Carrying non-aromatic P2 , New macrocycle of Factor XIA

Abstract

The present invention provides compounds of formula (I): or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein all variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. The present invention also relates to pharmaceutical compositions comprising these compounds and methods of using these compositions to treat thromboembolic and / or inflammatory conditions.

Description

[0001] The present application is a divisional application of the Chinese patent application No. 201680044102.0 (filing date: July 28, 2016, invention title: New macrocycle of Factor XIA carrying a non-aromatic P2′ group).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application Serial No. 62 / 198,188, filed on July 29, 2015, the entire contents of which are incorporated herein by reference. Technical Field

[0004] The present invention generally relates to novel macrocyclic compounds and analogs thereof that are inhibitors of factor XIa and / or plasma kallikrein, compositions containing them, and methods of using them, for example, for treating or preventing thromboembolic disorders, or for treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Background Art

[0005] Despite anticoagulants such as warfarin Heparin, low molecular weight heparin (LMWH), and synthetic pentasaccharides and antiplatelet agents such as aspirin and clopidogrel Available, but thromboembolic disease is still the main cause of death in developed countries. Oral anticoagulant warfarin inhibits the post-translational maturation of coagulation factors VII, IX, X and prothrombin (prothrombin), and has been shown to be effective in venous and arterial thrombosis. However, its use is limited by its narrow therapeutic index, slow onset of therapeutic action, numerous diets and drug interactions and the need for monitoring and dosage adjustment. Therefore, it is increasingly important to find and develop safe and effective oral anticoagulants for the prevention and treatment of a wide range of thromboembolic disorders.

[0006] One method is to inhibit thrombin generation by targeting the inhibition of coagulation factor XIa (FXIa). Factor XIa is a plasma serine protease involved in regulating the coagulation caused by the combination of tissue factor (TF) and factor VII (FVII) to produce factor VIIa (FVIIa). The generated TF:FVIIa complex activates factor IX (FIX) and factor X (FX), causing the generation of factor Xa (FXa). The generated FXa catalyzes the conversion of prothrombin into a small amount of thrombin, and then this pathway is closed by tissue factor pathway inhibitor (TFPI). The coagulation process is then further propagated by the feedback activation of factors V, VIII and XI via a catalytic amount of thrombin (Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27: 2507-2513 (2007)). The resulting thrombin burst converts fibrinogen to fibrin, which polymerizes to form the structural framework of the blood clot and activates platelets, which are key cellular components of coagulation (Hoffman, M., Blood Reviews, 17: S1-S5 (2003)). Therefore, factor XIa plays a key role in propagating this amplification loop and is therefore an attractive target for antithrombotic therapy.

[0007] Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present in 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 with factor XI. Plasma kallikrein is believed to play a role in many inflammatory conditions. The main inhibitor of plasma kallikrein is the serine protease inhibitor C1 esterase inhibitor. Patients with gene deletions in C1 esterase inhibitors suffer from hereditary angioedema (HAE), which causes intermittent swelling of the face, hands, throat, gastrointestinal tract, and genitals. The blisters formed during acute attacks contain high amounts of plasma kallikrein, which cleaves and releases high molecular weight kininogens of bradykinin that cause increased vascular permeability. Treatment with large protein plasma kallikrein inhibitors has been shown to be effective in treating HAE by preventing the release of bradykinin, which leads to increased vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert Opin. Biol. Ther. 8, p1187-99).

[0008] The plasma kallikrein-kinin system is abnormally abundant in patients with elderly diabetic macular edema. It has been published that vascular kallikrein promotes retinal vascular dysfunction in diabetic rats (A. Clermont et al. "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes, 2011, 60, p1590-98). In addition, the administration of the plasma kallikrein inhibitor ASP-440 slowed down the abnormalities of retinal vascular permeability and retinal blood flow in diabetic rats. Therefore, plasma kallikrein inhibitors should play a therapeutic role to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Other complications of diabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy and neuropathy (all of which are related to plasma kallikrein) may also be considered as targets of plasma kallikrein inhibitors.

[0009] To date, small molecule synthetic plasma kallikrein inhibitors have not been approved for medical use. Large protein plasma kallikrein inhibitors present the risk of allergic reactions, as has been reported for Ecallantide. Therefore, there is still a need for compounds that inhibit plasma kallikrein, which do not induce allergic reactions and are orally administrable. In addition, molecules in the known art are characterized by high polarity and ionizable guanidine or amidine functions. It is well known that such functions may limit intestinal permeability and therefore limit oral performance. SUMMARY OF THE INVENTION

[0010] The present invention provides novel macrocyclic compounds, their analogs, including stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, which are useful as selective inhibitors of serine proteases, particularly factor XIa and / or plasma kallikrein.

[0011] The present invention also provides methods and intermediates for preparing the compounds of the present invention.

[0012] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0013] The compounds of the present invention are useful for the treatment and / or prevention of thromboembolic disorders.

[0014] The compounds of the invention may be useful in treating retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

[0015] The compounds of the invention are useful in therapy.

[0016] The compounds of the present invention can be used for the preparation of medicaments for the treatment and / or prevention of thromboembolic disorders.

[0017] The compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one or two, other pharmaceutical agents.

[0018] These and other features of the present invention will be further described in the subsequent disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0019] In a first aspect, the present disclosure provides, inter alia, compounds of formula (I):

[0020]

[0021] or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein:

[0022] L is independently selected from

[0023]

[0024] ---- is an optional key;

[0025] Q is independently selected from O, NH and CH 2 ;

[0026] Y is independently selected from N and CR 7 ;

[0027] Ring A is independently selected from

[0028]

[0029] R 1 and R 2 independently selected from H, halogen, 0-4 R e Substituted C 1-4 Alkyl, OR b and 1-4 R 6 Substituted C 3-5 Cycloalkyl;

[0030] R 3 independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, 1-5 R 5 Substituted C 2-4 Alkenyl, 1-5 R 5 Substituted C 2-4 Alkynyl, CN, -(CH 2 ) n -OR b 、-(CH2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-(CH 2 ) n -NR a C(N-CN)NR a R a 、-(CH 2 ) n -NR a C(NH)NR a R a 、-(CH 2 ) n -N=CR b NR a R a 、-(CH 2 ) n -NR a C(=O)NR a R a 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NR a C(=S)NR a C(=O)R b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p NR aR a 、-(CH 2 ) n -NR a S(=O) p R c , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group; optionally, two adjacent R 3 The base can be formed by 1-5 R 5 substituted rings;

[0031] R 3a Independently selected from H and C 1-4 alkyl;

[0032] Alternatively, R 3a and R 3 Together, they form a carbon atom and 1 to 3 atoms selected from O, NR 3b , S, wherein the heterocyclic ring is R 3c replace;

[0033] R 3b independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, --(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NHC(=O)OR b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a , 1-5 R 5 Replaced-(CRd R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0034] R 3c Independently selected from H, NO 2 , =O, halogen, 1-5 R 5 Substituted C 1-4 Alkyl, 1-5 R 5 Substituted C 2-4 Alkenyl, 1-5 R 5 Substituted C 2-4 Alkynyl, CN, -(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-(CH 2 ) n -NR a C(N-CN)NR a R a 、-(CH 2 ) n -NR a C(NH)NR a R a 、-(CH 2 ) n -N=CR b NR a R a 、-(CH 2 ) n -NR a C(=O)NR a R a、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NR a C(=S)NR a C(=O)R b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p R c , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0035] R 4 are independently selected from H, halogen, CN, -(CH 2 ) n NR a R a , 1-5 R 10 Substituted C 1-6 Alkyl, --(CH 2 ) n OR b 、-(CH 2 ) n C(=O)R b 、-(CH 2 ) n C(=O)OR b 、-(CH 2 ) n -NR a C(=O)ORb 、-(CH 2 ) n -NR a C(=O)R b 、-(CH 2 ) n -NR a C(N-CN)NR a R a 、-(CH 2 ) n -NR a C(NH)NR a R a 、-(CH 2 ) n -N=CR b NR a R a 、-(CH 2 ) n -NR a C(=O)NR a R a 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NR a C(=S)NR a C(=O)R b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p R c , 1-5 R 10 Substituted -(CH 2 ) n -Aryl, 1-5 R 10 Substituted -(CH 2 ) n -C3-6 Cycloalkyl and 1-5 R 10 Substituted -(CH 2 ) n -4-6 membered heterocyclic group;

[0036] R 5 independently selected at each occurrence from H, D, -(CH 2 ) n -OR b ,=O,-(CH 2 ) n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -OR b , 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group, 0-5 R e Substituted -(CH 2 ) n -4- to 10-membered heterocyclic group and 0-5 R e substituted –O-4- to 10-membered heterocyclyl;

[0037] R 6 independently selected from H, OH, =O, -(CH 2 ) n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)OH, -(CH 2 ) n -C(=O)OC 1-4 Alkyl, -(CH 2 ) n -OC 1-4 Alkyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbon ring, surrounded by 0-5 R e Substituted-(CH 2 ) n -4- to 10-membered heterocyclic ring and 0-5 Re Substituted-(CH 2 ) n -4- to 10-membered heterocyclic ring;

[0038] R 7 Independently selected from H, CN, OR b , halogen, NR a R a and 0-5 R e Substituted C 1-3 alkyl;

[0039] R 8 Independently selected from H, OH, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, CF 3 , CN, C 3-6 Cycloalkyl, aryl and 5- to 6-membered heterocyclic rings;

[0040] R 10 is independently selected at each occurrence from H, halogen, CN, NO 2 , =O,

[0041] C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a ,

[0042] C(=NOH)NH 2 , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted aryl, 0-5 R e Substituted-(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted-(CH 2 ) n -O-4- to 10-membered heterocyclic group;

[0043] R a In each occurrence, independently selected from H, 0-5 Re Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n -heterocyclic group; or R a and R a Together with the nitrogen atoms connected to them, they form a group consisting of 0-5 R e substituted heterocycle;

[0044] R b In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n - heterocyclic group;

[0045] R c In each occurrence, independently selected from 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, C 3-6 Carbocyclic and heterocyclic groups;

[0046] R d independently selected at each occurrence from H and 0-5 R e Substituted C 1-4 alkyl;

[0047] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, 0-5 R f Substituted C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group, CO 2 H, -(CH 2 ) n OR f , SR f and -(CH 2 ) n NR f R f ;

[0048] R f is independently selected at each occurrence from H, C optionally substituted by F, Cl, Br 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl, or R f and R f Together with the nitrogen atoms attached to them, they form a 1-4 an alkyl optionally substituted heterocyclic ring;

[0049] n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and

[0050] p is an integer independently selected from 0, 1 and 2 at each occurrence.

[0051] In a second aspect, the present disclosure provides a compound of formula (I) within the scope of the first aspect, or a stereoisomer, tautomer, a pharmaceutically acceptable salt or a solvate thereof, wherein:

[0052] L is independently selected from

[0053]

[0054] R 1 and R 2 independently selected from H, halogen, C 1-4 Alkyl, OR b and C 3-5 Cycloalkyl;

[0055] R 3 independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, 1-5 R 5 Substituted C 2-4 Alkenyl, 1-5 R 5 Substituted C2-4 Alkynyl, CN, -OR b 、-(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-NR a C(=O)NR a R a 、-C(=O)NR a R a 、-NR a C(=S)NR a C(=O)R b 、-S(=O) p R c 、-S(=O) p NR a R a 、-NR a S(=O) p NR a R a 、-NR a S(=O) p R c , 1-5 R 5 Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 1-5 R 5 Substituted -(CH 2 ) n -4- to 10-membered heterocyclic group; optionally, two adjacent R 3 The base can be formed by 1-5 R 5 substituted rings;

[0056] R 3a Independently selected from H and C 1-4 alkyl;

[0057] Alternatively, R 3a and R 3Together they form a carbon atom and 1-3 NR 3b wherein the heterocyclic ring is R 3c replace;

[0058] R 3b independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, -(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NHC(=O)OR b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0059] R 3c Independently selected from H, NO 2 , =O, halogen and 1-5 R 5 Substituted C 1-4 alkyl;

[0060] R 4 independently selected from H, halogen, CN, 1-5 R 10 Substituted C 1-6 Alkyl, -OR b , 1-5 R 10 Substituted-(CH 2 ) n -Aryl, 1-5 R 10 Substituted-(CH 2 )n -C 3-6 Cycloalkyl and 1-5 R 10 Substituted -(CH 2 ) n -4-6 membered heterocyclic group;

[0061] R 5 independently selected at each occurrence from H, D, -(CH 2 ) n -OR b ,=O,-(CH 2 ) n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -OR b , 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group, 0-5 R e Substituted -(CH 2 ) n -4- to 10-membered heterocyclic group and 0-5 R e substituted –O-4- to 10-membered heterocyclyl;

[0062] R 7 Independently selected from H, OR b , halogen, NR a R a and C 1-3 alkyl;

[0063] R 10 is independently selected at each occurrence from H, halogen, CN, NO 2 , =O, C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a 、C(=NOH)NH 2 , 0-5 R e Substituted C 1-6 Alkyl, 0-5 Re Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted aryl, 0-5 R e Substituted -(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted -(CH 2 ) n -O-4- to 10-membered heterocyclic group;

[0064] R a In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted -(CH 2 ) n -heterocyclic group; or R a and R a Together with the nitrogen atoms connected to them, they form a group consisting of 0-5 R e substituted heterocycle;

[0065] R b In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted -(CH 2 ) n -heterocyclic group;

[0066] R c In each occurrence, independently selected from 0-5 R e Substituted C 1-6 Alkyl, 0-5 Re Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, C 3-6 Carbocyclic and heterocyclic groups;

[0067] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, 0-5 R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group, CO 2 H, -(CH 2 ) n OR f , SR f and -(CH 2 ) n NR f R f ;

[0068] R f is independently selected at each occurrence from H, C optionally substituted by F, Cl, Br 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl, or R f and R f Together with the nitrogen atoms attached to them, they form a 1-4 an alkyl optionally substituted heterocyclic ring;

[0069] n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and

[0070] p is an integer independently selected from 0, 1 and 2 at each occurrence.

[0071] In a third aspect, the present disclosure provides a compound of formula (II) within the scope of the first or second aspect:

[0072]

[0073] or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein:

[0074] L is independently selected from

[0075]

[0076] Ring A is independently selected from

[0077]

[0078] R 1 and R 2 independently selected from H, halogen, C 1-4 Alkyl and OH;

[0079] R 3 Independently selected from -(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-NR a C(=O)NR a R a 、-C(=O)NR a R a ;

[0080] R 3a Independently selected from H and C 1-4 alkyl;

[0081] Alternatively, R 3a and R 3 Together we form a selection

[0082] Heterocyclic ring;

[0083] R 3b independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, -(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -C(=O)NRa R a 、-(CH 2 ) n -NHC(=O)OR b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0084] R 3c independently selected from H, =O and 1-5 R 5 Substituted C 1-4 alkyl;

[0085] R 4a Independently selected from H, halogen, CN, OCH 3 、OCF 3 , CH 3 、C(=O)CH 3 , CHF 2 CF 3 , CCH 3 F 2 , OCHF 2 , aryl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic ring, wherein the aryl, cycloalkyl and heterocyclic ring are R 10 Optional substitution;

[0086] R 4b are independently selected from H and halogen;

[0087] R 4c independently selected from H, F, Cl, methyl, ethyl, isopropyl and OCH 3 ;

[0088] R 5 independently selected at each occurrence from H, D, -(CH 2 ) n -OR b ,=O,-(CH 2 )n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -OR b , 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group, 0-5 R e Substituted -(CH 2 ) n -4- to 10-membered heterocyclic group and 0-5 R e substituted –O-4- to 10-membered heterocyclyl;

[0089] R 7 Independently selected from H and C 1-3 alkyl;

[0090] R 10 is independently selected at each occurrence from H, halogen, CN, NO 2 , =O, C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a 、C(=NOH)NH 2 , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted aryl, 0-5 R e Substituted -(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted -(CH 2 ) n -O-4- to 10-membered heterocyclic group;

[0091] Ra In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted -(CH 2 ) n -heterocyclic group; or R a and R a Together with the nitrogen atoms connected to them, they form a group consisting of 0-5 R e substituted heterocycle;

[0092] R b In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted -(CH 2 ) n -heterocyclic group;

[0093] R c In each occurrence, independently selected from 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, C 3-6 Carbocyclic and heterocyclic groups;

[0094] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, 0-5 R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 )n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group, CO 2 H, -(CH 2 ) n OR f , SR f and -(CH 2 ) n NR f R f ;

[0095] R f is independently selected at each occurrence from H, C optionally substituted by F, Cl, Br 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl, or R f and R f Together with the nitrogen atoms attached to them, they form a 1-4 an alkyl optionally substituted heterocyclic ring;

[0096] n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and

[0097] p is an integer independently selected from 0, 1 and 2 at each occurrence.

[0098] In a fourth aspect, the present disclosure provides a compound of formula (III) within the scope of any one of the first, second and third aspects:

[0099]

[0100] or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein:

[0101] R 3b Independently selected from H, C 1-4 Alkyl, -(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -S(=O) p R c 、-S(=O) p NRa R a , 1-5 R 5 Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0102] R 3c independently selected from H and =O;

[0103] R 4a Independently selected from H, F, Cl, Br, CN, OCH 3 、OCF 3 , CH 3 、C(=O)C 1-4 Alkyl, C(=O)OC 1-4 Alkyl, CHF 2 CF 3 , CCH 3 F 2 , OCHF 2 ,

[0104]

[0105] R 4b independently selected from H and F;

[0106] R 4c independently selected from H, F, Cl, methyl, ethyl, isopropyl and OCH 3 ;

[0107] R 10 independently selected at each occurrence from H, F, Cl, Br, C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted aryl, 0-5 R e Substituted-(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 Re Substituted-(CH 2 ) n -O-4- to 10-membered heterocyclic group.

[0108] R a In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n - heterocyclic group;

[0109] R b In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n - heterocyclic group;

[0110] R c Each time it appears, it is hit by 0-5 R e Substituted C 1-6 alkyl;

[0111] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, 0-5 R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group, CO 2 H, -(CH 2 ) n OR f, SR f and -(CH 2 ) n NR f R f ;

[0112] R f is independently selected at each occurrence from H, C optionally substituted by F, Cl, Br 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl;

[0113] n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and

[0114] p is an integer independently selected from 0, 1 and 2 at each occurrence.

[0115] In a fifth aspect, the present disclosure provides a compound of formula (III) or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof within the scope of any one of the first, second, third and fourth aspects, wherein:

[0116] R 3b Independently selected from H, C 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -(CH 2 ) n -C(=O)OH, -(CH 2 ) n -C(=O)OC 1-4 Alkyl, -C(=O)NR a R a and 1-5 R 5 substituted-4- to 5-membered heterocyclic group;

[0117] R 3c independently selected from H and =O;

[0118] Independently selected

[0119]

[0120]

[0121]

[0122] R 5 independently selected at each occurrence from H, -C(=O)OC 1-4 Alkyl, OC 1-4 alkyl;

[0123] R 10 independently selected at each occurrence from H, F, Cl, Br, C(=O)NRa R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted aryl, 0-5 R e Substituted -(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted -(CH 2 ) n -O-4- to 10-membered heterocyclic group; and

[0124] n is an integer independently selected from 0, 1, 2 and 3 at each occurrence.

[0125] In a sixth aspect, the present disclosure provides a compound of formula (IV) within the scope of any one of the first, second and third aspects:

[0126]

[0127] or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein:

[0128] R 3b Independently selected from H, C 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -(CH 2 ) n -C(=O)OH, -(CH 2 ) n -C(=O)OC 1-4 Alkyl, -C(=O)NR a R a and 1-5 R 5 substituted-4- to 5-membered heterocyclic group;

[0129] R 3c independently selected from H and =O;

[0130] Independently selected

[0131]

[0132]

[0133] R 10 independently selected at each occurrence from H, F, Cl, Br, C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted aryl, 0-5 R e Substituted -(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted -(CH 2 ) n -O-4- to 10-membered heterocyclic group; and

[0134] n is an integer independently selected from 0, 1, 2 and 3 at each occurrence.

[0135] In a seventh aspect, the present disclosure provides a compound of formula (V) within the scope of any one of the first, second and third aspects:

[0136]

[0137] or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein:

[0138] R 3b Independently selected from H, C 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -(CH 2 ) n -C(=O)OH, -(CH 2 ) n -C(=O)OC 1-4 Alkyl and 1-5 R 5 substituted-4- to 5-membered heterocyclic group;

[0139] R 3c independently selected from H and =O;

[0140] R 4b independently selected from H and F;

[0141] R 4cindependently selected from H, F, Cl, methyl, ethyl, isopropyl and OCH 3 ; R 7 Independently selected from H and C 1-3 Alkyl; and

[0142] n is an integer independently selected from 0, 1, 2 and 3 at each occurrence.

[0143] In an eighth aspect, the present disclosure provides a compound of formula (III) or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof within the scope of any one of the first, second and third aspects, wherein:

[0144] L is independently selected from

[0145]

[0146] Ring A is

[0147] R 1 and R 2 Independently selected from H, C 1-4 Alkyl and OH;

[0148] R 3 Independently selected from -(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-NR a C(=O)NR a R a 、-C(=O)NR a R a ;

[0149] R 3a It is H;

[0150] Alternatively, R 3a and R 3 Together we form a selection

[0151] Heterocyclic ring;

[0152] R 3b Independently selected from H, C 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -(CH 2 ) n -C(=O)OH, -(CH 2 ) n -C(=O)OC 1-4 Alkyl, -C(=O)NR a R a and 1-5 R 5 substituted-4- to 6-membered heterocyclyl;

[0153] R 3c independently selected from H and =O;

[0154] Independently selected

[0155]

[0156] R 5 independently selected at each occurrence from H, -C(=O)OC 1-4 Alkyl,OC 1-4 alkyl;

[0157] R 7 Independently selected from H and C 1-3 alkyl;

[0158] R a In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n - heterocyclic group;

[0159] R b In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n - heterocyclic group;

[0160] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, C 1-6 Alkyl, haloalkyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group and CO 2 H; and

[0161] n is an integer independently selected from 0, 1, 2 and 3 at each occurrence.

[0162] In a ninth aspect, the present invention provides a compound selected from the exemplary embodiments or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a solvate thereof.

[0163] In another aspect, the invention provides a compound selected from any subgroup listing of compounds within the scope of the eighth aspect.

[0164] In another embodiment, the compounds of the invention have Factor XIA Ki values ​​≤ 10 μM, preferably Ki values ​​≤ 1 μM, more preferably Ki values ​​≤ 0.5 μM, even more preferably Ki values ​​≤ 0.1 μM using the assays disclosed herein.

[0165] In another embodiment, the compounds of the invention have plasma kallikrein Ki values ​​≤ 15 μM, preferably Ki values ​​≤ 10 μM, more preferably Ki values ​​≤ 1.0 μM, even more preferably Ki values ​​≤ 0.5 μM using the assays disclosed herein.

[0166] II. Other Embodiments of the Invention

[0167] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0168] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0169] In another embodiment, the present invention provides a pharmaceutical composition comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0170] In another embodiment, the present invention provides a process for preparing the compounds of the present invention.

[0171] In another embodiment, the present invention provides intermediates useful in preparing compounds of the present invention.

[0172] In another embodiment, the present invention provides a pharmaceutical composition further comprising one or more additional therapeutic agents. In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the one or more additional therapeutic agents are antiplatelet agents or a combination thereof. Preferably, the one or more antiplatelet agents are clopidogrel and / or aspirin or a combination thereof.

[0173] In another embodiment, the present invention provides a method for treating and / or preventing thromboembolic disorders, which method comprises administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0174] In another embodiment, the present invention provides a compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, for use in therapy.

[0175] In another embodiment, the present invention provides a compound of the present invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, for use in therapy for the treatment and / or prevention of a thromboembolic disorder.

[0176] In another embodiment, the present invention also provides the use of a compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment and / or prevention of thromboembolic disorders.

[0177] In another embodiment, the present invention provides a method for treating and / or preventing thromboembolic disorders, the method comprising: administering to a patient in need thereof therapeutically effective amounts of a first and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or solvate thereof, and the second therapeutic agent is at least one agent selected from the group consisting of factor Xa inhibitors such as apixaban, rivaroxaban, doxixaban, edoxaban, anticoagulants, antiplatelet agents, thrombin inhibitors such as dabigatran, thrombolytic agents and fibrinolytic agents. Preferably, the second therapeutic agent is at least one selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharides, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, desulfatohirudin, tissue plasminogen activator, activator, modified tissue plasminogen activator, anistreplase, urokinase and streptokinase. Preferably, the second therapeutic agent is at least one antiplatelet agent. Preferably, the one or more antiplatelet agents are clopidogrel and / or aspirin, or a combination thereof.

[0178] The thromboembolic disorders include arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders and venous cerebrovascular thromboembolic disorders. Examples of thromboembolic disorders include, but are not limited to, unstable angina, acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism. embolism, kidney embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or procedures in which blood is exposed to artificial surfaces that promote thrombosis.

[0179] In another embodiment, the present invention provides a method for treating and / or preventing an inflammatory condition, the method comprising administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof. Examples of inflammatory conditions include, but are not limited to, sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.

[0180] In another embodiment, the present invention provides a method for preventing a disease or condition in which plasma kallikrein activity is involved, comprising administering to a patient in need of such treatment and / or prevention a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, or solvate thereof.

[0181] Diseases or conditions in which plasma kallikrein activity is implicated include, but are not limited to, impaired visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, and cardiopulmonary bypass surgery.

[0182] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and one or more additional therapeutic agents for simultaneous, separate or sequential use in therapy.

[0183] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and one or more additional therapeutic agents for simultaneous, separate or sequential use in the treatment and / or prevention of thromboembolic disorders.

[0184] Without departing from the spirit or essential attributes of the present invention, the present invention may be implemented in other specific forms. The present invention encompasses all combinations of the preferred aspects of the present invention described herein. It should be understood that any and all embodiments of the present invention can be combined with any other one or more embodiments to describe other embodiments. It should also be understood that each individual element of the embodiment is an independent embodiment of itself. In addition, any element of the embodiment is intended to be combined with any and all other elements from any embodiment to describe other embodiments.

[0185] III. Chemistry

[0186] Throughout the specification and the appended claims, a given chemical formula or name will encompass all stereo and optical isomers and their racemates where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the present invention. Multiple geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like may also be present in the compounds, and all such stable isomers are encompassed by the present invention. Cis and trans (or E- and Z-) geometric isomers of the compounds of the present invention are described, and they may be separated in the form of a mixture of isomers or in the form of separate isomers. The compounds of the present invention may be separated in optically active or racemic forms. Optically active forms may be prepared by resolving racemic forms or by synthesis from optically active starting materials. All methods used to prepare the compounds of the present invention and the intermediates obtained therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are obtained, they may be separated by conventional methods, such as by chromatography or fractional crystallization. Depending on the process conditions, the final product of the present invention is obtained in free (neutral) or salt form. The free forms and salts of these final products are within the scope of the present invention. If necessary, one form of the compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into a free compound or another salt; a mixture of isomeric compounds of the present invention can be separated into single isomers. The compounds of the present invention, their free forms and salts can exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged accordingly. It should be understood that all tautomeric forms (as long as they can exist) are included in the present invention.

[0187] The term "stereoisomer" refers to isomers of identical constitution but differing in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The term "diastereomer" refers to stereoisomers that are not mirror images. The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species, wherein the composition is optically inactive.

[0188] The symbols "R" and "S" represent the configuration of substituents around one or more chiral carbon atoms. The isomeric descriptors "R" and "S" as described herein are used to indicate one or more atomic configurations relative to the core molecule and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68: 2193-2222 (1996)).

[0189] The term "chirality" refers to a structural feature of a molecule that makes it impossible to superimpose it on its mirror image. The term "homochiral" refers to the enantiomerically pure state. The term "optically active" refers to the degree to which a homochiral molecule or a non-racemic mixture of chiral molecules rotates the plane of polarized light.

[0190] As used herein, the term "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "C 1 -C 10 Alkyl" or "C 1-10 Alkyl" (or alkylene) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 and C 10 Alkyl. In addition, for example, "C 1 -C 6 Alkyl" or "C 1 -C 6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted, wherein at least one hydrogen is replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When "C 0 Alkyl" or "C 0 "alkylene" is intended to represent a direct bond.

[0191] "Alkynyl" or "alkynylene" is intended to include hydrocarbon chains having one or more (preferably 1 to 3) carbon-carbon triple bonds in a straight or branched configuration, which may be present at any stable point along the chain. 2 -C 6 Alkynyl" or "C 2-6 Alkynyl" (or alkynylene) is intended to include C 2 , C 3 , C 4 , C 5 and C 6 Alkynyl; for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0192] The term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. 1 -C 6 Alkoxy" or "C 1-6 Alkoxy" (or alkyloxy) is intended to include C 1 , C2 , C 3 , C 4 , C 5 and C 6 Alkoxy. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy. Similarly, "alkylthio" or "thioalkoxy" means an alkyl group as defined above having a specified number of carbon atoms attached via a sulfur bridge; for example, methyl-S- and ethyl-S-.

[0193] "Halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms substituted by one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Examples of haloalkyl also include "fluoroalkyl", which is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups with a specified number of carbon atoms substituted by one or more fluorine atoms.

[0194] "Haloalkoxy" or "haloalkyloxy" means a haloalkyl group as defined above having the indicated number of carbon atoms attached via an oxygen bridge. 1 -C 6 Haloalkoxy" or "C 1-6 "Haloalkoxy" is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 Halogenated alkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" means a haloalkyl group as defined above having a specified number of carbon atoms attached via a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl-S-.

[0195] The term "amino" as used herein refers to -NH 2 .

[0196] As used herein, the term "substituted amino" refers to those terms defined below with the suffix "amino", for example, "arylamino", "alkylamino", "arylamino" and the like.

[0197] The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0198] As used herein, the term "alkoxycarbonylamino" refers to -NHR, where R is alkoxycarbonyl.

[0199] As used herein, the term "alkylamino" refers to -NHR, where R is alkyl.

[0200] The term "alkylcarbonyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.

[0201] As used herein, the term "alkylcarbonylamino" refers to -NHR, where R is alkylcarbonyl.

[0202] The term "aminosulfonyl" as used herein refers to -SO 2 NH 2 .

[0203] As used herein, the term "arylalkyl" refers to an alkyl group substituted with one, two, or three aryl groups.

[0204] As used herein, the term "arylamino" refers to -NHR, where R is aryl.

[0205] The term "arylcarbonyl," as used herein, refers to an aryl group attached to the parent molecular moiety through a carbonyl group.

[0206] As used herein, the term "arylcarbonylamino" refers to -NHR, where R is arylcarbonyl.

[0207] The term "carbonyl" as used herein refers to -C(O)-.

[0208] As used herein, the term "cyano" refers to -CN.

[0209] As used herein, the term "cycloalkylamino" refers to -NHR, where R is cycloalkyl.

[0210] The term "cycloalkylcarbonyl," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group.

[0211] As used herein, the term "cycloalkylcarbonylamino" refers to -NHR, where R is cycloalkylcarbonyl.

[0212] The term "cycloalkyloxy," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0213] The term "dialkylamino" as used herein refers to NR 2 , wherein each R is an alkyl group. The two alkyl groups are the same or different.

[0214] The term "haloalkoxy," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0215] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one, two, three, or four halogen atoms.

[0216] As used herein, the term "haloalkylamino" refers to -NHR, where R is haloalkyl.

[0217] The term "carbonyl" refers to C(=O).

[0218] The term "carboxy" refers to C(=O)OH.

[0219] The term "haloalkylcarbonyl," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through a carbonyl group.

[0220] As used herein, the term "haloalkylcarbonylamino" refers to -NHR, where R is haloalkylcarbonyl.

[0221] The term "alkylcarbonyl" refers to an alkyl or substituted alkyl group bonded to a carbonyl group.

