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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Definitions

• the present invention relates generally to novel arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea compounds, and analogues thereof, which are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor XIa, factor Xa, factor IXa and/or factor Vila, and/or plasma kallikrein.
• thrombin factor XIa
• factor Xa factor Xa
• factor IXa and/or factor Vila and/or plasma kallikrein
• plasma kallikrein relates to compounds that 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 using the same.
• Factor XIa is a plasma serine protease involved in the regulation of blood coagulation. While blood coagulation is essential to the regulation of an organism's hemostasis, it is also involved in many pathological conditions. In thrombosis, a blood clot, or thrombus, may form and obstruct circulation locally, causing ischemia and organ damage. Alternatively, in a process known as embolism, the clot may dislodge and subsequently become trapped in a distal vessel, where it again causes ischemia and organ damage.
• thrombotic or thromboembolic disorders Diseases arising from pathological thrombus formation are collectively referred to as thrombotic or thromboembolic disorders and include acute coronary syndrome, unstable angina, myocardial infarction, thrombosis in the cavity of the heart, ischemic stroke, deep vein thrombosis, peripheral occlusive arterial disease, transient ischemic attack, and pulmonary embolism.
• thrombosis occurs on artificial surfaces in contact with blood, including catheters and artificial heart valves. Therefore, drugs that inhibit blood coagulation, or anticoagulants, are "pivotal agents for prevention and treatment of thromboembolic disorders" (Hirsh, J. et al. Blood 2005, 105, 453-463). Thromboembolic disorders are the largest cause of mortality and disability in the industrialized world.
• TF Factor VII
• FVIIa Factor Vila
• FIX Factor EX
• FXa Factor Xa
• the FXa that is generated catalyzes the transformation of prothrombin into small amounts of thrombin before this pathway is shut down by tissue factor pathway inhibitor (TFPI).
• TFPI tissue factor pathway inhibitor
• the process of coagulation is then further propagated via the feedback activation of Factors V, VHI and XI by catalytic amounts of thrombin.
• thrombin coverts fibrinogen to fibrin, which 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 2003, 17, S1-S5).
• Factor XIa plays a key role in propagating this amplification loop and is thus an attractive target for anti-thrombotic therapy.
• Factor XIIa has a number of target proteins, including plasma prekallikrein and factor XL Active plasma kallikrein further activates factor XII, leading to an amplification of contact activation.
• the serine protease prolylcarboxylpeptidase can activate plasma kallikrein complexed with high molecular weight kininogen in a multiprotein complex formed on the surface of cells and matrices (Shariat-Madar et al. Blood 2006, 108, 192-199).
• Contact activation is a surface mediated process responsible in part for the regulation of thrombosis and inflammation, and is mediated, at least in part, by fibrinolytic-, complement-, kininogen/kinin-, and other humoral and cellular pathways (for review, Coleman, R. Contact Activation Pathway, pages 103-122 in Hemostasis and Thrombosis, Lippincott Williams & Wilkins 2001; Schmaier A.H. Contact Activation, pages 105- 128 in Thrombosis and Hemorrhage, 1998).
• the biological relevance of the contact activation system for thromboembolic diseases is supported by the phenotype of factor Xn deficient mice.
• factor XII deficient mice were protected from thrombotic vascular occlusion in several thrombosis models as well as stroke models and the phenotype of the XII deficient mice was identical to XI deficient mice (Renne et al. J. Exp. Medicine 2005, 202, 271-281; Kleinschmitz et al. J. Exp.l Medicine, 2006, 203, 513-518).
• factor XI is down-stream from factor XIIa, combined with the identical phenotype of the XII and XI deficient mice suggest that the contact activation system could play a major role in factor XI activation in vivo.
• Factor XI is a zymogen of a trypsin-like serine protease and is present in plasma at a relatively low concentration. Proteolytic activation at an internal R369- 1370 bond yields a heavy chain (369 amino acids) and a light chain (238 amino acids). The latter contains a typical trypsin-like catalytic triad (H413, D464, and S557). Activation of factor XI by thrombin is believed to occur on negatively charged surfaces, most likely on the surface of activated platelets.
• Platelets contain high affinity (0.8 nM) specific sites (130-500/platelet) for activated factor XL After activation, factor XIa remains surface bound and recognizes factor IX as its normal macromolecular substrate.
• thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), a plasma carboxypeptidase that cleaves C-terminal lysine and arginine residues on fibrin, reducing the ability of fibrin to enhance tissue-type plasminogen activator (tPA) dependent plasminogen activation.
• TAFI thrombin activated fibrinolysis inhibitor
• tPA tissue-type plasminogen activator
• baboon cross-reactive, function blocking antibodies to human factor XI protect against baboon arterial - venous shunt thrombosis (Gruber et al, Blood 2003, 102, 953-955).
• Evidence for an antithrombotic effect of small molecule inhibitors of factor XIa is also disclosed in published U.S. Patent Application US20040180855A1. Taken together, these studies suggest that targeting factor XI will reduce the propensity for thrombotic and thromboembolic diseases.
• factor XI is not required for normal homeostasis, implying a superior safety profile of the factor XI mechanism compared to competing antithrombotic mechanisms.
• hemophilia A factor VIII deficiency
• hemophilia B factor IX deficiency
• mutations of the factor XI gene causing factor XI deficiency result in only a mild to moderate bleeding diathesis characterized primarily by postoperative or posttraumatic, but rarely spontaneous hemorrhage.
• Postoperative bleeding occurs mostly in tissue with high concentrations of endogenous fibrinolytic activity (e.g., oral cavity, and urogenital system). The majority of the cases are fortuitously identified by preoperative prolongation of APTT (intrinsic system) without any prior bleeding history.
• factor XI activation can be determined by complex formation with either Cl inhibitor or alpha 1 antitrypsin.
• AMI acute myocardial infarction
• approximately 25% of the patients had values above the upper normal range of the complex ELISA.
• This study can be viewed as evidence that at least in a subpopulation of patients with AMI, factor XI activation contributes to thrombin formation (Minnema, M.C. et al. Arterioscler.
• Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in plasma at 35 to 50 ⁇ g/mL.
• the gene structure is similar to that of factor XI.
• the amino acid sequence of plasma kallikrein has 58% homology to factor XI.
• Proteolytic activation by factor XIIa at an internal 1389- R390 bond yields a heavy chain (371 amino acids) and a light chain (248 amino acids).
• the active site of plasma kallikrein is contained in the light chain.
• the light chain of plasma kallikrein reacts with protease inhibitors, including alpha 2 macroglobulin and Cl- inhibitor.
• HMWK high molecular weight kininogen
• WO 01/27079 There are advantages in using small organic compounds, however, in preparing pharmaceuticals, e.g., small compounds generally have better oral bioavailability and compatibility in making formulations to aid in delivery of the drug as compared with large proteins or peptides.
• Small molecule inhibitors of Factor XIa are disclosed in U.S. Patent Application Publications, e.g., US20040235847A1, US20040220206A1, US20050228000A1, US20060009455A1, and US20050282805A1.
• the present invention provides novel arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea compounds, and analogues thereof, which are useful as selective inhibitors of serine protease enzymes, especially factor XIa and/or plasma kallikrein, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides a method for modulation of the coagulation cascade and/or the contact activation system comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides a method for treating inflammatory diseases disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.
• the present invention also provides the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for use in therapy.
• the present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment of a thrombotic or thromboembolic disorder.
• the present invention also provides the use of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment of an inflammatory disorder.
