alkyl), and —SO2N(C1-4 alkyl)2;
R3 is independently selected from the group consisting of:
H, ═O, halogen, OH, NH2, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, —CH2OH, CO2H, CO2(C1-4 alkyl), —C(O)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, —CH2CO2H, and C3-6 cycloalkyl;
R5 is, independently at each occurrence, selected from the group consisting of:
H, halogen, OH, and C1-4 alkyl;
R6 is, independently at each occurrence, selected from the group consisting of:
halogen, C1-4 alkyl, CN, OH, CF3, CO2H, CO2(C1-4 alkyl), —CH2CO2H, —(CH2)2CO2H, —CH2CO2(C1-4 alkyl), —(CH2)2CO2(C1-4 alkyl), NH2, —CH2NH2, —NHCO(C1-4 alkyl), —NHCOCF3, —NHCO2(C1-4 alkyl), —NHCO2(CH2)2O(C1-4 alkyl), —NHCO2(CH2)3O(C1-4 alkyl), —NHCO2CH2CH(C1-4 alkyl)O(C1-4 alkyl), —NHCO2(CH2)2OH, —NHCO2(CH2)2NH2, —NHCO2(CH2)2N(C1-4 alkyl)2, —NHCO2CH2CO2H, —CH2NHCO2(C1-4 alkyl), —NHC(O)NH(C1-4 alkyl), —NHC(O)N(C1-4 alkyl)2, —NHSO2(C1-4 alkyl), —SO2NH2, —SO2NH(C1-4 alkyl), —SO2NH(CH2)2OH, —SO2NH(CH2)2O(C1-4 alkyl), —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CH2CONH2, and —NHCO2(CH2)0-2R9;
R7 is, independently at each occurrence, selected from the group consisting of:
halogen, OH, NH2, CH2NH2, C1-4 haloalkyl, OCH2F, OCHF2, OCF3, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, C1-4 alkoxy, CH2OH, CH2O(C1-4 alkyl), CH2O(CH2)1-4O(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), CO2(CH2)2O(C1-4 alkyl), CO2(C1-4 haloalkyl), CO2(CH2)2SO2(C1-4 alkyl), CH2CO2H, CH2CO2(C1-4 alkyl), CONH2, CONH(C1-4 alkyl), CON(C1-4 alkyl)2, —OCO(C1-4 alkyl), —CH2NH(CH2)2O(C1-4 alkyl), —CONH(C1-4 alkoxy), —CO2(CH2)2O(C1-4 alkyl), —CO2(CH2)2N(C1-4 alkyl)2, —CONH(CH2)2O(C1-4 alkyl), —CONH(CH2)2N(C1-4 alkyl)2, —CON(C1-4 alkyl)(CH2)2O(C1-4 alkyl), —CON(C1-4 alkyl)(CH2)2N(C1-4 alkyl)2, C1-4 alkyl, —CONHBn, —CONH(OBn), —(CO)0-1(CH2)0-3—C3-6 carbocycle, and —(CH2)0-1—(CO)0-1—(W)0-1—(CH2)0-2-(4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), O, and S(O)p);
wherein said carbocycle and heterocycle are substituted with 0-2 R8;
R8 is, independently at each occurrence, selected from the group consisting of:
halogen, OH, CHF2, CF3, C1-4 alkoxy, CH2OH, CO2H, CO2(C1-4 alkyl), CONH2, and C1-4 alkyl;
R9 is a 4- to 6-membered heterocycle comprising:
carbon atoms and 1-4 heteroatoms selected from N, NH, N(C1-4 alkyl), N(CO2(C1-4 alkyl)), O, and S(O)p;
Ra is, independently at each occurrence, selected from the group consisting of:
halogen, OH, CF3, C1-4 alkoxy, and C1-4 alkyl;
W is independently selected from the group consisting of:
O, NH and N(C1-4 alkyl);
and
p is, independently at each occurrence, selected from the group consisting of:
0, 1, and 2.

31 more elements

Description94,378 words

Summary528 words

#The present invention relates generally to novel macrocyclic compounds, and their analogues thereof, which are inhibitors of Factor XIa and/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 description93,850 words

#I. Compounds of the Invention

#In a first aspect, the present invention provides, inter alia, a compound of Formula (I):

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

Facts

Application

13/024,544Filed 10 Feb 2011 · us provisional application

Priority

11 Feb 2010

Published

US 2012/0041190 A116 Feb 2012

Granted

27 Jan 2015

Term ends

5 Jul 2032

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment, including 511 days of 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.

Classification15 codes

C07D 471/08
In which the condensed system contains two hetero rings: bridged systems
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
C07D 225/08
Condensed with carbocyclic rings or ring systems: condensed with two six-membered rings
C07D 471/14
In which the condensed system contains three hetero rings: ortho-condensed systems

Timeline

11 Feb 2010Priority claimedParent application 61/303,423
10 Feb 2011Application filedUS 13/024,544
22 Mar 2011Assigned to Bristol-Myers Squibb Companyassignment of assignor's interest
16 Feb 2012PublishedUS 2012/0041190 A1
27 Jan 2015GrantedUS 8,940,720 B2
12 Oct 2026TodayWithin its term
5 Jul 2032Term endsEstimated, includes 511 days of adjustment

Macrocycles as factor XIa inhibitors

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Macrocycles as factor XIa inhibitors

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Abstract

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Claims4

Description94,378 words

Drawings

Classification15 codes

Life of this patent

Description94,378 words