[0222] The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0223] The term "hydroxy(hydroxy)" or "hydroxy(hydroxyl)" refers to OH.

[0224] The term "cycloalkyl" refers to a cyclized alkyl group, which includes monocyclic, bicyclic or polycyclic ring systems. 3 -C 7 Cycloalkyl" or "C 3-7 "Cycloalkyl" is intended to include C 3 , C 4 , C 5 , C 6 and C 7 Cycloalkyl. Example cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyls (e.g., 1-methylcyclopropyl and 2-methylcyclopropyl) are included in the definition of "cycloalkyl."

[0225] As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12- or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which 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] bicyclononane, [4.4.0] bicyclodecane (decalin), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, 1,2-dihydroindanyl, adamantyl, anthracenyl and tetrahydronaphthyl (1,2,3,4-tetrahydronaphthalene). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2] bicyclooctane). Unless otherwise indicated, preferred carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and 1,2-dihydroindanyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs 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 described for that ring may also be present on the bridge.

[0226] As used herein, the term "bicyclic carbocycle" or "bicyclic carbocyclyl" is intended to mean a stable 9- or 10-membered carbocyclic ring system containing two fused rings and consisting of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a saturated, partially unsaturated or unsaturated 5- or 6-membered carbocyclic ring. The bicyclic carbocyclyl may be attached to its side group at any carbon atom that results in a stable structure. The bicyclic carbocyclyl described herein may be substituted on any carbon if the resulting compound is stable. Examples of bicyclic carbocyclyls are, but are not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and 1,2-dihydroindanyl.

[0227] "Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon, including, for example, phenyl, naphthyl, and phenanthrenyl. Aryl moieties are well known and described, for example, in Hawley's Condensed Chemical Dictionary (13th Edition), Lewis, RJ, ed., J. Wiley & Sons, Inc., New York (1997). ... 6 or C 10 Aryl" or "C 6-10 "Aryl" refers to phenyl and naphthyl. Unless otherwise indicated, "aryl", "C 6 or C 10 Aryl" or "C 6-10"Aryl" or "aromatic residue" may be unsubstituted or substituted by 1 to 5 groups, preferably 1 to 3 groups OH, OCH 3 、Cl、F、Br、I、CN、NO 2 NH 2 、N(CH 3 )H、N(CH 3 ) 2 CF 3 、OCF 3 、C(=O)CH 3 , SCH 3 、S(=O)CH 3 、S(=O) 2 CH 3 , CH 3 , CH 2 CH 3 , CO 2 H and CO 2 CH 3 replace.

[0228] As used herein, the term "benzyl" refers to a methyl group in which one hydrogen atom is replaced by a phenyl group, wherein the phenyl group may be optionally replaced by 1 to 5 groups, preferably 1 to 3 groups, OH, OCH 3 、Cl、F、Br、I、CN、NO 2 NH 2 、N(CH 3 )H、N(CH 3 ) 2 CF 3 、OCF 3 、C(=O)CH 3 , SCH 3 、S(=O)CH 3 、S(=O) 2 CH 3 , CH 3 , CH 2 CH 3 , CO 2 H and CO 2 CH 3 replace.

[0229] As used herein, the term "heterocycle" or "heterocyclyl" is intended to mean a stable 3-, 4-, 5-, 6- or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered polycyclic heterocycle that is saturated, partially unsaturated or fully unsaturated and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; and includes any polycyclic group in which any of the above defined heterocycles is fused to a benzene ring. The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)p , wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that produces a stable structure. If the resulting compound is stable, the heterocyclic ring described herein may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocyclic ring may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocyclic ring does not exceed 1. When the term "heterocyclic ring" is used, it is intended to include heteroaryl groups.

[0230] Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, benzopyranyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazoline yl, imidazolyl, 1H-indazolyl, imidazopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, 1,5-naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, pyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2- The invention also includes 2H-pyrrolidinone, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Also included are fused rings and spiro compounds containing, for example, the above heterocycles.

[0231] Examples of 5- to 10-membered heterocyclic rings include, but are not limited to, pyridyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzo pyridyl, oxazolopyridyl, oxazolopyridyl, oxazolopyridyl, pyrid ...

[0232] Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl and triazolyl. Also included are fused rings and spiral compounds containing, for example, the above-mentioned heterocycles.

[0233] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclyl" is intended to mean a stable 9- or 10-membered heterocyclic ring system containing two fused rings and consisting of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring, including a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a saturated, partially unsaturated or unsaturated 5- or 6-membered monocyclic ring and includes a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided that when the second ring is a carbocycle, the first ring is not a benzo ring).

[0234] The bicyclic heterocyclic group may be attached to its side group at any heteroatom or carbon atom that produces a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. Preferably, when the total number of S and O atoms in the heterocyclic ring exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocyclic ring does not exceed 1.

[0235] Examples, but not limited to, of bicyclic heterocyclyls are quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, dihydroindolyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

[0236] As used herein, the term "aromatic heterocyclic group" or "heteroaryl" is intended to mean a stable monocyclic and polycyclic aromatic hydrocarbon including at least one heteroatom ring member (e.g., sulfur, oxygen, or nitrogen). Heteroaryl includes, but is not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl may be substituted or unsubstituted. Nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (ie, N→O and S(O) p , where p is 0, 1 or 2).

[0237] Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) connect two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one 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, substituents described for that ring may also be present on the bridge.

[0238] The term "counterion" is used to refer to negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

[0239] When a dotted line is used to mark a ring in a ring structure, it indicates that the ring structure may be saturated, partially saturated, or unsaturated.

[0240] As used herein, the term "substituted" means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution produces a stable compound. When the substituent is keto (i.e., =O), then 2 hydrogens on the atom are replaced. Keto substituents will not appear on aromatic moieties. When a ring system (e.g., a carbocycle or a heterocycle) is referred to as being substituted by a carbonyl or double bond, it is meant that the carbonyl or double bond is part of the ring (i.e., within the ring). As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0241] Where nitrogen atoms (e.g., amines) are present on the compounds of the invention, they can be converted to N-oxides by treatment with oxidizing agents (e.g., mCPBA and / or hydrogen peroxide) to provide other compounds of the invention. Thus, the nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide (N→O) derivatives.

[0242] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at all other occurrences. Thus, for example, if a group is shown to be substituted with 0-3 R groups, the group may be optionally substituted with up to 3 R groups, and R at each occurrence is independently selected from the definition of R. In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0243] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When substituents are listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0244] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response and / or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0245] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0246] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or in a mixture of the two; in general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

[0247] In addition, the compounds of Formula I may have a prodrug form. Any compound that will be converted in vivo to provide a bioactive agent (i.e., a compound of Formula I) is a prodrug within the scope and spirit of the present invention. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see:

[0248] a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985) and Widder, K. et al., eds., Methods in Enzymology, 112: 309-396, Academic Press (1985);

[0249] b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs," A Textbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991);

[0250] c) Bundgaard, H., Adv.Drug Deliv.Rev., 8:1-38 (1992);

[0251] d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

[0252] e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

[0253] Compounds containing a carboxyl group may form physiologically hydrolyzable esters useful as prodrugs because they are hydrolyzed in vivo to produce the compound of formula I itself. Since hydrolysis occurs in many cases primarily under the influence of digestive enzymes, such prodrugs are preferably administered orally. When the ester itself is active, or in those cases where hydrolysis occurs in the blood, parenteral administration may be used. Examples of physiologically hydrolyzable esters of compounds of formula I include C 1-6 Alkyl esters, C 1-6 Alkyl benzyl esters, 4-methoxybenzyl esters, indanyl esters, phthaloyl esters, methoxymethyl esters, C 1-6 Alkanoyloxy-C 1-6 Alkyl esters (e.g., acetoxymethyl ester, pivaloyloxymethyl ester, or propionyloxymethyl ester), C 1-6 Alkoxycarbonyloxy-C 1-6 Alkyl esters (e.g., methoxycarbonyl-oxymethyl ester or ethoxycarbonyloxymethyl ester), glycyloxymethyl ester, phenylglycyloxymethyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl ester) and other well-known physiologically hydrolyzable esters used in, for example, penicillin and cephalosporin technology. Such esters can be prepared by conventional techniques known in the art.

[0254] The preparation of prodrugs is known in the art and is described, for example, in King, FD, ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG, ed., The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999).

[0255] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Deuterium has one proton and one neutron in its nucleus and has twice the mass of ordinary hydrogen. Deuterium can be represented by " 2H” or “D”. The term “deuterium” as used herein, by itself or to modify a compound or group, means replacing one or more hydrogen atoms attached to carbon with deuterium atoms. Carbon isotopes include 13 C and 14 C.

[0256] Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed. Such compounds have a variety of potential uses, for example as standards and reagents for determining the ability of potential drug compounds to bind to target proteins or receptors, or for imaging compounds of the invention bound to biological receptors in vivo or in vitro.

[0257] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent. Preferably, the compounds of the invention contain no N-halogen, S(O) 2 H or S(O)H groups.

[0258] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to separate. The solvent molecules in the solvate can exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are generally known in the art.

[0259] Abbreviations as used herein are defined as follows: "1×" means once; "2×" means twice; "3×" means three times; "°C" means degrees Celsius; "eq" means equivalent; "g" means gram; "mg" means milligram; "L" means liter; "mL" means milliliter; "μL" means microliter; "N" means normal concentration; "M" means molar concentration; "mmol" means millimole; "min" means minute; "h" means hour;

[0260] "rt" means room temperature; "RT" means retention time; "RBF" means round bottom flask; "atm" means atmospheric pressure; "psi" means pounds per square inch; "conc." means concentrated; "RCM" means ex situ ring closure; "sat" or "sat'd" means saturated; "SFC" means supercritical fluid chromatography; "MW" means molecular weight; "mp" means melting point;

[0261] “ee” means enantiomeric excess; “MS” or “Mass Spec” means mass spectrometry; “ESI” means electrospray ionization mass spectrometry; “HR” means high resolution; “HRMS” means high resolution mass spectrometry; “LCMS” means liquid chromatography mass spectrometry; “HPLC” means high pressure liquid chromatography; “RP HPLC” means reversed phase HPLC; “TLC” or “tlc” means thin layer chromatography; “NMR” means nuclear magnetic resonance spectroscopy; “nOe” means nuclear Overhauser effect spectroscopy; “ 1 H” refers to proton; “δ” refers to delta; “s” refers to singlet; “d” refers to doublet; “t” refers to triplet; and “q” refers to quartet;

[0262] "m" refers to multiplet; "br" refers to broad; "Hz" refers to Hertz; and "α", "β", "R", "S", "E", and "Z" are stereochemical symbols familiar to those skilled in the art.

[0263] Me Methyl

[0264] Et Ethyl

[0265] Pr Propyl

[0266] i-Pr Isopropyl

[0267] Bu Butyl

[0268] i-Bu Isobutyl

[0269] t-Bu tert-butyl

[0270] Ph Phenyl

[0271] Bn Benzyl

[0272] Boc or BOC tert-butoxycarbonyl

[0273] Boc 2 O Di-tert-butyl dicarbonate

[0274] AcOH or HOAc Acetic acid

[0275] AlCl 3 Aluminum Chloride

[0276] AIBN Azobisisobutyronitrile

[0277] BBr 3 Boron tribromide

[0278] BCl 3 Boron trichloride

[0279] BEMP 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphine

[0280] BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

[0281] Burgess reagent 1-methoxy-N-triethylammoniumsulfonyl-methanimidate

[0282] Cbz benzyloxycarbonyl

[0283] DCM or CH 2 Cl 2 Dichloromethane

[0284] CH 3 CN or ACN Acetonitrile

[0285] CDCl 3 Deuterated chloroform

[0286] CHCl 3 Chloroform

[0287] mCPBA or m-CPBA m-Chloroperbenzoic acid

[0288] Cs 2 CO 3 Cesium carbonate

[0289] Cu(OAc) 2 Copper(II) acetate

[0290] CuI Copper(I) iodide

[0291] CuSO 4 Copper(II) sulfate

[0292] Cy 2 NMe N-Cyclohexyl-N-methylcyclohexylamine

[0293] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0294] DCE 1,2-Dichloroethane

[0295] DEA Diethylamine

[0296] Dess-Martin 1,1,1-tri(acetoxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one

[0297] DIC or DIPCDI Diisopropylcarbodiimide

[0298] DIEA, DIPEA or diisopropylethylamine

[0299] Hunig's base

[0300] DMAP 4-dimethylaminopyridine

[0301] DME 1,2-Dimethoxyethane

[0302] DMF Dimethylformamide

[0303] DMSO Dimethyl sulfoxide

[0304] cDNA complementary DNA

[0305] Dppp (R)-(+)-1,2-Bis(diphenylphosphino)propane

[0306] DuPhos (+)-1,2-Bis((2S,5S)-2,5-diethylphospholano)benzene

[0307] EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide

[0308] EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[0309] EDTA Ethylenediaminetetraacetic acid

[0310] (S,S)-EtDuPhosRh(I) (+)-1,2-Bis((2S,5S)-2,5-diethylphospholyl)benzene(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate

[0311] E 3 N or TEA Triethylamine

[0312] EtOAc Ethyl acetate

[0313] E 2 O Ether

[0314] EtOH

[0315] GMF Glass Microfiber Filter Paper

[0316] Grubbs II (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinyl)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium

[0317] HCl

[0318] HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

[0319] HEPES 4-(2-Hydroxyethyl)piperaxine-1-ethanesulfonic acid

[0320] Hex

[0321] HOBt or HOBT 1-Hydroxybenzotriazole

[0322] H 2 O 2 Hydrogen Peroxide

[0323] H 2 SO 4 sulfuric acid

[0324] IBX 2-iodooxybenzoic acid

[0325] InCl 3 Indium(III) chloride

[0326] Jones reagent CrO 3 In H 2 SO 4 In aqueous solution, 2M

[0327] K 2 CO 3 Potassium carbonate

[0328] K 2 HPO 4 Dipotassium hydrogen phosphate

[0329] K 3 PO 4 Tripotassium phosphate

[0330] KOAc Potassium acetate

[0331] K 3 PO 4 Potassium Phosphate

[0332] LAH Lithium Aluminum Hydride

[0333] LG Leaving Group

[0334] LiOH Lithium Hydroxide

[0335] MeOH Methanol

[0336] MgSO 4 Magnesium sulfate

[0337] MsOH or MSA Methanesulfonic acid

[0338] NaCl Sodium chloride

[0339] NaH Sodium hydride

[0340] NaHCO 3 Sodium bicarbonate

[0341] Na 2 CO 3 Sodium carbonate

[0342] NaOH Sodium hydroxide

[0343] Na 2 SO 3 Sodium sulfite

[0344] Na 2 SO 4 Sodium sulfate

[0345] NBS N-Bromosuccinimide

[0346] NCS N-chlorosuccinimide

[0347] NH 3 ammonia

[0348] NH 4 Cl Ammonium chloride

[0349] NH 4 OH Ammonium hydroxide

[0350] NH 4 COOH Ammonium formate

[0351] NMM N-Methylmorpholine

[0352] OTf trifluoromethanesulfonate or triflate

[0353] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)

[0354] Pd(OAc) 2 Palladium(II) acetate

[0355] Pd / C Palladium on Carbon

[0356] Pd(dppf)Cl 2 [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0357] Ph 3 PCl 2 Triphenylphosphine dichloride

[0358] PG Protective Group

[0359] POCl 3 Phosphorus oxychloride

[0360] i-PrOH or IPA Isopropyl alcohol

[0361] PS Polystyrene

[0362] rt room temperature

[0363] SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride

[0364] SiO 2 Silicon dioxide

[0365] SnCl 2 Tin(II) chloride

[0366] TBAI Tetra-n-butylammonium iodide

[0367] TFA Trifluoroacetic acid

[0368] THF Tetrahydrofuran

[0369] TMSCHN 2 Trimethylsilyldiazomethane

[0370] Propanephosphonic anhydride

[0371] TRIS Tris(hydroxymethyl)aminomethane

[0372] pTsOH p-Toluenesulfonic acid.

[0373] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis, which are described in more detail in Section VI.

[0374] IV. Biology

[0375] Although coagulation is necessary for regulating the hemostasis of an organism, it is also involved in many pathological conditions. In thrombosis, blood clots or thrombi may form locally and block circulation, causing ischemia and organ damage. Alternatively, in a process called embolism, clots may move and then be trapped in remote blood vessels, where they cause ischemia and organ damage again. Diseases caused by pathological thrombosis are collectively referred to as thromboembolic disorders and include acute coronary syndrome, unstable angina, myocardial infarction, intracardiac thrombosis (thrombosis in the cavity of the heart), ischemic stroke, deep vein thrombosis, peripheral occlusive arterial disease, transient ischemic attack and pulmonary embolism. In addition, thrombosis occurs on artificial surfaces in contact with blood, including catheters, stents, artificial heart valves and hemodialysis membranes.

[0376] Several conditions contribute to the risk of developing thrombosis. For example, changes in the vessel wall, altered blood flow, and changes in the composition of the vascular compartment. These risk factors are collectively referred to as Virchow's triad. (Colman, RW et al., eds., Hemostasis and Thrombosis, Basic Principles and Clinical Practice, 5th ed., p. 853, Lippincott Williams & Wilkins (2006)).

[0377] Antithrombotic agents are usually given to patients who are at risk of developing thromboembolic disease due to the presence of one or more predisposing risk factors in the Wilcoxon triad to prevent the formation of occlusive thrombi (primary prevention). For example, in orthopedic surgical settings (e.g., hip and knee replacements), antithrombotic agents are usually given before surgery. Antithrombotic agents balance the prothrombotic stimuli imposed by changes in vascular flow (stasis), potential surgical vessel wall damage, and changes in blood composition due to acute phase reactions associated with surgery. Another example of primary prevention using antithrombotic agents is the administration of aspirin, a platelet activation inhibitor, to patients at risk of developing thrombotic cardiovascular disease. Recognized risk factors in this setting include age, male gender, hypertension, diabetes, lipid changes, and obesity.

[0378] Antithrombotic agents are also indicated for secondary prevention after the initial thrombotic episode. For example, patients with Factor V (also known as Factor V Leiden) mutations and other risk factors (e.g., pregnancy) are administered anticoagulants to prevent recurrence of venous thrombosis. Another example is secondary prevention of cardiovascular events in patients with a history of acute myocardial infarction or acute coronary syndrome. In a clinical setting, a combination of aspirin and clopidogrel (or other thienopyridines) can be used to prevent secondary thrombotic events.

[0379] Antithrombotic agents are also administered to treat (i.e., prevent the development of) a disease condition after it has begun. For example, patients presenting with deep vein thrombosis are treated with anticoagulants (i.e., heparin, warfarin, or LMWH) to prevent further development of venous occlusions. These agents also cause regression of the disease condition over time, as the balance between prothrombotic factors and anticoagulant / profibrinolytic pathways shifts in favor of the latter. Examples of arterial vascular beds include treatment of patients with acute myocardial infarction or acute coronary syndrome with aspirin and clopidogrel to prevent further development of vascular occlusions and ultimately cause regression of thrombotic occlusions.

[0380] Therefore, antithrombotic agents are widely used for primary and secondary prevention (i.e., prevention or risk reduction) of thromboembolic disorders, as well as for treatment of existing thrombotic processes that already exist. Drugs that inhibit blood coagulation, or anticoagulants, are "key agents for the prevention and treatment of thromboembolic disorders" (Hirsh, J. et al., Blood, 105, 453-463 (2005)).

[0381] Another way to cause coagulation is when blood is exposed to an artificial surface (e.g., during hemodialysis, "on-pump" cardiovascular surgery, vascular transplantation, bacterial sepsis), on cell surfaces, cell receptors, cell debris, DNA, RNA, and extracellular matrix. This process is also called contact activation. The surface absorption of factor XII causes conformational changes in factor XII molecules, thereby promoting activation into proteolytically active factor XII molecules (factor XIIa and factor XIIf). Factor XIIa (or XIIf) has a variety of target proteins, including plasma prekallikrein (plasma prekallikrein) and factor XI. Active plasma kallikrein further activates factor XII, causing amplification of contact activation. Alternatively, serine protease prolyl carboxypeptidase can activate plasma kallikrein (Shariat-Madar et al., Blood, 108: 192-199 (2006)) in a multi-protein complex formed on the cell and matrix surface and compounded with a high molecular weight kininogen (kininogen). Contact activation is a surface-mediated process responsible in part for regulating thrombosis and inflammation, and is mediated at least in part by fibrinolysis, complement, kininogens / kinins, and other humoral and cellular pathways (for review, Coleman, R., "Contact Activation Pathway", Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier, AH, "Contact Activation", Thrombosis and Hemorrhage, pp. 105-128 (1998)). The biological relevance of the contact activation system to thromboembolic disease is supported by the phenotype of Factor XII-deficient mice. More specifically, factor XII-deficient mice are protected from thrombotic vascular occlusion in several thrombosis models as well as stroke models, and the phenotype of XII-deficient mice is identical to that of XI-deficient mice (Renne et al., J. Exp. Med., 202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518 (2006)). The fact that factor XI is downstream of factor XIIa combined with the identical phenotype of XII- and XI-deficient mice suggests that the contact activation system may play an important role in factor XI activation in vivo.

[0382] Factor XI is a zymogen of a trypsin-like serine protease and is present in plasma at relatively low concentrations. Proteolytic activation at the internal R369-I370 bond produces a heavy chain (369 amino acids) and a light chain (238 amino acids). The latter contains a typical trypsin-like catalytic triad (H413, D464, and S557). It is believed that thrombin activation of factor XI occurs on a negatively charged surface, most likely on the surface of activated platelets. Platelets contain specific sites (130-500 / platelet) with high affinity (0.8 nM) for activated factor XI. After activation, factor XIa maintains surface binding and recognizes factor IX as its normal macromolecular substrate (Galiani, D., Trends Cardiovasc. Med., 10: 198-204 (2000)).

[0383] In addition to the above-mentioned feedback activation mechanism, thrombin activates thrombin-activated fibrinolysis inhibitor (TAFI), which is a plasma carboxypeptidase that splits the C-terminal lysine and arginine residues on fibrin, thereby reducing the ability of fibrin to enhance tissue-type plasminogen activator (tPA)-dependent plasminogen activation. In the presence of antibodies for FXIa, clot dissolution can occur more rapidly independently of plasma TAFI concentration (Bouma, BN et al., Thromb. Res., 101: 329-354 (2001)). Therefore, it is expected that the inhibitor of factor XIa is an anticoagulant and a pro-fibrinolytic agent.

[0384] Additional evidence for the antithromboembolic effect of targeting factor XI comes from mice deficient in factor XI. Complete fXI deficiency has been shown to prevent mice from developing ferric chloride (FeCl 3 )-induced carotid artery thrombosis (Rosen et al., Thromb. Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost., 3:695-702 (2005)). In addition, factor XI deficiency rescues the perinatal lethal phenotype of complete protein C deficiency (Chan et al., Amer. J. Pathology, 158:469-479 (2001)). In addition, baboon cross-reactive function-blocking antibodies against human factor XI prevent arterial-venous shunt thrombosis in baboons (Gruber et al., Blood, 102:953-955 (2003)). Evidence for the antithrombotic effect of small molecule inhibitors of factor XIa is also disclosed in published U.S. Patent Publication No. 2004 / 0180855A1. Together, these studies suggest that targeting factor XI will reduce the propensity to develop thrombotic and thromboembolic disease.

[0385] Genetic evidence indicates that factor XI is not required for normal homeostasis, suggesting that the safety profile of the factor XI mechanism is superior to that of the competing antithrombotic mechanism. Compared with hemophilia A (factor VIII deficiency) or hemophilia B (factor IX deficiency), mutations in the factor XI gene that cause factor XI deficiency (hemophilia C) only lead to a mild to moderate bleeding diathesis characterized primarily by postoperative or posttraumatic bleeding, and rarely produce spontaneous bleeding. Most postoperative bleeding occurs in tissues with high concentrations of endogenous fibrinolytic activity (e.g., oral and genitourinary systems). Most cases are identified accidentally due to prolonged aPTT (intrinsic system) before surgery without any previous history of bleeding.

[0386] The increased safety of inhibiting XIa as an anticoagulant therapy is further supported by the fact that factor XI knockout mice without detectable factor XI protein undergo normal development and have a normal lifespan. No signs of spontaneous bleeding were noted. The aPTT (intrinsic system) was prolonged in a gene dose-dependent manner. Interestingly, even after a strong stimulation of the coagulation system (tail transection), there was no significant prolongation of bleeding time compared to wild-type and heterozygous littermates (Gailani, D., Frontiers in Bioscience, 6: 201-207 (2001); Gailani, D. et al., Coagulation and Fibrinolysis, 8: 134-144 (1997)). In summary, these observations suggest that high levels of inhibition of factor XIa should be well tolerated. This contrasts with gene targeting experiments using other coagulation factors other than factor XII.

[0387] The in vivo activation of factor XI can be determined by complex formation with C1 inhibitor or alpha 1 antitrypsin. In a study of 50 patients with acute myocardial infarction (AMI), about 25% of the patients had values ​​above the upper limit of the normal range of the complex ELISA. This study can be regarded as evidence that factor XI activation promotes thrombin formation at least in a subset of patients with AMI (Minnema, MC et al., Arterioscler. Thromb. Vasc. Biol., 20: 2489-2493 (2000)). A second study established a positive correlation between the degree of coronary artery atherosclerosis and the complexation of factor XIa with alpha 1 antitrypsin (Murakami, T. et al., Arterioscler. Thromb. Vasc. Biol., 15: 1107-1113 (1995)). In another study, factor XI levels above 90% in patients were found to be associated with a 2.2-fold increased risk of venous thrombosis (Meijers, JCM et al., N. Engl. J. Med., 342:696-701 (2000)).

[0388] Furthermore, novel compounds that show improved activity compared to known serine protease inhibitors in in vitro coagulation assays are preferred, such as the activated partial thromboplastin time (aPTT) or prothrombin time (PT) assays (for a description of the aPTT and PT assays, see Goodnight, SH et al., "Screening Tests of Hemostasis", Disorders of Thrombosis and Hemostasis: A Clinical Guide, 2nd ed., pp. 41-51, McGraw-Hill, New York (2001)).

[0389] It is also desirable and preferred to find compounds that have favorable and improved properties compared to known serine protease inhibitors in one or more of the following categories, which categories are given by way of example and are not intended to be limiting: (a) pharmacokinetic properties, including oral bioavailability, half-life, and clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that reduce the peak and trough characteristics of blood concentrations; (e) factors that increase active drug concentrations at receptors; (f) factors that reduce the susceptibility to clinical drug-drug interactions; (g) factors that reduce the potential for adverse side effects, including selectivity relative to other biological targets; and (h) factors that improve manufacturing cost or feasibility.

[0390] Preclinical studies have demonstrated that small molecule factor XIa inhibitors have significant antithrombotic effects in rabbit and rat models of arterial thrombosis at doses that maintain hemostasis. (Wong PC et al., American Heart Association Scientific Sessions, Abstract No. 6118, November 12-15, 2006; Schumacher, W. et al., Journal of Thrombosis and Haemostasis, 3 (Suppl. 1): P1228 (2005); Schumacher, WA et al., European Journal of Pharmacology, 167-174 (2007)). In addition, it was observed that the aPTT prolongation brought about by specific XIa inhibitors in vitro was a good predictor of efficacy in our thrombosis model. Therefore, the in vitro aPTT test can be used as a surrogate for in vivo efficacy.

[0391] The term "patient" as used herein encompasses all mammalian species.

[0392] As used herein, "treating" encompasses treating a disease condition in a mammal, particularly a human, and includes: (a) inhibiting the disease condition, ie, arresting its development; and / or (b) alleviating the disease condition, ie, causing regression of the disease condition.

[0393] As used herein, "prophylaxis" is the protective treatment of a disease condition by administering to a patient a therapeutically effective amount of at least one compound of the invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof to reduce and / or minimize the risk of the disease condition and / or reduce the risk of recurrence of the disease condition. Patients for prophylactic therapy may be selected based on factors known to increase the risk of clinical disease conditions compared to the general population. For prophylactic treatment, the clinical disease condition may or may not have yet been manifested. "Prophylactic" treatment can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treating patients who have not yet presented with a clinical disease condition to reduce or minimize the risk of the disease condition, while secondary prevention is defined as minimizing or reducing the risk of recurrence or secondary occurrence of the same or similar clinical disease condition.

[0394] As used herein, "prevention" encompasses prophylactic treatment of subclinical disease conditions in mammals, especially humans, with the intent to reduce the likelihood of developing a clinical disease condition. Patients for prophylactic therapy are selected based on factors known to increase the risk of a clinical disease condition compared to the general population.

[0395] As used herein, "risk reduction" encompasses therapies that reduce the incidence of developing a clinical disease condition. Thus, primary and secondary prevention therapies are examples of risk reduction.

[0396] A "therapeutically effective amount" is intended to include an amount of a compound of the invention that is effective to inhibit Factor XIa and / or plasma kallikrein and / or prevent or treat the conditions listed herein when administered alone or in combination. When applied to a combination, the term refers to combined amounts of the active ingredients that produce a prophylactic or therapeutic effect, whether administered in combination, either serially or simultaneously.

[0397] As used herein, the term "thrombosis" refers to the formation or presence of a thrombus; intravascular coagulation that may cause ischemia or infarction of tissue supplied by a blood vessel. As used herein, the term "embolism" refers to the sudden blockage of an artery caused by a clot or foreign material carried by the blood flow to a location of deposition. As used herein, the term "thromboembolism" refers to a vascular occlusion caused by thrombotic material carried by the blood flow from an initial location to block another blood vessel. The term "thromboembolic disorder" refers to "thrombotic" and "embolic" disorders (as defined above).

[0398] As used herein, the term "thromboembolic disorder" includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the heart chambers or peripheral circulation. As used herein, the term "thromboembolic disorder" also includes specific disorders selected from (but not limited to) the following: unstable angina or other acute coronary syndromes, atrial fibrillation, initial or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. Medical implants or devices include, but are not limited to, prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators, shunts, vascular interfaces, ventricular assist devices, and artificial hearts or heart chambers and vascular grafts. Surgeries include, but are not limited to, cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In another embodiment, the term "thromboembolic disorder" includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism.

[0399] In another embodiment, the present invention provides a method for treating a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. In another embodiment, the present invention provides a method for treating a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of acute coronary syndrome, stroke, venous thrombosis, atrial fibrillation, and thrombosis caused by medical implants and devices.

[0400] In another embodiment, the present invention provides a method for the primary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. In another embodiment, the present invention provides a method for the primary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of acute coronary syndrome, stroke, venous thrombosis, and thrombosis caused by medical implants and devices.

[0401] In another embodiment, the present invention provides a method for secondary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, and thrombosis caused by medical implants, devices, or surgeries in which blood is exposed to artificial surfaces that promote thrombosis. In another embodiment, the present invention provides a method for secondary prevention of a thromboembolic disorder, wherein the thromboembolic disorder is selected from the group consisting of acute coronary syndrome, stroke, atrial fibrillation, and venous thrombosis.

[0402] As used herein, the term "stroke" refers to an embolic stroke or an atherothrombotic stroke caused by occlusive thrombosis in the carotid communis, the internal carotid interna, or the intracerebral arteries.

[0403] It should be noted that thrombosis includes both vascular occlusion (e.g., after bypass surgery) and reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty). Thromboembolic disorders may be caused by conditions including, but not limited to, atherosclerosis, surgery or surgical complications, long-term immobilization, arterial fibrillation, congenital thrombophilia, cancer, diabetes, effects of drugs or hormones, and complications of pregnancy.

[0404] Thromboembolic disorders are often associated with patients with atherosclerosis. Risk factors for atherosclerosis include, but are not limited to, male gender, age, hypertension, lipid disorders, and diabetes. Risk factors for atherosclerosis are also risk factors for atherosclerotic complications (i.e., thromboembolic disorders).