• the present invention provides, inter alia, compounds of Formula (I):
• A is a C3.10 carbocycle substituted with 0-1 R 1 and 0-3 R 2 , or a 5- to 12- membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-1 R 1 and 0-3 R 2 ; provided that when A is a heterocycle containing one or more nitrogen atoms, A is not attached to Li via any of the nitrogen atoms on the A ring;
• R la is F, OCF 3 , CF 3 , OR a , SR a , CN, -NR 7 R 8 , -C(O)NR 8 R 9 , -NR 8 C(O)R 0 , -S(O) p NR 8 R 9 , -NR 8 SO 2 R 0 , or -(CF 2 )rCF 3 ;
• R 2a is F, OCF 3 , CF 3 , 0R a , SR a CN, -NR 7 R 8 , -C(O)NR 8 R 9 , -NR 8 C(O)R 0 , -NR 8 C(O)OR 0 , -NR 8 C(O)NR 8 R 0 , -S(O)pNR 8 R 9 , -NR 8 SO 2 R 0 , or -(CF 2 ) r CF 3 ;
• R 3 is, independently at each occurrence, -(CH 2 ) r -C 3 _io carbocycle substituted with 0-3 R 3a and 0-1 R 3d , or -(CH 2 ) r -5- to 12-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R 3a and 0-1 R 3d ;
• R 3d C 2 -6 alkenyl substituted with 0-2 R 3d , C 2- 6 alkynyl substituted with 0-2 R 3d , -(CH 2 )r-C3-io carbocycle substituted with 0-3 R 3d , or -(CH 2 ) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R 3d ;
• R 3c is, independently at each occurrence, Ci_6 alkyl substituted with 0-2 R 3d ,
• R 6 is, independently at each occurrence, H, F, or C1.4 alkyl;
• R 7 is, independently at each occurrence, H, Ci_6 alkyl, -(CH 2 VC 3 -Io carbocycle, -(CH 2 )n-(5- to 10-membered heteroaryl), -C(O)R 0 , -CHO, -C(O) 2 R 0 , -S(O) 2 R 0 , -CONR 8 R C , -OCONHRc, -C(O)O-(Ci -4 alkyl)OC(O)-(Ci_ 4 alkyl), or -C(O)O-(C i-4 alkyl)OC(0)-(C6-io aryl); wherein said alkyl, carbocycle, heteroaryl, and aryl are substituted with 0-2 R f ; wherein said heteroaryl comprises: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p;
• R 8 is, independently at each occurrence, H, Ci. ⁇ alkyl, -(CH 2 )n-phenyl, or -(CH2)n-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p; wherein said alkyl, phenyl and heterocycle are optionally substituted with 0-2 R f ; alternatively, R 7 and R 8 , when attached to the same nitrogen, combine to form a 5- to 10-membered heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, O, and S(O) p> wherein said heterocycle is substituted with 0-2 R f ;
• R 8a is H or C M alkyl
• R 9 is, independently at each occurrence, H, Ci.6 alkyl, or -(CH2)n-phenyl; wherein said alkyl and phenyl are optionally substituted with 0-2 R f ; alternatively, R 8 and R 9 , when attached to the same nitrogen, combine to form a 5- to 12-membered heterocycle comprising: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)P 5 wherein said heterocycle is substituted with 0-2 R d ; R 10 is, independently at each occurrence, H or Ci_6 alkyl substituted with 0-3
• R 1 1 is Ci-4 haloalkyl, -C(O)NR 8 R 9 , -CH 2 C(O)NR 8 R 9 , -CH 2 CH 2 C(O)NR 8 R 9 ,
• R a is, independently at each occurrence, H, CF 3 , Ci_6 alkyl, -(CH 2 ) r -C 3 -7 cycloalkyl, -(CH 2 ) r -C6-io aryl, or -(CH 2 )r-5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) 1 ), wherein said cycloalkyl, aryl or heterocycle groups are optionally substituted with 0-2 R f ;
• R b is, independently at each occurrence, CF 3 , OH, Ci_4 aUcoxy, C ⁇ _6 alkyl,
• R° is, independently at each occurrence, CF3, Ci_6 alkyl substituted with 0-2 R f , C 3 _6 cycloalkyl substituted with 0-2 R f , C6-10 aryl, 5- to 10-membered heteroaryl, (C6-io aryl)-Ci4 alkyl, or (5-to 10-membered heteroaryl)-Ci ⁇ alkyl, wherein said aryl is substituted with 0-3 R f and said heteroaryl comprises: carbon atoms and 1-4 heteroatoms selected from N, O, and S(0) p and substituted with 0-3 R f ;
• Rg is, independently at each occurrence, H, Ci -6 alkyl, or -(CH 2 )n-phenyl; n, at each occurrence, is selected from O, 1, 2, 3, and 4; p, at each occurrence, is selected from O, 1, and 2; and r, at each occurrence, is selected from O, 1, 2, 3, and 4; provided that: when M is an imidazole ring, Li is -C(R 5 R 6 )NH- or -CH 2 O-, and R 3 is unsubstituted phenyl, then R 11 is other than -CH 2 -(3-indolyl);
• M is an imidazole ring
• A is halogen substituted phenyl
• R 11 is -CH 2 -(pyridyl)
• R 3a is other than morpholyl which is optionally substituted.
• R 3 is, independently at each occurrence, phenyl substituted with 0-3 R 3a and 0-1 R 3d , naphthyl substituted with 0-3 R 3a and 0-1 R 3d , 1,2,3,4-tetrahydronaphthyl substituted with 0-3 R 3a and 0-1 R 3d , or -(CH2)r5- to 12-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 3a and 0-1 R 3d ;
• R 4 is, independently at each occurrence, H, Me, Et, Pr, F, Cl, Br, I, OCF3, CF 3 , CN, NO 2 , -(CH 2 ) r OH, -(CH 2 >C(O)OR a OR a , SR a , -C(O)R a , -C(O)OR a -NR 7 R 8 , -(CH 2 >NH 2 , -NR 8 (CH 2 ) r C(O)OR a , -(CH 2 ) r C(O)NR 8 R 9 , -NR 8 C(O)R 0 , -NR 8 C(O)ORc, -NR 8 C(O)NR 8 R 9 , -S(O) p NR 8 R 9 , -NR 8 S(O) p R°, or -S(O) 2 R 0 ; and
• R 11 is Ci- 4 haloalkyl, -CH 2 C(O)NR 8 R 9 , -CH 2 CH 2 C(O)NR 8 R 9 , -CH 2 C(O)R a , -CH 2 CH 2 C(O)R a -CH 2 C(O)OR a , -CH 2 CH 2 C(O)OR a , Ci -6 alkyl substituted with 0-2 R llc , C2-6 alkenyl substituted with 0-2 R l la , C 2 -6 alkynyl substituted with 0-2 R lla , -(CH.2hrC3.10 carbocycle substituted with 0-3 R l lb , or -(CH 2 ) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R l lb .
• the present invention includes compounds of Formula
• R 2 is, independently at each occurrence, F, Cl, Br, CF3, NO 2 , -(CH 2 ) r OR a , -(CH 2 )rSR a , -C(O)OR a , -C(O)NR 8 R 9 , -NR 8 C(O)R 0 , -NR 8 C(O)OR 0 , -NR 8 C(O)NR 8 R 0 , -S(O) p NR 8 R 9 , -NR 8 SO 2 R 0 , -NR 7 R 8 , -S(O)R 0 , -S(O) 2 R 0 , Ci_6 alkyl substituted with 0-1 R 2a , or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-2 R 2b ; alternately, when R 1 and R 2 groups are substituents
• R 3 is, independently at each occurrence, phenyl substituted with 0-2 R 3a and 0-1 R 3d , naphthyl substituted with 0-2 R 3a and 0-1 R 3d , 1,2,3,4-tetrahydronaphthyl substituted with 0-2 R 3a and 0-1 R 3d , or a 5- to 12-membered heterocycle substituted with 0-2 R 3a and 0-1 R 3d , wherein said heterocycle is selected from: thiophene, furan, thiazole, tetrazole, pyridine, pyridone, pyrrolidine, pyrrole, pyrazole, indole, 2-oxindole, isoindoline, indazole, 7-azaindole, benzofuran, benzothiophene, benzimidazole, benzisoxazole, benzoxazole, quinazoline, quinoline, isoquinoline, quinoxa
• R 4 is, independently at each occurrence, H, F, Cl, Br, OH, OMe, NH 2 , Me, Et, CF 3 , -CH 2 OH, -C(O) 2 H, CO 2 Me, CO 2 Et, -C(O)NH 2 , -C(O)NHMe, -C(O)N(Me) 2 , or -CH 2 CO 2 H; and
• R 11 is Ci -4 haloalkyl, -CH 2 C(O)NR 8 R 9 , -CH 2 CH 2 C(O)NR 8 R 9 , -CH 2 C(O)R a , -CH 2 CH 2 C(O)Ra -CH 2 C(0)0R a , -CH 2 CH 2 C(0)OR a , Ci -6 alkyl substituted with 0-2 R llc , -(CH 2 ) r -C3-7 cycloalkyl substituted with 0-2 R 1 lb , -(CH 2 )r-indanyl substituted with 0-2 R l lb , -(CH 2 ) r -indenyl substituted with 0-2 R l lb , -(CH 2 ) r phenyl substituted with 0-2 R 11 ⁇ , -(CH 2 ) r -naphthyl substituted with 0-2 Rl Ib, O
• the present invention includes compounds of
• A is substituted with 0-1 R 1 and 0-3 R 2 and selected from: C3-7 cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, pyridyl, indazolyl, indolyl, imidazolyl, furanyl, thienyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzothiophenyl, 3,4-methylenedioxy-phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and pyrazolyl;
• Li is -CH 2 CH 2 -, -CH(NH 2 )CH 2 -, -CH(NHCOMe)CH 2 -, -CH(NHCOEt)CH 2 -,
• R 3 is, independently at each occurrence, phenyl substituted with 0-2 R 3a , naphthyl substituted with 0-2 R 3a , 1,2,3,4-tetrahydro-naphthyl substituted with 0-3 R 3a and 0-1 R 3d , or a 5-to 12-membered heterocycle comprising: carbon atoms and 1-2 heteroatoms selected from N, O, and S(0) p , wherein said heterocycle is substituted with 0-2 R 3 a ;
• R 4 is, independently at each occurrence, H, F, Cl, Br, OMe, NH 2 , CF3, Me, Et, CO 2 H, CO 2 Me, or CO 2 Et;
• R 8a is H, Me or Et;
• Rl 1 is Ci ⁇ haloalkyl, -CH 2 C(O)NR8R9, -CH 2 CH 2 C(O)NRSR9, -CH 2 C(O)Ra
• the present invention includes compounds of Formula
