ES2370053T3 - HETEROCICLES OF SIX USEFUL MEMBERS AS INHIBITORS OF SERINA PROTEASA. - Google Patents

Abstract

A compound of Formula (I): or a stereoisomer or pharmaceutically acceptable salt or solvate thereof, wherein: A is substituted with 0-1 R1 and 0-2 R2 and is selected from; C3-7 cycloalkyl, phenyl, naphthyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl, benzoimidazolyl, benzoisoxazolyl, isoquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinazolinyl , 1H-quinazolin-4-onyl,. 2H-isoquinolin-1-onyl, 3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl, 2,3-dihydroisoindolinonyl and phthalazinyl; The group is selected from: Z is -CH (R11) -; L is -C (O) NH-; R1 is, independently each time it appears, F, Cl, Me, Et, -NH2, C (= NH) NH2, -C (O) NH2, -CH2NH2, - CH2CH2NH2, -CH2NHCO2Bn, -CH2NHCO2 (t-Bu) , -CH (Me) NH2, -CMe2NH2, -NHEt, -NHCO2 (f-Bu), -NHCO2Bn, - SO2NH2ORa or -CH2R1a; R1a is H, -C (= NR8a) NR7R8, -NHC (= NR8a) NR7R8, -NR8CR8 (= NR8a), -NR7R8, -C (O) NR8R9, F, OCF3, CF3, ORa, SRa, CN, - NR8SO2NR8R9, -NR8SO2Rc, -S (O) p-C1-4alkyl, -S (O) p-phenyl or - (CF2) rCF3; R2 is, independently each time it appears, H, = O, F, Cl, Br, I, OCF3, CF3, CHF2, CN, NO2, ORa, SRa, - C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7R8, -C (O) NR7R8, -NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) 2Rc, -S (O) Rc, -S (O) 2Rc, C1-6 alkyl substituted with 0-2 R2a, C2-6 alkenyl substituted with 0-2 R2a, C2-6 alkynyl substituted with 0-2 R2a, - (CH2) C3-10 carboxy substituted with 0-3 R2b or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-3 R2b; R2a is, independently each time it appears, H, F, Cl, Br, I, = O, = NR8, CN, OCF3, CF3, ORa, SRa, -NR7R8, -C (O) NR8R9, -NR7C (O) Rb, -S (O) pNR8R9, -NR8SO2Rc, -S (O) Rc or -S (O) 2Rc; R2b is, independently each time it appears, H, F, Cl, Br, I, = O, = NR8, CN, NO2, ORa, SRa, -C (O) Ra, - C (O) ORa, -OC ( O) Ra, -NR7R8, -C (O) NR7R8, -NR7C (O) Rb, -S (O) pNR8R9, -SO2Rc, -NR8SO2NR8R9, -NR8SO2Rc, - (CF2) rCF3, C1-6 alkyl, C2 alkenyl -6, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl or C1-4 haloalkyloxy; alternatively, when R1 and R2 are substituted on adjacent atoms in the ring, they can be taken together with the atoms in the ring to which they are attached to form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0- 4 heteroatoms selected from N, O and S (O) p, wherein said carbocycle or heterocycle is substituted with 0-2 R2b; R3 is -CO2H, -CO2Me, -C (O) NHCH2CO2H, -C (O) NHCH2CO2Et, -C (O) NH2, -C (O) NHMe, -C (O) NHBn, - (CH2) rhenyl substituted with 0-2 R3a and 0-1 R3d, naphthyl substituted with 0-2 R3a and 0-1 R3d, indanyl substituted with 0-2 R3a and 0-1 R3d or a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3a and 0-1 R3d; R38 is, independently each time it appears, = OF, Cl, Br, I, OCF3, CF3, CN, NO2, - (CH2) rOR3b, - (CH2) rSR3b, - (CH2) rNR7R8, -C (= NR8a) NR8R9, -NHC (= NR8a) NR7R8, -NR8CR8 (= NR8a), - (CH2) rNR8C (O) R3b, = NR8, - (CH2) rNR8C (O) R3b, - (CH2) rNR8C (O) 2R3b, - (CH2) rS (O) pNR8R9, - (CH2) rNR8S (O) pR3c, -S (O) R3c, -S (O) 2R3c, -C (O) - C1-4 alkyl, - (CH2) rCO2R3b , - (CH2) rC (O) NR8R9, - (CH2) rOC (O) NR8R9, -NHCOCF3, -NHSO2CF3, -SO2NHR3b, - SO2NHCOR3c, -SO2NHCO2R3c, -CONHSO2R3c, -NHSO2R3c, C1-halo, C1-4alkyl, C1-C3-C3-halo, C1-4 C1-4- haloalkyloxy, C1-6 alkyl substituted with R3d, C2-6 alkenyl substituted with R3d, C1-6 alkynyl substituted with R3d, C3-6 cycloalkyl substituted with 0-1 R3d, - (CH2) substituted C3-10 carboxy with 0-3 R3d or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O; and S (O) p, wherein said heterocycle is substituted with 0-3 R3d; alternatively, when two R3a groups are substituted on adjacent atoms, they can be taken together with the atoms to which they are attached to form a C3-10 carbocycle substituted with 0-2 R3d 20 or a 5-10 membered heterocycle comprising: atoms carbon and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3d; R3b is, independently each time it appears, H, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) C3 carboxy -10 substituted with 0-3 R3d or - (CH2) 5-10 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 R3d; R3c is, independently each time it appears, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) C3-10 carboxy substituted with 0-3 R3d or - (CH2) 5-10 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 R3d; R3d is, independently each time it appears, H, = O, - (CH2) rORa, F, Cl, Br, CN, NO2, - (CH2) rNR7R8, - C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7C (O) Rb, -C (O) NR8R9, -S (O) 2NR8R9, -NR8S (O) 2NR8R9, -NR8S (O) 2Rc, -S (O) pRc, - (CF2) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, - (CH2) C3-10 carbocycle, substituted with 0 -3 Rd or - (CH2) 5-10 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 Rd; R4 is H, F, Cl, Br, OMe, NH2, CF3, CO2H, CO2Me, CO2Et, -CONR8R9, C1-6 alkyl substituted with 0-2 R4a, phenyl substituted with 0-2 R4b or a 5-10 heterocycle members selected from: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-3 R4b; R4a is, independently each time it appears, H, F, = O, C1-4 alkyl, ORa, SRa, CF3, CN, NO2, -C (O) Ra40, - C (O) ORa, -NR7R8, -C (O) NR8R9, -NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) pRc, -S (O) Rc or -S (O) 2Rc; R4b is, independently each time it appears, H, = O, = NR8, F, Cl, Br, I, ORa, SRa, CN, NO2, -NR7R8; - C (O) Ra, -C (O) ORa, -NR7C (O) Rb, -C (O) NR8R9, -SO2NR8R9, -S (O) 2Rc, C1-6 alkyl, C2-6 alkenyl, C2 alkynyl -6, C3-6 cycloalkyl, C1-4 haloalkyl or C1-4 haloalkyloxy; alternatively, the R3 and R4 groups when located on adjacent atoms, can be taken together to form a C3-10 carbocycle substituted with 0-2 R3d or a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3d; R6 is H, R7 is, independently each time it appears, H, C1-6 alkyl, = (CH2) n-C3-10 carbocycle, - (CH2) n- (5-10 membered heteroaryl), -C (O ) Rc, -CHO, -C (O) 2Rc, -S (O) 2Rc, -CONR8Rc, -OCONHRc, -C (O) O- (C1-4 alkyl) OC (O) - (C1-4 alkyl) or -C (O) O- (C1-4 alkyl) OC (O) - (C6-10 aryl); wherein said alkyl, carbocycle, heteroaryl and aryl are optionally substituted with 0-2 Rf; R8 is, independently each time it appears, H, C1-6 alkyl, - (CH2) n-phenyl or - (CH2) 5-10 membered n-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 Rf; alternatively, R7 and R8, when bound to the same nitrogen, combine to form a 5-10 membered heterocycle comprising: additional carbon atoms and 0-2 heteroatoms selected from N, O and S (O) p, in the that said heterocycle is substituted with 0-2 Rd; R8a is, independently each time it appears, R7, OH, C1-6 alkyl, C1-4 alkoxy, (C6-10 aryl) -C1-4 alkoxy, - (CH2) n-phenyl, - (CH2) n- ( 5-10 membered heteroaryl); wherein said phenyl, aryl and heteroaryl are optionally substituted with 0-2 Rf R9 is, independently each time it appears, H, C1-6 alkyl or - (CH2) n-phenyl; wherein said alkyl and phenyl are optionally substituted with 0-2 Rf; R9a is, independently each time it appears, H, C1-6 alkyl or - (CH2) n-phenyl; alternatively, R8 and R9, when bound to the same nitrogen, combine to form a 5-10 membered heterocycle comprising: additional carbon atoms and 0-2 heteroatoms selected from N, O and S (O) p, in which said heterocycle is substituted with 0-2 Rd; R11 is phenylmethyl, 4-imidazolylmethyl, 4-thiazolylmethyl, 2-benzothiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4- pyridylmethyl, 3-indolylmethyl, 2-benzoimidazolylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, cyclohethylmethyl, cyclohethylmethyl, cyclomethyl-methyl (O) NHCH2-pyridin-2-yl or - (CH2) 2C (O) NHCH2-pyridin-2-yl, in which each phenyl, naphthyl, imidazolyl, thiazolyl, benzothiazolyl, pyridinyl or cyclohexyl group is substituted with 0- 2 R11b; R11b is, independently each time it appears, H, F, Cl, Br, CF3, OMe, OCF3; OCHF2, OPh, OBn, NO2, - NH2, -C (O) Ph, -NHC (O) Bn, -NHC (O) CH2CH2Ph, -NHS (O) 2Ph, -C (O) NR7R8, -NR7C (O ) Rb, -S (O) pNR8R9, -NR8S (O) pRc, Ph or Bn; alternatively, when two R11b groups are substituents on adjacent atoms, they can be taken together with the atoms to which they are attached to form a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O and S (O) py substituted with 0-2 Rg; Ra is, independently each time it appears, H, CF3, C1-6 alkyl, - (CH2) r3-7 cycloalkyl, - (CH2) C6-10 raryl or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p; wherein said cycloalkyl, aryl and heterocycle groups are optionally substituted with 0-2 Rf; Rb is, independently each time it appears, CF3, OH, C1-4 alkoxy, C1-6 alkyl, - (CH2) C3-10 carboxy substituted with 0-3 Rd or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p and substituted with 0-2 Rd; Rc is, independently each time it appears, CF3, C1-6 alkyl substituted with 0-2 Rf, C3-6 cycloalkyl substituted with 0-2 Rf30,

Description

Six-member heterocycles useful as serine protease inhibitors

Field of the Invention

The present invention relates, in general, to compounds that inhibit serine proteases. In particular, it refers to new six-member heterocycle derivatives of Formula (I):

or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, in which the variables A, L, Z, X1, X2, X3, X4 and X5 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and / or the contact activation system; for example thrombin, factor XIa, factor Xa, factor IXa, factor VIIa and / or plasma kallikrein. In particular, it refers to compounds that are selective factor XIa inhibitors or dual inhibitors of plasma fXIa and calicrein. The present invention also relates to pharmaceutical compositions comprising said compounds and methods of use thereof.

Background of the invention

Factor XIa is a plasma serine protease involved in the regulation of blood coagulation. Although blood coagulation is a necessary and important part of the regulation of homeostasis of an organism, abnormal blood coagulation can also have deleterious effects. For example, thrombosis is the formation

or presence of a blood clot inside a blood vessel or heart cavity. Said blood clot can lodge in a blood vessel, blocking circulation and inducing a heart attack or stroke. Thromboembolic disorders are the leading cause of mortality and disability in the industrialized world.

Blood coagulation is initiated in vivo by the binding of tissue factor (TF) to Factor VII (FVII) to generate Factor VIIa (FVIIa). The resulting TF: FVIIa complex activates Factor IX (FIX) and Factor X (FX) which leads to the production of Factor Xa (FXa). The FXa that is generated catalyzes the transformation of prothrombin into small amounts of thrombin before this route is closed by the tissue factor pathway inhibitor (TFPI). The coagulation process is then propagated by activating feedback from Factors V, VIII and XI by catalytic amounts of thrombin (Walsh, PN Thromb. Haemostasis. 1999, 82, 234-242.) Factor XIa plays a key role in The spread of this amplification loop and therefore is an attractive target for antithrombotic therapy.

An alternative mode of coagulation onset acts when blood is exposed to artificial surfaces (for example, during hemodialysis, cardiovascular surgery " with pump ", vascular grafts, bacterial sepsis). This process is also called contact activation. Surface absorption of factor XII leads to a conformational change in the factor XII molecule, thereby facilitating activation for active proteolytic factor XII molecules (factor XIIa and factor XIIf). Factor XIIa (or XIIf) has several target proteins, including plasma precalicrein and factor XI. The active plasma kallikrein additionally activates factor XII, which leads to contact activation amplification. 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, quininogen / quinine and other humoral and cellular routes (for review, Coleman,

R. Contact Activation Pathway, pages 103-122 in Hemostasis and Thrombosis, Lippincott Williams and Wilkins 2001; Schmaier A. H. Contact Activation, pages 105-128 in Thrombosis and Hemorrhage, 1998).

Factor XI is a zymogen of a trypsin-like serine protease and is present in plasma at a relatively low concentration. Proteolytic activation on an internal R369-I370 bond produces a heavy chain (369 amino acids) and a light chain (238 amino acids). The second contains a typical trypsin-type catalytic triad (H413, D464 and S557). It is believed that the activation of factor XI by thrombin occurs on negatively charged surfaces, most likely on the surface of activated platelets. Platelets contain sites

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high affinity (0.8 nM) (130-500 / platelet) for activated factor XI. After activation, factor XIa remains surface bound and recognizes factor IX as its normal macromolecular substrate. (Galiani, D. Trends Cardiovasc. Med. 2000, 10, 198-204).

In addition to the feedback activation mechanisms described above, thrombin activates thrombin-activated fibrinolysis inhibitor (TAFI), a plasma carboxypeptidase that cleaves C-terminal lysine and arginine residues in fibrin, reducing fibrin's ability to improve tissue plasminogen activator-dependent plasminogen activation (tPA). In the presence of antibodies to FXIa, clot lysis can occur more rapidly regardless of the concentration of TAFI in plasma (Bouma, B.

N. et al. Thromb. Res. 2001, 101, 329-354). Therefore, factor XIa inhibitors are expected to be anticoagulants and profibrinolytics.

Genetic evidence indicates that factor XI is not required for normal homeostasis, which implies a superior safety profile of the factor XI mechanism compared to competing antithrombotic mechanisms. Unlike hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency), mutations of the factor XI gene that cause factor XI deficiency (hemophilia C) result in only a slight bleeding diathesis. Moderate characterized mainly by postoperative or posttraumatic hemorrhage, but rarely spontaneous. Postoperative bleeding occurs mainly in tissue with high concentrations of endogenous fibrinolytic activity (for example, oral cavity and urogenital system). Most cases are accidentally identified by preoperative prolongation of APTT (intrinsic system) without any history of previous bleeding.

The increased safety of XIa inhibition as an anticoagulation therapy is further supported by the fact that the knock-out mice for factor XI, which have no detectable factor XI protein, undergo normal development and have a normal lifespan. No evidence for spontaneous bleeding has been observed. The APTT (intrinsic system) is prolonged in a gene dose dependent manner. Interestingly, even after severe stimulation of the coagulation system (tail transection), bleeding time is not significantly extended compared to wild-type and heterozygous littermates (Gailiani, D. Frontiers in Bioscience 2001, 6, 201 -207; Gailiani, D. et al. Blood Coagulation and Fibrinolysis 1997, 8, 134-144). Taken together, these observations suggest that high levels of factor XIa inhibition should be well tolerated. This differs from experiments targeting genes with other coagulation factors.

In vivo activation of factor XI can be determined by complex formation with C1 inhibitor or alpha antitrypsin

1. In a study of 50 patients with acute myocardial infarction (AMI), approximately 25% of the patients had values above the upper normal range of the complex ELISA. This study can be seen as proof that in at least one subpopulation of patients with AMI, the activation of factor XI contributes to thrombin formation (Minnema, MC et al. Arterioscler. Thromb. Vasc. Biol. 2000, 20, 2489- 2493). A second study establishes a positive correlation between the extent of coronary arteriosclerosis and factor XIa in complex with alpha 1 antitrypsin (Murakami, T. et al. Arterioscler Thromb Vasc Biol 1995, 15, 1107-1113.). In another study, Factor XI levels above the 90th percentile in patients were associated with a 2.2-fold increased risk of venous thrombosis (Meijers, JCM et al. N. Engl. J. Med. 2000, 342, 696- 701.).

Plasma kallikrein is a trypsin-like serine protease zymogen and is present in the plasma at 35 to 50 µg / ml. The gene structure is similar to that of factor XI, in general, the amino acid sequence of plasma kallikrein has 58% homology to factor XI. Proteolytic activation by factor XIIa on an internal I 389-R390 link produces a heavy chain (371 amino acids) and a light chain (248 amino acids). The active site of kallikrein is contained in the light chain. The plasma kallikrein light chain reacts with protease inhibitors, including alpha 2 macroglobulin and C1 inhibitor. Interestingly, heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in the presence of high molecular weight quininogen (HMWK). In blood, most plasma kallikrein circulates in complex with HMWK. Calicrein cleaves HMWK to release bradykinin. The release of bradykinin results in increased vascular permeability and vasodilation (for a review, Coleman, R. Contact Activation Pathway, pages 103122 in Hemostasis and Thrombosis; Lippincott Williams & Wilkins 2001; chmaier AH Contact Activation, pages 105-128 in Thrombosis and Hemorrhage, 1998).

Proteins or peptides that have been reported to inhibit XIa are disclosed in WO 01/27079. There are advantages in the use of small organic compounds, however, when preparing pharmaceutical agents, for example, small compounds generally have better oral bioavailability and compatibility when preparing

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Formulations to aid in drug delivery compared to large proteins or peptides. Small Factor XIa inhibitor molecules are disclosed in United States Patent Application Publication US20040235847A1 and United States Patent Application Publication US20040220206A1.

In addition, it is also desirable to find new compounds with improved pharmacological characteristics compared to known serine protease inhibitors. For example, it is preferred to find new compounds with enhanced factor XIa inhibitory activity and selectivity for factor XIa over other serine proteases. In addition, it is preferred to find new compounds with enhanced plasma kallikrein inhibitory activity and selectivity for plasma kallikrein against other serine proteases. It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories, but without limitation: (a) pharmaceutical properties; (b) dosage requirements; (c) factors that reduce blood concentration characteristics from maximum to minimum; (d) factors that increase the concentration of active drug in the recipient; (e) factors that reduce the disadvantage of clinical drug-drug integrations; (f) factors that reduce the potential for adverse side effects; and (g) factors that improve manufacturing or viability costs.

WO 02/42273 discloses certain acid derivatives that are useful as serine protease inhibitors, particularly inhibitors of factors VIIa, IXa, Xa and / or XIa.

WO 2004/014844 discloses compounds, processes for their preparation and compositions comprising them that are useful as partial antagonists / antagonists of factor IX.

WO 2005/007627 discloses phenylpyridine compounds useful as herbicides.

WO 2005/085198 discloses amino cyclopropane carboxamide derivatives, useful as antagonists or inverse agonists of bradykinin B1.

WO 2005/063690 discloses α-hydroxyamide derivatives useful as agonists or inverse agonists of bradykinin B1.

Summary of the invention

The present invention provides novel six-membered heterocycle derivatives and analogs thereof, which are useful as selective inhibitors of serine protease enzymes, especially factor XIa and / or plasma kallikrein, or stereoisomers or pharmaceutically acceptable salts or solvates thereof.

The present invention also provides methods and intermediates for preparing the compounds of the present invention or a stereoisomer or a pharmaceutically acceptable salt, solvate or prodrug form thereof.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or solvate form thereof.

The present invention also provides compounds of the present invention or a pharmaceutically acceptable salt or solvate form thereof for use in modulation of the coagulation cascade and / or the contact activation system.

The present invention also provides compounds of the present invention or a pharmaceutically acceptable salt or solvate form thereof for use in the treatment of thromboembolic disorders.

The present invention also provides compounds of the present invention or a pharmaceutically acceptable salt or solvate form thereof for use in the treatment of inflammatory disorders.

The present invention also provides novel six-membered heterocycle derivatives, and analogs thereof, for use in therapy.

The present invention also provides the use of six-membered heterocycle derivatives, and analogs thereof, for the preparation of a medicament for the treatment of a thromboembolic disorder.

The present invention also provides the use of six-membered heterocycle derivatives, and analogs of the

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themselves, for the preparation of a medicament for the treatment of an inflammatory disorder.

These and other embodiments, which will be apparent during the following detailed description, have been achieved by the inventors' discovery that the novel compounds presently claimed from the present invention or pharmaceutically acceptable salt form thereof, are factor XIa inhibitors and / or effective plasma kallikrein inhibitors.

Detailed description of the invention

In a first aspect, the present invention provides, among others, a compound of the Formula (I):

or a stereoisomer or pharmaceutically acceptable salt or solvate thereof, in which:

10 A is substituted with 0-1 R1 and 0-2 R2 and is selected from; C3-7 cycloalkyl, phenyl, naphthyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl, benzoimidazolyl, benzoisoxazolyl, isoquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinazolinyl, 1H -quinazolin-4-onyl, 2H-isoquinolin-1-onyl, 3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl, 2,3-dihydroisoindolinonyl and phthalazinyl; the group

is selected from:

Z is -CH (R11) -; L is -C (O) NH-; R1

is, independently each time it appears, F, Cl, Me, Et, -NH2, C (= NH) NH2, -C (O) NH2, -CH2NH2,

CH2CH2NH2, -CH2NHCO2Bn, -CH2NHCO2 (t-Bu), -CH (Me) NH2, -CMe2NH2, -NHEt, -NHCO2 (t-Bu), -NHCO2Bn, -SO2NH2, ORa or -CH2R1a; R1a is H, -C (= NR8a) NR7R8, -NHC (= NR8a) NR7R8, -NR8CR8 (= NR8a), -NR7R8, -C (O) NR8R9, F, OCF3, CF3, ORa, SRa, CN, - NR8SO2NR8R9, -NR8SO2Rc, -S (O) p-C1-4 alkyl, -S (O) p-phenyl, or - (CF2) rCF3; R2 is, independently each time it appears, H, = O, F, Cl, Br, I, OCF3, CF3, CHF2, CN, NO2, ORa, SRa,

25 C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7R8, -C (O) NR7R8, -NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) 2Rc, -S (O) Rc, -S (O) 2Rc, C1-6 alkyl substituted with 0-2 R2a, C2-6 alkenyl substituted with 0-2 R2a, C2-6 alkynyl substituted with 0-2 R28, ( CH2) C3-10 r-carbocycle substituted with 0-3 R2b, or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p , wherein said heterocycle is substituted with

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0-3 R2b; R2a is, independently each time it appears, H, F, Cl, Br, I, = O, = NR8, CN, OCF3, CF3, ORa, SRa, -NR7R8, -C (O) NR8R9, -NR7C (O) Rb, -S (O) pNR8R9, -NR8SO2Rc, -S (O) Rc or -S (O) 2Rc; R2b is, independently each time it appears, H, F, Cl, Br, I, = O, = NR8, CN, NO2, ORa, SRa, -C (O) Ra, C (O) ORa, -OC (O ) Ra, -NR7R8, -C (0) NR7R8, -NR7C (O) Rb, -S (O) pNR8R9, -SO2Rc, -NR8SO2NR8R9, -NR8SO2Rc, (CF2) rCF3, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl or C1-4 haloalkyloxy; alternatively, when R1 and R2 are substituted on adjacent atoms in the ring, they can be taken together with the atoms in the ring to which they are attached to form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0- 4 heteroatoms selected from N, O and S (O) p, wherein said carbocycle

or heterocycle is substituted with 0-2 R2b; R3 is -CO2H, -CO2Me, -C (O) NHCH2CO2H, -C (O) NHCH2CO2Et, C (O) NH2, -C (O) NHMe, -C (O) NHBn, - (CH2) substituted r-phenyl with 0-2 R3a and 0-1 R3d, naphthyl substituted with 0-2 R3a and 0-1 R3d, indanyl substituted with 0-2 R3a and 0-1 R3d or a 5-10 membered heterocycle selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3a and 0-1 R3d;

R3a

is, independently each time it appears, = O, F, Cl, Br, I, OCF3, CF3, CN, NO2, - (CH2) rOR3b, (CH2) rSR3b, - (CH2) rNR7R8, -C (= NR8a) NR8R9, -NHC (= NR8a) NR7R8, -NR8CR8 (= NR8a), - (CH2) rNR8C (O) R3b, = NR8, (CH2) rNR 8C (O) R 3b, - (CH2) rNR8C (O) 2R3b , - (CH2) rS (O) pNR8R9, - (CH2) rNR8S (O) pR3c, -S (O) R3c, -S (O) 2R3c, -C (O) C1-4 alkyl, - (CH2) rCO2R3b , - (CH2) rC (O) NR8R9, - (CH2) rOC (O) NR8R9, -NHCOCF3, -NHSO2CF3, -SO2NHR3b, -SO2NHCOR3c, -SO2NHCO2R3c, -CONHSO2R3c, -NHSO2R3c, halo-C1-C3-C3-C3-halo, C1-4- haloalkyloxy, C1-6 alkyl substituted with R3d, C2-6 alkenyl substituted with R3d, C1-6 alkynyl substituted with R3d, C3-6 cycloalkyl substituted with 0-1 R3d, - (CH2) substituted C3-10 carboxy with 0-3 R3d or - (CH2) 5-10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0 -3 R3d; alternatively, when two R3a groups are substituted on adjacent carbon atoms, they can be taken together with the atoms to which they are attached to form a C310 carbocycle substituted with 0-2 R3d, or a 5-10 membered heterocycle comprising: atoms carbon and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3d; R3b is, independently each time it appears, H, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) r- C3-10 carbocycle substituted with 0-3 R3d or - (CH2) 5-10 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 R3d; R3c is, independently each time it appears, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) r-carbocycle C3 -10 substituted with 0-3 R3d, or- (CH2) 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, in which said heterocycle is substituted with 0-3 R3d;

R3d

is, independently each time it appears, H, = O, - (CH2) rORa, F, Cl, Br, CN, NO2, - (CH2) rNR7R8, C (O) Ra, -C (O) ORa, -OC (O) R8, -NR7C (O) Rb, -C (O) NR8R9, -S (O) 2NR8R9, -NR8S (O) 2NR8R9, -NR8S (O) 2Rc, S (O) pRc, - (CF2) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, - (CH2) C3-10 carboxy substituted with 0-3 Rd or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-3 Rd; R4 is H, F, Cl, Br, OMe, NH2, CF3, CO2H, CO2Me, CO2Et, -CONR8R9, C1-6 alkyl substituted with 0-2 R4a, phenyl substituted with 0-2 R4b or a 5-10 heterocycle members selected from: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-3 R4b; R4a is, independently each time it appears, H, F, = O, C1-4 alkyl, ORa, SRa, CF3, CN, NO2, -C (O) Ra, C (O) ORa, -NR7R8, -C ( O) NR8R9, -NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) pRc, -S (O) Rc, or -S (O) 2Rc; R4b is, independently each time it appears, H, = O, = NR8, F, Cl, Br, I, ORa, SRa, CN, NO2, -NR7R8, C (O) Ra, -C (O) OR8, - NR7C (O) Rb, -C (O) NR8R9, -SO2NR8R9, -S (O) 2Rc, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl or C1 haloalkyloxy -4-; alternatively, the R3 and R4 groups when located in adjacent atoms, can be taken together to form a C3-10 carbocycle substituted with 0-2 R3d or a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2

R3d

; R6 is H, R7 is, independently each time it appears, H, C1-6 alkyl, - (CH2) n-C3-10 carbocycle, - (CH2) n- (5-10 membered heteroaryl), -C (O ) Rc, -CHO, -C (O) 2Rc, -S (O) 2Rc, -CONR8Rc, -OCONHRc, -C (O) O- (C1-4 alkyl) OC (O) - (C1-4 alkyl) , or -C (O) O- (C1-4 alkyl) OC (O) - (C6-10 aryl); wherein said alkyl, carbocycle, heteroaryl and aryl are optionally substituted with 0-2 Rf; R8 is, independently each time it appears, H, C1-6 alkyl, - (CH2) n-phenyl or - (CH2) 5-10 membered n-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N , O and S (O) p; in which

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said alkyl, phenyl and heterocycle are optionally substituted with 0-2 Rf; alternatively, R7 and R8, when bound to the same nitrogen, combine to form a heterocycle of 5 to 10 members comprising: additional carbon atoms and 0-2 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 Rd;

R8a

is, independently each time it appears, R7, OH, C1-6 alkyl, C1-4 alkoxy, (C6-10 aryl) -C 1-4 alkoxy, (CH2) n-phenyl, - (CH2) n- (heteroaryl of 5-10 members); wherein said phenyl, aryl and heteroaryl are optionally substituted with 0-2 Rf; R9 is, independently each time it appears, H, C1-6 alkyl or - (CH2) nphenyl; wherein said alkyl and phenyl are optionally substituted with 0-2 Rf; R9a is, independently each time it appears, H, C1-6 alkyl or - (CH2) n-phenyl; alternatively, R8 and R9, when bound to the same nitrogen, combine to form a 5-10 membered heterocycle comprising: additional carbon atoms and 0-2 heteroatoms selected from N, O and S (O) p, in which said heterocycle is substituted with 0-2 Rd;