[0405] Similarly, arterial fibrillation is often associated with thromboembolic disorders. Risk factors for arterial fibrillation and subsequent thromboembolic disorders include cardiovascular disease, rheumatic heart disease, non-rheumatic mitral valve disease, hypertensive cardiovascular disease, chronic lung disease and multiple miscellaneous cardiac abnormalities, and thyrotoxicosis.

[0406] Diabetes is often associated with atherosclerotic and thromboembolic disorders. Risk factors for the more common type 2 include, but are not limited to, family history, obesity, physical inactivity, previously impaired fasting blood sugar or glucose tolerance testing, a history of gestational diabetes or the birth of a "big baby," high blood pressure, low HDL cholesterol, and polycystic ovary syndrome.

[0407] Risk factors for congenital thrombophilia include gain of function mutations of coagulation factors or loss of function mutations in the anticoagulant or fibrinolytic pathways.

[0408] Thrombosis has been found to be associated with a variety of tumor types, such as pancreatic cancer, breast cancer, brain tumors, lung cancer, ovarian cancer, prostate cancer, gastrointestinal malignancies, and Hodgkins or non-Hodgkins lymphomas. Recent studies have shown that the incidence of cancer in patients with thrombosis reflects the incidence of specific cancer types in the general population (Levitan, N. et al., Medicine (Baltimore), 78 (5): 285-291 (1999); Levine M. et al., N. Engl. J. Med., 334 (11): 677-681 (1996); Blom, JW et al., JAMA, 293 (6): 715-722 (2005)). Thus, the most common cancers associated with thrombosis in men are prostate cancer, colorectal cancer, brain cancer, and lung cancer, and in women are breast cancer, ovarian cancer, and lung cancer. The venous thromboembolism (VTE) rate observed in cancer patients is significant. The different VTE rates between different tumor types are likely related to the selection of patient populations. Cancer patients at risk of thrombosis may have any or all of the following risk factors: (i) cancer stage (i.e., presence of metastasis), (ii) presence of central venous catheter, (iii) surgical intervention and anticancer therapy, including chemotherapy and (iv) hormone and anti-angiogenic drugs. Therefore, common clinical practice is to give heparin or low molecular weight heparin to patients with advanced tumors to prevent thromboembolic disorders. A variety of low molecular weight heparin preparations have been approved by the FDA for these indications.

[0409] There are three main clinical scenarios when considering the prevention of VTE in medical cancer patients: (i) patients who are bedridden for an extended period of time; (ii) ambulatory patients who are receiving chemotherapy or radiation; and (iii) patients with a central venous catheter. Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effective antithrombotic agents for cancer patients undergoing surgery (Mismetti, P. et al., British Journal of Surgery., 88:913-930 (2001)).

[0410] A. In vitro assay

[0411] The efficacy of the compounds of the invention as inhibitors of coagulation factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikrein, chymotrypsin, trypsin or thrombin can be determined using the relevant purified serine protease and the appropriate synthetic substrate, respectively. The hydrolysis rate of the chromogenic or fluorescent substrate of the relevant serine protease can be determined in the absence and presence of the compounds of the invention. The hydrolysis of the substrate leads to the release of pNA (p-nitroaniline), which is monitored by the increase in absorbance at 405nm measured by spectrophotometry, or the release of AMC (aminomethylcoumarin), which is monitored by the increase in emission at 460nm (wherein excitation is at 380nm) measured by spectrofluorimetry. A decrease in the rate of change in absorbance or fluorescence in the presence of an inhibitor indicates enzyme inhibition. Such methods are known to those skilled in the art. The result of this test is expressed as the inhibition constant K i .

[0412] Factor XIa assays were performed in 50 mM HEPES buffer (pH 7.4) containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethylene glycol; JT Baker or Fisher Scientific). The assay used purified human factor XIa (Haematologic Technologies) at a final concentration of 25-200 pM and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; or AnaSpec).

[0413] Factor VIIa assays were performed in 0.005 M calcium chloride, 0.15 M sodium chloride, 0.05 M HEPES buffer (pH 7.5) containing 0.1% PEG 8000. The assays used purified human Factor VIIa (Haematologic Technologies) or recombinant human Factor VIIa (Novo Nordisk) at final assay concentrations of 0.5-10 nM, recombinant soluble tissue factor at concentrations of 10-40 nM, and the synthetic substrate HD-Ile-Pro-Arg-pNA (S-2288; or BMPM-2; AnaSpec).

[0414] Factor IXa assays were performed in 0.005M calcium chloride, 0.1M sodium chloride, 0.0000001M Refludan (Berlex), 0.05M Tris base, and 0.5% PEG 8000 (pH 7.4). Refludan was added to inhibit the small amount of thrombin in the commercial preparation of human Factor IXa. The assays were performed using purified human Factor IXa (Haematologic Technologies) at a final assay 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 0.0004-0.0005M.

[0415] Factor Xa assays were performed in 0.1 M sodium phosphate buffer (pH 7.5) containing 0.2 M sodium chloride and 0.5% PEG 8000. The assay utilized purified human Factor Xa (Haematologic Technologies) at a final assay concentration of 150-1000 pM and the synthetic substrate S-2222 (Bz-Ile-Glu(γ-OMe, 50%)-Gly-Arg-pNA; )conduct.

[0416] The Factor XIIa assay was performed in 0.05 M HEPES buffer (pH 7.4) containing 0.145 M NaCl, 0.05 M KCl and 0.1% PEG 8000. The assay utilized purified human Factor XIIa (American Diagnostica) at a final concentration of 4 nM and synthetic substrate at a concentration of 0.00015 M. #312 (HD-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica).

[0417] The plasma kallikrein assay was performed in 0.1 M sodium phosphate buffer (pH 7.5) containing 0.1-0.2 M sodium chloride and 0.5% PEG 8000. The assay utilized purified human plasma kallikrein (Enzyme Research Laboratories) at a final assay concentration of 200 pM and the synthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; )conduct.

[0418] Thrombin assays were performed in 0.1 M sodium phosphate buffer (pH 7.5) containing 0.2 M sodium chloride and 0.5% PEG 8000. The assay utilized purified human α-thrombin (Haematologic Technologies or Enzyme Research Laboratories) at a final assay concentration of 200-250 pM and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA; or AnaSpec).

[0419] The Michaelis constant K of each protease for substrate hydrolysis m The assay was performed at 25°C or 37°C in the absence of inhibitors. i The K value is determined by reacting the protease with the substrate in the presence of an inhibitor. The reaction is allowed to proceed for 20-180 minutes (depending on the protease) and the velocity (rate of change of absorbance or fluorescence over time) is determined. The following relationship is used to calculate K i value:

[0420] (V max *S) / (K m +S)

[0421] (v o -v s ) / v s =I / (K i *(1+S / K m )), for competitive inhibitors with one binding site; or

[0422] v s / v o＝ A+((BA) / (1+(IC 50 / (I) n );and

[0423] K i =IC 50 / (1+S / K m ), for competitive inhibitors

[0424] in:

[0425] v o is the velocity of the control in the absence of inhibitor;

[0426] v s is the velocity in the presence of the inhibitor;

[0427] V max is the maximum reaction speed;

[0428] I is the concentration of the inhibitor;

[0429] A is the minimum activity to be retained (usually locked to zero);

[0430] B is the maximum activity retained (usually locked at 1.0);

[0431] n is the Hill coefficient, a measure of the number of possible inhibitor binding sites and cooperativity;

[0432] IC 50 is the inhibitor concentration that produces 50% inhibition under the test conditions;

[0433] K i is the dissociation constant of the enzyme:inhibitor complex;

[0434] S is the substrate concentration; and

[0435] K m is the Michaelis constant of the substrate.

[0436] The selectivity of a compound can be determined by obtaining the K i The K values ​​of the studied proteases i The selectivity for FXIa relative to proteinase P was evaluated by the ratio of the K values ​​of proteinase P. i / FXIa K i ). Compounds with selectivity ratios > 20 were considered selective.

[0437] The efficacy of the compounds of the present invention as coagulation inhibitors can be determined using standard or modified coagulation tests. The increase in plasma coagulation time in the presence of an inhibitor indicates an anticoagulant effect. The relative coagulation time is the coagulation time in the presence of an inhibitor divided by the coagulation time in the absence of an inhibitor. The results of the assay can be expressed as IC1.5× or IC2×, which are the inhibitor concentrations required to increase the coagulation time to 1.5 times or 2 times relative to the coagulation time in the absence of an inhibitor, respectively. Using inhibitor concentrations covering IC1.5× or IC2×, IC1.5× or IC2× is known from a relative coagulation time versus inhibitor concentration graph by linear interpolation.

[0438] The clotting time is determined using normal human plasma containing citrate and plasma obtained from multiple laboratory animal species (e.g., rats or rabbits). The compound is diluted in plasma, starting with a 10 mM DMSO stock solution. The final concentration of DMSO is less than 2%. Plasma clotting tests are performed in an automated coagulation analyzer (Sysmex, Dade-Behring, Illinois). Similarly, the clotting time of laboratory animal species or humans administered the compounds of the invention can be determined.

[0439] Activated partial thromboplastin time (aPTT) FSL (Dade-Behring, Illinois) was measured according to the instructions in the drug package insert. Plasma (0.05 mL) was warmed to 37°C for 1 min. FSL ( FSL (0.05 mL) and incubate for another 2 to 5 minutes. Calcium chloride (25 mM, 0.05 mL) was added to the reaction to initiate coagulation. The clotting time is the time in seconds from the moment of calcium chloride addition until coagulation is detected.

[0440] Prothrombin time (PT) is measured using thromboplastin (Thromboplastin C Plus or Dade-Behring, Illinois) was used to determine the blood coagulation. Plasma (0.05 mL) was warmed to 37°C for 1 minute. Thromboplastin (0.1 mL) was added to the plasma to initiate coagulation. The clotting time was the time in seconds from the moment of thromboplastin addition until coagulation was detected.

[0441] The chymotrypsin assay was performed in 50 mM HEPES buffer, pH 7.4, containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethylene glycol moiety; JT Baker or Fisher Scientific). The assay was performed using: purified human chymotrypsin at a final concentration of 0.2-2 nM (CalbiOChem); and the synthetic substrate S-2586 (methoxy-succinyl-Arg-Pro-Tyr-pNA; Chromogenix) at a concentration of 0.0005-0.005 M.

[0442] The trypsin assay was performed in 0.1 M sodium phosphate buffer, pH 7.5, containing 0.2 M sodium chloride and 0.5% PEG 8000. The assay was performed using: purified human trypsin (Sigma) at a final assay concentration of 0.1-1 nM; and the synthetic substrate S-2222 (Bz-Ile-Glu(gamma-OMe, 50%)-Gly-Arg-pNA; Chromogenix) at a concentration of 0.0005-0.005 M.

[0443] The exemplary embodiments disclosed below were tested in the above Factor XIa assay and found to have Factor XIa inhibitory activity. Factor XIa inhibitory activity (Ki values) were observed to range from ≤ 1.5 μM (1500 nM).

[0444] The exemplary examples disclosed below were tested in the plasma kallikrein assay described above and were found to have plasma kallikrein inhibitory activity. Plasma kallikrein inhibitory activity (Ki values) in the range of ≤ 15 μM (15000 nM) was observed.

[0445] In vivo assay

[0446] The effectiveness of the compounds of the invention as antithrombotic agents can be determined using relevant in vivo thrombosis models, including the in vivo electrically induced carotid artery thrombosis model and the in vivo rabbit arteriovenous shunt thrombosis model.

[0447] a. In vivo electrically induced carotid artery thrombosis (ECAT) model

[0448] The rabbit ECAT model is described by Wong et al. (J. Pharmacol. Exp. Ther., 295: 212-218 (2000)) and can be used for this study. Male New Zealand white rabbits are anesthetized with ketamine (50 mg / kg + 50 mg / kg / h IM) and xylazine (10 mg / kg + 10 mg / kg / h IM). These anesthetics are supplemented as needed. An electromagnetic flow probe is placed on an isolated carotid segment to monitor blood flow. Test agents or vehicles (iv, ip, sc or oral) are administered before or after the onset of thrombosis. Drug treatment before the onset of thrombosis is used to simulate the ability of the test agent to prevent and reduce the risk of thrombosis, while administration after the onset is used to simulate the ability to treat existing thrombotic diseases. Thrombosis is induced by electrically stimulating the carotid artery for 3 min at 4 mA using an external stainless steel bipolar electrode. Carotid blood flow is continuously measured over a period of 90 minutes to monitor thrombus-induced occlusion. Total carotid blood flow within 90 minutes is calculated by the trapezoidal rule. The mean carotid flow over 90 minutes was then determined by converting the total carotid blood flow over 90 minutes to a percentage of the total control carotid blood flow, which was obtained when the control blood flow had been maintained for 90 minutes. 50 The dose that increased mean carotid blood flow over 90 min to 50% of control was estimated by a nonlinear least squares regression procedure using the Hill sigmoid E max Formula (DeltaGraph; SPSS Inc., Chicago, IL).

[0449] b. In vivo rabbit arteriovenous (AV) shunt thrombosis model

[0450] The rabbit AV shunt model was described by Wong et al. (Wong, PC et al., J. Pharmacol. Exp. Ther. 292: 351-357 (2000)) and was used for this study. Male New Zealand white rabbits were anesthetized with ketamine (50 mg / kg + 50 mg / kg / h IM) and xylazine (10 mg / kg + 10 mg / kg / h IM). These anesthetics were supplemented as needed. The femoral artery, jugular vein, and femoral vein were isolated and cannulated. A saline-filled AV shunt device was connected between the femoral artery and femoral vein cannulas. The AV shunt device consisted of a polyethylene tubing outer piece (length = 8 cm; internal diameter = 7.9 mm) and a tubing inner piece (length = 2.5 cm; internal diameter = 4.8 mm). The AV shunt also contained an 8-cm long 2-0 silk thread (Ethicon, Somerville, NJ). Blood flowed from the femoral artery into the femoral vein via the AV-shunt. Exposure of flowing blood to the silk thread induced significant thrombosis. Forty minutes later, the shunt was disconnected and the thrombus-covered silk thread was weighed. Test agent or vehicle was administered (iv, ip, sc or orally) prior to opening the AV shunt. The percent inhibition of thrombus formation was determined for each treatment group. 50 The value (dose producing 50% inhibition of thrombus formation) was estimated by a nonlinear least squares regression procedure using the Hill sigmoid E max Formula (DeltaGraph; SPSS Inc., Chicago, IL).

[0451] The anti-inflammatory effects of these compounds can be demonstrated in an Evans blue dye extravasation assay using C1-esterase inhibitor deficient mice. In this model, mice are administered compounds of the invention, Evans blue dye is injected via the tail vein and the extravasation of the blue dye is measured from tissue extracts by spectrophotometric means.

[0452] The ability of the compounds of the invention to reduce or prevent systemic inflammatory response syndrome, such as observed during on-pump cardiovascular procedures, can be tested in an extracorporeal perfusion system, or by on-pump surgical procedures in larger mammals, including dogs and baboons. Readouts for assessing the benefits of the compounds of the invention include, for example, reduced platelet loss, reduced platelet / leukocyte complexes, reduced neutrophil elastase levels in plasma, reduced complement factor activation, and reduced contact activated protein (plasma kallikrein, factor XII, factor XI, high molecular weight kininogen, C1-esterase inhibitor) activation and / or depletion.

[0453] The compounds of the invention may also be used as inhibitors of other serine proteases, particularly human thrombin, human plasma kallikrein and human plasmin. Due to their inhibitory effects, these compounds are shown to be useful for preventing or treating physiological reactions, including coagulation, fibrinolysis, blood pressure regulation and inflammation and wound healing catalyzed by the aforementioned enzymes. Specifically, the compounds have utility as drugs for treating diseases (e.g., myocardial infarction) caused by elevated thrombin activity of the aforementioned serine proteases and as reagents used as anticoagulants in processing blood into plasma for diagnosis and other commercial purposes.

[0454] V. Pharmaceutical Compositions, Formulations and Combinations

[0455] The compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (each of which includes sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. They can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular forms, all of which use dosage forms known to those of ordinary skill in the medical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected route of administration and standard medical practice.

[0456] The term "pharmaceutical composition" means a composition comprising a compound of the invention and at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, especially a mammal, including (i.e.) adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form. Pharmaceutically acceptable carriers are formulated according to many factors that are completely within the skill of ordinary technicians in the art. These factors include, but are not limited to: the type and nature of the formulated active agent; the individual to whom the composition containing the medicament is administered; the intended route of administration of the composition and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may include a variety of different ingredients and additives in addition to the active agent, and such other ingredients are included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., stabilization of the active agent, binding agents, etc.) Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in a variety of readily available resources, such as Remington's Pharmaceutical Sciences, 18th Edition (1990).

[0457] Of course, the dosage regimen of the compounds of the invention will vary depending on known factors, such as the pharmacokinetic 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 kind of concurrent treatment; the frequency of treatment; the route of administration; the patient's renal and liver function; and the desired effect. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, reverse or arrest the development of a thromboembolic disorder.

[0458] As a general guide, when used for a given effect, the daily oral dosage range of each active ingredient is from about 0.001 to about 1000 mg / kg body weight, preferably from about 0.01 to about 100 mg / kg body weight / day, and most preferably from about 0.1 to about 20 mg / kg / day. When administered intravenously, the most preferred dosage range is from about 0.001 to about 10 mg / kg / minute during a constant rate infusion. The compounds of the invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses twice, three times, or four times daily.

[0459] The compounds of the present invention can also be administered parenterally (e.g., intravenously, intraarterially, intramuscularly or subcutaneously). When administered intravenously or intraarterially, the dosage can be given continuously or intermittently. In addition, the preparation can be developed for intramuscular and subcutaneous delivery to ensure that the active pharmaceutical ingredient is gradually released. In one embodiment, the pharmaceutical composition is a solid preparation, such as a spray-dried composition, which can be used as is or a physician or patient can add a solvent and / or a diluent thereto before use.

[0460] The compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0461] The compounds are usually administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected for the intended administration form (eg, oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0462] For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with the following oral, non-toxic, pharmaceutically acceptable inert carriers: lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral drug component can be combined with any of the following oral, non-toxic, pharmaceutically acceptable inert carriers: ethanol, glycerol, water, etc. In addition, suitable binders, lubricants, disintegrants and colorants can also be incorporated into the mixture when desired or necessary. Suitable binders include starch; gelatin; natural sugars such as glucose or β-lactose; corn sweeteners; natural and synthetic gums such as acacia, tragacanth or sodium alginate; carboxymethylcellulose; polyethylene glycol; wax; etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0463] The compounds of the 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 phosphatidylcholine.

[0464] The compounds of the present invention can also be combined with soluble polymers as targetable drug carriers. Such polymers may include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine phenol or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be combined with, for example, a class of biodegradable polymers for achieving controlled release of drugs: crosslinked or amphiphilic block copolymers of polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels. Solid dispersions are also referred to as solid dispersions. In some embodiments, any compound described herein is formulated into a spray-dried dispersion (SDD). SDD is a single-phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution prepared by dissolving a drug and a polymer in a solvent (e.g., acetone, methanol, etc.) and spray-drying the solution. The solvent evaporates rapidly from the droplets, which rapidly solidify the polymer and drug mixture, which entraps the drug in an amorphous form, into an amorphous molecular dispersion.

[0465] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 1000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is generally present in an amount of about 0.1-95% by weight based on the total weight of the composition.

[0466] Gelatin capsules may contain active ingredients and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents may be used to make compressed tablets. Both tablets and capsules may be manufactured as sustained release products to provide continuous release of the drug over a period of hours. Compressed tablets may be coated with a sugar coating or a film to mask any unpleasant taste and protect the tablet from atmospheric influences, or may be enteric coated to selectively disintegrate in the gastrointestinal tract.

[0467] Liquid dosage forms for oral administration may contain coloring and flavoring to increase patient acceptance.

[0468] In general, water, suitable oil, physiological saline, aqueous dextrose (glucose) and related sugar solutions and glycols (e.g., propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain water-soluble salts of active ingredients, suitable stabilizers, and, if necessary, buffer substances. Antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts and EDTA sodium salt are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl or propyl parahydroxybenzoate and chlorobutanol.

[0469] Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference work in the field.

[0470] In the case of combining the compounds of the invention with other anticoagulants, for example, the daily dose may be about 0.1 to about 100 mg of the compounds of the invention and about 0.1 to about 100 mg per kg of patient body weight. For tablet dosage forms, the compounds of the invention may generally be present in an amount of about 5 to about 300 mg per dosage unit, and the amount of the second anticoagulant is about 1 to about 500 mg per dosage unit.

[0471] In the case where the compound of the present invention is administered in combination with an antiplatelet agent, as a general guide, the usual daily dose may be about 0.01 to about 300 mg of the compound of the present invention and about 50 to about 150 mg of the antiplatelet agent per kg of patient body weight, preferably about 0.1 to about 4 mg of the compound of the present invention and about 1 to about 3 mg of the antiplatelet agent.

[0472] In the case where the compound of the present invention is administered in combination with a thrombolytic agent, the usual daily dose may be about 0.1 to about 100 mg of the compound of the present invention per kg of patient body weight, and in the case of a thrombolytic agent, the usual dose of the thrombolytic agent when administered alone may be reduced by about 50-80% when administered together with the compound of the present invention.

[0473] In particular, when provided in the form of a single dose unit, there is a possibility of chemical interaction between the active ingredients of the combination. For this reason, when the compounds of the present invention are combined with a second therapeutic agent in a single dose unit, they are formulated so that although the active ingredients are combined in a single dose unit, the physical contact between the active ingredients is minimized (i.e., reduced). For example, an active ingredient can be enteric coated. By making one of the active ingredients enteric coated, it is possible not only to minimize the contact between the active ingredients of the combination, but also to control the release of one of these components in the gastrointestinal tract so that one of these components is not released in the stomach but released in the intestine. One of the active ingredients can also be coated with a material that affects the sustained release in the entire gastrointestinal tract and is also used to minimize the physical contact between the active ingredients of the combination. In addition, the component of sustained release can be additionally enteric coated so that the release of this component occurs only in the intestine. Yet another approach would involve the formulation of a combination product where one component is coated with a sustained and / or enteric release polymer and the other component is also coated with a polymer (e.g., low viscosity grade hydroxypropylmethylcellulose (HPMC) or other suitable substances known in the art) to further isolate the active component. The polymer coating is used to form an additional barrier to interaction with the other components.

[0474] These and other ways of minimizing contact between the components of the combination products of the invention (whether administered in a single dosage form or in separate forms but administered simultaneously in the same manner) will be apparent to those skilled in the art in light of this disclosure.

[0475] In another embodiment, the present invention provides a pharmaceutical composition further comprising one or more additional therapeutic agents selected from the group consisting of potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, antiatherosclerotic agents, anticoagulants, antithrombotics, prothrombin lytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, adenosine triphosphatase (ATPase) inhibitors, mineralocorticoid receptor antagonists, phosphodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis regulators, antiosteoporosis agents, hormone replacement therapy agents, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and / or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antifungal agents, cholesterol / lipid lowering agents and lipid profile therapeutic agents and agents that simulate ischemic preconditioning and / or myocardial stunning. stunning) agent, or a combination thereof.

[0476] In another embodiment, the present invention provides a pharmaceutical composition further comprising one or more additional therapeutic agents selected from the group consisting of antiarrhythmic agents, antihypertensive agents, anticoagulants, antiplatelet agents, thrombin inhibitors, thrombolytic agents, fibrinolytic agents, calcium channel blockers, potassium channel blockers, cholesterol / lipid lowering agents, or a combination thereof.

[0477] In another embodiment, the present invention provides a pharmaceutical composition further comprising one or more additional therapeutic agents selected from the group consisting of warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharides, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam, diclofenac, sulfinpyrazone, sulphadone, dapoxetine ... ulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase and streptokinase, or a combination thereof.

[0478] In another embodiment, the present invention provides a pharmaceutical composition wherein the additional therapeutic agent is an antihypertensive agent selected from the group consisting of ACE inhibitors, AT-1 receptor antagonists, β-adrenergic receptor antagonists, ETA receptor antagonists, dual ETA / AT-1 receptor antagonists, renin inhibitors (alliskerin) and vasopeptidase inhibitors; an antiarrhythmic agent selected from the group consisting of Kurinhibitor; an anticoagulant selected from thrombin inhibitors, antithrombin III activators, heparin cofactor II activators, other factor XIa inhibitors, other kallikrein inhibitors, plasminogen activator inhibitor (PAI-1) antagonists, thrombin-activated fibrinolysis inhibitor (TAFI) inhibitors, factor VIIa inhibitors, factor IXa inhibitors and factor Xa inhibitors; or an antiplatelet agent selected from GPIIb / IIIa blockers, GP Ib / IX blockers, protease-activated receptor 1 (PAR-1) antagonists, protease-activated receptor 4 (PAR-4) antagonists, prostaglandin E2 receptor EP3 antagonists, collagen receptor antagonists, phosphodiesterase-III inhibitors, P2Y 1 Receptor antagonists, P2Y 12 antagonists, thromboxane receptor antagonists, cyclooxygenase-1 inhibitors and aspirin; or a combination thereof.

[0479] In another embodiment, the present invention provides a pharmaceutical composition wherein the one or more additional therapeutic agents is an antiplatelet agent or a combination thereof.

[0480] In another embodiment, the present invention provides a pharmaceutical composition wherein the additional therapeutic agent is the antiplatelet agent clopidogrel.

[0481] The compounds of the invention may be administered alone or in combination with one or more additional therapeutic agents. "Combination administration" or "combination therapy" means that the compounds of the invention and one or more additional therapeutic agents are co-administered to the mammal being treated. When administered in combination, the components may be administered simultaneously or sequentially in any order at different time points. Thus, the components may be administered separately but sufficiently close in time to provide the desired therapeutic effect.

[0482] Compounds that may 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 anti-ischemic agents.

[0483] Other anticoagulants (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, e.g. ), synthetic pentasaccharides, direct-acting thrombin inhibitors (including hirudin and argatroban), and other factor VIIa inhibitors, factor IXa inhibitors, factor Xa inhibitors (e.g. apixaban, rivaroxaban, LY-517717, DU-176b, DX-9065a and those disclosed in WO 98 / 57951, WO 03 / 026652, WO 01 / 047919 and WO 00 / 076970), factor XIa inhibitors and inhibitors of activated TAFI and PAI-1 known in the art.

[0484] As used herein, the term antiplatelet agent (or platelet inhibitor) refers to an agent that inhibits platelet function, such as by inhibiting platelet aggregation, adhesion or granular inclusion secretion. Such agents include, but are not limited to, various known nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen, aspirin, codeine, diclofenac, droxicam, fentanyl, ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen, phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, and pharmaceutically acceptable salts or prodrugs thereof. Among NSAIDs, aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Other suitable platelet inhibitors include glycoprotein IIb / IIIa antagonists (e.g., tirofiban, eptifibatide, abciximab and integrelin), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole, cilostazol) and PDE-V inhibitors (e.g., sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g., E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), and pharmaceutically acceptable salts or prodrugs thereof.

[0485] Other examples of antiplatelet agents suitable for use in combination with the compounds of the present invention with or without aspirin are ADP (adenosine diphosphate) receptor antagonists, preferably the purinergic receptor P2Y 1 and P2Y 12 antagonists, including P2Y 12 Even more preferred. Preferred P2Y 12Receptor antagonists include clopidogrel, ticlopidine, prasugrel, ticagrelor and cangrelor and pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine and clopidogrel are also preferred compounds because they are known to be milder than aspirin in their use in the gastrointestinal tract. Clopidogrel is an even more preferred agent.

[0486] A preferred example is a triple combination of a compound of the present invention, aspirin and another antiplatelet agent. The antiplatelet agent is preferably clopidogrel or prasugrel, more preferably clopidogrel.

[0487] As used herein, the term thrombin inhibitor (or antithrombin agent) represents an inhibitor of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (i.e., secretion of platelet aggregation and / or platelet granule inclusions (including serotonin)) and / or fibrin formation are disturbed. Many thrombin inhibitors are known to those skilled in the art and are expected to be used in combination with the compounds of this invention. Such inhibitors include, but are not limited to, those disclosed in boroarginine derivatives, boropeptides, heparin, hirudin, argatroban, dabigatran, AZD-0837, and WO 98 / 37075 and WO 02 / 044145, and pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boro peptides include N-acetyl and peptide derivatives of boric acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and its corresponding isothiouronium analogs. As used herein, the term hirudin includes suitable derivatives or analogs of hirudin (eg, hirudin disulfate) referred to herein as hirulogs.

[0488] As used herein, the term thrombolytic (or fibrinolytic) agent (or thrombolytic or fibrinolytic agent) refers to an agent that dissolves a blood clot (thrombus). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa and XIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complexes, including pharmaceutically acceptable salts or prodrugs thereof. As used herein, the term anistreplase refers to the methoxybenzoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is incorporated herein by reference. As used herein, the term urokinase is intended to represent both double-chain and single-chain urokinase, the latter also referred to herein as prourokinase.

[0489] Examples of suitable cholesterol / lipid lowering agents and lipid profile therapeutic agents for use in combination with the compounds of the invention include HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin and other statins), low-density lipoprotein (LDL) receptor activity modulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants (e.g., cholestyramine and colestipol), nicotinic acid or its derivatives (e.g., ), GPR109B (nicotinic acid receptor) modulators, fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate, and benzafibrate) and other peroxisome proliferator-activated receptor (PPAR) alpha modulators, PPAR delta modulators (e.g., GW-501516), PPAR gamma modulators (e.g., rosiglitazone), multifunctional compounds that modulate the activity of various combinations of PPAR alpha, PPAR gamma, and PPAR delta, probucol or its derivatives (e.g., AGI-1067), cholesterol absorption inhibitors, and / or Niemann-Pic k) C1-like transporter inhibitors (e.g. ezetimibe), cholesterol ester transfer protein inhibitors (e.g. CP-529414), squalene synthetase inhibitors and / or squalene epoxidase inhibitors or mixtures thereof, acyl-CoA:cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2 inhibitors, dual ACAT1 / 2 inhibitors, ileal bile acid transport inhibitors (or apical sodium co-dependent bile acid transport inhibitors), microsomal triglyceride transfer protein inhibitors, liver-X-receptor (LXR) α modulators, LXR β modulators, LXR dual α / β modulators, FXR modulators, ω3 fatty acids (e.g. 3-PUFA), phytosterols and / or fatty acid esters of phytosterols (e.g. for dihydrositosterol esters in margarine), endothelial lipase inhibitors, and HDL function mimetics that activate reverse cholesterol transport (such as apoAI derivatives or apoAI peptide mimetics).

[0490] The compounds of the present invention can also be used as standard or reference compounds, for example as quality standards or controls in tests or assays involving inhibition of thrombin, factor VIIa, IXa, Xa, XIa and / or plasma kallikrein. Such compounds can be provided in commercial kits, for example for use in pharmaceutical research involving thrombin, factor VIIa, IXa, Xa, XIa and / or plasma kallikrein. XIa. For example, the compounds of the present invention can be used as references in assays to compare their known activity with compounds having unknown activity. Especially when the test compound is a derivative of the reference compound, this will allow the experimenter to ensure that the assay is properly performed and provide a basis for comparison. When developing new assays or protocols, the compounds of the present invention can be used to test their efficacy.

[0491] The compounds of the invention can also be used in diagnostic tests involving thrombin, factor 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 can be determined by adding a relevant chromogenic substrate (e.g., S2366 for factor XIa) to a series of solutions containing a test sample and one of the optional compounds of the invention. If pNA generation is observed in a solution containing a test sample, but not observed in the presence of the compounds of the invention, it is inferred that factor XIa is present.

[0492] K for target protease i values ​​less than or equal to 0.001 μM and K values ​​for other proteases i The highly potent and selective compounds of the invention having values ​​greater than or equal to 0.1 μM can also be used in diagnostic tests involving quantification of thrombin, factor VIIa, IXa, Xa, XIa and / or plasma kallikrein in serum samples. For example, the amount of factor XIa in a serum sample can be determined by careful titration of protease activity with a potent and factor XIa inhibitor of the invention in the presence of the relevant chromogenic substrate S2366.