• -CH 2 NHSO 2 (4-Cl-Bn), -CH 2 NHSO 2 CH 2 CH 2 Ph, -CH 2 NHSO 2 CH 2 CH 2 (2-Cl-Ph), -CH 2 NHSO 2 CH 2 CH 2 (3-Cl-Ph), -CH 2 NHSO 2 CH 2 CH 2 (4-Cl-Ph), -CH 2 NHSO 2 (3,4-dimethyl-isoxazol-4-yl), 1-pyrrolidinyl, 2-oxo-l-pyrrolidinyl, 3-carboxy-N-piperidinyl, pyrazol-1-yl, 4-carboxy-pyrazol-l-yl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, l,2,3-triazol-2-yl, 4-carboxy-l,2,3-triazol-l-yl,
• R 3 is, independently at each occurrence, phenyl substituted with 0-2 R 3a , naphthyl substituted with 0-2 R 3a , 1,2,3,4-tetrahydro-naphthyl substituted with 0-2 R 3a , or a 5- to 12-membered heterocycle substituted with 0-2 R 3a and selected from: thiophene, furan, thiazole, tetrazole, pyridine, pyridinone, pyrimidine, pyrrole, pyrazole, indole, 2-oxindole, isoindolin-1-one, indazole, iH-indazole-3-one, 7-azaindole, benzofuran, benzothiophene, benzimidazole, benzisoxazole, benzoxazole, quinazoline, quinoline, isoquinoline, 3H-quinazolin-4-one, phthalazine, 2H-phthal
• the present invention includes compounds of Formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, within the scope of the first aspect wherein:
• A is phenyl, 2-fiuorophenyl, 3 -fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,
• R 3 is, independently at each occurrence, phenyl, 3-biphenyl, 4-biphenyl, 3-aminophenyl, 4-aminophenyl, 3-N,N-dimethylaminophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-(/-butoxymethyl)-phenyl, 4-methylsulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl s 3-carboxyphenyl, 4-carboxypheny 1, 3 -methoxycarbonylphenyl, 4-methoxy
• R 4 is, independently at each occurrence, H, Me, F, Br, Cl, CF3, CO2H, C ⁇ 2Me, or CU2Et;
• R 11 is methyl, n-propyl, n-butyl, neopentyl, cyclohexylmethyl, carboxymethyl, benzylaminocarbonylethyl, N-phenethylaminocarbonylethyl, N-benzyl-N-methylaminocarbonylethyl, N-[(pyridin-2-yl)methyl]aminocarbonylethyl, N-[(5-methylpyrazin-2-yl)methyl]aminoethyl, N-(thiazol-2-ylmethyl)aminocarbonylethyl,
• 2-hy droxy-indan-5-ylmethyl 4-methylpiperazin- 1 -ylcarbonylmethyl, piperazin-1-ylcarbonylmethyl, 4-methylcarbonylpiperazin-l-ylcarbonylmethyl, pyrrolidin-1-ylcarbonylmethyl, 2-methoxypyrrolidin-l-ylcarbonylmetliyl, aziridin-1 -ylcarbonylmethyl, [3-(4-methoxyphenoxy)-azetidin-l-yl]carbonylmethyl,
• the present invention includes compounds of
• A is 3-chlorophenyl, 3-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 2,5-dichlorophenyl, 5-chloro-2-fluorophenyl, 5-bromo-2 -fluorophenyl, 3 -chloro-2-fluorophenyl, 2-methy 1-5 -chlorophenyl, 2-methoxy-5 -chlorophenyl, 2-methylthio-5-chlorophenyl, 2-ethylthio-5-chlorophenyl,
• R 3 is, independently at each occurrence
• R 4 is H, Me or Cl
• R 11 is methyl, n-butyl, carboxymethyl, cyclopropylmethyl, benzyl, 4-fluoro-benzyl, (benzyloxycarbonyl)methyl, 3-carboxy-ben2yl, 3-carbamoyl-benzyl, 3-(N-methylcarbamoyl)-benzyl, 3-(N,N-dimethylcarbamoyl)-benzyl, (l-methylpyrazol-3-yl)methyl, (l-methylpyrazol-4-yl)methyl, (l-ethylpyrazol-4-yl)methyl, (1 -n-propylpyrazol-4-yl)methyl, ( 1 -isopropylpyrazol-4-yl)methyl, 1 -ethylpyrazol-3 -ylmethyl, 3 -pyrazolylmethyl, l-(4-methoxybenzyl)-pyrazol-3-yl]methyl, (l,5-dimethylpyrazol
• the present invention provides a compound selected from the exemplified examples or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
• the present invention provides a process for preparing compounds of formulae (VIE), (IX) or (X):
• A-CR 5 CH-CO 2 H
• the present invention provides a process for preparing compounds of formula (XJI): or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein A, R 3 , R 4 , and R 11 are each the same as defined in the first aspect; which comprises: contacting compounds of formula (IV)
• R 3 , R 4 , and R 11 are each the same as defined in the first aspect; in an inert solvent with p-nitrochloroformate or carbonyl dimidiazole to form an activated acylamine species, which is further reacted, either in situ or after isolation, in an inert solvent, if appropriate in the presence of abase, with amines of formula ACH2NH2, wherein A is the same as defined in the first aspect.
• the present invention provides a process for preparing compounds of formula (XIIa):
• the present invention provides a process for preparing compounds of formula (XI):
• R 3 , R 4 , and R 11 are each the same as defined in the first aspect; with chloroformate reagents of formula ACH ⁇ OC(O)Cl wherein A is the same as defined in the first aspect.
• the present invention provides a process for preparing compounds of formula (XIa):
• the present invention includes compounds of
• A is substituted with 0-1 R 1 and 0-3 R 2 and selected from: phenyl and pyridyl,
• R 1 is, independently at each occurrence, Cl, Br, OMe, or Me;
• R 2 is, independently at each occurrence, F, Cl, Br, Me, OMe, or a 5-7 membered heterocycle substituted with 0-2 R 2b and selected from: pyrazolyl, triazolyl, or tetrazolyl; alternately, when R 1 and R 2 groups are substituents on adjacent atoms they may be taken together with the atoms to which they are attached to form a 5- to 6- membered heterocycle comprising carbon atoms and 0-4 heteroatoms selected from N, O, and S(O)p;
• R 3 is, independently at each occurrence, phenyl substituted with 0-2 R 3a , or a 5-to 12-membered heterocycle comprising: carbon atoms and 1-2 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 3a ;
• R 11 is -CH 2 C(O)NR 8 R 9 , -CH 2 C(O)OR a , Ci_ 6 alkyl substituted with 0-2 R 1 Ic, -(CH2)r-C3_7 cycloalkyl substituted with 0-2 R l lb , -(CH2)r-phenyl substituted with 0- 2 R l lb , -(CH2)r-indanyl substituted with 0-2 R l lb , -(CH 2 ) r -naphthyl substituted with 0-2 R 1 lb , or -(CH2)r-5- to 10-membered heteroaryl substituted with 0-2 R 1 lb and selected from thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl
• the present invention includes compounds of
• A is substituted with 0-2 R 2 and selected from:
• R 2 is, independently at each occurrence, F, Cl, Br, Me, CF3, OMe, OEt, pyrazol-1-yl, 4-carboxy-pyrazol-l-yl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, l,2,3-triazol-2-yl, 4-carboxy-l,2,3-triazol-l-yl, 4-(ethoxycarbonyl)-l,2,3-triazol-l-yl, tetrazol-1-yl, or tetrazol-5-yl;
• R 3 is, independently at each occurrence, phenyl substituted with 0-2 R 3a , or a 5- to 12-membered heterocycle substituted with 0-2 R 3a and selected from: pyridine, pyridinone, indole, indolin-2-one, indazole, 7-azaindole, quinazoline, quinoline, iH-quinolin-2-one, 3,4-dihydro-iH-quinolin ⁇ 2-one; and
• R 4 is, independently at each occurrence, ⁇ , Me, F, Br, Cl, CF 3 , CO 2 ⁇ , C ⁇ 2 Me, or CO 2 Et.
• the present invention includes compounds of
• A is 2-(pyrazol-l-yl)-5-chlorophenyl
• R 3 is, independently at each occurrence
• R 4 is H or Cl
• R 11 is methyl, n-butyl, carboxymethyl, benzyl, 4-fluoro-ben2yl, 3-carboxy-benzyl, 3-(N,N-dimethylcarbamoyl)-benzyl,
• A is substituted with 0-1 R 1 and 0-3 R 2 and selected from: C3.7 cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, pyridyl, indazolyl, indolyl, imidazolyl, furanyl, thienyl, benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzothiophenyl, 3,4-methylenedioxy-phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, and pyrazolyl.
• A is substituted with 0-2 R 2 and selected from:
• A is substituted with 0-2 R 2 and selected from:
• A is phenyl, 2-fluorophenyl, 3 -fluorophenyl,
• A is 3-chlorophenyl, 3-bromophenyl,
• Li is -CH2CH2-, -CH(NH2)CH 2 -,
• -C C-, -CH 2 NH-, -CH 2 O-, -NHNH-, -SCH 2 -, -SO 2 CH 2 - or -OCH 2 -.
• Li is -CH 2 CH 2 - or -CH 2 NH-.
• Li is -CH 2 CH 2 -.
• Li is -CH 2 NH-.
• M is
• M is N
• M is N
• M is N
• M is .
• M is N
• M is N
• R 2 is, independently at each occurrence, F, Cl, Br, CF 3 , NO 2 , -(CH 2 ) r OR a , -(CH 2 ) r SR a , -C(O)OR a , -C(O)NR 8 R 9 , -NR 8 C(O)R 0 , -NR 8 C(O)ORc, -NR 8 C(O)NR 8 Rc, -S(O)pNR 8 R 9 , -NR 8 SO 2 R 0 , -NR 7 R 8 , -S(O)R 0 , -S(O) 2 R 0 , Ci_6 alkyl substituted with 0-1 R 2a , or a 5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 2b .
• R 2 is substituted with 0-2 R 2b and selected from: pyrazolyl, triazolyl and tetrazolyl.
• R 3 is, independently at each occurrence, phenyl substituted with 0-3 R 3a and 0-1 R 3d , naphthyl substituted with 0-3 R 3a and 0-1 R 3d , 1,2,3,4-tetrahydronaphthyl substituted with 0-3 R 3a and 0-1 R 3d , or -(CH 2 )r-5- to 12-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R 3a and O- 1 R 3d .