R11

it is phenylmethyl, 4-imidazolylmethyl, 4-thiazolylmethyl, 2-benzothiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 3-indolylmethyl, 2-benzoimidazolylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, cyclohexyl-NH2, cyclohexyl-methyl, cyclohexyl-NH2, cyclohexyl-methyl, cyclohexyl-NH2, cyclohexyl-methyl, cyclohexyl-NH2, cyclohexyl-methyl, cyclohexyl-NH2, cyclohexyl-methyl, cyclohexyl-NH2, cyclohexyl-methyl, cyclohexyl-NH2, cyclohexyl-methyl, cyclohexyl-NH2-cyclohexyl-methyl, cyclohexyl-NH2-cyclohexyl-methyl, cyclohexyl-NH2-cyclohexyl-methyl, cyclohexyl-NH2-cyclohexylmethyl -2-yl or - (CH2) 2C (O) NHCH2-pyridin-2-yl, wherein each phenyl, naphthyl, imidazolyl, thiaolyl, benzothiazolyl, pyridinyl or cyclohexyl group is substituted with 0-2 R11b; R11b is, independently each time it appears, H, F, Cl, Br, CF3, OMe, OCF3, OCHF2, OPh, OBn, NO2, -NH2, -C (O) Ph, -NHC (O) Bn, -NHC (O) CH2CH2Ph, -NHS (O) 2Ph, -C (O) NR7R8, -NR7C (O) Rb, -S (O) pNR8R9, NR8S (O) pRc, Ph or Bn; alternatively, when two R11b groups are substituents on adjacent atoms, they can be taken together with the atoms to which they are attached to form a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O and S (O) py substituted with 0-2 Rg; Ra is, independently each time it appears, H, CF3, C1-6 alkyl, - (CH2) r-C3-7 cycloalkyl, - (CH2) r-C6-10 aryl or - (CH2) r-heterocycle from 5 to 10 members comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p; wherein said cycloalkyl, aryl and heterocycle groups are optionally substituted with 02 Rf;

Rb

is, independently each time it appears, CF3, OH, C1-4 alkoxy, C1-6 alkyl, - (CH2) C3-10 carboxy substituted with 0-3 Rd or - (CH2) 5 to 10 membered r-heterocycle which comprises: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p and substituted with 0-2 Rd; Rc is, independently each time it appears, CF3, C1-6 alkyl substituted with 0-2 Rf, C3-6 cycloalkyl substituted with 0-2 Rf, C6-10 aryl, 5-10 membered heteroaryl, (C6-10 aryl ) -C 1-4 alkyl or (5-10 membered heteroaryl) -C 1-4 alkyl, wherein said aryl and heteroaryl groups are substituted with 0-3 Rf; Rd is, independently each time it appears, H, = O, = NR8, ORa, F, Cl, Br, I, CN, NO2, -NR7R8, -C (O) Ra, C (O) ORa, -OC ( O) Ra, -NR8C (O) Ra, -C (O) NR7R8, -SO2NR8R9, -NR8SO2NR8R9, -NR8SO2-C1-4 alkyl, -NR8SO2CF3, -NR8SO2-phenyl, -S (O) 2CF3, -S ( O) p-C1-4 alkyl, -S (O) p-phenyl, - (CF2) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re or C2-6 alkynyl substituted with 0-2 Re; Re is, independently each time it appears, = O, ORa, F, Cl, Br, I, CN, NO2, -NR8R9, -C (O) Ra, -C (O) ORa, -NR8C (O) Ra, -C (O) NR7R8, -SO2NR8R9, -NR8SO2NR8R9, -NR8SO2-C1-4 alkyl, -NR8SO2CF3, -NR8SO2-phenyl, S (O) 2CF3, -S (O) p-C1-4 alkyl. -S (O) p-phenyl or - (CF2) rCF3; Rf is, independently each time it appears, H, = O, - (CH2) rORg, F, Cl, Br, I, CN, NO2, -NR9aR9a, -C (O) Rg, C (O) ORg, -NR9aC (O) Rg, -C (O) NR9aR9a, -SO2NR9aR9a, -NR9aSO2NR9aR9a, -NR9aSO2-C1-4 alkyl, -NR9aSO2CF3, NR9aSO2-phenyl, -S (O) 2CF3, -S (O) p-C1-alkyl 4, -S (O) p-phenyl, - (CF2) rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or - (CH2) n-phenyl; Rg is, independently each time it appears, H, C1-6 alkyl or - (CH2) n-phenyl; n, each time it appears, is selected from 0, 1, 2, 3 and 4; p, each time it appears, is selected between 0, 1 and 2; and r, each time it appears, is selected from 0, 1, 2, 3 and 4.

In a second aspect, the present invention includes a compound of Formula (I), within the scope of the first aspect, in which:

R3 is phenyl substituted with 0-2 R3a, naphthyl substituted with 0-2 R3a, indanone substituted with 0-2 R3a or a 5-10 membered heterocycle substituted with 0-2 R3a and selected from: pyridine, pyridinone, pyrimidine, pyrrole , pyrazole, indole, 2oxoindole, indazol, benzofuran, benzothiophene, benzoimidazole, benzoisoxazole, benzoxazol, quinazoline, 3H-quinazolin4-one, phthalazine, 2H-phthalazin-1-one, 1H-quinolin-4-2, one isoquin , 4-dihydroisoquinolin-1-one.

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A is 4-aminomethyl-cyclohexyl, 4-carbamoyl-cyclohexyl, 4-amidino-phenyl, 4-benzyloxycarbonylamino-cyclohexyl, phenyl, 1,2,3,4-tetrahydronaft-2-yl, 4-aminomethyl-phenyl, 4- carbamoyl-phenyl, 4 aminomethyl-2-fluorophenyl, 2-F-5-OMe-phenyl, 2-F4-Me-phenyl, 2-F-4-Cl-phenyl, 2-F-4-carbamoyl-phenyl, 2 -OMe-4-carbamoyl-phenyl, 3-OMe-4-carbamoyl-phenyl, 2-Et-4aminomethyl-phenyl, 2-NH2-pyridin-4-yl, 2-ethylamino-4-aminomethyl-phenyl, 1-aminoisoquinolin -6-yl, 1-NH2-5,6,7,8-tetrahydroisoquinolin-6-yl, 1-NH2-1,2,3,4-tetrahydroisoquinolin-6-yl, 3-NH2-benzisoxazol-5-yl, 3 -NH2-benzoisoxazol6-yl, 3-NH2-indazol-6-yl, 3-NH2-indazol-5-yl, 1-Me-3-NH2-indazolyl-6-yl, 1,2,3,4-tetrahydroisoquinolin -3-yl, 1,2,3,4-tetrahydroisoquinolin-1-on-6-yl, isoquinolin-6-yl, 1-NH2-isoquinolin-6-yl, 1-NH2-5,6,7,8-tetrahydroisoquinolin -6-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl, 3H-quinazolin-4-onyl, 3,4-dihydro2H-isoquinolin -1-onyl, 2,3-dihydroisoindolinonyl or 1-NH2 -phthalazin-6-yl; Y

R3 is phenyl, 3-OH-phenyl, 3,4-methylenedioxyphenyl, 2-naphthyl, 1-naphthyl, 3-NMe2-phenyl, 4-benzyloxyphenyl, 4-t-butoxyphenyl, 4-methylsulfonylphenyl, 4-Cl-phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-Brphenyl, 3-CF3-phenyl, 3-NH2- phenyl, 4-NH2-phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-CO2H-phenyl, 4-CO2H-phenyl, 3-CO2Mephenyl, 4-CO2Me-phenyl, 3-OH-phenyl, 3- CH2CO2H-phenyl, 3-CH2CO2Me-phenyl, 3-CH2CO2Et-phenyl, 3-CONH2-phenyl, 4CONH2-phenyl, 4-CH2CO2Et-phenyl, 3-CH2C (O) NH2-phenyl, 4-C (O) NHMe- phenyl, 3-NHCOMe-phenyl, 4-NHCO2Me-phenyl, 2,4-diF-phenyl, 3-F-4-CN-phenyl, 3-CN-4-F-phenyl, 3-OMe-4-CONH2- phenyl, 3-OH-4-CONH2-phenyl, 3-NH2-4-CONH2phenyl, 3-CO2Me-4-NH2-phenyl, 3-CO2H-4-NH2-phenyl, 3-CONH2-4-NH2-phenyl, 3-CO2H-4-F-phenyl, pyrrole-3-yl, pyrazol-3-yl, pyrazol-4-yl, 3-NH2-pyrazol-5-yl, pyridyl-2-yl, pyrid-3-yl, pyrid- 4-yl, 2-F-pyrid-4-yl, 2-F-pyrid-5-yl, 2-OMe-pyrid-4-yl, 2-OMe-pyrid-5-yl, 2-NH2-pyrid- 3-yl, 2-NH2-pyrid-4-yl, 2-NH2-pyrid- 5-yl, 2-NH2-pyrid-6-yl, 2-NHMe-pyrid-4-yl, 2-NMe2pyrid-4-yl, 2-CONH2-pyrid-4-yl, 2-CO2H-pyrid-4- yl, 2-CONH2-pyrid-5-yl, 2-OMe-6-NH2-pyridyl-4-yl, 4-NH2-pyrimidin-6yl, 4-NH2-pyrimidin-2-yl, 2-NH2-pyrimidin- 4-yl, 2-NH2-pyrimidin-5-yl, indole-5-yl, indole-6-yl, indazol-5-yl, indazol-6-yl, 3-OH-indazol-5-yl, 3- OH-indazol-6-yl, 3-OMe-indazol-5-yl, 3-OMe-indazol-6-yl, 3-NH2-indazol-5-yl, 3-NH2-indazol6-yl, benzoisoxalol-6- ilo, benzoisoxazol-5-yl, 3-NH2-benzoisoxazol-5-yl, 3-NH2-benzoisoxazol-6-yl, 4-OMe-quinolin6-yl, 1-NH2-phthalazin-6-yl, 1-NH2- phthalazin-7-yl, 4-NH2-quinazolin-6-yl, 2-Me-4-amino-quinazolin-6-yl, 4-NH2quinazolin-7-yl, 2-Me-4-NH2-quinazolin-7- ilo, 2,4-di-NH2-quinazolin-7-yl,

In a fourth aspect, the present invention includes compounds of Formula (I), within the scope of the first aspect, in which:

R1

is, independently each time it appears, F, Cl, Me, Et, -NH2, -C (= NH) NH2, -C (O) NH2, -CH2NH2, -CH2NHCO2Bn, -CH2NHCO2 (t-Bu), -CH (Me) NH2, -CMe2NH2, -NHEt, -NHCO2 (t-Bu), -NHCO2Bn, -SO2NH2, ORa or -CH2R1a;

R2 is, independently each time it appears, F, Cl, Me, OMe, OEt, Bn, -CH2OMe, -CH2OEt or -CH2OPh;

R3 is -CO2H, -CO2Me, -C (O) NHCH2CO2H, -C (O) NHCH2CO2Et, -C (O) NH2, -C (O) NHMe, -C (O) NHBn, phenyl substituted with 0-2 R3a , naphthyl substituted with 0-2 R3a, indane substituted with 0-2 R3a or a 5-10 membered heterocycle selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3a;

R3a is, independently each time it appears, = O, F, Cl, Br, Me, CN, OH, NH2, OMe, O (f-Bu), OBn, CF3, CO2H, CO2Me, -CH2CO2H, -CH2CO2Me, - CH2CO2Et, -NHCOMe, -CONH2, -CH2CONH2, -CONHMe, -CONMe2, -C (= NH) NH2, -NR7R8, SO2Me, -SO2NH2, Ph or 2-oxo-piperidin-1-yl; wherein two of the R3a groups located on adjacent atoms can be taken together to form a 5-10 membered heterocycle with 0-2 R3d;

10-13-2011

R3d is, independently each time it appears, H, = O - (CH2) rORa, F, Cl, Br, CN, NO2, - (CH2) rNR7R8, -C (O) Ra, C (O) ORa, -OC (O) Ra, -NR7C (O) Rb, -C (O) NR8R9, -S (O) 2NR8R9 -NR8S (O) 2NR8R9, -NR8S (O) 2Rc, -S (O) pRc, - (CF2) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, - (CH2) C3-10 carboxy substituted with 0-3 Rd or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-3 Rd; R4 is H, F, Cl, Br, OMe or NH2; R6 is H; and R8a is, independently each time it appears, R7, OH, C1-6 alkyl, C1-4 alkoxy, (C6-10 aryl) -C 1-4 alkoxy; wherein said aryl is optionally substituted with 0-2 Rf

In a fifth aspect, the present invention includes compounds of Formula (I), within the scope of the fourth aspect, in which:

R3 is phenyl substituted with 0-2 R3a, naphthyl substituted with 0-2 R3a, indanone substituted with 0-2 R3a or a 5-10 membered heterocycle substituted with 0-2 R3a and selected from: pyridine, pyridinone, pyrimidine, pyrrole , pyrazole, indole, 2oxoindole, indazol, benzofuran, benzothiophene, benzoimidazole, benzoisoxazole, benzoxazol, quinazoline, 3H-quinazolin4-one, phthalazine, 2H-phthalazin-1-one, 1H-quinolin-4-2, isoquin , 4-dihydroisoquinolin-1-one.

In a sixth aspect, the present invention includes compounds of Formula (I), within the scope within the scope of the fifth aspect, in which:

A is 4-aminomethyl-cyclohexyl, 4-carbamoyl-cyclohexyl, 4-amidino-phenyl, 4-benzyloxycarbonylamino-cyclohexyl, phenyl, 1,2,3,4-tetrahydronaft-2-yl, 4-aminomethyl-phenyl, 4- carbamoyl-phenyl, 4 aminomethyl-2-fluoro-phenyl, 2-F-5-OMe-phenyl, 2F-4-Me-phenyl, 2-F-4-Cl-phenyl, 2-F-4-carbamoyl-phenyl , 2-OMe-4-carbamoyl-phenyl, 3-OMe-4-carbamoyl-phenyl, 2-Et-4aminomethyl-phenyl, 2-NH2-pyridin-4-yl, 2-ethylamino-4-aminomethyl-phenyl, 1 -aminoisoquinolin-6-yl, 1-NH2-5,6,7,8tetrahydroisoquinolin-6-yl, 1-NH2-1,2,3,4-tetrahydroisoquinolin-6-yl, 3-NH2-benzisoxazol-5-yl , 3-NH2-benzoisoxazol6-yl, 3-NH2-indazol-6-yl, 3-NH2-indazol-5-yl, 1-Me-3-NH2-indazolyl-6-yl, 1,2,3,4 -tetrahydroisoquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-1-on-6-yl, isoquinolin-6-yl, 1-NH2-isoquinolin-6-yl, 1-NH2-5,6,7,8 -tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl, 3H-quinazolin-4-onyl, 3,4-dihydro2H -isoquinolin-1-onyl, 2,3-dihydroisoindolinonyl or 1-N H2-phthalazin-6-yl; Y

R3 is phenyl, 3-OH-phenyl, 3,4-methylenedioxyphenyl, 2-naphthyl, 1-naphthyl, 3-NMe2-phenyl, 4-benzyloxyphenyl, 4-t-butoxyphenyl, 4-methylsulfonylphenyl, 4-Cl-phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 4-Brphenyl, 3-CF3-phenyl, 3-NH2- phenyl, 4-NH2-phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-CO2H-phenyl, 4-CO2H-phenyl, 3-CO2Mephenyl, 4-CO2Me-phenyl, 3-OH-phenyl, 3- CH2CO2H-phenyl, 3-CH2CO2Me-phenyl, 3-CH2CO2Et-phenyl, 3-CONH2-phenyl, 4CONH2-phenyl, 4-CH2CO2Et-phenyl, 3-CH2C (O) NH2-phenyl, 4-C (O) NHMe- phenyl, 3-NHCOMe-phenyl, 4-NHCO2Me-phenyl, 2,4-diF-phenyl, 3-F-4-CN-phenyl, 3-CN-4-F-phenyl, 3-OMe-4-CONH2- phenyl, 3-OH-4-CONH2-phenyl, 3-NH2-4-CONH2phenyl, 3-CO2Me-4-NH2-phenyl, 3-CO2H-4-NH2-phenyl, 3-CONH2-4-NH2-phenyl, 3-CO2H-4-F-phenyl, pyrrole-3-yl, pyrazol-3-yl, pyrazol-4-yl, 3-NH2-pyrazol-5-yl, pyridyl-2-yl, pyrid-3-yl, pyrid- 4-yl, 2-F-pyrid-4-yl, 2-F-pyrid-5-yl, 2-OMe-pyrid-4-yl, 2-OMe-pyrid-5-yl, 2-NH2-pyrid- 3-yl, 2-NH2-pyrid-4-yl, 2-NH2-pyrid -5-yl, 2-NH2-pyrid-6-yl, 2-NHMe-pyrid-4-yl, 2-NMe2pyrid-4-yl, 2-CONH2-pyrid-4-yl, 2-CO2H-pyrid-4 -yl, 2-CONH2-pyrid-5-yl, 2-OMe-6-NH2-pyridyl-4-yl, 4-NH2-pyrimidin-6yl, 4-NH2-pyrimidin-2-yl, 2-NH2-pyrimidin -4-yl, 2-NH2-pyrimidin-5-yl, indole-5-yl, indole-6-yl, indazol-5-yl, indazol-6-yl, 3-OH-indazol-5-yl, 3 -OH-indazol-6-yl, 3-OMe-indazol-5-yl, 3-OMe-indazol-6-yl, 3-NH2-indazol-5-yl, 3-NH2-indazol6-yl, benzoisoxalol-6 -yl, benzoisoxazol-5-yl, 3-NH2-benzoisoxazol-5-yl, 3-NH2-benzoisoxazol-6-yl, 4-OMe-quinolin6-yl, 1-NH2-phthalazin-6-yl, 1-NH2 -phthalazin-7-yl, 4-NH2-quinazolin-6-yl, 2-Me-4-amino-quinazolin-6-yl, 4-NH2quinazolin-7-yl, 2-Me-4-NH2-quinazolin-7 -yl, 2,4-di-NH2-quinazolin-7-yl,

10-13-2011

In a seventh aspect, the present invention includes compounds of Formula (I), within the scope of the sixth aspect, in which: A is 4-aminomethyl-cyclohexyl; and the group

or

In an eighth aspect, the present invention provides a compound selected from the illustrated examples or stereoisomers or pharmaceutically acceptable salts or solvates thereof.

In another embodiment, the present invention provides a new pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a stereoisomer or a pharmaceutically acceptable salt or solvate form thereof.

In another embodiment, the present invention provides pharmaceutical composition further comprising an agent.

or additional therapeutic agents selected from potassium channel opening agents, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, anti-atherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists,

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diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, anti-osteoporosis agents, hormone replacement therapies, hormonal receptor modulators, oral contraceptives, oral agents, antidepressants, anti-anxiety agents, antisychotic agents, anti-proliferative agents, anti-tumor agents, antiulcer agents and gastroesophageal reflux disease, growth hormone agents and / or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antifungal agents, lipid / cholesterol reducing agents and lipid profile therapies and agents that mimic ischemic preconditioning and / or myocardial stunning or a combination thereof.

In another embodiment, the present invention provides a pharmaceutical composition further comprising an additional therapeutic agent or agents selected from an antiarrhythmic agent, an antihypertensive agent, an anticoagulant agent, an antiplatelet agent, a thrombin inhibitor agent, a thrombolytic agent, an agent. fibrinolytic, a calcium channel blocker, a lipid / cholesterol reducing agent or a combination thereof.

In another embodiment, the present invention provides a pharmaceutical composition further comprising an additional therapeutic agent or agents selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin , mefenamate, dipyridamole, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, thyrofiban, eptifibatide, abciximab, melagatran, ximelagatran, disulfatohirudin, tissue plasminogen activator, t-plasminogen-activated combination of a plasminogen activator same.

In a preferred embodiment, the present invention provides a pharmaceutical composition wherein the additional therapeutic agent is an antihypertensive agent selected from ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists, ET / AII receptor antagonists. dual and vasopepsidase inhibitors, an antiarrhythmic agent selected from IKur inhibitors or an antithrombotic agent selected from anticoagulants selected from thrombin inhibitors, other factor XIa inhibitors, other calicrein inhibitors, factor VIIa inhibitors and factor Xa inhibitors and antiplatelet agents selected from GPIIb / IIIa blockers, P2Y1 and P2Y12 antagonists, thromboxane and aspirin receptor antagonists or a combination thereof.

In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent or agents are an antiplatelet agent or a combination thereof.

In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent is the clopidogrel antiplatelet agent.

In another embodiment, the present invention provides compounds of the present invention or a pharmaceutically acceptable salt or solvate form thereof for use in coagulation cascade modulation and / or contact activation system.

In another embodiment, the present invention provides compounds of the present invention or a pharmaceutically acceptable salt or solvate form thereof for use in the treatment of thromboembolic disorders.

In another embodiment, the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders and venous cerebral thromboembolic disorders.

In another embodiment, the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic 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, renal embolism, pulmonary embolism and thrombosis resulting from (a) prosthetic valves or other implants, (b) permanent catheters, (c) vascular stents , (d) cardiopulmonary bypass, (e) hemodialysis and (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.

In another embodiment, the present invention provides compounds of the present invention or a pharmaceutically acceptable salt form thereof for use in the treatment of inflammatory disorders.

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In another embodiment, the inflammatory disorder is selected from the group consisting of sepsis, acute respiratory distress syndrome and systemic inflammatory response syndrome.

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate form thereof in an amount effective to treat a thromboembolic disorder for use in the treatment of a patient in need of a disorder treatment. thromboembolic

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat an inflammatory disorder for use in the treatment of a patient in need of treatment of inflammatory disorder.

In another embodiment, the present invention provides a manufacturing article, comprising:

10 (a) a first container;

(b) a pharmaceutical composition located within the first container, the composition comprising: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt or solvate form thereof; Y

(c) a leaflet indicating that the pharmaceutical composition can be used for the treatment of a thromboembolic and / or inflammatory disorder.

In another preferred embodiment, the present invention provides a manufacturing article, further comprising:

(d) a second container;

wherein components (a) and (b) are located within the second container and component (c) is located within 20 or outside the second container.

In another embodiment, the present invention provides a manufacturing article, comprising:

(to)

a first container;

(b)

a pharmaceutical composition located within the first container, the composition comprising:

a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt or solvate form thereof; Y

(c) a leaflet indicating that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat a thromboembolic and / or inflammatory disorder.

In another preferred embodiment, the present invention provides a manufacturing article, further comprising:

30 (d) a second container;

wherein components (a) and (b) are located within the second container and component (c) is located within

or out of the second container.

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate form thereof in an amount effective to treat a thromboembolic and / or inflammatory disorder.

In another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt or solvate form thereof, for use in therapy.

In another embodiment, the present invention also provides the use of a compound of the present invention or a pharmaceutically acceptable salt or solvate form thereof, for the manufacture of a medicament for the treatment of a thromboembolic and / or inflammatory disorder.

The present invention can be carried out in other specific ways without departing from the essential attributes thereof. The present invention encompasses all combinations of preferred aspects of the invention indicated herein. It is understood that each and every embodiment of the present invention may be taken in conjunction with any other embodiment or embodiments to describe further additional preferred embodiments. It should also be understood that each individual element of the preferred embodiments is its own embodiment.

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independent preferred. In addition, it is intended to combine any element of one embodiment with each and every other element of any embodiment to describe an additional embodiment.

Definitions

The compounds of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral forms (enantiomeric and diastereomeric) and racemic forms of the compounds of the present invention are included in the present invention. Many geometric isomers of olifines, double C = N bonds and the like, may also be present in the compounds and all such stable isomers are contemplated in the present invention. Accordingly, the compounds of the present invention can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral (enantiomeric and diastereomeric) and racemic forms, and all genometric isomeric forms of a structure, unless the specific stereochemistry or isomeric form is specifically indicated. All tautomers of the compounds shown or described are also considered part of the present invention.

Preferably, the molecular weight of the compounds of the present invention is less than about 500, 550, 600, 650, 700,750 or 800 grams per mole. Preferably, the molecular weight is less than about 800 grams per mole. More preferably, the molecular weight is less than about 750 grams per mole. And even more preferably, the molecular weight is less than about 700 grams per mole.

As used herein, the term " alkyl " or "alkylene" It is intended to include groups of saturated straight chain and branched chain aliphatic hydrocarbons having the specified number of carbon atoms. For example, "C1-C10 alkyl" or "C1-10 alkyl" (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example, "C1-6 alkyl" represents an alkyl having 1 to 6 carbon atoms. The alkyl groups may be unsubstituted or substituted so that one or more of their hydrogens are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (for example, n-propyl and isopropyl), butyl (for example, n-butyl, isobutyl, t-butyl), pentyl (for example, n-pentyl, isopentyl, neopentyl) and the like.

"Alkenyl" or "alkenylene" It is intended to include hydrocarbon chains of linear or branched configuration having one or more carbon-carbon double bonds that can appear at any stable point along the chain. For example, "C2-6 alkenyl" (or alkenylene), is intended to include C2, C3, C4, C5 and C6 alkenyl groups. Examples of 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" It is intended to include hydrocarbon chains of linear or branched configuration and having one or more triple carbon-carbon bonds that can appear in any stable position along the chain. For example, "C2-6 alkynyl" (or alkynylene), is intended to include C2, C3, C4, C5 and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentinyl, hexinyl and the like.

"Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" refers to a linear or branched chain that has one or more halogen substituents. Examples of haloalkyl include, but are not limited to, CF3, C2F5, CHF2, CCl3, CHCl2, C2C5 and the like.

The term " alkoxy " or "alkyloxy" refers to a group -O-alkyl. " Alcoxi C1-6 " (or alkyloxy), is intended to include C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (for example, n-propoxy and isopropoxy), t-butoxy and the like. Similarly, "alkylthio" or "thioalkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge; for example methyl-S-, ethyl-S- and the like.

" Haloalkoxy " or "haloalkyloxy" represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through oxygen bridge. For example, "haloalkoxy C1-6" intends to include haloalkoxy groups C1, C2, C3, C4, C5 and C6. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluorotoxy and the like. Similarly, "haloalkylthio" or "thiohaloalkoxy" represents a haloalkyl group, as defined above, with the indicated number of carbon atoms attached through a sulfur bridge; for example trifluoromethyl-S-, pentafluoroethyl-S- and the like.

The term " cycloalkyl " Cyclic alkyl groups are referred to, including mono-, bi- or polycyclic ring systems.

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C3-7 cycloalkyl is intended to include C3, C4, C5, C6 and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like.

As used herein, "carbocycle" or "carbocyclic residue" It is intended to indicate a stable monocyclic or bicyclic ring of 3,4, 5, 6 or 7 members or bicyclic or tricyclic of 7, 8, 9, 10, 11, 12 or 13, and any one may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such 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] biciclononano, [4,4,0] bicyclodecane, [2,2,2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (for example, [2,2,2] bicyclooctane). Preferred carbocycles are, unless otherwise indicated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and indanyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring appears when one or more carbon atoms connect two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents listed for the ring may also be present on the bridge.

The groups " arilo " refers to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, phenanthranyl and the like. The aryl moieties are well known and are described, for example, in Hawley's Condensed Chemical Dictionary (13 ed.), R.J. Lewis, ed., J. Wiley & Sons, Inc., New York (1997) .Aryl groups may be substituted or unsubstituted.

As used herein, the term "heterocycle" or "heterocyclic group" it is intended to indicate a stable heterocyclic monocyclic ring of 5.6 or 7 members or bicyclic of 7, 8, 9, 10, 11, 12, 13 or 14 members that is saturated, partially saturated or totally unsaturated, and consisting 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 heterocyclic ring defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may be optionally oxidized (ie, N → O and S (O) p). The nitrogen atom may be unsubstituted or substituted (ie, N or NR, wherein R is H or other 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 a carbon or nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may be optionally 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 each other. It is preferred that the total number of S and O atoms in the heterocycle does not exceed 1. When the term "heterocycle" is used, this is intended to include heteroaryl.

Examples of 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-1,5,2-dithiazinyl, dihydrofuro [2,3-ib] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl isotinoílo, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3oxadiazolilo, 1,2,4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, fenantrolin yl, phenazinyl, phenothiazinyl, fenoxatinilo, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranoyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiazolyl 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Also included are condensed rings and spiro compounds containing, for example, the above heterocycles.

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, oxazolidinyl, tetrahydrazinyl, tetrahydrazinyl, tetrahydrazinyl, tetrahydrazinyl thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzoimidazolyl, 1 Hindazolyl, benzofuranyl, benzothiofuranyl, benzotetrazolyl, benzotriazolyl, benzoisoxazolyl, benzoxazolyl,

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oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

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, oxazolidinyl, tetrahydrazinyl, tetrahydrazinyl, tetrahydrazinyl, tetrahydroxyninyl thiadiazolyl, thiazolyl, triazinyl and triazolyl. Also included are condensed rings and spirocomposites containing, for example, the above heterocycles.

As used herein, the expression "aromatic heterocyclic group" or "heteroaryl" It is intended to indicate monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom in a member of the ring, 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, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzoimidazolyl, indolinyl, benzodioxolanyl, benzodioxane and the like. Heteroaryl groups may be substituted or unsubstituted. The nitrogen atom may be substituted or unsubstituted (ie, N or NR, wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (ie, N → O and S (O) p). It should be noted that the toral number of S and O atoms in the aromatic heterocycle is not greater than 1. Bridged rings are also included in the definition of heterocycle. A bridged ring appears when one or more atoms (i.e., C, O, N or S) connect two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, a carbon atom, two carbon atoms, a nitrogen atom, two nitrogen atoms and a carbon-nitrogen group. It should be noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents listed for the ring may also be present on the bridge.