[0493] The present invention also encompasses articles of manufacture. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packages. The articles of manufacture of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (c) a package insert stating that the pharmaceutical composition can be used to treat thromboembolic and / or inflammatory conditions (as previously defined). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination with a second therapeutic agent (as previously defined) to treat thromboembolic and / or inflammatory conditions. The article of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located inside or outside the second container. Being located within the first and second containers means that each container contains the item within its boundaries.

[0494] The first container is a container for holding a pharmaceutical composition. This container can be used for manufacturing, storage, transportation and / or individual / batch sales. The first container is intended to include a bottle, a jar, a vial, a flask, a syringe, a tube (e.g., for cream formulations) or any other container for manufacturing, holding, storing or dispensing a pharmaceutical product.

[0495] The second container is a container for accommodating the first container and optional drug instructions. The example of the second container includes but is not limited to a box (e.g., cardboard or plastic), a crate, a carton, a bag (e.g., a paper bag or a plastic bag), a pouch, and a sack. The drug instructions can be physically attached to the outside of the first container via tape, glue, nails, or other attachment methods, or can be placed inside the second container without being attached to the first container by any physical means. Alternatively, the drug instructions are located outside the second container. When located outside the second container, preferably the drug instructions are physically attached via tape, glue, nails, or other attachment methods. Alternatively, it can be adjacent to or in contact with the outside of the second container instead of being physically attached.

[0496] The package insert is a label, tag, sign, or the like that states information related to the pharmaceutical composition located in the first container. The information stated is generally determined by the regulatory agency (e.g., the United States Food and Drug Administration) that manages the region in which the product is to be sold. Preferably, the package insert specifically states the indications for which the pharmaceutical composition has been approved for use. The package insert can be made of any material from which a person can read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).

[0497] Other features of the present invention will become apparent during the description of the following exemplary embodiments, which are given for the purpose of illustrating the present invention and are not intended to limit the present invention.The following examples have been prepared, isolated and characterized using the methods disclosed herein.

[0498] VI. General Synthesis, Including Schemes

[0499] The compounds of the present invention can be synthesized by a variety of methods available to those skilled in the art of organic chemistry (Maffrand, JP et al., Heterocycles, 16(1):35-37 (1981)). General synthetic schemes for preparing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art may use to prepare the compounds disclosed herein. Different methods for preparing the compounds of the present invention will be apparent to those skilled in the art. In addition, the steps in the synthesis can be performed in an alternate order to obtain one or more target compounds.

[0500] Examples of compounds of the invention prepared by the methods described in the general schemes are given in the Intermediates and Examples section described below. The preparation of the homochiral examples can be carried out by techniques known to those skilled in the art. For example, the homochiral compounds can be prepared by separation of the racemic products by chiral phase preparative HPLC. Alternatively, the example compounds can be prepared by methods known to give enantiomerically enriched products. These include, but are not limited to, racemic intermediates into which chiral auxiliary functional groups are introduced to control the diastereoselectivity of the transformation, providing enantiomerically enriched products after cleavage of the chiral auxiliary.

[0501] The compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below and synthetic methods known in the field of synthetic organic chemistry or by variations thereof understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent or solvent mixture suitable for and suitable for the reagents and materials for the conversion. It is understood by those skilled in the art of organic synthesis that the functional groups present on the molecule should be consistent with the planned conversion. Sometimes it is necessary to judge to change the order of the synthesis steps or to select a specific process scheme instead of another to obtain the desired compound of the present invention.

[0502] It is also understood that another major consideration in planning any synthetic route in this art is the judicious choice of protecting groups for protecting reactive functional groups present in the compounds described in this invention. An authoritative explanation describing many alternatives for the trained practitioner is Greene et al. (Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience (2006)).

[0503] General solution

[0504] Representative pyrimidinone compounds 1c of the present invention can be prepared as described in Scheme 1. Using a modified procedure described by Xiao (Organic Letters, 11:1421 (2009)), appropriately substituted pyrimidin-4-ol derivatives 1b can be reacted with appropriately substituted macrocyclic amines 1a in the presence of HATU and DBU in a solvent such as CH 3 CN coupling to provide pyrimidinone compound 1c.

[0505] Solution 1

[0506]

[0507] Representative dihydropyridone compounds 2f of the present invention can be prepared as shown in Scheme 2. Starting from aldehyde 2a, vinyl Grignard addition (generating allylic alcohol 2b) followed by oxidation affords vinyl ketone 2c. Michael addition of appropriately substituted macrocyclic amine 1a followed by acylation with 2d affords compound 2e, which upon cyclization with base affords dihydropyridone 2f.

[0508] Solution 2

[0509]

[0510] Representative azole compounds 3b of the present invention can be prepared as shown in Scheme 3 by coupling intermediate 3a and appropriately substituted macrocyclic amine 1a using HATU and Hunig's base in DMF.

[0511] Solution 3

[0512]

[0513] Representative macrocyclic amines 4g of the present invention can be prepared as shown in Scheme 4. Starting from 4a, copper (I) iodide and K 2 CO 3 Coupling with 4b in DMSO gave 4c. Coupling of 4c with 4d using T3P gave 4e, which was subjected to GrubbII conditions to form macrocyclic 4f. The double bond and Cbz protecting group can then be removed under hydrogenation conditions to give macrocyclic amine 4g.

[0514]

[0515] In some cases, macrocyclic amines carrying protecting groups such as Boc are first coupled using Schemes 1-3 to give 5a. The Boc group is then removed using HCl in dioxane to give 5b. Various R 3b To obtain 5c.

[0516] Solution 5

[0517]

[0518] Representative macrocyclic amines 6h of the present invention can be prepared as shown in Scheme 6. Starting from 6a, coupling with 6b using copper (I) iodide and CsF in DMSO gives 6c. Basic hydrolysis of 6c gives 6d. 6d is coupled with 6e using T3P to give 6f, which is subjected to Grubb II reaction conditions to form macrocyclic 6g. The double bond and Boc protecting group can then be removed under hydrogenation, followed by acidic conditions, followed by free basification to give macrocyclic amine 6h.

[0519] Solution 6

[0520]

[0521] Purification of intermediates and final products was carried out by normal phase or reverse phase chromatography. Pre-stacked SiO2 was used with a gradient of hexanes and eluted with EtOAc, DCM and MeOH. 2 Normal phase chromatography was performed using a column unless otherwise specified. Using a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA, UV 220nm) or a gradient of solvent A (90% water, 10% ACN, 0.1% TFA) and solvent B (10% water, 90% ACN, 0.1% TFA, UV 220nm) or a gradient of solvent A (98% water, 2% ACN, 0.05% TFA) and solvent B (98% ACN, 2% water, 0.05% TFA, UV 220nm) (or) Sunfire Prep C18 OBD 5u 30x100mm, 25 min gradient 0-100% BA=H 2 O / ACN / TFA 90:10:0.1.B=ACN / H 2 Reverse phase preparative HPLC was performed on a C18 column with O / TFA 90:10:0.1.

[0522] Unless otherwise stated, analysis of final products was performed by reverse phase analytical HPLC.

[0523] Method A: Waters SunFire column (3.5 μm C18, 3.0 x 150 mm). Gradient elution was used: (0.5 mL / min) 10-100% solvent B for 12 minutes, then 100% solvent B for 3 minutes. Solvent A was (95% water, 5% acetonitrile, 0.05% TFA), and solvent B was (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

[0524] Method B: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3 min, then hold at 100% B for 0.75-min; Flow rate: 1.11 mL / min.

[0525] Method C: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 min, then hold at 100% B for 0.75-min; Flow rate: 1.11 mL / min.

[0526] Method X: Phenomenex Luna 3u C18 column (2.0x50mm). Gradient elution was used: (0.8mL / min) 0-100% solvent B for 4 minutes, then 100% solvent B for 2 minutes. Solvent A was (90% water, 10% MeOH, 0.1% TFA), solvent B was (10% water, 90% MeOH, 0.1% TFA, UV 220nm).

[0527] Intermediate 1. Preparation of tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate.

[0528]

[0529] 1A. Preparation of (R)-N-[(1E)-(3-bromophenyl)methylene]-2-methylpropane-2-sulfenamide .

[0530] To 3-bromobenzaldehyde (7.8 g, 42.2 mmol) were added (R)-2-methylpropane-2-sulfenamide (5.11 g, 42.2 mmol), Cs 2 CO 3 (20.60 g, 63.2 mmol) in DCM (211 ml) and the resulting reaction mixture was stirred for 5 days. The reaction mixture was then partitioned between brine (50 ml) and DCM (50 ml). The aqueous layer was extracted with DCM (2 x 50 ml). The combined organic layers were washed with brine (25 ml), dried (Na 2 SO 4 ), filtered and concentrated. Purification by normal phase chromatography using hexanes and EtOAc as eluents gave (R)-N-[(1E)-(3-bromophenyl)methylene]-2-methylpropane-2-sulfenamide (11.8 g, 97%) as an amber oil. 1 H NMR (400 MHz, CDCl 3 )δ8.53(s,1H),8.02(t,J=1.8Hz,1H),7.74(dt,J=7.7,1.2Hz,1H),7.64(ddd,J=8.0,2.0,1.0Hz,1H),7.36(t,J=7.8Hz,1H),1.34-1.22(m,9H). MS(ESI)m / z:290(M+H) + .

[0531] 1B. Preparation of (R)-N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfenamide.

[0532] To a solution of (R)-N-[(1E)-(3-bromophenyl)methylene]-2-methylpropane-2-sulfenamide (11.8 g, 40.9 mmol) in THF (190 ml) cooled to 0°C in a 3-necked flask was added allyl bromide (3.90 ml, 45.0 mmol) and In (6.58 g, 57.3 mmol). After stirring at rt for 18 h, the reaction was heated to 50°C for 6 h and then stirred at rt for 18 h. The reaction mixture was stirred by The mixture was filtered and the filtrate was quenched with water (100 ml). A thick transparent gel-like material formed in the aqueous layer. The organics were extracted with EtOAc (4 x 75 ml). The combined organic layers were washed with brine, MgSO 4 Drying, filtration and concentration gave (R)-N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfenamide as a clear oil (9.6 g, 71%). 1 H NMR (400 MHz, CDCl 3 )δ7.48(t,J=1.8Hz,1H),7.41(dt,J=7.6,1.6Hz,1H),7.26-7.18(m,2H),5.79-5.66(m,1H),5.23-5.16(m,2 H), 4.46 (ddd, J = 8.1, 5.6, 2.0Hz, 1H), 3.69 (s, 1H), 2.63-2.53 (m, 1H), 2.53-2.40 (m, 1H), 1.23-1.19 (m, 9H).

[0533] 1C. Preparation of tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate.

[0534]

[0535] To a solution of (R)-N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide (9.6 g, 29.1 mmol) in MeOH (300 ml) was added concentrated HCl (4 ml). After 3 h, the reaction was concentrated and the residue was dissolved in DCM (300 ml), cooled to 0 °C, and then TEA (16.20 ml, 116 mmol) and Boc 2 O (6.75 ml, 29.1 mmol) in DCM (20 ml). After 18 h, additional Boc 2O (1 g), and the reaction was stirred for 4 h. The reaction was quenched with water (100 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were washed with brine (50 ml), dried (Na 2 SO 4 ), filtered and concentrated. Purification by normal phase chromatography using hexane and EtOAc as eluents gave tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (7.3 g, 77%) as a white solid. MS (ESI) m / z: 326.08 (M+H) + .

[0536] Intermediate 2. Preparation of benzyl (S)-(1-(3-bromophenyl)but-3-en-1-yl)carbamate.

[0537]

[0538] To a round bottom flask was added tert-butyl (S)-(1-(3-bromophenyl)but-3-en-1-yl)carbamate (5 g, 15.33 mmol), dioxane (10 mL) and 4N HCl (7.66 mL, 30.7 mmol) in dioxane. The reaction was stirred at rt overnight. The reaction was concentrated and dried. To the residue was added CH 2 Cl 2 (30 mL), Hunig's base (8.03 mL, 46.0 mmol) and Cbz-Cl (2.188 mL, 15.33 mmol). The reaction was stirred at rt for 2 hours. The reaction was then treated with CH 2 Cl 2 (50 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was purified by MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (S)-benzyl (1-(3-bromophenyl)but-3-en-1-yl)carbamate (5.03 g, 13.96 mmol, 91% yield) as a white solid. MS (ESI) m / z: 360.0 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.48-7.30(m,7H),7.22(d,J=5.0Hz,2H),5.67(ddt,J=17.1,10.1,7.0Hz,1H),5.21-5.05(m,5H),4.79(br.s.,1H),2.65-2.39(m,2H).

[0539] Intermediate 5. Preparation of 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol.

[0540]

[0541] 5A. Preparation of 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0542]

[0543] In a 20 mL microwave vial were added 2-bromo-4-chloroaniline (3 g, 14.53 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (5.53 g, 21.80 mmol), KOAc (3.66 g, 37.3 mmol), Pd(dppf)Cl 2 -CH 2 Cl 2 adduct (0.32 g, 0.44 mmol) and DMSO (9 mL). 2 Purge, cap and heat at 80 °C for 22h. Cool the reaction to rt. Add water to dissolve the salts and filter the reaction. Suspend the residual solid in DCM and filter the insoluble solid. Concentrate the filtrate and purify by normal phase chromatography to give 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.15 g, 86% yield) as a white solid. MS (ESI) m / z: 172.3 (MC 6 H 10 +H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.54(d,J=2.6Hz,1H),7.13(dd,J=8.8,2.6Hz,1H),6.52(d,J=8.6Hz,1H),4.72(br.s.,2H),1.34(s,12H).

[0544] 5B. Preparation of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline.

[0545]

[0546] The mixture contained 4-chloro-6-methoxypyrimidine (3.13 g, 21.62 mmol), 4-chloro-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7.31 g, 21.62 mmol), Na 2 CO 3 (2.29 g, 21.62 mmol), DME (86 ml), EtOH (10.81 ml) and water (10.81 ml) were added to an RBF equipped with a condenser. The mixture was purged with Ar for several minutes, and then Pd(dppf)Cl was added. 2 -CH2 Cl 2 Adduct (1.77 g, 2.16 mmol). The reaction was heated at 90 °C for 5 h. The reaction was cooled to rt, diluted with water and extracted with EtOAc. The organic layer was washed with brine, concentrated and purified by normal phase chromatography to give 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (2.86 g, 56.1% yield) as a yellow solid. MS (ESI) m / z: 236.0 (M+H) + . 1 HNMR (500MHz, CDCl 3 )δ8.78(d,J=1.1Hz,1H),7.49(d,J=2.5Hz,1H),7.15(dd,J=8.8,2.5Hz,1H), 6.99(d,J=1.1Hz,1H), 6.67(d,J=8.8Hz,1H), 5.89(br.s.,2H), 4.03(s,3H).

[0547] 5C. Preparation of 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxy Pyrimidine.

[0548]

[0549] To a 0°C solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.5 g, 6.36 mmol) in ACN (90 ml) was added 3-methylbutyronitrile (1.28 ml, 9.55 mmol), followed by dropwise addition of TMSN 3 (1.26 ml, 9.55 mmol). Gas evolution was observed. After 10 minutes, the ice bath was removed and the reaction was allowed to warm to rt. After 1 h, ethynyltrimethylsilane (2.72 ml, 19.09 mmol) and Cu 2 O (0.09 g, 0.64 mmol) and the reaction was stirred for another 1 h. The reaction was stirred in EtOAc and sat NH 4 The organic layer was washed with brine, purified by MgSO 4 Dry, filter and concentrate. Purify by normal phase chromatography to give 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (2.13 g, 5.92 mmol, 93% yield) as a yellow solid. MS (ESI) m / z: 360.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ8.71(d,J=1.1Hz,1H),7.82(d,J=2.2Hz,1H),7.61-7.56(m,1H),7.54-7.48(m,2H),6.20(d,J=1.1Hz,1H),3.92(s,3H),0.32-0.28(m,9H).

[0550] 5D. Preparation of 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine.

[0551]

[0552] To a solution of 4-{5-chloro-2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (1.56 g, 4.33 mmol) in ACN (28.9 ml) was added NCS (2.03 g, 15.17 mmol) and silica gel (6.51 g, 108 mmol). The reaction was stirred at 80 °C for 1 h. The reaction was then filtered to remove the silica gel and the collected silica gel was washed with EtOAc. The filtrate was washed with water (2x), brine and concentrated. Purification by normal phase chromatography gave 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine (0.90 g, 64.5% yield) as a yellow foam. MS (ESI) m / z: 322.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ8.70(d,J=1.1Hz,1H),7.75(d,J=2.4Hz,1H),7.66-7.55(m,2H),7.50(d,J=8.6Hz,1H),6.52(d,J=0.9Hz,1H),3.98(s,3H).

[0553] 5E. Preparation of 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol.

[0554]

[0555] To a solution of 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-methoxypyrimidine (900 mg, 2.79 mmol) in AcOH (6 ml) was added 48% aq HBr (3 ml, 26.5 mmol). The mixture was stirred at 85 °C for 1 h. The reaction was concentrated to dryness and then partitioned between EtOAc and saturated aqueous NaHCO3. The mixture was separated and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, concentrated, and the residue was purified by normal phase chromatography to give a white solid. The solid was suspended in Et 2 O, filtration and Et 2O washing, to obtain 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (610 mg, 70.9% yield) as a white solid. MS (ESI) m / z: 308.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.96(s,1H),7.74-7.67(m,2H),7.62(dd,J=8.5,2.3Hz,1H),7.47(d,J=8.4Hz,1H),6.44(d,J=0.9Hz,1H).

[0556] Intermediate 6. Preparation of 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidine-4- alcohol.

[0557]

[0558] 6A. Preparation of 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine.

[0559]

[0560] To a 0°C solution of 4-chloro-2-(6-methoxypyrimidin-4-yl)aniline (1.0 g, 4.24 mmol) in ACN (60.6 ml) was added 3-methylbutyronitrile (0.86 ml, 6.36 mmol), followed by dropwise addition of TMSN. 3 (0.84 ml, 6.36 mmol). Gas evolution was observed. After 10 min, the ice bath was removed and the reaction was allowed to warm to rt. After 2 h, Cu 2 O (61 mg, 0.42 mmol), followed by slow bubbling of 3,3,3-trifluoroprop-1-yne gas over 5 minutes. After another 10 minutes, the reaction was stirred in DCM and sat NH 4 The organic layer was washed with brine, purified by MgSO 4 Dry, filter and concentrate. Purify by normal phase chromatography to give 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (1.46 g, 97% yield) as a yellow solid. MS (ESI) m / z: 356.1 (M+H) + . 1 HNMR (400MHz, CDCl 3)δ8.62(d,J=1.1Hz,1H),8.00(d,J=0.7Hz,1H),7.75(d,J=2.4Hz,1H),7.6 6-7.60(m,1H),7.52(d,J=8.6Hz,1H),6.60(d,J=1.1Hz,1H),3.98(s,3H). 19 F NMR (376 MHz, CDCl 3 )δ-61.10(s).

[0561] 6B. Preparation of 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol.

[0562]

[0563] To a solution of 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-methoxypyrimidine (1.46 g, 4.10 mmol) in AcOH (10 ml) was added 48% aq HBr (5 ml, 44.2 mmol). The mixture was stirred at 85 °C for 1 h. The reaction was concentrated to dryness and then partitioned between EtOAc and sat NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined and washed with sat NaHCO 3 , washed with brine, and MgSO 4 Dry, filter and remove the solvent under reduced pressure until some solid begins to form. 2 O. The solid was filtered and washed with Et 2 O washing, to obtain 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (1 g, 71.3% yield) as a light yellow solid. MS (ESI) m / z: 342.0 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.83(d,J=0.7Hz,1H),7.99(d,J=0.9Hz,1H),7.87(d,J=2.2Hz,1H),7.79-7.72(m,1H),7.70-7.62(m,1H),6.45(d,J=0.9Hz,1H). 19 F NMR (376MHz, CD 3 OD)δ-62.61(s).

[0564] Intermediate 7. Preparation of 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol.

[0565]

[0566] 7A. Preparation of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide.

[0567] In N 2 4-Chloro-3-fluoroaniline (10.67 g, 73.3 mmol) and Na 2 CO 3 (24.5 g, 125 mmol) Et 2 O (300 mL) suspension was added dropwise with TFAA (12.23 mL, 88 mmol). The mixture was allowed to warm to rt and then stirred for 18 h. The reaction mixture was diluted with hexane (300 mL) and filtered. The filtrate was washed with ice water, 10% aq NaHCO 3 and brine, and washed with Na 2 SO 4 Drying and concentration. Obtained as a light yellow solid as N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (17 g, 96% yield). MS (ESI) m / z: 242.1 (M+H) + .

[0568] 7B. Preparation of (6-amino-3-chloro-2-fluorophenyl)boronic acid.

[0569] To a cooled (-78°C) clear colorless solution of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (5 g, 20.70 mmol) in THF (69.0 ml) was added 2.5 M BuLi in hexanes (16.56 ml, 41.4 mmol) dropwise over 15 min, keeping the internal temperature below -60°C. The resulting clear yellow solution was stirred at -78°C for 10 min, then the reaction was allowed to warm to -50°C over 1 h. The resulting clear brown solution was cooled to -78°C, then B(O-iPr) 3 (10.51 ml, 45.5 mmol). The reaction was stirred at -78 °C for 10 minutes, then the ice bath was removed and the reaction was allowed to warm to rt. The resulting orange suspension was stirred at rt for 2 h, then cooled in an ice bath and quenched with 1N HCl (40 ml). The reaction mixture was warmed to 40 °C for 1 h, then cooled to rt. The reaction was diluted with EtOAc and the layers were separated. The organic layer was washed with brine and concentrated. Purification by normal phase chromatography gave (6-amino-3-chloro-2-fluorophenyl)boronic acid (3 g, 76.6% yield). MS (ESI) m / z: 190.1 (M+H) + .

[0570] 7C. Preparation of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline.

[0571] The reaction was completed in a 350 ml pressure bottle. A solution of 4-chloro-6-methoxypyrimidine (1.784 g, 12.34 mmol) and (6-amino-3-chloro-2-fluorophenyl)boronic acid (3.3 g, 12.34 mmol) in toluene (25 ml) and EtOH (25 ml) was stirred with N 2 Purge for several minutes. Add DIEA (4.31 ml, 24.68 mmol), followed by Pd (Ph 3 P) 4 (1.426 g, 1.234 mmol). The flask was capped and the reaction was heated at 120 °C for 2 h, then cooled to rt and concentrated. Purification by normal phase chromatography gave 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2 g, 45.2% yield) as a yellow solid. MS (ESI) m / z: 254.0 (M+H) + .

[0572] 7D. Preparation of 4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6- Methoxypyrimidine.

[0573]

[0574] To a cooled (0°C) clear yellow solution of 4-chloro-3-fluoro-2-(6-methoxypyrimidin-4-yl)aniline (2.1 g, 8.28 mmol) in ACN (118 ml) was added isoamyl nitrite (1.67 ml, 12.42 mmol) followed by dropwise addition of TMSN 3 (1.63 ml, 12.42 mmol). After 10 min, the cooling bath was removed and the reaction was allowed to warm to rt. After 2 h, ethynyltrimethylsilane (3.54 ml, 24.84 mmol) and Cu 2 O (0.118 g, 0.83 mmol) and the reaction was stirred at rt for 1.5 h. The reaction was then diluted with EtOAc and treated with sat NH 4 Cl, washed with brine, and MgSO 4 Drying, filtration and concentration gave a brown oil. Purification by normal phase chromatography gave 4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine (2.71 g, 87% yield) as a brown solid. MS (ESI) m / z: 378.1 (M+H) + .

[0575] 7E. Preparation of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine.

[0576]

[0577] 4-(3-chloro-2-fluoro-6-(4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-methoxypyrimidine (2.71 g, 7.17 mmol), NCS (3.35 g, 25.1 mmol) and silica gel (10.77 g, 179 mmol) were added to a RBF equipped with a stirring bar and a condenser, followed by ACN (47.8 ml). The reaction was heated at 80 °C for 1 h and then cooled to rt. The reaction was filtered and the filtrate was concentrated. The residue was redissolved in EtOAc and eluted with sat NaHCO 3 , water, brine and concentrated. Purification by normal phase chromatography gave 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine (1.05 g, 43.0% yield) as a yellow solid. MS (ESI) m / z: 340.0 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ8.68(d,J=0.7Hz,1H),7.71-7.62(m,2H),7.37(dd,J=8.6,1.8Hz,1H),6.84(s,1H),4.02(s,3H).

[0578] 7F. Preparation of 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol.

[0579]

[0580] A clear yellow solution of 4-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)-6-methoxypyrimidine (1.05 g, 3.09 mmol) in HOAc (15.43 ml) and 48% aq HBr (17.46 ml, 154 mmol) was warmed to 65 °C for 3 h, then cooled to rt and concentrated. The yellow gum was suspended in EtOAc and treated with sat NaHCO 3 (2x), washed with brine, and washed with Na 2 SO 4 Dry, filter and concentrate. Add Et 2 O (10 ml) and the resulting suspension was sonicated and then filtered. The solid was washed with Et 2 O (2 ml), and air-dried under suction to obtain 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (0.79 g, 78% yield) as a white solid. MS (ESI) m / z: 326.3 (M+H) + . 1 H NMR (400MHz, CD3 OD)δ8.35(s,1H),8.08(d,J=0.7Hz,1H),7.85(dd,J=8.7,7.6Hz,1H),7.54(dd,J=8.6,1.5Hz,1H),6.57(s,1H).

[0581] Intermediate 8. Preparation of 1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one.

[0582]

[0583] 8A. Preparation of 2-azido-5-chlorobenzaldehyde.

[0584] A solution of 5-chloro-2-fluorobenzaldehyde (1.38 g, 8.70 mmol) and sodium azide (0.58 g, 8.92 mmol) in DMF (4 mL) was stirred at 55 °C for 8 h and then cooled to rt. The reaction mixture was diluted with diethyl ether and water and then acidified to pH 4 with 1N HCl. The ether layer was washed with water (3x), then brine (3x), and then precipitated with MgSO 4 Dry and filter.The organic layer was then concentrated in vacuo to give 1.47 g of 2-azido-5-chlorobenzaldehyde (93%) as a light yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ10.30(s,1H),7.86(d,J=2.6Hz,1H),7.58(dd,J=8.7,2.5Hz,1H),7.24(d,J=8.6Hz,1H)

[0585] 8B. Preparation of 5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde.

[0586] A solution of 2-azido-5-chlorobenzaldehyde (386 mg, 2.126 mmol) and tributylstannyl acetylene (0.646 mL, 2.126 mmol) in toluene (5 mL) was heated at 100 °C for 5 h before cooling to rt. After 5 h, the reaction mixture was concentrated and purified directly using normal phase chromatography to give 495 mg of 5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (43%) as a light yellow oil. MS (ESI) m / z: 498.1 (M+H)+.

[0587] 8C. Preparation of 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde.

[0588] To a solution of 5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (459 mg, 0.924 mmol) in ACN (5 mL) was added N-chlorosuccinimide (185 mg, 1.386 mmol), and the reaction was heated at 60 °C for 15 h. After 15 h, the reaction mixture was concentrated and directly purified using normal phase chromatography to give 117 mg of 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde (52%) as a white solid. MS (ESI) m / z: 242.0 (M+H, chlorine isotope peak)+.

[0589] 8D. Preparation of 1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one.

[0590] Preparation of 1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one using a procedure similar to that used to prepare Intermediate 1 by replacing 3-chloro-2,6-difluorobenzaldehyde with 5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde. MS (ESI) m / z: 268.3 (M+H)+. 1 H NMR (400 MHz, CDCl 3 )δ7.71-7.66(m,1H),7.62-7.52(m,2H),7.44(d,J=8.4Hz,1H),6.29(dd,J=17.6,10.6Hz,1H),5.98-5.79(m,2H).

[0591] Intermediate 11. Preparation of 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid.

[0592]

[0593] 11A. Preparation of ethyl 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate.

[0594] A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g, 2.79 mmol), (3-chloro-2-fluorophenyl)hydrazine hydrochloride (0.500 g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirred at rt. After 10 minutes, the reaction mixture was concentrated and purified by silica gel chromatography. The desired product, ethyl 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (200 mg, 28%), was obtained as a creamy white solid. MS (ESI) m / z: 283.1 (M+H) + .

[0595] Intermediate 11. Preparation of 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid.

[0596] To a solution of ethyl 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (50 mg, 0.177 mmol) in MeOH (0.884 mL) was added 1 N NaOH (aq.) (1.061 mL, 1.061 mmol) and the reaction was stirred in a sealed vial at 50 °C for 3 h. The reaction mixture was then cooled to rt and concentrated. The residue was then partitioned between 1 N HCl and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine and concentrated to give intermediate 25 as a cream solid (48 mg, 107%). MS (ESI) m / z: 255.0 (M+H) + .

[0597] Intermediate 13 Preparation of 5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid.

[0598]

[0599] 13A. Preparation of ethyl 5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate.

[0600] To a mixture of (3-chloro-2-fluorophenyl)hydrazine hydrochloride (0.67 g, 3.40 mmol), (E)-2-cyano-3-ethoxyacrylate ethyl ester (0.633 g, 3.72 mmol) and sodium acetate (0.586 g, 7.12 mmol) was added AcOH and H 2 O to form a slurry. The reaction mixture was stirred at room temperature for 0.25 h and then heated at 100 °C overnight. After overnight stirring, the reaction mixture was heated with H 2 O (200 mL) and the yellowish brown solid was isolated. The solid was filtered and washed with H 2 O was washed thoroughly. The residue was redissolved in DCM, dried and evaporated to a brown solid as the desired product (0.76 g, 78%). MS (ESI) m / z: 284.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.76(s,1H),7.51-7.29(m,2H),7.27-7.03(m,1H),5.30-5.06(m,2H),4.24(q,J=7.2Hz,2H),1.38-1.04(m,3H)ppm.

[0601] 13B。To acetonitrile (7 ml) was added butyronitrile (0.381 ml, 3.25 mmol) followed by CuCl2 (0.437 g, 3.25 mmol). After stirring the pyrazole for 0.5 h, a solution of 5-amino-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.615 g, 2.168 mmol) in acetonitrile (3 ml) was added dropwise via a syringe. The reaction mixture was then stirred at rt for 2 h. The organics were quenched with water (100 ml) and extracted with EtOAc (2 x 100 ml), dried (MgSO4) and evaporated to a yellow oil. Purified by 40 g silica gel ISCO column and eluted with Hex / EtOAc. The pure product was eluted at approximately 20% EtOAc. Concentrated to a slightly yellowish brown oil (0.61 g, 93%). LCMS m / z 303.0 (M+H).

[0602] 13. Preparation of 5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylic acid.

[0603] Intermediate 13B (0.61 g, 2.01 mmol) was dissolved in THF (10 ml) and LiOH (0.2 g) and methanol (5 ml) and water (7 ml) were added to the solution in sequence. The reaction mixture was stirred at rt for 2 h. It was quenched with dil HCl (1 N, 100 ml) and the organics were extracted with EtOAc (2 x 100 ml), dried and evaporated to a white solid. Purification by prep HPLC gave the desired product as a white solid (0.26 g, 46%). LCMs m / z = 275.1 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.24 (s, 1H), 7.53-7.46 (m, 1H), 7.41-7.36 (m, 1H), 7.23-7.19 (m, 1H).

[0604] Example 1. Preparation of (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16, Tert-butyl 18-triene-5-carboxylate.

[0605]

[0606] 1A. Preparation of (S)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3- Tert-butyl (but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate.