• R 3 is, independently at each occurrence, phenyl substituted with 0-2 R 3a and 0-1 R 3d , naphthyl substituted with 0-2 R 3a and 0-1 R 3d , 1,2,3,4-tetrahydronaphthyl substituted with 0-2 R 3a and 0-1 R 3d , or a 5- to 12-membered heterocycle substituted with 0-2 R 3a and 0-1 R 3d , wherein said heterocycle is selected from: thiophene, furan, thiazole, tetrazole, pyridine, pyridone, pyrimidine, pyrrole, pyrazole, indole, 2-oxindole, isoindoline, indazole, 7-azaindole, benzofuran, benzothiophene, benzimidazole, benzisoxazole, benzoxazole, quinazoline, quinoline, is
• R 3 is, independently at each occurrence, phenyl substituted with 0-2 R 3a , naphthyl substituted with 0-2 R 3a ,
• R 3 is, independently at each occurrence, phenyl, 3-biphenyl, 4-biphenyl, 3-aminophenyl, 4-aminophenyl, 3-N,N-dimethylaminophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-(/-butoxymethyl)-phenyl, 4-methylsulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3-methoxycarbonylphenyl
• R 3 is, independently at each occurrence
• R 3 is, independently at each occurrence
• R 3 is, independently at each occurrence
• R 3 is, independently at each occurrence
• R 3 is, independently at each occurrence
• R 4 is H, F, Cl, Br, OH, OMe, NH 2 , Me, Et,
• R 4 is H, F, Cl, Br, OMe, NH 2 , CF3, Me, Et,
• R 4 is H, Me, F, Br, Cl, CF3, CO 2 H, CO 2 Me, or CO 2 Et.
• R 4 is H, Me or Cl.
• R 4 is H or Cl. [0082] In another embodiment, R 4 is Cl.
• Rl 1 is Ci -4 haloalkyl, -CH 2 C(O)NR 8 R 9 ,
• Rl 1 is Ci -4 haloalkyl, -CH 2 C(O)NR 8 R 9 ,
• RH is methyl, n-propyl, n-butyl, neopentyl, cyclohexylmethyl, carboxymethyl, benzylaminocarbonylethyl,
• 2-hydroxy-indan-5-ylmethyl 4-methylpiperazin- 1 -ylcarbonylmethyl, piperazin-1-ylcarbonylmethyl, 4-methylcarbonylpiperazin-l-ylcarbonylmethyl, pyrrolidin- 1 -ylcarbonylmethyl, 2-methoxypyrrolidin- 1 -ylcarbonylmethyl, aziridin- 1 -ylcarbonylmethyl, [3 ⁇ (4-methoxyphenoxy)-azetidin- 1 -yl] carbonylmethyl, 2-hydroxy ethylaminocarbony lmethyl, 2-methoxy ethylaminocarbony lmethyl, 2-ethoxyethylaminocarbonylmethyl, bis(2-methoxyethyl)aminocarbonylmethyl, 4-dimethy laminopyrrolidin- 1 -ylcarbonylmethyl, (3-phenyl-pyrrolidin-l-yl)carbonylmethyl, (3 ,3 -di
• R 11 is methyl, n-butyl, carboxymethyl, cyclopropylmethyl, benzyl, 4-fluoro-benzyl, (benzyloxycarbonyl)methyl, 3-carboxy-benzyl, 3-carbamoyl-benzyl, 3-(N-methylcarbamoyl)-benzyl, 3-(N,N-dimethylcarbamoyl)-benzyl, (l-methylpyrazol-3-yl)methyl, ( 1 -methylpyrazol-4-yl)methyl, ( 1 -ethylpyrazol-4-yl)methyl, (l-n-propylpyrazol-4-yl)methyl, (1 -isopropylpyrazol-4-yl)methyl, 1 -ethylpyrazol-3 -ylmethy 1, 3 -pyrazolylmethyl, l-(4-methoxybenzyl)-pyrazol-3-yl]methyl, (l,
• R 11 is -CH2C(O)NR 8 R 9 .
• R 11 is -(CH2)r-C3.7 cycloalkyl substituted with 0-2 R 11 ⁇ .
• R 11 is Ci_6 alkyl substituted with 0-2 R l lc .
• R 1 1 is -(CH2)r-phenyl substituted with
• R 1 * is or -(CH2) r -5- to 10-membered heteroaryl substituted with 0-2 R 1 lb and selected from thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and 2,2-dioxo-2,3-dihydro-lH-2 ⁇ 6 -benzo[c]thiophen
• the present invention provides, inter alia, compounds of Formula (II):
• M is a 5- to 6-membered heterocycle selected from:
• R la is F, OCF 3 , CF 3 , 0R a , SR a , CN, -NR 7 R 8 , -C(O)NR 8 R 9 , -NR 8 C(O)Rc, -S(O) P NR 8 R9, -NR 8 SO 2 Rc, or _(CF 2 )rCF3;
• R 2a is F, OCF 3 , CF 3 , OR a SR a , CN, -NR 7 R 8 , -C(O)NR 8 R 9 , -NR 8 C(O)R C , -NR 8 C(O)OR C , -NR 8 C(O)NR 8 Rc, -S(O)pNR 8 R 9 , -NR 8 SO 2 Rc, or -(CF 2 )rCF3;
• R 3 is, independently at each occurrence, -(CH 2 ) r -C 3 -io carbocycle substituted with 0-3 R 3a and 0-1 R 3d , or -(CH 2 ) r -5- to 12-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R 3a and 0-1 R 3d ;
• R 3d C2-6 alkenyl substituted with 0-2 R 3d , C2-6 alkynyl substituted with 0-2 R 3d , -(CH2)r-C3.io carbocycle substituted with 0-3 R 3d , or -(CH2) r -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said heterocycle is substituted with 0-3 R 3d ; R 3c is, independently at each occurrence, Ci-6 alkyl substituted with 0-2 R 3d ,
• R 6 is, independently at each occurrence, H, F, or Ci -4 alkyl;
• R 7 is, independently at each occurrence, H, Ci_6 alkyl, -(CH 2 ) n -C3_io carbocycle, -(CH 2 )n-(5- to 10-membered heteroaryl), -C(O)R 0 , -CHO, -C(O) 2 R 0 , -S(O) 2 R 0 , -CONR 8 R 0 , -OCONHR 0 , -C(O)O-(Ci -4 alkyl)OC(O)-(Ci.
• R 8 is, independently at each occurrence, H, C ⁇ g alkyl, -(CH 2 ) n -phenyl, or -(CH 2 )n-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) 1 ,; wherein said alkyl, phenyl and heterocycle are optionally substituted with 0-2 R f ; alternatively, R 7 and R 8 , when attached to the same nitrogen, combine to form a 5- to 10-membered heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, O, and S(O) 1 ), wherein said heterocycle is substituted with 0-2 R f ; R 8a is H or C M alkyl;
• R 9 is, independently at each occurrence, H, Ci_6 alkyl, or -(CBkVpherryl; wherein said alkyl and phenyl are optionally substituted with 0-2 R f ; alternatively, R 8 and R 9 , when attached to the same nitrogen, combine to form a 5- to 12-membered heterocycle comprising: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O)P 1 wherein said heterocycle is substituted with 0-2 R d ;
• R 10 is, independently at each occurrence, H or Ci-6 alkyl substituted with 0-3
• R 11 is Ci -4 haloalkyl, -C(O)NR 8 R 9 , -CH 2 C(O)NR 8 R 9 , -CH 2 CH 2 C(O)NR 8 R ⁇ , -C(0)R a , -CH 2 C(O)R a , -CH 2 CH 2 C(O)R a , -C(O)OR a , -CH 2 C(O)OR a , -CH 2 CH 2 C(O)OR* 1 , Ci-6 alkyl substituted with 0-3 R l lc , C 2- 6 alkenyl substituted with 0-3 R 1 la , C 2 _6 alkynyl substituted with 0-3 R 1 la , -(CR 14 R 15 ) r -C3.io carbocycle substituted with 0-3 R l lb , or -(CR 14 R 15 )r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatom
• R 14 and R 15 are, independently at each occurrence, H, F, or Ci_4 alkyl;
• R a is, independently at each occurrence, H, CF3, Ci-6 alkyl, -(CH2)r-C3 -7 cycloalkyl, -(CH2) r -C6-io aryl, or -(CH2) r -5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p, wherein said cycloalkyl, aryl or heterocycle groups are optionally substituted with 0-2 R f ;
• R b is, independently at each occurrence, CF3, OH, C1-4 alkoxy, Ci_6 alkyl, -(CH2)r-C3.io carbocycle substituted with 0-2 R d or -(CH2)r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p and substituted with 0-3 R d ;
• R c is, independently at each occurrence, CF3, Ci_g alkyl substituted with 0-2 R f , C3-6 cycloalkyl substituted with 0-2 R f , C6-10 aryl 5- to 10-membered heteroaryl, (C6-10 a ryl)-Ci-4 alkyl, or (5-to 10-membered heteroaryl)-Ci_4 alkyl, wherein said aryl is substituted with 0-3 R f and said heteroaryl comprises: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)p and substituted with 0-3 R f ;
• the present invention provides a compound wherein: L is -CH 2 CH 2 CONH- or -CH 2 NHCONH-.
• the present invention provides a compound wherein: L is -CH 2 CH 2 CONH-. [00100] In another embodiment the present invention provides a compound wherein: L is -CH 2 NHCONH-.
• the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.
• the present invention provides a pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
• the present invention provides a novel process for making a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
• the present invention provides a novel intermediate for making a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
• the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s) selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, antiatherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antit
• the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s) selected from an anti-arrhythmic agent, an anti-hypertensive agent, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, a potassium channel blocker, a cholesterol/lipid lowering agent, or a combination thereof.
• additional therapeutic agent(s) selected from an anti-arrhythmic agent, an anti-hypertensive agent, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, a potassium channel blocker, a cholesterol/lipid lowering agent, or a combination thereof.
• the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s) selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase, or a combination thereof.
• additional therapeutic agent(s) selected from warfarin, unfractionated heparin, low molecular weight heparin
• the present invention provides a pharmaceutical composition wherein the additional therapeutic agent is an antihypertensive agent selected from ACE inhibitors, AT-I receptor antagonists, beta- adrenergic receptor antagonists, ETA receptor antagonists, dual ETA/AT- 1 receptor antagonists, and vasopepsidase inhibitors, an antiarrythmic agent selected from IKur inhibitors, an anticoagulant selected from thrombin inhibitors, antithrombin-III activators, heparin co-factor ⁇ activators, other factor XIa inhibitors, other kallikrein inhibitors, plasminogen activator inhibitor (PAI-I) antagonists, thrombin activatable fibrinolysis inhibitor (TAFI) inhibitors, factor Vila inhibitors, factor IXa inhibitors, and factor Xa inhibitors, or an antiplatelet agent selected from GP ⁇ b/IIIa blockers, protease activated receptor (PAR-I) antagonists, phosphodiesterase-III inhibitors, an antiarrythmic agent selected
• the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent is the anti- platelet agent clopidogrel.