The term " counterion " they are joined to represent a negatively charged small species, such as chloride, bromide, hydroxide, acetate and sulfate.

As indicated herein, the term " replaced " it means that one or more hydrogen atoms are replaced with a group that is not hydrogen, provided that normal valences are maintained and that the substitution results in a stable compound. When a substituent is keto (i.e., = O), then 2 hydrogens, two hydrogens in the atom are replaced. Keto substituents are not present in aromatic moieties. When a ring system (eg, carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, the carbonyl or double bond group is intended to be part (i.e., be inside) of the ring.

When any variable (for example, R2a, R2b, etc.) appears more than once in any constituent or formula for a compound, its definition every time it appears is independent of its definition in any other case. Therefore, for example, if it is shown that a group is substituted with 0-3 R2b, then that group may be optionally substituted with up to three groups R2b and R2b each time it appears it is independently selected from the definition of R2b. In addition, combinations of substituents and / or variables are only allowed if such combinations result in stable compounds.

When it is shown that a substituent bond crosses a bond that connects two atoms in a ring, then said substituents may be linked to any atom in the ring. When a substituent is listed without indicating the atom by which said substituent is linked to the remainder of the compound of a given formula, then said substituent may be attached through any atom of said substituent. Combinations of substituents and / or variables are only allowed without such combinations resulting in stable compounds.

When a dotted ring is used, this indicates that the ring structure may be saturated, partially saturated or unsaturated.

The expression "pharmaceutically acceptable" it is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritability, allergic response or other problems or complications, consistent with a reasonable benefit / risk ratio.

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The expression "pharmaceutically acceptable salt" refers to salts of acids or bases of the compounds described herein. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of organic or mineral acids from basic residues, such as amines; organic or alkaline salts of acidic residues, such as carboxylic acids; and the like Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the acid or base free forms of these compounds with a stoichiometric amount of the appropriate base or acid in water, in an organic solvent or in a mixture of both; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of the same is incorporated herein by reference in its entirety. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of organic or mineral acids from basic residues, such as amines; organic or alkaline salts of acidic residues, such as carboxylic acids; Similar. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the precursor compound formed, for example, from suitable inorganic or organic acids. Such conventional non-toxic salts include those obtained from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxyleleic, phenylacetic, glutamic, benzoic, salicylic, sulfanyl, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isotionic and the like.

In addition, the compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (ie, a compound of formula 1) is a prodrug. Various forms of prodrugs are well known in the art. For examples of such proraco derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, at p.

309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5,

" Design and Application of Prodrugs, " by H. Bundgaard, on pages. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol. 77, p. 285 (1988); Y

e) N. Kakeya, et al., Chem Phar Bull., Vol. 32, p. 692 (1984).

The preparation of prodrugs is well known in the art and is described in, for example, Medicinal Chemistry: Principles and Practice, ed. F. D. King, The Royal Society of Chemistry, Cambridge, United Kingdom, 1994.

Radiolabeled compounds of the present invention are also provided herein, that is, in which one or more of the atoms described are replaced by a radioactive isotope of that atom (eg, C replaced by 13C or 14C; and hydrogen isotopes include tritium and deuterium). Such compounds have a variety of potential uses, for example, as standards and reagents in determining the ability of a potential drug to bind to proteins or target receptors, or for imaging of compounds of the present invention bound to biological receptors. in vivo or in vitro.

The compounds of the present invention, after their preparation, are isolated and purified to obtain a composition containing an amount by weight equal to or greater than 98%, preferably 99%, of the compound of the present invention ("substantially pure") , which is then used or formulated as described herein. Such compounds "substantially pure" They are also contemplated herein as part of the present invention.

"Stable compound" and "stable structure" They are intended to indicate a compound that is robust enough to survive isolation to a useful degree of purity from a reaction mixture, and to the formulation in an effective therapeutic agent. It is preferred that the compounds of the present invention do not contain any Nhalo, S (O) 2H or S (O) H groups.

It should also be understood that the solvates (eg, hydrates) of the compounds of the present invention are also within the scope of the present invention. Solvation procedures are generally known in the art.

As used herein, "treat" or "treatment" covers the treatment of a pathology in a mammal, particularly in a human being and includes: (a) preventing the onset of pathology in a mammal, in

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particularly, when said mammal is predisposed to the pathology but has not yet been diagnosed to have it; (b) inhibit the pathology, that is, stop its development; and / or (c) alleviate the pathology, that is, cause the pathology to recede.

"Therapeutically effective amount" It is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit a factor XIa and / or plasma kallikrein. "Therapeutically effective amount" It is also intended to include an amount of the combination of claimed compounds that is effective in inhibiting factor XIa and / or plasma kallikrein. The combination of the compounds is preferably a synergistic combination. Synergy appears, as described in, for example, Chou and Talalay, Adv. Enzyme Regul. 1984, 22: 27-55, when the effect (in this case, inhibition of XIa and / or plasma kallikrein) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone or in form of a single agent. In general, a synergistic effect is most clearly demonstrated at concentrations below the optimum of the compounds. The synergy can be compared, in terms of low cytotoxicity, increased antithrombotic and / or inflammatory effect or some other beneficial effect of the combination, with the individual components.

In addition, the present invention includes one or more compounds of the present invention and a pharmaceutically acceptable carrier.

A "pharmaceutically acceptable vehicle" refers to a medium generally accepted in the art for the administration of biologically active agents to animals, in particular mammals. Pharmaceutically acceptable vehicles are formulated according to a variety of factors and competencies within the scope of those skilled in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to whom the composition containing the agent will be administered; the desired route of administration of the composition; and the therapeutic indication to follow. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such vehicles may include a variety of different ingredients and additives in addition to the active agent, said additional ingredients being included in the formulation for a variety of reasons, for example, stabilization of the active agent, binders, etc., well known to those skilled in the art. matter. Descriptions of pharmaceutically acceptable vehicles and factors involved in their selection are found in a variety and readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985.

Synthesis

The compounds of the present invention can be prepared in a variety of ways known to the person skilled in the art of organic synthesis: The compounds of the present invention can be synthesized using the procedures described below, together with the synthetic procedures known in the art of synthesis of organic chemistry or variations thereof as those skilled in the art will appreciate. Preferred procedures include, but are not limited to, those described below. The reactions are carried out in a solvent suitable for the reagents and materials used and suitable for the transformations that are being carried out. Experts in the field of organic synthesis will understand that the functionality present in the molecule must be consistent with the proposed transformations. This will sometimes require a criterion to modify the order of the synthetic steps or to select a particular process scheme over the others to obtain a desired compound of the invention. Also, in the description of the synthetic procedures described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and treatment procedures, are selected so that they are conventional conditions for the reaction, which should be easily recognized by one skilled in the art. It will be understood by an expert in the field of organic synthesis that the functionality present in various portions of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents that are compatible with the reaction conditions will be apparent to the person skilled in the art and alternative procedures should be used.

It will also be recognized that other main considerations in the planning of any synthetic route in this field is the conscientious choice of the protective group used for the protection of the reactive functional groups present in the compounds described in the present invention. A reliable description that describes the many alternatives for the trained professional is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley-Interscience, 3rd Edition, 1999).

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Methods for the synthesis of a wide variety of pyridone and substituted pyridine compounds useful as starting materials for the preparation of compounds of the present invention are well known in the art and have been extensively studied. (For examples of useful procedures for the preparation of pyridine and pyridone starting materials see: Krohnke, F. Synthesis, 1976, 1,; Piridine and Its Derivatives. In The Chemistry of Heterocyclic Compounds, Abramovitch, RA, Ed .; John Wiley and Sons: New York, 1974; Vol 14; Supplemental 1-4 ;; Comprehensive Heterocyclic Chemistry, Vol. 2, Boulton, AJ and McKillop, A, Eds. Pergamon Press, New York, 1984, pp. 165-524; Comprehensive Heterociclic Chemistry, Vol. 5, McKillop, A, Ed. Pergamon Press, New York, 1996, pp. 1-300). of a wide variety of pyrimidone and substituted pyrimidine compounds useful as starting materials for the preparation of compounds of the present invention and have been studied extensively. (Examples of useful procedures for the preparation of pyrimidine and pyrimidone starting materials see: The Pirimidines. In The Chemistry of Heterocyclic Compounds, Taylor, E.C., Ed .; John Wiley and Sons: New York, 1993; Vol 52).

Representative pyridone compounds of the present invention can be prepared as shown in Scheme 1. Suzuki coupling between an appropriately functionalized pyridine, such as 1a and an optionally substituted aryl or heteroaryl boronic acid or ester 1b in the presence of a base, such as anhydrous potassium carbonate in a solvent, such as methanol or THE, using a catalyst, such as PXPd2 provides the biaryl compound. Using a modification of the procedure described by Schlosser (Schlosser, M. and Cottet, F. Eur.J. Org. Chem., 2002, 24, 4181-4184), the 2-chloropyridine derivative is treated with trimethylsilyl bromide in propionitrile at elevated temperature in a microwave to give the 2-bromopyridine 1c derivative. The metal-halogen exchange with n-butyl·thio and inactivation of the intermediate anion with a suitable formyl source, such as 1formyl piperidine or DMF provides the aldehyde 1d. Using a modification of the procedure described by Hart (Hart, DJ et al. J. Org. Chem., 1983, 48 (3), 289-294), in situ generation of N-trimethylsilyldimines from 1d and lithium bis (trimethylsilyl) ) amide, followed by the addition of Grignard or alkyl·litio reagents give, after treatment, the primary amine 1e. The amide coupling between 1e and appropriately substituted carboxylic acid (1f), for example, Boc-tranexamic acid, using suitable coupling reagents, such as EDCI, HOBt and base, generates 1g (for alternative coupling reagents see: Han, SY ; Kim, Y. Tetrahedron, 2004, 60, 2447). Alternative manipulation of functional groups in A, using methods known to one skilled in the art of organic synthesis will provide additional compounds of the invention. For example, when A is a Boc-tranexamic acid moiety, the Boc group can be deprotected with TFA to give the cyclohexyl methyl amine derivative. The 1h pyridine N-oxide derivatives can be prepared by oxidation of 1g with a suitable oxidant, such as m-chloroperbenzoic acid in chloroform. Further manipulation of functional groups in R3 and R4 using methods known to one skilled in the art of organic synthesis will provide additional compounds of the invention.

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Alternatively, the R3 moiety can be introduced by a Suzuki coupling strategy later in the synthesis shown in Scheme 2. Compound 2c can be prepared in three stages according to a modified procedure described by Negi (Negi, S. et al. Synthesis, 1996, 991). The addition of 5 Grignard or lithium reagents to a properly substituted Weinreb ester or amide 2a produces ketone 2b. Condensation of 2b with hydroxylamine hydrochloride generates the oxime that can be reduced to give primary amine 2c with zinc powder and TFA. The amide coupling between 2c and the carboxylic acid 1f using suitable coupling reagents as described in Scheme 1 produces 2d. Suzuki coupling between 4-chloropyridine 2d and an optionally substituted aryl or heteroaryl boronic acid or ester 1b in the presence of a base, such as anhydrous cesium carbonate, potassium fluoride or potassium phosphate in a solvent, such as dioxane, dimethyl sulfoxide or dimethylformamide, using a catalyst, such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipaladium (0) and tri-t-butylphosphonium tetrafluoroborate or Pd (dppf) 2Cl2 · CH2Cl2 complex provides the biaryl compound 1g. Further manipulation of functional groups in A, R3 and R4 using procedures known to one skilled in the art of organic synthesis will provide additional compounds.

15 of the invention.

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In cases where properly substituted boronic acids are not commercially available, a modification to this approach may be adopted, in which an aryl halide is subjected to a palladium-mediated coupling with a kind of boron, such as bis ( pinacolato) diboro, to provide the corresponding 4,4,5,55 tetramethyl- [1,3,2] dioxaborolane intermediate, using the method of Ishiyama, T. et al. (J. Org. Chem. 1995, 60 (23), 7508-7510). Alternatively, this same intermediate can be prepared by reacting the intermediate halide with the corresponding dialkoxyhydroborane as described as Murata et al. (J. Org. Chem. 1997, 62 (19), 64586459). Boron pinacolate intermediates can be used instead of boronic acids to couple aryl / heteroaryl halides or triflates or boron pinacolate intermediate can be converted to boronic acids. How

Alternatively, the corresponding boronic acids by metal-halogen exchange of the aryl / heteroaryl halide, inactivating with a trialkoxyborate reagent and aqueous treatment to provide the boronic acids (Miyaura, N .; Suzuki, A. Chem. Review, 1995, 95 , 2457).

It is also clear that the scope of intermediate synthesis can be extended outside the use of Suzuki methodologies since the precursor aryl halides or triflates are also precursors

15 for cross-coupling methodologies of the Stille, Negishi, Hiyama and Kumada type (Tsuji, J. Transition Metal Reagents and Catalysts: Innovations in Organic Synthesis, John Wiley & Sons, 2000; Tsuji, J. Palladium Reagents and Catalysts: Innovations in Organic Synthesis, John Wiley & Sons, 1996.)

Representative pyrimidine and pyrimidone compounds of the present invention can be prepared as shown in Scheme 3. A suitably substituted amino nitrile 3a can be converted to the corresponding amidine 3b20 by treatment with N-acetyl-cysteine and ammonium acetate in the presence of dithiothreitol. Condensation of amidine 3b with a suitably substituted aryl propinone 3g in the presence of a base such as sodium carbonate and in a solvent, such as acetonitrile, provides the pyrimidine compound 3c (Bagley, C. Synlett 2003, 2, 259-261) . After deprotection with TFA, the amine is coupled with carboxylic acid 1f using suitable amide coupling conditions such as those described in Scheme 1 to produce 3d. The pyrimidone 3e derivatives can be prepared similarly by condensation of the amidine 3b with an appropriately substituted aryl 3hlate in the presence of a base, such as Hunig's base and in a solvent, such as ethanol (Gupta, KA, and col. Indian J. Chem., 1983, 22B, 384). After deprotection with TFA, the amine is coupled with the 1f carboxylic acid as described above to produce 3f. Additional manipulation of functional groups in A and R3 using procedures known to one skilled in the art of organic synthesis

30 will provide additional compounds of the invention.

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Pyridone compounds of the present invention can be prepared as shown in Scheme 4. Compound 4d can be prepared in two steps according to a modified procedure described by Resmini (Resmini, M. et al., Tetrahedron Asymmetry, 2004.15, 1847). A suitably substituted amino ester 4a can be converted into the corresponding β-ketophosphonate 4b by treatment with lithium dimethylmethylphosphonate. The Horner-Wadsworth-Emmons reaction of 4b and a suitably substituted aldehyde 4c in the presence of a base, such as potassium carbonate, in a solvent such as ethanol or tetrahydrofuran provides the ketone α, β-unsaturated 4d. Condensation of 4d with 1- (ethoxycarbonylmethyl) -pyridinium chloride or 1- (carbamoylmethyl) -pyridinium chloride in the presence of ammonium acetate, in a solvent, such as ethanol or glacial acetic acid, generates pyridone 4e.

10 After deprotection with TFA, the amine is coupled with carboxylic acid 1f using suitable amide coupling reagents as described in Scheme 1 to produce 4f. Further manipulation of functional groups in A and R3 using methods known to one skilled in the art of organic synthesis will provide additional compounds of the invention.

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Alternatively, pyridine and pyridone compounds of the present invention can be prepared as shown in Scheme 5. Compound 5c can be prepared in two steps from β-ketophosphonate 5a as described in Scheme 4. Selective O-alkylation as described by Rao (Rao, JM, et al Tetrahedron, 1989, 45 (22), 5 7093 and references cited therein) can be achieved with silver carbonate and an alkyl iodide, such as methyl iodide, in a solvent, such as benzene or chloroform, to give 5d. Alternatively, 5c can be treated with phosphorus oxychloride to give chloropyridine 5e. Dibromation of 5d / 5e with NBS and subsequent reaction with morpholine at elevated temperatures followed by hydrolysis provides the aldehydes 5f and 5g that can be converted into 5j and 5k, respectively, as described in Scheme 1. The 5k chlorine compound is converted to the amine 10 51 by a modification of the procedure described by Buchwald (Buchwald, SL et al, Tetrahedron Letters, 1997, 38 (36), 6363). After 5h demethylation with HCl or BBr3, the amine is converted to the imine by transimidation with benzophenone imine according to a modified procedure described by O'Donnell (O'Donnell, MJ, Polt, RLJ Org. Chem., 1982, 47, 2663). Deprotonation of pyridone with a base, such as sodium hydride, in a solvent, such as THF or DMF and inactivation with an alkyl halide, such as iodide of

15 methyl, provides the N-alkyl derivative. Following hydrolysis of the imine with aqueous HCl, the amine is coupled with carboxylic acid 1f, using suitable amide coupling reagents as described in Scheme 1 to produce 5m. Further manipulation of functional groups in A and R3 using methods known to one skilled in the art of organic synthesis will provide additional compounds of the invention.

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Hydrazine monohydrate in n-butanol provides 3-aminoindazole 6d and 3-hydroxy · indazole 6e, respectively. The reaction of 6a with acetohydroxamic acid and potassium tert-butoxide in DMF according to a modified procedure described by Palermo (Palermo, M.G. Tetrahedron Letters, 1996, 37 (17), 2885) provides 3-aminobenzoisoxazole 6f. Alternatively, heating 6a with formamidine acetate or 5 acetamidine acetate in DMA, according to a modified procedure described by Lam (Lam, PYS et al, J. Med. Chem. 2003, 46, 4405,) provides 4-amino quinazolines 6g and 6h. Quinazolinone 6k can be prepared similarly by heating the corresponding 6ran anthranilic acid derivatives with formamide as described by Alexandre et al. (Tet. Lett. 2002 43, 3911). Alternatively, quinazolinone 6k can be prepared by heating 6j with ammonium acetate and trimethyl orthoformate according to a modified process of

10 WO patent document published WO2005 / 012264.

It is understood that the pyrimidine ring system depicted in Scheme 6 can be exchanged with pyrimidine, pyrimidone, pyridone and additional ring systems claimed in the present invention.

A suitably substituted carboxylic acid (A-CO2H, 1f) is used in the amide coupling shown in the

15 Scheme 1-5. Many of these carboxylic acids are available in the market. In cases where carboxylic acids are not commercially available, they can be prepared using methods known in the art.

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(Scheme 7). Suitable carboxylic acids can be obtained for use in the preparation of the compounds of the present invention through the oxidation of the corresponding alcohol 7a or aldehyde 7b as explained in "Advanced Organic Chemistry"; (Jerry March, Wiley Interscience, 4th Edition, pp. 1196 and 701-703 and references therein). Alternatively, oxidation of the aromatic secondary chains in 7c provides aromatic carboxylic acids as explained in "Advanced Organic Chemistry". (Jerry March, Wiley Interscience, 4th Edition, p. 1183-1184 and references therein). Alternatively, hydrolysis of esters 7d or nitriles 7e provides the carboxylic acid as explained in "Advanced Organic Chemistry". (Jerry March, Wiley Interscience, 4th Edition, p. 378-383 and 887-889 and references therein). Alternatively, the carbonylation of bromide 7f provides the carboxylic acid as explained in "Advanced Organic Chemistry". (Jerry March, Wiley Interscience, 10 4th Edition, p. 484-486, 546-547 and 664-665 and references therein). The R1 and R2 groups can be further manipulated using methods known in the art to provide additional compounds of the present invention. For example, when R1 is a cyano group, it can be reduced to give CH2NH2 with a suitable reducing agent. The nitrile can also be converted to an amidine by reaction with hydroxylamine followed by hydrogenolysis with a palladium catalyst in a hydrogen atmosphere or after a Pinner reaction followed

15 of aminonólosis.

Schemes 8 and 9 describe the synthesis of additional examples of A-CO2 H (1f) acids useful for preparing the compounds of the present invention. When A is an isoquinoline moiety, a modified procedure of United States patent published US2004 / 0077865 is followed. Heating the 2-methylbenzonitrile derivative 8 to 20 with 1- (t-butoxy) -N-N-N'-N'-tetramethyl-methanediamine, in a suitable solvent, such as DMF of enamine 8b. Condensation of enamine 8b and 2,4-dimethoxybenzylamine in DMPU at elevated temperatures provides the structure of 1-imino-1,2-dihydroisoquinoline and subsequent hydrolysis provides 8c. Debenzylation of 8c with anisole in TFA at elevated temperatures provides 1-amino-isoquinoline 8d. When A is a 5,6,7,8 tetrahydroisoquinoline moiety, a modified procedure described by McEachern (McEachern, E.J. et al. J. Org.

25 Chem. 2002, 67, 7890). Acid 8c becomes ester 8e. Debenzylation of 8e with anisole in TFA at elevated temperatures and acetylation with acetyl chloride and triethylamine provides 8f. Hydrogenation over platinum oxide in the presence of TFA provides 1-amino-5,6,7,8-tetrahydroisoquinoline. Saponification of the ester with NaOH and hydrolysis of the amide under acidic conditions provides 8g.

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Scheme 9 describes the synthesis of specific examples of A-CO2H (1f) when A is the 4-aminoquinazoline moiety. Heating of an ortho-fluoro benzonitrile 9a suitably substituted with formamidine acetate

or acetamidine acetate in DMA, according to a modified procedure described by Lam (Lam, P.Y. S. et al. J. Med Chem. 2003, 46, 4405,) provides the 4-amino quinazolines 9b and 9c. Saponification of the ester under basic conditions provides 9d and 9e.

In cases where suitably substituted aldehydes 4c are not commercially available, suitable aldehydes useful for the synthesis of the compounds in Schemes 4 and 5 are from a variety of 10 direct chemical transformations known to the person skilled in the art. matter. As indicated in Scheme 10, the aldehydes 4c (when R3 is phenyl) suitable for use in the preparation of the compounds of the present invention can be obtained through the oxidation of the corresponding alcohols or halides 10a as explained in " Advanced Organic Chemistry " (Jerry March, Wiley Interscience, 4th Edition, pp. 1167-1171, 1190 and 1193, and references therein). Alternatively, suitable aldehydes can be prepared by hydrogenation of the corresponding carboxylic acids 10b in the presence of palladium and pivotal anhydride complexes (Nagayama

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et al. Chemistry Letters 1998, 27, 1143-1144) or by reduction of the corresponding carboxylic acid 10b with borane followed by oxidation of the intermediate alcohol with Dess-Martin manganese or periodyne dioxide. In addition, the ester (10b; R = alkyl) can be reduced with DIBAL-H (Chandrasekhar et al. Tetrahedron Letters 1998, 39, 909-910) to give the aldehyde 4c. Additional aryl aldehydes can be obtained from the corresponding toluene derivatives 10c 5 by direct oxidation or by a two-stage process that involves the formation of the dibromide intermediate and subsequent conversion into the aldehyde with a silver salt, hexamethylene tetramine or morpholine (with silver : Demir, AS; Reis, O. Tetrahedron, 2004, 60, 3803; hexamethylene tetramine: Tidwell, RR; et al. J Med. Chem., 1978, 21 (7), 613; morpholine: WO patent published WO2002 / 32884) . Additional suitable aldehydes can be prepared through aromatic ring formilation 10d as explained in "Advanced Organic Chemistry" (Jerry March,

10 Wiley Interscience, 4th Edition, p. 542-546 and references therein).

A modification of Scheme 2 is shown in Scheme 11. The reaction of 4-chloropyridine 2b with TMSBr or acetyl bromide at elevated temperatures as described in Scheme 1 provides 4-bromopyridine 11a. Compound 11a can be carried through the sequence described in Scheme 2 to give 1g. As an alternative, Suzuki's coupling strategy can be reversed. 4-Bromopyridine 11c can be converted into the boronate or boronic acid derivative as described above to produce 11d. Suzuki coupling between 4-pyridineboronic acid 11d and a suitably substituted aryl or heteroaryl halide or pseudohalide 11e in the presence of a base, such as anhydrous cesium carbonate, potassium fluoride or potassium phosphate in a solvent, such as dioxane, dimethyl sulfoxide or dimethylformamide, using a catalyst, such as tetrakis (triphenylphosphine) palladium

20 (0), tris (dibenzylideneacetone) dipaladium (0) and tri-t-butylphosphonium tetrafluoroborate or Pd (dppf) 2Cl2 · CH2Cl2 complex provides the biaryl compound 1g. Further manipulation of functional groups in A, R3, and R4 using methods known to one skilled in the art of organic synthesis will provide additional compounds of the invention.

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Representative examples of manipulation of functional groups in R3 using procedures known to one skilled in the art of organic synthesis are shown in Scheme 12. Fluoropyridine 12a can be displaced with amines, such as ammonium hydroxide, to give aminopyridine 12b, alkoxides. , such as sodium methoxide, to give 12c or sodium hydroxide to give 12d according to modified procedures described by Queguiner (Queguiner, G. et al. J. Org. Chem., 1988, 53, 2740).

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Representative examples of the present invention when R3 is a pyrimidine ring system are shown in Schemes 13 and 14. The condensation of amidine 13b, which can be synthesized from cyanopyridine 13a by the Pinner reaction, with a propriolate Properly substituted may provide pyrimidone 13c. 5 Pyrimidone 13c can be converted to aminopyrimidine 13d in two stages. A synthesis of regioisomeric pyrimidine is shown in Scheme 14. β-Ketonitrile 14b can be prepared from acid 14a according to a modified procedure described by Katritzky (Katritzky, AR et al. J. Org. Chem., 2003, 68 , 4932). Condensation of 14b with formamide and ammonia according to a modified Hirota procedure (Hirota, T. et al. Synthesis, 1991, 303) can provide aminopyrimidine 14c. Β-Ketonitrile 14b

10 can also be used to synthesize pyrazoles (Watson, S.P. et al. Tetrahedron Letters, 1997, 38, 9065).

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Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are provided to illustrate the invention and are not intended to be limiting thereof.

The proportion of the solution expresses a volume ratio, unless otherwise indicated. NMR chemical shifts (8) are indicated in parts per million. Flash chromatography was performed on silica gel according to the Still procedure (Still, W. C. et al. J. Org. Chem. 1978, 43, 2923). HPLC

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Preparative was performed on Phenomenex Luna columns with the specific conditions in the experiments with the following solvent system: Solvent A: 90% water, 10% methanol and 0.1% TFA. Solvent B: 10% water, 90% methanol and 0.1% TFA.

As used throughout the specification, the following abbreviations for chemical reagents apply:

AcOH or HOAc = acetic acid Bn = benzyl Bu = butyl t-Bu = Tertiary Butyl Boc = tert-butyloxycarbonyl CH2Cl2 = dichloromethane DCE = 1,2-dichloroethane DMF = dimethylformamide DMSO = dimethylsulfoxide DTT = dithiothreitol EDCI = 1- (3- (dimethylamine) propyl) -3-ethylcarbodiimide hydrochloride Et = ethyl Et2O = diethyl ether EtOH = ethanol EtOAc = ethyl acetate HCl = hydrochloric acid HOAt = 7-aza-1-hydroxybenzotriazole HOBt = 1-hydroxybenzotriazole LiHMDS = Lithium hexamethyldisilazide Me = methyl MeOH = methanol mCPBA = m-chloroperbenzoic acid NaOAc = sodium acetate Na2SO4 = sodium sulfate NMM = N-methylinorpholine OAc = acetate Ph = phenyl Pr = propyl i-Pr = isopropyl i-PrOH = isopropanol PXPd2 = Bis [di-tert-butyl phosphine-kP chloride] di-m-chlorodichloro dipaladium TFA = trifluoroacetic acid THF = tetrahydrofuran C = degrees Celsius anh = anhydrous atm = atmosphere conc. = concentrated equiv. = equivalent or equivalent h = hour or hours g = gram or grams mg = milligram or milligrams L = liter or liters ml = milliliter or milliliters µl = microliter or microliters mmol = millimolar M = molar mequiv. = milliequivalent or milliequivalents min = minute or minutes PM = molecular weight mp = melting point

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ta or TA = room temperature

sat = saturated

sec. = second or seconds

IEN = electrospray ionization mass spectroscopy

HPLC = high performance liquid chromatography

MS = mass spectrometry

LC / MS = liquid chromatography / mass spectrometry

NMR = nuclear magnetic resonance spectroscopy

TLC = thin layer chromatography

" α ", " P ", " R ", " S ", " E " and "Z" These are familiar stereochemical designations for the person skilled in the art. A stereoisomer of a compound of Formula I may show superior activity compared to the others. Therefore, each stereoisomer of a compound of Formula I is considered to be part of the present invention. When needed, separation of the racemic material can be achieved by HPLC, using a chiral column or by resolution using a resolution agent, such as that described in Wilen, SH Tables of Resolving Agents and Optical Resolutions 1972, 308 or using enantiomerically pure acids or bases.

The following examples have been prepared, isolated and characterized using the procedures described herein. The following Examples demonstrate partial scope of the invention and are not intended to limit the scope of the invention.

