N-((HET)arylmethyl)-heteroaryl-carboxamide compounds as plasma kallikrein inhibitor

Abstract

To provide enzyme inhibitors that are inhibitors of plasma kallikrein, pharmaceutical compositions containing such inhibitors, the uses of such inhibitors in therapeutic methods, and methods of treating patients using such compounds.SOLUTION: The present invention provides compounds of a formula (I).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein, as well as pharmaceutical compositions containing such inhibitors and uses of such inhibitors. [Background technology]

[0002] The heterocyclic derivatives of the present invention are inhibitors of plasma kallikrein and have several therapeutic uses, particularly in the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

[0003] Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see KD Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, pp. 483-493; JW Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters", Cardiovascular and haematological agents in medicinal chemistry, vol. 7, pp. 234-250, 2009; KD Bhoola et al., Pharmacological Rev., 1992, vol. 44, p. 1; and DJ Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research, 2000, vol. 33, pp. 665-677). Plasma kallikrein is an essential member of the intrinsic blood coagulation cascade, but its role in this cascade does not involve the release or enzymatic cleavage of bradykinin. Plasma prekallikrein is encoded by a single gene and synthesized in the liver. It is secreted by hepatocytes as inactive plasma prekallikrein, which circulates in plasma as a heterodimeric complex bound to high molecular weight kininogen, and activation of inactive plasma prekallikrein produces active plasma kallikrein. Kinins are potent mediators of inflammation, acting through G protein-coupled receptors, and kinin antagonists (such as bradykinin antagonists) have already been explored as potential therapeutic agents for the treatment of several disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, vol. 3, pp. 845-852).

[0004] Plasma kallikrein is thought to play a role in several inflammatory disorders. The major inhibitor of plasma kallikrein is serpin C1 esterase inhibitor. Patients with a genetic deficiency of C1 esterase inhibitor suffer from hereditary angioedema (HAE), which causes intermittent swelling of the face, hands, throat, gastrointestinal tract, and genitals. The blisters that form during acute episodes contain high levels of plasma kallikrein, which cleaves high molecular weight kininogen to liberate bradykinin, resulting in increased vascular permeability. Treatment with large protein plasma kallikrein inhibitors has been shown to effectively treat HAE by blocking the release of bradykinin, which increases 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., Vol. 8, pp. 1187-99).

[0005] The plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has been recently published that plasma kallikrein contributes to 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, vol. 60, pp. 1590-98). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 alleviated both retinal vascular permeability abnormalities and retinal blood flow abnormalities in diabetic rats. Thus, plasma kallikrein inhibitors should have utility as therapeutic agents for reducing retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

[0006] Other diabetic complications such as cerebral hemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have an association with plasma kallikrein, may also be considered targets for plasma kallikrein inhibitors.

[0007] Synthetic low-molecular-weight plasma kallikrein inhibitors have already been described, for example, by Garrett et al. ("Peptide aldehyde...", J. Peptide Res., vol. 52, pp. 62-71 (1998)), T. Griesbacher et al. ("Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats", British Journal of Pharmacology, vol. 137, pp. 692-700 (2002)), Evans ("Selective dipeptide inhibitors of kallikrein", WO 03 / 076458), Szelke et al. ("Kininogenase inhibitors", WO 92 / 04371), DM Evans et al. (Immunolpharmacology, vol. 32, pp. 115-116 (1996)), Szelke et al. ("Kininogen inhibitors" WO95 / 07921), Antonsson et al. ("New peptide derivatives" WO94 / 29335), J. Corte et al. ("Six membered heterocycles useful as serine protease inhibitors" WO2005 / 123680), J. Sturzbecher et al. (Brazilian J.Med.Biol.Res vol. 27, pp. 1929-34 (1994)), Kettner et al. (US5,187,157), N. Teno et al. (Chem.Pharm.Bull. vol. 41, pp. 1079-1090 (1993)), WBYoung et al. ("Small molecule inhibitors of plasma kallikrein" Bioorg.Med.Chem.Letts.16, pp. 2034-2036 (2006)), Okada et al. ("Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship", Chem. Pharm. Bull. 48, pp. 1964-72 (2000)), Steinmetzer et al. ("Trypsin-like serine protease inhibitors and their preparation and use", WO08 / 049595), Zhang et al. ("Discovery of highly potent small molecule kallikrein inhibitors", Medicinal Chemistry 2, pp. 545-553 (2006)), Sinha et al. ("Inhibitors of plasma kallikrein", WO08 / 016883), Shigenaga et al. ("Plasma Kallikrein ("Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor", British Journal of Pharmacology (2011), vol. 162(7), pp. 1639-1649). Similarly, Steinmetzer et al. ("Serine protease inhibitors", WO2012 / 004678) describe cyclized peptide analogs that are inhibitors of human plasmin and plasma kallikrein.

[0008] To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. The molecules described in the prior art have limitations such as poor selectivity against related enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. Large protein plasma kallikrein inhibitors pose the risk of anaphylactic reactions, as has been reported for ecallantide. Therefore, there is a need for compounds that selectively inhibit plasma kallikrein, do not induce anaphylaxis, and are orally available. Furthermore, the majority of molecules in the prior art are characterized by highly polar, ionizable guanidine or amidine functional groups. It is well known that such functional groups can limit permeability through the digestive tract, and therefore limit oral availability. For example, it has been reported by Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral Drug Candidate for Diabetic Macular Edema", ARVO2012 May 6-May 9, 2012, Fort Lauderdale, Florida, Presentation 2240) that benzamidine ASP-440 has poor oral availability. It has also been reported that absorption can be improved by the development of prodrugs such as ASP-634. However, it is well known that prodrugs may have some drawbacks, such as poor chemical stability and potential toxicity due to inert carriers or unexpected metabolites. In another report, indole amides have been claimed as compounds that may overcome the challenges associated with drugs with poor or insufficient ADME-tox and physicochemical properties, but inhibition of plasma kallikrein has not been presented or claimed (Griffioen et al., "Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases", WO2010,142801).

[0009] BioCryst Pharmaceuticals Inc. has reported the discovery of an orally available plasma kallikrein inhibitor, BCX4161 ("BCX4161, An Oral Kallikrein Inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study In Healthy Volunteers", Journal of Allergy and Clinical Immunology, Vol. 133, No. 2, Suppl. 2014, Feb. AB39 and "A Simple, Sensitive and Selective Fluorogenic Assay to Monitor Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma", Journal of Allergy and Clinical Immunology, Vol. 133, No. 2, Suppl. 2014, Feb. AB40). However, the human dose is relatively large, and a dose of 400 mg three times a day is currently being tested in proof-of-concept studies.

[0010] There are few reports of plasma kallikrein inhibitors that do not feature guanidine or amidine functional groups. One example is Brandl et al. ("N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein" WO2012 / 017020), who described compounds that feature amino-pyridine functional groups. Oral efficacy in rat models has been demonstrated at relatively high doses of 30 mg / kg and 100 mg / kg, but pharmacokinetic profiles have not been reported. Thus, it remains unknown whether such compounds will provide oral availability or efficacy sufficient to transition to the clinic. Other examples are Brandl et al. ("Aminopyridine derivatives as plasma kallikrein inhibitors" WO2013 / 111107) and Flohr et al. ("5-membered heteroarylcarboxamide derivatives as plasma kallikrein inhibitors" WO2013 / 111108). However, none of these publications report any in vivo data, and therefore it remains unknown whether such compounds would provide sufficient oral availability or efficacy to be translated into the clinic. Another example is Allen et al. "Benzylamine derivatives" WO2014 / 108679. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2003 / 076458 [Patent Document 2] WO 92 / 04371 [Patent Document 3] WO 95 / 07921 [Patent Document 4] WO 94 / 29335 [Patent Document 5] International Publication No. 2005 / 123680 [Patent Document 6] U.S. Pat. No. 5,187,157 [Patent Document 7] International Publication No. 2008 / 049595 [Patent Document 8] International Publication No. 2008 / 016883 [Patent Document 9] International Publication No. 2011 / 118672 [Patent Document 10] International Publication No. 2012 / 004678 [Patent Document 11] International Publication No. 2010 / 142801 [Patent Document 12] International Publication No. 2012 / 017020 [Patent Document 13] International Publication No. 2013 / 111107 [Patent Document 14] International Publication No. 2013 / 111108 [Patent Document 15] International Publication No. 2014 / 108679 [Non-patent literature]

[0012] [Non-Patent Document 1] KDBhoola et al., “Kallikrein-Kinin Cascade,” Encyclopedia of Respiratory Medicine, pp. 483-493. [Non-Patent Document 2] JWBryant et al., “Human plasma kallikrein-kinin system: physiological and biochemical parameters,” Cardiovascular and haematological agents in medicinal chemistry, vol. 7, pp. 234-250, 2009. [Non-Patent Document 3] KD Bhoola et al., Pharmacological Rev., 1992, vol. 44, p. 1 [Non-Patent Document 4] DJ Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides," Brazilian Journal of Medical and Biological Research 2000, vol. 33, pp. 665-677. [Non-Patent Document 5] F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, vol. 3, pp. 845-852 [Non-Patent Document 6] 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. vol. 8, pp. 1187-99 [Non-Patent Document 7] A. Clermont et al., “Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats,” Diabetes, 2011, vol. 60, pp. 1590-98. [Non-Patent Document 8] Garrett et al., "Peptide aldehyde...", J. Peptide Res., Vol. 52, pp. 62-71 (1998) [Non-Patent Document 9] T. Griesbacher et al., “Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats,” British Journal of Pharmacology vol. 137, pp. 692-700 (2002) [Non-Patent Document 10] DMEvans et al., Immunolpharmacology, 32, 115-116 (1996) [Non-Patent Document 11] J. Sturzbecher et al., Brazilian J. Med. Biol. Res 27, 1929-34 (1994) [Non-Patent Document 12] N. Teno et al., Chem. Pharm. Bull. 41, 1079-1090 (1993) [Non-Patent Document 13] W. B. Young et al., "Small molecule inhibitors of plasma kallikrein," Bioorg. Med. Chem. Letts. 16, 2034-2036 (2006) [Non-Patent Document 14] Okada et al., "Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship," Chem. Pharm. Bull., vol. 48, pp. 1964-72 (2000) [Non-Patent Document 15] Zhang et al., "Discovery of highly potent small molecular kallikrein inhibitors," Medicinal Chemistry, vol. 2, pp. 545-553 (2006) [Non-Patent Document 16] Kolte et al., "Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor," British Journal of Pharmacology (2011), Vol. 162 (No. 7), pp. 1639-1649 [Non-Patent Document 17] Tamie J. Chilcote and Sukanto Sinha, "ASP-634: An Oral Drug Candidate for Diabetic Macular Edema," ARVO2012, May 6-9, 2012, Fort Lauderdale, Florida, Presentation 2240 [Non-Patent Document 18] "BCX4161, An Oral Kallikrein Inhibitor: Safety and Pharmacokinetic Results Of a Phase 1 Study In Healthy Volunteers", Journal of Allergy and Clinical Immunology, Vol. 133, No. 2, Supplementary Edition, February 2014, AB39 [Non-Patent Document 19] "A Simple, Sensitive and Selective Fluorogenic Assay to Monitor Plasma Kallikrein Inhibitory Activity of BCX4161 in Activated Plasma", Journal of Allergy and Clinical Immunology, Vol. 133, No. 2, Supplementary Edition, February 2014, AB40 Summary of the Invention [Problem to be solved by the invention]

[0013] Thus, there remains a need to develop new plasma kallikrein inhibitors that have utility for treating a wide range of disorders, particularly for reducing retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Preferred compounds have good pharmacokinetic profiles and are particularly suitable as drugs for oral delivery.