• the present invention provides a method for modulation of the coagulation cascade and/or contact activation system comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
• the present invention provides a novel method for treating thrombotic or thromboembolic disorders comprising: administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
• the present invention provides a novel method, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
• the present invention provides a novel method, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
• the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral
• the present invention provides a method for treating inflammatory disorders comprising: administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.
• the present invention provides a method, wherein the inflammatory disorder is selected from the group consisting of sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.
• the present invention provides a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug form thereof in an amount effective to treat a thrombotic or thromboembolic disorder.
• the present invention provides a method of treating a patient in need of inflammatory disorder treatment, comprising: administering a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug form thereof in an amount effective to treat an inflammatory disorder.
• the present invention provides a novel article of manufacture, comprising: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention; and (c) a package insert stating that the pharmaceutical composition can be used for the treatment of a thromboembolic and/or inflammatory disorder.
• the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
• the present invention provides a novel article of manufacture, comprising: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention; and (c) a package insert stating that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat a thromboembolic and/or inflammatory disorder.
• the present invention provides a novel article of manufacture, further comprising: (d) a second container; wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
• the present invention provides a novel method, comprising: administering a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug form thereof in an amount effective to treat a thromboembolic and/or inflammatory disorder.
• the present invention provides a compound of the present invention for use in therapy.
• the present invention provides a compound of the present invention for use in therapy for treating a thromboembolic and/or inflammatory disorder.
• the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of a thromboembolic and/or inflammatory disorder.
• the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional more preferred embodiments. It is also to be understood that each individual element of the preferred embodiments is its own independent preferred embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment. DEFINITIONS
• enantiomeric or diastereomeric products When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods, for example, by chromatography or fractional crystallization.
• Compounds of the present invention, and salts thereof may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
• the inventive compounds may be in the free or hydrate form.
• the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole.
• the molecular weight is less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. Even more preferably, the molecular weight is less than about 700 grams per mole.
• alkyl or alkylene is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
• Ci_io alkyl (or alkylene), is intended to include Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, and Cio alkyl groups.
• Ci-C ⁇ alkyl denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group.
• Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
• Alkenyl or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more double carbon- carbon bonds that may occur in any stable point along the chain.
• C2-6 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, and C(, alkenyl groups.
• alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3 -pentenyl, and the like.
• Alkynyl or “alkynylene” is intended to include hydrocarbon chains of either straight or branched configuration and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain.
• C2-6 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
• alkoxy or “alkyloxy” refers to an -O-alkyl group.
• Ci_6 alkoxy (or alkyloxy), is intended to include Ci, C2, C3, C4, C5, and Ce alkoxy groups.
• Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy, and the like.
• alkylthio or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S-, ethyl-S-, and the like.
• Halo or "halogen” includes fluoro, chloro, bromo, and iodo.
• Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen.
• haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
• haloalkyl also include “fluoroalkyl” which is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.
• fluoroalkyl or “haloalkyloxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
• Ci_6 haloalkoxy is intended to include Ci, C2, C3, C4, C5, and Ce haloalkoxy groups.
• haloalkoxy examples include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluorothoxy, and the like.
• haloalkylthio or “thiohaloalkoxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S-, pentafiuoroethyl-S-, and the like.
• cycloalkyl refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems.
• C3-7 cycloalkyl is intended to include C3, C4, C5, Ce, and Cj cycloalkyl groups.
• Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopen ⁇ yl, cyclohexyl, norbornyl, and the like.
• “carbocycle” or “carbocyclic residue” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic.
• carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,
• bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).
• Preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
• carbocycle unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl.
• a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
• Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
• Aryl groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, phenanthranyl, and the like. Aryl moieties are well known and described, for example, in Hawley's Condensed Chemical Dictionary (13 ed.), RJ. Lewis, ed., J. Wiley & Sons, Inc., New York (1997).
• heterocycle or “heterocyclic group” is intended to mean a stable 5, 6, or 7- membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, 13, or 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or fully unsaturated, and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O) p ).
• the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
• the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
• the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
• a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term "heterocycle" is used, it is intended to include heteroaryl.
• heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydromro[2,3-Z?]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolen
• Preferred 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, lH-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisox
• Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
• aromatic heterocyclic group or “heteroaryl” is intended to mean a stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
• Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, benzodioxane, and the like.
• Heteroaryl groups can be substituted or unsubstituted.
• the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined).
• the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N ⁇ O and S(O)p). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
• Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
• Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
• counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
• nitrogen atoms e.g., amines
• these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention.
• an oxidizing agent e.g., mCPBA and/or hydrogen peroxides
• shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N-»O) derivative.
• these can be replaced by silicon atoms, provided they do not form Si-N or Si-O bond.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
• the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, the disclosure of which is hereby incorporated by reference.
• compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (Le., a compound of formula I) is a prodrug within the scope and spirit of the invention.
• a prodrug within the scope and spirit of the invention.
• Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K. Widder, et. al. (Academic
• compositions containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se.
• prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood.
• physiologically hydrolyzable esters of compounds of formula I include C ⁇ alkyl , Ci.galkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, Ci_6 alkanoyloxy-C ⁇ galkyl, e.g. acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl,
• esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.
• prodrugs are well known in the art and described in, for example, Medicinal Chemistry: Principles and Practice, ed. F. D. King, The Royal Society of Chemistry, Cambridge, UK, 1994, which is incorporated herein by reference in its entirety.
• Isotopically labeled compounds of the present invention Le., wherein one or more of the atoms described are replaced by an isotope of that atom ⁇ e.g., C replaced by 13 C or by 14 C; and isotopes of hydrogen include tritium and deuterium), are also provided herein.
• Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.
• Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 98%, preferably 99%, compound of the present invention ("substantially pure"), which is then used or formulated as described herein. Such “substantially pure” compounds are also contemplated herein as part of the present invention.
• “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that compounds of the present invention do not contain aN-halo, S(O ⁇ H, or S(O)H group.
• solvate means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• solvent encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates and the like. Methods of solvation are generally known in the art.
• patient encompasses all mammalian species.
• treating cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
• Therapeutically effective amount is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit factor XIa and/or plasma kallikrein or to treat the disorders listed herein.
• the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
• the combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect (in this case, prevention of thrombosis) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent.
• composition means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier.
• a “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.
• Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art.
• compositions include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted.
• Pharmaceutically acceptable carriers include both aqueous and nonaqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art.
• LiHMDS Lithium bis(trimethylsilyl) amide mCPBA or m-CPBA met ⁇ -chloroperbenzoic acid
• the compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis.
• the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
• the reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.
• ureas of formula Ic of this invention can be prepared by condensation of an amine intermediate Ia with carbonyl diimidazole in a solvent such as tetrahydrofuran or N,N-dimethylformamide followed by treatment in situ with an suitably substituted benzyl amine Id.
• Urea linked compounds of this invention of formula Ic can also be prepared by condensation of amine intermediate Ia withp- nitrophenylchloroformate in the presence of a suitable base such as triethylamine, followed by treatment of the resulting ⁇ -nitrophenylcarbamate with an appropriate substituted amine Id.
• Isocyanates of formula Ib used in Scheme 1 above are either commercially available or can be readily prepared from the corresponding amines Id by treatment with phosgene or by various other methods known in the art (see for example, H. Eckert & B. Forster, Angew. Chem. Int. Ed. 1987, 26, 894; H. Knolker & T. Braxmeier, Synlett, 1997, 925; S. Porwanski et al. Tetrahedron Lett. 2004, 45, 5027).
• Amines of formula Id are also available commercially or can be prepared by those knowledgeable in the art from a variety of easily accessible starting materials such as nitriles, aldehydes, alcohols, halides, acids and esters by methods including, but not limited to those outlined in Scheme 2.
• Hydrazine reagents of formula 3b used to prepare compounds of this invention in Scheme 3 are commercially available or can be prepared by those knowledgeable in the art of organic synthesis by other methods.
• A is an aryl or heteroaryl group
• the requisite hydrazine reagent is readily available via diazotization of a starting aryl or heteroarylamine 4a followed by reduction of the resulting diazonium salt with tin chloride to the corresponding arylhydrazine 4b as illustrated in Scheme 4.
• Reagent combinations which may be employed for the coupling of amines of formula Ia with suitably substituted carboxylic acids include, but are not limited to: BOP-reagent and triethylamine, EDCI, HOBt, and N-methylmorpholine, or HATU and Hunig's base (DIP EA). Solvents suitable for this transformation include, but are not limited to tetrahydrofuran and dimethylformamide.
• Coupling of amines of formula Ia with suitably substituted carboxylic acid chlorides or mixed anhydrides can be carried out in solvents such as methylene chloride or tetrahydrofuran in the presence of a base such as triethylamine, N,N-dirnethyaminopyridine (DMAP) or potassium carbonate.
• a base such as triethylamine, N,N-dirnethyaminopyridine (DMAP) or potassium carbonate.
• DMAP N,N-dirnethyaminopyridine
• A-(CH 2 ) 2 CO 2 H) 5a are either commercially available, or they can be prepared from the corresponding bromides, alcohols, aldehydes, or esters as shown in Scheme 5 using methods known to one skilled in the art.
• imidazole compounds of this invention can be prepared by introduction of R 3 groups via palladium-mediated coupling to an intermediate 4-bromo-5-chloroimidazole intermediate prepared as shown in Scheme 11.