Examples

Example 1

4-Aminomethyl-cyclohexanecarboxylic acid [2-phenyl-1- (4-phenyl-pyridin-2-yl) -ethyl] -amide, bistifluoroacetic acid salt

1A. 2-Chloro-4-phenylpyridine: A flask was charged with 2-chloro-4-iodine pyridine (2.5 g, 10.4 mmol), phenylboronic acid (1.33 g, 10.96 mmol), K2CO3 (4 , 54 g, 32.88 mmol), PXPd2 (0.186 g, 0.261 mmol) and methanol (34.8 ml). Argon was blown through a flask for 30 sec. The dark brown suspension was stirred for 3 h and then filtered and washed with methanol. The filtrate was concentrated to give 2.15 g as a brown solid. Column chromatography (120 g silica gel column; gradient circumvention; 0-35% ethyl acetate / hexane) provided 1A (1.79 g, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 8.43 (d, J = 5.3 Hz, 1H), 7.61 (dd, J = 8.2, 1.5 Hz, 2H), 7.54 ( d, J = 2.2 Hz, 1H), 7.52-7.47 (m, 3H), 7.43 (dd, J = 5.1, 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ: 152.2, 151.5, 149.9, 136.8, 129.6, 129.2, 127.0, 122.0, 120.4, MS 190.0 (M + H) + and 192.0 (M + 2 + H) +.

1 B. 4-Phenyl-pyridin-2-carbaldehyde: To a clear and colorless solution of 1A (0.850 g, 4.5 mmol) in propionitrile (4.5 mmol) was added trimethylsilyl bromide (2.95 ml, 22.4 mmol). The resulting orange suspension was heated in the microwave in a tightly sealed tube at 150 ° C for 10 min. The reaction was cooled to rt and poured into 1.0 N NaOH containing ice. The aqueous phase was extracted with diethyl ether (2 x). The combined organic phases were washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated, giving 1.07 g of 2-bromo-4-phenyl pyridine as an off-white solid. MS 233.9 (M + H) + and 235.9 (M + 2 + H) +.

To a cooled solution (-78 ° C) transparent, slightly yellow in color of 2-bromo-4-phenyl-pyridine (0.500 g, 2.14 mmol) in THF (8.6 ml) n-BuLi was added dropwise 2.5 M in hexane (0.86 ml, 2.14 mmol). The resulting red solution was stirred at -78 ° C for 1 h, then 1-formylpiperidine (0.48 ml, 4.28 mmol) was added dropwise. The reaction was allowed to warm to 0 ° C for 1 h and then stirred at 0 ° C for 1 h. The reaction was stopped with 1.0 N HCl. The reaction was extracted with ethyl acetate. The combined organic phases were washed with saturated NaHCO3 and brine, washed over Na2SO4, filtered and concentrated to give 0.555 g of a golden oil. Column chromatography (silica gel 40 g; gradient circumvention; 0-40% ethyl acetate / hexane) provided 1B (0.194 g, 49%) as a yellow solid 1 H NMR (400 MHz, CDCl3) ) δ: 10.16 (s, 1H), 8.84 (d, J = 5.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.75 (dd, J = 5.3.1.8 Hz, 1H), 7.71-7.69 (m, 2H), 7.55-7.48 (m, 3H). MS 184.1 (M + H) +.

1 C. 2-Phenyl-1- (4-phenylpyridin-2-yl) -ethanamine, bis-trifluoroacetic acid salt: To a cooled solution, (0 ° C), clear yellow 1B (0.184 g, 1.00 mmol) in THF (2.0 ml) was added dropwise

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1.0 N lithium bis (trimethylsilyl) amide in THF (1.10 ml, 1.10 mmol). The brown-yellow solution was stirred at 0 ° C for 15 min. Subsequently, a solution of 2.0 M benzylmagnesium chloride in THF (0.60 ml, 1.20 mmol) was added dropwise, giving a red solution. The reaction was stirred at 0 ° C for 20 min and then heated to rt. After 30 min, the reaction was stopped with saturated NH4Cl and diluted with water and diethyl ether. The phases were separated and the organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to a thick orange residue. Preparative HPLC [21.2 x 100 mm; 10 min gradient .; 20-100% B; 20 ml / min.] Provided 1C (0.238 g, 47%) as a white foam. 1H NMR (500 MHz, MeOD4) δ: 8.69 (d, J = 5.5 Hz, 1H); 7.64 (dd, J = 5.5.1.6 Hz, 1H), 7.56-7.51 (m, 2H), 7.47-7.42 (m, 3H), 7.297.23 ( m, 4H), 7.11-7.09 (m, 2H), 5.25 (sa, 2H), 4.77 (dd, J = 9.4, 6.0 Hz, 1H), 3.41 (dd, J = 13.2, 6.0 Hz, 1H), 3.22 (dd, J = 13.2, 9.4 Hz, 1H). MS 275.1 (M + H) +.

1D. {4- [2-Phenyl-1- (4-phenylpyridin-2-yl) -ethylcarbamoyl] -cyclohexylmethyl} -carbamic acid tert-butyl ester: At a cooled solution (0 ° C), clear, orange of 1C (0.138 g, 0.275 mmol) in DMF (0.9 ml) Hunig's base (0.11 ml, 0.605 mmol) was added. To the resulting clear yellow solution, BOC-transexamic acid (0.078 g, 0.302 mmol), HOBt (0.0557 g, 0.412 mmol) and EDCI (0.079 g, 0.412 mmol) were added sequentially. After 15 min at 0 ° C, the suspension was heated to rt. After 2.5 h, the solution was diluted with water to give a suspension. The reaction was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to give 1D (0.155 g) as an off-white solid. The material was taken to the next stage without further purification or characterization. MS 514.22 (M + H) +.

1E. Example 1: To a clear and colorless solution of 1D (0.086 g, 0.167 mmol) in CH2Cl2 (3.0 ml) was added TFA (0.9 ml). After 1 h, the reaction was concentrated. CH2Cl2 was added and the reaction was concentrated again. The above procedure was repeated again, giving a yellow residue. Preparative HPLC [21.2 x 100 mm; 10 min gradient .; 20-100% B; 20 ml / min.] Gave Example 1 (0.0484 g, 45%) as a white solid. 1H NMR (500 MHz, MeOD4) δ: 8.68 (d, J = 6.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.86-7.84 (m, 2H ), 7.61-7.58 (m, 3H), 7.29-7.26 (m, 2H), 7.23-7.20 (m, 3H), 5.38 (t, J = 8 , 1 Hz, 1H), 3.34-3.26 (m, 2H), 2.77 (d, J = 7.4 Hz, 2H), 2.34-2.28 (m, 1H), 1 , 85-1.83 (m, 3H), 1.77-1.75 (m, 1H), 1.61-1.53 (m, 1H), 1.42-1.31 (m, 2H) , 1.11-1.02 (m, 2H). EMAR m / z calc. for C27H32N3O (M + H) +: 414.2545. Found 414.2545.

Example 2

4-Aminomethyl-cyclohexanecarboxylic acid [1- (1-Oxi-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -amide, bistrifluoroacetic acid salt

To a slightly yellow transparent solution of 1D (0.069 g, 0.134 mmol) in chloroform (0.54 ml) was added m-chloroperbenzoic acid (0.039 g, 0.174 mmol). After 2 h, the reaction was diluted with CH2Cl2 and washed with saturated sodium sulphite, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give an off-white solid. This solid was dissolved in 30% TFA in CH2Cl2 (3 ml). After 1 h, the reaction was concentrated. CH2Cl2 was added and the reaction was concentrated again. The above procedure was repeated again giving a yellow residue. Preparative HPLC [21.2 x 100 mm; 10 min gradient .; 20-100% B; 20 ml / min.] Gave Example 2 (0.0328 g, 45%) as a white solid. 1H NMR (500 MHz, MeOD4) δ: 8.40 (d, J = 6.6 Hz, 1H), 7.74 (dd, J = 6.6, 2.8 Hz, 1H), 7.72 ( d, J = 2.8 Hz, 1H), 7.68-7.66 (m, 2H), 7.52-7.44 (m, 3H), 7.32 (d, J = 7.2 Hz , 2H), 7.27 (t, J = 7.4 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 5.76 (dd, J = 9.6, 4, 7 Hz, 1H), 3.48 (dd, J = 13.8, 4.4 Hz, 1H), 2.91 (dd, J = 13.2, 9.9 Hz, 1H), 2.76 ( d, J = 7.2 Hz, 2H), 2.28-2.22 (m, 1H), 1.87-1.81 (m, 3H), 1.68-1.65 (m, 1H) , 1.59-1.51 (m, 1H), 1.43-1.27 (m, 2H), 1.09-0.99 (m, 2H). EMAR m / z calc. for C27H32N3O2 (M + H) +: 430.2495. Found 430.2480.

Example 3

3- (2- {1 - [(4-Aminomethyl-cyclohexanecarbonyl) -amino] -2-phenylethyl} -pyridin-4-yl) -benzoic acid methyl ester, bistrifluoroacetic acid salt.

3A. 4-Chloro-pyridin-2-carboxylic acid methyl ester (according to a modified procedure described by Varlet, D. et al, Heterocycles, 2000, 53 (4), 797): A green suspension of acid 2- Picolinic (50.0 g, 406 mmol) in thionyl chloride (200 ml) was heated to reflux. After 41 h, the clear orange-red solution was cooled to rt and the excess thionyl chloride was removed by rotary evaporation to give a red-orange liquid containing a small amount of solid. Dichloroethane (200 ml) was added and the reaction was concentrated. The above procedure was repeated a second time, giving an orange residue. Ether was added

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Diethyl (1.4 L) giving a suspension and the reaction mixture was cooled to 0 ° C and stirred vigorously as methanol (200 ml) was added. The resulting yellow suspension was stirred at 0 ° C for 30 min, then heated to rt and stirred for 1 h. Filtration provided a yellow solid that was washed with diethyl ether, air dried and dried in vacuo to obtain 21.20 g (95% pure) of solid 1. The filtrate was concentrated to dryness, diethyl ether was added ( 500 ml) and the ultrasonic treatment provided a fine solution. The filtrate provided a yellow solid that was washed with diethyl ether, air dried and dried in vacuo to give 35.5 g (50% pure) of solid 2.

To a cooled suspension (0 ° C) of solid 2 (35.5 g) in CH2Cl2 (500 ml) was added saturated NaHCO3 (300 ml). The suspension was vigorously stirred to dissolve most of the solids. The phases were separated and the aqueous phase was extracted with CH2Cl2 (200 ml). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated, giving an orange liquid weighing 28 g. Column chromatography on silica gel (0-10% ethyl acetate in CH2Cl2 and then CH2Cl2: ethyl acetate 15: 1) yielded 13.0 g of 3A as a white solid. Solid 1 was neutralized as described in the previous procedure, giving 17.4 g more than 3A as a white solid. A total of 30.4 g (44%) of 3A were obtained. 1H NMR (400 MHz, CDCl3) δ: 8.66 (d, J = 5.2 Hz, 1H), 8.15 (d, J = 2.6 Hz, 1H), 7.50 (dd, J = 5.0, 2.0 Hz, 1H), 4.02 (s, 3H).

3B.1- (4-Chloro-pyridin-2-yl) -2-phenyl-ethanone: To a cooled solution (-40 ° C) of 3A (14.5 g, 84.5 mmol) in THF (192 ml) a transparent brown solution (-40 ° C) of 0.6 M benzylmagnesium chloride (142 ml, 84.5 mmol) in THF was rapidly added by cannula. The resulting clear orange solution was stirred at -40 ° C for 1 h and then the reaction was quenched with glacial acetic acid (5.4 ml, 93 mmol). The reaction was allowed to warm to rt. The reaction was partitioned between ethyl acetate and saturated NaHCO3. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated, giving 21.6 g of a red-brown liquid. Column chromatography on silica gel (CH2Cl2: hexane 1.5: 1) gave 3B (10.1 g, 52%) as an orange liquid. 1H NMR (500 MHz, CDCl3) δ: 8.63 (d, J = 5.5 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 5.0, 2.2 Hz, 1H), 7.34-7.28 (m, 4H), 7.27-7.22 (m, 1H), 4.52 (s, 2H). MS 232.1 (M + H) + and 234.0 (M + 2 + H) +.

3C. 1- (4-Chloropyridin-2-yl) -2-phenylethanamine: To a clear yellow solution of 3B (3.96 g, 17.1 mmol) in methanol (34 ml) was added hydroxylamine hydrochloride (3 , 56 g, 51.3 mmol). The suspension was stirred at rt. Over time the hydroxylamine hydrochloride dissolved. After 14 h, the reaction was concentrated to produce a yellow solid. The solid was dissolved in ethyl acetate and washed with saturated NaHCO3. The phases were separated and the aqueous phases were extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated, giving the oxime as a pink solid weighing 4.13 g.

To a transparent solution (5 ° C) transparent yellow oxime (4.13 g) in TFA (39.5 ml) zinc powder (11.18 g, 171 mmol) was added portionwise so that the temperature it remained below 25 ° C. After 1.5 h, the reaction was filtered through a bed of cotton to remove most of the zinc and the zinc residue was rinsed with TFA (50 ml). The filtrate was slowly poured into a vigorously stirred, cooled suspension (0 ° C) of 2M NaOH (700 ml) and CH2Cl2 (500 ml). The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to obtain 3.64 g of the product as a clear orange-brown liquid. Column chromatography (5% methanol in CH2Cl2 with 0.5% ammonium hydroxide) provided 3C (2.93 g, 74%) as a clear yellow oil. 1H NMR (500 MHz, CDCl3) δ: 8.47 (d, J = 5.0 Hz, 1H), 7.317.25 (m, 3H), 7.23-7.20 (m, 1H), 7, 17-7.14 (m, 3H), 4.21 (dd, J = 8.8, 5.5 Hz, 1H), 3.15 (dd, J = 13.8, 5.0 Hz, 1H) , 2.82 (dd, J = 13.8, 8.8 Hz, 1H). MS 233.1 (M + H) + and 235.1 (M + 2 + H) +.

3D {4- [1- (4-Chloropyridin-2-yl) -2-phenyl-ethylcarbamoyl] -cyclohexylmethyl} -carbamic acid tert-butyl ester: To a yellow, transparent solution (0 ° C) of 3C (2 , 93 g, 12.6 mmol) in DMF (42 ml) was added sequentially, Boc-tranexamic acid (3.56 g, 13.8 mmol), HOBt (2.55 g, 18.8 mmol) and EDC (3.62 g, 18.8 mmol). After 15 min at 0 ° C, the reaction was heated to rt. After 4 h, the reaction was poured into vigorously stirred cold water (0 ° C, 200 ml), obtaining a white suspension. Filtration in a Buchner funnel generated a white solid that was washed with water. The white solid was dissolved in CH2Cl2 and washed with water, 0.5 M HCl, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated, giving 11 g as a white solid. Column chromatography on silica gel (CH2Cl2: ethyl acetate 3: 1) gave 3D (3.91 g, 66%) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 8.41 (d, J = 5.4 Hz, 1H), 7.23-7.16

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(m, 4H), 6.93-6.92 (m, 2H), 6.89 (d, J = 1.3 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H) , 5.22 (dd, J = 13.8, 7.7 Hz, 1H), 4.58 (sa, 1H), 3.16 (dd, J = 12.8, 6.0 Hz, 1H), 3.03 (dd, J = 13.4, 7.4 Hz, 1H), 2.97-2.95 (m, 2H), 2.07-2.02 (m, 1H), 1.89- 1.79 (m, 4H), 1.50-1.37 (m, 12H), 0.97-0.88 (m, 2H). EMAR m / z calc. for C26H35N3O3Cl (M + M) +: 472.2367. Found 472.2357.

The separation of the 3D enantiomers on a Daicel Chiralcel OD column gave the enantiomer A [[α] D25 = +1.68 (c = 1.0; CHCl3)] as (+) - 3D and the enantiomer B [[α ] D25 = -1.79 (c = 1.1; CHCl3)] as (-) - 3D.

3E. Example 3: 3D (0.050 g, 0.106 mmol), 3- (methoxycarbonyl) phenylboronic acid (0.0248 g, 0.138 mmol), tris (dibenzylideneacetone) were added in a 1-drachm flame-dried vial (with teflon cap) ) dipaladium (0) (0.0048 g, 0.0053 mmol), tris-t-butylphosphonium tetrafluoroborate (0.0037 g, 0.0127 mmol) and cesium carbonate (0.069 g, 0.212 mmol). The vial was purged with argon for several minutes and degassed dioxane (0.53 ml) was added. The vial was covered with a Teflon coated lid under an argon blanket. The purple suspension was stirred at rt for 1 h and then placed in an oil bath or a preheated stirrer (90 ° C). After 15.5 h, the reaction was cooled to rt, diluted with CH2Cl2, filtered through a 0.45 µm nylon filter and the filtrate was concentrated yielding a yellow residue. The residue was dissolved in CH2Cl2 (2.5 ml) followed by the addition of TFA (0.75 ml). The bright yellow solution was stirred at rt for 45 min and then concentrated. Preparative HPLC [21.2 x 100 mm; 10 min gradient .; 0-100% B; 25 ml / min.] Gave Example 3 (0.035 g, 47%) as a white solid. 1H NMR (500 MHz, MeOD4) δ: 8.66 (d, J = 6.0 Hz, 1H), 8.35 (sa, 1H), 8.17 (d, J = 7.7 Hz, 1H) , 7.99 (d, J = 6.6 Hz, 1H), 7.87 (dd, J = 5.5, 1.6 Hz, 1H), 7.80 (s, 1H), 7.68 ( t, J = 7.7 Hz, 1H), 7.28-7.25 (m, 2H), 7.22-7.19 (m, 3H), 5.33 (dd, J = 8.8, 7.2 Hz, 1H), 3.97 (s, 3H), 3.26 (dd, J = 13.8, 7.2 Hz, 1H), 3.18 (dd, J = 13.8, 8 , 8 Hz, 1H), 2.77 (d, J = 7.2 Hz, 2H), 2.29-2.25 (m, 3H), 1.86-1.84 (m, 3H), 1 , 75-1.73 (m, 1H), 1.60-1.53 (m, 1H), 1.42-1.35 (m, 2H), 1.10-1.04 (m, 2H) . EMAR m / z calc. for C29H34N3O3 (M + H) +: 472.2600. Found 472.2607.

Example 4

4-Aminomethyl-cyclohezanecarboxylic acid {1- [4- (3-Acetylaminophenyl) -pyridin-2-yl] -2-phenylethyl} -amide, bistrifluoroacetic acid salt

This compound was prepared from 3D following the procedures described in 3E using 3acetamidobenzeneboronic acid instead of 3- (methoxycarbonyl) phenylboronic acid. 1H NMR (500 MHz, MeOD4) δ: 8.65 (d, J = 5.5 Hz, 1H), 8.27 (s, 1H), 8.03-8.01 (m, 2H), 7, 58-7.53 (m, 3H), 7.28-7.25 (m, 2H), 7.23-7.19 (m, 3H), 5.34 (t, J = 8.0 Hz, 1H), 3.28 (d, J = 8.3 Hz, 2H), 2.76 (d, J = 6.6 Hz, 2H), 2.31-2.26 (m, 1H), 2, 18 (s, 3H), 1.86-1.84 (m, 3H), 1.77-1.74 (m, 1H), 1.57-1.55 (m, 1H), 1.39- 1.34 (m, 2H), 1.09-1.02 (m, 2H). EMAR m / z calc. for C29H35N4O2 (M + H) +: 471.2760. Found 471.2772.

Example 5

4-Aminomethyl-cyclohexanecarboxylic acid {1- [4- (3-Hydroxyphenyl) -pyridin-2-yl] -2-phenylethyl} -amide, bistrifluoroacetic acid salt

This compound was prepared from 3D following the procedures described in 3E using 3-hydroxyphenylboronic acid instead of 3- (methoxycarbonyl) phenylboronic acid. 1H NMR (500 MHz, DMSO-d6) δ: 8.60 (d, J = 5.5 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.66 (sa, 4H), 7.61 (d, J = 4.4 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 7.26-7.20 (m, 4H), 7, 18-7.16 (m, 2H), 7.12 (s, 1H), 6.90 (dd, J = 7.7, 2.2 Hz, 1H), 5.22-5.18 (m, 1H), 3.17 (dd, J = 13.8, 5.0 Hz, 1H), 2.98 (dd, J = 13.8, 9.9 Hz, 1H), 2.64-2.61 (m, 2H), 2.13-2.09 (m, 1H), 1.73-1.65 (m, 3H), 1.57-1.55 (m, 1H), 1.46-1 , 40 (m, 1H), 1.22-1.12 (m, 2H), 0.93-0.86 (m, 2H). EMAR m / z calc. For C27H32N3O2 (M + H) +: 430.2495. Found 430.2493.

Example 6

4-Aminomethyl-cyclohexanecarboxylic acid {1- [4- (3-Aminophenyl) -pyridin-2-yl] -2-phenylethyl} -amide, tristrifluoroacetic acid salt

This compound was prepared from 3D following the procedures described in 3E using 3-aminophenylboronic acid hydrochloride instead of 3- (methoxycarbonyl) phenylboronic acid. 1H NMR (500 MHz, MeOD4) δ: 8.64 (d, J = 5.5 Hz, 1H), 7.85 (d, J = 5.5 Hz, 1H), 7.82 (s, 1H) , 7.51 (t, J = 8.0 Hz, 1H), 7.48-7.46 (m, 1H), 7.43 (sa, 1H), 7.277.24 (m, 3H), 7, 21-7.17 (m, 3H), 5.32 (t, J = 8.0 Hz, 1H), 3.24-3.22 (m, 2H), 2.76 (d, J = 7, 2 Hz, 2H), 2.29-2.24 (m, 1H), 1.85-1.73 (m, 4H), 1.57-1.54 (m, 1H), 1.40-1 , 34 (m, 2H), 1.08-1.01 (m, 2H). EMAR m / z calc. for C27H33N4O

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(M + H) +: 429.2654. Found 429.2658.

Example 7

4-Aminomethyl-cyclohexanecarboxylic acid [(S) -2-Phenyl-1- (4-phenyl-pyrimidin-2-yl) -ethyl] -amide, trifluoroacetic acid salt

7A. ((S) -1-carbamimidoyl-2-phenylethyl) -carbamic acid tert-butyl ester: To a solution containing (S) -terc-butyl (500 mg, 2.05 mmol) 1cyano-2-phenylethylcarbamate in MeOH (25 ml), N-acetylcysteine (335 mg, 2.05 mmol) and NH4OAc (316 mg, 4.10 mmol) were added. The reaction mixture was heated at reflux overnight. More N-acetylcysteine (335 mg, 2.05 mmol) and NH4OAc (335 mg, 2.05 mmol) were added to the reaction mixture and refluxing was continued for an additional 24 h. The reaction was cooled to rt and evaporated in vacuo. The residue was dissolved again in MeOH / H2O (9: 1) containing 0.1% TFA and purified by preparative HPLC to provide 228 mg (33%) of 7A. MS 264.1 (M + H) +.

7B.1-Phenyl-propinone: To a solution of 1-phenylprop-2-in-1-ol (0.5 g, 3.8 mmol) in CH2Cl2 (10 ml) was added Dess-Martin periodine (1, 6 g, 3.8 mmol). The reaction was stirred at rt for 5 min. The reaction was diluted with CH2Cl2 (10 ml) and washed with a 1: 1 mixture of 10% aqueous Na2S2O3 and saturated aqueous NaHCPO3 (200 ml), water and brine. The organic phase was dried over MgSO4, filtered and evaporated in vacuo to provide 1.12 g of a light brown solid. The crude product was purified by silica gel chromatography to provide 600 mg of a white solid that was used in the next step without further purification. 1H NMR (500 MHz, d-CHCl3) δ 3.45 (s, 1H) 7.51 (t, J = 7.97 Hz, 2H) 7.64 (t, J = 7.42 Hz, 1H) 8 , 17 (d, J = 7.15 Hz, 2H).

7C. [(S) -2-Phenyl-1- (4-phenyl-pyrimidin-2-yl) -ethyl] -carbamic acid tert-butyl ester: 7A (57 mg, 0.15 mmol), 7B ( 16 mg, 0.12 mmol) and Na2CO3 (31 mg, 0.30 mmol) in acetonitrile and heated at 120 ° C for 40 min using microwave radiation. The reaction was cooled to rt and filtered. The filtrate was dried in vacuo yielding 75 mg (100%) of 7C which was taken to the next stage without further purification. MS 276.1 (M + 1) +.

7D. (S) -2-Phenyl-1- (4-phenylpyrimidin-2-yl) ethanamine: 7C (56 mg, 0.15 mmol) was dissolved in CH2Cl2 (2.7 mL) and treated with TFA (0.3 ml, 10% v / v) for 24 hours at rt. The solvent and TFA were evaporated in vacuo and the residue was dissolved again in MeOH. The MeOH was evaporated, yielding 59 mg (100%) of b. MS 276.1 (M + 1) +.

7E. {4 - [(S) -2-Phenyl-1- (4-phenyl-pyrimidin-2-yl) -ethylcarbamoyl] -cyclohexylmethyl} -carbamic acid tert-butyl ester: 7D (59 mg, 0.15) mmol), N-Boc-tranexamic acid (39 mg, 0.15 mmol) and HOBt (24 mg, 0.18 mmol) in DMF (1 ml). N-methylmorpholine (61 mg, 0.6 mmol) and EDCI (35 mg, 0.18 mmol) were added sequentially and the reaction mixture was stirred at rt for 4 h. The reaction was diluted with EtOAc, washed with an aqueous solution of sodium chloride (5 x), dried over MgSO4, filtered and evaporated to dryness, yielding 75 mg (97%) of 7E. MS 515.1 (M + H) +.

7F. Example 7: 7E was treated according to the procedure described for 1E. The crude product was dissolved again in MeOH / H2O (9: 1) containing 0.1% TFA and purified by preparative HPLC to provide 40 mg (42%) of Example 7. 1H NMR (500 MHz, d4 -MeOH) δ1.40 (m, 2H) 1.57 (m, 1H) 1.76 (da, J = 13.20 Hz, 1H) 1.84 (da, J = 12.65 Hz, 3H) 2 , 29 (tt, J = 12.10.3.57 Hz, 1H) 2.77 (d, J = 6.60 Hz, 2H) 3.14 (dd, J = 13.75, 8.80 Hz, 1H) 3.37 (dd, J = 13.92, 6.25 Hz, 1H) 5.42 (dd, J = 8.80, 6.05 Hz, 1H) 7.16 (m, 3H) 7, 21 (m, 2H) 7.53 (m, 3H) 7.83 (d, J = 5.50 Hz, 1H) 8.17 (d, J = 7.70 Hz, 2H) 8.73 (d, J = 5.50 Hz, 1H). EMAR m / z calc. for C26H31N4O (M + H) +: 415.2498. Found 415.2488.

Example 8

4-Aminomethylcyclohexanecarboxylic acid [(S) -1- (6-Oxo4-phenyl-1,6-dihydro-pyrimidin-2-yl) -2-phenyl-ethyl] -amide, trifluoroacetic acid salt

8A: [(S) -1- (6-Oxo4-phenyl-1,6-dihydro-pyrimidin-2-yl) -2-phenylethyl] -carbamic acid tert-butyl ester: 7A (50 mg, 0 , 13 mmol), ethyl 3-phenylpropiolate (46 mg, 0.26 mmol) and Hunig's base (34 mg, 0.26 mmol) in EtOH (1 mL) and heated at reflux for 3 days. The reaction was cooled to rt and the solvent was evaporated to dryness in vacuo. The residue was dissolved again in MeOH / H2O (9: 1) containing 0.1% TFA and isolated by preparative HPLC, yielding 16 mg of the desired product (31% yield). MS 392.1 (M + H) +.

8B. Example 8: 8A (16 mg, 0.041 mmol) was converted into Example 8 using the procedure described in 7D-F with the exception that HOAt was used instead of HOBt. 1H NMR (500 MHz, d4-MeOH) δ 1.05 (m, 2H) 1.39 (m, 2H) 1.56

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(m, 1H) 1.73 (da, J = 12.10 Hz, 1H) 1.85 (ta, J = 14.57 Hz, 3H) 2.26 (tt, J = 12.40, 3.60 Hz, 1H) 2.76 (d, J = 7.15 Hz, 2H) 3.13 (dd, J = 13.20, 8.0 Hz, 1H) 5.06 (m, 1H) 6.74 ( s, 1H) 7.23 (m, 5H) 7.48 (m, 3H) 8.05 (d, J = 8.25 Hz, 2H) 8.47 (d, J = 7.70 Hz, 0, 5H). EMAR m / z calc. for C26H30N4O2 (M + H) +: 431.2447, Found 431.2467.

Example 10

3- (2- {1 - [(4-Aminomethyl-cyclohexanecarbonyl) -amino] -2-phenyl-ethyl} -pyridin-4-yl) -benzoic acid, bistrifluoroacetic acid salt

A clear and colorless solution of 3E (0.013 g, 0.018 mmol) in MeOH (0.55 ml) and 1.0 N NaOH (0.15 ml, 0.15 mmol) was heated to 60 ° C. After 1 h, the reaction was cooled to rt, acidified with TFA and concentrated. Preparative HPLC [21.2 x 100 mm; 10 min gradient .; 0-100% B, 25 ml / min] provided Example 10 (0.013 g, quantitative) as a white solid. 1H NMR (500 MHz, CD3OD) δ: 8.72 (d, J = 6.0 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H) , 8.11-8.06 (m, 3H), 7.72 (t, J = 8.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.24-7.21 (m, 3H), 5.38 (t, J = 8.0 Hz, 1H), 3.31-3.28 (m, 2H), 2.77 (d, J = 7.2 Hz, 2H) , 2.32-2.28 (m, 1H), 1.86-1.84 (m, 3H), 1.77-1.75 (m, 1H), 1.58-1.55 (m, 1H), 1.42-1.32 (m, 2H), 1.10-1.02 (m, 2H). EMAR m / z calc. for C28H32N3O3 (M + H) +: 458.2444. Found 458.2453.