[0014] Summary of the Invention The present invention relates to a series of heterocyclic derivatives that are inhibitors of plasma kallikrein.These compounds demonstrate good selectivity for plasma kallikrein and are potentially useful in the treatment of visual impairment, diabetic retinopathy, macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and postoperative bleeding.The present invention further relates to pharmaceutical compositions of the inhibitors, the use of the compositions as therapeutic agents, and methods of treatment with these compositions. [Means for solving the problem]

[0015] In a first aspect, the present invention provides a compound of formula I

[0016] [ka] (In the formula, B is alkyl b phenyl substituted by 1 to 4 substituents selected from alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 and CF3; Or, B is selected from benzothiophenyl, benzofuranyl, benzomorpholinyl, and a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, said 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic, and said benzothiophenyl, said benzofuranyl, said benzomorpholinyl or said 5- or 6-membered heterocyclic ring is selected from alkyl,b , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 and CF3; W is C; X, Y and Z are independently selected from C, N, O and S, such that the ring containing W, X, Y and Z is a 5-membered aromatic heterocycle; R5 and R6 are independently selected from absent or H, alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9, and CF3, wherein at least one of R5 and R6 is present and is not H; R7 is H; A is selected from aryl and heteroaryl, where aryl is alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, -(CH2) 0-3 -O-heteroaryl, aryl b , -O-aryl b , -(CH2) 1-3 -aryl b , -(CH2) 1-3 -heteroaryl, -COOR10, -CONR10R11, -(CH2) 0-3 Substituted by one, two or three substituents independently selected from -NR10R11, OCF3 and CF3, heteroaryl being alkyl, alkoxy, OH, OCF3, halo, CN, aryl, -(CH2) 1-3 -aryl, -(CH2) 0-3 -NR10R11, heteroaryl b , -COOR10, -CONR10R11 and CF3; R8 and R9 are independently selected from H and alkyl; Alkyl is a group containing up to 10 carbon atoms (C1-C 10) or linear saturated hydrocarbons having between 3 and 10 carbon atoms (C3-C 10 wherein the alkyl is optionally substituted by one or two substituents independently selected from (C1-C6)alkoxy, OH, CN, CF3, COOR10, CONR10R11, fluoro, and NR10R11; Alkyl b is a linear saturated hydrocarbon having up to six carbon atoms or a branched saturated hydrocarbon consisting of between three and six carbon atoms (C3-C6), and is b is optionally substituted by one or two substituents independently selected from (C1-C6)alkoxy, OH, CN, CF3, COOR10, CONR10R11 and fluoro; Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6 carbon atoms; Alkoxy is an O-linked straight chain hydrocarbon of between 1 and 6 carbon atoms (C1-C6) or an O-linked branched hydrocarbon of between 3 and 6 carbon atoms (C3-C6), which is optionally substituted with one or two substituents independently selected from OH, CN, CF3, COOR10, CONR10R11, fluoro and NR10R11; Aryl is phenyl, biphenyl or naphthyl, and aryl is alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, -(CH2) 0-3 -O-heteroaryl, aryl b , -O-aryl b , -(CH2) 1-3 -aryl b , -(CH2) 1-3 -heteroaryl, -COOR10, -CONR10R11, -(CH2) 0-3 optionally substituted by 1, 2 or 3 substituents independently selected from -NR10R11, OCF3 and CF3; Aryl bis phenyl, biphenyl or naphthyl, which is optionally substituted by 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF3 and NR10R11; Heteroaryl is a 5-, 6-, 9-, or 10-membered monocyclic or bicyclic aromatic ring containing, where possible, 1, 2, 3, or 4 ring members independently selected from N, NR8, S, and O, and heteroaryl is alkyl, alkoxy, OH, OCF3, halo, CN, aryl, -(CH2) 1-3 -aryl, -(CH2) 0-3 -NR10R11, heteroaryl b , -COOR10, -CONR10R11 and CF3; Heteroaryl b is a 5-, 6-, 9- or 10-membered monocyclic or bicyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and O; heteroaryl b is alkyl, alkoxy, OH, halo, CN, aryl, -(CH2) 1-3 -optionally substituted by 1, 2 or 3 substituents independently selected from -aryl, -COOR10, -CONR10R11, CF3 and NR10R11; R10 and R11 are H, alkyl, aryl b and heteroaryl b or R10 and R11 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic carbon-containing ring which may contain additional heteroatoms selected from N, S and O, which may be saturated or unsaturated with one or two double bonds and may be mono- or disubstituted with substituents selected from oxo, alkyl, alkoxy, OH, halo and CF3. and the tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-scalemic mixtures thereof), pharma- ceutically acceptable salts, and solvates thereof. to provide.

[0017] In another aspect, the present invention provides a prodrug of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, as defined herein.

[0018] In yet another aspect, the present invention provides an N-oxide of a compound of formula (I), as defined herein, or a prodrug or a pharma- ceutically acceptable salt thereof.

[0019] It is understood that certain compounds of the present invention may exist in solvated forms, including hydrated forms as well as unsolvated forms, and it is to be understood that the present invention encompasses all such solvated forms.

[0020] In a further embodiment, B is selected from phenyl, thiophenyl, benzothiophenyl, and pyridyl, each of which is an alkyl b , alkoxy, halo, CN, COOR8, CONR8R9, OCF3 and CF3; b , alkoxy, R8 and R9 are as defined above; W is C and X, Y and Z are independently selected from C and N such that the ring containing W, X, Y and Z is a 5-membered aromatic heterocycle; R5 and R6 are independently absent or independently selected from H, CHOCH, cycloalkyl, -NRR, -NRCOR, and CF, and at least one of R and R is present and is not H; R7 is H; A,

[0021] [ka] is selected from Alkyl, cycloalkyl, alkoxy, R8 and R9 are as defined above A compound of formula (I), As well as tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), pharma- ceutically acceptable salts, and solvates thereof are also provided.

[0022] In a further embodiment, B is selected from phenyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from methyl, ethyl, methoxy, ethoxy, CF3, CN, and F; W is C, X is N, and Y and Z are selected from C and N; R7 is H; R5 and R6 are independently absent or independently selected from H, CHOCH, cyclopropyl, NH, and CF, and at least one of R5 and R6 is present and not H; A,

[0023] [ka] Selected from A compound of formula (I), and the tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), pharma- ceutically acceptable salts, and solvates thereof. will also be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The above aspects of the invention may also include the following features: B is alkyl b, alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 and CF3, or B is selected from benzothiophenyl, benzofuranyl, benzomorpholinyl and a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, said 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic, and said benzothiophenyl, said benzofuranyl, said benzomorpholinyl or said 5- or 6-membered heterocyclic ring is selected from alkyl, alkyl, aryl ... b , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 and CF3. B is alkyl b , alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 and CF3, or B is selected from benzothiophenyl, benzofuranyl, and a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, said 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic, and said benzothiophenyl, said benzofuranyl, or said 5- or 6-membered heterocyclic ring is selected from alkyl, alkyl, aryl ... b , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF3 and CF3; b , alkoxy, R8 and R9 are as defined above. B is selected from phenyl, pyridyl, pyrimidon, pyrimidine, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiophenyl, benzothiophenyl and furanyl, each of which may be selected from alkyl, aryl ... b, alkoxy, OH, oxo, halo, CN, COOR8, CONR8R9, OCF3 and CF3; b , alkoxy, R8 and R9 are as defined above. B is selected from phenyl, pyridyl, pyrimidon, thiazolyl, pyrazolyl, isoxazolyl, thiophenyl, benzothiophenyl and furanyl, each of which, where possible, is selected from alkyl, b , alkoxy, OH, oxo, halo, CN, COOR8, CONR8R9, OCF3 and CF3; b , alkoxy, R8 and R9 are as defined above. B is selected from phenyl, thiophenyl, benzothiphenyl, and pyridyl, each of which is an alkyl group; b , alkoxy, halo, CN, COOR8, CONR8R9, OCF3 and CF3; b , alkoxy, R8 and R9 are as defined above. B is selected from phenyl and pyridyl, each of which is alkyl; b , alkoxy, CN, CF3, and halo; b and alkoxy is as defined above. B is selected from phenyl and pyridyl, each of which is alkyl; b , alkoxy, CF3, and halo; b and alkoxy is as defined above. B is selected from phenyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from methyl, ethylmethoxy, ethoxy, CF3, CN and F. B is selected from phenyl and pyridyl, each of which is substituted with 1 to 3 substituents selected from methyl, ethyl, methoxy, ethoxy, CF3, Cl, CHF2 and F. B is selected from phenyl substituted with from 1 to 3 substituents selected from methyl, ethyl, methoxy, ethoxy, CN, CF3, Cl, CHF2 and F. B is selected from phenyl substituted with from 1 to 3 substituents selected from methyl, ethyl, methoxy, ethoxy, CF3, Cl, CHF2 and F. W is C, and X, Y and Z are independently selected from C and N such that the ring containing W, X, Y and Z is a 5-membered aromatic heterocycle. W is C and X, Y and Z are independently selected from C and N such that the ring containing W, X, Y and Z is selected from pyrrole, pyrazole, imidazole and 1,2,3-triazole. W is C, and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is selected from pyrazole and imidazole. W is C. X is N. W is C, X is N, and Y and Z are selected from C and N. W is C, X is N, Y is N, and Z is C. W is C, X is N, Y is C, and Z is N. R5 and R6 are independently absent or selected from H, alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9 and CF3, where at least one of R5 and R6 is present and is not H and is alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, R8 and R9 are as defined above. R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, -NR8R9, CN, -NR8COR9 and CF3, where at least one of R5 and R6 is present and not H, alkyl, cycloalkyl, R8 and R9 are as defined above. R5 and R6 are independently absent or independently selected from H, CHOCH, cycloalkyl, CN, -NRR, -NRCOR and CF, wherein at least one of R and R is present and not H, cycloalkyl, R and R are as defined above. R5 and R6 are independently absent or independently selected from H, cycloalkyl, CN, -NR8R9, -NR8COR9 and CF3, wherein at least one of R5 and R6 is present and not H, cycloalkyl, R8 and R9 are as defined above. R5 and R6 are independently not present or independently selected from H, CHOCH, cycloalkyl, CN, NRR, and CF, where R and R are H and cycloalkyl is as defined above, and at least one of R and R is present and is not H. R7 is H. R7 is H; and R5 and R6 are independently absent or independently selected from H, CH2OCH3, cyclopropyl, CN, NH2, and CF3, and at least one of R5 and R6 is present and not H. R7 is H; and R5 and R6 are independently absent or independently selected from H, CH2OCH3, cyclopropyl, NH2, CN, and CF3, and at least one of R5 and R6 is present and not H. R7 is H; and R5 and R6 are independently absent or independently selected from H, CH2OCH3, cyclopropyl, NH2, and CF3, and at least one of R5 and R6 is present and not H. R7 is H, R6 is absent, and R5 is selected from CH2OCH3, cyclopropyl, NH2, and CF3. R7 is H, R6 is absent, and R5 is CH2OCH3. W is C, X is N, Y and Z are selected from C and N, R7 is H, R5 and R6 are independently absent or independently selected from H, CHOCH, cycloalkyl, NRR and CF, R8 and R9 are H, and cycloalkyl is as defined above. W is C, X is N, Y is N, Z is C, R7 is H, R6 is absent, and R5 is selected from CH2OCH3, cyclopropyl, NH2, and CF3. A is selected from aryl and heteroaryl, each of which is substituted as specified above. A is phenyl, pyridyl, thiophenyl, or quinolinyl, each of which is alkyl, alkoxy, halo, CN, aryl, b , -(CH2) 1-3 -aryl b , -(CH2) 1-3 -heteroaryl, -(CH2) 0-3 - substituted with one, two or three substituents independently selected from NR10R11 and CF3, alkyl, alkoxy, heteroaryl, aryl b , R10 and R11 are as defined above. A is phenyl or pyridyl, each of which is an alkyl, alkoxy, halo, -(CH2) 1-3 -aryl b , -(CH2) 1-3 -heteroaryl, CF3 and -(CH2) 0-3 -NR10R11 is substituted by one, two or three substituents independently selected from alkyl, alkoxy, heteroaryl, aryl b , R10 and R11 are as defined above. A is alkyl, halo, or heteroaryl. b, CF3 and -NR10R11; b , R10 and R11 are as defined above. A is heteroaryl b or pyridyl substituted by -NR10R11, optionally substituted by one or two additional substituents independently selected from alkyl, halo, and CF3, wherein alkyl, heteroaryl b , R10 and R11 are as defined above. A is alkyl, halo, -(CH2) 1-3 -heteroaryl, CF3 and -(CH2) 1-3 -phenyl substituted with one, two or three substituents independently selected from -NR10R11, alkyl, heteroaryl, R10 and R11 are as defined above. A is -(CH2) 1-3 -heteroaryl or -(CH2) 1-3 Phenyl substituted by -NR10R11, optionally substituted by one or two additional substituents independently selected from alkyl, halo, and CF3, where alkyl, heteroaryl, R10 and R11 are as defined above. A is

[0025] [ka] Selected from TIFF2025000918000005.tif222161. A is

[0026] [ka] is selected from. A is

[0027] [ka] is selected from. A is

[0028] [ka] is selected from. A is

[0029] [ka] It is. A is

[0030] [ka] It is. R8 and R9 are independently selected from H and alkyl, where alkyl is defined above. R8 and R9 are independently selected from H, methyl, ethyl, n-propyl, and isopropyl. R8 and R9 are independently selected from H and methyl. R10 and R11 are H, alkyl, aryl b and heteroaryl b or R10 and R11 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic carbon-containing ring which may contain additional heteroatoms selected from N, S and O, which may be saturated or unsaturated by one or two double bonds and which may be mono- or disubstituted by substituents selected from oxo, alkyl, alkoxy, OH, halo and CF3, and which may be alkyl, alkoxy, aryl ... b and heteroaryl b is as defined above. R10 and R11 are independently selected from H and alkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic carbon-containing ring, which may contain an additional N atom, which may be saturated or unsaturated by one or two double bonds and which may be mono- or di-substituted by substituents selected from oxo, alkyl, alkoxy, OH, Cl, F and CF3, where alkyl and alkoxy are as defined above. R10 and R11 are independently selected from H and alkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic carbon-containing ring which may contain an additional N atom, which may be saturated or unsaturated with one or two double bonds and which may be mono- or di-substituted with substituents selected from oxo, methyl, Cl and F, and alkyl is as defined above. R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic carbon-containing ring, which may contain an additional N atom, which may be saturated or unsaturated by one or two double bonds and which may be mono- or di-substituted by substituents selected from oxo, methyl, Cl and F. R10 and R11 together with the nitrogen atom to which they are attached form a 6-membered heterocyclic carbon-containing ring, which may contain an additional N atom, and which may be saturated or unsaturated by one or two double bonds and which may be oxo-substituted. R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic carbon-containing ring. R10 and R11 are H and alkyl b and independently selected from alkyl, b is as defined above.