• Alternate boronic acid or boronic ester coupling partners that are commercially available or readily synthesized by methods known to one skilled in the art may be employed in this palladium-mediated step to afford additional compounds of this invention.
• Chiral amino acids usefiil for the synthesis of imidazole compounds of this invention are either commercially available or can be prepared by any of a number of methods known in the art.
• didehydroamino acid derivatives of formula 12c may be reduced to provide protected ( ⁇ S)-amino acids of formula 12 d by hydrogenation in the presence of a chiral catalyst such as ()S,5)-EtDuPhosRh(I) using a modified procedure of Burk (J. Am. Chem. Soc, 1991, 113, 8518).
• Didehydroamino acid derivatives of formula 12c can be prepared via several methods, such as for example, a Heck coupling between an aryl iodide, bromide, or tosylate of formula 12a and Boc didehydroalanine ben2yl ester, using a modified procedure of Carlstr ⁇ m, et al. ⁇ Synthesis, 1989, 414).
• protected didehydroaminoacids of formula 12c may be prepared by Horner-Emmons type condensation of an aldehyde of formula 12b with Boc-methyl-2- (dimethylphosphono)glycinate, using modifications of literature procedures (Wang, et al. Tetrahedron, 2002, 55, 3101).
• Protected amino acids of formula 12d may also be prepared by alkylation of methyl 2-(diphenylmethyleneamino)acetate with an appropriately substituted benzylbromide in the presence of a chiral cinchonidinium catalyst in a suitable solvent, such as methylene chloride, using a procedure similar to that described by O'Donnell, et al ⁇ Tetrahedron, 1999, 55, 6347), followed by mild acidic workup and reprotection of the amino functionality with a Boc group according to methods known to one skilled in the art.
• a suitable solvent such as methylene chloride
• Representative pyridine compounds of this invention can be prepared as shown in Scheme 13. Suzuki coupling between an appropriately functionalized pyridine, such as 13a and an appropriately substituted aryl or heteroaryl boronic acid or ester 13b in the presence of a base such as anhydrous potassium carbonate in a solvent such as methanol or THF using a catalyst such as PXPd2 provides the biaryl compound.
• a base such as anhydrous potassium carbonate
• a solvent such as methanol or THF
• PXPd2 a catalyst
• the 2-chloropyridine derivative is treated with trimethylsilyl bromide in propionitrile at elevated temperature in a microwave to give the 2-bromopyridine derivative 13c.
• Metal- halogen exchange with n-butyllithium and quenching the intermediate anion with a suitable formyl source such as 1-formyl piperidine or DMF provides aldehyde 13d.
• EDCI, HOBt, and base generates 13h, 13i, and 13n.
• the pyridine N-oxide derivatives 13j-m and 13o can be prepared by oxidation of 13f-i and 13n with a suitable oxidant such as r ⁇ -chloroperbenzoic acid in chloroform. Further manipulation of functional groups on A, R 3 , and R 4 using methods known to one skilled in the art of organic synthesis will give additional compounds of the invention.
• R 3 moiety can be introduced via a Suzuki coupling strategy later in the synthesis as shown in Scheme 14.
• Compound 14c can be prepared in three steps according to a modified procedure described by Negi (Negi, S. et al. Synthesis, 1996, 991). Addition of Grignard or lithium reagents to a suitably substituted ester or Weinreb amide 14a yields ketone 14b. Condensation of 14b with hydroxylamine hydrochloride generates the oxime which can be reduced to the primary amine 14c with zinc dust and TFA. Boc protection of 14c gives 14d.
• amide coupling between 13e and 5a, 6b, 6c, or 6d employing suitable coupling reagents, such as EDCI, HOBt, and base generates 13h, 13i, and 13n. (for alternative coupling reagents see: Han, S-Y; Kim, Y-A. Tetrahedron, 2004, 60, 2447).
• the pyridine N-oxide derivatives 13j-m and 13o can be prepared by oxidation of 13f-i and 13n with a suitable oxidant such as m-chloroperbenzoic acid in chloroform. Further manipulation of functional groups on A, R 3 , and R 4 using methods known to one skilled in the art of organic synthesis will give additional compounds of the invention.
• the boron pinacolate intermediates can be used in place of boronic acids for coupling to the aryl/heteroaryl halides or triflates or the boron pinacolate intermediate can be converted to the boronic acids.
• the corresponding boronic acids can be prepared by metal-halogen exchange of the aryl/heteroaryl halide, quenching with a trialkoxyborate reagent, and aqueous workup to provide the boronic acids (Miyaura, N.; Suzuki, A. Chem. Review, 1995, 95, 2457).
• Representative pyridone compounds of this invention can be prepared as shown in Scheme 15.
• Compound 15d can be prepared in two steps according to a modified procedure described by Resmini (Resmini, M. et ah, Tetrahedron
• a suitably substituted amino ester 15a can be converted to the corresponding ⁇ -ketophosphonate 15b by treatment with lithium dimethylmethylphosphonate.
• amide coupling between 15f and 5a, 6b, 6c, or 6d employing suitable coupling reagents, such as EDCI, HOBt, and base generates 15i, 15j, or 15k.
• suitable coupling reagents such as EDCI, HOBt, and base
• Reverse phase preparative HPLC was carried out using a Shimadzu Preparative HPLC system running DiscoveryVP software using Method A: YMC Sunfire 5 ⁇ m Cl 8 30x100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm), Method B: Phenomenex AXIA Luna 5 ⁇ m Cl 8 30 x 75 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm),
• Method C Phenomenex Luna 5 ⁇ m C18 30 x 100 mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm), or Method D: Phenomenex Luna 5 ⁇ m C18 3O x lOO mm column with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm).
• reverse phase preparative HPLC was carried out using a Varian ProStar Preparative HPLC System running Star 6.2 Chromatography Workstation software using Method E: Dynamax 10 ⁇ m C18 41.4 x 250 mm column with a 30 min gradient at 30 mL/min from 10%B to 100% B (A 98% water, 2% acetonitrile, 0.05% TFA; B: 98% acetonitrile, 2% water, 0.05% TFA, UV 254 nm).
• LCMS chromatograms were obtained on a Shimadzu HPLC system running DiscoveryVP software, coupled with a Waters ZQ mass spectrometer running MassLynx version 3.5 software using the same columns and conditions as utilized for analytical described above.
• IB 4-(2-Bromoacetyl)-2-fluorobenzonitrile: IA (4.0 g of 90% pure material, 0.02 mol) was dissolved in CH 2 Cl 2 (50 mL). To it was added dropwise oxalyl chloride over 15 minutes (2.3 mL, 0.026 mol). The mixture was stirred at rt for 1 h and then heated at reflux for 1 h under N 2 . The solvent was removed, and the residue was redissolved in CH 3 CN (50 mL). This solution was cooled to -15 0 C, and to it was added (trimethylsilyl)diazomethane (11.5 mL of 2.0M in hexane) dropwise over 20 min.
• Example 1 To a THF (2 mL) solution of IE (0.09 g, 0.26 mmol) and (E)-3-(3-chlorophenyl)acrylic acid (0.04 g, 0.26 mmol) was added BOP reagent (0.12 g, 0.26 mmol) and triethylamine (0.3 mL). The reaction mixture was stirred at rt overnight. The mixture was quenched with NaOH (IN, 50 mL) and the organics were extracted with ethyl acetate (2 x 50 mL), dried (MgSO 4 ) and evaporated to an oil which was used directly in the next step.
• BOP reagent 0.12 g, 0.26 mmol
• triethylamine 0.3 mL
• Example 2 2A (0.07 g), was dissolved in n-butanol (2 mL) and transferred into a microwave flask. To this mixture was added hydrazine (0.1 mL) and the flask was capped. The mixture was irradiated in a microwave oven at 150 °C for 15 min, cooled, and purified by prep, reverse phase HPLC (acetonitrile: water: 0.05%TFA). Pure fractions were collected and lyophilized to a colorless powder (0.02 g). LCMS m/z 517.35 (M+H) + . 1 HNMR (CD 3 OD, 400MHz) ⁇ : 7.80 (m, IH),
• Example 3 The crude product from 3A (0.05 g) was treated with hydrazine (0.1 mL) in n-butanol (2 mL), irradiated in a microwave oven as described previously and purified via reverse phase HPLC (acetonitrile:water: 0.05%TFA) and lyophilized to afford the desired product as a colorless solid. (0.05 g). HPLC purity >95%. LCMS m/z 515.37 (M+H) + .
• Example 4 was prepared in a similar fashion as described above for
• Example 5 was prepared in a similar fashion described previously for
• Example 3 Colorless solid. HPLC purity >95%. LCMS m/z 519.33 (M+H) + ; 543.34 (M+Na) + .
• Examples 6-12 in Table 1 were prepared in a parallel library fashion from IE (-40 mg) in anhydrous THF (2 mL) and an equivalent amount of the appropriate acid, BOP reagent and triethylamine (0.4 mL). The reactions were stirred at rt overnight. Workup followed by hydrazine treatment and purification as described in the previous examples afforded the target compounds.
• Example 11 iV- ⁇ (S)-l-[4-(3-Amino-lH-indazol-6-yl)-5-chloro-lH r -imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(2,5-dichloro-phenyl)-propionamide
• Example 12 iV- ⁇ (S)-l-[4-(3-Amino-lH-indazol-6-yl)-5-chloro-lH r -imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(2,5-dichloro-phenyl)-propionamide
• Example 13 was prepared by the coupling (BOP reagemVTEA, THF) of commercially available 2-(3-chlorophenylthio)acetic acid and IE followed by treatment with hydrazine in a microwave as described for Example 2.
• the desired product was obtained as a colorless solid following purification via reverse phase chromatography and lyophilization.
• Example 14 was obtained by treatment of Example 13 with mCPBA (2.5 eq) in dichloromethane. Reverse phase HPLC purification followed by lyophilization of the pure fractions afforded the desired product as a colorless solid.