Example 13

4-Aminomethyl-cyclohexanecarboxylic acid {2-phenyl-1- [4- (1H-pyrrol-3-yl) -pyridin-2-yl] -ethyl} -amide, bistrifluoroacetic acid

13A. 4-Aminomethylcyclohexanecarboxylic acid {2-phenyl-1- [4- (1-triisopropylsilanyl-1H-pyrrol-3-yl) -pyridin-2-yl] -ethyl} -amide, bis-trifluoroacetic acid salt: This compound it was prepared from 3D following the procedures described in example 3E using 1- (triisopropylsilyl) pyrrol-3-boronic acid instead of 3 (methoxycarbonyl) phenylboronic acid to give 13A (0.013 g, 16%) as a residue of Dun. MS 559.3 (M + H) +.

13B. Example 13: To a transparent brown solution of 13A (0.013 g, 0.0165 mmol) in THF (0.23 ml) was added 1.0 M TBAF in THF (0.046 ml, 0.046 mmol). After 30 min, a few drops of water were added and the reaction was concentrated to give a brown residue. Preparative HPLC [21.2 x 100 mm; 8 min gradient .; 0-100% B, 25 ml / min.] Provided Example 13 (0.0044 g, 42%) as an off-white solid. 1H NMR (500 MHz, CD3OD) δ: 8.29 (d, J = 6.6 Hz, 1H), 7.92 (sa, 1H), 7.89 (dd, J = 6.6, 1.6 Hz, 1H), 7.75 (t, J = 1.6 Hz, 1H), 7.29-7.26 (m, 2H), 7.24-7.20 (m, 3H), 6.96 (dd, J = 3.3, 1.6 Hz, 1H), 6.76 (dd, J = 3.3, 1.6 Hz, 1H), 5.23 (t, J = 8.2 Hz, 1H), 3.27-3.21 (m, 2H), 2.77 (d, J = 7.2 Hz, 2H), 2.29-2.25 (m, 1H), 1.89-1 , 83 (m, 3H), 1.76-1.73 (m, 1H), 1,701.64 (m, 1H), 1.43-1.33 (m, 2H), 1.10-1.04 (m, 2H). EMAR m / z calc. for C25H31N4O (M + H) +: 403.2498. Found 403.2483.

Example 15

4-Aminomethyl-cyclohexanecarboxylic acid [1- (2'-Amino- [4,4 '] bipyridinyl-2-yl) -2-phenyl-ethyl] -amide, tris-trifluoroacetic acid salt

In a vial that can be hermetically sealed with a Teflon cap, 3D (0.094 g, 0.2 mmol), Pd (dppf) Cl2CH2Cl2 complex (0.122 g, 0.15 mmol), K3PO4 (0.106 g, 0.5) was added mmol), 2-fluropyridin-4-boronic acid (0.042 g, 0.3 mmol) and DMSO (3 ml). The mixture was degassed by bubbling argon for 10 min, the tube was sealed and the reaction was placed in a preheated oil bath (95 ° C). After 18 h, the reaction mixture was cooled to rt, diluted with EtOAc (10 ml), washed with water (10 ml) and brine (10 ml), dried over Na2SO4, filtered and concentrated. The residue was dissolved in 50% TFA / CH2Cl2 (2 ml). After 18 h, the reaction was concentrated. Preparative HPLC [30 x 100 mm, 12 min. Gradient, 30 to 100% B, 30 ml / min.) Provided 0.096 g of bipyridyl derivative as a white solid.

A suspension of bipyridyl derivative was concentrated in NH4OH (5 ml), microwaved at 140 ° C for 140 min. The reaction mixture was cooled to rt, filtered and concentrated. Preparative HPLC [30 x 100 mm, 10 min. Gradient, 20 to 100% B, 30 ml / min.) Gave Example 15 (0.0030 g, 1.9%) as a colored solid White. 1H NMR (500 MHz, CD3OD) δ: 0.98-1.09 (m, 2H), 1.33-1.44 (m, 2H), 1.54-1.59 (m, 1H), 1 , 72-1.85 (m, 4H), 2.21-2.27 (m, 1H), 2.76 (d, J = 7.2 Hz, 2H), 3.12-3.23 (m , 2H), 5.30-5.33 (m, 1H), 7.10-7.23 (m, 7H), 7.50 (s, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.94 (d, J = 6.6 Hz, 1H), 8.74 (d, J = 5.5 Hz, 1H). EMAR m / z calc. for C26H32N5O (M + H) +: 430.2607, Found 430.2601.

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Example 21

4-Aminomethyl-cyclohexanecarboxylic acid {1- [4- (4-Cyano-3-fluoro-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -amide, bis-trifluoroacetic acid salt

In a flame-dried flask 3D (0.150 g, 0.318 mmol), 4-cyano-3-fluorophenylboronic acid (0.131 g, 0.795 mmol), tris (dibenzylideneacetone) dipaladium (0) (0.0146 g, 0, were added 0159 mmol), tri-t-butylphosphonium tetrafluoroborate (0.0111 g, 0.038 mmol) and cesium carbonate (0.207 g, 0.636 mmol). The flask was purged with argon for several minutes and degassed dioxane (1.6 ml) was added. The purple suspension was stirred at rt for 1 h and then placed in a preheated oil bath (90 ° C). After 14 h, the reaction was cooled to rt, diluted with CH2Cl2, filtered through a 0.45 µm nylon filter and the filtrate was concentrated yielding a yellow solid. The solid was dissolved in CH2Cl2, NH4OH was added and the biphasic mixture was vigorously stirred for 10 min. The phases were separated and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give an off-white solid weighing 0.200 g. The solid was dissolved in 30% TFA in CH2Cl2 (10 ml). The reaction was stirred at rt for 1 h and then concentrated. HPLC [21.2x 100 mm; 8 min gradient .; B at 0100%; 25 ml / min.] Gave Example 21 (0.146 g, 67%) as a white solid. 1H NMR (500 MHz, CD3OD) δ: 8.70 (d, J = 5.0 Hz, 1H), 7.93-7.90 (m, 1H), 7.77 (dd, J = 5.5 , 1.6 Hz, 1H), 7.74 (dd, J = 10.4, 1.6 Hz, 1H), 7.71-7.68 (m, 2H), 7.25-7.23 ( m, 2H), 7.20-7.17 (m, 3H), 5.33 (dd, J = 8.8, 7.2 Hz, 1H), 3.24 (dd, J = 13.5, 6.9 Hz, 1H), 3.16 (dd, J = 13.5, 8.5 Hz, 1H), 2.76 (d, J = 7.2 Hz, 2H), 2.28-2, 23 (m, 1H), 1.85-1.72 (m, 4H), 1.58-1.54 (m, 1H), 1.41-1.34 (m, 2H), 1.08- 1.00 (m, 2H). 19F NMR (470 MHz, CD3OD) δ: -77.27, -108.45, EMAR m / z calc. for C28H30N4OF (M + H) +: 457.2404. Found 457.2420.

Example 22

4-Aminomethyl-cyclohexanecarboxylic acid {1- [4- (4-Cyano-3-fluoro-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -amide, bis-trifluoroacetic acid salt

In a flame-dried flask (+) - 3D (0.258 g, 0.546 mmol), 4-cyano-3-fluorophenylboronic acid (0.225 g, 1.36 mmol), tris (dibenzylideneacetone) dipaladium (0) (0) (0) (0) was added , 0247 g, 0.027 mmol), tri-t-butylphosphonium tetrafluoroborate (0.0188 g, 0.065 mmol) and cesium carbonate (0.355 g, 1.09 mmol). The flask was purged with argon for several minutes and degassed dioxane (2.7 ml) was added. The purple suspension was stirred at rt for 1 h and then placed in a preheated oil bath (90 ° C). After 14 h, the reaction was cooled to rt, diluted with CH2Cl2 and filtered through a 0.45 µm nylon filter and the filtrate was concentrated yielding a yellow residue weighing 0.419 g. The residue was dissolved in CH2Cl2 (10 ml) followed by the addition of TFA (4.0 ml). The reaction was stirred at rt for 1 h and then concentrated. Preparative HPLC [30 x 100 mm; 12 min gradient .; 25-100% B; 30 ml / min.] Gave Example 22 (0.119 g, 32%) as a white solid.

Example 23

4-Aminomethyl-cyclohexanecarboxylic acid {1- [4- (4-Cyano-3-fluoro-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -amide, bis-trifluoroacetic acid salt

In a flame-dried flask (-) - 3D (0.234 g, 0.495 mmol), 4-cyano-3-fluorophenylboronic acid (0.204 g, 1.24 mmol), tris (dibenzylideneacetone) dipaladium (0) (0) (0) (0) was added , 0226 g, 0.025 mmol), tri-t-butylphosphonium tetrafluoroborate (0.0172 g, 0.059 mmol) and cesium carbonate (0.322 g, 0.99 mmol). The flask was purged with argon for several minutes and degassed dioxane (2.5 ml) was added. The purple suspension was stirred at rt for 1 h and then placed in a preheated oil bath (90 ° C). After 14 h, the reaction was cooled to rt, diluted with CH2Cl2, filtered through a 0.45 µm nylon filter and the filtrate was concentrated to yield a yellow residue weighing 0.420 g. The residue was dissolved in CH2Cl2 (10 ml), followed by the addition of TFA (4.0 ml). The reaction was stirred at rt for 1 h and then concentrated. Preparative HPLC [30 x 100 mm; 12 min gradient .; 25-100% B; 30 ml / min.] Gave Example 23 (0.142 g, 42%) as a white solid.

Alternative coupling procedure: In a flame-dried flask, (-) - Non-racemic chiral 3D (0.300 g, 0.635 mmol), 4-cyano-3-fluorophenylboronic acid (0.262 g, 1.59 mmol), Pd (dppf) Cl2CH2Cl2 (0.0518 g, 0.0635 mmol) and K3PO4 (0.337 g, 1.59 mmol). The flask was purged with argon for several minutes and then DMSO (degassed, 4.20 ml) was added. The suspension was heated to 90 ° C. After 15 h, the reaction was cooled to rt and additional 4-cyano-3-fluorophenylboronic acid (0.105 g, 0.635 mmol), Pd (dppf) Cl2CH2Cl2 (0.0518 g, 0.0635 mmol) and K3PO4 ( 0.134 g, 0.635 mmol). Argon was bubbled through the reaction for 5 min. and then the reaction was put in a preheated oil bath (90 ° C). After 5 h, the reaction was cooled to rt,

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it was diluted with CH2Cl2 (400 ml), washed with water, 2.0 N Na2CO3 and brine, dried over MgSO4, filtered and concentrated, yielding 0.575 g as a red-brown solid. The red-brown solid was dissolved in 30% TFA / CH2Cl2 (30 ml). After 30 min, the reaction was concentrated. Preparative HPLC [30 x 250 mm, 30 min gradient, 30-100% B, 30 ml / min.] Provided Example 23 (0.234 g, 54%) as a white solid.

Example 25

4-Aminomethyl-cyclohexanecarboxylic acid, bis-trifluoroacetic acid, {1- [4- (3-Amino-1H-indazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide

A suspension of Example 21 (0.0261 g, 0.038 mmol) in n-butanol (0.38 ml) and hydrazine monohydrate (0.14 ml, 4.56 mmol) was microwaved at 150 ° C for 10 min. The resulting clear yellow solution was concentrated. Preparative HPLC [21.2 x 100 mm; 8 min gradient .; 0-100% B, 25 ml / min] provided Example 25 (0.0195 g, 63%) as a yellow solid. 1H NMR (500 MHz, CD3OD) δ: 8.69 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.92 (dd, J = 5.8, 1.9 Hz, 1H), 7.85 (sa, 1H), 7.75 (sa, 1H), 7.49 (dd, J = 8.5, 1.4 Hz, 1H), 7.28-7.25 (m, 2H), 7.22-7.19 (m, 3H), 5.35 (t, J = 7.7 Hz, 1H), 3.25 (d, J = 8.2 Hz, 2H), 2.77 (d, J = 6.6 Hz, 2H), 2.30-2.25 (m, 1H), 1.86-1.74 (m, 4H), 1.59-1.54 (m, 1H), 1.43-1.33 (m, 2H), 1.10-1.01 (m, 2H). EMAR m / z calc. for C28H33N6O (M + H) +: 469.2716, found 469.2699.

Example 26

(+) - 4-Aminomethylcyclohexanecarboxylic acid, bis-trifluoroacetic acid {1- [4- (3-Amino-1H-indazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide

A suspension of Example 23 (0.095 g) in n-butanol (3.0 ml) and hydrazine monohydrate (1.0 ml) was microwaved at 150 ° C for 10 min. The resulting clear bright yellow solution was concentrated. Preparative HPLC [21.2 x 100 mm; 8 min gradient .; 20-100% B, 20 ml / min.] Gave Example 26 (0.069 g, 71%) as a yellow solid. [α] D25.2 = +5.52 (c = 0.80; MeOH).

Example 27

4-Aminomethylcyclohexanecarboxylic acid {bis-trifluoroacetic acid {1- [4- (3-Amino-1,2-benzoisoxazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide

To a clear and colorless solution of acetohydroxamic acid (0.0148 g, 0.197 mmol) in DMF (0.66 ml) was added potassium tert-butoxide (0.0221 g, 0.197 mmol). The resulting white suspension was vigorously stirred for 30 min and then Example 21 (0.030 g, 0.0438 mmol) was added. After 7.5 h, the reaction was stopped by adding brine and extracted with EtOAc (5 x). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated, giving a colorless clear residue. Preparative HPLC [21.2 x 100 mm; 8 min gradient .; 0-100% B, 20 ml / min.] Provided Example 27 (0.0073 g, 20%) as a pale yellow solid 1 H NMR (500 MHz, CD3OD) δ: 8.69 (d, J = 6.0 Hz, 1H), 8.00 (dd, J = 5.8, 2.0 Hz, 1H), 7.97 (sa, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.65 (dd, J = 8.2, 1.6 Hz, 1H), 7.29-7.26 (m, 2H), 7.23 -7.20 (m, 3H), 5.36 (t, J = 8.0 Hz, 1H), 3.28-3.25 (m, 2H), 2.77 (d, J = 7.2 Hz, 2H), 2.31-2.26 (m, 1H), 1,851.82 (m, 3H), 1.76-1.74 (m, 1H), 1.57-1.54 (m, 1H), 1.41-1.34 (m, 2H), 1.10-1.04 (m, 2H). EMAR m / z calc. for C28H32N5O2 (M + H) +: 470.2555, found 470.2549.

Example 28

(+) - 4-Aminomethylcyclohexanecarboxylic acid {- [4- (3-Amino-1,2-benzoisoxazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide, bis- trifluoroacetic

Example 28 was prepared from Example 22 following the procedures described in Example 27. [α] D25 = +3.14 (c = 1.0; MeOH).

Example 29

(-) - 4-Aminomethylcyclohexanecarboxylic acid {- [4- (3-Amino-1,2-benzoisoxazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide, bis- trifluoroacetic

Example 29 was prepared from 23 following the procedures described in Example 27.

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Example 33

4-Aminomethyl-cyclohexanecarboxylic acid {1- [4- (3-Hydroxy-1H-indazol-5-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide, bis-trifluoroacetic acid salt

33A. 2-Fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -benzoic acid methyl ester: A suspension of 5-bromo-2-fluorobenzoic acid (1,116 g , 5.1 mmol) and thionyl chloride (1.49 ml, 20.4 mmol) in 1,2-dichloroethane (10 ml) was heated to 85 ° C. After 3.5 h, the reaction was cooled to rt and concentrated. Methanol (10 ml) was added carefully and the resulting solution was stirred at rt. After 30 min, the reaction was concentrated. The residue was dissolved in EtOAc (25 ml), washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give the ester (1.18 g, 99%) as a colorless oil. MS 233.0 (M + H) +.

In a round bottom flask equipped with a condenser, the ester (0.7 g, 3.0 mmol), Pd (dppf) Cl2 · CH2Cl2 complex (0.073 g, 0.090 mmol), KOAc (0.884 g, 9.0) was added mmol), bis (pinacolato) diboro (1,524 g, 6.0 mmol) and DMSO (20 ml). The mixture was degassed by bubbling argon for 10 min and then the reaction was heated to 80 ° C. After 4 h, the reaction was cooled to rt, diluted with EtOAc, washed with water and brine, Na2SO4 copper dried, filtered and concentrated. Column chromatography on silica gel (gradient elution 010% EtOAc / Hexane, then 10% EtOAc / Hexane) yielded 33A (1.2 g) as a white solid. MS 281.09 (M + H) +.

33B. Example 33: In a hermetically sealed tube complex Pd (dppf) Cl2 · CH2Cl2 (0.016 g, 0.15 mmol), K3PO4 (0.106 g, 0.5 mmol), 33A (0.168 g, 0.6 mmol) was added, 3D (0.095 g, 0.2 mmol) and DMSO (3 ml). The mixture was degassed by bubbling argon for 10 min and then the reaction was heated to 95 ° C. After 18 h, the reaction was cooled to rt, diluted with EtOAc (10 ml), washed with water (10 ml) and brine (10 ml), dried over Na2SO4, filtered and concentrated. The residue was dissolved in 50% TFA / CH2Cl2 (2 ml) and stirred at rt. After 2 h, the reaction was concentrated. HPLC (30 x 100 mm, 12 min. Gradient, 30 to 100% B, 30 ml / min.) Provided the biphenyl compound (0.054 g) as a white solid.

A suspension of the biphenyl compound (0.054 g) in 1-butanol (3 ml) and hydrazine monohydrate (1 ml) was heated in a microwave at 150 ° C for 10 min. The reaction was cooled to rt and concentrated. Preparative HPLC (21.2, x 100 mm, 8 min. Gradient, 20 to 100% B, 20 ml / min.) Provided Example 33 (0.008 g, 6%) as a yellow solid. . 1H NMR (500 MHz, CD3OD) δ: 1.03-1.10 (m, 2H), 1.32-1.43 (m, 2H), 1.54-1.60 (m, 1H), 1 , 75-1.77 (m, 1H), 1.84-1.86 (m, 3H), 2.27-2.32 (m, 1H), 2.77 (d, J = 7.1 Hz , 2H), 3.27-3.34 (m, 2H), 5.33-5.36 (m, 1H), 7.21-7.29 (m, 5H), 7.48 (d, J = 8.8 Hz, 1H), 7.91 (dd, J = 1.6 Hz, 8.8 Hz, 1H), 8.05-8.06 (m, 2H), 8.26 (d, J = 1.6 Hz, 1H), 8.59 (d, J = 6.6 Hz, 1H). HRMS m / z Calc. For C28H32N5O2 (M + H) +: 470.2555 Found 470.2566.

Alternative preparation of Example 33: A mixture of Example 52 in 1-butanol and hydrazine monohydrate was heated in the microwave at 160 ° C for 1 h. Concentration and purification by preparative HPLC as described above provided Example 33.

Example 34

[1- (6-Methoxy-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -amide of 4-aminomethyl-cyclohexanecarboxylic acid, bistrifluoroacetic acid salt

34A. 2-Methoxy-6-methyl-4-phenylpyridine: A solution of 6-methyl-4-phenyl-1H-pyridin-2-one (0.185 g, 1 mmol, was prepared according to a modified procedure described by Thesing, J and Muller, A. Chem. Ber., 1957, 90, 711,) in chloroform (4 ml), Ag2CO3 (0.386 g, 1.4 mmol) and iodomethane (0.62 ml, 10 mmol) were added. The resulting suspension was stirred in the dark for 18 h. The reaction was filtered and the solid was washed with CH2Cl2. The filtrate was concentrated to give a residue. Column chromatography on silica gel (0-10% EtOAc / Hexane) provided 34A (0.14 g, 70%) as a clear and colorless oil. MS 200.2 (M + H) +.

34B. 6-Methoxy-4-phenyl-pyridin-2-carbaldehyde: A solution of the compound of 34A (0.14 g, 0.7 mmol)), Nbromosuccinimide (0.25 g, 1.4 mmol) and benzoyl peroxide ( 0.0085 g, 0.035 mmol) in CCl4 (3 ml) was heated to 80 ° C. After 24 h, the reaction was cooled to rt, diluted with EtOAc (10 mL), washed with water, saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give a brown residue. The brown residue was dissolved in morpholine (2 ml), heated at 60 ° C for 3 h and then cooled to rt. The reaction mixture was diluted with EtOAc (15 ml), washed with a 5% citric acid solution (until the aqueous phase had a pH 4), saturated NaHCO3 and brine, dried over Na2SO4, filtered and filtered. concentrated. Column chromatography on silica gel (0-5% EtOAc) provided 34B (0.055 g, 37%) as a white solid. 1H NMR (400

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MHz, CDCl3) δ: 4.08 (s, 3H), 7.18 (d, J = 1.3 Hz, 1H), 7.46-7.52 (m, 3H), 7.64-7, 67 (m, 2H), 7.83 (d, J = 1.3 Hz, 1H), 10.02 (s, 1H). HRMS m / z Calc. For C13H12NO2 (M + H) +: 214.0868. Found 214.0868.

34C. 1- (6-Methoxy-4-phenyl-pyridin-2-yl) -2-phenyl-ethylamine, bis-trifluoroacetic acid salt: To a cooled solution (0 ° C) of 34B (0.055 g, 0.26 mmol) in THF (0.52 ml) 1.0 M LiHMDS in THF (0.28 ml, 0.28 mmol) was added. After 15 min, 2.0 M BnMgCl in THF (0.15 ml, 0.30 mmol) was added dropwise. The resulting solution was stirred at 0 ° C for 30 min and then quenched with saturated NH4Cl (1 ml) and then diluted with water. The reaction was extracted with EtOAc (15 ml). The combined organic phases were washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. Preparative HPLC (30 x 100 mm, 12 min. Gradient, 30 to 100% B, 30 ml / min.) Provided 34C (0.067 g, 48%) as a white solid. 1H NMR (500 MHz, CD3OD) δ: 3.24 (dd, J = 9.3 Hz, 13.2 Hz, 1H), 3.30-3.35 (m, 1H), 4.04 (s, 3H), 4.65 (dd, J = 6.1 Hz, 8.8 Hz, 1H), 6.82 (d, J = 1.1 Hz, 1H), 6.98 (d, J = 1, 1 Hz, 1H), 7.11-7.13 (m, 2H), 7.23-7.30 (m, 3H), 7.39-7.49 (m, 5H). HRMS m / z Calc. For C20H21N2O (M + H) +: 305.1654. Found 305.1645.

34D. Example 34: To a solution of 34C (0.067 g, 0.13 mmol) in DMF (2 ml) was added Boc-tranexamic acid (0.036 ml, 0.14 mmol), triethylamine (0.088 ml, 0.63 mmol) , HOBt (0.026 g, 0.19 mmol) and EDCI (0.036 g, 0.19 mmol). The reaction mixture was stirred at rt for 2 h, at 40 ° C for 2 h and then at rt for 18 h. The reaction mixture was diluted with EtOAc (25 ml), washed with water, saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to provide the amide (0.090 g) as a yellow solid. MS 544.4 (M + H) +.

The yellow solid (0.045 g, 0.08 mmol) was dissolved in 50% TFA / CH2Cl2 (2 ml). After 2 h, the reaction was concentrated to give a residue. Preparative HPLC (30 x 250 mm, 20 min. Gradient, 30 to 100% B, 30 ml / min.) Provided Example 34 (0.024 g, 57%) as a white solid. 1H NMR (500 MHz, CD3OD) δ: 1.01-1.09 (m, 2H), 1.34-1.48 (m, 2H), 1.53-1.60 (m, 1H), 1 , 70-1.73 (m, 1H), 1.83-1.85 (m, 3H), 2.22-2.29 (m, 1H), 2.76 (d, J = 7.2 Hz , 2H), 3.07 (dd, J = 8.8 Hz, 13.8 Hz, 1H), 3.27-3.31 (m, 1H), 4.00 (s, 3H), 5.21 -5.24 (m, 1H), 6.91 (d, J = 1.1 Hz, 1H), 7.04 (d, J = 0.8 Hz, 1H), 7.15-7.25 ( m, 5H), 7.40-7.47 (m, 3H), 7.58-7.60 (m, 2H). HRMS m / z Calc. For C28H34N3O2 (M + H) +: 444.2651. Found 444.2646.

Example 35

4-Aminomethyl-cyclohexanecarboxylic acid [1- (6-Oxo-4-phenyl-1,6-dihydro-pyridin-2-yl) -2-phenyl-ethyl] -amide, trifluoroacetic acid salt

To a cooled solution (0 ° C) of the 34D amide (0.045 g, 0.08 mmol) in CH2Cl2 (1 ml) was added BBr3 (0.078 ml, 0.8 mmol). The reaction was heated to rt. After 2 h, the reaction was cooled to 0 ° C, quenched with MeOH and then concentrated. Preparative HPLC (30 x 250 mm, 20 min. Gradient, 30 to 100% B, 30 ml / min.) Produced the bis-TFA salt of the cyclohexylmethylamine derivative (0.034 g, 61%) as a solid White color.

A solution of the bis-TFA salt of the cyclohexylmethylamine derivative (0.028 g, 0.042 mmol) and BBr3 (1.0 M in CH2Cl2, 0.42 ml, 0.42 mmol) in CH2Cl2 (1 ml) was heated to 60 ° C . After 2 h, the reaction was cooled to 0 ° C, quenched with MeOH and concentrated. Preparative HPLC (21.2 x 100 mm, 8 min. Gradient, 20 to 100% B, 20 ml / min.) Provided Example 35 (0.008 g, 35%) as a pink solid. 1H NMR (500 MHz, CD3OD) δ: 0.961.09 (m, 2H), 1.27-1.46 (m, 2H), 1.51-1.62 (m, 2H), 1.81-1 , 85 (m, 3H), 2.15-2.22 (m, 1H), 2.76 (d, J = 7.2 Hz, 2H), 3.02 (dd, J = 9.9 Hz, 13.7 Hz, 1H), 3.23 (dd, J = 6.0 Hz, 13.7 Hz, 1H), 5.11 (dd, J = 6.0 Hz, 9.9 Hz, 1H), 6.62 (s, 2H), 7.18-7.31 (m, 5H), 7.46-7.51 (m, 3H), 7.60-7.62 (m, 2H). EMAR m / z Calc. For C27H32N3O2 (M + H) +: 430.2495. Found 430.2497.

Example 36

4-Aminomethylcyclohexanecarboxylic acid [1- (1-Methyl-6-oxo-4-phenyl-1,6-dihydro-pyridin-2-yl) -2-phenyl-ethyl] -amide, trifluoroacetic acid salt

36A. 6- (1-amino-2-phenyl-ethyl) -1-methyl-4-phenyl-1H-pyridin-2-one: A solution of 34C (0.15 g, 0.28 mmol) in concentrated HCl (1 ml) was heated to 130 ° C. After 3 h, the reaction was cooled to rt and concentrated. The residue was suspended in CH2Cl2 (4 ml) and benzophenone imine (0.047 ml, 0.28 mmol) was added. The reaction was stirred at rt with moisture exclusion through a drying tube. After 18 h, triethylamine (0.039 ml, 0.28 mmol) and additional benzophenone imine (0.047 ml, 0.28 mmol) were added and the mixture was heated to reflux. After 18 h, the reaction was cooled to rt, diluted with CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel (0-10% EtOAc / hexane, then 10% EtOAc / hexanes and then 100% EtOAc) provided the imine (0.18 g) as an off-white gum. EMAR m / z Calc.

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for C32H27N2O (M + H) +: 455.2123. Found 455: 2114.

To a solution of the imine in DMF (4 ml) was added NaH (60% dispersion in mineral oil, 0.018 g, 0.44 mmol). The brown suspension was stirred at rt for 30 min and then iodomethane (0.027 ml, 0.44 mmol) was added. After 1 h, the reaction was stopped with water and extracted with EtOAc. The combined organic phases were washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel (0-50% EtOAc / hexane) provided a 2: 1 mixture of N-methyl pyridone and O-methyl pyridone (0.12 g) as a brown oil.

A solution of a mixture of N-methyl pyridone and O-methyl pyridone (0.12 g, 0.26 mmol) in ether (4 ml) and 1.0 N HCl (3 ml) was stirred at rt. After 18 h, the reaction was concentrated. Preparative HPLC (21.2 x 250 mm, 30 min. Gradient, 30 to 100% B, 30 ml / min.) Provided 36A (0.050 g, 43%) as a white solid. 1H NMR (500 MHz, CD3OD) δ: 3.29-3.34 (m, 4H), 3.41 (dd, J = 6.1 Hz, 13.2 Hz, 1H), 5.03 (dd, J = 6.6 Hz, 8.8 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.20 -7.22 (m, 2H), 7.29-7.35 (m, 3H), 7.49-7.54 (m, 3H), 7.71-7.73 (m, 2H). HRMS m / z Calc. For C20H21N2O (M + H) +: 305.1654. Found 305.1645.

36B. Example 36: Compound 36A was converted to Example 36 according to the procedures described in 34D. 1H NMR (500 MHz, CD3OD) δ: 0.99-1.08 (m, 2H), 1.36-1.43 (m, 2H), 1.53-1.58 (m, 1H), - 1.69-1.71 (m, 1H), 1.79-1.85 (m, 3H), 2.18-2.24 (m, 1H), 2.75 (d, J = 7.2 Hz, 2H), 3.10 (dd, J = 8.8 Hz, 13.8 Hz, 1H), 3.23 (dd, J = 6.6 Hz, 13.8 Hz, 1H), 3.55 (s, 3H), 5.37-5.41 (m, 1H), 6.70 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H) , 7.21-7.30 (m, 5H), 7.46-7.53 (m, 3H), 7.66-7.68 (m, 2H). HRMS m / z Calc. For C28H33N3O2 (M + H) +: 444.2651. Found 444.2669.