[0031] The present invention includes, but is not limited to, the compounds listed below: N-(3,5-dimethoxybenzyl)-3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide; 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide; 1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(3-ethoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; 1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2,4-dimethoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-4-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-chloro-6-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(4-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(3-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(3-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(5-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2,6-dichlorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[5-chloro-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2,4-dimethylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2,6-dimethylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; 1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)-N-[(2,4,6-trimethylphenyl)methyl]pyrazole-4-carboxamide; N-[(3-fluoro-2-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(3-fluoropyridin-2-yl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(4-chloropyridin-2-yl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrazole-4-carboxamide; 3-(Methoxymethyl)-N-[(6-methylpyridin-3-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(4-fluoro-5-methoxypyridin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(4-acetamidopyridin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[4-fluoro-2-(trifluoromethyl)pyridin-3-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(trifluoromethyl)pyridin-3-yl]methyl}pyrazole-4-carboxamide; 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrazole-4-carboxamide; N-[(4-fluoropyridin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(Methoxymethyl)-N-[(6-methylpyridin-3-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(Methoxymethyl)-N-[(6-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-fluoro-6-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-chlorothiophen-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-chloro-5-methylthiophen-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide; N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoylphenyl)methyl]-3-cyclopropyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-carbamoylphenyl)methyl]-3-cyclopropyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(4-carbamoylphenyl)methyl]-3-cyclopropyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; 3-Cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3,6-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(ethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(isopropylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethoxy)phenyl]methyl}pyrazole-4-carboxamide; 3-(Dimethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-chloro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-acetamido-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(N-methylacetamido)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-chloro-2,6-difluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxy-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-2-cyanophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[3-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[6-(difluoromethyl)-2-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-chloro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 2-({[3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazol-4-yl]formamido}methyl)benzoic acid N-{[2-fluoro-6-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-fluoro-5-(1,2,3,4-tetrazol-1-yl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[3-(difluoromethoxy)-2-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[3-(difluoromethoxy)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluoro-4-methylphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,5-difluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,5-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-6-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-fluoro-3-methoxy-6-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-fluoro-4-methyl-6-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[4-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-cyano-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-hydroxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-[(2-fluoro-3-hydroxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; Methyl 2-({[3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazol-4-yl]formamido}methyl)benzoate N-[(3-ethyl-2-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(Methoxymethyl)-N-[(3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyrazin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(4-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(4-methyl-2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(4-ethoxy-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-methoxy-4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[5-(2-oxopyridin-1-yl)thiophen-3-yl]methyl}pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]thiophen-3-yl}methyl)pyrazole-4-carboxamide; 3-Amino-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Methoxymethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide; 3-Methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide; 1-(2-Pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-fluoro-6-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; 1-({4-[(2-chloro-6-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({2-[(methylamino)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(methylamino)pyridin-4-yl]methyl}pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(2,2,2-trifluoroethyl)phenyl]methyl}pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(trifluoromethoxy)phenyl]methyl}pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; 2-Amino-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; 2-Cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-2-(trifluoromethyl)imidazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-2-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide; 3-amino-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide; 3-Methoxymethyl-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide; 1-(6-Pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide; 3-Amino-N-[(7-chloro-4-methyl-2,3-dihydro-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide as well as pharma- ceutical acceptable salts and solvates thereof.

[0032] The present invention includes, but is not limited to, the compounds listed below: 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; 3-Cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3,6-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(Dimethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-acetamido-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-chloro-2,6-difluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-2-cyanophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[3-(difluoromethoxy)-2-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,5-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-6-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-[(2-fluoro-3-hydroxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-ethyl-2-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(Methoxymethyl)-N-[(3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(4-methyl-2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-2-(trifluoromethyl)imidazole-4-carboxamide; 3-Amino-N-[(7-chloro-4-methyl-2,3-dihydro-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide as well as pharma- ceutical acceptable salts and solvates thereof.

[0033] The present invention includes, but is not limited to, the compounds listed below: 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide; N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; 3-Cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3,6-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(Dimethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-2-cyanophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,5-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(Methoxymethyl)-N-[(3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; 3-Amino-N-[(7-chloro-4-methyl-2,3-dihydro-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-Amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide as well as pharma- ceutical acceptable salts and solvates thereof.

[0034] therapeutic use As already mentioned, the compounds of the present invention are potent and selective inhibitors of plasma kallikrein, and are therefore useful in the treatment of disease states in which hyperactivity of plasma kallikrein is a causative factor.

[0035] Thus, the present invention provides a compound of formula (I) for use in medicine.

[0036] The invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with plasma kallikrein activity.

[0037] The present invention also provides a compound of formula (I) for use in the treatment or prevention of a disease or condition associated with plasma kallikrein activity.

[0038] The present invention also provides a method of treatment comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need of treatment for a disease or condition associated with plasma kallikrein activity.

[0039] In one embodiment, the disease or condition associated with plasma kallikrein activity is selected from vision impairment, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and post-operative bleeding.

[0040] In a preferred embodiment, the disease or condition associated with plasma kallikrein activity is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

[0041] Combination therapy The compounds of the present invention may be administered in combination with other therapeutic agents.Suitable combination therapy includes the compound of formula (I) combined with one or more agents selected from platelet-derived growth factor (PDGF), endothelial growth factor (VEGF), agents that inhibit integrin alpha5beta1, steroids, other agents that inhibit plasma kallikrein, and other inflammation inhibitors.Specific examples of therapeutic agents that may be combined with the compounds of the present invention include the therapeutic agents disclosed in EP2281885A and those disclosed by S.Patel in Retina, June 2009; Vol. 29 (Suppl. No. 6): S45-8.

[0042] When combination therapy is used, the compound of the present invention and said combination agent may be present in the same or different pharmaceutical compositions and may be administered separately, sequentially or simultaneously.

[0043] In another embodiment, the compound of the present invention may be administered in combination with retinal laser treatment.The combination of laser therapy and intravitreal injection of VEGF inhibitors for treating diabetic macular edema is known (Elman M, Aiello L, Beck R et al. "Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema", Ophthalmology. April 27, 2010).

[0044] definition The term "alkyl" embraces saturated hydrocarbon residues, including: Up to 10 carbon atoms (C1-C 10 ), or a straight-chain group of up to six carbon atoms (C1-C6), or up to four carbon atoms (C1-C4). Examples of such alkyl groups include, but are not limited to, C1-methyl, C2-ethyl, C3-propyl, and C4-n-butyl. Between 3 and 10 carbon atoms (C3-C 10 ), or branched groups of up to seven carbon atoms (C3-C7), or up to four carbon atoms (C3-C4). Examples of such alkyl groups include, but are not limited to, C3-iso-propyl, C4-sec-butyl, C4-iso-butyl, C4-tert-butyl, and C5-neo-pentyl.

[0045] Each of the above groups may be optionally substituted as described above.

[0046] Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 7 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Cycloalkyl may be substituted by a substituent selected from alkyl, alkoxy, and NR12R13, where R12 and R13 are independently selected from H and alkyl, or R12 and R13 together with the nitrogen to which they are attached form a 4-, 5-, 6-, or 7-membered heterocyclic ring that may be saturated or unsaturated by one or two double bonds, and may be mono- or di-substituted by a substituent selected from oxo, alkyl, alkoxy, OH, F, and CF3. Cycloalkyl groups may contain 3 to 7 carbon atoms, or 3 to 6 carbon atoms, or 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0047] The term "alkoxy" includes O-linked hydrocarbon residues, including: Straight-chain groups consisting of between 1 and 6 carbon atoms (C1-C6), or between 1 and 4 carbon atoms (C1-C4). Examples of such alkoxy groups include, but are not limited to, C1-methoxy, C2-ethoxy, C3-n-propoxy, and C4-n-butoxy. Branched groups consisting of between 3 and 6 carbon atoms (C3-C6), or between 3 and 4 carbon atoms (C3-C4). Examples of such alkoxy groups include, but are not limited to, C3-iso-propoxy, and C4-sec-butoxy and tert-butoxy.

[0048] Each of the above groups may be optionally substituted as described above.

[0049] Unless otherwise specified, halo is selected from Cl, F, Br, and I.

[0050] Aryl is as defined above. Typically, aryl may be substituted by one, two or three substituents. Optional substituents are selected from those described above. Examples of suitable aryl groups include phenyl and naphthyl, each of which may be substituted as described above. Preferably, aryl is selected from phenyl, substituted phenyl, the substituents being selected from those described above, and naphthyl.

[0051] Heteroaryl is as defined above. Usually, heteroaryl may be substituted by one, two or three substituents. Optional substituents are selected from those described above. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinolinyl (optionally substituted as described above).

[0052] The term "N-linked," as in "N-linked pyrrolidinyl," means that the heterocycloalkyl group is attached to the remainder of the molecule through a ring nitrogen atom.

[0053] The term "O-linked" as in "O-linked hydrocarbon residue" means that the hydrocarbon residue is attached to the remainder of the molecule via an oxygen atom.

[0054] -(CH2) 1-3 In groups such as -aryl, the "-" represents the point of attachment of the substituent to the remainder of the molecule.

[0055] "Pharmaceutically acceptable salts" means salts that are physiologically or toxicologically tolerated and includes, where appropriate, pharma- ceutically acceptable base addition salts and pharma- ceutically acceptable acid addition salts. For example, (i) when the compounds of the invention contain one or more acidic groups, such as a carboxy group, pharma- ceutically acceptable base addition salts which may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines such as diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g., lysine), and (ii) when the compounds of the invention contain a basic group, such as an amino group, pharma-ceutically acceptable acid addition salts which may be formed include hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, lactate, tartrate, mesylate, succinate, oxalate, phosphate, esylate, tosylate, benzenesulfonate, naphthalene disulfonate, maleate, adipate, fumarate, hippurate, camphorate, xinafoate, p-acetamidobenzoate, dihydroxybenzoate, hydroxynaphthoate, succinate, ascorbate, oleate and bisulfate, and the like.

[0056] Hemi-salts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.

[0057] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0058] "Prodrug" refers to a compound that can be converted in vivo to a compound of the present invention by metabolic means (e.g., hydrolysis, reduction or oxidation). Suitable groups for forming prodrugs are described in The Practice of Medicinal Chemistry, 2nd ed., pp. 561-585 (2003) and FJ Leinweber, Drug Metab.Res., 1987, vol. 18, p. 379.

[0059] The compound of the present invention can exist in both non-solvated and solvated form.The term "solvate" is used herein to describe the molecular complex that comprises the compound of the present invention and one or more stoichiometric amounts of pharma- ceutical acceptable solvent molecules, such as ethanol.The term "hydrate" is used when the solvent is water.