• Example 15 was prepared from 2-(3-chlorophenoxy)acetic acid and IE following the procedures described under Example 2 to provide Example 15 as a colorless solid.
• LCMS m/z 521.38 (M+H) + .
• Example 18 l- ⁇ (S)-l-[4-(3-Amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(3,5-dichloro-benzyl)-urea
• Example 19 l- ⁇ (S)-l-[4-(3-Amino-l J H-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(3-methyl-benzyl)-urea
• Example 26 l- ⁇ (S)-l-[4-(3-Amino-l J ⁇ -indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(3-chloro-4-methyl-benzyl)-urea
• Example 27 l- ⁇ (S)-l-[4-(3-Amino-l J H-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(6-chloro-2-fluoro-3-methyl-benzyl)-urea
• Example 33 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(3-aminomethyl-benzyl)-urea, trifluoroacetic acid salt [00210]
• Example 33 was prepared from commercially available fert-butyl 3- (aminomethyl)-benzylcarbamate following the procedure outlined for Example 16.
• Example 34 was prepared according to the procedure described for Example 16 from commercially available (2,3-dichloro-6-nitrophenyl)methanamine hydrochloride. The nitro group was reduced with tin chloride followed by conversion to the aminoindazole and purification as previously described for Example 16.
• Example 35 was prepared from commercially available (5-chloro-2-
• Example 36 3-(3- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -ureidomethyl)-benzamide, trifluoroacetic acid salt [00213]
• Example 36 was prepared from commercially available 3-
• Example 37 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(2-aminomethyl-5-chloro-benzyl)-urea, trifluoroacetic acid salt [00214]
• Example 37 was prepared from tert-butyl 2-(aminomethyl)-4- chlorobenzyl-carbamate-3-(aminomethyl)benzamide (Morissette, M.M. et. al. Bioorg. Med. Chem. Lett.
• Example 38 l-(2-amino-5-chloro-benzyl)-3- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH- imidazol-2-yl]-2-phenyl-ethyl ⁇ -urea, trifluoroacetic acid salt [00215]
• Example 38 was prepared from 2-(aminornethyi)-4-chloroaniline according to the procedure described for Example 16.
• Example 39 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(5-chloro-2-pyrazol-l-yl-benzyl)-urea, trifluoroacetic acid salt [00216]
• Example 39 was prepared from (5-chloro-2-(lH-pyrazol-l-yl)phenyl)- methanamine (prepared according to a similar procedure of Young, M. B. et. al J. Med. Chem. 2004, 47, 2995) according to the procedure described for Example 16.
• Example 40 was prepared from 4OA according to the procedure described for Example 16.
• 41A (2-(benzyloxy)-5-chlorophenyl)methanamine: 41A was prepared by the nucleophilic aromatic displacement of 2-fluoro-5-chlorobenzonitrile with benzylalcohol followed by reduction of the nitrile with LA ⁇ in anhydrous T ⁇ F. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL), dried (MgSC ⁇ ) and purified via silica gel column chromatography (hexane:ethyl acetate 1:1) to afford the product as a colorless solid.
• 1 HNMR (CDCI 3 ,
• 42A (5-chloro-2-(methylthio)phenyl)methanamine: 42A was prepared by the nucleophilic aromatic displacement of 2-fluoro-5-chlorobenzonitrile with sodium thiomethoxide followed by reduction of the nitrile with LAH in anhydrous THF. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL), dried (MgSC ⁇ ) and concentrated to a yellow oil.
• 43A was prepared by procedures analogous to 89A, 89B, 89C, 89F, 89G, and 89 ⁇ starting from Boc-Phe in place of 84C. [00224] 43B.
• Example 43 was prepared according to the procedure for urea formation described for Example 16 from tert-butyl 2-(aminomethyl)-4- chlorobenzylcarbamate and 43A according to the procedure described for Example 16.
• Example 44 Removal of the Boc protecting group from Example 43 with TFA followed by reverse phase ⁇ PLC (acetonitrile/water/0.05 TFA) purification and lyophilization afforded Example 44 as a colorless solid.
• Example 45 was prepared according to the procedure described for
• Example 16 from (5-chloro-2-(l ⁇ -tetrazol-l-yl)phenyl)methanamine (Young, M. B. et. alJ. Med. Chem. 2004, 47, 2995) and 43A. Reverse phase HPLC purification and lyophilization afforded Example 45 as a colorless solid.
• Example 46 was prepared from (5-chloro-2-
• Example 47 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(5-chloro-2-tetrazol-l-yl-benzyl)-urea, trifluoroacetic acid salt [00228]
• Example 47 was prepared from (5-chloro-2-(l ⁇ -tetrazol-l- yl)phenyl)methanamine according to the procedure described for Example 16.
• Example 48 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(5-chloro-2-ethylsulfanyl-benzyl)-urea, trifluoroacetic acid salt [00229]
• Example 48 was prepared according to the procedure described for
• Example 16 from (5-chloro-2-(ethylthio)phenyl)methanamine.
• LCMS m/z 580.3 (M+H) + .
• Example 49 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(5-chloro-2-propylsulfanyl-benzyl)-urea, trifluoroacetic acid salt [00230]
• Example 49 was prepared according to the procedure described for
• Example 50 l- ⁇ (S)-l-[4-(3-amino-lH r -indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(3-fluoro-benzyl)-urea, trifluoroacetic acid salt [00231]
• Example 50 was prepared according to the procedure described for
• Example 51 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(2,5-difluoro-ben2yl)-urea, trifluoroacetic acid salt [00232]
• Example 51 was prepared according to the procedure described for
• Example 16 with readily accessible 3,5-fluorobenzylamine with IE and p- nitrophenyl-chloroformate.
• 1 HNMR (CD 3 OD, 400 MHz) ⁇ : 7.84 (d, J 8.9z, IH), 7.59 (s, IH),
• Example 52C was prepared according to the procedure described for urea formation in Example 16 by the coupling of (5-chloro-2-(lH-tetrazol-l- yl)phenyl)methanamine (prepared according to a similar procedure of Young, M. B. et al. J. of Med. Chem. 2004, 47, 2995), with 52B and p-nitrophenyl-chloroformate.
• Example 52 Reverse phase HPLC purification and lyophilization afforded Example 52 as a colorless solid.
• Example 53 l-[6-(5-chloro-2- ⁇ (S)-l-[3-(5-chloro-2-tetrazol-l-yl-benzyl)-ureido]-2-phenyl- ethyl ⁇ -lH-imidazol-4-yl)-lH-indazol-3-yl]-3-(5-chloro-2-pentazol-l-yl-benzyl)- urea, trifluoroacetic acid salt [00236]
• Example 53 was prepared according to the procedure for urea formation described for Example 16 using excess (5-chloro-2-(lH-tetrazol-l- yl)phenyl)methanamme and (S)-6-(2-( 1 -amino-2-phenylethy l)-5-chloro- 1 H-imidazol- 4-yl)-lH-indazol-3-amine. Reverse phase HPLC purification and lyophilization the bis
• Example 54 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(5-chloro-2-[l,2,4]triazol-l-yl-benzyl)-urea, trifluoroacetic acid salt [00237]
• Example 54 was prepared according to the procedure described for
• 1 HNMR (CD 3 OD, 400 MHz) ⁇ : 8.66 (s, IH), 8.13 (s, IH), 7.87 (d, / 8.6Hz, IH), 7.59 (m, IH), 7.42 (m, 2H), 7.22-7.04 (m, 7H), 4.97 (t, IH), 4.08 (q, IH), 3.20 (m, 2H).
• Example 55 was prepared by the oxidation of Example 46 with mCPBA in dichloromethane. Reverse phase ⁇ PLC purification and lyophilization afforded Example 55 as a colorless solid.
• 1 HNMR (CD 3 OD, 400 MHz) ⁇ : 7.94 (d, J 8.2Hz, IH), 7.53-7.48 (m, 6H), 7.29-7.11 (m, 5H), 5.06 (t, IH), 4.62 (q(AB), 2H), 4.28 (m, 2H), 3.64 (m, 2H), 3.38 (s, 3H), 3.20 (d, 2H), 3.16 (s, 3H).
• Example 56 [4-(2- ⁇ (S)-l-[3-(2-benzylsulfanyl-5-chloro-benzyl)-ureido]-2-phenyl-ethyl ⁇ -5- chloro-lS/-imidazol-4-yl)-phenyl]-carbamic acid methyl ester, trifluoroacetic acid salt [00239]
• Example 56 was prepared according to the procedure described for
• Example 16 from (2-(benzylthio)-5-chlorophenyl)methanamine and 52B. Reverse phase HPLC purification and lyophilization afforded Example 56 as a colorless solid.
• LCMS m/z 660.16 (M+H ) + .
• Example 57 was prepared from N-(2-(aminomethyl)-4- chlorophenyl)methanesulfonamide hydrochloride and 43A according to the procedure described for Example 16. Reverse phase HPLC purification and lyophilization afforded Example 57 as a colorless solid.
• Example 58 l- ⁇ (S)-l-[4-(3-amino-lH-indazol-6-yl)-5-chloro-lH-imidazol-2-yl]-2-phenyl- ethyl ⁇ -3-(2-benzylsulfanyl-5-chloro-benzyl)-urea, trifluoroacetic acid salt [00241]
• Example 58 was prepared according to the procedure described for
• 59B.4-bromomethyl-2-chloro-thiophene PBr 3 (0.14O mL, 1.487 mmol) was syringed into a clear solution of 59A (170 mg, 1.144 mmol) in DCM (5 mL). The resultant mixture was stirred at rt for 15 min. The mixture was quenched with water (15 mL), and stirred at rt for 1 h. The organics were extracted with DCM (2 x 10 mL), dried (Na 2 SO ⁇ , filtered and concentrated to a colorless oil (224 mg) which was used directly in the next step.