Example 37

4-Aminomethyl-cyclohexanecarboxylic acid [1- (6-Amino-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -amide, bis-trifluoroacetic acid salt

37A. 2-Chloro-6-methyl-4-phenylpyridine: A suspension of 6-methyl-4-phenyl-1H-pyridin-2-one (0.185 g, 1.0 mmol) and POCl3 (0.56 ml, 6) was heated mmol) in DMF (1 ml) at 110 ° C. After 1.5 h, the reaction was cooled to rt, quenched with water and extracted with EtOAc. The combined organic phases were washed with saturated NaHCO3 and brine, dried over saturated Na2SO4, filtered and concentrated. Column chromatography on silica gel (0-10% EtOAc / Hexane) provided 37A (0.143 g, 70%) as a yellow oil. MS 204.1 (M + H) + and 206.1 (M + 2 + H) +.

37B. 1- (6-Chloro-4-phenyl-pyridin-2-yl) -2-phenyl-ethylamine, bis-trifluoroacetic acid salt: Compound 37A was converted to 37B according to the procedures described in examples 34B and 34C . 1H NMR (400 MHz, CD3OD) δ: 3.16-3.35 (m, 2H), 4.74 (dd, J = 6.6 Hz, 8.8 Hz, 1H), 7.14 (d, J = 6.2 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 7.25-7.33 (m, 4H), 7.46-7.54 (m, 5H ), 7.71 (d, J = 1.8 Hz, 1H). HRMS m / z Calc. For C19H18ClN2 (M + H) +: 309.1159. Found 309.1151.

37C {4- [1- (6-Chloro-4-phenyl-pyridin-2-yl) -2-phenyl-ethylcarbamoyl] -cyclohexylmethyl} carbamic acid tert-butyl ester: To a solution of 37B (0.067 g, 0, 12 mmol) in DMF (3 ml) was added Boc-tranexamic acid (0.035 ml, 0.14 mmol), triethylamine (0.087 ml, 0.62 mmol), HOBt (0.025 g, 0.19 mmol) and EDCI ( 0.036 g, 0.19 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with EtOAc (25 ml), washed with water, saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel (0-50% EtOAc / hexane) gave amide 37C (0.045 g, 68%) as a white solid. MS 548.3 (M + H) + and 550.4 (M + 2 + H) +.

37D. Example 37: 37C (0.045 g, 0.082 mmol), benzophenone imine (0.028 ml, 0.16 mmol), Pd (OAc) 2 (0.0018 g, 0.0082 mmol) were added in a tightly sealed tube BINAP (0.0077 g, 0.012 mmol), Cs2CO3 (0.064 g, 0.2 mmol) and DMSO (0.55 ml). The mixture was degassed by bubbling argon for 10 min, the tube was sealed and the reaction was heated to 85 ° C. After 18 h, the reaction was cooled to rt, poured into water and extracted with CH2Cl2 (3 x). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give the benzophenone imine derivative (0.10 g) as a yellow oil. MS 693.2 (M + H) +.

The benzophenone imine derivative was dissolved in THF (1 ml) and 4.0 M HCl in 1,4-dioxane (1.0 ml) was added followed by water (0.5 ml). After 1 h, the solvent was removed and the residue was dissolved in 50% TFA / CH2Cl2 (4 ml). After 0.5 h, the reaction was concentrated. Preparative HPLC (21.2 x 100 mm, 8 min gradient, 20 to 100% B, 20 ml / min.) Gave Example 37 (0.020 g, 37%) as a white solid. 1H NMR (500 MHz,

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CD3OD) δ: 1.00-1.08 (m, 2H), 1.28-1.44 (m, 2H), 1.52-1.60 (m, 1H), 1.69-1.72 (m, 1H), 1.82-1.85 (m, 3H), 2.21-2.26 (m, 1H), 2.76 (d, J = 7.2 Hz, 2H), 3, 15-3.26 (m, 2H), 5.15-5.18 (m, 1H), 7.05 (s, 2H), 7.22-7.31 (m, 5H), 7.53- 7.56 (m, 3H), 7.68-7.70 (m, 2H). EMAR m / z Calc. For C27H33N4O (M + H) +: 429.2654. Found 429.2655.

Example 38

4-Aminomethyl-cyclohexanecarboxylic acid [1- (6-Chloro-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -amide, bis-trifluoroacetic acid salt

Example 38 can be prepared by deprotection of 37C protected with Boc, with TFA as described above. 1H NMR (500 MHz, CD3OD) δ: 1.00-1.09 (m, 2H), 1.31-1.46 (m, 2H), 1.51-1.59 (m, 1H), 1 , 67-1.73 (m, 1H), 1.80-1.87 (m, 3H), 2.20-2.27 (m, 1H), 2.76 (d, J = 7.2 Hz , 2H), 3.07 (dd, J = 9.6 Hz, 13.5 Hz, 1H), 3.21 (dd, J = 6.3 Hz, 13.5 Hz, 1H), 5.24- 5.27 (m, 1H), 7.15-7.26 (m, 5H), 7.37 (s, 1H), 7.44-7.51 (m, 3H), 7.58 (d, J = 1.6 Hz, 1H), 7.61-7.63 (m, 2H). HRMS m / z Calc. For C27H31ClN3O (M + H) +: 448.2156. Found 448.2157.

Example 39

4-Aminomethylcyclohexanecarboxylic acid {1- [4- (3-Amino-1H-indazol-6-yl) -6-oxo-1,6-dihydro-pyridin-2-yl] -2-phenyl-ethyl} -amide , trifluoroacetic acid salt

39A. [(E) -1-Benzyl-4- (4-cyano-3-fluoro-phenyl) -2-oxo-but-3-enyl] -carbamic acid tert-butyl ester: To a clear and colorless solution of the ester (3-tert-Butoxycarbonylamino-2-oxo-4-phenyl-butyl) phosphonic acid dimethyl (5.45 g, 14.7 mmol; Resmini, M. et al., Tetrahedron Asymmetry, 2004,15,1847,) and 2-fluoro-4-formylbenzonitrile (2.19 g, 14.7 mmol; Graham, S., J. Med Chem., 2003, 46 (14), 2973) in THF (210 ml) was added potassium carbonate (2.02 g, 14.7 mmol). The resulting suspension was vigorously stirred at rt to give a cloudy yellow suspension. After 54 h, more (3-tert-butoxycarbonylamino-2-oxo-4-phenylbutyl) -phosphonic acid dimethyl ester (2.72 g, 7.35 mmol) and potassium carbonate (1.0 g, 7.35 mmol). After 2 h, the reaction was stopped, filtered to remove the solid and the solid was rinsed with ethyl acetate. The filtrate was diluted with ethyl acetate and then washed with water and brine, dried over Na2SO4, filtered and concentrated to give 10.38 g as a yellow solid. Column chromatography on silica gel (20% CH2Cl2 / hexane, then 20-100% CH2Cl2 / hexane, then 40% EtOAc / hexane) gave 39A (4.37 g, 75%) as a solid pale yellow. 1H NMR (500 MHz, CDCl3) δ: 7.63 (t, J = 7.2 Hz, 1H), 7.48 (d, J = 16.5 Hz, 1H), 7.31-7.22 ( m, 5H), 7.17 (d, J = 8.2, 2H), 6.65 (d, J = 16.0 Hz, 1H), 5.27 (d, J = 7.2 Hz, 1H ), 4.86-4.82 (m, 1H), 3.14-3.05 (m, 2H), 1.43 (sa, 9H). 19 F NMR (470 MHz, CDCl 3) 8: -105.4, MS 417.1 (M + Na) + and 295.1 (M-C5H9O2 + H) +.

39B. 4- [6- (1-Amino-2-phenyl-ethyl) -2-oxo-1,2-dihydro-pyridin4-yl] -2-fluoro-benzonitrile: A suspension of 39A (3.17 g, 8, 0 mmol), (1.62 g, 8.0 mmol) and ammonium acetate (12.4 g, 161 mmol) in ethanol (40 ml) was stirred at rt for 10 min. and then placed in a preheated oil bath (80 ° C). After 20-30 min, an orange transparent solution formed and then a precipitate formed. More ethanol (100 ml) was added to facilitate stirring. After 4 h, the reaction was cooled to rt, filtered to collect the solid, the solid was rinsed with ethanol, air dried and dried in vacuo to give pyridone (2.09 g, 60%) as of a white solid similar to a cloth. 1H NMR (500 MHz, DMSO-d6) δ: 8.07 (t, J = 7.7 Hz, 1H), 7.84 (d, J = 11.0 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.33-7.26 (m, 4H), 7.20-7.16 (m, 1H), 6.63 (sa, 1H), 6.53 (sa , 1H), 4.76-4.70 (m, 1H), 3.16-2.99 (m, 1H), 2.83-2.76 (m, 1H), 1.25 (s, 9H ). 19F NMR (470 MHz, DMSO-d6) δ: -107.6, EMAR m / z Calc. For C25H25N3O3F (M + H) +: 434.1880. Found 434.1885.

To a suspension of pyridone (2.09 g, 4.82 mmol) in dichloromethane (120 ml) was added TFA (30 ml) giving a slightly yellow clear solution. After 1.5 h, the reaction was concentrated, dissolved again in dichloromethane and then concentrated. The above procedure was repeated. The residue was dissolved in dichloromethane and washed with saturated NaHCO3. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to give 39B (1.60 g, 100%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.71 (dd, J = 7.9, 6.6 Hz, 1H), 7.40 (dd, J = 7.9, 1.3 Hz, 1H), 7.35-7.31 (m, 3H), 7.28-7.22 (m, 3H), 6.65 (d, J = 1.8 Hz, 1H), 6.26 (d, J = 1.6 Hz, 1H), 4.20 (dd, J = 8.4, 5.7 Hz, 1H), 3.17 (dd, J = 13.2, 5.7 Hz, 1H), 2, 95 (dd, J = 13.2, 8.5 Hz, 1H). 19F NMR (375 MHz, CDCl3) 8: -105.1 (d, J = 9.2 Hz). EMAR m / z Calc. For C20H17N3OF (M + H) +: 334.1356. Found 334.1363.

39C. 4-Aminomethyl acid {1- [4- (4-Cyano-3-fluoro-phenyl) -6-oxo-1,6-dihydro-pyridin-2-yl] -2-phenyl-ethyl} -amide

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Cyclohexanecarboxylic acid: To a solution of 39B (0.096 g, 0.29 mmol) in DMF (4 ml) was added Boctranexamic acid (0.082 ml, 0.32 mmol), triethylamine (0.2 ml, 1.44 mmol), HOBt (0.058 g, 0.43 mmol) and EDCI (0.083 g, 0.43 mmol). The reaction mixture was stirred at rt for 2 h and more DMF (3 ml) was added. After 2 h, water was added, providing a white solid. The solid was collected, giving the amide (0.16 g, 96%) as a white solid. MS 573.3 (M + H) +.

To a suspension of the amide (0.16 g, 0.28 mmol) in CH2Cl2 (2 ml) was added TFA (2 ml). The resulting clear solution was stirred for 2 h and then concentrated, giving 39C (0.25 g) as a white solid. 1H NMR (400 MHz, CD3OD) δ: 0.98-1.08 (m, 2H), 1.25-1.45 (m, 2H), 1.50-1.65 (m, 2H), 1 , 80-1.86 (m, 3H), 2.15-2.21 (m, 1H), 2.76 (d, J = 7.0 Hz, 2H), 2.99-3.05 (dd , J = 10.1 Hz, 14.1 Hz, 1H), 3.22 (dd, J = 6.2 Hz, 14.1 Hz, 1H), 5.08-5.12 (m, 1H), 6.57 (s, 1H), 6.68 (d, J = 1.8 Hz, 1H), 7.20-7.30 (m, 5H), 7.60-7.65 (m, 2H) , 7.86-7.90 (m, 1H). MS 473.2 (M + H) +.

39D. Example 39: A suspension of 39C (0.125 g), 1-butanol (3 ml) and hydrazine monohydrate (1 ml) was heated in a microwave at 150 ° C for 10 min. The reaction mixture was cooled to rt and concentrated, giving a residue. Preparative HPLC (30 x 250 mm, 20 min gradient. 30 to 100% B, 30 ml / min.) Gave Example 39 (0.029 g, 33% in three steps) as a white solid. 1H NMR (500 MHz, CD3OD) δ: 0.98-1.08 (m, 2H), 1,281.46 (m, 2H), 1.52-1.66 (m, 2H), 1.81-1 , 85 (m, 3H), 2.17-2.24 (m, 1H), 2.75 (d, J = 7.2 Hz, 2H), 3.06 (dd, J = 9.9 Hz, 13.7 Hz, 1H), 3.06 (dd, J = 6.3 Hz, 13.7 Hz, 1H), 5.08-5.15 (m, 1H), 6.63 (d, J = 1.1 Hz, 1H), 6.68 (d, J = 1.7 Hz, 1H), 7.20-7.31 (m, 5H), 7.38-7.40 (m, 1H), 7.61 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H). HRMS m / z Calc. For C28H33N6O2 (M + H) +: 485.2665. Found 485.2686.

Example 40

4 1- [4- (3-Amino-1,2-bencisoxazol-6-yl) -6-oxo-1,6-dihydro-pyridin-2-yl] -2-phenyl-ethyl} -amide acid 4 -aminomethylcyclohexanecarboxylic acid, trifluoroacetic acid salt

To a solution of acetohydroxamic acid (0.023 g, 0.31 mmol) in DMF (2 ml) was added t-BuOK (0.034 g, 0.31 mmol). This suspension was vigorously stirred for 30 min and then 39C (0.040 g, 0.068 mmol) was added. After 18 h, the reaction mixture was quenched with water and extracted with EtOAc (3 x 10 ml). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. Preparative HPLC (21.2 x 100 mm, 8 min. Gradient, 20 to 100% B, 20 ml / min.) Provided Example 40 (0.0050 g, 12%) as a colored solid. White. 1H NMR (500 MHz, CD3OD) δ: 0.98-1.08 (m, 2H), 1.28-1.45 (m, 2H), 1.50-1.65 (m, 2H), 1 , 81-1.85 (m, 3H), 2.16-2.22 (m, 1H), 2.75 (d, J = 6.6 Hz, 2H), 3.02 (dd, J = 9 , 9 Hz, 13.8 Hz, 1H), 3.24 (dd, J = 6.0 Hz, 13.8 Hz, 1H), 5.10-5.15 (m, 1H), 6.65 ( s, 1H), 6.69 (s, 1H), 7.21-7.31 (m, 5H), 7.50 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H ), 7.86 (d, J = 8.2 Hz, 1H). HRMS m / z Calc. For C28H32N5O3 (M + H) +: 486,2505. Found 486.2519.

Example 52

5- (2- {1 - [(4-Aminomethyl-cyclohexanecarbonyl) -amino] -2-phenyl-ethyl} -pyridin-4-yl) -2-fluoro-benzoic acid, bis-trifluoroacetic acid salt

Example 52 was prepared from 3D, following the procedures described in 3E and using 3-carboxy-4-fluorophenyl boronic acid instead of 3- (methoxycarbonyl) phenylboronic acid. 1H NMR (500 MHz, CD3OD) δ: 1.01-1.10 (m, 2H), 1.32-1.43 (m, 2H), 1.52-1.60 (m, 1H), 1 , 73-1.86 (m, 4H), 2.26-2.31 (m, 1H), 2.77 (d, J = 7.2 Hz, 2H), 3.23-3.26 (m , 2H), 5.33-5.36 (m, 1H), 7.19-7.28 (m, 5H), 7.43 (dd, J = 8.8 Hz, 9.9 Hz, 1H) , 7.92 (s, 1H), 7.96 (dd, J = 1.6 Hz, 6.0 Hz, 1H), 8.03-8.05 (m, 1H), 8.33 (dd, J = 2.7 Hz, 6.6 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H). HRMS m / z Calc. For C28H31FN3O3 [M + H] +: 476.2349. Found 476.2342.

Example 54

2-Amino-5- (2- {1 - [(4-aminomethyl-cyclohexanecarbonyl) -amino] -2-phenyl-ethyl} -pyridin-4-yl) benzoic acid methyl ester, bis-trifluuroacetic acid salt

54A 2-Amino-5- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl) -benzoic acid methyl ester: In a flame-dried flask equipped with a condenser, acid methyl ester was added 2-amino-5-bromo-benzoic acid (0.7 g, 3.0 mmol), Pd (dppf) Cl2 · CH2Cl2 complex (0.106 g, 0.135 mmol), KOAc (1.28 g, 13.0 mmol) and bis (neopentyl glycolate) diboro (1.08 g, 4.78 mmol). Then, degassed DMSO (29 ml) was added and the reaction was stirred at 80 ° C. After 5 h, the reaction was cooled to rt, diluted with EtOAc (100 ml), washed with water and brine,

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dried over Na2SO4, filtered and concentrated. Column chromatography on silica gel (gradient elution 0-20% EtOAc / Hexane) gave 54A (0.858 g, 75%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.01 (s, 6H), 3.74 (s, 4H), 3.86 (s, 3H), 5.91 (sa, 2H), 6.63 ( d, J = 8.3 Hz, 1H), 7.66-7.68 (m, 1H), 8.33 (s, 1H). MS 196.1 (M-C5H8 + H) +.

54B. 2-Amino-5- [2- (1 - {[4- (tert-butoxycarbonylamino-methyl) -cyclohexanecarbonyl] amino} -2-phenyl-ethyl) -pyridin-4-yl] -benzoic acid methyl ester: Se prepared 54B from 3D following the procedures described in 3E and using 54A instead of 3- (methoxycarbonyl) phenylboronic acid. MS 587.41 (M + H) +.

54C Example 54: Deprotection of 54B followed by the 1E procedure gave Example 54. 1H NMR (500 MHz, CD3OD) δ: 1.03-1.12 (m, 2H), 1.32-1.43 (m, 2H), 1.52-1.60 (m, 1H), 1.73-1.86 (m, 4H), 2.26-2.31 (m, 1H), 2.77 (d, J = 6.6 Hz, 2H), 3.25-3.31 (m, 2H), 3.03 (s, 3H), 5.28-5.31 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 7.20-7.30 (m, 5H), 7.86 (dd, J = 2.2 Hz, 8.8 Hz, 1H), 8.02-8.05 (m, 2H), 8.43 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 6.6 Hz, 1H). HRMS m / z Calc. For C29H35N4O3 [M + H] +: 487.2709. Found 487.2710.

Example 55

4-Aminomethylcyclohexanecarboxylic acid {1- [4- (4-Oxo-3,4-dihydro-quinazolin-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide, bis- trifluoroacetic

A yellow suspension of 54B (0.085 g, 0.145 mmol), ammonium acetate (0.122 g, 1.45 mmol) and trimethyl orthoformate (0.15 ml, 1.45 mmol) in methanol (1.4 ml) are heated to 100 ° C in a tightly sealed tube. After 8 h, the reaction was filtered hot and the solid was rinsed with methanol, air dried and dried in vacuo to give a white solid. The solid was dissolved in 30% TFA / CH2Cl2 (5 ml). After 30 min, the reaction was concentrated. Preparative HPLC [21.1 x 100 mm; grad. 8 min. B of 30-100%; 20 ml / min) then gave lyophilization, Example 55 (0.034 g, 33%) as a white solid. 1H NMR (500 MHz, CD3OD) δ: 8.69 (t, J = 4.7 Hz, 1H), 8.63 (sa, 1H), 8.26-8.23 (m, 2H), 8, 18-7.96 (m, 2H), 7.88 (d, J = 8.8 Hz, 1H), 7.29-7.26 (m, 2H), 7.22-7.18 (m, 3H), 5.40-5.35 (m, 1H), 3.30-3.20 (m, 2H), 2.77 (d, J = 6.6 Hz, 2H), 2.32-2 , 26 (m, 1H), 1.87-1.82 (m, 3H), 1.77-1.74 (m, 1H), 1.62-1.52 (m, 1H), 1.42 -1.34 (m, 2H), 1.10-1.02 (m, 2H). HRMS m / z Calc. For C29H32N5O2 (M + H) +: 485.2556. Found 485.2532.

Example 56

2-amino-5- (2- {1 - [(4-aminomethyl-cyclohexanecarbonyl) -amino] -2-phenyl-ethyl} -pyridin-4-yl) -benzoic acid, bis-trifluoroacetic acid salt

A yellow suspension of 54B (0.036 g, 0.061 mmol) and 1.0 N NaOH (0.31 ml) in methanol (0.60 ml) was heated to 60 ° C. After 4 h, the yellow transparent solution was concentrated, giving a yellow residue. The yellow residue was dissolved in 30% TFA / CH2Cl2 (5 ml). After 30 min, the reaction was concentrated. Preparative HPLC [21.1 x 100 mm; grad. 8 min. B of 30-100%; 20 ml / min) gave Example 56 (0.0031 g, 7%) as a yellow solid. 1H NMR (500 MHz, CD3OD) δ: 8.47-8.44 (m, 2H), 8.01-7.97 (m, 2H), 7.85-7.81 (m, 1H), 7 , 31-7.26 (m, 2H), 7.25-7.19 (m, 3H), 6.93 (d, J = 8.8 Hz, 1H), 5.29 (t, J = 8 , 0 Hz, 1H), 3.29-3.22 (m, 2H), 2.77 (d, J = 7.2 Hz, 2H), 2.33-2.26 (m, 1H), 1 , 89-1.83 (m, 3H), 1.79-1.73 (m, 1H), 1.62-1.54 (m, 1H), 1,421.32 (m, 2H), 1.10 -1.03 (m, 2H). HRMS m / z Calc. For C28H33N4O3 (M + H) +: 473.2553. Found 473.2531.

Example 57

4-Aminomethyl-cyclohexanecarboxylic acid {1- [4- (4-Methoxy-quinolin-6-yl) -pyridin-2-yl) -2-phenyl-ethyl} -amide, bis-trifluoroacetic acid salt

Example 57 was prepared from 3D, following the procedures described in 3E and using 6- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl) -4-methoxyquinoline, prepared following procedure 54A, instead of 3 (methoxycarbonyl) phenylboronic acid. 1H NMR (500 MHz, CD3OD) δ: 1.01-1.12 (m, 2H), 1.32-1.46 (m, 2H), 1.53-1.60 (m, 1H), 1 , 75-1.86 (m, 4H), 2.26-2.31 (m, 1H), 2.77 (d, J = 7.2 Hz, 2H), 3.25 (d, J = 7 , 7 Hz, 2H), 4.44 (s, 3H), 5.36 (t, J = 7.7 Hz, 1H), 7.19-7.28 (m, 5H), 7.60 (d , J = 6.6 Hz, 1H), 7.85 (s, 1H), 7.95 (dd, J = 1.7 Hz, 5.5 Hz, 1H), 8.25 (d, J = 9 , 3 Hz, 1H), 8.43 (dd, J = 2.2 Hz, 9.3 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H), 8.77 (d, J = 5.5 Hz, 1H), 9.10 (d, J = 6.6 Hz, 1H). HRMS m / z Calc. For C31H35N4O2 [M + H] +: 495.2760. Found 495.2773.

Example 58

4-Aminomethyl acid {1- [4- (4-Ozo-1,4-dihydro-quinolin-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -amide

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cyclohexanecarboxylic acid, bis-trifluoroacetic acid salt

58A. 6- [2- (1-Amino-2-phenyl-ethyl) -pyridin-4-yl] -1H-quinolin-4-one, bis-trifluoroacetic acid salt: A mixture of 57 (0.062 g, 0.074 mmol) in concentrated HCl (0.5 ml) and 1,2-dichloroethane (1.0 ml) was heated at 130 ° C in a tightly sealed tube. After 22 h, the reaction was concentrated. Preparative HPLC (Phenomenex Luna 5u,

5 21.2 x 100 mm; 8 min. gradient, 20 to 100% B; 20 ml / min.) Gave 58A (0.031 g, 92%) as a clear and colorless oil. MS 342.2 (M + H) +.

58B. Example 58: To a solution of DMF oil (2 ml) was added Boc-tranexamic acid (0.023 g, 0.089 mmol), BOP reagent (0.0393 g, 0.089 mmol) and triethylamine (0.041 ml, 0.30 mmol ). After 2 h, water was added and the reaction was extracted with EtOAc. The combined organic phases were washed with brine, dried over 10 Na2SO4, filtered and concentrated. Preparative HPLC (Phenomenex Luna 5u, 21.2 x 100 mm; 8 min. Gradient, 30 to 100% B; 20 ml / min.) Gave 0.014 g of the amide as a white solid. The solid was dissolved in 50% TFA in CH2Cl2 (2 ml). After 1 h, the reaction was concentrated. Preparative HPLC (Phenomenex Luna 5u, 21.2 x 100 mm; 8 min. Gradient, 20 to 100% B; 25 ml / min.) Gave, after lyophilization, Example 58 (0.010 g, 16% in three stages) in the form of a pale yellow solid. 1H NMR

15 (500 MHz, CD3OD) δ: 1.01-1.11 (m, 2H), 1.34-1.45 (m, 2H), 1.55-1.60 (m, 1H), 1, 75-1.90 (m, 4H), 2.28-2.33 (m, IH), 2.78 (d, J = 7.2 Hz, 2H), 3.27-3.31 (m, 2H), 5.35-5.38 (m, 1H), 6.53 (d, J = 7.2 Hz, 1H), 7.22-7.30 (m, 5H), 7.85 (d , J = 8.8 Hz, 1H), 8.11-8.13 (m, 2H), 8.16 (d, J = 7.2 Hz, 1H), 8.23 (dd, J = 1, 6 Hz, 8.8 Hz, 1H), 8.69 (d, J = 6.1 Hz, 1H), 8.76 (d, J = 1.6 Hz, 1H). MS 481.4 (M + H) +.

Examples 9, 11-12, 14, 16-20, 24, 30-32, 41-51, 53 and 59-60 were prepared using procedures similar to those

20 described above. Next, Table 1 summarizes the representative examples of the compounds in the present invention.

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Using combinations of the synthetic routes and experimental procedures, together with procedures known to an expert in the field of organic synthesis, additional compounds of the present invention can be prepared, such as Examples 61-321, shown below in Table 2 and Examples 322-580 that are shown later in Table 3.

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Utility

The compounds of the present invention are inhibitors of factor XIa and are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals (i.e. disorders associated with factor XIa). In general, a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases that involve fibrin formation, platelet activation and / or platelet aggregation). The expression "thromboembolic disorders" as used herein includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders and thromboembolic disorders in the chambers of the heart. The expression "thromboembolic disorders" as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction, sudden ischemic death, transient ischemic attack, stroke, atherosclerosis, arterial disease peripheral occlusive, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis resulting from (a) prostate valves or other implants, (b) permanent catheters, (c) vascular stents, (d) cardiopulmonary bypass, (e) hemodialysis or

(f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It is noted that thrombosis includes occlusion (for example, after a shunt) and reocclusion (for example during or after percutaneous transluminal coronary angioplasty). Thromboembolic disorders may result from conditions that include but are not limited to atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or hormones, and pregnancy complications. It is believed that the anticoagulant effect of compounds of the present invention is due to the inhibition of serine proteases involved in the coagulation cascade and / or contact activation system, more specifically, inhibition of coagulation factors: factor XIa, factor VIIa , factor IXa, factor Xa, plasma kallikrein or thrombin.

The compounds of the present invention are also plasma kallikrein inhibitors and are useful as anti-inflammatory agents for the treatment or prevention of diseases associated with an activation of the contact activation system (i.e. disorders associated with plasma kallikrein). In general, a contact activation system disorder is a disease caused by activation of blood on artificial surfaces, including prostate valves or other implants, permanent catheters, stents, cardiopulmonary bypass, hemodialysis, microorganism (e.g., bacteria, viruses) or other procedures in which the blood is exposed to an artificial surface that promotes contact activation, blood clots (i.e. diseases that involve fibrin formation, platelet activation and / or platelet aggregation. It also includes systemic inflammatory response syndrome , sepsis, acute respiratory distress syndrome, hereditary angioedema or other inherited or acquired deficiencies of contact activation components or their inhibitors (plasma kallikrein, factor XIIa, high molecular weight quininogen, C1-esterase inhibitor). acute and chronic inflammations of joints, vessels or other mammalian organs.

The efficacy of the compounds of the present invention as inhibitors of coagulation factors XIa, VIIa, IXa, Xa, plasma kallikrein or thrombin, can be determined using a relevant purified serine protease, respectively, and an appropriate synthetic substrate. The rate of hydrolysis of the chromogenic or fluorogenic substrate by the relevant serine protease was measured both in the absence and in the presence of compounds of the present invention. Substrate hydrolysis resulted in the release of pNA (for nitroaniline), which was spectrophotometrically controlled by measuring the increase in absorbance at 405 nm or the release of AMC (amino methyl coumarin, which was controlled spectrofluorometrically by measuring the increase in emission at 460 nm with excitation at 380 nm. A reduction in the absorbance rate or fluorescence change in the presence of the inhibitor is indicative of enzymatic inhibition. Such procedures are known to one skilled in the art. The results of this assay are expressed as the inhibitory constant , Ki.