[0607]

[0608] To a sealed tube were added tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (0.8 g, 2.221 mmol), (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (0.562 g, 2.443 mmol), K 2 CO 3 (0.921 g, 6.66 mmol) and DMSO (2.22 ml). The reaction was purged with Ar and then CuI (0.021 g, 0.111 mmol) was added. The reaction was sealed and stirred at 110°C overnight. The reaction was partitioned between water (40 ml) and EtOAc (50 ml). The organic layer was separated and washed with saturated NH 4 The layers were separated and the organic layer was washed with aqueous Cl solution (40 ml), water (40 ml) and brine (40 ml). 4 Drying, filtering and concentration gave crude (S)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid as a light green gum. To this crude material was then added EtOAc (5 mL), but-3-en-1-amine (112 mg, 1.57 mmol) and pyridine (0.254 mL, 3.14 mmol) followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphahexane-2,4,6-trioxide (1 g, 1.570 mmol). The reaction was stirred at rt overnight. The reaction was diluted with EtOAc (30 ml) and the reaction was washed with saturated NaHCO 3 The organic layer was separated and purified by MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (S)-tert-butyl 4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate (180 mg, 0.320 mmol, 20.4% yield) as a white solid. (ESI) m / z: 563.4 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ7.36(br.s.,4H),7.27-7.23(m,1H),6.85(d,J=7.7Hz,1H),6.73(d,J=6.2Hz,2H),6.65( br.s.,1H),5.78-5.54(m,2H),5.21-5.06(m,5H),5.03-4.92(m,2H),4.76(br.s.,1H),4.23 -4.10(m,1H),3.99(br.s.,1H),3.78-3.64(m,2H),3.55(ddd,J=13.0,9.7,3.6Hz,1H),3.4 9-3.42(m,1H),3.41-3.23(m,3H),2.62-2.44(m,2H),2.24-2.09(m,2H),1.52-1.48(m,9H).

[0609] 1B. Preparation of (7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclic [14.3.1.0 2 , 7 ]Eicosyl-1(20),12,16,18-tetraene-5-carboxylic acid tert-butyl ester.

[0610]

[0611] To the RBF was added (S)-tert-butyl 4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate (170 mg, 0.302 mmol) and DCE (40 mL). The reaction was purged with Ar for 5 min, then Grubbs II (103 mg, 0.121 mmol) was added and the reaction was stirred at 50 °C under Ar for 5 h. The reaction was concentrated and purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosane-1(20),12,16,18-tetraene-5-carboxylate (150 mg, 0.281 mmol, 93% yield) as a light-colored solid. (ESI) m / z: 535.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ7.43-7.32(m,5H),7.30-7.27(m,4H),6.90-6.82(m,2H),6.60(s,1H),6.04(br. s.,1H),5.58-5.47(m,1H),5.29(br.s.,1H),4.95-4.83(m,1H),4.79(br.s.,1H),4 .04(t,J=4.5Hz,1H),3.74(d,J=5.5Hz,1H),3.62(br.s.,2H),3.41-3.25(m,3H),3. 05(br.s.,1H),2.54(br.s.,1H),2.45(br.s.,2H),2.20-2.05(m,1H),1.50(s,9H).

[0612] 1C. Preparation of (7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), tert-butyl 16,18-triene-5-carboxylate.

[0613]

[0614] To the 3-necked RBF was added (7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (150 mg, 0.281 mmol), EtOH (5 mL) and Pd / C (59.7 mg, 0.056 mmol). The reaction was stirred under a hydrogen balloon for 2 h. The reaction was then carefully filtered through Celite. The filtrate was concentrated to give (7S, 15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (110 mg, 0.286 mmol, 99% yield) as a light-colored solid. (ESI) m / z: 403.2 (M+H) + .

[0615] Example 1. Preparation of (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16, Tert-butyl 18-triene-5-carboxylate.

[0616]

[0617] To the RBF was added 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (97 mg, 0.314 mmol), ACN (5 mL), HATU (141 mg, 0.371 mmol) and DBU (0.065 mL, 0.429 mmol), prepared as described in Intermediate 5 (6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol). The suspension turned into a solution after the addition of DBU. The reaction was stirred at rt for 10 minutes. Then (7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (115 mg, 0.286 mmol) and the reaction was stirred at rt overnight. The reaction was purified using RP prep-HPLC to give (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (115 mg, 0.166 mmol, 58.0% yield) as a beige solid. (ESI) m / z: 693.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ8.22(br.s.,1H),7.70(s,1H),7.68(d,J=2.2Hz,1H),7.61(dd,J=8.5,2.3Hz,1H),7.46(d,J=8.4Hz,1H),7.37 -7.31(m,1H),7.04(d,J=9.5Hz,1H),6.95(d,J=7.5Hz,1H),6.85(br.s.,1H),6.53(br.s.,1H),6.44(s,1H),5.78 (dd, J = 12.1, 3.1 Hz, 1H), 4.02 (br. s., 2H), 3.87 (d, J = 13.2 Hz, 2H), 3.68-3.59 (m, 2H), 3.56-3.47 (m, 2H), 3.35 (br. s., 1H), 1.98 (dd, J = 8.0, 4.7 Hz, 1H), 1.92-1.78 (m, 1H), 1.50 (s, 11H), 1.43 (d, J = 6.4 Hz, 3H), 1.11 (br. s., 1H). Analytical HPLC (Method X) RT = 3.788 min, purity = 96%. Factor XIA Ki = 955 nM, plasma kallikrein Ki = 3473 nM.

[0618] Example 2. Preparation of (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene- 8-Keto hydrochloride.

[0619]

[0620] To RBF was added (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (110 mg, 0.159 mmol), dioxane (1 mL) and 4N HCl in dioxane (0.145 mL, 4.76 mmol) were added. The reaction was stirred at rt for 30 minutes. The reaction was concentrated to give (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-triene-8-one hydrochloride (85 mg, 0.125 mmol, 79% yield) as a beige solid. (ESI) m / z: 593.3 (M+H)+ . 1 H NMR (400MHz, CD 3 OD)δ8.76(d,J=19.1Hz,1H),8.40-8.36(m,1H),7.91-7.87(m,1H),7.78-7.75(m,1H),7.70-7.66(m, 1H),7.45-7.39(m,1H),7.24-7.18(m,2H),6.94(d,J=7.5Hz,1H),6.41(s,1H),5.60(d,J=12.3Hz,1H) ,4.37-4.28 (m, 1H), 3.85-3.74 (m, 2H), 3.72-3.66 (m, 2H), 3.63-3.38 (m, 5H), 2.78-2.67 (m, 1H), 2.42-2.26 (m, 1H), 2.15-2.05 (m, 1H), 1.68-1.56 (m, 1H), 1.49 (br.s., 2H), 1.01 (dt, J = 13.8, 7.0 Hz, 1H). Analytical HPLC (Method X) RT = 2.880 min, purity = 95%. Factor XIA Ki = 542 nM, plasma kallikrein Ki = 7292 nM.

[0621] Example 3. Preparation of (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16, 18-Triene-5-carboxylic acid methyl ester.

[0622]

[0623] Add (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16,18-triene-8-one hydrochloride (13 mg, 0.021 mmol), Et 3 N (14.38 μl, 0.103 mmol), THF (0.5 ml) and methyl chloroformate (2.145 mg, 0.023 mmol). The reaction was stirred at rt for 10 minutes. The reaction was concentrated, then dissolved in MeOH and purified using RP Prep-HPLC to give (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 ,7 ] Eicosapentaenoic acid methyl ester (10.7 mg, 0.016 mmol, 76% yield) as a beige solid. (ESI) m / z: 651.2 (M+H) + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.71(s,1H),8.46(s,1H),8.04(d,J=8.2Hz,1H),7.89(d,J=2.4Hz,1H),7.81(dd,J=8.4,2.3Hz,1H),7.75-7.70(m,1H ),7.21-7.16(m,1H),7.01(s,1H),6.93(d,J=8.5Hz,1H),6.72(d,J=7.6Hz,1H),6.44(s,1H),5.71(dd,J=12.8,3.4Hz,1 3H), 4.24 (br.s., 1H), 3.84 (dd, J = 13.3, 4.4 Hz, 1H), 3.77-3.72 (m, 1H), 3.68 (dd, J = 13.4, 4.0 Hz, 1H), 3.61 (br.s., 3H), 3.55-3.49 (m, 1H), 2.93 (d, J = 13.1 Hz, 1H), 2.63 (d, J = 13.7 Hz, 2H), 1.62 (br.s., 1H), 1.53 (br.s., 3H), 1.31-1.12 (m, 5H). Analytical HPLC (Method C) RT = 1.689 min, purity = 95%. Factor XIA Ki = 643 nM, plasma kallikrein Ki = 4111 nM.

[0624] Examples 4 and 5. Preparation of (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- 6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), tert-butyl 16,18-triene-5-carboxylate and (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1- yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]two Tert-butyl decacarbon-1(20),16,18-triene-5-carboxylate.

[0625]

[0626] 4A. Preparation of (R)-3-((2-(Benzyloxy)-2-oxoethyl)amino)-2-(((Benzyloxy)carbonyl)amino) Methyl propionate.

[0627]

[0628] (R)-3-amino-2-(((benzyloxy)carbonyl)amino)propanoic acid (2.6 g, 10.91 mmol) and MeOH (50 mL) were added to RBF. The reaction was cooled to 0°C. SOCl was then added dropwise over 10 min. 2(5.58 mL, 76 mmol) and the reaction was slowly warmed to rt and stirred at rt overnight. The reaction was concentrated to give (R)-3-amino-2-(((benzyloxy)carbonyl)amino)propionic acid methyl ester hydrochloride (3.15 g, 10.91 mmol, 100% yield) as a white solid. THF (40 mL) and Hunig's base (5.72 mL, 32.7 mmol) were then added to the solid. The solution was stirred at rt for 10 minutes, and then 2-bromoacetic acid benzyl ester (3.46 mL, 21.82 mmol) was added. The reaction was stirred at rt for 4 h. The reaction was partitioned between water (40 ml) and EtOAc (60 ml). The organic layer was separated, washed with water (2 x 40 ml) and brine (2 x 40 ml), filtered through MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (R)-methyl 3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate (1.92 g, 4.79 mmol, 43.9% yield) as a clear oil. (ESI) m / z: 401.1 (M+H) + . 1 H NMR (500MHz,,CDCl 3 )δ7.43-7.33(m,10H),5.78(d,J=7.2Hz,1H),5.20-5.13(m,4H),4.56-4.39(m,1H),3.7 7(s,3H),3.50-3.39(m,2H),3.15(dd,J=12.4,4.7Hz,1H),3.00(dd,J=12.5,4.3Hz,1H).

[0629] 4B. Preparation of (R)-3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyl 4-(4-(4-oxy)carbonyl)amino)propionic acid methyl ester.

[0630]

[0631] To a RBF was added (R)-methyl 3-((2-(benzyloxy)-2-oxoethyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate (3.19 g, 7.97 mmol), THF (40 mL), Hunig's base (4.17 mL, 23.90 mmol) followed by BOC-anhydride (3.70 mL, 15.93 mmol). The reaction was stirred at rt overnight. The reaction was partitioned between EtOAc (50 mL) and water (40 mL). The organic layer was separated, washed with water (40 mL) and brine (40 mL), filtered through MgSO 4Dry, filter and concentrate. The residue was purified using an ISCO system (0-60% EtOAc / Hex gradient) to give (R)-methyl 3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate (2.25 g, 4.50 mmol, 56.4% yield) as a clear oil. (ESI) m / z: 501.1 (M+H) + . 1 H NMR (500MHz,,CDCl 3 )δ7.44-7.30(m,10H),6.17-5.69(m,1H),5.23-5.05(m,4H),4.64-4.42(m,1H ),4.00-3.91(m,2H),3.87-3.79(m,1H),3.77-3.52(m,4H),1.49-1.35(m,9H).

[0632] 4C. Preparation of (R)-2-((2-amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)acetic acid.

[0633]

[0634] To a 3-neck RBF was added (R)-methyl 3-((2-(benzyloxy)-2-oxoethyl)(tert-butoxycarbonyl)amino)-2-(((benzyloxy)carbonyl)amino)propanoate (2.25 g, 4.50 mmol), EtOH (30 mL) and Pd / C (0.024 g, 0.225 mmol). The reaction was stirred under hydrogen atmosphere (balloon) for 2 h. The reaction was carefully filtered and the filtrate was concentrated to give (R)-2-((2-amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)acetic acid (850 mg, 3.08 mmol, 68.4% yield) as a white solid. (ESI) m / z: 277.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD) δ4.34(dd,J=9.7,4.4Hz,1H),3.91(dd,J=14.9,4.3Hz,1H),3.87-3.85(m,3H),3.83-3.72(m,1H),3.70-3.60(m,1H),1.51-1.41(m,9H).

[0635] 4D. Preparation of (R)-1-tert-butyl 3-methyl 5-oxopiperazine-1,3-dicarboxylate.

[0636]

[0637] To the RBF was added (R)-2-((2-amino-3-methoxy-3-oxopropyl)(tert-butoxycarbonyl)amino)acetic acid (850 mg, 3.08 mmol) and CH 2 Cl 2 (100 mL). The reaction was cooled to 0°C and DCC (952 mg, 4.61 mmol) was added. The reaction was stirred in an ice-water bath for 4 h, then Et 3 N (0.858mL, 6.15mmol) was added to the reaction and the reaction was stirred at rt over the weekend. The reaction was concentrated and the residue was stirred in EtOAc (50ml). The suspension was filtered and the filtrate was concentrated. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (R)-5-oxopiperazine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester (700mg, 2.71mmol, 88% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ6.43(br.s.,1H),4.30-4.00(m,4H),3.90-3.80(m,3H),3.70(d,J=7.5Hz,1H),1.53-1.44(m,9H).

[0638] 4E. Preparation of (R)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxo 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate.

[0639]

[0640] To a RBF was added tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (0.65 g, 1.804 mmol), (R)-1-tert-butyl 3-methyl 5-oxopiperazine-1,3-dicarboxylate (0.699 g, 2.71 mmol), CsF (1.370 g, 9.02 mmol), THF (3.61 ml) and N,N′-dimethylethylenediamine (0.039 ml, 0.361 mmol). The reaction was purged with Ar, then CuI (0.034 g, 0.180 mmol) was added and the reaction was capped and stirred at rt for 2 days. The reaction was partitioned between EtOAc (40 ml) and water (20 ml). The organic layer was separated and washed with saturated NH 4 The mixture was washed with aqueous Cl solution (30 ml), water (30 ml) and brine (30 ml), and then with MgSO 4Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (R)-3-tert-butyl 4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-1,3-dicarboxylic acid 1-tert-butyl 3-methyl ester (280 mg, 0.521 mmol, 28.9% yield) as a white solid. (ESI) m / z: 538.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.46-7.29(m,6H),7.25(d,J=7.5Hz,1H),7.19(d,J=7.3Hz,2H),5.79-5.61(m,1H),5.20-5.02(m,5H),4.83(br.s.,1H),4.62(d, J=18.0Hz,2H),4.38(br.s.,1H),4.02(d,J=18.7Hz,1H),3.77-3.69(m,3H),3.53(d,J=10.3Hz,1H),2.65-2.43(m,2H),1.50(s,9H).

[0641] 4F. Preparation of (R)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3- Tert-butyl (but-3-en-1-ylcarbamoyl)-5-oxopiperazine-1-carboxylate.

[0642]

[0643] To the RBF was added 1-tert-butyl 3-methyl (R)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-1,3-dicarboxylate (280 mg, 0.521 mmol) and THF (5 mL). 2A solution of (R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)-6-oxopiperazine-2-carboxylic acid (270 mg, 0.516 mmol, 99% yield) was added to the reaction and the reaction was stirred at rt for 2 h. The reaction was concentrated to give (R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)-6-oxopiperazine-2-carboxylic acid (270 mg, 0.516 mmol, 99% yield) as the lithium salt. To this material was added (R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)-6-oxopiperazine-2-carboxylic acid (270 mg, 0.516 mmol), THF (5 mL), Hunig's base (0.270 mL, 1.547 mmol), but-3-en-1-amine (73.4 mg, 1.031 mmol) and HATU (392 mg, 1.031 mmol). The reaction was stirred at rt for 4 h. The reaction was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was separated, washed with water (30 mL) and brine (30 mL), purified by MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (R)-tert-butyl 4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)-5-oxopiperazine-1-carboxylate (280 mg, 0.486 mmol, 94% yield) as a white solid. (ESI) m / z: 577.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.44-7.32(m,5H),7.25-7.11(m,3H),5.79-5.58(m,2H),5.24-5.04(m,6H),4.80(br.s.,1H),4.64-4.35(m,2H),4.32-4.16(m ,1H),4.09(d,J=17.8Hz,1H),3.61(d,J=13.4Hz,1H),3.30(br.s.,2H),2.68-2.42(m,2H),2.27-2.10(m,2H),1.57-1.45(m,10H).

[0644] 4G. Preparation of (7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triaza Three rings [14.3.1.0 2 , 7 ] tert-butyl ester of eicosane-1(20),12,16,18-tetraene-5-carboxylate and (7S,12E,15S)-15- {[(Benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), 12,16,18-Tetraene-5-carboxylic acid tert-butyl ester.

[0645]

[0646] To the RBF was added (R)-tert-butyl 4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)-5-oxopiperazine-1-carboxylate (275 mg, 0.477 mmol) and DCE (50 mL). The reaction was purged with Ar for 5 min, then Grubbs II (121 mg, 0.143 mmol) was added and the reaction was stirred at 50 °C under Ar for 2 h. The reaction was concentrated and purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl ester of eicosapentaenoic acid 1(20),12,16,18-tetraene-5-carboxylate and (7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] A mixture of tert-butyl eicosapentaenoate (200 mg, 0.365 mmol, 76% yield) as a light solid. (ESI) m / z: 549.1 (M+H) + .

[0647] 4H. Preparation of (7R,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]twenty Carbon-1(20),16,18-triene-5-carboxylic acid tert-butyl ester and (7S,15S)-15-amino-3,8-dioxo-2,5,9-triaza Three rings [14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate.

[0648]

[0649] To a 2-necked RBF was added (7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl ester of eicosapentaenoic acid 1(20),12,16,18-tetraene-5-carboxylate and (7S,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7] a mixture of tert-butyl eicosapentaenoate (190 mg, 0.346 mmol), EtOH (10 mL) and Pd / C (73.7 mg, 0.069 mmol). The reaction was stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction was carefully filtered through Celite and the filtrate was concentrated to give (7R,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl ester of 1(20),16,18-triene-5-carboxylate and (7S,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] A mixture of tert-butyl eicosapentaenoate (140 mg, 0.336 mmol, 97% yield) as a beige solid. (ESI) m / z: 417.4 (M+H) + .

[0650] Examples 4 and 5. Preparation of (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]- 6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), tert-butyl 16,18-triene-5-carboxylate and (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1- yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]two Tert-butyl decacarbon-1(20),16,18-triene-5-carboxylate.

[0651]

[0652] 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (110 mg, 0.357 mmol), ACN (3 ml), HATU (160 mg, 0.421 mmol) and DBU (73.3 μl, 0.486 mmol) were added to RBF. The suspension turned into a solution after the addition of DBU. The reaction was stirred at rt for 10 minutes. Then (7R,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl ester of 1(20),16,18-triene-5-carboxylate and (7S,15S)-15-amino-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7] a mixture of tert-butyl eicosapentaenoic acid 1(20),16,18-triene-5-carboxylate (135 mg, 0.324 mmol) and the reaction was stirred at rt overnight. The reaction was purified using RP prep-HPLC. Two diastereoisomers were separated. The first peak to elute (with a shorter retention time) was (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene-5-carboxylic acid tert-butyl ester (62 mg, 0.083 mmol, 25.7% yield). (ESI) m / z: 707.3 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.52(s,1H),8.33(s,1H),8.07(d,J=7.3Hz,1H),7.88(d,J=2.2Hz,1H),7.78-7.72(m,1H),7.69-7.64(m ,1H),7.54-7.48(m,1H),7.39-7.32(m,2H),7.23(d,J=7.0Hz,1H),6.45(s,1H),5.72(dd,J=11.7,3.3Hz,1H) ,4.66-4.44 (m, 1H),4.33-4.01 (m, 3H),3.91-3.83 (m, 1H),3.67 (d, J = 11.0 Hz, 1H),2.91 (br.s., 1H),2.31-2.19 (m, 1H),2.18-2.05 (m, 1H),1.63 (d, J = 10.3 Hz, 1H),1.51 (br.s., 9H),1.43-1.34 (m, 4H),1.13 (br.s., 1H). Analytical HPLC (Method X) RT = 3.563 min, purity = 95%. Factor XIA Ki = 9020 nM, plasma kallikrein Ki = 3136 nM. The second eluting peak (with a longer retention time) was (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene-5-carboxylic acid tert-butyl ester (62 mg, 0.083 mmol, 25.7% yield). (ESI) m / z: 707.2 (M+H)+ . 1 H NMR (400MHz, CD 3 OD)δ8.42-8.30(m,3H),7.89-7.85(m,1H),7.76-7.70(m,1H),7.64(d,J=8.4Hz,1H),7.53-7.48(m,1H),7. 43(s,1H),7.40-7.36(m,1H),7.33(d,J=7.5Hz,1H),6.38(d,J=0.4Hz,1H),5.85(dd,J=12.4,3.0Hz,1H),4 .69-4.44 (m, 1H), 4.31-3.99 (m, 3H), 3.93-3.78 (m, 1H), 3.64 (br.s., 1H), 2.88 (br.s., 1H), 2.47 (dt, J = 13.0, 6.6 Hz, 1H), 1.90 (dd, J = 13.4, 3.1 Hz, 2H), 1.51 (br.s., 10H), 1.44-1.38 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H). Analytical HPLC (Method X) RT = 3.633 min, purity = 95%. Factor XIA Ki = 276 nM, plasma kallikrein Ki = 6001 nM.

[0653] Example 6. Preparation of (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene- 3,8-Diketone hydrochloride.

[0654]

[0655] To RBF was added (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (62 mg, 0.088 mmol) and MeOH (0.5 mL) were added, followed by a 4N HCl solution in dioxane (0.266 mL, 8.76 mmol). The reaction was stirred at rt for 15 minutes. The reaction was concentrated to give (7S,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7] Eicosapentaenoic acid-1(20),16,18-triene-3,8-dione hydrochloride (40 mg, 0.059 mmol, 67.3% yield) as a milky white solid. (ESI) m / z: 607.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.71(s,1H),8.40-8.32(m,1H),8.19(d,J=7.9Hz,1H),7.88(d,J=2.4Hz,1H),7.79-7.73(m,1H ),7.71-7.65(m,1H),7.63-7.53(m,1H),7.44-7.29(m,3H),6.41(s,1H),5.64(dd,J=12.3,3.5Hz,1H ), 4.49 (br.s., 1H), 4.24-4.04 (m, 2H), 3.89 (d, J = 3.5 Hz, 2H), 3.76-3.59 (m, 3H), 2.83 (d, J = 13.9 Hz, 1H), 2.36-2.12 (m, 2H), 1.66-1.51 (m, 1H), 1.47-1.42 (m, 1H), 1.14-1.01 (m, 1H), 0.71-0.48 (m, 1H). Analytical HPLC (Method X) RT = 2.735 minutes, purity = 95%. Factor XIA Ki = 6004 nM, plasma kallikrein Ki = 13020 nM.

[0656] Example 7. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene- 3,8-Diketone hydrochloride.

[0657]

[0658] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7] tert-butyl eicosapentaenoate (62 mg, 0.088 mmol) and MeOH (0.5 mL) were added, followed by 4N HCl in dioxane (0.266 mL, 8.76 mmol). The reaction was stirred at rt for 15 minutes. The reaction was concentrated to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16,18-triene-3,8-dione hydrochloride (40 mg, 0.059 mmol, 67.3% yield) as a milky white solid. (ESI) m / z: 607.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.65-8.54(m,1H),8.40(s,1H),8.34(s,1H),7.86(d,J=2.2Hz,1H),7.77-7.70(m,1H),7.67 -7.61(m,1H),7.60-7.54(m,1H),7.52-7.46(m,2H),7.41(d,J=8.1Hz,1H),6.36(s,1H),5.84(dd , J = 12.3, 2.6 Hz, 1H), 4.46-4.40 (m, 1H), 4.22-4.09 (m, 2H), 3.92-3.87 (m, 2H), 3.80-3.57 (m, 9H), 2.74-2.57 (m, 2H), 2.02-1.83 (m, 2H), 1.68-1.55 (m, 2H), 1.35-1.30 (m, 1H), 1.05-0.91 (m, 1H). Analytical HPLC (Method X) RT = 2.806 min, purity = 95%. Factor XIA Ki = 97 nM, plasma kallikrein Ki = 4780 nM.

[0659] Example 8. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16, Tert-butyl 18-triene-5-carboxylate.

[0660]

[0661] 8A. Preparation of (R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert- 4-Butyloxycarbonyl)piperazine-2-carboxylic acid.

[0662]

[0663] To a sealed tube were added tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (1 g, 2.78 mmol), (R)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (0.767 g, 3.33 mmol), K 2 CO 3 (1.151 g, 8.33 mmol) and DMSO (2.78 ml). The reaction was purged with Ar and then CuI (0.026 g, 0.139 mmol) was added. The reaction was sealed and stirred at 110 °C for 30 h. The reaction was partitioned between water (40 ml) and EtOAc (50 ml). The organic layer was separated and washed with saturated NH 4 The mixture was washed with aqueous Cl solution (40 ml), water (40 ml) and brine (40 ml), and then with MgSO 4 Drying, filtration and concentration gave the crude mixture as a light green gum. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (400 mg, 0.785 mmol, 28.3% yield) as a white solid. (ESI) m / z: 510.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.43-7.30(m,5H),7.23(d,J=7.0Hz,1H),6.87-6.71(m,3H),5.68(br.s.,1H),5.19-4.99(m,5H),4.76(br.s.,1H),4. 66-4.33(m,2H),4.16-3.99(m,1H),3.59-3.47(m,1H),3.39(br.s.,2H),3.16(br.s.,1H),2.54(br.s.,2H),1.48(s,9H).

[0664] 8B. Preparation of (R)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3- Tert-butyl (but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate.

[0665]

[0666] To a RBF was added (R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (220 mg, 0.432 mmol), THF (5 mL), Hunig's base (0.226 mL, 1.295 mmol), but-3-en-1-amine (61.4 mg, 0.864 mmol) and HATU (328 mg, 0.863 mmol). The reaction was stirred at rt for 3 h. The reaction was partitioned between EtOAc (50 ml) and water (30 ml). The organic layer was separated, washed with water (30 ml) and brine (30 ml), purified by MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (R)-tert-butyl 4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate (220 mg, 0.391 mmol, 91% yield) as a white solid. (ESI) m / z: 563.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.36(br.s.,4H),7.27-7.23(m,1H),6.85(d,J=7.5Hz,1H),6.79-6.70(m,2H),6.6 2(br.s.,1H),5.78-5.49(m,2H),5.22-5.03(m,5H),5.03-4.90(m,2H),4.77(d,J=5. 5Hz,1H),4.13(dd,J=13.4,4.4Hz,1H),3.99(br.s.,1H),3.72(d,J=12.8Hz,2H),3.6 0-3.22(m,5H),2.62-2.45(m,2H),2.24-2.06(m,2H),1.50(s,9H),1.34-1.24(m,1H).

[0667] 8C. Preparation of (7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclic [14.3.1.0 2 , 7 ]Eicosyl-1(20),12,16,18-tetraene-5-carboxylic acid tert-butyl ester.

[0668]

[0669] To the RBF was added (R)-tert-butyl 4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-3-(but-3-en-1-ylcarbamoyl)piperazine-1-carboxylate (220 mg, 0.391 mmol) and DCE (40 mL). The reaction was purged with Ar for 5 min, then Grubbs II (66.4 mg, 0.078 mmol) was added and the reaction was stirred at 50 °C under Ar for 5 h. The reaction was concentrated and purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosane-1(20),12,16,18-tetraene-5-carboxylate (170 mg, 0.318 mmol, 81% yield) as a light-colored solid. (ESI) m / z: 535.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.44-7.30(m,6H),6.85(dd,J=8.3,1.9Hz,1H),6.81(d,J=7.0Hz,1H),6.51(br.s.,1H),5.95(br.s.,1H),5. 47-5.35(m,1H),5.28(br.s.,1H),5.16-5.07(m,2H),4.86(dt,J=14.3,7.2Hz,1H),4.66(br.s.,1H),4.25-4.1 0(m,1H),4.05(br.s.,1H),3.76(br.s.,1H),3.62(br.s.,2H),3.53(d,J=8.1Hz,1H),3.44-3.36(m,1H),3.33( br.s.,1H),2.88(br.s.,1H),2.66-2.50(m,2H),2.21-2.12(m,1H),2.08(dd,J=13.9,4.8Hz,1H),1.51(s,9H).

[0670] 8D. Preparation of (7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]20-carbon- (20), tert-butyl 16,18-triene-5-carboxylate.

[0671]

[0672] To the 2-necked RBF was added (7R,12E,15S)-15-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 ,7 ] tert-butyl eicosapentaenoate (165 mg, 0.309 mmol), EtOH (10 mL) and Pd / C (65.7 mg, 0.062 mmol). The reaction was stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction was carefully filtered through Celite and the filtrate was concentrated to give (7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (120 mg, 0.298 mmol, 97% yield) as a beige solid. (ESI) m / z: 403.2 (M+H) + .

[0673] Example 8. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16, Tert-butyl 18-triene-5-carboxylate.

[0674]

[0675] To the RBF was added 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol prepared as described in Intermediate 5, ACN (5 mL), HATU (147 mg, 0.388 mmol) and DBU (0.067 mL, 0.447 mmol). The suspension turned into a solution after the addition of DBU. The reaction was stirred at rt for 10 minutes. Then (7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (120 mg, 0.298 mmol) and the reaction was stirred at rt overnight. The reaction was purified using RP prep-HPLC to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (50 mg, 0.068 mmol, 22.97% yield) as a beige solid. (ESI) m / z: 693.3 (M+H) + . 1 H NMR (400MHz, CD 3OD)δ8.71-8.65(m,1H),8.35(s,1H),8.25(d,J=6.8Hz,1H),7.90(d,J=2.2Hz,1H),7.79-7.72(m,1H),7 .69-7.65(m,1H),7.31(t,J=7.8Hz,1H),7.09-6.99(m,2H),6.57(d,J=7.3Hz,1H),6.44-6.37(m,1H),5 .70(dd,J=13.0,2.6Hz,1H),4.17(t,J=5.0Hz,1H),3.89-3.52(m,6H),3.23(br.s.,1H),2.93(d,J=13. 2Hz,1H),2.40-2.24(m,1H),2.03-1.89(m,1H),1.88-1.73(m,2H),1.66-1.54(m,1H),1.49(s,9H),1.38

[0676] -1.29 (m, 1H), 1.26-1.18 (m, 1H), 1.12 (d, J = 12.3 Hz, 1H). Analytical HPLC (Method X) RT = 3.758 min, purity = 95%. Factor XIA Ki = 21 nM, plasma kallikrein Ki = 1087 nM.

[0677] Example 9. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene- 8-Keto hydrochloride.

[0678]

[0679] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (50 mg, 0.072 mmol), MeOH (0.5 mL), dioxane (1 mL) and 4N HCl in dioxane (1.802 mL, 7.21 mmol). The reaction was stirred at rt for 15 minutes. The reaction was concentrated to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7] Eicosa-1(20),16,18-triene-8-one hydrochloride (40 mg, 0.062 mmol, 85% yield) as a beige solid. (ESI) m / z: 593.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.81-8.74(m,1H),8.42-8.36(m,1H),7.93-7.84(m,2H),7.80-7.72(m,1H),7.69-7.59(m,1H),7 .44-7.34(m,1H),7.22-7.13(m,2H),7.04(d,J=7.7Hz,1H),6.45(s,1H),5.68(dd,J=12.8,2.9Hz,1H), 4.26 (t, J = 3.9 Hz, 1H), 3.93-3.81 (m, 1H), 3.79-3.56 (m, 5H), 3.44-3.38 (m, 1H), 2.66-2.47 (m, 2H), 2.05-1.87 (m, 1H), 1.68-1.49 (m, 2H), 1.48-1.36 (m, 2H), 1.05 (dd, J = 8.0, 3.9 Hz, 1H), 0.97-0.83 (m, 1H). Analytical HPLC (Method X) RT = 2.883 min, purity = 97%. Factor XIA Ki = 11 nM, plasma kallikrein Ki = 1821 nM.