• 59C.4-azidomethyl-2-chloro-thiophene 59B (220 mg, 1.040 mmol) was dissolved in DMF (4 mL). Sodium azide (0.366 mL, 10.40 mmol) was added to this solution. The reaction mixture was stirred at rt for 16 h. The mixture was quenched with water (30 mL), and the organics were extracted with EtOAc (25 mL), washed with brine, dried (Na 2 SO ⁇ , filtered and concentrated to a colorless oil (168 mg) which was used directly in the next step.
• 59D 5-chloro-(thiophen-3-yl)-methylamine: 10% palladium on carbon was added to a solution of 59C (80 mg, 0.415 mmol) in MeOH (5 mL). The resultant mixture was stirred under a hydrogen balloon for 40 min. The catalyst was removed by filteration through Celite . The filtrate was concentrated to a colorless oil. The oil was dissolved in HCl (0.5N, 7 mL), and washed with EtOAc (10 mL).
• Example 60 was prepared according to the procedure described for urea formation in Example 16 from thiophen-3-ylmethanamine and 52B. Purification via reverse phase HPLC (acetonitrile/water and 0.05%TFA), lyophilization of the pure fraction afforded Example 60 as a colorless solid. LCMS m/z 510.2 (M+H) + .
• Example 61 (4- ⁇ 5-chloro-2-[(S)-l-(3-lH-imidazol-4-yl-propionylamino)-2-phenyl-ethyl]-lH- imidazol-4-yl ⁇ -phenyl)-carbamic acid methyl ester, trifluoroacetic acid salt
• Example 61 was prepared according to the procedure described for 3A from commercially available 3-(l ⁇ -imidazol-4-yl)propanoic acid and 52B. Purification via reverse phase HPLC (acetonitrile/water and 0.05%TFA), lyophilization of the pure fraction afforded Example 61 as a colorless solid. LCMS m/z 493.2 (M+H) + . 1 HNMR (CD 3 OD, 400 MHz) ⁇ : 2.54 - 2.65 (m, 2 H), 2.94 (d,
• 62B can be prepared as follows. To a cold suspension
• Example 62 To vial containing 62B (0.030 g, 0.120 mmol), the free base of 52B (0.044 g, 0.120 mmol), EDC (0.029 g, 0.150 mmol), and HOBt (0.023 g, 0.150 mmol) was added DMF (0.399 mL) and Hunig's base (0.042 mL, 0.239 mmol). The resulting clear, yellow solution was stirred at rt for 6 h. The reaction was diluted with water to give a suspension and then extracted with EtOAc (2 x). The combined organic layers were washed with 1.0 N HCl, sat. NaHCO3, brine, dried over Na 2 SO 4 , filtered and concentrated.
• Example 62 (0.053 g, 62%) as a fluffy off-white solid.
• LCMS m/z 603.1 (M+H) + .
• 63A.3-(5-chloro-2-tetrazol-l-yl-phenyl)-propionic acid To a suspension of 62B (0.030 g, 0.120 mmol) in MeOH (5.0 mL) was added platinum oxide (0.005 g, 0.022 mmol). Hydrogen from a balloon was bubbled through the reaction for 1-2 min and then the reaction was stirred vigorously under a hydrogen atmosphere. Additional amounts of platinum oxide (0.010 g, 0.044 mmol) were added over the course of the reaction. After 27 h, the reaction was filtered, and the filtrate was concentrated to give a brown residue.
• 64A ⁇ l-[4-(4-Nitro-phenyl)-6-oxo-l,6-dihydro-pyridin-2-yl]-2- phenyl-ethyl ⁇ -carbamic acid tert-butyl ester: A suspension of (( ⁇ )-3-tert- butoxycarbonylamino-2-oxo-4-phenyl-butyl)-phosphonic acid dimethyl ester (1.114 g, 3 mmol, Resmini, M.
• the aniline was suspended in dichloromethane (10 mL), then pyridine (0.35 mL, 4.4 mmol) and methyl chloroformate (0.25 mL, 3.3 mmol) were added. The reaction mixture was stirred at rt. After 30 min, the reaction was diluted with dichloromethane, washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated to give a residue. To a cooled solution (0 0 C) of the residue in MeOH (10 mL) was added 1 N NaOH (2 mL). After 30 min, the reaction was mixture was quenched with 1 N HCl (2.4 mL) to give a suspension.
• Example 64 was prepared by coupling 64B (enantiomer A) and
• 65B (S)-tert-butyl l-(4-(4-nitrophenyl)-lH-imidazol-2-yl)-2- phenylethylcarbamate: To a solution of 65A (21.6 g, 47.5 mmol) in m-xylene (250 mL) was added ammonium acetate (18.3 g, 238 mmol). The reaction was allowed to stir at 140 0 C for 1 h. The reaction was cooled to rt and solvent was removed under reduced pressure. The residue was taken up into ethyl acetate, which was washed with IN HCl, saturated sodium bicarbonate and brine.
• 65D (S)-tart-butyl l-(4-(4-aminophenyl)-5-chloro-lH-imidazol-2- yl)-2-phenylethylcarbamate: To a degassed solution of 65C (7.86 g, 17.8 mmol) in EtOH/MeOH/EtOAc (150 mL/100 mL/50 mL) was added a slurry of Raney-Ni (Aldrich 2400 slurry in water, 3 mL). Hydrogen was supplied by a hydrogen balloon and the reaction was stirred at rt. After about 8 h, the reaction was complete as shown by LCMS.
• Example 65 To a solution of (3-chloro-2- fluorophenyl)methanamine (70 mg, 0.439 mmol) in DMF (1 ml) was added pyridine (0.1 mL, 1.236 mmol) and 65H (40 mg, 0.098 mmol) at rt. The reaction mixture was stirred under nitrogen at rt for 5 h. The crude product was purified by HPLC (CH 3 CN/H 2 O with 0.1%TFA).
• Example 65 (43.8 mg, 65.5%) as a white solid.
• 1 HNMR 400 MHz, CD 3 OD
• LCMS m/z 566.14 (M+H) + .
• Example 66 (S)-l-(l-(5-chloro-4-(4-hydroxy-2-oxo-l,2-dihydroquinolin-6-yl)-lH-imidazol-2- yl)-2-phenylethyl)-3-(2-fluoro-3-(trifluoromethyl)benzyl)urea, trifluoroacetic acid salt [00268]
• Example 67 l-(5-Bromo-2-fluoro-benzyl)-3- ⁇ (S)-l-[5-chloro-4-(4-hydroxy-2-oxo-l,2-dihydro- quinolin-6-yl)-lH-imidazol-2-yl]-2-phenyl-ethyl ⁇ -urea, trifluoroacetic acid salt [00269]
• Example 67 was prepared following a procedure similar to that described for Example 65.
• 1 HNMR (400 MHz, CD 3 OD) ⁇ : 3.21 (d, J 7.91 Hz, 2 H),
• Example 68 was prepared following a procedure similar to that described for Example 65. 1 HNMR (400 MHz, CD 3 OD) ⁇ : 2.27 (s, 3 H), 2.68 (t,
• Example 70 was prepared following a procedure similar to that described for Example 65.
• 1 HNMR 400 MHz, CD 3 OD
• LCMS m/z 580.20 (M+H) + .
• Example 71 was prepared following a procedure similar to that described for Example 65.
• 72A.3-(5-chloro-2-phenylcarbamoyl-phenyl)-propionic acid Ethyl 3-(5-chloro-2-(phenylcarbamoyl)phenyl)propanoate (0.287 g, 0.865 mmol) and lithium hydroxide (21 mg, 0.865 mmol) were stirred in THF (10 mL) with water (0.5 mL) for 2 days. The reaction was quenched with water and washed with EtOAc. The aqueous layer was acidified with IN HCl and extracted with EtOAc (2 x ), dried (MgSO 4 ), and evaporated to give 72A (0.21 g, quantitative). LCMS m/z 304.3
• Example 73 was prepared following a procedure similar to that described for Example 65.
• 1 HNMR (400 MHz, CD 3 OD) ⁇ : 3.21 (d, J 7.47 Hz, 2
• Example 74 was prepared following a procedure similar to that described for Example 65.
• 1 HNMR (400 MHz, CD 3 OD) ⁇ : 3.21 (d, J 7.47 Hz, 2
• Example 75 was prepared following a procedure similar to that described for Example 65.
• 1 HNMR 400 MHz, CD 3 OD
• LCMS m/z 554.31 (M+H) + .
• Example 77 was prepared from compounds 65G and 76A following the procedure described for 76E.
• 1 HNMR 400 MHz, CD 3 OD
• ⁇ : 3.22 (d, J 7.91 Hz,
• Example 78 was prepared using procedures similar to those described for Example 76.
• 1 HNMR (400 MHz, CD 3 OD) ⁇ : 3.20 (d, / 7.47 Hz, 2 H), 4.04 -
• Example 79 as a white solid ((7.6 mg, 7.92%).
• LCMS m/z 502.99 (M+H) + .
• Example 80 was prepared from 65G using the procedure similar to that described for Example 79. 1 HNMR (400 MHz, CD 3 OD) ⁇ : 3.21 - 3.28 (m, 2 H),
• 82E (4- ⁇ 2-[(S)-l-fert-butoxycarbonylamino-2-(l-methyl-lH- pyrazol-3-yl)-ethyl]-lH-imidazol-4-yl ⁇ -phenyl)-carbamic acid methyl ester: 82C (0.79 g, 2.93 mmol) was dissolved in DMF (10 mL) and KHCO 3 (0.352 g, 3.52 mmol) was added. The mixture was stirred at rt under nitrogen for 0.5-1 h, then cooled in an ice bath while a solution of 82D (0.958 g, 3.52 mmol) in 5 mL DMF was added dropwise.

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