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4 containing 145 mM NaCl, 5 mM KCl and 8000 PEG (polyethylene glycol; JT Baker or Fisher Scientific) 0.1%. Determinations were made using purified human Factor XIa at a final concentration of 75-200 pM (Haematologic Technologies) and the synthetic substrate S-2366 (piroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002-0,00025 M. In general, it has been identified that the preferred compounds of the present invention, such as the particular compounds disclosed in the previous examples, are active and show Ki equal to or less than 15 µM in the Factor XIa assay, thereby demonstrating the utility of the compounds of the present invention as especially effective inhibitors of coagulation factor XIa. The most preferred compounds have Ki equal to or less than 5 µM, preferably equal to or less than 1 µM, more preferably equal to or less than 0.5 µM.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 M sodium chloride, 0.05 M HEPES buffer containing 0.5% PEG 8000 at a pH of 7.4. Determinations were made using purified human Factor VIIa (Haematologic Technologies) or recombinant human Factor VIIa (Novo Nordisk) at a final test concentration of 2-5 nM, recombinant soluble tissue factor at a concentration of 18-35 nM and the synthetic substrate HD -Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; AnaSpec) at a concentration of 0.001 M. In general, the compounds tested in the Factor VIIa assay are considered to be active if they show an equal Ki or less than 15 µM.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 M sodium chloride, 0.05 M TRIS base and 0.5% PEG 8000 at a pH of 7.4. Determinations were made using purified human Factor IXa (Haematologic Technologies) at a final test concentration of 20-100 nM and the synthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688 (HD-Leu-Ph'Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0,0005

M. In general, the compounds tested in the Factor IXa assay are considered active if they show a Ki equal to or less than 15 µM.

Factor Xa determinations were performed in 0.1 M sodium phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000. Determinations were made using purified human Factor Xa (Haematologic Technologies) at a final test concentration of 150-1000 pM and the synthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%) - Gly-Arg-pNA ; Chromogenix) at a concentration of 0.0002-0,0003 M. In general, the compounds tested in the Factor Xa test are considered active if they show a Ki equal to or less than 15 µM.

Plasma kallikrein determinations were made in 0.1 M sodium phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000. Determinations were made using purified human calicrein enzyme (Research Laboratories) at a final test concentration of 200 pM and the synthetic substrate S2302 (H- (D) -Pro-Phe-Arg-pNA; Chromogenix) at a concentration of 0, 00008-0,0004 M. The value of Km used for the calculation of Ki was from 0.00005 to 0.00007 M. In general, the compounds tested in the plasma kallikrein assay are considered to be active if they show a Ki equal to or less than 15 µM.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000. Determinations were made using purified human thrombin alpha (Haematologic Technologies or Enzyme Research Laboratories) at a final test concentration of 200-250 pM and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0 , 0002 M. In general, the compounds tested in the thrombin assay are considered to be active if they show a Ki equal to or less than 15 µM.

In general, preferred compounds of the present invention have demonstrated Ki values equal to or less than 15 µM in at least one of the above assays, thereby confirming the usefulness of the compounds of the present invention as effective cascade inhibitors. coagulation and / or contact activation system and useful as anticoagulants for the prevention or treatment of thromboembolic disorders in mammals and / or as

5 anti-inflammatory agents for the prevention or treatment of inflammatory disorders in mammals.

The Michaelis constant, Km, for substrate hydrolysis for each protease was determined at 25 ° C using the method of Lineweaver and Burk. Ki values were determined by allowing the protease to react with the substrate in the presence of the inhibitor. The reactions were allowed to continue for periods of 20-180 minutes (depending on the protease) and the velocities (absorbance rate or fluorescence change against the

10 time) The following relationships were used to calculate Ki values:

(vo-vs) / vs = I / (Ki (1 + S / Km)) for a competitive inhibitor with a binding site; or

(vs / vo) = A + ((B-A) / 1 + ((IC50 / (I) n)))

Y

Ki = IC50 / (1 + S / Km) for a competitive inhibitor

15 in which:

vo is the speed of control in the absence of inhibitor,

vs is the speed in the presence of inhibitor;

I is the inhibitor concentration;

A is the minimum remaining activity (usually set to zero);

20 B is the maximum remaining activity (usually set to 1.0);

n is the Hill coefficient, a measure of the number and cooperativity of potential inhibitor binding sites;

IC50 is the concentration of inhibitor that produces 50% inhibition under test conditions;

Ki is the dissociation constant of the enzyme complex: inhibitor;

25 S is the substrate concentration; Y

Km is the Michaelis constant for the substrate.

The efficacy of the compounds of the present invention as inhibitors of coagulation factors XIa, VIIa, IXa, Xa, or thrombin, can be determined using relevant in vivo thrombosis models, including electrically induced Carotid Artery thrombosis thrombosis models. Live and Thrombosis Models of Arteriovenous Shunt

30 Rabbit In Vivo.

Model of electrically induced carotid artery thrombosis in vivo:

The antithrombotic effect of the compounds of the present invention can be demonstrated in the electrically induced carotid artery thrombosis (ECAT) model in rabbits. In this model, rabbits are anesthetized with a mixture of ketamine (50 mg / kg i.m.) and xylazine (10 mg / kg i.m.). Catheters are isolated and inserted into a vein

35 femoral and a femoral artery. The carotid artery is also isolated so that its blood flow can be measured with a calibrated flow probe that is attached to a flowmeter. A stainless steel bipolar hook electrode is placed in the carotid artery and positioned in a caudal direction in relation to the flow probe as a means to apply electrical stimuli. To protect the surrounding tissue, a piece of Parafilm is placed under the electrode.

40 Test compounds are considered to be effective as anticoagulants based on their ability to maintain blood flow in the carotid artery after induction of thrombosis by an electrical stimulus. A test compound or vehicle is provided as a continuous intravenous infusion through the femoral vein, beginning 1 hour before electrical stimulation and continuing until the end of the test. Thrombosis is induced by applying a direct electrical current of 4 mA for 3 minutes to the external arterial surface, using a constant current unit and a d.c. stimulator. Carotid blood flow is monitored and the time to occlusion (reduction of blood flow to zero after induction of thrombosis) is observed in minutes. The change in observed blood flow is calculated as a percentage of blood flow before the induction of thrombosis and provides a measure of the effect of a test compound when compared to the case in which no compound is administered. This information is used to estimate the value of ED50, the dose that increases blood flow to 50% of the control (blood flow before thrombosis induction) and is achieved by nonlinear least squares regression.

Rabbit arteriovenous shunt thrombosis model in vivo:

The antithrombotic effect of the compounds of the present invention can be demonstrated in a thrombosis model of rabbit arteriovenous shunt (AV). In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg / kg i.m.) and ketamine (50 mg / kg i.m.) are used. An AV shunt device loaded with saline is connected between the cannulas of the femoral artery and the femoral vein. The AV shunt device consists of a piece of 6 cm tygon tube that contains a piece of silk thread. Blood will flow from the femoral artery through the AV shunt to the femoral vein. Exposure of blood flow to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle (i.v., i.p., s.c. or oral) will be provided prior to the opening of the AV shunt. The percentage of thrombus formation inhibition is determined for each treatment group. The values of DI50 (dose that produces 50% inhibition of thrombus formation) are estimated by linear regression.

The anti-inflammatory effect of these compounds can be demonstrated in an Evans Blue dye extravasation assay using mice deficient in C1-esterase inhibitor. In this model, the mice are dosed with a compound of the present invention, Evans Blue is injected through the tail vein and the extravasation of the blue dye is determined by spectrophotometric means of the tissue extracts.

The ability of the compounds of the present invention to reduce or prevent systemic inflammatory response syndrome, for example, as seen during cardiovascular pump procedures, can be tested in in vitro perfusion systems or by surgical procedures with pump in larger mammals. , including dogs and baboons. Readings to assess the benefit of the compounds of the present invention include, for example, reduction of platelet loss, reduction of platelet / white blood cell complexes, reduction of plasma neutrophil elastase levels, reduction of activation of complement factors and reduction of activation and / or consumption of contact activation proteins (plasma kallikrein, factor XII, factor XI, high molecular weight quininogen, C1-esterase inhibitors).

The utility of the compounds of the present invention to reduce or prevent the morbidity and / or mortality of sepsis can be evaluated by injecting a mammalian host with bacteria or viruses or extracts thereof and compounds of the present invention. Typical readings of efficacy include changes in LD50 and blood pressure conservation.

The compounds of the present invention may also be useful as additional serine protease inhibitors, notably human thrombin, human plasma kallikrein and human plasmin. Due to their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, including blood coagulation, fibronilysis, blood pressure regulation and inflammation and wound healing catalyzed by the aforementioned class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity of the above-mentioned serine proteases, such as myocardial infarction and as reagents used as anticoagulants in the processing of plasma blood for diagnosis and others. commercial purposes

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anticoagulant agents or coagulation inhibitors, platelet or antiplatelet inhibitors, anti-inflammatory agents, thrombin inhibitors or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. For "therapeutically effective" it is understood an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective in treating (i.e. preventing, inhibiting or alleviating) thromboembolic and / or inflammatory disease or Treat disease progression in a host.

The compounds of the invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as defined below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds is preferably, but not necessarily 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, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated in suboptimal concentrations of the compounds. The synergy may be in terms of lower cytotoxicity, increased anticoagulant effect or some other beneficial effect of the combination compared to the individual components.

By " managed in combination " or "combination therapy" It is understood that the compound of the present invention and one or more additional therapeutic agents are simultaneously administered to the mammal to be treated. When administered in combination each component can be administered simultaneously or sequentially in any order at different points in time. Therefore, each component can be administered separately but closely enough over time to provide the desired therapeutic effect.

Compounds that can be administered in combination with the compounds of the present invention include, but are not limited to, anticoagulants, antithrombin agents, antiplatelet agents, fibrinolytic agents, hypolipidemic agents, antihypertensive agents and antiischemic agents.

Other anticoagulant agents (or coagulation inhibitors) that can be used in combination with the compounds of the present invention include warfarin, heparin (unfractionated heparin or any commercially available low molecular weight heparin, for example LOVENOX ™, aprotinin, synthetic pentasaccharide, direct-acting thrombin inhibitors including hirudin and argatroban, as well as other factor VIIa, VIIIa, IXa, Xa, XIa, thrombin, Tafi and fibrinogen inhibitors known in the art.

The term "antiplatelet agents" (or platelet inhibitors) as used herein, indicates agents that inhibit platelet function, for example, by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDs, aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Other suitable platelet inhibiting agents include IIb / IIIa antagonists (e.g., tirofiban, eptifibatide and abciximab), thromboxane-A2 receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, phosphodiesterase-III inhibitors (PDE-III) (for example, dipyridamole, cilostazol) and PDE V inhibitors (such as sildenafil) and pharmaceutically acceptable salts or prodrugs thereof.

The term "antiplatelet agents" (or platelet inhibitors), as used herein, is also intended to include ADP receptor antagonists (adenosine diphosphate), preferably antagonists of the purinergic receptors P2Y1 and P2Y12, with P2Y12 being more preferred. Preferred P2Y12 receptor antagonists include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be mild in use in the gastrointestinal tract. The compounds of the present invention can also be dosed in combination with aprotinin.

The term thrombin inhibitors (or antithrombin agents), as used herein, indicates serine protease thrombin inhibitors. By inhibiting thrombin, various thrombin-mediated processes are interrupted, such as thrombin-mediated platelet activation (i.e., for example, platelet aggregation and / or granular secretion of plasminogen activator inhibitor and / or serotonin), activation of endothelial cells, inflammatory reactions and / or fibrin formation. Several thrombin inhibitors are known to those skilled in the art and it is contemplated that these inhibitors are used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include peptide and N-acetyl boronic acid derivatives, such as lysine terminal C-terminal amino-boronic acid derivatives, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirologists, such as bisulfatohirudin.

The term thrombolytic (or fibrinolytic) (or thrombolytic or fibrinolytic) agents, as used herein, indicates agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, PAI-I inhibitors (i.e. inactivators of tissue plasminogen activator inhibitors), alpha-2-antiplasmin inhibitors and anisolated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisolated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is incorporated herein by This document by reference. The term urokinase, as used herein, is intended to indicate both dual and single chain urokinase, the second also being referred to herein as prourokinase.

Examples of suitable antiarrhythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class II agents (such as carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, acimilide and ibutilide); Class IV agents (such as dithiazem and verapamil); K + channel opening agents such as IAch inhibitors and IKur inhibitors (for example compounds such as those disclosed in WO 01/40231).

The term antihypertensive agents, as used herein, includes: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (for example, diltiazem, verapamil, nifedipine, amlodipine and mibefradil); diuretics (for example, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, trichrinephene of ethacrynic acid, chlorthalidone, furosemide, musolimine, bumetanone, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidone, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidone, trimethanoidone, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide, trimethanoidide; renin inhibitors; angiotensin converting enzyme (ACE) inhibitors (eg, captopril, lisinopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramiprile, lisinopril); angiotensin-II receptor antagonists (for example, irbestatin, losartan, valsartan); ET receptor inhibitors (for example, sitaxsentan, atrasentan and compounds disclosed in US Patent Nos. 5,612,359 and 6,043,265); Dual ET / AII antagonists (for example, compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual ACE / NEP inhibitors, for example, omapatrilat, gemopatrilat, nitrates); and β-blockers (for example, propanolol, nadolol or carvedilol).

Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.

Examples of mineralocorticoid receptor antagonists suitable for use in combination with the compounds of the present invention include spironolactone and eplirinone.

Examples of suitable lipid / cholesterol reducing agents and lipid profile therapies for use in combination with the compounds of the present invention include: HMG-CoA reductase inhibitors (eg, pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK -104 (also known as itavastatin, nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin, atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questrane); ACAT inhibitors, MTP inhibitors; lipoxygenase inhibitors; cholesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (for example, CP-529414).

Examples of antidiabetic agents suitable for use in combination with the compounds of the present invention include: biguanides (eg, metformin); glucosidase inhibitors (for example, acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (for example, repaglinide); sulfonylureas (for example, glimepiride, glyburide and glipicide); combinations of biguanide / glyburide (for example, glucovance), thiozolidinediones (for example, troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, dual PPAR alpha / gamma agonists, SGLT2 inhibitors, inhibitors of SGLT2, inhibitors fatty acid binding proteins (aP2) such as those disclosed in WO00 / 59506, glucagon 1 peptide (GLP-1) and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable antidepressant agents for use in combination with the compounds of the present invention include nefazodone and sertraline.

Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include: prednisone; dexamethasone; enbrel; protein tyrosine kinase (PTK) inhibitors; cyclooxygenase inhibitors (including NSAIDs and COX-1 and / or COX-2 inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen; celecoxib; and / or rofecoxib.

Examples of antiosteoporosis agents suitable for use in combination with the compounds of the present invention include alendronate and raloxifene.

Examples of hormone replacement therapies suitable for use in combination with the compounds of the present invention include estrogen (eg, conjugated estrogens) and estradiol.

Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include orlistat and aP2 inhibitors (such as those disclosed in WO 00/59506).

Examples of suitable anti-aging agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone and hydroxyzine pamoate.

Examples of suitable anti-aging agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone and hydroxyzine pamoate.

Examples of suitable antiproliferative agents for use in combination with the compounds of the present invention include cyclosporin A, paclitaxel, adriamycin; epitilones, cisplatin and carboplatin.

Examples of antiulcer agents and gastroesophageal reflux disease suitable for use in combination with the compounds of the present invention include famotidine, ranitidine and omeprazole.

Administration of the compounds of the present invention (i.e., a first therapeutic agent) in combination with at least one additional therapeutic agent (i.e., a second therapeutic agent), preferably provides an advantage of efficacy over the compounds and agents alone. , preferably allowing at the same time the use of smaller doses of each. A lower dosage minimizes the potential for side effects, thus providing an increase in the safety margin. It is preferred that at least one of the therapeutic agents be administered in a subtherapeutic dose. It is even more preferred that all therapeutic agents be administered in subtherapeutic doses. It is intended that subtherapeutic means an amount of a therapeutic agent that by itself does not provide the desired therapeutic effect for the condition or disease to be treated. It is intended that synergistic combination means that the observed effect of the combination is greater than the sum of the individual agents administered alone.

The compounds of the present invention are also useful as reference or conventional compounds, for example as a quality or control standard, in assay or tests involving the inhibition of thrombin, Factor VIIa, IXa, Xa, XIa and / or kallikrein of plasma. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving thrombin, Factor VIIa., IXa, Xa, XIa and / or plasma kallikrein. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity with a compound with an unknown activity. This would assure the experimenter that the test was being performed properly and would provide a basis for comparison, especially if the test compound were a derivative of the reference compound. When new assays or protocols are developed, compounds according to the present invention could be used to test their efficacy.

The compounds of the present invention can also be used in diagnostic assays involving thrombin, VIIa, IXa, Xa, XIa and / or plasma kallikrein. For example, the presence of thrombin, Factor VIIa, IXa, Xa XIa and / or plasma kallikrein in an unknown sample could be determined by adding the relevant chromogenic substrate, for example S2366 for Factor XIa, to a series of solutions containing test sample and optionally one of the compounds of the present invention. If the production of pNA and solutions containing test samples is observed, but not in the presence of a compound of the present invention, then it would be concluded that Factor XIa is present.

Extremely potent and selective compounds of the present invention, which have Ki values less than or equal to 0.001 µM against the target protease and greater than or equal to 0.1 µM against the other proteases, can also be used in assays of Diagnostics involving the quantification of thrombin, Factor VIIa, IXa, Xa, XIa and / or plasma kallikrein in serum samples. For example, the amount of Factor XIa in serum samples could be determined by careful assessment of protease activity in the presence of the relevant chromogenic substrate, S2366, with a potent and selective Factor XIa inhibitor of the present invention.

The present invention also encompasses a manufacturing article. As used herein, the article of manufacture is intended to include, but not limited to, kits and containers. The article of manufacture of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, the composition comprising: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a leaflet indicating that the pharmaceutical composition can be used for the treatment of a thromboembolic and / or inflammatory disorder (as defined above). In another embodiment, the package leaflet indicates that the pharmaceutical composition may be used in combination (as previously defined) with a second therapeutic agent to treat a thromboembolic and / or inflammatory disorder. The article of manufacture may additionally comprise: (d) a second container in which components (a) and (b) are located within the second container and the component

(c) it is located inside or outside the second container. Located inside the first and second containers means that the respective container contains the article within its limits.

The first container is a receptacle used to contain a pharmaceutical composition. This container can be for manufacturing, storage, shipping and / or individual / bulk sale. The first container is intended to encompass a bottle, jar, vial, flask, syringe, tube (for example, for a cream preparation) or any other container used for manufacturing, maintenance, storage or distribution of a pharmaceutical product.

The second container is one used to hold the first container and, optionally, the leaflet. Examples of the second container include, but are not limited to, boxes (for example, of cardboard or plastic), drawers, cartons, bags (for example, paper or plastic bags), pockets and sacks. The leaflet can be physically attached to the outside of the first container by tape, glue, staple or other joining procedure or it can be left inside the second container without any physical means of joining the first container. Alternatively, the leaflet is located on the outside of the second container. When it is located on the outside of the second container, it is preferable that the leaflet is physically joined by tape, glue, staple or other bonding procedures. Alternatively, it may be adjacent to or touching the outside of the second container without being physically attached.

The leaflet is a brand, label, marker, etc., which lists the information in relation to the pharmaceutical composition located within the first container. The training listed will usually be determined by the regulatory agency that governs the area in which the article of manufacture is to be sold (for example, the United States Food and Drug Administration). Preferably, the leaflet specifically lists the indications for which the pharmaceutical composition has been approved. The leaflet can be made of any material in which a person can read information contained in or about him. Preferably, the leaflet is a printable material (for example, paper, plastic, cardboard, aluminum foil, adhesive or plastic obverse paper, etc.) in which the desired information (for example, printed or applied) has been formed.

Dosage and formulation

The compounds of the present invention can be administered in such oral pharmaceutical forms as tablets, capsules (each of which includes time-release or prolonged-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They can also be administered intravenously (embolate or infusion), intraperitoneal, subcutaneous or intramuscular, all using pharmaceutical forms well known to those skilled in the pharmaceutical field. They can be administered alone, but will generally be administered with a selected pharmaceutical vehicle based on the selected route of administration and conventional pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and extent of symptoms; the type of simultaneous treatment; the frequency of treatment; the route of administration, the renal and empathic function of the patient and the desired effect. A doctor or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counteract or stop the progress of thromboembolic disorder.

As a general guide, the daily oral dosage of each active ingredient, when used for the indicated effects, will vary between approximately 0.001 and 1000 mg / kg body weight, preferably between approximately 0.01 and 100 mg / kg body weight per day and more preferably between about 1.0 and 20 mg / kg / day. Intravenously, the most preferred doses will vary from about 1 to about 10 mg / kg / minute during a constant rate infusion. The compounds of the present invention may be administered in a single daily dose or the total daily dosage may be administered in divided doses two, three or four times a day.

The compounds of the present invention can be administered intranasally by topical use of suitable intranasal vehicles or by transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, dosing administration will, of course, be continuous rather than intermittent throughout the dosing regimen.

The compounds are typically administered in admixture with pharmaceutically suitable diluents, excipients or vehicles (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules, elixirs, syrups and the like and consistent with conventional pharmaceutical practices.

For example, for oral administration in the form of a tablet or capsule, the active pharmacological component may be combined with a non-toxic, pharmaceutically acceptable, inert oral vehicle such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate , calcium sulfate, mannitol, sorbitol and the like; For oral administration in liquid form, the oral pharmacological components may be combined with any pharmaceutically acceptable inert, non-toxic oral vehicle such as ethanol, glycerol, water and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes and the like. The lubricants used in these pharmaceutical forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the present invention can also be coupled with suitable polymers as addressable pharmacological vehicles. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethylapartamidaphenol or polyethylenoxide-polylysine substituted with pamitoyl moieties. In addition, the compounds of the present invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, caprolactone polyepsilon, polyhydroxy, butyric acid, polyorthoesters , polyacetals, polyhydropyran, polycyanoacrylates and block copolymers unfriendly or crosslinked hydrogels.

The pharmaceutical forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per pharmaceutical unit. In these pharmaceutical compositions the active ingredient will usually be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

The gelatin capsules may contain active substance and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid or the like. Similar diluents can be used to prepare tablets in compressed form. Both tablets and capsules can be manufactured as prolonged release products to provide continuous medication release over a period of hours. Tablets in compressed form may be coated with sugar or coated with film to mask any unpleasant taste and protect the tablet from the atmosphere or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid pharmaceutical forms for oral administration may contain dye and saporiferous to increase patient acceptance.

In general, water, a suitable oil, saline solution, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable vehicles for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulphite or ascorbic acid, alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical vehicles are described in Remington’s Pharmaceutical Sciences, Mack Publishing Company, a conventional reference text in this field.

When the compounds of the present invention are combined with other anticoagulant agents, for example, a daily dosage may be from about 0.1 to 100 milligrams of the compound of the present invention and from about 1 to 7.5 milligrams of the second anticoagulant, by kilogram of body weight of the patient. For a tablet dosage form, the compounds of the present invention can generally be present in an amount of about 5 to 10 milligrams per pharmaceutical unit and the second anticoagulant in an amount of about 1 to 5 milligrams per pharmaceutical unit.

When the compounds of the present invention are administered in combination with an antiplatelet agent, as a general guide, typically a daily dosage may be from about 0.01 to 25 milligrams of the compound of the present invention and from about 50 to 150 milligrams of the antiplatelet agent. , preferably about 0.1 to 1 milligram of the compound of the present invention and about 1 to 3 milligrams of antiplatelet agents, per kilogram of the patient's body weight.

When the compounds of the present invention are administered in combination with thrombolytic agent, typically a daily dosage may be from about 0.1 to 1 milligram of the compound of the present invention, per kilogram of the patient's body weight and, in the case of thrombolytic agents, the usual dosage of the thrombolytic agent when administered can only be reduced by approximately 70-80% when administered with a compound of the present invention.

When two or more of the above second therapeutic agents are administered with the compound of the present invention, generally the amount of each dwarf compound typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of therapeutic agents when administered in combination.

Particularly when provided as a simple pharmaceutical unit, there is the potential of a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single pharmaceutical unit they are formulated so that although the activity principles are combined in a single pharmaceutical unit, the physical contact between the active ingredients is minimized (it is say, it comes down). For example, an active ingredient may be enteric coated. By enteric coating of one of the active ingredients, it is possible not only to minimize contact between the combined active ingredients, but it is also possible to control the release of one of these components in the gastrointestinal tract so that one of these components is not free in the stomach but free in the intestines. One of the active ingredients can also be coated with a material that effects prolonged release along the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. In addition, the extended-release component may be enteric coated additionally so that the release of this component occurs only in the intestine. Another approach would involve the formulation of a combination product in which one component is coated with an enteric and / or prolonged release polymer and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as are known in the art, to further separate the active components. The polymeric coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, administered in a simple pharmaceutical form or administered separately but at the same time, will be readily apparent to those skilled in the art. , once they have the present disclosure.

Claims (13)