[0060] When the compounds of the present invention exist in one or more geometric isomers, optical isomers, enantiomers, diastereomeric forms and tautomeric forms, they include, but are not limited to, cis and trans forms, E and Z forms, R forms, S and meso forms, keto and enol forms.Unless otherwise specified, reference to a particular compound includes all such isomers, including racemic mixtures and other mixtures thereof.If appropriate, such isomers can be separated from these mixtures by application or adaptation of known methods, such as chromatographic techniques and recrystallization techniques.If appropriate, such isomers can be prepared by application or adaptation of known methods, such as asymmetric synthesis.

[0061] Unless otherwise specified, the compounds of the invention include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, a hydrogen atom is replaced by deuterium or tritium, or a carbon atom is replaced by 13 C or 14 Compounds in which C is replaced are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0062] In the context of the present invention, references herein to "treatment" include references to curative treatment, palliative treatment and prophylactic treatment.

[0063] general law The compound of formula (I) should be evaluated for its biopharmaceutical properties, such as solubility and solution stability (at all pH), permeability, etc., in order to select the dosage form and route of administration most suitable for the treatment of the proposed indication. The compound of formula (I) may be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more additional drugs (or any combination thereof). In general, the compound of formula (I) is administered as a formulation together with one or more pharma- ceutically acceptable excipients. The term "excipient" is used herein to describe any component other than the compound of the invention that can impart functional (i.e., drug release rate control) and / or non-functional (i.e., processing aid or diluent) properties to the formulation. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0064] The compound of the present invention intended for pharmaceutical use may be administered as solid or liquid, such as tablet, capsule or solution.The pharmaceutical composition suitable for delivery of the compound of the present invention and its preparation method are easily clear to those skilled in the art.Such compositions and its preparation method can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

[0065] Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharma- ceutically acceptable carrier, diluent or excipient.

[0066] For the treatment of conditions such as diabetic retinopathy and retinal vascular permeability associated with diabetic macular edema, the compound of the present invention can be administered in a form suitable for injection into the ocular region of patients, and in particular, in a form suitable for intravitreal injection.It is envisaged that the preparation suitable for such use will take the form of the sterile solution of the compound of the present invention in suitable aqueous vehicle.This composition can be administered to patients under the supervision of a physician in charge.

[0067] The compound of the present invention may also be administered directly into the bloodstream, into subcutaneous tissue, into muscle or into internal organs.Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.Suitable devices for parenteral administration include needle-type (including microneedle-type) injectors, needle-free injectors and infusion techniques.

[0068] Parenteral formulations are usually aqueous or oily solutions. Where the solution is an aqueous vehicle such as sugars (including but not limited to glucose, mannitol, sorbitol, etc.), salts, carbohydrates and buffers (preferably to a pH of 3 to 9), as is the case for some applications, parenteral formulations may more preferably be formulated as sterile non-aqueous solutions or as dry forms to be used with a suitable vehicle such as sterile pyrogen-free water.

[0069] Parenteral formulations can include implants derived from degradable polymers such as polyesters (i.e., polylactic acid, polylactide, polylactide-co-glycolide, polycaprolactone, polyhydroxybutyrate), polyorthoesters, and polyanhydrides. These formulations can be administered into subcutaneous tissue through a surgical incision, into muscle tissue, or directly into a specific organ.

[0070] The preparation of parenteral formulations under sterile conditions, for example by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0071] The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be enhanced by the use of appropriate formulation techniques, such as the incorporation of cosolvents and / or solubility-enhancing agents such as surfactants, micellar structures and cyclodextrins.

[0072] In one embodiment, the compounds of the invention may be administered orally, which may include swallowing, so that the compound enters the gastrointestinal tract, and / or buccal, lingual, or sublingual administration, where the compound enters the bloodstream directly from the mouth.

[0073] Formulations suitable for oral administration include solid plugs, solid particulates, semi-solids and liquids (including multiphase or dispersion systems), such as tablets, multiparticulates or nanoparticles, soft or hard capsules containing liquids, emulsions or powders, lozenges (including those pre-filled with liquids), chewables, gels, fast dispersing dosage forms, films, ovules, sprays, and buccal / mucoadhesive patches.

[0074] Formulations suitable for oral administration may also be designed to deliver the compounds of the present invention in an immediate or sustained manner, with the release profile being delayed, pulsed, controlled, sustained, or delayed and sustained, or modified, to optimize the therapeutic efficacy of the compound. Means for delivering compounds in a sustained manner are known in the art and include slow release polymers that can be formulated with the compound to control the release of the compound.

[0075] Examples of rate-sustaining polymers include degradable and non-degradable polymers that can be used to release the compound by diffusion or a combination of diffusion and polymer erosion. Examples of rate-sustaining polymers include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, polymethacrylates, polyethylene oxide, and polyethylene glycol.

[0076] Liquid formulations (including multi-phase and dispersion systems) include emulsions, solutions, syrups and elixirs. Such formulations may be provided as fillers in soft or hard capsules (e.g., made from gelatin or hydroxypropylmethylcellulose), and usually contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations may also be prepared by reconstituting a solid, for example, from a sachet.

[0077] The compounds of the invention may also be used in fast dissolving and fast disintegrating dosage forms, such as those described by Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, Vol. 11(6), pp. 981-986.

[0078] Tablet formulation is discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0079] For administration to human patients, the total daily dose of the compounds of the invention will typically range from 0.01 mg to 1000 mg, or between 0.1 mg and 250 mg, or between 1 mg and 50 mg, depending, of course, on the mode of administration.

[0080] Total dose can be administered in single dose or divided dose, and at the discretion of the physician, may not be within the typical range shown herein.These doses are based on the average human subject with a body weight of about 60kg to 70kg.Physicians can easily determine the dose for subjects whose body weight is not within this range, such as children and the elderly.

[0081] Synthesis method The compounds of the present invention can be prepared according to the procedures of the following schemes and examples using appropriate materials, and are further illustrated by the specific examples presented herein below. Moreover, by utilizing the procedures described herein, one skilled in the art can easily prepare additional compounds that fall within the scope of the invention claimed herein. However, the compounds illustrated in the examples should not be construed as forming the only genus considered as the invention. The examples further illustrate the details regarding the preparation of the compounds of the present invention. One skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds.

[0082] The compounds of the present invention may be isolated in the form of their pharma- ceutically acceptable salts, such as those already described hereinabove.

[0083] Protection of reactive functional groups (e.g., hydroxy, amino, thio, or carboxy) in intermediates used in the preparation of the compounds of the present invention may be necessary to avoid undesired participation of these functional groups in the reaction forming the compounds. Conventional protecting groups, such as those described in "Protective groups in organic chemistry" by TW Greene and PG M Huts, John Wiley and Sons, 4th Edition, 2006, may be used. For example, a common amino protecting group suitable for use herein is tert-butoxycarbonyl (Boc), which is easily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane. Alternatively, the amino protecting group may be a benzyloxycarbonyl (Z) group, which may be removed by palladium-catalyzed hydrogenation under a hydrogen atmosphere, or a 9-fluorenylmethyloxycarbonyl (Fmoc) group, which may be removed by a solution of an organic secondary amine such as diethylamine or piperidine in an organic solvent. Carboxyl groups are usually protected as esters such as methyl, ethyl, benzyl or tert-butyl, all of which can be removed by hydrolysis in the presence of a base such as lithium or sodium hydroxide. Benzyl protecting groups can also be removed by palladium-catalyzed hydrogenation under a hydrogen atmosphere, while tert-butyl groups can also be removed by trifluoroacetic acid. Alternatively, trichloroethyl ester protecting groups are removed by zinc in acetic acid. A common hydroxy protecting group suitable for use herein is the methyl ether, and deprotection conditions include refluxing in aqueous 48% HBr for 1-24 hours, or by stirring with borane tribromide in dichloromethane for 1-24 hours. Alternatively, if the hydroxy group is protected as a benzyl ether, deprotection conditions include palladium-catalyzed hydrogenation under a hydrogen atmosphere.

[0084] Examples of synthetic methods that can be used to prepare 4-carboxyimidazoles are described in EP1426364A1 ("Imidazole-derivatives as factor Xa inhibitors", pages 27-28).

[0085] Compounds according to general formula I can be prepared using conventional synthetic methods, such as, but not limited to, the route outlined in Scheme 1. Amine 2 is coupled with acid 1 to give compound 3. This coupling is usually carried out using standard coupling conditions such as hydroxybenzotriazole and a carbodiimide, such as a water-soluble carbodiimide, in the presence of an organic base. Other standard coupling methods include the reaction of an acid with an amine in the presence of an organic base such as triethylamine, diisopropylethylamine or N-methylmorpholine in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate, 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate or bromo-trispyrrolidino-phosphonium hexafluorophosphate. Alternatively, the amide formation can be carried out via an acid chloride in the presence of an organic base. Such acid chlorides can be formed by methods well known in the literature, for example, by reaction of an acid with oxalyl chloride or thionyl chloride.

[0086] [ka]

[0087] Alternatively, compounds according to general formula I can be prepared using the route outlined in scheme 2a. Acid 4 can be coupled with amine 2 using a suitable coupling method already described to give compound 5. In a typical second step, the nitrogen of the heterocyclic ring is alkylated with compound 6 to give compound 7. This alkylation can be carried out in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate or sodium hydride, where the leaving group is a halide or sulfonate ion. Alternatively, this alkylation can be carried out using an alcohol under Mitsunobu conditions in the presence of triphenylphosphine.

[0088] [ka]

[0089] In a variation of scheme 2a, compounds according to general formula I can be prepared using the route outlined in scheme 2b. Scheme 2b differs from scheme 2a in that moiety Y is the same as N, and therefore a protecting group strategy can be used and the synthetic steps can be performed in a different order. Compound 8, a pyrazole carboxylic acid protected as an ester (PG) as previously described, is alkylated with compound 6. This alkylation can be carried out in the presence of a base such as potassium carbonate, cesium carbonate, sodium carbonate or sodium hydride, in which case the leaving group is a halide or sulfonate ion. Alternatively, this alkylation can be carried out using an alcohol under Mitsunobu conditions in the presence of triphenylphosphine. In this case, alkylation can occur at the two nitrogens, and thus two regioisomers 9 and 10 can form. Compounds 9 and 10 can be separated at this stage or at a later stage in the synthesis by separation methods well known to those skilled in the art, for example by chromatography or by fractional crystallization. The protecting group of compound 9 can be removed by hydrolysis using standard methods previously described to give the corresponding acid 11. Compound 11 can be coupled with amine 2 to give compound 12 using suitable coupling methods previously described.

[0090] [ka]

[0091] Alternatively, compounds according to general formula I can be prepared using the route outlined in scheme 3. Pyrroles 17 can be formed in two steps, the first of which involves the reaction of the sodium salt of an alkylketoacetic acid 13, usually protected by a protecting group (PG) as previously described, with a chloroketone 14 in the presence of a base such as potassium carbonate to give compound 15, which in a typical second step reacts with an amine 16 in the presence of an acid such as, but not limited to, a sulfonic acid derivative, for example, p-toluenesulfonic acid, to give compound 17, which in a typical third step is subsequently hydrolyzed to the corresponding acid 18 using standard methods as previously described. In a typical fourth step, acid 18 can be coupled with amine 2 using suitable coupling methods as previously described to give compound 19.

[0092] [ka]

[0093] Compound 2, an amine, can be prepared using conventional synthetic methods, such as, but not limited to, the route outlined in Scheme 4. The nitrile of compound 20 is reduced with standard reducing agents, including, but not limited to, lithium aluminum hydride, sodium borohydride, sodium borohydride with nickel chloride, sodium borohydride with cobalt chloride, borane, and catalytic hydrogenation over a catalyst such as palladium, platinum, or Raney nickel. In some cases, for example, when the reducing agent is sodium borohydride or catalytic hydrogenation is used, it is possible to perform in situ protection of the resulting amino group, for example to a carbamate 21, such as tert-butoxycarbamate. This can help, for example, to allow purification of intermediate compound 21 by chromatography. The protecting group is then removed using standard conditions previously described to give compound 2.

[0094] [ka] EXAMPLES

[0095] The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:

[0096] [Table 1]

[0097] All reactions were carried out under a nitrogen atmosphere unless otherwise stated.

[0098] 1 1 H NMR spectra were recorded on a Bruker (400 MHz) spectrometer at room temperature using deuterated solvents as standards.

[0099] Molecular ions were obtained using LCMS performed using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient of 10% to 90% 0.1% HCOH / MeCN in 0.1% HCOH / H2O over 13 minutes at a flow rate of 1.5 mL / min, or using an Agilent, X-Select, acidic, 5-95% MeCN / water over 4 minutes. Data were collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionization interfaced with a Thermofinnigan Surveyor LC system.

[0100] Where products were purified by flash chromatography, "silica" refers to chromatographic grade silica gel 0.035-0.070 mm (220-440 mesh) (e.g., Merck silica gel 60), with column elution accelerated by applied nitrogen pressure up to 10 psi. Reverse-phase preparative HPLC purifications were performed using a Waters 2525 binary gradient pumping system with a Waters 2996 photodiode array detector, typically at a flow rate of 20 mL / min.

[0101] All solvents and commercial reagents were used as received.

[0102] Chemical names were generated using automated software such as the Autonom software provided as part of the ISIS Draw package from MDL Information Systems, or the Chemaxon software provided as a component of MarvinSketch or as a component of the IDBS E-WorkBook.

[0103] A. 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one 4-(Chloromethyl)benzyl alcohol (5.0 g, 31.93 mmol) was dissolved in acetone (150 mL). 2-Hydroxypyridine (3.64 g, 38.3 mmol) and potassium carbonate (13.24 g, 95.78 mmol) were added and the reaction mixture was stirred at 50° C. for 3 h, after which the solvent was removed in vacuo and the residue was dissolved in chloroform (100 mL). The solution was washed with water (30 mL), brine (30 mL), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica) (eluent 3% MeOH / 97% CHCl3) to give a white solid identified as 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (5.30 g, 24.62 mmol, 77% yield). [M+Na] + =238

[0104] B1. 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (8.45 g, 39.3 mmol), anhydrous DCM (80 mL) and triethylamine (7.66 ml, 55.0 mmol) were cooled in an ice bath. Methanesulfonyl chloride (3.95 ml, 51.0 mmol) was added and stirred in the ice bath for 15 min. The ice bath was removed and stirring was continued at room temperature overnight. The reaction mixture was partitioned between DCM (100 mL) and saturated aqueous NH4Cl (100 mL). The aqueous layer was extracted with additional DCM (2 x 50 mL) and the combined organics were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one (8.65 g, 36.6 mmol, 93% yield) as a pale yellow solid. [MH] + =234.1

[0105] B2. 1-(4-Bromomethyl-benzyl)-1H-pyridin-2-one 1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (2.30 g, 6.97 mmol) was dissolved in DCM (250 mL). To this solution was added phosphorus tribromide (5.78 g, 21.37 mmol). The reaction mixture was stirred at room temperature for 18 h and diluted with CHCl3 (250 mL). The filtrate was washed with saturated NaHCO3 (aq) (30 mL), water (30 mL), brine (30 mL), dried (Na2SO4) and the solvent evaporated in vacuo to give a white solid identified as 1-(4-bromomethyl-benzyl)-1H-pyridin-2-one (2.90 g, 10.43 mmol, 98%). [M+H] + =277.7

[0106] C. Methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (320 mg, 1.88 mmol; CAS number 318496-66-1 (synthesized according to the method described in WO2012 / 009009)) and 1-(4-(chloromethyl)benzyl)pyridin-2(1H)-one (527 mg, 2.26 mmol) in DMF (5 mL) was added potassium carbonate (519 mg, 3.76 mmol) and heated at 60° C. overnight. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (2×100 mL), dried over magnesium sulfate, filtered and reduced in vacuo. The crude product was purified by flash chromatography (40 g column, 0-100% EtOAc in isohexane) to give the two regioisomers. The second isomer off the column was collected to give methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (378 mg, 1.01 mmol, 53.7% yield) as a colorless gum. [MH] + =368.2

[0107] D. 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid To methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (3.77 g, 10.26 mmol) in THF (5 mL) and MeOH (5 mL) was added 2M NaOH solution (15.39 ml, 30.8 mmol) and stirred at room temperature overnight. 1M HCl (50 mL) was added and extracted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and reduced in vacuo to give 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (1.22 g, 3.45 mmol, 33.6% yield) as a white powder. [MH]+ =354.2

[0108] G. [4-(4-methyl-pyrazol-1-ylmethyl)-phenyl]-methanol 4-(Chloromethyl)benzyl alcohol (5.47 g, 34.9 mmol) was dissolved in acetone (50 mL). 4-Methylpyrazole (2.86 g, 34.9 mmol) and potassium carbonate (5.07 g, 36.7 mmol) were added and the reaction mixture was stirred at room temperature for 18 h and at 60° C. for 30 h, after which time the solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (30 mL), brine (30 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica) (eluent gradient 10 to 80% EtOAc in iso-hexane) and the combined fractions were evaporated in vacuo to give a white solid identified as [4-(4-methyl-pyrazol-1-ylmethyl)-phenyl]-methanol (3.94 g, 18.90 mmol, 54% yield). [MH] + =203

[0109] H. 1-(4-chloromethyl-benzyl)-4-methyl-1H-pyrazole [4-(4-Methyl-pyrazol-1-ylmethyl)-phenyl]-methanol (2.03 g, 10.04 mmol) and triethylamine (1.13 g, 11.54 mmol) were dissolved in DCM (40 mL). To this solution was added methanesulfonyl chloride (1.26 g, 11.04 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 h and diluted with CHCl3 (250 mL). The mixture was washed with saturated aqueous NH4Cl (30 mL), water (30 mL), brine (30 mL), dried (Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by flash chromatography (silica) (eluent gradient of 0 to 60% EtOAc in iso-hexane) and the fractions combined and the solvent evaporated in vacuo to give a white solid identified as 1-(4-chloromethyl-benzyl)-4-methyl-1H-pyrazole (1.49 g, 6.62 mmol, 60% yield). [MH] + =221, 223

[0110] M. 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester 1-(4-Bromomethyl-benzyl)-1H-pyridin-2-one (850 mg, 3.06 mmol) was dissolved in DMF (10 mL). 5-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (522 mg, 3.36 mmol) and cesium carbonate (1.99 g, 6.11 mmol) were added and the reaction mixture was stirred at 50° C. for 18 h, after which time the reaction mixture was diluted with EtOAc (100 mL). The solution was washed with water (30 mL), brine (30 mL), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica) (eluent gradient from 30% petroleum ether / 70% EtOAc to 100% EtOAc) to give two regioisomers. The second isomer that exited the column was collected to give 3-amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester (480 mg, 1.36 mmol, 45% yield) as a white solid. [MH] + =353.1

[0111] N. 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester (480 mg, 1.36 mmol) was dissolved in THF (50 mL) and water (5 mL). Lithium hydroxide (163 mg, 6.81 mmol) was added. The reaction mixture was stirred at 50° C. for 18 h, after which time the volatiles were removed in vacuo and the aqueous residue was washed with CHCl3 (150 mL). The aqueous layer was acidified to pH 7 with 1M HCl and extracted with CHCl3 (3×50 mL). The combined extracts were washed with water (30 mL), brine (30 mL), dried (Na2SO4) and the solvent evaporated in vacuo to give a white solid identified as 3-amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (370 mg, 1.14 mmol, 84% yield). [MH] + =325.2

[0112] P. (2-Fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester 2-Fluoro-3-methoxybenzonitrile (500 mg, 3.31 mmol) was dissolved in methanol (40 mL). The solution was cooled to 0° C. Nickel(II) chloride hexahydrate (79 mg, 0.33 mmol) and di-tert-butyl dicarbonate (1.44 g, 6.62 mmol) were added in small portions, followed by sodium borohydride (876 mg, 23.16 mmol). The reaction mixture was stirred, warmed to room temperature, and stirred for 3 days. MeOH was removed in vacuo. The residue was dissolved in CHCl3 (150 mL), washed with saturated NaHCO3 (aq) (50 mL), water (50 mL), brine (50 mL), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (silica) (eluent: 20% EtOAc / 80% petroleum ether) to give a white solid identified as (2-fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester (540 mg, 0.2 mmol, 64% yield). [MH] +=255.8

[0113] Q. 2-Fluoro-3-methoxy-benzylamine hydrochloride (2-Fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester (600 mg, 2.35 mmol) was dissolved in 4 M HCl in dioxane (40 mL). After 2 h at room temperature, the solvent was removed in vacuo to give a pale yellow solid identified as 2-fluoro-3-methoxy-benzylamine hydrochloride (414 mg, 2.17 mmol, 92% yield). [MH] + =155.9

[0114] T. 1-tert-Butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate To 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester (250 mg, 1.61 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (352 mg, 1.61 mmol) and diisopropylethylamine (702 μL, 521 mg, 4.03 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM, separated with water, washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography afforded 1-tert-butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate as a white solid (122 mg, 30% yield). [MH] + =256.2

[0115] U. Ethyl 3-acetamido-1H-pyrazole-4-carboxylate A mixture of 1-tert-butyl 4-ethyl 3-aminopyrazole-1,4-dicarboxylate and acetyl chloride was stirred at 0° C. and then heated to reflux for 2 h. Excess acetyl chloride was removed in vacuo. Water was added and the mixture was stirred at room temperature for 18 h. The precipitate was collected by vacuum filtration and dried to give ethyl 3-acetamido-1H-pyrazole-4-carboxylate as a white solid (46 mg). The aqueous filtrate was extracted with DCM (4×15 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a further crop of ethyl 3-acetamido-1H-pyrazole-4-carboxylate (48 mg) (total yield 94 mg, 99%). [MH] + =197.8

[0116] V. 5-Dimethylamino-1H-pyrazole-4-carboxylic acid ester 5-Amino-1H-pyrazole-4-carboxylic acid ester (1.0 g, 6.45 mmol) was dissolved in methanol (200 mL) and the solution was purged with nitrogen. Formaldehyde (37 wt%, 4.5 mL, 21.18 mmol) was added followed by 10% Pd / C (1.0 g). The reaction mixture was shaken in a Parr hydrogenator at 10 psi for 18 hours. The reaction mixture was filtered through Celite to remove the catalyst and the residue was washed with methanol (200 mL) and water (20 mL). The combined filtrate was evaporated in vacuo. The crude residue was triturated with methanol / diethyl ether and the filtrate was concentrated to give a colorless oil identified as the title compound (1.1 g, 6.00 mmol, 93% yield). [MH] + =183.7

[0117] [Example 1] N-(3,5-dimethoxybenzyl)-3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide

[0118] [ka]

[0119] To a mixture of 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (80 mg, 0.226 mmol), (3,5-dimethoxyphenyl)methanamine (45.4 mg, 0.272 mmol) and HATU (95 mg, 0.249 mmol) in anhydrous DCM (1.5 mL) and anhydrous DMF (0.3 mL) was added N,N-diisopropylethylamine (99 μl, 0.566 mmol) and the mixture was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue was purified by flash chromatography loaded into DCM and eluted with a gradient of 1% to 10% MeOH (containing 0.3% NH3) / DCM to give a gum. This was dissolved in acetonitrile (0.5 mL) and water (3 mL) was added, causing a precipitate to form which was sonicated, then filtered and dried under vacuum to give N-(3,5-dimethoxybenzyl)-3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide (76 mg, 0.150 mmol, 66.1% yield) as a sticky pale yellow solid. NMR (d6-DMSO) δ: 3.20 (3H, s), 3.71 (6H, s), 4.32 (2H, d, J = 5.8Hz), 4.53 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J = 6.7, 1.4Hz), 6.37 (1H, t, J = 2.3Hz), 6.40 (1H, dd, J = 9.2, 1.4Hz), 6.44 (2H, d, J = 2.3Hz), 7.20-7.29 (4H, m), 7.41 (1H, ddd, J = 9.1, 6.6, 2.1Hz), 7.76 (1H, dd, J = 6.8, 2.1Hz), 8.24 (1H, s), 8.32 (1H, t, J = 5.9Hz). [MH] + =503.3

[0120] [Example 2] 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide

[0121] [ka]

[0122] 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (75 mg, 0.23 mmol) was dissolved in DCM (20 mL) and DMF (1 ml). The solution was cooled to 0° C. 2-Fluoro-3-methoxy-benzylamine hydrochloride (53 mg, 0.28 mmol) was added, followed by HOBt (34 mg, 0.25 mmol) and triethylamine (70 mg, 0.69 mmol). Then, water-soluble carbodiimide (53 mg, 0.28 mmol) was added. The reaction mixture was stirred, allowed to warm to room temperature and stirred for 3 days. The mixture was diluted with chloroform (200 mL), washed with NaHCO3 (aq) (50 mL), water (50 mL) and brine (50 mL), dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica) (eluent 4% MeOH / 96% CHCl3) to give a white solid identified as 3-amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide (92 mg, 0.20 mmol, 86% yield). [MH] + =462.2 1 H NMR: (d6-DMSO) δ: 3.82 (3H, s), 4.36 (2H, d, J = 5.7Hz), 5.04 (2H, s), 5.07 (2H, s), 5.38 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, t, J = 0.7Hz), 6.86-6.87 (1H, m), 7.04-7.07 (2H, m), 7.20 (2H, d, J = 8.1Hz), 7.26 (2H, d, J = 8.1Hz), 7.39-7.43 (1H, m), 7.76 (1H, dd, J = 6.6, 1.6Hz), 8.00 (1H, s), 8.27 (1H, t, J = 5.9Hz).

[0123] [Example 3] 1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide

[0124] [ka] (7-Chloro-quinolin-3-yl)-methanol 7-Chloroquinoline-3-carboxylic acid (500 mg, 2.4 mmol) was dissolved in anhydrous THF (20 mL) and cooled to -20°C. To this solution was added triethylamine (1.0 mL, 7.23 mmol) and isobutyl chloroformate (0.38 mL, 2.9 mmol). The reaction mixture was stirred at -20°C for 20 min and then poured into a solution of sodium borohydride (731 mg, 19 mmol) in water (2 mL) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was diluted with EtOAc (50 mL) and the layers were separated. The organic layer was washed with water (20 mL), brine (20 mL), dried (Na2SO4), filtered, and the solvent was evaporated in vacuo to give a yellow solid. This solid was purified by chromatography on silica eluting with EtOAc / petroleum ether to give (7-chloro-quinolin-3-yl)-methanol as an off-white solid (134 mg, 29% yield). [MH] + =194.1

[0125] 3-Bromomethyl-7-chloro-quinoline (7-Chloro-quinolin-3-yl)-methanol (134 mg, 0.692 mmol) was dissolved in DCM (5 mL). PBr3 (65 μL, 0.692 mmol) was added and the reaction was stirred at room temperature for 3 h. Upon completion, the reaction mixture was quenched with dilute NaHCO3 (aq) (10 mL). The layers were separated and the organics were washed with water (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid (78 mg, 44% yield) identified as 3-bromomethyl-7-chloro-quinoline (78 mg, 44% yield). [MH] + =257.6

[0126] 1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (51 mg, 0.304 mmol, CAS number 318496-66-1 (synthesized according to the method described in WO2012 / 009009)) was dissolved in DMF (2 mL) and treated with potassium carbonate (84 mg, 0.608 mmol) and 3-bromomethyl-7-chloro-quinoline (78 mg, 0.304 mmol). The reaction was stirred at room temperature overnight. EtOAc (60 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with water (3×10 mL), brine (10 mL), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified by chromatography eluting with EtOAc / petroleum ether to give two isomeric products. The faster migrating product was identified as the undesired regioisomer. The slower running product gave a yellow oil and was identified as 1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (53 mg, 50% yield). [MH] + =345.8

[0127] 1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid To 1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (53 mg, 0.153 mmol) in ethanol (10 mL) was added sodium hydroxide (61 mg, 1.53 mmol) and the reaction was heated to vigorous reflux for 4.5 h. The mixture was cooled and concentrated in vacuo. The residue was diluted with water (5 mL), adjusted to pH 3.6 with 2 M HCl, and extracted with 90% chlorofrom / 10% iso-propyl alcohol (6×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give 1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid as a pale yellow solid (50 mg, 98% yield). [MH] + =332

[0128] 1-(7-Chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide At 0°C, 1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid (25 mg, 0.075 mmol) was dissolved in DCM (5 mL). To this solution was added triethylamine (52 μL, 0.377 mmol), HOBt (12 mg, 0.09 mmol) and water-soluble carbodiimide (20 mg, 0.106 mmol). After 15 min, 2-fluoro-3-methoxy-benzylamine hydrochloride (14 mg, 0.075 mmol) was added and the reaction was allowed to warm to room temperature and stirred over the weekend. The reaction was diluted with CHCl3 (50 ml) and washed with saturated aqueous NaHCO3 (20 ml), followed by water (20 mL) and brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with 6% methanol / 94% DCM to give a white solid identified as 1-(7-chloro-quinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide (16 mg, 45% yield). [MH] + =469 1H NMR (DMSO): 3.20 (3H, s), 3.82 (3H, s), 4.41 (2H, d, J = 5.8 Hz), 4.54 (2H, s), 5.57 (2H, s), 6.87-6.91 (1H, m), 7.03-7.09 (2H, m), 7.67 (1H, dd, J = 8.8, 2.1 Hz), 8.07 (1H, d, J = 8.8 Hz), 8.10 (1H, d, J = 1.9 Hz), 8.30 (1H, d, J = 1.7 Hz), 8.37 (1H, s), 8.39 (1H, t, J = 5.8 Hz), 8.92 (1H, d, J = 2.2Hz)

[0129] [Example 41] 3-Fluoro-4-methoxy-pyridine-2-carbonitrile To a large microwave vial was added copper cyano (1.304 g, 14.56 mmol) to a solution of 2-bromo-3-fluoro-4-methoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The reaction vial was sealed and heated to 100° C. for 16 h. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). Additional water (40 mL) and EtOAc (2×50 mL) were required when sonicating the thick suspension to break up the precipitated solid. The combined layers were filtered through a plug of Celite and the isolated organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to give a pale green solid identified as the desired compound, 3-fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol, 12% yield).

[0130] (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester 3-Fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.578 mmol) was dissolved in anhydrous methanol (10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added followed by di-tert-butyl dicarbonate (255 mg, 1.157 mmol). The resulting pale green solution was cooled to -5°C in an ice-salt bath and then sodium borohydride (153 mg, 4.05 mmol) was added in small portions while maintaining the reaction temperature at about 0°C. The dark brown solution was stirred at 0°C, slowly warmed to room temperature and then stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness at 40°C to give a black residue which was diluted with DCM (10 mL) and washed with sodium bicarbonate (10 mL). An emulsion was formed and the organics were separated and concentrated using a phase separation cartridge. The crude liquid was purified by chromatography eluting with EtOAc / iso-hexane to give the title compound, (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester, as a clear yellow oil (108 mg, 62% yield). [MH] + =257

[0131] C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (108 mg, 0.358 mmol) was dissolved in iso-propyl alcohol (1 mL), then HCl (6N in iso-propyl alcohol) (1 mL, 0.578 mmol) was added at room temperature and stirred for 2 hours at 40° C. The reaction mixture was concentrated under reduced pressure, then triturated with ether, sonicated, and decanted to give a cream-colored solid (75 mg, 55% yield) identified as C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride. [MH] + =157

[0132] 3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (75 mg, 0.212 mmol), C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride (49 mg, 0.212 mmol) and HATU (89 mg, 0.233 mmol) were suspended in anhydrous DCM (3 mL) to which triethylamine (177 μL, 1.270 mmol) was added, sonicated and then stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the resulting residue was quenched with ammonium chloride solution (5 mL). The resulting off-white solid was sonicated, filtered under reduced pressure and washed with water and then placed in a vacuum oven at 40° C. overnight. The crude material was purified by chromatography eluting with (1% ammonia-methanol) / DCM to give 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide as a white solid (67 mg, 64% yield). [MH] + =492 NMR (d 6 -DMSO) δ: 3.25 (3H, s), 3.92 (3H, s), 4.46-4.57 (4H, m), 5.07 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J = 1.4, 6.7Hz), 6.39 (1H, ddd, J = 0.7, 1.4, 9.2Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J = 2.1, 6.6, 8.9Hz), 7.75 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J = 5.4Hz)

[0133] [Example 77] 6-Bromo-2-fluoro-3-methoxy-benzoic acid To a suspension of 2-fluoro-3-methoxybenzoic acid (10 g, 58.8 mmol) in acetic acid (50 mL) and water (50 mL) was added bromine (6.06 mL, 118 mmol) dropwise at room temperature. The reaction was then heated to 60° C. for 1 hour. The reaction was cooled to room temperature and the white precipitate was filtered. The solid was washed with water (200 mL) and iso-hexane (50 mL) to give 6-bromo-2-fluoro-3-methoxy-benzoic acid as a white solid (12.098 g, 82% yield). [MH] + =249 / 251

[0134] (6-Bromo-2-fluoro-3-methoxy-phenyl)-methanol To a stirred solution of 6-bromo-2-fluoro-3-methoxy-benzoic acid (4.13 g, 16.58 mmol) in THF (20 mL) was added 4-methylmorpholine (1.914 mL, 17.41 mmol), followed by isobutyl chloroformate (2.15 mL, 16.58 mmol). After 1 h, the reaction mixture was filtered to remove any salts formed and the solid was washed with additional THF (10 mL). The filtrate and washings were combined and cooled to 0° C. in an ice bath, then NaBH4 (0.659 g, 17.41 mmol) in cold water (10 mL) was added in one portion (gas evolution), then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched by careful addition of 1 M HCl (30 mL) until an acidic pH was obtained. The product was extracted into diethyl ether (150 mL). The organic layer was then washed with 2M NaOH (2×100 mL) to remove the starting carboxylic acid, then acidified by washing with 1M HCl (100 mL) followed by brine (100 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The crude product was purified by chromatography eluting with 0-50% EtOAc / iso-hexane to give (6-bromo-2-fluoro-3-methoxy-phenyl)-methanol as a colorless oil (1.37 g, 50% yield). [MH] + =217 / 219

[0135] 1-Bromo-2-chloromethyl-3-fluoro-4-methoxy-benzene A solution of (6-bromo-2-fluoro-3-methoxy-phenyl)-methanol (500 mg, 2.127 mmol) in anhydrous DCM (4 mL) was treated with triethylamine (415 μL, 2.98 mmol) followed by methanesulfonyl chloride (214 μL, 2.77 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between DCM (50 mL) and saturated aqueous NH4Cl (40 mL). The organic layer was collected and the aqueous layer was further extracted with DCM (40 mL). The combined organics were washed with water (40 mL), brine (40 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography eluting with a gradient of 0 to 30% EtOAc / iso-hexane to give 1-bromo-2-chloromethyl-3-fluoro-4-methoxy-benzene (468 mg, 86% yield) as a white solid.

[0136] 2-(6-Bromo-2-fluoro-3-methoxy-benzyl)-isoindole-1,3-dione To a solution of 1-bromo-2-chloromethyl-3-fluoro-4-methoxy-benzene (460 mg, 1.815 mmol) in anhydrous DMF (5 mL) was added potassium phthalimide (403 mg, 2.178 mmol) and the mixture was heated at 90° C. overnight. The mixture was diluted with EtOAc (75 mL), washed with water (3×35 mL), brine (35 mL), dried (Na2SO4), and concentrated to a yellow solid. The crude material was purified by flash chromatography eluting with a gradient of 0 to 50% EtOAc / iso-hexane. The desired product, 2-(6-bromo-2-fluoro-3-methoxy-benzyl)-isoindole-1,3-dione, was isolated as white needles (372 mg, 56% yield). [MH] + =364.0 / 366.0

[0137] 6-Bromo-2-fluoro-3-methoxy-benzylamine A suspension of 2-(6-bromo-2-fluoro-3-methoxy-benzyl)-isoindole-1,3-dione (0.368 g, 1.011 mmol) in methanol (7.5 mL) was treated with hydrazine hydrate (0.064 mL, 1.314 mmol) and the reaction mixture was heated to reflux for 5 h. The crude mixture was directly loaded onto an SCX column (8 g), washed with MeOH, and eluted with 1% NH3 / MeOH to give 6-bromo-2-fluoro-3-methoxy-benzylamine (204 mg, 85% yield) as a yellow oil. [MH] + =233.9 / 235.9

[0138] 3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 6-bromo-2-fluoro-3-methoxy-benzylamide A 25 mL flask was charged with 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (130 mg, 0.368 mmol), (6-bromo-2-fluoro-3-methoxy-benzylamine (86 mg, 0.368 mmol), HATU (154 mg, 0.405 mmol), anhydrous DCM (3 mL) and anhydrous DMF (0.5 mL). N,N-disopropylethylamine (160 μL, 0.920 mmol) was added and the mixture was allowed to stand at ambient temperature. The reaction was concentrated in vacuo, redissolved in MeOH (4 mL), then washed with MeOH and purified by SCX eluting with 1% NH3 / MeOH. The residue was further purified by chromatography eluting with a gradient of 0 to 10% MeOH (containing 0.3% NH3) / DCM to give 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 6-bromo-2-fluoro-3-methoxy-benzylamide (191 mg, 89% yield) as a white foam. [MH] + =569.2 / 571.2

[0139] 3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide To a solution of dicyanozinc (24.13 mg, 0.205 mmol) and 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 6-bromo-2-fluoro-3-methoxy-benzylamide (90 mg, 0.158 mmol) in degassed dimethylacetamide (1.2 mL) was added tetrakis(triphenylphosphine)palladium(0) (18.26 mg, 0.016 mmol) and the mixture was heated to 110° C. overnight. The mixture was purified by chromatography eluting with a gradient of 0 to 10% (0.3% NH3 / MeOH) / DCM to give 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide as a pale yellow foam (21 mg, 25% yield). [MH] + =516.3 1 H NMR (d 6 -DMSO) δ: 3.21 (3H, s), 3.92 (3H, s), 4.47-4.55 (4H, m), 5.06 (2H, s), 5.27 (2H, s), 6.21 (1H, td, J = 6.7, 1.4Hz), 6.39 (1H, d, J = 9.1Hz), 7.17-7.31 (5H, m), 7.40 (1H, ddd, J = 8.9, 6.6, 2.1Hz), 7.67 (1H, dd, J = 8.6, 1.5Hz), 7.75 (1H, dd, J = 6.8, 2.1Hz), 8.20 (1H, s), 8.40 (1H, t, J = 5.2Hz)

[0140] [Example 83] 2-Chloro-3-fluoro-6-methoxy-benzaldehyde Sodium hydride (1.318 g, 33.0 mmol) was added slowly to a flask containing ice-salt cooled methanol (8 mL, 198 mmol). Once the addition was complete, the cooling bath was removed and then warmed to room temperature. In a second vessel (250 mL flask), 2-chloro-3,6-difluorobenzaldehyde (5 g, 27.5 mmol) was dissolved in a mixture of anhydrous methanol (60 mL, 1483 mmol) and THF (25 mL, 305 mmol) and warmed to 60° C. While at 60° C., sodium methoxide solution was added slowly to the reaction mixture. Once the addition was complete, the reaction mixture was heated to 60° C. overnight. The solvent was removed under reduced pressure to give a pale yellow solid, which was quenched with water (100 mL), sonicated, and then stirred for 30 min. The resulting yellow solid was filtered and washed with water, then dried under reduced pressure and placed in a vacuum oven overnight at 40° C. The crude material was purified by chromatography eluting with EtOAc / iso-hexane to give the desired compound 2-chloro-3-fluoro-6-methoxy-benzaldehyde as an off-white solid (3.19 g, 61% yield). [MH] + =189 / 191

[0141] 2-Chloro-3-difluoromethyl-1-fluoro-4-methoxy-benzene 2-Chloro-3-fluoro-6-methoxy-benzaldehyde (2 g, 10.61 mmol) was dissolved in anhydrous DCM (30 mL, 466 mmol) under a nitrogen filled balloon and cooled in a salt-ice bath. To this solution was added diethylaminosulfur trifluoride (4.20 mL, 31.8 mmol) dropwise to form a yellow solution. The reaction was stirred at 0° C. for 5 min, then the cooling bath was removed and the reaction was allowed to warm to room temperature overnight. The reaction mixture was slowly quenched into saturated sodium bicarbonate (100 mL) and the organic layer was separated, washed with brine (100 mL) and dried using a phase separation cartridge. The solvent was removed under reduced pressure to give an orange oil which was purified by chromatography eluting with EtOAc / iso-hexane. 2-Chloro-3-difluoromethyl-1-fluoro-4-methoxy-benzene (1.0 g, 43% yield) was isolated as a pale yellow oil which solidified on standing.

[0142] 2-Difluoromethyl-6-fluoro-3-methoxy-benzonitrile 2-Chloro-3-difluoromethyl-1-fluoro-4-methoxy-benzene (1 g, 4.75 mmol) was dissolved in anhydrous dimethylacetamide (7 mL, 74.7 mmol) and dicyanozinc (0.558 g, 4.75 mmol) was added. Nitrogen was bubbled through the reaction mixture for 20 min, and then tris(dibenzylideneacetone)dipalladium(0) (0.087 g, 0.095 mmol) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.139 g, 0.190 mmol) were added. Under nitrogen atmosphere, the reaction mixture was heated to 150° C. overnight. The reaction mixture was quenched into water (100 mL) and then extracted with EtOAc (3×200 mL). The combined organics were washed with brine (3 x 200 mL), dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to give a dark brown oil. The crude product was purified by chromatography eluting with EtOAc / iso-hexane to give 2-difluoromethyl-6-fluoro-3-methoxy-benzonitrile (182 mg, 17% yield) as a brown solid. [MH] + =202.1

[0143] (2-Difluoromethyl-6-fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester 2-(Difluoromethyl)-6-fluoro-3-methoxy-benzonitrile (182 mg, 0.778 mmol) was dissolved in anhydrous methanol (5 mL, 124 mmol) to which nickel chloride hexahydrate (19 mg, 0.078 mmol) was added followed by di-tert-butyl dicarbonate (343 mg, 1.556 mmol). The resulting pale green solution was cooled to -5°C in an ice-salt bath and then sodium borohydride (206 mg, 5.45 mmol) was added in small portions while maintaining the reaction temperature at about 0°C. The dark brown solution was stirred at 0°C and allowed to warm slowly to room temperature overnight. The solvent was removed under reduced pressure and then partitioned between DCM (10 mL) and water (10 mL). The aqueous layer was re-extracted with DCM (2 x 10 mL). The combined organics were washed with brine (10 mL), dried using a phase separation cartridge and concentrated in vacuo. The crude product was purified by chromatography eluting with EtOAc / iso-hexane to give (2-difluoromethyl-6-fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester as a waxy white solid (158 mg, 63% yield). [MNa] + =328

[0144] 2-Difluoromethyl-6-fluoro-3-methoxy-benzylamine hydrochloride (2-Difluoromethyl-6-fluoro-3-methoxy-benzyl)-carbamic acid tert-butyl ester (158 mg, 0.492 mmol) was dissolved in iso-propyl alcohol (1 mL), then HCl (6N in iso-propyl alcohol) (1 mL, 0.778 mmol) was added and stirred for 1 h at 40° C. The off-white precipitate that formed was collected by suction filtration and washed with iso-propyl alcohol (1 mL) to give the desired product, 2-difluoromethyl-6-fluoro-3-methoxy-benzylamine hydrochloride, as an off-white solid (43 mg, 22% yield). [MH] + =206

[0145] 3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-difluoromethyl-6-fluoro-3-methoxy-benzylamide To a suspension of 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (58 mg, 0.162 mmol), 2-difluoromethyl-6-fluoro-3-methoxy-benzylamine hydrochloride (40.2 mg, 0.163 mmol) and HATU (68.3 mg, 0.180 mmol) in anhydrous DCM (3 mL) was added triethylamine (91 μL, 0.653 mmol), sonicated, and then stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was quenched with ammonium chloride solution (5 mL) to give a light brown solid that was stirred at room temperature over the weekend. The solid was filtered under reduced pressure, washed with water, dried under reduced pressure, and placed in a desiccator at 50° C. for 3 h. The desired product, 3-ethoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-difluoromethyl-6-fluoro-3-methoxy-benzylamide (74 mg, 83% yield), was isolated as a free-flowing cream solid. [MH] + =541.2 NMR (d 6 -DMSO) δ 3.12 (3H, s), 3.83 (3H, s), 4.43 (2H, s), 4.52-4.59 (2H, m), 5.05 (2H, s), 5.25 (2H, s), 6.21 (1H, td, J = 1.4, 6.7Hz), 6.39 (1H, dt, J = 1.0, 9.2Hz), 7.15-7.44 (8H, m), 7.75 (1H, ddd, J = 0.7, 2.1, 6.8Hz), 8.08 (1H, t, J = 4.9Hz), 8.22 (1H, s)

[0146] [Example 126] 5-Bromomethyl-2-fluoro-pyridine 2-fuoro-5-methylpyridine (5.0 g, 45 mmol) was dissolved in 1,2-dichloroethane (120 mL). To this solution was added N-bromosuccinimide (9.61 g, 54 mmol) and azobisisobutyronitrile (739 mg, 4.5 mmol). The reaction was stirred at reflux (95° C.) for 5 hours, and then the reaction was cooled to room temperature. The reaction mixture was diluted with CHCl3 (50 mL), washed with saturated NaHCO3 (1×20 mL), water (1×20 mL), then brine (1×20 mL), dried (Na2SO4), filtered through PS paper, and the solvent was evaporated in vacuum. The residue was purified by chromatography (silica) eluting with 10% EtOAc, 90% petroleum ether to give a colourless oil identified as 5-bromomethyl-2-fluoro-pyridine (5.9 g, 69% yield). [MH] + =191.76 NMR (CDCl3): 4.46 (2H, s), 6.93 (1H, dd, J = 8.4, 3.0 Hz), 7.84 (1H, td, J = 7.8, 2.6 Hz), 8.23 ​​(1H, d, J = 2.2 Hz)

[0147] 1-(6-Fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester Ethyl 3-trifluoromethyl-1H-pyrazole-4-carboxylate (1.57 g, 7.53 mmol) was dissolved in DMF (20 mL) and 5-bromomethyl-2-fluoro-pyridine (1.3 g, 6.84 mmol) and cesium carbonate (6.69 g, 20.53 mmol) were added. The reaction mixture was stirred at 50° C. for 18 h, after which time the reaction mixture was diluted with EtOAc (100 mL) and the solution was washed with water (1×30 mL), brine (1×30 mL), dried (Na2SO4), filtered through PS paper and the solvent evaporated under vacuum. The residue was purified by chromatography (silica) eluted with 85% petroleum ether, 15% EtOAc to give a white foamy solid (1.26 g, 58% yield) identified as 1-(6-fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester. [MMeCN] + =358.75

[0148] 1-(6-fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 1-(6-Fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.26 g, 3.97 mmol) was dissolved in THF (50 mL) and water (5 mL), then lithium hydroxide (476 mg, 19.86 mmol) was added. The reaction mixture was stirred at 50° C. for 18 h, after which time the solvent was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). The aqueous layer was extracted, acidified to pH 2 with 1M HCl, and extracted with CHCl3 (3×50 mL). The combined extracts were washed with water (1×30 mL), then brine (1×30 mL), dried (Na2SO4), filtered through PS paper, and the solvent was evaporated in vacuo. The residue was purified by chromatography (silica) eluted with 3% MeOH, 97% CHCl3 to give a colorless oil identified as 1-(6-fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (946 mg, 82% yield). [MH] + =289.82

[0149] 1-(6-Pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 1-(6-fluoro-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (300 mg, 1.04 mmol) was dissolved in dioxane (25 mL) and pyrrolidine (2 mL) and the reaction mixture was stirred at 80° C. for 18 hours. Upon completion, the reaction mixture was diluted with EtOAc (100 mL) and the solution was washed with water (1×30 mL), brine (1×30 mL), dried (Na2SO4), filtered through PS paper and the solvent evaporated under vacuum. The residue was purified by chromatography eluting with 1% AcOH, 9% MeOH, 90% CHCl3 to give a white foamy solid (267 mg, 76% yield) identified as 1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid. [MH] + =340.72

[0150] 1-(6-Pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide 2-Fluoro-3-methoxy-benzylamine hydrochloride (56 mg, 0.294 mmol) and 1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.294 mmol) were combined and dissolved in DCM (10 mL) at 0° C. To this solution was added HOBt (48 mg, 0.353 mmol), triethylamine (205 μL, 1.469 mmol) and water-soluble carbodiimide (79 mg, 0.411 mmol). The reaction was allowed to warm to room temperature and stirred for 3 days. The reaction was diluted with CHCl3 (50 mL) and saturated aqueous NaHCO3 (20 mL) was added. The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography eluting with MeOH / DCM to give the desired product, 1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide, as a white solid (95 mg, 68% yield). [MH] + =478.0 1 H NMR (DMSO) δ: 1.90-1.94 (4H,m), 3.31-3.37 (4H, m), 3.82 (3H, s), 4.39 (2H, d, J = 5.6Hz), 5.26 (2H, s), 6.44 (1H, d, J = 8.6Hz), 6.85-6.90 (1H, m), 7.03-7.10 (2H, m), 7.50 (1H, dd, J = 8.8, 2.4Hz), 8.14 (1H, d, J = 2.3Hz), 8.36 (1H, d, J = 0.6Hz), 8.74 (1H, t, J = 5.8Hz)

[0151] [Table 2] TIFF2025000918000021.tif117159

[0152] [Table 3]

[0153]

Table 4

[0154]

Table 5

[0155]

Table 6

[0156]

Table 7

[0157]

Table 8

[0158]

Table 9

[0159]

Table 10

[0160]

Table 11

[0161] [Table 12]

[0162] [Table 13] TIFF2025000918000039.tif224166TIFF2025000918000040.tif236167TIFF2025000918000041.tif236164TIFF2025000918000042.tif23716 7TIFF2025000918000043.tif237167TIFF2025000918000044.tif231166TIFF2025000918000045.tif239167TIFF2025000918000046.tif93166

[0163] [Table 14] TIFF2025000918000048.tif228165TIFF2025000918000049.tif227169TIFF202 5000918000050.tif237164TIFF2025000918000051.tif229166TIFF20250009180 00052.tif227167TIFF2025000918000053.tif233167TIFF2025000918000054.t if234165TIFF2025000918000055.tif221167TIFF2025000918000056.tif153164

[0164] biological methods The ability of the compounds of formula (I) to inhibit plasma kallikrein may be determined using the following biological assay.

[0165] IC for plasma kallikrein 50 Decision In vitro plasma kallikrein inhibitory activity was determined using published standard methods (see, e.g., Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol. 1992, 43, 1209; Sturzebecher et al., Biol. Chem. Hoppe-Seyler 1992, 373, 1025). Human plasma kallikrein (Protogen) was incubated at 25°C with the fluorogenic substrate H-DPro-Phe-Arg-AFC and various concentrations of test compounds. Residual enzyme activity (initial reaction rate) was determined by measuring the change in optical absorbance at 410 nm and the IC of the test compounds was calculated. 50 value was determined.

[0166] The data obtained from these assays are presented in Table 14.

[0167] Selected compounds were further screened for inhibitory activity against the related enzyme, KLK1. The ability of the compounds of formula (I) to inhibit KLK1 can be determined using the following biological assay.

[0168] KLK1 IC 50 Decision In vitro KLK1 inhibitory activity was determined using published standard methods (see, e.g., Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol. 1992, 43, 1209; Sturzebecher et al., Biol. Chem. Hoppe-Seyler 1992, 373, 1025). Human KLK1 (Callbiochem) was incubated with the fluorogenic substrate H-DVal-Leu-Arg-AFC and various concentrations of test compounds at 25°C. Residual enzyme activity (initial reaction rate) was determined by measuring the change in optical absorbance at 410 nm and the IC of the test compounds was calculated. 50 value was determined.

[0169] The data obtained from this assay is presented in Table 14.

[0170] Selected compounds were further screened for inhibitory activity against the related enzyme, FXIa. The ability of compounds of formula (I) to inhibit FXIa can be determined using the following biological assay.

[0171] Determination of % inhibition of FXIa In vitro FXIa inhibitory activity was determined using standard published methods (see, e.g., Johansen et al., Int. J. Tiss. Reac. 1986, 8, 185; Shori et al., Biochem. Pharmacol. 1992, 43, 1209; Sturzebecher et al., Biol. Chem. Hoppe-Seyler 1992, 373, 1025). Human FXIa (Enzyme Research Laboratories) was incubated with the fluorogenic substrate Z-Gly-Pro-Arg-AFC and 40 μM of test compound at 25° C. Residual enzyme activity (initial rate of reaction) was determined by measuring the change in optical absorbance at 410 nm.

[0172] The data obtained from this assay is presented in Table 14.

[0173] [Table 15] TIFF2025000918000058.tif239159TIFF2025000918000059.tif240158TIFF2025000918 000060.tif234159TIFF2025000918000061.tif241160TIFF2025000918000062.tif35160

[0174] Pharmacokinetics Pharmacokinetic studies of the compounds in Table 15 were conducted to evaluate the pharmacokinetics following a single oral dose in male Sprague-Dawley rats. Two rats were given a single oral dose of 5mL / kg of test compound in vehicle at a nominal composition of 2mg / mL (10mg / kg). After dosing, blood samples were collected over a 24 hour period. Sample times were 5 minutes, 15 minutes, and 30 minutes, followed by 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 12 hours. After collection, blood samples were centrifuged and plasma fractions were analyzed for test compound concentration by LCMS. Oral exposure data obtained from these studies are presented below.

[0175] [Table 16]

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, B is an alkyl ｂ , alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ３ and C.F. ３ and wherein the phenyl is substituted by 1 to 4 substituents selected from or selected from benzothiophenyl, benzofuranyl, benzomorpholinyl, and a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, the 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic, and the benzothiophenyl, benzofuranyl, benzomorpholinyl, or 5- or 6-membered heterocyclic ring is selected from alkyl, ｂ , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ３ and C.F. ３ and is substituted with 1 to 3 substituents selected from W is C; X, Y and Z are independently selected from C, N, O and S, such that the ring containing W, X, Y and Z is a 5-membered aromatic heterocycle; R5 and R6 are independently absent or H, alkyl, cycloalkyl, alkoxy, halo, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9, and CF ３ wherein at least one of R5 and R6 is present and is not H; R7 is H; A is selected from aryl and heteroaryl, where aryl is alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, -(CH ２ ) ０－３ -O-heteroaryl, aryl ｂ , —O-aryl ｂ , -(CH ２ ) １－３ -Aryl ｂ , -(CH ２ ) １－３ -heteroaryl, -COOR10, -CONR10R11, -(CH ２ ) ０－３ -NR10R11, OCF ３ and C.F. ３ and heteroaryl is substituted by one, two or three substituents independently selected from alkyl, alkoxy, OH, OCF ３ , halo, CN, aryl, -(CH ２ ) １－３ -aryl, -(CH ２ ) ０－３ -NR10R11, heteroaryl ｂ , -COOR10, -CONR10R11 and CF ３ and is substituted by one, two or three substituents independently selected from R8 and R9 are independently selected from H and alkyl; Alkyl is a group having up to 10 carbon atoms (C １ -C １０ ) or a linear saturated hydrocarbon having between 3 and 10 carbon atoms (C ３ -C １０ ) wherein the alkyl is a branched saturated hydrocarbon consisting of (C １ -C ６ ) Alkoxy, OH, CN, CF ３ , COOR10, CONR10R11, fluoro and NR10R11; Alkyl ｂ is a linear saturated hydrocarbon having up to 6 carbon atoms or between 3 and 6 carbon atoms (C ３ -C ６ ) is a branched saturated hydrocarbon consisting of alkyl ｂ (C １ -C ６ ) Alkoxy, OH, CN, CF ３ , COOR10, CONR10R11 and fluoro; Cycloalkyl is a monocyclic saturated hydrocarbon of between 3 and 6 carbon atoms; Alkoxy is an alkyl group having between 1 and 6 carbon atoms (C １ -C ６ ) or an O-linked straight chain hydrocarbon having between 3 and 6 carbon atoms (C ３ -C ６ ) is an O-linked branched hydrocarbon, and alkoxy is OH, CN, CF ３ , COOR10, CONR10R11, fluoro and NR10R11; Aryl is phenyl, biphenyl or naphthyl, and aryl is alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, heteroaryl, -(CH ２ ) ０－３ -O-heteroaryl, aryl ｂ , —O-aryl ｂ , -(CH ２ ) １－３ -Aryl ｂ , -(CH ２ ) １－３ -heteroaryl, -COOR10, -CONR10R11, -(CH ２ ) ０－３ -NR10R11, OCF ３ and C.F. ３ and optionally substituted by one, two or three substituents independently selected from Aryl ｂ is phenyl, biphenyl or naphthyl, which is alkyl, alkoxy, OH, halo, CN, -COOR10, -CONR10R11, CF ３ and NR10R11, Heteroaryl is a 5-, 6-, 9-, or 10-membered monocyclic or bicyclic aromatic ring containing, where possible, 1, 2, 3, or 4 ring members independently selected from N, NR8, S, and O, and heteroaryl is alkyl, alkoxy, OH, OCF ３ , halo, CN, aryl, -(CH ２ ) １－３ -aryl, -(CH ２ ) ０－３ -NR10R11, heteroaryl ｂ , -COOR10, -CONR10R11 and CF ３ and Heteroaryl ｂ is a 5-, 6-, 9- or 10-membered monocyclic or bicyclic aromatic ring, where possible containing 1, 2 or 3 ring members independently selected from N, NR8, S and O; heteroaryl ｂ is alkyl, alkoxy, OH, halo, CN, aryl, -(CH ２ ) １－３ -aryl, -COOR10, -CONR10R11, CF ３ and NR10R11, R10 and R11 are H, alkyl, aryl. ｂ and heteroaryl ｂ or R and R together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocyclic carbon-containing ring which may contain additional heteroatoms selected from N, S and O, which may be saturated or unsaturated by one or two double bonds, and may be selected from oxo, alkyl, alkoxy, OH, halo and CF ３ may be mono- or di-substituted with a substituent selected from and the tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), pharma- ceutically acceptable salts, and solvates thereof.

2. B is an alkyl ｂ , alkoxy, OH, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ３ and C.F. ３ or B is selected from benzothiophenyl, benzofuranyl, and a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, the 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic, and the benzothiophenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring is selected from alkyl, ｂ , alkoxy, OH, oxo, halo, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ３ and C.F. ３ and is substituted with one to three substituents selected from ｂ 2. The compound according to claim 1, wherein R 8 and R 9 are as defined in claim 1.

3. B is selected from phenyl, thiophenyl, benzothiophenyl, and pyridyl, each of which is alkyl. ｂ , alkoxy, halo, CN, COOR8, CONR8R9, OCF ３ and C.F. ３ and is substituted with one to three substituents selected from ｂ 3. A compound according to claim 1 or claim 2, wherein R8 and R9 are as defined in claim 1.

4. B is selected from phenyl and pyridyl, each of which is alkyl. ｂ , alkoxy, CF ３ and halo; ｂ 4. The compound according to any one of claims 1 to 3, wherein and alkoxy are as defined in claim 1.

5. 5. The compound of claim 1, wherein W is C, and X, Y and Z are independently selected from C and N, such that the ring containing W, X, Y and Z is a 5-membered aromatic heterocycle.

6. 6. The compound according to claim 1, wherein W is C, X is N, and Y and Z are selected from C and N.

7. R5 and R6 are independently absent, H, CH ２ OCH ３ , cycloalkyl, -NR8R9, -NR8COR9, CN and CF ３ 7. The compound according to claim 1, wherein R is independently selected from the group consisting of cycloalkyl, R and R are as defined in claim 1, and at least one of R and R is present and is not H.

8. A is -(CH ２ ) １－３ -heteroaryl or -(CH ２ ) １－３ Phenyl substituted by -NR10R11, including alkyl, halo and CF ３ 8. The compound according to claim 1, wherein R is phenyl, optionally substituted with one or two additional substituents independently selected from alkyl, heteroaryl, R and R are as defined in claim 1.

9. A is heteroaryl ｂ or pyridyl substituted by -NR10R11, which is selected from alkyl, halo and CF ３ and pyridyl, optionally substituted by one or two additional substituents independently selected from: ｂ 8. The compound according to any one of claims 1 to 7, wherein R10 and R11 are as defined in claim 1.

10. 3-amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxy-benzylamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-{[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4-carboxamide; 3-cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-3,6-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(dimethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-amino-N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-acetamido-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-chloro-2,6-difluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(5-chloro-2-cyanophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethyl)-6-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-carbamoyl-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[3-(difluoromethoxy)-2-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,5-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2-fluoro-6-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-amino-N-[(2-fluoro-3-hydroxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(3-ethyl-2-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(4-methyl-2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide; N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-2-(trifluoromethyl)imidazole-4-carboxamide; 3-amino-N-[(7-chloro-4-methyl-2,3-dihydro-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 3-amino-N-[(7-chloro-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 2. The compound of claim 1 selected from: and pharma- ceutically acceptable salts and solvates thereof.

11. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharma- ceutically acceptable carrier, diluent or excipient.

12. 11. A compound according to any one of claims 1 to 10 for use in medicine.

13. 13. Use of a compound according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment or prevention of a disease or condition associated with plasma kallikrein activity.

14. 13. A method of treatment comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 10 to a subject in need of treatment for a disease or condition associated with plasma kallikrein activity.

15. 11. A compound according to any one of claims 1 to 10 for use in a method for the treatment of a disease or condition associated with plasma kallikrein activity.

16. 16. The use according to claim 13, the method according to claim 14, or the compound for use according to claim 15, wherein the disease or condition associated with plasma kallikrein activity is selected from visual impairment, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, cardiopulmonary bypass surgery and post-operative bleeding.

17. The use according to claim 13, the method according to claim 14, or the compound for use according to claim 15, wherein the disease or condition associated with plasma kallikrein activity is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

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