[0680] Example 10. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16, 18-Triene-5-carboxylic acid methyl ester.

[0681]

[0682] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-triene-8-one hydrochloride (12 mg, 0.019 mmol), THF (0.5 mL), Et 3N (0.013 mL, 0.095 mmol) and methyl chloroformate (1.800 mg, 0.019 mmol). The reaction was stirred at rt for 2 h. The reaction was purified by RPprep-HPLC to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid methyl ester (6 mg, 8.75 μmol, 45.9% yield) as a beige solid. (ESI) m / z: 651.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.69(s,1H),8.37-8.34(m,1H),7.89(d,J=2.4Hz,1H),7.77-7.73(m,1H),7.69-7.65(m,1H),7.31(t,J=7.9Hz,1H),7.08 -6.99(m,2H),6.59(d,J=7.7Hz,1H),6.42(d,J=0.7Hz,1H),5.70(dd,J=13.0,2.6Hz,1H),4.18(br.s.,1H),3.91(dd,J=13.6, 4.2 Hz, 1H), 3.77-3.69 (m, 6H), 3.63-3.56 (m, 1H), 3.55-3.45 (m, 1H), 3.27-3.16 (m, 1H), 2.97-2.84 (m, 1H), 2.39-2.24 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.72 (m, 2H), 1.62-1.53 ​​(m, 1H), 1.38-1.27 (m, 1H), 1.22 (t, J = 12.0 Hz, 1H), 1.13 (t, J = 12.3 Hz, 1H). Analytical HPLC (Method A) RT = 7.666 min, purity = 95%. Factor XIA Ki = 5 nM, plasma kallikrein Ki = 862 nM.

[0683] Example 11. Preparation of 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), 16,18-trien-5-yl] tert-butyl acetate trifluoromethyl acetate.

[0684]

[0685] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16,18-triene-8-one hydrochloride (18 mg, 0.029 mmol), K 2 CO 3 (19.74 mg, 0.143 mmol), THF (0.5 mL) and tert-butyl 2-bromoacetate (6.69 mg, 0.034 mmol). The reaction was stirred at rt for 5 h. Then Et 3 N (30ul) and DMF (0.3ml) and the reaction was stirred at rt overnight. The reaction was purified by RP prep-HPLC to give 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-trien-5-yl]acetic acid tert-butyl ester trifluoromethyl acetate (14 mg, 0.017 mmol, 57.8% yield) as a white solid. (ESI) m / z: 707.2 (M+H) + . 1 HNMR (400MHz, CD 3OD)δ8.73(s,1H),8.40(s,1H),7.96(br.s.,1H),7.87(d,J=2.4Hz,1H),7.77-7.71(m,1H),7.67-7.61(m,1H),7.42-7.35(m, 1H),7.22-7.15(m,2H),7.10(d,J=7.3Hz,1H),6.47(s,1H),5.67(dd,J=12.8,2.6Hz,1H),4.29(t,J=3.4Hz,1H),4.04-3.94( m, 1H), 3.86 (d, J = 9.0 Hz, 1H), 3.74 (d, J = 11.9 Hz, 1H), 3.67 (dd, J = 12.2, 3.2 Hz, 2H), 3.58-3.47 (m, 1H), 3.42-3.36 (m, 1H), 2.67-2.46 (m, 2H), 1.92 (t, J = 11.0 Hz, 1H), 1.66-1.49 (m, 12H), 1.34 (d, J = 7.5 Hz, 1H), 1.01 (d, J = 8.1 Hz, 1H), 0.71 (br.s., 1H). Analytical HPLC (Method A) RT = 6.613 min, purity = 97%. Factor XIA Ki = 11 nM, plasma kallikrein Ki = 460 nM.

[0686] Example 12. Preparation of (7R,15S)-5-acetyl-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazole-1- yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), 16,18-Triene-8-one.

[0687]

[0688] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-triene-8-one hydrochloride (12 mg, 0.019 mmol), THF (0.5 mL), Et 3 N (0.013 mL, 0.095 mmol) and acetyl chloride (1.495 mg, 0.019 mmol). The reaction was stirred at rt for 2 h. The reaction was purified using an RP prep-HPLC system to give (7R,15S)-5-acetyl-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 ,7 ] Eicosa-1(20),16,18-triene-8-one (6 mg, 8.97 μmol, 47.1% yield) as a white solid. (ESI) m / z: 635.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.73-8.60(m,1H),8.35(s,1H),7.89(s,1H),7.77-7.73(m,1H),7.68(s,1H),7.36-7.27 (m,1H),7.09-6.99(m,2H),6.64-6.52(m,1H),6.44-6.38(m,1H),5.75-5.66(m,1H),4.28-4. 14 (m, 1H), 4.03-3.56 (m, 6H), 3.55-3.44 (m, 1H), 3.02-2.82 (m, 1H), 2.38-2.23 (m, 1H), 2.15 (d, J = 8.8 Hz, 3H), 2.01-1.89 (m, 1H), 1.87-1.73 (m, 2H), 1.65-1.51 (m, 1H), 1.43-1.05 (m, 3H). Analytical HPLC (Method A) RT = 6.898 min, purity = 95%. Factor XIA Ki = 6 nM, plasma kallikrein Ki = 1053 nM.

[0689] Example 13. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-5-methyl-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16, 18-Trien-8-one trifluoromethyl acetate.

[0690]

[0691] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7] Eicosa-1(20),16,18-triene-8-one hydrochloride (12 mg, 0.019 mmol), DCM (0.5 mL), AcOH (5.45 μl, 0.095 mmol), paraformaldehyde (5.72 mg, 0.190 mmol) and sodium triacetoxyborohydride (6.06 mg, 0.029 mmol). The reaction was stirred at rt overnight. HPLC showed that the starting material still remained, so additional amounts of paraformaldehyde (5.72 mg, 0.190 mmol) and sodium triacetoxyborohydride (6.06 mg, 0.029 mmol) were added and the reaction was stirred at rt for another 5 h. The reaction mixture was concentrated and purified using RP Prep-HPLC to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-methyl-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-trien-8-one trifluoromethyl acetate (6.5 mg, 8.83 μmol, 46.3% yield) as a white solid. (ESI) m / z: 607.2 (M+H) + . 1 HNMR (400MHz, CD 3 OD)δ8.72(s,1H),8.40-8.38(m,1H),7.90-7.85(m,1H),7.78-7.73(m,1H),7.68-7.63(m, 1H),7.43-7.36(m,1H),7.21-7.14(m,2H),7.09(br.s.,1H),6.45(s,1H),5.67(dd,J=12.8 , 2.9 Hz, 1H), 4.29 (br.s., 1H), 4.02-3.47 (m, 6H), 3.38 (br.s., 1H), 3.01 (s, 3H), 2.71-2.38 (m, 2H), 1.95 (d, J = 11.2 Hz, 1H), 1.69-1.23 (m, 4H), 1.04 (br.s., 1H), 0.76-0.51 (m, 1H). Analytical HPLC (Method A) RT = 5.256 min, purity = 98%. Factor XIA Ki = 10 nM, plasma kallikrein Ki = 441 nM.

[0692] Example 14. Preparation of 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20),16,18-trien-5-yl]acetic acid trifluoromethyl acetate.

[0693]

[0694] RBF was added with 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-trien-5-yl]acetic acid tert-butyl ester trifluoromethyl acetate (14 mg, 0.020 mmol), CH 2 Cl 2 (0.2 mL) and TFA (0.152 mL, 1.978 mmol). The reaction was stirred at rt overnight. The reaction was concentrated and the residue was purified using RP prep-HPLC to give 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-trien-5-yl]acetic acid trifluoromethyl acetate (8 mg, 9.93 μmol, 50.2% yield) as a white solid. (ESI) m / z: 651.2 (M+H) + . 1 H NMR (400MHz, CD 3OD)δ8.72(s,1H),8.39-8.37(m,1H),7.99-7.90(m,1H),7.87(d,J=2.4Hz,1H),7.77-7.73(m,1H),7.67-7.63(m,1H),7.43-7.37(m,1H) ,7.21-7.16(m,2H),7.11(d,J=7.5Hz,1H),6.46(d,J=0.7Hz,1H),5.68(dd,J=12.8,2.9Hz,1H),4.30(t,J=3.5Hz,1H),4.18(d,J=2.0Hz, HPLC (method A) RT = 5.321 min, purity = 95%. Factor XIA Ki = 5 nM, plasma kallikrein Ki = 107 nM.

[0695] Example 15. Preparation of (7R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7 ]Nineteen carbon-1(19),15, tert-Butyl 17-triene-5-carboxylate trifluoromethyl acetate.

[0696]

[0697] Example 15A. Preparation of (R)-3-(allylcarbamoyl)-4-(3-((S)-1-(((benzyloxy)carbonyl) tert-butyl 1-amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate.

[0698]

[0699] To the RBF was added (R)-1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (220 mg, 0.432 mmol), THF (3 mL), Et 3 N (0.120 mL, 0.863 mmol), prop-2-en-1-amine (49.3 mg, 0.863 mmol) and HATU (328 mg, 0.863 mmol). The reaction was stirred at rt for 3 h. The reaction was partitioned between EtOAc (50 ml) and water (30 ml). The organic layer was separated, washed with water (30 mL) and brine (30 ml), filtered through MgSO4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (R)-tert-butyl 3-(allylcarbamoyl)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate (170 mg, 0.310 mmol, 71.8% yield) as a white solid. (ESI) m / z: 549.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.36(br.s.,5H),7.30-7.24(m,1H),6.86(d,J=7.7Hz,1H),6.77(d,J=6.6Hz,2H),6 .66(br.s.,1H),5.77-5.58(m,2H),5.24-4.92(m,7H),4.76(br.s.,1H),4.14(dd,J=1 3.3,4.5Hz,1H),4.03(br.s.,1H),3.85(t,J=5.2Hz,2H),3.80-3.67(m,2H),3.60-3.4 5(m,2H),3.42-3.30(m,1H),2.59-2.42(m,2H),1.52-1.46(m,9H),1.36-1.30(m,1H).

[0700] Example 15B. Preparation of (7R,11E,14S)-14-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazine Azatricyclic [13.3.1.0 2 , 7 ]Nineteen-carbon-1(19),11,15,17-tetraene-5-carboxylic acid tert-butyl ester.

[0701]

[0702] To the RBF was added (R)-tert-butyl 3-(allylcarbamoyl)-4-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)piperazine-1-carboxylate (150 mg, 0.273 mmol) and DCE (30 mL), prepared as described in Example 15A. The reaction was purged with Ar for 5 min, then Grubbs II (46.4 mg, 0.055 mmol) was added and the reaction was stirred at 50 °C under Ar for 5 h. The reaction was concentrated and purified using an ISCO system (0-100% EtOAc / Hex gradient) to give (7R,11E,14S)-14-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7]Nonadecan-1(19),11,15,17-tetraene-5-carboxylic acid tert-butyl ester (55 mg, 0.106 mmol, 38.6% yield) as a light-colored solid. (ESI) m / z: 521.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ7.51-7.21(m,5H),7.13-6.93(m,2H),6.87-6.72(m,1H),6.58(br.s .,1H),5.83-5.63(m,1H),5.17-4.94(m,2H),4.70(dd,J=16.1,8.6Hz,2H ),4.08(d,J=13.2Hz,1H),4.03-3.90(m,1H),3.66-3.40(m,3H),3.02-2. 91(m,1H),2.52-2.27(m,2H),2.18(d,J=19.1Hz,1H),1.57-1.37(m,9H).

[0703] Example 15C. Preparation of (7R,14S)-14-amino-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7 ]ten Nonacarbon-1(19),15,17-triene-5-carboxylic acid tert-butyl ester.

[0704]

[0705] To a 3-necked RBF was added (7R,11E,14S)-14-{[(benzyloxy)carbonyl]amino}-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7 ] tert-butyl 19-carbon-1(19),11,15,17-tetraene-5-carboxylate (53 mg, 0.102 mmol), EtOH (5 mL) and Pd / C (10.83 mg, 10.18 μmol). The reaction was stirred under a hydrogen atmosphere (balloon) for 3 h. The reaction was carefully filtered through Celite. The filtrate was concentrated to give (7R,14S)-14-amino-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7 ]Nineteen-carbon-1(19),15,17-triene-5-carboxylic acid tert-butyl ester (25 mg, 0.064 mmol, 63.2% yield) as a milky white solid. (ESI) m / z: 389.2 (M+H) + .

[0706] Example 15. Preparation of (7R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7 ]Nineteen carbon-1(19),15, 17-Triene-5-carboxylic acid tert-butyl ester trifluoromethylacetate.

[0707]

[0708] To the RBF was added 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol (21.81 mg, 0.071 mmol), ACN (1 mL), HATU (31.8 mg, 0.084 mmol) and DBU (0.015 mL, 0.097 mmol) prepared as described in Intermediate 5. The suspension turned into a solution after the addition of DBU. The reaction was stirred at rt for 10 minutes. Then (7R,14S)-14-amino-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7 ] tert-butyl nonadeca-1(19),15,17-triene-5-carboxylate (25 mg, 0.064 mmol) and the reaction was stirred at rt overnight. The reaction was purified using RP prep-HPLC to give (7R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[13.3.1.0 2 , 7 ]Nonadecan-1(19),15,17-triene-5-carboxylic acid tert-butyl ester trifluoromethyl acetate (12 mg, 0.014 mmol, 22.32% yield) as a beige solid. (ESI) m / z: 679.2 (M+H) + . 1 H NMR (400MHz, CD 3OD)δ8.48(s,1H),8.38-8.35(m,1H),7.89(d,J=2.2Hz,1H),7.78-7.73(m,1H),7.68-7.63(m,1H),7.36-7.28(m,1H),7 .19(br.s.,1H),7.10(dd,J=8.3,2.1Hz,1H),6.63(d,J=7.5Hz,1H),6.44(s,1H),5.70(dd,J=11.8,3.2Hz,1H),4.10-3. 97 (m, 1H), 3.91 (d, J = 10.8 Hz, 1H), 3.81 (dd, J = 8.5, 3.6 Hz, 1H), 3.70-3.55 (m, 2H), 3.52-3.42 (m, 2H), 3.13 (d, J = 9.0 Hz, 1H), 2.89 (d, J = 12.5 Hz, 1H), 2.14-2.06 (m, 1H), 2.02-1.94 (m, 1H), 1.60-1.54 (m, 1H), 1.50 (s, 9H), 1.45-1.29 (m, 3H). Analytical HPLC (Method A) RT = 12.616 min, purity = 95%. Factor XIA Ki = 492 nM, plasma kallikrein Ki = 3432 nM.

[0709] Example 16. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-5-(oxetane-3-yl)-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]twenty Carbon-1(20),16,18-triene-8-one trifluoromethylacetate.

[0710]

[0711] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-triene-8-one hydrochloride (10 mg, 0.016 mmol), DCM (0.5 mL), AcOH (4.54 μl, 0.079 mmol), oxetane-3-one (11.44 mg, 0.159 mmol) and sodium triacetoxyborohydride (33.6 mg, 0.159 mmol). The reaction was stirred overnight at rt. The reaction mixture was concentrated and the residue was purified using RP prep-HPLC to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-5-(oxetane-3-yl)-2,5,9-triazatricyclo[14.3.1.02 , 7 ] Eicosa-1(20),16,18-triene-8-one trifluoromethyl acetate (6.5 mg, 8.09 μmol, 50.9% yield) as a white solid. (ESI) m / z: 649.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.74-8.65(m,1H),8.40-8.31(m,1H),8.03(br.s.,1H),7.91-7.84(m,1H),7.79-7.72(m,1H),7.70-7.61(m,1H),7.43-7 .33(m,1H),7.23-7.11(m,2H),7.04-6.94(m,1H),6.46-6.39(m,1H),5.68(dd,J=12.9,3.0Hz,1H),4.99-4.90(m,2H),4.89-4 .82 (m, 4H), 4.56-4.47 (m, 1H), 4.34-4.25 (m, 1H), 3.93-3.78 (m, 1H), 3.67-3.56 (m, 2H), 3.55-3.47 (m, 1H), 3.45-3.38 (m, 1H), 2.80-2.63 (m, 1H), 2.58-2.43 (m, 1H), 1.96 (dd, J = 12.7, 10.0 Hz, 1H), 1.69-1.46 (m, 3H), 1.42-1.30 (m, 1H), 1.09 (br.s., 2H). Analytical HPLC (Method A) RT = 8.049 min, purity = 95%. Factor XIA Ki = 13 nM, plasma kallikrein Ki = 528 nM.

[0712] Example 17. Preparation of 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20),16,18-Trien-5-yl]-1,3-oxazole-5-carboxylic acid ethyl ester trifluoromethyl acetate (trifluoromethylacetate).

[0713]

[0714] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-triene-8-one hydrochloride (12 mg, 0.019 mmol), DMF (0.2 mL), Et 3N (0.013 mL, 0.095 mmol) and ethyl 2-chlorooxazole-5-carboxylate (6.69 mg, 0.038 mmol). The reaction was stirred at 80 ° C overnight. The reaction was purified by RP prep-HPLC to give 2-[(7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosa-1(20),16,18-trien-5-yl]-1,3-oxazole-5-carboxylic acid ethyl ester trifluoromethyl acetate (5 mg, 5.61 μmol, 29.5% yield) as a light brown solid. (ESI) m / z: 732.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.69(s,1H),8.36(s,1H),8.31(d,J=8.1Hz,1H),7.90(d,J=2.2Hz,1H),7.77-7.73(m,1H),7.69-7.65(m,1H),7.64-7.59(m,1 H),7.32(t,J=7.8Hz,1H),7.12-7.03(m,2H),6.62(d,J=7.7Hz,1H),6.42(s,1H),5.71(dd,J=13.0,2.4Hz,1H),4.33(q,J=7.2Hz,3H ), 4.29-4.23 (m, 1H), 4.09-4.01 (m, 1H), 3.97-3.82 (m, 3H), 3.73-3.63 (m, 1H), 3.55-3.44 (m, 1H), 2.94-2.84 (m, 1H), 2.38-2.27 (m, 1H), 2.00-1.90 (m, 1H), 1.84-1.71 (m, 2H), 1.63-1.54 (m, 1H), 1.36 (t, J = 7.2 Hz, 5H), 1.23 (d, J = 6.8 Hz, 1H), 1.12 (d, J = 12.3 Hz, 1H). Analytical HPLC (Method A) RT = 12.214 min, purity = 95%. Factor XIA Ki = 16 nM, plasma kallikrein Ki = 1218 nM.

[0715] Example 18. Preparation of (7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amide]- 8-Oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene-5-carboxylic acid tert-butyl ester trifluoro Methyl acetate (trifluoromethylacetate).

[0716]

[0717] To RBF was added (7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (17 mg, 0.036 mmol), 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (9.10 mg, 0.036 mmol), HATU (20.39 mg, 0.054 mmol), Hunig's base (0.031 mL, 0.179 mmol) and DMF (0.5 mL) were added. The reaction was stirred at rt for 1 h. The reaction was diluted with MeOH and a few drops of water and purified using a RP prep-HPLC system. The desired product was concentrated to give (7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amide]-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid tert-butyl ester trifluoromethyl acetate (15 mg, 0.019 mmol, 53.5% yield) as a milky white solid. (ESI) m / z: 639.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.30(d,J=6.8Hz,1H),8.25(s,1H),7.73(ddd,J=8.3,6.7,1.8Hz,1H),7.48(ddd,J=8.1,6.5,1.7Hz,1 H),7.44-7.30(m,2H),7.12-6.99(m,3H),5.01(dd,J=10.6,5.3Hz,1H),4.21(dd,J=7.5,4.0Hz,1H),3.68-3 .57 (m, 3H), 3.56-3.44 (m, 2H), 3.24 (br. s., 1H), 2.90 (d, J = 13.6 Hz, 1H), 2.39 (d, J = 0.9 Hz, 3H), 1.89 (td, J = 9.7, 5.0 Hz, 2H), 1.84-1.68 (m, 2H), 1.59-1.52 (m, 1H), 1.50 (s, 10H), 1.26-1.11 (m, 2H), 1.02-0.86 (m, 1H). Analytical HPLC (Method X) RT = 3.770 min, purity = 95%. Factor XIA Ki = 3314 nM, plasma kallikrein Ki = 3827 nM.

[0718] Example 19. Preparation of (7R,15S)-15-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorobenzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), 16,18-Triene-5-carboxylic acid tert-butyl ester trifluoromethylacetate.

[0719]

[0720] (7R,15S)-15-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-(20),16,18-triene-5-carboxylate trifluoromethyl acetate (4 mg, 4.51 μmol, 22.67% yield) was prepared by replacing (6-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-4-ol) with 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol as described in Intermediate 7. (ESI) m / z: 711.6 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.69(s,1H),8.34(s,1H),8.25(d,J=6.6Hz,1H),7.91-7.85(m,1H),7.58(dd,J=8.6,1.3Hz ,1H),7.32(t,J=7.9Hz,1H),7.07-6.97(m,2H),6.63(s,1H),6.51(d,J=7.5Hz,1H),5.71(dd,J= 13.0, 2.6 Hz, 1H), 4.17 (br. s., 1H), 3.94-3.49 (m, 8H), 2.94 (d, J = 11.9 Hz, 1H), 2.34-2.25 (m, 1H), 1.97 (t, J = 11.8 Hz, 1H), 1.87-1.76 (m, 2H), 1.63-1.56 (m, 1H), 1.49 (s, 9H), 1.37-1.08 (m, 4H). Analytical HPLC (Method A) RT = 12.844 min, purity = 95%. Factor XIA Ki = 5 nM, plasma kallikrein Ki = 345 nM.

[0721] Example 20. Preparation of 1-(3-chloro-2-fluorophenyl)-5-methyl-N-[(7R,15S)-8-oxo-2,5,9-triazepine Three rings [14.3.1.0 2 , 7 ]eicosyl-1(20),16,18-trien-15-yl]-1H-pyrazole-4-carboxamide hydrochloride.

[0722]

[0723] To RBF was added (7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amido]-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl ester trifluoromethyl acetate (13 mg, 0.020 mmol) and 4N HCl in dioxane (0.254 mL, 1.017 mmol) were added. The reaction was stirred at rt for 1 h. The reaction was concentrated to give 1-(3-chloro-2-fluorophenyl)-5-methyl-N-[(7R,15S)-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]eicosyl-1(20),16,18-trien-15-yl]-1H-pyrazole-4-carboxamide hydrochloride (10 mg, 0.017 mmol, 81% yield) as a white solid. (ESI) m / z: 539.2 (M+H) + Analytical HPLC (Method A) RT = 7.801 min, purity = 95%. Factor XIA Ki = 1306 nM, plasma kallikrein Ki = 2550 nM.

[0724] Example 21. Preparation of (7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amide]- 8-Oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosapentaenoic acid 1(20),16,18-triene-5-carboxylic acid methyl ester trifluoromethyl Trifluoromethylacetate.

[0725]

[0726] To RBF was added 1-(3-chloro-2-fluorophenyl)-5-methyl-N-[(7R,15S)-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]eicosyl-1(20),16,18-trien-15-yl]-1H-pyrazole-4-carboxamide hydrochloride (15 mg, 0.025 mmol), Et 3 N (0.017 mL, 0.123 mmol) and THF (0.5 mL) were added, followed by methyl chloroformate (2.278 μl, 0.029 mmol). The reaction was stirred at rt for 10 minutes. The reaction was diluted with MeOH and purified using RP Prep-HPLC to give (7R,15S)-15-[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-amide]-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7] Eicosapentaenoic acid-1(20),16,18-triene-5-carboxylate trifluoromethyl acetate (5 mg, 6.61 μmol, 27.0% yield) as a milky white solid. (ESI) m / z: 597.2 (M+H) + . 1 HNMR (400MHz, CDCl 3 )δ8.44-8.37(m,1H),8.31(br.s.,1H),7.90-7.76(m,2H),7.60-7.42(m,3H),7.25 -7.09(m,3H),5.22-5.09(m,2H),4.32-4.14(m,2H),4.01-3.94(m,1H),3.93-3.87 (m, 3H), 3.83-3.62 (m, 4H), 3.28 (d, J = 8.6 Hz, 1H), 3.09 (br. s., 1H), 2.63-2.53 (m, 3H), 2.09-1.82 (m, 4H), 1.68 (br. s., 1H), 1.33 (br. s., 2H), 1.09 (d, J = 11.2 Hz, 1H). Analytical HPLC (Method A) RT = 11.019 min, purity = 94%. Factor XIA Ki = 1059 nM, plasma kallikrein Ki = 9168 nM.

[0727] Example 22. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), 16,18-Triene-5-carboxylic acid methyl ester trifluoromethylacetate.

[0728]

[0729] 22A. Preparation of (7R,15S)-15-(N-{3-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-3-oxo 2-(diethoxyphosphoryl)acetamido)-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]twenty Carbon-1(20),16,18-triene-5-carboxylic acid tert-butyl ester.

[0730]

[0731] To RBF was added (7R,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7] tert-butyl eicosapenta-(20),16,18-triene-5-carboxylate (15 mg, 0.032 mmol), DCM (1.5 mL) and DIEA (0.039 mL, 0.221 mmol) were added, followed by 1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one prepared in Intermediate 8, 1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (8.46 mg, 0.032 mmol). The reaction was stirred at rt for 50 minutes. The reaction was then cooled to 0 °C and pyridine (0.013 mL, 0.158 mmol) was added, followed by 2-(diethoxyphosphoryl)acetic acid (18.56 mg, 0.095 mmol). POCl was then added dropwise 3 (5.88 μl, 0.063 mmol) and the reaction was stirred at 0 °C for 10 minutes. The reaction was then treated with CH 2 Cl 2 (15 ml) and diluted with saturated NaHCO 3 The organic layer was separated, washed with water (10 ml) and brine (10 ml), and purified by MgSO 4 Dry, filter and concentrate. The residue was purified by ISCO system (0-30% MeOH / CH 2 Cl 2 Gradient) purification to give (7R,15S)-15-(N-{3-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}-2-(diethoxyphosphoryl)acetamido)-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl eicosapentaenoate (25 mg, 0.029 mmol, 93% yield) as a light brown solid. (ESI) m / z: 848.3 (M+H) + .

[0732] 22B. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16,18- Triene-5-carboxylic acid tert-butyl ester trifluoromethyl acetate.

[0733]

[0734] To RBF was added (7R,15S)-15-(N-{3-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}-2-(diethoxyphosphoryl)acetamido)-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2, 7 ] tert-butyl eicosapentaenoate (28 mg, 0.033 mmol) and MeOH (0.5 mL). The reaction was cooled to 0 °C, then NaOMe (21.39 mg, 0.099 mmol) was added and the reaction was stirred at 0 °C for 30 minutes. The reaction was then neutralized with 1N HCl (0.066 mL, 0.066 mmol). The reaction was diluted with MeOH and purified using RP Prep-HPLC to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid tert-butyl ester trifluoromethyl acetate (15 mg, 0.019 mmol, 56.2% yield) as a brown film. (ESI) m / z: 694.7 (M+H) + .

[0735] 22C. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo- 1,2,3,6-tetrahydropyridin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene-8- Ketone hydrochloride.

[0736]

[0737] To RBF was added (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl 2-(20),16,18-triene-5-carboxylate trifluoromethyl acetate (15 mg, 0.019 mmol) and 4N HCl in dioxane (0.232 mL, 0.927 mmol) and MeOH (0.2 mL). The reaction was stirred at rt for 1 h. The reaction was concentrated to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-triene-8-one hydrochloride (10 mg, 0.016 mmol, 85% yield) as a beige solid. (ESI) m / z: 594.2 (M+H) + .

[0738] Example 22. Preparation of (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid (20), 16,18-Triene-5-carboxylic acid methyl ester trifluoromethylacetate.

[0739]

[0740] Add (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosa-1(20),16,18-triene-8-one hydrochloride (15 mg, 0.022 mmol), THF (0.5 mL), Et 3 N (0.016 mL, 0.112 mmol), followed by methyl chloroformate (2.61 μl, 0.034 mmol). The reaction was stirred at rt for 10 minutes. The reaction was diluted with MeOH and purified using RPPrep-HPLC to give (7R,15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid methyl ester trifluoromethyl acetate (5 mg, 6.39 μmol, 28.4% yield) as a white solid. (ESI) m / z: 652.2 (M+H) + . 1 H NMR (400MHz, CD 3OD)δ8.49-8.44(m,1H),8.22(d,J=4.8Hz,1H),7.69-7.57(m,3H),7.34-7.27(m,1H),7.04(d,J=8.1Hz,1H),6.97(s,1H ),6.93(d,J=7.5Hz,1H),5.80(s,1H),5.40(dd,J=12.3,3.1Hz,1H),4.07(br.s.,1H),3.94(dd,J=13.5,4.1Hz,1H),3.7 6-3.68 (m, 8H), 3.57 (dd, J = 11.4, 4.0 Hz, 1H), 3.43 (d, J = 12.3 Hz, 1H), 3.19 (ddd, J = 11.7, 7.3, 4.1 Hz, 1H), 2.93-2.77 (m, 1H), 2.37-2.22 (m, 2H), 2.16-2.04 (m, 1H), 1.79-1.50 (m, 4H), 1.35-1.25 (m, 1H), 1.23-1.12 (m, 1H), 1.09-0.93 (m, 1H). Analytical HPLC (Method A) RT = 11.641 min, purity = 98%. Factor XIA Ki = 5 nM, plasma kallikrein Ki = 189 nM.

[0741] Example 23. Preparation of N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12, 1,4-Trien-3-yl]methyl}carbamic acid methyl ester trifluoromethylacetate.

[0742]

[0743] 23A. Preparation of (R)-2-((3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)amino tert-Butyl)-3-((tert-butoxycarbonyl)amino)propanoic acid.

[0744]

[0745] Into a sealed tube were added intermediate 2(S)-(1-(3-bromophenyl)but-3-en-1-yl)carbamic acid benzyl ester (1, 2.78 mmol), (R)-2-amino-3-((tert-butoxycarbonyl)amino)propanoic acid (680 mg, 3.33 mmol), K 2 CO 3 (1151 mg, 8.33 mmol) and DMSO (5552 μl). The reaction was purged with Ar and then CuI (26.4 mg, 0.139 mmol) was added. The reaction was sealed and stirred at 110 °C for 30 h. The reaction was partitioned between water (40 ml) and EtOAc (50 ml). The organic layer was separated and washed with saturated NH 4 The mixture was washed with aqueous Cl solution (40 ml), water (40 ml) and brine (40 ml), and then with MgSO 4Drying, filtration and concentration gave (R)-2-((3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)amino)-3-((tert-butoxycarbonyl)amino)propanoic acid (800 mg, 1.654 mmol, 59.6% yield) as a light green gum. (ESI) m / z: 484.1 (M+H) + .

[0746] 23B. Preparation of N-[(1S)-1-(3-{[(1R)-1-[(but-3-en-1-yl)carbamoyl]-2-{[(tert-butyloxy

[0063] benzyl]carbamate.

[0747]

[0748] To a RBF was added (R)-2-((3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)amino)-3-((tert-butoxycarbonyl)amino)propanoic acid (800 mg, 1.654 mmol), THF (15 mL), Hunig's base (0.867 mL, 4.96 mmol), but-3-en-1-amine (235 mg, 3.31 mmol) and HATU (1258 mg, 3.31 mmol). The reaction was stirred at rt for 3 h. The reaction was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was separated, washed with water (30 mL) and brine (30 mL), purified by MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give benzyl N-[(1S)-1-(3-{[(1R)-1-[(but-3-en-1-yl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}ethyl]amino}phenyl)but-3-en-1-yl]carbamate (440 mg, 0.820 mmol, 49.6% yield) as a white solid. (ESI) m / z: 537.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6)δ7.97(d,J=5.3Hz,1H),7.71(d,J=8.8Hz,1H),7.42-7.24(m,5H),7.03(t,J=7.8Hz,1H),6 .87(t,J=5.8Hz,1H),6.59(d,J=7.5Hz,1H),6.51(s,1H),6.37(d,J=7.7Hz,1H),5.82-5.64( m,2H),5.60(d,J=6.4Hz,1H),5.13-4.86(m,6H),4.55-4.34(m,1H),3.83-3.61(m,1H),3.3 2-3.26(m,1H),3.25-2.99(m,3H),2.44-2.25(m,2H),2.19-2.01(m,2H),1.43-1.32(m,9H).

[0749] 23C. Preparation of N-[(3R,8E,11S)-3-({[(tert-butyloxy)carbonyl]amino}methyl)-4-oxo-2,5-diazo Benzyl heterobicyclo[10.3.1]hexadeca-1(16),8,12,14-tetraen-11-yl]carbamate.

[0750]

[0751] Benzyl N-[(1S)-1-(3-{[(1R)-1-[(but-3-en-1-yl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}ethyl]amino}phenyl)but-3-en-1-yl]carbamate (385 mg, 0.717 mmol), pTsOH·H 2 O (136 mg, 0.717 mmol) and DCE (70 mL). The reaction was purged with Ar for 15 min, then Grubbs II (122 mg, 0.143 mmol) was added and the reaction was stirred at 50 °C under Ar for 5 h. The reaction was cooled and saturated NaHCO 3 Aqueous solution (20 ml) was added and the reaction was stirred at rt for 15 minutes. The reaction mixture was separated. The organic layer was washed with water (30 mL) and brine (30 ml), filtered through MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-10% CH2Cl2 / MeOH gradient) to give the product. 2 Cl 2(10 ml) / MeOH (10 ml) / EtOAc (5 ml) / heptane (15 ml) was tritiated. The solid was collected by filtration to give benzyl N-[(3R,8E,11S)-3-({[(tert-butyloxy)carbonyl]amino}methyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),8,12,14-tetraen-11-yl]carbamate (135 mg, 0.265 mmol, 37.0% yield) as a light-colored solid. (ESI) m / z: 509.3 (M+H) + . 1 H NMR (400 MHz, CDCl 3 )δ7.38(br.s.,5H),7.16(t,J=7.8Hz,1H),6.70(br.s.,1H),6.64(br.s.,1H),6.59(d,J =7.5Hz,1H),6.15(br.s.,1H),5.56(br.s.,1H),5.44(br.s.,1H),5.23(br.s.,1H),5.1 2(s,2H),5.05-4.92(m,2H),4.59(br.s.,1H),3.83(br.s.,1H),3.72-3.64(m,3H),2.90 -2.79(m,1H),2.75-2.64(m,2H),2.14-2.05(m,1H),1.98(q,J=11.3Hz,1H),1.48(s,9H).

[0752] 23D. Preparation of N-{[(3R,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadecane-1 (16), tert-butyl 1,2,14-trien-3-yl]methyl}carbamate.

[0753]

[0754] To a 2-neck RBF was added benzyl N-[(3R,8E,11S)-3-({[(tert-butoxy)carbonyl]amino}methyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),8,12,14-tetraen-11-yl]carbamate (135 mg, 0.265 mmol), EtOH (10 mL) and Pd / C (56.5 mg, 0.053 mmol). The reaction was stirred under hydrogen atmosphere (balloon) for 6 h. The reaction was carefully filtered through Celite and the filtrate was concentrated to give tert-butyl N-{[(3R,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]methyl}carbamate (99 mg, 0.263 mmol, 99% yield) as a beige solid. (ESI) m / z: 377.2 (M+H) +.

[0755] 23E. Preparation of N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-triene- 3-yl]methyl}carbamic acid tert-butyl ester.

[0756]

[0757] In a manner similar to the procedure described in Example 1, tert-butyl N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]methyl}carbamate (75 mg, 0.112 mmol, 42.7% yield) was prepared by reacting (7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl 2-eicosyl-1(20),16,18-triene-5-carboxylate was replaced by tert-butyl N-{[(3R,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-triene-3-yl]methyl}carbamate. (ESI) m / z: 667.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.64(s,1H),8.36(s,1H),7.90(d,J=2.2Hz,1H),7.78-7.72(m,1H),7.69-7.66(m,1H) ,7.13(t,J=7.8Hz,1H),6.75-6.65(m,2H),6.44(s,1H),6.27(d,J=7.7Hz,1H),5.69(dd,J=1 3.0,2.9Hz,1H),4.14(t,J=6.5Hz,1H),3.61-3.37(m,4H),3.00(dt,J=13.8,4.5Hz,1H),2. 25(t,J=12.2Hz,1H),2.00-1.80(m,3H),1.64-1.54(m,1H),1.48(s,9H),1.26-1.15(m,2H).

[0758] 23F. Preparation of (3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-triazine En-4-one hydrochloride.

[0759]

[0760] To the RBF was added (3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one hydrochloride (15 mg, 0.022 mmol), MeOH (0.2 mL) and 4N HCl in dioxane (0.034 mL, 1.123 mmol). The reaction was stirred at rt for 30 min. The reaction was concentrated to give (3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-4-one trihydrochloride (15 mg, 0.022 mmol, 99% yield) as a white solid. (ESI) m / z: 567.2 (M+H) + .

[0761] Example 23. Preparation of N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12, 1,4-Trien-3-yl]methyl}carbamic acid methyl ester trifluoromethylacetate.

[0762]

[0763] To RBF were added (3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-4-one hydrochloride (9.5 mg, 0.014 mmol), THF (0.3 mL), Et 3 N (9.78 μl, 0.070 mmol) and methyl chloroformate (1.087 μl, 0.014 mmol). The reaction was stirred at rt for 10 minutes. The reaction was purified using RP prep-HPLC to give N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]methyl}carbamic acid methyl ester trifluoromethyl acetate (2 mg, 2.60 μmol, 18.50% yield) as a white solid. (ESI) m / z: 625.2 (M+H) + . 1 H NMR (400MHz, CD3 OD)δ8.64(s,1H),8.35(d,J=0.7Hz,1H),7.91-7.87(m,1H),7.79-7.73(m,1H),7.69-7.65(m,1 H),7.13(t,J=7.7Hz,1H),6.73-6.67(m,2H),6.43(s,1H),6.29(d,J=7.7Hz,1H),5.69(dd,J=12 .9,2.5Hz,1H),4.17(t,J=6.4Hz,1H),3.69(s,3H),3.56-3.46(m,3H),3.00(d,J=13.4Hz,1H),2.30-2.19(m,1H),1.99-1.77(m,3H),1.64-1.54(m,1H),1.38-1.35(m,1H),1.23-1.12(m,2H). Analytical HPLC (Method A) RT=10.784min, purity=96%. Factor XIA Ki=27nM, plasma kallikrein Ki=2715nM.

[0764] Example 24. Preparation of N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12, 1,4-Trien-3-yl]methyl}pyridine-3-carboxamide trifluoromethylacetate.

[0765]

[0766] To RBF were added (3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-4-one hydrochloride (9.5 mg, 0.014 mmol), nicotinic acid (1.728 mg, 0.014 mmol), THF (0.5 mL), Et 3 N (9.78 μl, 0.070 mmol) and HATU (5.34 mg, 0.014 mmol). The reaction was stirred at rt for 1 h. The reaction was purified using RP prep-HPLC to give N-{[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]methyl}pyridine-3-carboxamide trifluoromethyl acetate (8 mg, 7.93 μmol, 56.5% yield) as a cream solid. (ESI) m / z: 672.1 (M+H) + . 1H NMR (400MHz, CD 3 OD)δ9.11(br.s.,1H),8.81(d,J=4.2Hz,1H),8.64(s,1H),8.52(d,J=8.4Hz,1H),8.39(d,J=5.5Hz,1H),8.35(s,1H ),7.94-7.87(m,1H),7.82-7.72(m,2H),7.70-7.62(m,1H),7.14(t,J=7.8Hz,1H),6.79-6.69(m,2H),6.42(s,1H),6 .32 (d, J = 7.5 Hz, 1H), 5.68 (d, J = 10.8 Hz, 1H), 4.35 (t, J = 6.4 Hz, 1H), 3.90-3.76 (m, 2H), 3.54 (br.s., 1H), 3.01 (d, J = 13.2 Hz, 1H), 2.25 (t, J = 10.1 Hz, 1H), 1.98-1.91 (m, 1H), 1.83 (br.s., 2H), 1.59 (d, J = 4.4 Hz, 1H), 1.40-1.10 (m, 4H). Analytical HPLC (Method A) RT = 8.844 min, purity = 98%. Factor XIA Ki = 62 nM, plasma kallikrein Ki = 5203 nM.

[0767] Example 25. Preparation of (15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo 1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene-4, 8-diketone.

[0768]

[0769] 25A. Preparation of 1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine Oxazine-2-carboxylic acid.

[0770]

[0771] To a sealed tube were added tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (0.92 g, 2.55 mmol) prepared as in Intermediate 2(S)-(1-(3-bromophenyl)but-3-en-1-yl)carbamate benzyl ester, 5-oxopiperazine-2-carboxylic acid (0.442 g, 3.06 mmol) and K 2 CO 3(1.059 g, 7.66 mmol) and DMSO (5.11 ml). The reaction was purged with Ar and then CuI (24 mg, 0.13 mmol) was added. The reaction was sealed and stirred at 110 °C for 48 h. The reaction was partitioned between water (40 ml) and EtOAc (50 ml). The aqueous layer was separated and treated with 1N HCl until the pH was less than 4. The aqueous layer was then extracted with EtOAc (2 x 30 ml). The combined organic layers were washed with brine (30 ml), purified by MgSO 4 Drying, filtration and concentration gave 1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-2-carboxylic acid (300 mg, 0.708 mmol, 27.7% yield) as a light green oil. (ESI) m / z: 424.5 (M+H) + .

[0772] 25B. Preparation of ((1S)-1-(3-(2-(but-3-en-1-ylcarbamoyl)-5-oxopiperazin-1-yl)phenyl) Benzyl 2-but-3-en-1-yl)carbamate.

[0773]

[0774] To a RBF was added 1-(3-((S)-1-(((benzyloxy)carbonyl)amino)but-3-en-1-yl)phenyl)-5-oxopiperazine-2-carboxylic acid (300 mg, 0.708 mmol), THF (15 mL), Hunig's base (0.371 mL, 2.125 mmol), but-3-en-1-amine (235 mg, 3.31 mmol) and HATU (539 mg, 1.417 mmol). The reaction was stirred at rt for 3.5 h. The reaction was partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was separated, washed with water (30 mL) and brine (30 mL), purified by MgSO 4 Dry, filter and concentrate. The residue was purified using an ISCO system (0-100% EtOAc / Hex gradient) to give benzyl ((1S)-1-(3-(2-(but-3-en-1-ylcarbamoyl)-5-oxopiperazin-1-yl)phenyl)but-3-en-1-yl)carbamate (30 mg, 0.063 mmol, 8.89% yield) as a white solid. (ESI) m / z: 477.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ7.37(br.s.,5H),7.31-7.26(m,1H),6.86(d,J=7.5Hz,1H),6.72(br.s.,1H),6.65(d d,J=8.4,2.4Hz,1H),6.60(br.s.,1H),6.24(br.s.,1H),5.78-5.58(m,2H),5.37(br.s. ,1H),5.22-4.88(m,7H),4.78(d,J=4.4Hz,1H),4.21(dd,J=4.0,2.0Hz,1H),4.09-3.90( m, 3H), 3.64 (d, J = 9.5Hz, 1H), 3.34 (d, J = 5.9Hz, 2H), 2.53 (br.s., 2H), 2.21 (br.s., 2H).

[0775] 25C. Preparation of N-[(12E,15S)-4,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]20-carbon- (20),12,16,18-tetraen-15-yl]carbamic acid benzyl ester.

[0776]

[0777] To the RBF was added benzyl ((1S)-1-(3-(2-(but-3-en-1-ylcarbamoyl)-5-oxopiperazin-1-yl)phenyl)but-3-en-1-yl)carbamate (30 mg, 0.063 mmol) and DCE (7 mL). The reaction was purged with Ar for 5 min, then Grubbs II (10.69 mg, 0.013 mmol) was added and the reaction was stirred at 50 °C under Ar for 2.5 h. The reaction was concentrated and purified using an ISCO system (0-100% EtOAc / Hex gradient) to give N-[(12E,15S)-4,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]2-Eicosyl-(20),12,16,18-tetraen-15-yl]carbamic acid benzyl ester (25 mg, 0.056 mmol, 89% yield) as a light-colored solid. (ESI) m / z: 477.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3)δ7.38-7.20(m,6H),6.73(br.s.,1H),6.65-6.47(m,2H),6.32(br.s.,1H),6 .18(br.s.,1H),5.52(br.s.,2H),5.07-4.88(m,3H),4.81(br.s.,1H),4.23( br.s.,1H),4.04(br.s.,1H),3.96-3.81(m,2H),3.56(br.s.,2H),2.77(d,J= 12.3Hz, 1H), 2.67 (d, J = 12.3Hz, 1H), 2.51 (d, J = 9.9Hz, 1H), 2.21-1.96 (m, 2H).

[0778] 25D. Preparation of (15S)-15-amino-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16,18- Triene-4,8-dione.

[0779]

[0780] Add N-[(12E,15S)-4,8-dioxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]eicosyl-(20),12,16,18-tetraen-15-yl]carbamic acid benzyl ester (25 mg, 0.056 mmol), EtOH (3 mL) and Pd / C (11.86 mg, 0.011 mmol). The reaction was stirred under a hydrogen atmosphere (balloon) for 1 h. The reaction was carefully filtered and the filtrate was concentrated to give (15S)-15-amino-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] Eicosapentaenoic acid-1(20),16,18-triene-4,8-dione (10 mg, 0.032 mmol, 56.7% yield) as a beige solid. (ESI) m / z: 317.2 (M+H) + .

[0781] Example 25. Preparation of (15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo 1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene-4, 8-diketone.

[0782]

[0783] (15S)-15-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5,9-triazatricyclo[14.3.1.0 2 , 7] Eicosapentaenoic acid-1(20),16,18-triene-4,8-dione trifluoromethyl acetate (4 mg, 5.27 μmol, 16.66% yield) was reacted with (7S,15S)-15-amino-8-oxo-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ] tert-butyl ester of 20-16,18-triene-5-carboxylate was replaced by (15S)-15-amino-2,5,9-triazatricyclo[14.3.1.0 2 , 7 ]Eicosyl-1(20),16,18-triene-4,8-dione. (ESI) m / z: 607.2 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.32-8.30(m,1H),8.24(s,1H),7.86-7.83(m,1H),7.75-7.71(m,1H),7.65-7.61(m,1H),7.33(t,J=7 .8Hz,1H),6.96-6.89(m,2H),6.79(d,J=7.7Hz,1H),6.44(d,J=0.4Hz,1H),5.82(dd,J=12.4,3.2Hz,1H),4. 42 (t, J = 4.0 Hz, 1H), 4.21-4.07 (m, 2H), 3.88-3.72 (m, 2H), 3.22-3.11 (m, 1H), 2.51 (dt, J = 13.0, 6.5 Hz, 1H), 1.90-1.72 (m, 2H), 1.57 (dd, J = 12.5, 6.2 Hz, 1H), 1.50-1.42 (m, 2H), 1.41-1.32 (m, 2H), 1.18-0.92 (m, 1H). Analytical HPLC (Method A) RT = 10.106 min, purity = 95%. Factor XIA Ki = 51 nM, plasma kallikrein Ki = 6748 nM.

[0784] Example 26. Preparation of N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12, 1,4-Trien-3-yl]ethyl}carbamic acid tert-butyl ester trifluoromethylacetate.

[0785]

[0786] N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamic acid tert-butyl ester trifluoromethyl acetate (45 mg, 0.053 mmol) was prepared in a manner similar to the procedure described in Example 23E by replacing (R)-2-amino-3-((tert-butoxycarbonyl)amino)propanoic acid with (R)-2-amino-4-((tert-butoxycarbonyl)amino)butanoic acid. (ESI) m / z: 681.3 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.65(s,1H),8.35(s,1H),8.31-8.25(m,1H),7.90(d,J=2.2Hz,1H),7.78-7.73(m,1H),7.70-7 .66(m,1H),7.13(t,J=7.8Hz,1H),6.78-6.70(m,2H),6.43(s,1H),6.31(d,J=7.7Hz,1H),5.70(dd, J = 13.0, 2.9 Hz, 1H), 4.08 (t, J = 7.2 Hz, 1H), 3.61-3.46 (m, 1H), 3.29-3.19 (m, 2H), 2.98 (d, J = 11.4 Hz, 1H), 2.27 (t, J = 12.7 Hz, 1H), 2.00-1.81 (m, 6H), 1.69-1.55 (m, 1H), 1.48 (s, 9H), 1.25-1.14 (m, 1H). Analytical HPLC (Method X) RT = 3.831 min, purity = 95%. Factor XIA Ki = 24 nM, plasma kallikrein Ki = 430 nM.

[0787] Example 27. Preparation of (3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazine oxazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadec-1(16), 12,14-Triene-4-one hydrochloride.

[0788]

[0789] To the RBF was added tert-butyl N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate trifluoromethyl acetate (45 mg, 0.066 mmol) and 4N HCl in dioxane (0.825 mL, 3.30 mmol). The reaction was stirred at rt for 15 minutes. The reaction was concentrated to give (3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-triene-4-one hydrochloride (45 mg, 0.061 mmol, 93% yield) as a creamy white solid. (ESI) m / z: 581.4 (M+H) + Analytical HPLC (Method X) RT = 3.145 min, purity = 95%. Factor XIA Ki = 871 nM, plasma kallikrein Ki = 14030 nM.

[0790] Example 28. Preparation of N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12, 1,4-Trien-3-yl]ethyl}carbamic acid methyl ester trifluoromethylacetate.

[0791]

[0792] In a manner similar to the procedure described in Example 23, methyl N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate trifluoromethyl acetate (8.5 mg, 10.72 μmol, 74.0% yield) was prepared by reacting (3R,11S)-3-(aminomethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate trifluoromethyl acetate (8.5 mg, 10.72 μmol, 74.0% yield). -1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one hydrochloride was replaced by (3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-4-one hydrochloride prepared as described in Example 27. (ESI) m / z: 639.2 (M+H) + . 1 HNMR (400MHz, CD 3 OD)δ8.65(s,1H),8.35(s,1H),7.89(d,J=2.4Hz,1H),7.77-7.73(m,1H),7.69-7.65(m,1H),7.20(t,J=7. 8Hz,1H),6.88-6.80(m,2H),6.49(d,J=7.5Hz,1H),6.43-6.37(m,1H),5.69(dd,J=12.8,2.9Hz,1H),4.11( t, J = 7.2 Hz, 1H), 3.68 (s, 3H), 3.59-3.47 (m, 1H), 3.32-3.23 (m, 2H), 2.99-2.87 (m, 1H), 2.31 (td, J = 12.4, 4.1 Hz, 1H), 2.04-1.92 (m, 3H), 1.84-1.70 (m, 2H), 1.68-1.59 (m, 1H), 1.41-1.32 (m, 1H), 1.27-1.13 (m, 2H). Analytical HPLC (Method A) RT = 10.956 min, purity = 95%. Factor XIA Ki = 5 nM, plasma kallikrein Ki = 83 nM.

[0793] Example 29. Preparation of N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12, 1-(1,4-trien-3-yl)ethyl}-1-(difluoromethyl)-1H-pyrazole-3-carboxamide trifluoromethyl acetate (trifluoromethyl acetate).

[0794]

[0795] To RBF were added (3R,11S)-3-(2-aminoethyl)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-4-one hydrochloride (9.5 mg, 0.014 mmol), 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (2.229 mg, 0.014 mmol), THF (0.5 mL), Et 3 N (9.58 μl, 0.069 mmol) and HATU (5.23 mg, 0.014 mmol). The reaction was stirred at rt for 1 h. The reaction was purified using RP prep-HPLC to give N-{2-[(3R,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]ethyl}-1-(difluoromethyl)-1H-pyrazole-3-carboxamide trifluoromethyl acetate (6 mg, 6.79 μmol, 49.4% yield) as a cream solid. (ESI) m / z: 725.2 (M+H) + . 1 HNMR (400MHz, CD 3OD)δ8.64(s,1H),8.34(s,1H),8.18-8.14(m,1H),7.89(d,J=2.2Hz,1H),7.78-7.73(m,1H),7.69-7.65(m,1H ),7.60-7.58(m,1H),7.15(t,J=7.8Hz,1H),6.95(d,J=2.6Hz,1H),6.80-6.74(m,2H),6.42(s,1H),6.35(d,J =7.7 Hz, 1H), 5.69 (dd, J = 13.0, 2.6 Hz, 1H), 4.15 (t, J = 7.0 Hz, 1H), 3.68-3.49 (m, 3H), 2.99-2.91 (m, 1H), 2.34-2.22 (m, 1H), 2.17-2.02 (m, 2H), 1.97-1.78 (m, 3H), 1.64-1.53 ​​(m, 1H), 1.39-1.30 (m, 1H), 1.27-1.11 (m, 2H). Analytical HPLC (Method X) RT = 3.515 min, purity = 95%. Factor XIA Ki = 5 nM, plasma kallikrein Ki = 49 nM.

[0796] Example 30. Preparation of N-{2-[(3S,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12, 1,4-Trien-3-yl]ethyl}carbamic acid methyl ester trifluoromethylacetate.

[0797]

[0798] Methyl N-{2-[(3S,11S)-11-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate trifluoromethylacetate (6.5 mg, 8.11 μmol) was prepared in a manner similar to the procedure described in Example 28 by replacing (R)-2-amino-4-((tert-butoxycarbonyl)amino)butyric acid with (S)-2-amino-4-((tert-butoxycarbonyl)amino)butyric acid. (ESI) m / z: 639.4 (M+H) + . 1 H NMR (400MHz, CD 3OD)δ8.36-8.32(m,2H),8.19(dd,J=7.8,2.8Hz,1H),7.85(d,J=2.2Hz,1H),7.75-7.71(m,1H),7.66-7.61(m,1H),7.24-7.1 5(m,1H),6.91(d,J=8.1Hz,1H),6.84(br.s.,1H),6.78-6.71(m,1H),6.41(d,J=0.7Hz,1H),5.73(dd,J=12.4,3.2Hz,1H),3. 96 (t, J = 6.9 Hz, 1H), 3.70-3.64 (m, 3H), 3.40-3.27 (m, 3H), 3.23-3.09 (m, 1H), 2.44 (dt, J = 12.9, 6.4 Hz, 1H), 2.02 (ddt, J = 17.6, 13.8, 6.9 Hz, 2H), 1.95-1.83 (m, 1H), 1.80-1.64 (m, 1H), 1.62-1.50 (m, 1H), 1.45 (quin, J = 6.6 Hz, 2H), 1.31-1.12 (m, 2H). Analytical HPLC (Method A) RT = 9.937 min, purity = 94%. Factor XIA Ki = 515 nM, plasma kallikrein Ki = 5682 nM.

[0799] Example 31. Preparation of N-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide 4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]ethyl}carbamate Ester trifluoromethyl acetate (trifluoromethyl acetate).

[0800]

[0801] 31A. Preparation of N-{2-[(3S,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1 (16), 1,2,14-trien-3-yl]ethyl}carbamic acid tert-butyl ester.

[0802]

[0803] N-{2-[(3S,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamic acid tert-butyl ester (95 mg, 0.182 mmol) was prepared in a manner similar to the procedure described in Example 23D by replacing (R)-2-amino-3-((tert-butoxycarbonyl)amino)propanoic acid with (S)-2-amino-4-((tert-butoxycarbonyl)amino)butanoic acid. (ESI) m / z: 391.2 (M+H) + .

[0804] 31B. Preparation of N-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amide]- tert-Butyl 4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]ethyl}carbamate Ester trifluoromethyl acetate.

[0805]

[0806] To the RBF was added tert-butyl N-{2-[(3S,11S)-11-amino-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]ethyl}carbamate (13 mg, 0.033 mmol), intermediate 13 (9.16 mg, 0.033 mmol), HATU (18.99 mg, 0.050 mmol), Hunig's base (0.012 mL, 0.067 mmol) and DMF (0.5 mL). The reaction was stirred at rt for 16 h. The reaction was diluted with MeOH and a few drops of water and purified using a RP prep-HPLC system. The peak was concentrated to give N-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amide]-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]ethyl}carbamic acid tert-butyl ester trifluoromethyl acetate (17 mg, 0.022 mmol, 67.1% yield) as a milky white solid. (ESI) m / z: 669.4 (M+Na) + .

[0807] 31C. Preparation of N-[(3S,11S)-3-(2-aminoethyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadecene [carbon-1(16),12,14-trien-11-yl]-5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide hydrochloride.

[0808]

[0809] To the RBF was added tert-butyl N-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazol-4-amido]-4-oxo-2,5-diazabicyclo[10.3.1]hexadeca-1(16),12,14-trien-3-yl]ethyl}carbamate trifluoromethylacetate (17 mg, 0.026 mmol), dioxane (0.5 mL) and HCl (0.656 mL, 2.63 mmol). The reaction was stirred at rt for 15 min. The reaction was concentrated to give N-[(3S,11S)-3-(2-aminoethyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-11-yl]-5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide trihydrochloride (17 mg, 0.026 mmol, 99% yield) as a creamy white solid. (ESI) m / z: 547.1 (M+H) + .

[0810] Example 31. Preparation of N-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide 4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]ethyl}carbamate Ester trifluoromethyl acetate (trifluoromethyl acetate).

[0811]

[0812] To RBF were added N-[(3S,11S)-3-(2-aminoethyl)-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-11-yl]-5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide hydrochloride (17 mg, 0.026 mmol), THF (0.5 mL), Et 3 N (0.018 mL, 0.129 mmol) and then methyl chloroformate (2.005 μl, 0.026 mmol) were added. The reaction was stirred at rt for 10 minutes. The reaction was purified using RP prep-HPLC to give N-{2-[(3S,11S)-11-[5-chloro-1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-amide]-4-oxo-2,5-diazabicyclo[10.3.1]hexadec-1(16),12,14-trien-3-yl]ethyl}carbamic acid methyl ester trifluoromethyl acetate (7 mg, 9.24 μmol, 35.7% yield) as a white solid. (ESI) m / z: 605.4 (M+H) + . 1 H NMR (400MHz, CD 3 OD)δ8.24(s,1H),7.94(d,J=3.5Hz,1H),7.77(ddd,J=8.2,6.8,1.5Hz,1H),7.52(ddd,J=8.0,6.5,1.8 Hz,1H),7.46-7.35(m,2H),7.23-7.10(m,2H),6.98(br.s.,1H),4.90(d,J=4.6Hz,1H),3.94(t,J=7.0 Hz, 1H), 3.67 (s, 3H), 3.41-3.26 (m, 3H), 3.09 (d, J = 10.3 Hz, 1H), 2.20-2.02 (m, 3H), 1.99-1.83 (m, 1H), 1.54 (br. s., 1H), 1.41 (d, J = 4.6 Hz, 1H), 1.38-1.31 (m, 2H), 0.83-0.69 (m, 1H), 0.59 (d, J = 6.6 Hz, 1H). Analytical HPLC (Method A) RT = 6.516 min, purity = 95%. Factor XIA Ki = 1834 nM, plasma kallikrein Ki = 9494 nM.

[0813] Example 32. Preparation of (6R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorobenzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-2,8-diazatricyclo[12.3.1.0 2 , 6 ]Octadecan-1(18), 14,16-Triene-3,7-dione

[0814]

[0815] 32A. Preparation of (R)-N-[(1E)-(3-bromo-5-fluorophenyl)methylene]-2-methylpropane-2-sulfenamide.

[0816]

[0817] To 3-bromo-5-fluorobenzaldehyde (25 g, 123 mol) dissolved in DCM (200 ml) was added (R)-2-methylpropane-2-sulfenamide (14.96 g, 123 mol) and Cs 2 CO 3 (40.2 g, 123 mol). The reaction mixture was stirred overnight at rt. After this time, the reaction mixture was filtered and concentrated to give a yellow oil. The yellow oil was purified using a 120 g silica gel ISCO column eluted with hexanes and EtOAc to give (R)-N-[(1E)-(3-bromo-5-fluorophenyl)methylene]-2-methylpropane-2-sulfinamide (35 g, 93%) as a yellow oil. 1 H NMR (500MHz, DMSO-d6) δ8.58-8.55(m,1H),8.05-7.98(m,1H),7.84-7.76(m,2H),1.20(s,9H). LCMS m / z 306.1(M+H).

[0818] 32B. Preparation of (R)-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinyl Amide.

[0819]

[0820] N-[(1E)-(3-bromo-5-fluorophenyl)methylene]-2,2-dimethylpropanamide (35 g, 114 mol) was dissolved in THF (500 ml) in a large 3-neck RBF and flushed with Ar. The solution was cooled to 0 °C and In powder (18.4 g, 160 mol) was added followed by allyl bromide (15.2 g, 126 mol) dropwise. The reaction was stirred at 0 °C for 2 h, then the ice bath was removed and the reaction mixture was stirred at rt overnight. The reaction was quenched with water (2 L) and the gel-like material was removed by Filter. Concentrate the filtrate in vacuo to an oily mass. The crude material was dissolved in water (2 L) and the organics were extracted with EtOAc (4 x 200 ml), purified by MgSO 4Drying, filtration and concentration gave an oil. The oil was purified by silica gel ISCO column and eluted with DCM / MeOH to give (R)-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfenamide (34.9 g, 88% yield) as a semi-solid mass. LCMS m / z 348.2 (M+H). 1 H NMR(500MHz,DMSO-d6)δ7.44-7.38(m,2H),7.26-7.20(m,1H),5.79-5.65(m,1H),5.46-5.42(m ,1H),5.04-4.98(m,2H),4.41-4.34(m,1H),2.69-2.59(m,1H),2.49-2.43(m,1H),1.09(s,9H)

[0821] 32C. Preparation of tert-butyl N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate.

[0822]

[0823] To a cooled 0°C solution of (R)-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide (21.9 g, 100 mol) in MeOH (100 ml) was added concentrated HCl (50 ml) dropwise and then stirred at 0°C for 48 h. After this time, the reaction mixture was concentrated to give a white solid mass. The residue was dissolved in water (1000 ml) and the organics were extracted with EtOAc (2 x 200 ml), purified by MgSO 4 Dry, filter and concentrate to a brown oil (11.5 g). The aqueous layer was basified with NaOH and the organics were extracted with EtOAc (2 x 300 ml), purified by MgSO 4 Dry, filter and concentrate to a brown oil (18 g). The combined oil was dissolved in DCM (500 ml) and Boc 2 O (22g), followed by addition of TEA (15ml) and the reaction mixture was stirred overnight at rt. The reaction mixture was concentrated in vacuo and purified by a 330g silica gel ISCO column eluted with hexane and EtOAc to give a white solid. The white solid was triturated with hexane and the precipitate was collected by filtration to give N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-ene-1-yl]carbamate (29.5g, 87% yield).

[0824] 32D. Preparation of (2R)-1-{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-5-fluorobenzene 1-[4-(4 ...nitrophenyl)-1-yl)-5-oxopyrrolidine-2-carboxylic acid methyl ester.

[0825]

[0826] A mixture of (S)-tert-butyl (1-(3-bromo-5-fluorophenyl)but-3-en-1-yl)carbamate (0.5 g, 1.453 mmol), (R)-methyl 5-oxopyrrolidine-2-carboxylate (0.250 g, 1.743 mmol), CsF (0.552 g, 3.63 mmol), N,N′-dimethylethylenediamine (0.016 ml, 0.145 mmol) in THF (2.91 ml) was degassed with Ar. CuI (0.014 g, 0.073 mmol) was added and the reaction was stirred for 72 h. The mixture was diluted with EtOAc and washed with saturated NH 4 The solution was quenched with aqueous Cl solution. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The crude residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in hexanes. The combined fractions were concentrated to give 366 mg (62%) of a white solid. LCMS m / z 351.4 (M+H-tert-butyl) + . 1 H NMR (400 MHz, CHCl 3 -d) δ7.36-7.29(m,1H),7.12(s,1H),6.79(dt,J=9.0,1.7Hz,1H),5.64(dd t,J=17.1,10.2,7.0Hz,1H),5.17-5.07(m,2H),4.86(br.s.,1H),4.76-4.6 5(m,2H),3.77-3.73(m,3H),2.76(dt,J=16.7,9.5Hz,1H),2.62-2.55(m,1H ), 2.53-2.42 (m, 3H), 2.18 (ddt, J = 12.6, 9.6, 2.8Hz, 1H), 1.48 (br.s., 9H).

[0827] 32E. Preparation of (2R)-1-{3-[(1S)-1-{[(tert-butoxy)carbonyl]amino}but-3-en-1-yl]-5-fluorobenzene 1-[4-[4-( ...nitrophenyl)-2-yl)-5-oxopyrrolidine-2-carboxylic acid.

[0828]

[0829] To a solution of (R)-1-(3-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-fluorophenyl)-5-oxopyrrolidine-2-carboxylic acid methyl ester (0.366 g, 0.900 mmol) in THF (5 ml) / water (2 ml) cooled to 0°C was added LiOH·H 2O (0.151 g, 3.60 mmol). After 2 h, the reaction was partitioned with 1N HCl (5 ml) and EtOAc (30 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml). The combined organic layers were washed with brine (15 ml) and dried (MgSO 4 ). Filtration and concentration gave 0.35 g (99%) of a white solid. LCMS m / z 337.4 (M+H-tert-butyl) + . 1 H NMR (400 MHz, CHCl 3 -d) δ7.02-6.83(m,1H),6.74(br.s.,2H),5.72-5.54(m,1H),5.06(d,J=11.0Hz,2H),4.77(br.s. ,1H),2.91-2.72(m,1H),2.62-2.47(m,2H),2.41(br.s.,2H),2.29(br.s.,1H),1.51-1.25(m,9H)

[0830] 32F. Preparation of N-[(1S)-1-{3-fluoro-5-[(5R)-2-oxo-5-[(prop-2-en-1-yl)carbamoyl]pyrrolidone

[0045] tert-butyl]pyridin-1-yl]phenyl}but-3-en-1-yl]carbamate.

[0831]

[0832] To a solution of (R)-1-(3-((S)-1-((tert-butoxycarbonyl)amino)but-3-en-1-yl)-5-fluorophenyl)-5-oxopyrrolidine-2-carboxylic acid (0.357 g, 0.910 mmol) in DCM (5 ml) cooled to 0°C were added prop-2-en-1-amine (0.052 g, 0.910 mmol), pyridine (0.368 ml, 4.55 mmol) and POCl 3 (0.085 ml, 0.910 mmol). After 30 minutes, the reaction was treated with saturated NaHCO 3 The mixture was quenched with aqueous solution (5 ml) and extracted with EtOAc (3 x 10 ml). The combined organic layers were washed with brine (5 ml) and dried (MgSO 4 ). The crude residue was purified by silica gel chromatography eluting with 0-100% EtOAc in hexanes. The combined fractions were concentrated to give 248 mg (63%) of a white solid. LCMS m / z 376.4 (M+H-tert-butyl) + .

[0833] 32G. Preparation of N-[(6R,10E,13S)-16-fluoro-3,7-dioxo-2,8-diazatricyclo[12.3.1.0 2 , 6 ]ten Octacarbon-1(18),10,14,16-tetraen-13-yl]carbamic acid tert-butyl ester.

[0834]

[0835] To a solution of tert-butyl N-[(1S)-1-{3-fluoro-5-[(5R)-2-oxo-5-[(prop-2-en-1-yl)carbamoyl]pyrrolidin-1-yl]phenyl}but-3-en-1-yl]carbamate in DCE (37 ml) degassed with Ar was added Grubbs II (0.102 g, 0.121 mmol) and the reaction was heated to 40°C. After 48 h, the reaction was concentrated and the residue was purified by silica gel chromatography eluting with DCM / 0-10% MeOH. The material was repurified by reverse phase HPLC to give 6 mg (4.9%) of a white solid. LCMS m / z 348.3 (M+H-tert-butyl). +1 H NMR (400 MHz, CH 3 Cl-d)δ7.83(br.s.,1H),6.83(d,J=8.6Hz,1H),6.29(br.s.,1H),5.84(br.s., 1H),5.74(dt,J=15.4,7.6Hz,1H),5.13(br.s.,1H),4.91(br.s.,1H),4.62(br. s.,1H),4.44(br.s.,1H),3.78(br.s.,1H),3.61(br.s.,1H),2.80-2.59(m,2H) ,2.50(d,J=7.0Hz,2H),2.21-2.12(m,1H),2.05(br.s.,1H),1.56-1.20(m,9H).

[0836] 32F. Preparation of (6R,13S)-13-amino-16-fluoro-2,8-diazatricyclic [12.3.1.0 2 , 6 ]Octadecan-1 (18),14,16-triene-3,7-dione.

[0837]

[0838] N-[(6R,10E,13S)-16-fluoro-3,7-dioxo-2,8-diazatricyclo[12.3.1.0 2 , 6 A solution of tert-butyl]octadec-1(18),10,14,16-tetraen-13-yl]carbamate (6 mg, 0.015 mmol) in EtOH (5 ml) was placed under a 55 psi hydrogen atmosphere in the presence of PtO2 (3 mg). After 5 h, the reaction mixture was filtered and the filtrate was concentrated. The reduced product was deprotected in 50% TFA / DCM (2 ml). After 24 h, the reaction mixture was concentrated to dryness and the product was dissolved in DCM / MeOH, filtered through a basic column and the filtrate was concentrated to give (4 mg, 88%) free base. LCMS m / z 306.08 (M+H) + .

[0839] Example 32. Preparation of ((6R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorobenzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-2,8-diazatricyclo[12.3.1.0 2 , 6 ]Octadecan-1(18), 14,16-Triene-3,7-dione.

[0840] To a vial containing 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol, 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol (4.27 mg, 0.013 mmol) and HATU (6.48 mg, 0.017 mmol) prepared in Intermediate 7 was added a solution of DBU (2.96 μl, 0.020 mmol) in AcN (0.2 ml). After 30 minutes, (6R,13S)-13-amino-16-fluoro-2,8-diazatricyclo[12.3.1.0 2 , 6 ] octadeca-1(18),14,16-triene-3,7-dione (0.004 g, 0.013 mmol) was mixed with DMF (0.2 ml) and the reaction was stirred for 24 h. The reaction mixture was filtered and purified by reverse phase HPLC to give (6R,13S)-13-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-16-fluoro-2,8-diazatricyclo[12.3.1.0 2 , 6 ]Octadeca-1(18),14,16-triene-3,7-dione (1.8 mgs, 21%). LCMS m / z 614.4 (M+H) + . 1 H NMR (500 MHz, DMSO-d 6 )δ8.73(d,J=7.3Hz,1H),8.70(s,1H),8.65(s,1H),8.01(t,J=8.1Hz,1H),7.77-7. 64(m,2H),7.19-7.09(m,1H),6.68(s,1H),6.46(d,J=9.2Hz,1H),5.57(d,J=10.4H z, 1H), 4.87 (t, J = 7.5 Hz, 1H), 2.72-2.60 (m, 3H), 2.36-2.25 (m, 2H), 2.10 (br. s., 1H), 2.03-1.97 (m, 1H), 1.55-1.44 (m, 2H), 1.20 (br. s., 1H), 1.05 (d, J = 6.1 Hz, 2H). Analytical HPLC (Method C) RT = 1.475 min, purity = 96%; Factor XIA Ki = 77.5 nM, plasma kallikrein Ki 5304 nM.

[0841] Example 33 (6R, 14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzene yl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclic [13.3.1.0 2 , 6 ]19-carbon-1(19),15,17-tri Ene-3,7-dione.

[0842]

[0843] 33A. Preparation of (6R,14S)-14-amino-2,8-diazatricyclic [13.3.1.0 2 , 6 ]Nineteen carbon-1(19),15, 17-Triene-3,7-dione.

[0844]

[0845] With (6R,13S)-13-amino-16-fluoro-2,8-diazatricyclo[12.3.1.0 2 , 6 ] octadecan-1(18),14,16-triene-3,7-dione was prepared in a similar manner to (6R,14S)-14-amino-2,8-diazatricyclo[13.3.1.0 2 , 6 ]Nonadeca-1(19),15,17-triene-3,7-dione was obtained by substituting (S)-(1-(3-bromophenyl)but-3-en-1-yl)carbamic acid tert-butyl ester, N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamic acid tert-butyl ester prepared as described in Intermediate 1 for (S)-(1-(3-bromo-5-fluorophenyl)but-3-en-1-yl)carbamic acid tert-butyl ester and but-3-en-1-amine for prop-2-en-1-amine (41 mg, 50%) as a dark solid. LCMS m / z 302.08 (M+H) + .

[0846] Example 33. Preparation of (6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl] phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclic [13.3.1.0 2 , 6 ]Nineteen-carbon-1(19),15,17- Triene-3,7-dione.

[0847] To a vial containing 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol (0.018 g, 0.053 mmol) and HATU (0.026 g, 0.069 mmol), prepared as described in Intermediate 6, was added a solution of DBU (0.012 ml, 0.080 mmol) in AcN (0.4 ml). After 30 minutes, (6R,14S)-14-amino-2,8-diazatricyclo[13.3.1.0 2 , 6]Nineteen carbon-1 (19), 15, 17-triene-3, 7-dione (0.016 g, 0.053 mmol) in DMF (0.2 ml). After 24 h, the reaction mixture was purified by reverse phase HPLC and freeze-dried to give (7.8 mg, 22%) of a white solid. LCMS (ESI) m / z: 626.08 (M+H). +1 H NMR (400MHz, CD 3 OD-d 4 )δ7.97-7.89(m,2H),7.82-7.76(m,1H),7.75-7.69(m,1H),7.40(t,J=8.0Hz,1H),7.21-7.15(m,1H ),6.99-6.87(m,1H),6.52-6.44(m,1H),5.74(dd,J=13.2,3.1Hz,1H),5.02-4.94(m,1H),3.68-3.54 (m, 1H), 2.93-2.84 (m, 1H), 2.77-2.68 (m, 2H), 2.55-2.42 (m, 2H), 2.38-2.33 (m, 2H), 2.21-2.11 (m, 1H), 2.03-1.92 (m, 2H), 1.89-1.79 (m, 2H), 1.72-1.64 (m, 1H), 1.45-1.32 (m, 2H), 1.14-1.05 (m, 1H). Analytical HPLC (Method A) RT = 8.18 min, purity = 95%; Factor XIA Ki = 12 nM, plasma kallikrein Ki 319.2 nM.

[0848] Example 34. Preparation of (6R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorobenzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclic[13.3.1.0 2 , 6 ]19-carbon-1(19),15,17-tri Ene-3,7-dione.

[0849]

[0850] The reaction mixture was prepared by mixing with (6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclo[13.3.1.0 2 , 6 ]Nineteen carbon-1 (19), 15,17-triene-3,7-dione was prepared in a similar manner to (6R, 14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0 2 , 6]Nonadecan-1(19),15,17-triene-3,7-dione (10.9 mg, 28%), 6-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl)pyrimidin-4-ol was used to replace 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol. LCMS (ESI) m / z: 610.3 (M+H). +1 H NMR (500MHz, CD 3 OD)δ8.68(s,1H),8.43-8.29(m,1H),7.95(dd,J=8.1,1.5Hz,1H),7.87(dd,J=8.7,7.6Hz,1H),7.63-7.55(m,1H),7.44 (t,J=8.0Hz,1H),7.18(s,1H),6.87(d,J=7.7Hz,1H),6.62(s,1H),5.75(dd,J=13.1,2.9Hz,1H),4.95(t,J=7.4Hz,1H), 3.80 (s, 1H), 3.69-3.57 (m, 1H), 2.89 (dt, J = 13.8, 4.2 Hz, 1H), 2.77-2.64 (m, 2H), 2.52-2.41 (m, 1H), 2.41-2.34 (m, 1H), 2.23-2.09 (m, 1H), 2.00-1.93 (m, 1H), 1.86-1.75 (m, 2H), 1.71-1.61 (m, 1H), 1.49-1.28 (m, 2H), 1.08 (d, J = 12.7 Hz, 1H). Analytical HPLC (Method C) RT = 1.53 min, purity = 100%; Factor XIA Ki = 6 nM, plasma kallikrein Ki 133.5 nM.

[0851] Example 35. Preparation of (6S,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorobenzene yl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclic[13.3.1.0 2 , 6 ]19-carbon-1(19),15,17-tri Ene-3,7-dione.

[0852]

[0853] The reaction mixture was prepared by mixing with (6R,14S)-14-{4-[3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0 2 , 6]Nineteen carbon-1 (19), 15, 17-triene-3, 7-dione was prepared in a similar manner to (6S, 14S)-14-{4-[3-chloro-6-(4-chloro-1H-1, 2, 3-triazol-1-yl)-2-fluorophenyl]-6-oxo-1, 6-dihydropyrimidin-1-yl}-2, 8-diazatricyclo[13.3.1.0 2 , 6 ]Nineteen-carbon-1(19),15,17-triene-3,7-dione (14 mg, 27.9%), (R)-5-oxopyrrolidine-2-carboxylic acid ethyl ester was replaced with (S)-5-oxopyrrolidine-2-carboxylic acid ethyl ester. LCMS (ESI) m / z: 610.08 (M+H). +1 H NMR (400MHz, CD 3 OD)δ8.42-8.34(m,1H),8.34-8.28(m,2H),8.09(dd,J=8.3,1.2Hz,1H),7.93-7.82(m,1H),7.60-7.53 (m,1H),7.44(t,J=8.0Hz,1H),7.22(s,1H),7.14(d,J=7.7Hz,1H),6.69-6.60(m,1H),5.81(dd,J=12.4 , 3.4 Hz, 1H), 3.69-3.55 (m, 1H), 3.52-3.45 (m, 1H), 3.10-2.97 (m, 1H), 2.86-2.71 (m, 1H), 2.71-2.59 (m, 1H), 2.53-2.43 (m, 2H), 2.21-2.11 (m, 1H), 2.01-1.92 (m, 1H), 1.75-1.61 (m, 2H), 1.41-1.33 (m, 3H). Analytical HPLC (Method A) RT = 7.54 min, purity = 97%; Factor XIA Ki = 5168 nM, plasma kallikrein Ki 11, 140 nM.

[0854] Example 36. Preparation of (6R,14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- Oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclic[13.3.1.0 2 , 6 ]Nineteen-carbon-1(19),15,17-triene-7- ketone.

[0855]

[0856] The reaction mixture was prepared by mixing with (6R,14S)-14-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyrimidin-1-yl)-2,8-diazatricyclo[13.3.1.0 2 , 6]Nineteen carbon-1 (19), 15,17-triene-3,7-dione was prepared in a similar manner to (6R, 14S)-14-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-2,8-diazatricyclo[13.3.1.0 2 , 6 ]Nineteen carbon-1(19),15,17-triene-7-one (5.1 mg, 8%), with K 2 CO 3 Instead of CsF, (R)-pyrrolidine-2-carboxylic acid was used instead of (R)-5-oxopyrrolidine-2-carboxylic acid methyl ester and 6-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]pyrimidin-4-ol prepared in Intermediate 5 was used instead of 6-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}pyrimidin-4-ol. LCMS (ESI) m / z: 578.3 (M+H). +1 H NMR (400MHz, CD 3 OD)δ8.59(s,1H),8.36(s,1H),8.24(d,J=4.8Hz,1H),7.93-7.89(m,1H),7.80-7.75(m,1H),7.72-7.67(m,1H ),7.21(t,J=7.9Hz,1H),6.69-6.60(m,2H),6.45(d,J=0.9Hz,1H),6.18(d,J=7.9Hz,1H),5.73(dd,J=12.5,2. 6 Hz, 1H), 4.37 (dd, J = 8.4, 4.8 Hz, 1H), 3.66-3.52 (m, 2H), 3.50-3.42 (m, 1H), 3.13-3.02 (m, 1H), 2.47-2.37 (m, 1H), 2.28-2.16 (m, 2H), 2.11-2.03 (m, 2H), 1.96-1.84 (m, 2H), 1.61 (dd, J = 9.8, 5.6 Hz, 1H), 1.41-1.25 (m, 3H). Analytical HPLC (Method A) RT = 8.89 min, purity = 95%; Factor XIA Ki = 8 nM, plasma kallikrein Ki 133.2 nM.

[0857] In summary, this application includes but is not limited to the following:

[0858] 1. Compound of formula (I):

[0859]

[0860] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:

[0861] L is independently selected from

[0862]

[0863] ---- is an optional key;

[0864] Q is independently selected from O, NH and CH 2 ;

[0865] Y is independently selected from N and CR 7 ;

[0866] Ring A is independently selected from

[0867]

[0868] R 1 and R 2 independently selected from H, halogen, 0-4 R e Substituted C 1-4 Alkyl, OR b and 1-4 R 6 Substituted C 3-5 Cycloalkyl;

[0869] R 3 independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, 1-5 R 5 Substituted C 2-4 Alkenyl, 1-5 R 5 Substituted C 2-4 Alkynyl, CN, -(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-(CH 2 )n -NR a C(N-CN)NR a R a 、-(CH 2 ) n -NR a C(NH)NR a R a 、-(CH 2 ) n -N=CR b NR a R a 、-(CH 2 ) n -NR a C(=O)NR a R a 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NR a C(=S)NR a C(=O)R b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p R c , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group; optionally, two adjacent R 3 The base can be formed by 1-5 R 5substituted rings;

[0870] R 3a Independently selected from H and C 1-4 alkyl;

[0871] Alternatively, R 3a and R 3 Together, they form a carbon atom and 1 to 3 atoms selected from O, NR 3b , S, wherein the heterocyclic ring is R 3c replace;

[0872] R 3b independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, --(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NHC(=O)OR b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0873] R 3c Independently selected from H, NO 2 , =O, halogen, 1-5 R 5 Substituted C 1-4 Alkyl, 1-5 R 5 Substituted C 2-4 Alkenyl, 1-5 R 5 Substituted C 2-4Alkynyl, CN, -(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-(CH 2 ) n -NR a C(N-CN)NR a R a 、-(CH 2 ) n -NR a C(NH)NR a R a 、-(CH 2 ) n -N=CR b NR a R a 、-(CH 2 ) n -NR a C(=O)NR a R a 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NR a C(=S)NR a C(=O)R b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a 、-(CH 2 )n -NR a S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p R c , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0874] R 4 are independently selected from H, halogen, CN, -(CH 2 ) n NR a R a , 1-5 R 10 Substituted C 1-6 Alkyl, --(CH 2 ) n OR b 、-(CH 2 ) n C(=O)R b 、-(CH 2 ) n C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-(CH 2 ) n -NR a C(N-CN)NR a R a 、-(CH 2 ) n -NR a C(NH)NR a R a 、-(CH 2 ) n -N=CR b NR a R a、-(CH 2 ) n -NR a C(=O)NR a R a 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NR a C(=S)NR a C(=O)R b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p NR a R a 、-(CH 2 ) n -NR a S(=O) p R c , 1-5 R 10 Substituted -(CH 2 ) n -Aryl, 1-5 R 10 Substituted -(CH 2 ) n -C 3-6 Cycloalkyl and 1-5 R 10 Substituted -(CH 2 ) n -4-6 membered heterocyclic group;

[0875] R 5 independently selected at each occurrence from H, D, -(CH 2 ) n -OR b ,=O,-(CH 2 ) n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)ORb 、-(CH 2 ) n -OR b , 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group, 0-5 R e Substituted -(CH 2 ) n -4- to 10-membered heterocyclic group and 0-5 R e substituted –O-4- to 10-membered heterocyclyl;

[0876] R 6 independently selected from H, OH, =O, -(CH 2 ) n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)OH, -(CH 2 ) n -C(=O)OC 1-4 Alkyl, -(CH 2 ) n -OC 1-4 Alkyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbon ring, surrounded by 0-5 R e Substituted -(CH 2 ) n -4- to 10-membered heterocyclic ring and 0-5 R e Substituted -(CH 2 ) n -4- to 10-membered heterocyclic ring;

[0877] R 7 Independently selected from H, CN, OR b , halogen, NR a R a and 0-5 R e Substituted C 1-3 alkyl;

[0878] R 8 Independently selected from H, OH, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, CF 3 , CN, C 3-6Cycloalkyl, aryl and 5- to 6-membered heterocyclic rings;

[0879] R 10 is independently selected at each occurrence from H, halogen, CN, NO 2 , =O,

[0880] C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a 、C(=NOH)NH 2 , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted aryl, 0-5 R e Substituted-(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted-(CH 2 ) n -O-4- to 10-membered heterocyclic group;

[0881] R a In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n -heterocyclic group; or R a and R a Together with the nitrogen atoms connected to them, they form a group consisting of 0-5 R e substituted heterocycle;

[0882] R bIn each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n - heterocyclic group;

[0883] R c In each occurrence, independently selected from 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, C 3-6 Carbocyclic and heterocyclic groups;

[0884] R d independently selected at each occurrence from H and 0-5 R e Substituted C 1-4 alkyl;

[0885] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, 0-5 R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group, CO 2 H, -(CH 2 ) n OR f , SR f and -(CH 2 ) n NR f R f ;

[0886] R fis independently selected at each occurrence from H, C optionally substituted by F, Cl, Br 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl, or R f and R f Together with the nitrogen atoms attached to them, they form a 1-4 an alkyl optionally substituted heterocyclic ring;

[0887] n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and

[0888] p is an integer independently selected from 0, 1 and 2 at each occurrence.

[0889] 2. The compound of item 1 or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein:

[0890] L is independently selected from

[0891]

[0892] R 1 and R 2 independently selected from H, halogen, C 1-4 Alkyl, OR b and C 3-5 Cycloalkyl;

[0893] R 3 independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, 1-5 R 5 Substituted C 2-4 Alkenyl, 1-5 R 5 Substituted C 2-4 Alkynyl, CN, -OR b 、-(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-NR a C(=O)NR a Ra 、-C(=O)NR a R a 、-NR a C(=S)NR a C(=O)R b 、-S(=O) p R c 、-S(=O) p NR a R a 、-NR a S(=O) p NR a R a 、-NR a S(=O) p R c , 1-5 R 5 Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 1-5 R 5 Substituted -(CH 2 ) n -4- to 10-membered heterocyclic group; optionally, two adjacent R 3 The base can be formed by 1-5 R 5 substituted rings;

[0894] R 3a Independently selected from H and C 1-4 alkyl;

[0895] Alternatively, R 3a and R 3 Together they form a carbon atom and 1-3 NR 3b wherein the heterocyclic ring is R 3c replace;

[0896] R 3b independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, -(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NHC(=O)OR b 、-(CH2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0897] R 3c Independently selected from H, NO 2 , =O, halogen and 1-5 R 5 Substituted C 1-4 alkyl;

[0898] R 4 independently selected from H, halogen, CN, 1-5 R 10 Substituted C 1-6 Alkyl, -OR b , 1-5 R 10 Substituted -(CH 2 ) n -Aryl, 1-5 R 10 Substituted -(CH 2 ) n -C 3-6 Cycloalkyl and 1-5 R 10 Substituted -(CH 2 ) n -4-6 membered heterocyclic group;

[0899] R 5 independently selected at each occurrence from H, D, -(CH 2 ) n -OR b ,=O,-(CH 2 ) n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n-OR b , 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group, 0-5 R e Substituted-(CH 2 ) n -4- to 10-membered heterocyclic group and 0-5 R e substituted –O-4- to 10-membered heterocyclyl;

[0900] R 7 Independently selected from H, OR b , halogen, NR a R a and C 1-3 alkyl;

[0901] R 10 is independently selected at each occurrence from H, halogen, CN, NO 2 , =O, C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a 、C(=NOH)NH 2 , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted aryl, 0-5 R e Substituted-(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted-(CH 2 ) n -O-4- to 10-membered heterocyclic group;

[0902] R a In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R eSubstituted C 2-6 Alkynyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted -(CH 2 ) n -heterocyclic group; or R a and R a Together with the nitrogen atoms connected to them, they form a group consisting of 0-5 R e substituted heterocycle;

[0903] R b In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted -(CH 2 ) n -heterocyclic group;

[0904] R c In each occurrence, independently selected from 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, C 3-6 Carbocyclic and heterocyclic groups;

[0905] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, 0-5 R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group, CO 2H, -(CH 2 ) n OR f , SR f and -(CH 2 ) n NR f R f ;

[0906] R f is independently selected at each occurrence from H, C optionally substituted by F, Cl, Br 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl, or R f and R f Together with the nitrogen atoms attached to them, they form a 1-4 an alkyl optionally substituted heterocyclic ring;

[0907] n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and

[0908] p is an integer independently selected from 0, 1 and 2 at each occurrence.

[0909] 3. The compound of item 2 or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein the compound has formula (II):

[0910]

[0911] in:

[0912] L is independently selected from

[0913]

[0914] Ring A is independently selected from

[0915]

[0916] R 1 and R 2 independently selected from H, halogen, C 1-4 Alkyl and OH;

[0917] R 3 Independently selected from -(CH 2 ) n -NR a R a 、-(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n-NR a C(=O)OR b 、-(CH 2 ) n -NR a C(=O)R b 、-NR a C(=O)NR a R a 、-C(=O)NR a R a ;

[0918] R 3a Independently selected from H and C 1-4 alkyl;

[0919] Alternatively, R 3a and R 3 Together we form a selection Heterocyclic ring;

[0920] R 3b independently selected from H, 1-5 R 5 Substituted C 1-4 Alkyl, -(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -C(=O)NR a R a 、-(CH 2 ) n -NHC(=O)OR b 、-(CH 2 ) n -S(=O) p R c 、-(CH 2 ) n -S(=O) p NR a R a , 1-5 R 5 Replaced-(CR d R d ) n -C 3-10 Carbocyclic group and 1-5 R 5 Replaced-(CR d R d ) n -4- to 10-membered heterocyclic group;

[0921] R 3cindependently selected from H, =O and 1-5 R 5 Substituted C 1-4 alkyl;

[0922] R 4a Independently selected from H, halogen, CN, OCH 3 、OCF 3 , CH 3 、C(=O)CH 3 , CHF 2 CF 3 , CCH 3 F 2 , OCHF 2 , aryl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic ring, wherein the aryl, cycloalkyl and heterocyclic ring are R 10 Optional substitution;

[0923] R 4b are independently selected from H and halogen;

[0924] R 4c independently selected from H, F, Cl, methyl, ethyl, isopropyl and OCH 3 ;

[0925] R 5 independently selected at each occurrence from H, D, -(CH 2 ) n -OR b ,=O,-(CH 2 ) n NH 2 、-(CH 2 ) n CN, halogen, C 1-6 Alkyl, -(CH 2 ) n -C(=O)OR b 、-(CH 2 ) n -OR b , 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group, 0-5 R e Substituted -(CH 2 ) n -4- to 10-membered heterocyclic group and 0-5 R e substituted –O-4- to 10-membered heterocyclyl;

[0926] R 7 Independently selected from H and C 1-3 alkyl;

[0927] R 10 is independently selected at each occurrence from H, halogen, CN, NO 2 , =O,

[0928] C(=O)NR a R a 、C(=O)OR b 、-(CH 2 ) n -OR b 、-(CH 2 ) n -NR a R a ,

[0929] C(=NOH)NH 2 , 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted aryl, 0-5 R e Substituted -(CH 2 ) n -C 3-6 Cycloalkyl, 0-5 R e Substituted -(CH 2 ) n -O-4- to 10-membered heterocyclic group;

[0930] R a In each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted -(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted -(CH 2 ) n -heterocyclic group; or R a and R a Together with the nitrogen atoms connected to them, they form a group consisting of 0-5 R e substituted heterocycle;

[0931] R bIn each occurrence, independently selected from H, 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, 0-5 R e Substituted-(CH 2 ) n -C 3-10 Carbocyclic group and 0-5 R e Substituted-(CH 2 ) n - heterocyclic group;

[0932] R c In each occurrence, independently selected from 0-5 R e Substituted C 1-6 Alkyl, 0-5 R e Substituted C 2-6 Alkenyl, 0-5 R e Substituted C 2-6 Alkynyl, C 3-6 Carbocyclic and heterocyclic groups;

[0933] R e independently selected at each occurrence from F, Cl, Br, CN, NO 2 , =O, 0-5 R f Substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH 2 ) n -C 3-6 Cycloalkyl, -(CH 2 ) n -aryl, -(CH 2 ) n -Heterocyclic group, CO 2 H, -(CH 2 ) n OR f , SR f and -(CH 2 ) n NR f R f ;

[0934] R f is independently selected at each occurrence from H, C optionally substituted by F, Cl, Br 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl, or R f and R fTogether with the nitrogen atoms attached to them, they form a 1-4 an alkyl optionally substituted heterocyclic ring;

[0935] n, at each occurrence, is an integer independently selected from 0, 1, 2, 3, and 4; and

[0936] p is an integer independently selected from 0, 1 ...

Claims

1. A compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III): in: R 3b Independently selected from H, C 1-4 Alkyl, -(CH 2 ) n -C(=O)R b 、-(CH 2 ) n -C(=O)OR b and 1-5 R 5 substituted-4- to 5-membered monocyclic heterocyclyl; wherein the heterocyclic group is saturated, partially unsaturated or fully unsaturated and contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; R 3c independently selected from H and =O; R 4a Independently selected R 4b independently selected from H and F; R 4c independently selected from H, F, Cl, methyl, ethyl, isopropyl and OCH 3 ; R 5 is independently selected at each occurrence from H and -(CH 2 ) n -C(=O)OR b ; R 10 is independently selected at each occurrence from H, F, Cl, Br; R b independently selected at each occurrence from H and 0-5 R e Substituted C 1-6 alkyl; R e independently selected at each occurrence from F, Cl, Br and 0-5 R f Substituted C 1-6 alkyl; R f In each occurrence, independently selected from H, C 1-5 Alkyl, C 3-6 Cycloalkyl and phenyl, the C 1-5 The alkyl group is optionally substituted with F, Cl, or Br; n is an integer independently selected from 0, 1, 2, 3 and 4 at each occurrence.

2. The compound of claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, in: R 3b Independently selected from H, C 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -(CH 2 ) n -C(=O)OH, -(CH 2 ) n -C(=O)OC 1-4 Alkyl and 1-5 R 5 substituted-4- to 5-membered monocyclic heterocyclyl; wherein the heterocyclic group is saturated or partially unsaturated and contains carbon atoms and 1 or 2 heteroatoms independently selected from N and O; Independently selected n is an integer independently selected from 0, 1, 2 and 3 at each occurrence.

3. The compound of claim 1 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, in: Independently selected R e independently selected at each occurrence from F, Cl, Br and C 1-6 alkyl; and n is an integer independently selected from 0, 1, 2, and 3 at each occurrence.

4. A compound selected from: or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

5. Use of a compound according to any one of claims 1 to 4 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating thromboembolic disorders.

6. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent.

7. Use of a compound according to any one of claims 1 to 4 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of thromboembolic disorders, wherein the thromboembolic disorder is selected from arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders and thromboembolic disorders in the cardiac chambers or peripheral circulation.

8. The method of claim 7, wherein the thromboembolic disorder is selected from the group consisting of unstable angina, acute coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral artery thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis caused by medical implants, devices or surgeries in which blood is exposed to artificial surfaces that promote thrombosis.

9. The use according to claim 7, wherein the thromboembolic disorder is deep vein thrombosis.

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