1. A compound of Formula (I): or a stereoisomer or pharmaceutically acceptable salt or solvate thereof, in which: A is substituted with 0-1 R1 and 0-2 R2 and is selected from; C3-7 cycloalkyl, phenyl, naphthyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl, benzoimidazolyl, benzoisoxazolyl, isoquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinazolinyl, 1H -quinazolin-4-onyl,. 2H-isoquinolin-1-onyl, 3H-quinazolin-4onyl, 3,4-dihydro-2H-isoquinolin-1-onyl, 2,3-dihydroisoindolinonyl and phthalazinyl; the group is selected from: Z is -CH (R11) -; L is -C (O) NH-; R1 is, independently each time it appears, F, Cl, Me, Et, -NH2, C (= NH) NH2, -C (O) NH2, -CH2NH2, CH2CH2NH2, -CH2NHCO2Bn, -CH2NHCO2 (t-Bu), -CH (Me) NH2, -CMe2NH2, -NHEt, -NHCO2 (f-Bu), -NHCO2Bn, -SO2NH2ORa or -CH2R1a; R1a is H, -C (= NR8a) NR7R8, -NHC (= NR8a) NR7R8, -NR8CR8 (= NR8a), -NR7R8, -C (O) NR8R9, F, OCF3, CF3, ORa, SRa, CN, - NR8SO2NR8R9, -NR8SO2Rc, -S (O) p-C1-4alkyl, -S (O) p-phenyl or - (CF2) rCF3; R2 is, independently each time it appears, H, = O, F, Cl, Br, I, OCF3, CF3, CHF2, CN, NO2, ORa, SRa, 20 C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7R8, -C (O) NR7R8, -NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) 2Rc, -S (O) Rc, -S (O) 2Rc, C1-6 alkyl substituted with 0-2 R2a, C2-6 alkenyl substituted with 0-2 R2a, C2-6 alkynyl substituted with 0-2 R2a, ( CH2) C3-10carbocycle substituted with 0-3 R2b or - (CH2) 5-10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, in the that said heterocycle is substituted with 0-3 R2b; R2a is, independently each time it appears, H, F, Cl, Br, I, = O, = NR8, CN, OCF3, CF3, ORa, SRa, -NR7R8, -C (O) NR8R9, -NR7C (O ) Rb, -S (O) pNR8R9, -NR8SO2Rc, -S (O) Rc or -S (O) 2Rc; R2b is, independently each time it appears, H, F, Cl, Br, I, = O, = NR8, CN, NO2, ORa, SRa, -C (O) Ra, C (O) ORa, -OC (O ) Ra, -NR7R8, -C (O) NR7R8, -NR7C (O) Rb, -S (O) pNR8R9, -SO2Rc, -NR8SO2NR8R9, -NR8SO2Rc, (CF2) rCF3, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C3-6 cycloalkyl, C1-4 haloalkyl or C1-4 haloalkyloxy; alternatively, when R1 and R2 are substituted on adjacent atoms in the ring, they can be taken together with the atoms in the ring to which they are attached to form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0- 4 heteroatoms selected from N, O and S (O) p, wherein said carbocycle or heterocycle is substituted with 0-2 R2b; R3 is -CO2H, -CO2Me, -C (O) NHCH2CO2H, -C (O) NHCH2CO2Et, -C (O) NH2, -C (O) NHMe, -C (O) NHBn, - (CH2) rhenyl substituted with 0 -2 R3a and 0-1 R3d, naphthyl substituted with 0-2 R3a and 0-1 R3d, indanyl substituted with 0-2 R3a and 0-1 R3d or a 5-10 membered heterocycle comprising: carbon atoms and 1 -4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3a and 0-1 R3d; R38 is, independently each time it appears, = OF, Cl, Br, I, OCF3, CF3, CN, NO2, - (CH2) rOR3b, (CH2) rSR3b, - (CH2) rNR7R8, -C (= NR8a) NR8R9, -NHC (= NR8a) NR7R8, -NR8CR8 (= NR8a), - (CH2) rNR8C (O) R3b, = NR8, (CH2) rNR8C (O) R3b, - (CH2) rNR8C (O) 2R3b, - (CH2 ) rS (O) pNR8R9, - (CH2) rNR8S (O) pR3c, -S (O) R3c, -S (O) 2R3c, -C (O) C1-4 alkyl, - (CH2) rCO2R3b, - (CH2 ) rC (O) NR8R9, - (CH2) rOC (O) NR8R9, -NHCOCF3, -NHSO2CF3, -SO2NHR3b, -SO2NHCOR3c, -SO2NHCO2R3c, -CONHSO2R3c, -NHSO2R3c, -CalHalkyl-4, haloalkyl-4-haloalkyl-4-haloalkyl-4-haloalkyl-4 -, C1-6 alkyl substituted with R3d, C2-6 alkenyl substituted with R3d, C1-6 alkynyl substituted with R3d, C3-6 cycloalkyl substituted with 0-1 R3d, - (CH2) C3-10 carboxy substituted with 0-3 R3d or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O; and S (O) p, wherein said heterocycle is substituted with 0-3 R3d; alternatively, when two R3a groups are substituted on adjacent atoms, they can be taken together with the atoms to which they are attached to form a C3-10 carbocycle substituted with 0-2 R3d or a 5-10 membered heterocycle comprising: atoms of carbon and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3d; R3b is, independently each time it appears, H, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) C3 carboxy -10 substituted with 0-3 R3d or - (CH2) 5-10 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 R3d; R3c is, independently each time it appears, C1-6 alkyl substituted with 0-2 R3d, C2-6 alkenyl substituted with 0-2 R3d, C2-6 alkynyl substituted with 0-2 R3d, - (CH2) C3-10 carboxy substituted with 0-3 R3d or - (CH2) 5-10 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 R3d; R3d is, independently each time it appears, H, = O, - (CH2) rORa, F, Cl, Br, CN, NO2, - (CH2) rNR7R8, C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7C (O) Rb, -C (O) NR8R9, -S (O) 2NR8R9, -NR8S (O) 2NR8R9, -NR8S (O) 2Rc, -S (O) pRc, - (CF2 ) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, - (CH2) C3-10 carbocarcycle, substituted with 0-3 Rd or - (CH2) 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 Rd; R4 is H, F, Cl, Br, OMe, NH2, CF3, CO2H, CO2Me, CO2Et, -CONR8R9, C1-6 alkyl substituted with 0-2 R4a, phenyl substituted with 0-2 R4b or a 5-10 heterocycle members selected from: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-3 R4b; R4a is, independently each time it appears, H, F, = O, C1-4 alkyl, ORa, SRa, CF3, CN, NO2, -C (O) Ra, C (O) ORa, -NR7R8, -C ( O) NR8R9, -NR7C (O) Rb, -S (O) pNR8R9, -NR8S (O) pRc, -S (O) Rc or -S (O) 2Rc; R4b is, independently each time it appears, H, = O, = NR8, F, Cl, Br, I, ORa, SRa, CN, NO2, -NR7R8; C (O) Ra, -C (O) ORa, -NR7C (O) Rb, -C (O) NR8R9, -SO2NR8R9, -S (O) 2Rc, C1-6 alkyl, C2-6 alkenyl, C2- alkynyl 6, C3-6 cycloalkyl, C1-4 haloalkyl or C1-4 haloalkyloxy; alternatively, the R3 and R4 groups when located in adjacent atoms, can be taken together to form a C3-10 carbocycle substituted with 0-2 R3d or a 5-10 membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 02 R3d; R6 is H, R7 is, independently each time it appears, H, C1-6 alkyl, = (CH2) n-C3-10 carbocycle, - (CH2) n- (5-10 membered heteroaryl), -C (O ) Rc, -CHO, -C (O) 2Rc, -S (O) 2Rc, -CONR8Rc, -OCONHRc, -C (O) O- (C1-4 alkyl) OC (O) (C1-4 alkyl) or -C (O) O- (C1-4 alkyl) OC (O) - (C6-10 aryl); wherein said alkyl, carbocycle, heteroaryl and aryl are optionally substituted with 0-2 Rf; R8 is, independently each time it appears, H, C1-6 alkyl, - (CH2) n-phenyl or - (CH2) 5-10 membered n-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 Rf; alternatively, R7 and R8, when bound to the same nitrogen, combine to form a 5-10 membered heterocycle comprising: additional carbon atoms and 0-2 heteroatoms selected from N, O and S (O) p, in the that said heterocycle is substituted with 0-2 Rd; R8a is, independently each time it appears, R7, OH, C1-6 alkyl, C1-4 alkoxy, (C6-10 aryl) -C 1-4 alkoxy, (CH2) n-phenyl, - (CH2) n- (heteroaryl of 5-10 members); wherein said phenyl, aryl and heteroaryl are optionally substituted with 0-2 Rf R9 is, independently each time it appears, H, C1-6 alkyl or - (CH2) n-phenyl; wherein said alkyl and phenyl are optionally substituted with 0-2 Rf; R9a is, independently each time it appears, H, C1-6 alkyl or - (CH2) n-phenyl; alternatively, R8 and R9, when bound to the same nitrogen, combine to form a 5-10 membered heterocycle comprising: additional carbon atoms and 0-2 heteroatoms selected from N, O and S (O) p, in which said heterocycle is substituted with 0-2 Rd; R11 it is phenylmethyl, 4-imidazolylmethyl, 4-thiazolylmethyl, 2-benzothiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 3-indolylmethyl, 2-benzoimidazolylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, CH2-methylhethyl, CH2-CH2methyl NH, cyclohethyl2CH, cyclohethyl2CH, cyclohethyl2CH, cyclohethyl2CH, cyclohethyl2CH, cyclohethyl2CH, cyclohethyl2CH, cyclohethyl2CH, cyclohethylmethyl, CH2-CH2methyl NH, cyclohethyl2CH, cyclohethyl2CH, cyclohethyl2H, NH2 -pyridin-2-yl or - (CH2) 2C (O) NHCH2-pyridin-2-yl, wherein each phenyl, naphthyl, imidazolyl, thiazolyl, benzothiazolyl, pyridinyl or cyclohexyl group is substituted with 0-2 R11b; R11b is, independently each time it appears, H, F, Cl, Br, CF3, OMe, OCF3; OCHF2, OPh, OBn, NO2, -NH2, -C (O) Ph, -NHC (O) Bn, -NHC (O) CH2CH2Ph, -NHS (O) 2Ph, -C (O) NR7R8, -NR7C (O ) Rb, -S (O) pNR8R9, -NR8S (O) pRc, Ph or Bn; alternatively, when two R11b groups are substituents on adjacent atoms, they can be taken together with the atoms to which they are attached to form a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O and S (O) py substituted with 0-2 Rg; Ra is, independently each time it appears, H, CF3, C1-6 alkyl, - (CH2) r3-7 cycloalkyl, - (CH2) C6-10 raryl or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p; wherein said cycloalkyl, aryl and heterocycle groups are optionally substituted with 0-2 Rf; Rb is, independently each time it appears, CF3, OH, C1-4 alkoxy, C1-6 alkyl, - (CH2) C3-10 carboxy substituted with 0-3 Rd or - (CH2) 5 to 10 membered r-heterocycle which comprises: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p and substituted with 0-2 Rd; Rc is, independently each time it appears, CF3, C1-6 alkyl substituted with 0-2 Rf, C3-6 cycloalkyl substituted with 0-2 Rf, C6-10 aryl, 5-10 membered heteroaryl, (C6-10 aryl ) -C 1-4 alkyl or (5-10 membered heteroaryl) -C 1-4 alkyl, wherein said aryl and heteroaryl groups are substituted with 0-3 Rf; Rd is, independently each time it appears, H, = O, = NR8, ORa, F, Cl, Br, I, CN, NO2, -NR7R8, -C (O) Ra, C (O) ORa, -OC ( O) Ra, -NR8C (O) Ra, -C (O) NR7R8, -SO2NR8R9, -NR8SO2NR8R9, -NR8SO2-C1-4 alkyl, -NR8SO2CF3, -NR8SO2-phenyl, -S (O) 2CF3, -S ( O) p-C1-4 alkyl, -S (O) p-phenyl, - (CF2) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re or C2-6 alkynyl substituted with 0-2 Re; Re is, independently each time it appears, = O ORa, F, Cl, Br, I, CN, NO2, -NR8R9, -C (O) Ra, -C (O) ORa, -NR8C (O) Ra, - C (O) NR7R8, -SO2NR8R9, -NR8SO2NR8R9, -NR8SO2-C1-4 alkyl, -NR8SO2CF3, -NR8SO2-phenyl, S (O) 2CF3, -S (O) p-C1-4 alkyl, -S (O ) p-phenyl or - (CF2) rCF3; Rf is, independently each time it appears, H, = O, - (CH2) rORg, F, Cl, Br, I, CN, NO2, -NR9aR9a, -C (O) Rg, C (O) ORg, -NR9aC (O) Rg, -C (O) NR9aR9a, -SO2NR9aR9a, -NR9aSO2NR9aR9a, -NR9aSO2-C1-4 alkyl, -NR9aSO2CF3, NR9aSO2-phenyl, -S (O) 2CF3, -S (O) p-C1-alkyl 4, -S (O) p-phenyl, - (CF2) rCF3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or - (CH2) n-phenyl; Rg is, independently each time it appears, H, C1-6 alkyl, or - (CH2) n-phenyl; n, each time it appears, is selected from 0, 1, 2, 3 and 4; p, each time it appears, is selected between 0, 1 and 2; and r, each time it appears, is selected from 0, 1, 2, 3 and 4.

2.

A compound according to claim 1, wherein:

R3 is phenyl substituted with 0-2 R3a, naphthyl substituted with 0-2 R3a, indanone substituted with 0-2 R3a or a 5-10 membered heterocycle substituted with 0-2 R3a and selected from: pyridine, pyridinone, pyrimidine, pyrrole , pyrazole, indole, 2-oxoindole, indazole, benzofuran, benzothiophene, benzoimidazole, benzoisoxazole, benzoxazole, quinazoline, 3H-quinazolin-4-one, phthalazine, 2H-phthalazin-1-one, 1H-quinolin-4-one and 2H-3,4-dihydroisoquinolin-1one.

3.

A compound according to claim 2, wherein:

A is 4-aminomethyl-cyclohexyl, 4-carbamoyl-cyclohexyl, 4-amidino-phenyl, 4-benzyloxycarbonylamino-cyclohexyl, phenyl, 1,2,3,4-tetrahydronaft-2-yl, 4-aminomethyl-phenyl, 4-carbamoyl-phenyl, 4-aminomethyl-2-fluorophenyl, 2-F-5-OMephenyl, 2-F-4- Me-phenyl, 2-F-4-Cl-phenyl, 2-F-4-carbamoylphenyl, 2-OMe-4-carbamoyl-phenyl, 3-OMe-4-carbamoylphenyl, 2-Et-4-aminomethyl-phenyl, 2-NH2-pyridin-4-yl, 2-ethylamino-4-aminomethyl-phenyl, 1-aminoisoquinolin-6-yl, 1NH2-5,6,7,8-tetrahydroisoquinolin-6-yl, 1-NH2-1, 2,3,4-tetrahydroisoquinotin-6-yl, 3-NH2-benzoisoxazol-5-yl, 3NH2-benzoisoxazol-6-yl, 3-NH2-indazol-6-yl, 3-NH2-indazol-5-yl, 1-Me-3-NH2-indazoli-6-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-1-on-6-yl, isoquinolin-6-yl, 1-NH2-isoquinolin-6-yl, 1-NH25,6,7,8-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 1H-quinazolin-4-onyl, 2H- soquinolin-1-onyl, 3H-quinazolin-4-onyl, 3,4-dihydro-2H-isoquinolin-1-onyl, 2,3-dihydroisoindolinonyl or 1-NH2-phthalazin-6-yl; Y R3 it is phenyl, 3-OH-phenyl, 3,4-methylenedioxyphenyl, 2-naphthyl, 1-naphthyl, 3-NMe2-phenyl, 4-benzyloxy-phenyl, 4-tbutoxyphenyl, 4-methylsulfonylphenyl, 4-Cl-phenyl, 2 -OMe-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 2-F-phenyl, 3-F-phenyl, 4-Fphenyl, 4-Br-phenyl, 3-CF3-phenyl, 3-NH2-phenyl , 4-NH2-phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-CO2H-phenyl, 4-CO2Hphenyl, 3-CO2Me-phenyl, 4-CO2Me-phenyl, 3-OH-phenyl, 3-CH2CO2H -phenyl, 3-CH2CO2Me-phenyl, 3-CH2CO2Et-phenyl, 3-CONH2-phenyl, 4-CONH2-phenyl, 4-CH2CO2Et-phenyl, 3-CH2C (O) NH2-phenyl, 4-C (O) NHMe -phenyl, 3-NHCOMphenyl, 4-NHCO2Me-phenyl, 2,4-diF-phenyl, 3-F-4-CN-phenyl, 3-CN-4-F-phenyl, 3-OMe-4-CONH2-phenyl , 3-OH-4CONH2-phenyl, 3-NH2-4-CONH2-phenyl, 3-CO2Me-4-NH2-phenyl, 3-CO2H-4-NH2-phenyl, 3-CONH2-4-NH2-phenyl, 3CO2H -4-F-phenyl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, 3-NH2-pyrazol-5-yl, pyridyl-2-yl, pyrid-3-yl, pyrid-4 -yl, 2-Fpyrid-4-yl, 2-F-pyrid-5-yl, 2-OMe-pyrid-4-yl, 2-OMe-pyrid-5-yl, 2-NH2-pyrid-3-yl , 2-NH2-pyrid-4-yl, 2-NH2-pyrid-5-yl or, 2-NH2-pyrid-6-yl, -2-NHMe-pyrid-4-yl, 2-NMe2-pyrid-4-yl, 2-CONH2-pyrid-4-yl, 2-CO2H-pyrid-4 -yl, 2-CONH2-pyrid-5yl, 2-OMe-6-NH2-pyridyl-4-yl, 4-NH2-pyrimidin-6-yl, 4-NH2-pyrimidin-2-yl, 2-NH2-pyrimidin -4-yl, 2-NH2-pyrimidin-5yl, indole-5-yl, indole-6-yl, indazol-5-yl, indazol-6-yl, 3-OH-indazol-5-yl, 3-OH -indazol-6-yl, 3-OMe-indazol-5-yl, 3-OMe-indazol-6-yl, 3-NH2-indazol-5-yl, 3-NH2-indazol-6-yl, benzoisoxalol-6 -yl, benzoisoxazol-5-yl, 3-NH2benzoisoxazol-5-yl, 3-NH2-benzoisoxazol-6-yl, 4-OMe-quinolin-6-yl, 1-NH2-phthalazin-6-yl, 1-NH2 -phthalazin-7-yl, 4NH2-quinazolin-6-yl, 2-Me-4-amino-quinazolin-6-yl, 4-NH2-quinazolin-7-yl, 2-Me-4-NH2-quinazolin-7 -yl, 2,4-diNH2-quinazolin-7-yl, 4. A compound according to claim 1, wherein: R1 is, independently each time it appears, F, Cl, Me, Et, -NH2, -C (= NH) NH2, = C (O) NH2, -CH2NH2, - CH2NHCO2Bn, -CH2NHCO2 (t-Bu), -CH (Me) NH2, -CMe2NH2, -NHEt, -NHCO2 (t-Bu), -NHCO2Bn, -SO2NH2, ORa or - CH2R1a; R2 is, independently each time it appears, F, Cl, Me, OMe, OEt, Bn, -CH2OMe, -CH2OEt or -CH2OPh; R3 is -CO2H, -CO2Me, -C (O) NHCH2CO2H, -C (O) NHCH2CO2Et, -C (O) NH2, -C (O) NHMe, -C (O) NHBn, substituted phenyl with 0-2 R3a, naphthyl substituted with 0-2 R3a, indane substituted with 0-2 R3a or a 5-10 membered heterocycle that comprises: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-2 R3a; R3a is, independently each time it appears, = O, F, Cl, Br, Me, CN, OH, NH2, OMe, O (t-Bu), OBn, CF3, CO2H, CO2Me, -CH2CO2H, -CH2CO2Me, -CH2CO2Et, -NHCOMe, -CONH2, -CH2CONH2, -CONHMe, -CONMe2, C (= NH) NH2, -NR7R8, SO2M -SO2NH2, Ph or 2-oxo-piperidin-1-yl; in which two of the R3a groups located in Adjacent atoms can be taken together to form a 5-10 membered heterocycle with 0-2 R3d; R3d is, independently each time it appears, H, = O, - (CH2) rORa, F, Cl, Br, CN, NO2, - (CH2) rNR7R8, C (O) Ra, -C (O) ORa, -OC (O) Ra, -NR7C (O) Rb, -C (O) NR8R9, -S (O) 2NR8R9, -NR8S (O) 2NR8R9, -NR8S (O) 2Rc, -S (O) pRc, - (CF2 ) rCF3, C1-6 alkyl substituted with 0-2 Re, C2-6 alkenyl substituted with 0-2 Re, C2-6 alkynyl substituted with 0-2 Re, - (CH2) C3-10 r-carbocycle substituted with 0- 3 Rd or - (CH2) 5 to 10 membered r-heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O and S (O) p, wherein said heterocycle is substituted with 0-3 Rd; R4 is H, F, Cl, Br, OMe or NH2; R6 is H; Y R8a is, independently each time it appears, R7, OH, C1-6 alkyl, C1-4 alkoxy, (C6-10 aryl) -C 1-4 alkoxy; at that said aryl is optionally substituted with 0-2 Rf.

5.

A compound according to claim 4, wherein:

R3 is phenyl substituted with 0-2 R3a, naphthyl substituted with 0-2 R3a, indanone substituted with 0-2 R3a or a 5-10 membered heterocycle substituted with 0-2 R3a and selected from: pyridine, pyridinone, pyrimidine, pyrrole , pyrazole, indole, 2-oxoindole, indazole, benzofuran, benzothiophene, benzoimidazole, benzoisoxazole, benzoxazole, quinazoline, 3H-quinazolin-4-one, phthalazine, 2H-phthalazin-1-one, 7H-quinolin4-2, isoH -3,4-dihydroisoquinolin-1one.

6.

A compound according to claim 5, wherein:

A is 4-aminomethyl-cyclohexyl, 4-carbamoyl-cyclohexyl, 4-amidino-phenyl, 4-benzyloxycarbonylamino-cyclohexyl, phenyl, 1,2,3,4-tetrahydronaft-2-yl, 4-aminomethyl-phenyl, 4- carbamoyl-phenyl, 4-aminomethyl-2-fluorophenyl, 2-F-5-OMephenyl, 2-F-4-Me-phenyl, 2-F-4-Cl-phenyl, 2-F-4-carbamoyl-phenyl, 2-OMe-4-carbamoyl-phenyl, 3-OMe-4-carbamoylphenyl, 2-Et-4-aminomethyl-phenyl, 2-NH2-pyridin-4-yl, 2-ethylamino-4-aminomethyl-phenyl, 1- aminoisoquinolin-6-yl, 1NH2-5,6,7,8-tetrahydroisoquinolin-6-yl, 1-NH2-1,2,3,4-tetrahydroisoquinolin-6-yl, 3-NH2-benzoisoxazol-5-yl, 3NH2-benzoisoxazol-6-yl, 3-NH2-indazol-6-yl, 3-NH2-indazol-5-yl, 1-Me-3-NH2-indazoli-6-yl, 1,2,3,4-tetrahydroisoquinolin- 3-yl, 1,2,3,4-tetrahydroisoquinolin-1-on-6-yl, isoquinolin-6-yl, 1-NH2-isoquinolin-6-yl, 1-NH25,6,7,8-tetrahydroisoquinolin- 6-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 1H-quinazolin-4-onyl, 2H-isoquinolin-1-onyl, 3H-quinazolin-4-onyl, 3,4-dihydro-2H- isoquinolin-1-onyl, 2,3-dihydroisoindolinonyl or 1-NH2 -phthalazin-6-yl; Y R3 it is phenyl, 3-OH-phenyl, 3,4-methylenedioxyphenyl, 2-naphthyl, 1-naphthyl, 3-NMe2-phenyl, 4-benzyloxyphenyl, 4-tbutoxyphenyl, 4-methylsulfonylphenyl, 4-Cl-phenyl, 2-OMe -phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 2-F-phenyl, 3-F-phenyl, 4-Phenyl, 4-Br-phenyl, 3-CF3-phenyl, 3-NH2-phenyl, 4 -NH2-phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-CO2H-phenyl, 4-CO2Hphenyl, 3-CO2Me-phenyl, 4-CO2Me-phenyl, 3-OH-phenyl, 3-CH2CO2H-phenyl , 3-CH2CO2Me-phenyl, 3-CH2CO2Et-phenyl, 3-CONH2-phenyl, 4-CONH2-phenyl, 4-CH2CO2Et-phenyl, 3-CH2C (O) NH2-phenyl, 4-C (O) NHMe-phenyl , 3-NHCOMephenyl, 4-NHCO2Me-phenyl, 2,4-diF-phenyl, 3-F-4-CN-phenyl, 3-CN-4-F-phenyl, 3-OMe-4-CONH2-phenyl, 3 -OH-4CONH2-phenyl, 3-NH2-4-CONH2-phenyl, 3-CO2Me-4-NH2-phenyl, 3-CO2H-4-NH2-phenyl, 3-CONH2-4-NH2-phenyl, 3CO2H-4 -F-phenyl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, 3-NH2-pyrazol-5-yl, pyridyl-2-yl, pyrid-3-yl, pyrid-4-yl , 2-Fpirid-4-yl, 2-F-pyrid-5-yl, 2-OMe-pyrid-4-yl, 2-OMe-pyrid-5-yl, 2-NH2-pyrid-3-yl, 2 -NH2-pyrid-4-yl, 2-NH2-pyrid-5-yl , 2-NH2-pyrid-6-yl, 2-NHMe-pyrid-4-yl, 2-NMe2-pyrid-4-yl, 2-CONH2-pyrid-4-yl, 2-CO2H-pyrid-4-yl , 2-CONH2-pyrid-5yl, 2-OMe-6-NH2-pyridyl-4-yl, 4-NH2-pyrimidin-6-yl, 4-NH2-pyrimidin-2-yl, 2-NH2-pyrimidin-4 -yl, 2-NH2-pyrimidin-5yl, indole-5-yl, indole-6-yl, indazol-5-yl, indazol-6-yl, 3-OH-indazol-5-yl, 3-OH-indazole -6-yl, 3-OMe-indazol-5-yl, 3-OMe-indazol-6-yl, 3-NH2-indazol-5-yl, 3-NH2-indazol-6-yl, benzoisoxalol-6-yl , benzoisoxazol-5-yl, 3-NH2benzoisoxazol-5-yl, 3-NH2-benzoisoxazol-6-yl, 4-OMe-quinolin-6-yl, 1-NH2-phthalazin-6-yl, 1-NH2-phthalazin -7-yl, 4NH2-quinazolin-6-yl, 2-Me-4-amino-quinazolin-6-yl, 4-NH2-quinazolin-7-yl, 2-Me-4-NH2-quinazolin-7-yl , 2,4-diNH2-quinazolin-7-yl, 7. A compound according to claim 6, wherein: A is 4-aminomethyl-cyclohexyl; and the group is or 8. A compound according to claim 4, wherein the compound is selected from: 4-aminomethyl- [2-phenyl-1- (4-phenyl-pyridin-2-yl) -ethyl] -trans cyclohexanecarboxamide, 10 4-Aminomethyl- [1- (1-oxy-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -cyclohexanecarboxamide, 3- (2- {1- [trans- (4-Acid) methyl ester -aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} -pyridin-4-yl) -benzoic, 4-aminomethyl- {1- [4- (3-acetylamino-phenyl) -pyridin-2-yl] -2-phenyl -ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl- {1- [4- (3-hydroxy-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl- {1 - [4- (3-amino-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-Aminomethyl - [(S) -2-phenyl-1- (4-phenyl-pyrimidin-2-yl) -ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl - [(S) -1- (6-oxo -4-phenyl-1,6-dihydro-pyrimidin-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl-N- {1- [4- (3-cyano-phenyl) -pyridine -2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 3- (2- {1- [trans- (4-aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} -pyridin-4-yl) -benzoic acid, 4-aminomethyl-N- {1- [4- (4-methoxy-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-Aminomethyl-N- {1- [4- (3-methoxy-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N- {2-phenyl- 1- [4- (1H-Pyrrol-3-yl) -pyridin-2-yl] -ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N- (1- [3,4 '] bipyridinyl-2'-yl -2-phenyl-ethyl) -trans-cyclohexanecarboxamide, 4-aminomethyl- [1- (2'-amino- [4,4 '] bipyridinyl-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4 -aminomethyl-N- {1- [4- (2-methoxy-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-Aminomethyl-N- {1- [4- (3-cyano-4-fluoro-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 3- (2- {1 - [(4-Aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} -pyridin-4-yl) -benzamide, 4- (2- {1 - [(4-aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} -pyridin-4-yl) -benzoic, 4-aminomethyl-N- {1- [4- (4-cyano-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, (+ ) -4-aminomethyl-N- {1- [4- (4-cyano-3-fluoro-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 30 (-) - 4-aminomethyl-N- {1- [4- (4-cyano-3-fluoro-phenyl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4- ( 2- {1 - [(4-aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} -pyridin-4-yl) -benzamide, 4-aminomethyl- {1- [4- (3-amino-1H-indazol-6 -yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, (+) - 4-aminomethyl-N- {1- [4- (3-amino-1H-indazol-6-yl ) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N- {1- [4- (3-amino-1,2-benzoisoxazol-6-yl) -pyridin- 2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 35 (+) - 4-aminomethyl-N- {1- [4- (3-amino-1,2-benzoisoxazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide , (-) - 4-aminomethyl-N- {1- [4- (3-amino-1,2-benzoisoxazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide , 4-aminomethyl-N- {1- [4- (3-hydroxy-1H-indazol-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N - {1- [4- (3-amino-1H-indazol-5-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N- {1- [4 - (3-amino-1,2-benzoisoxazol-5-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-Aminomethyl-N- {1- [4- (3-hydroxy-1H-indazol-5-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl- [1- (6-methoxy-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl- [1- (6-oxo-4-phenyl- 1,6-dihydro-pyridin-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl- [1- (1-methyl-6-oxo-4-phenyl-1,6-dihydro- pyridin-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl- [1- (6-amino-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -trans- cyclohexanecarboxamide, 4-aminomethyl- [1- (6-chloro-4-phenyl-pyridin-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl-N- {1- [4- (3 -amino-1H-indazol-6-yl) -6-oxo-1,6-dihydro-pyridin-2-yl] -2-phenyl-ethyl} -transcyclohexanecarboxamide, 4-aminomethyl-N- {1- [4- (3-amino-1,2-benzoisoxazol-6-yl) -6-oxo-1,6-dihydro-pyridin-2-yl] -2-phenyl-ethyl} -transcyclohexanecarboxamide, 4-aminomethyl-N- {1 - [4- (1H-indazol-5-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N- (1- [4,4 '] bipyridinyl-2 -yl-2-phenyl-ethyl) -trans-cyclohexanecarboxamide, 4-aminomethyl-N- (1- (2'-fluoro- [4,4 '] bipyridinyl-2-yl-2-phenyl-ethyl) -trans- cyclohexane carboxamide, 4-aminomethyl-N- [1- (2'-methylamino- [4,4 '] bipyridinyl-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl-N- [1- (2'-dimethylamino- [4,4 '] bipyridinyl-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl-N- [1- (2'-methoxy- [4,4' ] bipyridinyl-2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl-N- [1- (2'-oxo-1 ', 2'-dihydro- [4,4'] bipyridinyl- 2-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 4-aminomethyl-N- (1- (6-fluoro- [3,4 '] bipyridinyl-2'-yl-2-phenyl-ethyl) - trans-cyclohexanecarboxamide, 4-aminomethyl-N- (1- (6-amino- [3,4 '] bipyridinyl-2'-yl-2-phenyl-ethyl) -trans-cyclohexanecarboxamide, 4-aminomethyl-N- (1 - (6-Methoxy- [3,4 '] bipyridinyl-2'-yl-2-phenyl-ethyl) -trans-cyclohexanecarboxamide, 4-aminomethyl-N- [1- (6-oxo-1,6-dihydro- [3,4 '] bipyridinyl-2'-yl) -2-phenyl-ethyl] -trans-cyclohexanecarboxamide, 5- (2- {1 - [(4-aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} - pyridin-4-yl) -2-fluoro-benzoic, 4-aminomethyl-N- {2-phenyl-1- [4- (1H-pyrazol-4-yl) -pyridin-2-yl] -ethyl} -trans -cyclohexane carboxamide, 2-amino-5- (2- {1- [trans- (4-aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} -pyridin-4-yl) benzoic acid methyl ester, 4-aminomethyl-N- {1- [4- (4-Oxo-3,4-dihydro-quinazolin-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexane-carboxamide, 2-amino-5 acid - (2- {1- [trans-4-aminomethyl-cyclohexanecarboxamido] -2-phenyl-ethyl} -pyridin-4-yl) -benzoic acid, 4-aminomethyl-N- {1- [4- (4-methoxy- quinolin-6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N- {1- [4- (4-oxo-1,4-dihydro-quinolin- 6-yl) -pyridin-2-yl] -2-phenyl-ethyl} -trans-cyclohexanecarboxamide, 4-aminomethyl-N- {1- [4- (4-amino-phenyl) -pyridin-2-yl] - 2-Phenyl-ethyl} -trans-cyclohexanecarboxamide and [4- (2- {1- [4-aminomethyl-cyclohexanecarboamido] -2-phenyl-ethyl} -pyridine-4-yl) -phenyl] -carbamic acid methyl ester , or a stereoisomer or pharmaceutically acceptable salt or solvate thereof.

9.

A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1-8.

10.

A compound of any one of claims 1-8 for use in therapy.

eleven.

The use of a compound of any one of claims 1-8 for the preparation of a medicament for the treatment of a thromboembolic disorder.

12.

Use according to claim 11, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders and thromboembolic disorders in the chambers of the heart.

13.

Use according to claim 11, wherein the thromboembolic disorder is selected from the unstable angina group, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, sudden ischemic 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, renal embolism, pulmonary embolism and thrombosis resulting from

(a) prosthetic valves or other implants, (b) permanent catheters, (c) vascular stents, (d) cardiopulmonary bypass, (e) hemodialysis or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis