RU2821520C2 - N-((het)arylmethyl)-heteroaryl-carboxamide compounds as plasma kallikrein inhibitors - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical compositions for treating diseases or conditions associated with plasma kallikrein activity. Disclosed is a pharmaceutical composition for treating a disease or condition associated with plasma kallikrein activity, containing: (i) a pharmaceutically acceptable carrier, diluent or excipient and (ii) a compound of formula (I), wherein R5, R6, R7, A, B, W, X, Y and Z are as defined in the claims, or a pharmaceutically acceptable compound thereof salt or solvate. Also disclosed are a compound of formula (I), its use in a method of treating a disease or condition which is associated with plasma kallikrein activity, a corresponding method of treating, as well as a pharmaceutical composition having the ability to inhibit plasma kallikrein activity.

EFFECT: content of low-molecular compounds in the pharmaceutical composition, which selectively inhibit plasma kallikrein, improves oral accessibility.

24 cl, 15 tbl, 140 ex

Description

The present invention relates to enzyme inhibitors that are inhibitors of plasma kallikrein, and to pharmaceutical compositions containing such inhibitors, and to uses of such inhibitors.

Prerequisites for creating the invention

The heterocyclic derivatives of the present invention are inhibitors of plasma kallikrein and have various therapeutic applications, in particular for the treatment of retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Plasma kallikrein is a trypsin-like serine protease that can release kinins from kininogens (see K. D. Bhoola et al ., “Kallikrein-Kinin Cascade,” Encyclopedia of Respiratory Medicine , p483-493; J. W. Bryant et al ., “Human plasma kallikrein” -kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry , 7, p234-250, 2009; KD Bhoola et al ., Pharmacological Rev. , 1992, 44, 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, 33, 665-677). It is an integral member of the intrinsic blood coagulation cascade, although its role in this cascade does not involve bradykinin release or enzymatic degradation. 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 the plasma as a heterodimeric complex associated with high molecular weight kininogen, which is activated to form active plasma kallikrein. Kinins are potent inflammatory mediators that act through G protein-coupled receptors, and kinin antagonists (such as bradykinin antagonists) have previously been investigated as potential therapeutics for a number of disorders (F. Marceau and D. Regoli, Nature Rev., Drug Discovery, 2004, 3, 845-852).

Plasma kallikrein is thought to play a role in a number of inflammatory disorders. The main inhibitor of plasma kallikrein is the C1 esterase inhibitor serpin. Patients with a genetic C1 esterase inhibitor deficiency suffer from hereditary angioedema (HAE), which results in periodic swelling of the face, hands, throat, gastrointestinal tract and genitals. Blisters produced during acute attacks contain high levels of plasma kallikrein, which breaks down high molecular weight kininogen, releasing bradykinin, leading to increased vascular permeability. Treatment with plasma kallikrein inhibitors, which are large proteins, has been shown to be effective in treating HAE by interfering with the release of bradykinin, which causes increased vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery" Expert Opin. Biol. The r. 8, p. 1187-99).

The plasma kallikrein-kinin system is present at abnormally high levels in patients with advanced diabetic macular edema. Recently published work reported that plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats (A. Clermont et al . "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes , 2011, 60, p1590-98 ). In addition, administration of the plasma kallikrein inhibitor ASP-440 alleviated both retinal vascular permeability and retinal vascular perfusion disorders in diabetic rats. Therefore, a plasma kallikrein inhibitor should find use as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Other complications of diabetes, such as intracerebral hemorrhage, nephropathy, cardiomyopathy and neuropathy, which are all related to plasma kallikrein, may also be considered targets for a plasma kallikrein inhibitor.

Synthetic and small molecule inhibitors of plasma kallikrein have been described previously, for example, Garrett et al. (“Peptide aldehyde...” J. Peptide Res . 52, p62-71 (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 137, p692-700 (2002)), Evans (“Selective dipeptide inhibitors of kallikrein” WO03/ 076458), Szelke et al . (“Kininogenase inhibitors” WO92/04371), DM Evans et al . ( Immunolpharmacology , 32, p115-116 (1996)), Szelke et al . (“Kininogen inhibitors” WO95/07921), Antonsson et al . (“New peptides derivatives” WO94/29335), J. Corte et al. ('Six membered heterocycles useful as serine protease inhibitors' WO2005/123680), J. Stürzbecher et al . ( Brazilian J. Med. Biol. Res 27, p1929-34 (1994)), Kettner et al . (US 5,187,157), N. Teno et al . ( Chem. Pharm. Bull . 41, p1079-1090 (1993)), W. B. Young et al . (“Small molecule inhibitors of plasma kallikrein” Bioorg. Med. Chem. Letts. 16, p2034-2036 (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, p1964-72 (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 , p545-553 (2006)), Sinha et al . (“Inhibitors of plasma kallikrein” WO08/016883), Shigenaga et al. (Plasma Kallikrein Inhibitors WO2011/118672), and Kolte et al. (Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor, British Journal of Pharmacology (2011), 162(7), 1639-1649). Also, Steinmetzer et al. (Serine protease inhibitors WO2012/004678) describe cyclized peptide analogues that are inhibitors of human plasmin and plasma kallikrein.

To date, no small molecule synthetic plasma kallikrein inhibitor has been approved for medical use. The molecules described in the prior art have disadvantages such as poor selectivity for related enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. Plasma kallikrein inhibitors, which are large proteins, are associated with a risk of anaphylactic reactions, as reported for Ecallantide. Thus, there remains a need for compounds that selectively inhibit plasma kallikrein, that do not cause anaphylaxis, and that are orally available. In addition, the vast majority of molecules in the prior art are characterized by containing a highly polar and ionizable guanidine or amidine functional group. It is well known that such functional groups can be limiting for intestinal permeability and therefore oral availability. For example, there was a report by Tamie J. Chilcote and Sukanto Sinha (ʺASP-634: An Oral Drug Candidate for Diabetic Macular Edemaʺ, ARVO 2012 May ^6th - May ^9th , 2012, Fort Lauderdale, Florida, Presentation 2240) that ASP-440, benzamidine suffers from poor oral availability. It has also been reported that absorption can be improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs may have some disadvantages, such as poor chemical stability and potential toxicity associated with an inert carrier or unanticipated metabolites. In another report, indolamides are claimed as compounds that could overcome the problems associated with drugs having severe or disproportionate ADME toxicity and poor physicochemical properties, although no inhibition against plasma kallikrein has been presented or claimed ( Griffioen et al, “Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases,” WO2010, 142801).

There was a message from BioCryst Pharmaceuticals Inc. on 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, Volume 133, Issue 2, Supplement, February 2014, page 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, Volume 133, Issue 2, Supplement February 2014, page AB40). However, human doses are relatively high, with experimental studies currently underway at doses of 400 mg three times daily.

There have been only a few reports of plasma kallikrein inhibitors that do not contain guanidine or amidine functional groups. One example is Brandl et al . (N-((6-amino-pyridin-3-yl)methyl)-heteroarylcarboxamides as plasma kallikrein inhibitors WO2012/017020), which describes compounds that contain an aminopyridine functionality. Oral efficacy in a rat model has been demonstrated at relatively high doses of 30 mg/kg and 100 mg/kg, but the pharmacokinetic profile is not presented. Thus, it remains to be seen whether or not such compounds will provide sufficient oral availability or efficacy to be promoted for clinical use. 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 papers present any in vivo data, and therefore it is still unknown whether such compounds will provide sufficient oral availability or efficacy to be promoted for clinical use. Another example is Allen et al . “Benzylamine derivatives” WO2014/108679.

Therefore, there remains a need to develop new plasma kallikrein inhibitors that will be useful for the treatment of a wide range of different disorders, in particular for reducing retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. Preferred compounds should have a good pharmacokinetic profile and, in particular, should be suitable as drugs for oral delivery.

The essence of the invention

The present invention relates to a series of heterocyclic derivatives that are inhibitors of plasma kallikrein. These compounds show good selectivity for plasma kallikrein and are potentially useful in the treatment of decreased visual acuity, diabetic retinopathy, macular edema, hereditary angioedema, diabetes, pancreatitis, intracerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, surgery under cardiopulmonary bypass, and bleeding after surgery. The invention also relates to pharmaceutical compositions of such inhibitors, to the use of the compositions as therapeutic agents and to methods of treatment using these compositions.

In a first aspect, the present invention provides compounds of formula I

Where

B is phenyl substituted with 1-4 substituents selected from alkyl ^b , alkoxy, OH, halogen, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ₃ and CF ₃ ;

or B is selected from benzothiophenyl, benzofuranyl, benzomorpholinyl and a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein said 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl, said benzomorpholinyl or said 5- or 6-membered heterocyclic ring is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, OH, oxo, halogen, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ₃ and CF ₃ ;

W represents C, and 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 five-membered aromatic heterocycle;

R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, alkoxy, halogen, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9 and CF ₃ ; where at least one of R5 and R6 is present and is not H;

R7 represents H;

A is selected from aryl and heteroaryl; wherein aryl is substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halogen, CN, heteroaryl, -( _CH2 ) _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 CF ₃ ; and heteroaryl is substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF ₃ , halogen, CN, aryl, -(CH ₂ ) _1-3 -aryl, -(CH ₂ ) _0-3 -NR10R11, heteroaryl ^b , -COOR10, -CONR10R11 and CF ₃ ;

R8 and R9 are independently selected from H and alkyl;

alkyl is a linear saturated hydrocarbon containing up to 10 carbon atoms (C ₁ -C ₁₀ ), or a branched saturated hydrocarbon containing from 3 to 10 carbon atoms (C ₃ -C ₁₀ ); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C ₁ -C ₆ )alkoxy, OH, CN, CF ₃ , COOR10, CONR10R11, fluorine and NR10R11;

alkyl ^b is a linear saturated hydrocarbon containing up to 6 carbon atoms, or a branched saturated hydrocarbon containing from 3 to 6 carbon atoms (C _3-6 ); alkyl ^b may optionally be substituted with 1 or 2 substituents independently selected from (C ₁ -C ₆ )alkoxy, OH, CN, CF ₃ , COOR10, CONR10R11 and fluorine;

cycloalkyl is a monocyclic saturated hydrocarbon containing from 3 to 6 carbon atoms;

alkoxy is a linear O-linked hydrocarbon containing from 1 to 6 carbon atoms (C ₁ -C ₆ ), or a branched O-linked hydrocarbon containing from 3 to 6 carbon atoms (C ₃ -C ₆ ); alkoxy may optionally be substituted with 1 or 2 substituents independently selected from OH, CN, CF ₃ , COOR10, CONR10R11, fluorine and NR10R11;

aryl is phenyl, biphenyl or naphthyl; aryl may optionally be substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halogen, CN, heteroaryl, -( _CH2 ) _0-3 -O-heteroaryl, ^arylb , -O- aryl ^b , -(CH ₂ ) _1-3 -aryl ^b , -(CH ₂ ) _1-3 -heteroaryl, -COOR10, -CONR10R11, -(CH ₂ ) _0-3 -NR10R11, OCF ₃ and CF ₃ ;

aryl ^b is phenyl, biphenyl or naphthyl, which may optionally be substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halogen, CN, -COOR10, -CONR10R11, CF ₃ and NR10R11;

heteroaryl is a 5, 6, 9 or 10 membered mono- or bicyclic aromatic ring containing, where possible, 1, 2, 3 or 4 ring members independently selected from N, NR8, S and O; heteroaryl may optionally be substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, OCF ₃ , halogen, CN, aryl, -(CH ₂ ) _1-3 -aryl, -(CH ₂ ) _0-3 - NR10R11, heteroaryl ^b , -COOR10, -CONR10R11 and CF ₃ ;

heteroaryl ^b is a 5, 6, 9 or 10 membered mono- or bicyclic aromatic ring containing, where possible, 1, 2 or 3 ring members independently selected from N, NR8, S and O; wherein heteroaryl ^b may optionally be substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halogen, CN, aryl, -(CH ₂ ) _1-3 -aryl, -COOR10, -CONR10R11, CF ₃ and NR10R11 ;

R10 and R11 are independently selected from H, alkyl, aryl ^b and heteroaryl ^b , or R10 and R11 together with the nitrogen atom to which they are bonded form a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds, and which may optionally be mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, halogen and CF ₃ ;

and their tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates.

In another aspect, the present invention provides a prodrug of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

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

It should be understood that some of the compounds of the present invention may exist in solvated, eg hydrated, as well as unsolvated form. It should be understood that the present invention covers all such solvated forms.

In yet another aspect, compounds of formula (I) are also provided, wherein:

B is selected from phenyl, thiophenyl, benzothiophenyl and pyridyl, each of which is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, halogen, CN, COOR8, CONR8R9, OCF ₃ and CF ₃ ; where alkyl ^b , alkoxy, R8 and R9 are as defined above;

W represents 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 five-membered aromatic heterocycle;

R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cycloalkyl, -NR8R9, -NR8COR9 and CF ₃ ; where at least one of R5 and R6 is present and is not H;

R7 represents H;

A selected from:

where alkyl, cycloalkyl, alkoxy, R8 and R9 are as defined above;

and their tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates.

In yet another aspect, compounds of formula (I) are also provided, wherein:

B is selected from phenyl and pyridyl, each of which is substituted with 1-3 substituents selected from methyl, ethyl, methoxy, ethoxy, CF ₃ , CN and F;

W is C, X is N, and Y and Z are selected from C and N;

R7 is H, and R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cyclopropyl, NH ₂ and CF ₃ ; where at least one of R5 and R6 is present and is not H;

A selected from:

and their tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates.

The aspects of the present invention described above may also include the following features:

- B is phenyl substituted with 1-4 substituents selected from alkyl ^b , alkoxy, OH, halogen, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ₃ and CF ₃ ; or B is selected from benzothiophenyl, benzofuranyl, benzomorpholinyl and a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein said 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl, said benzomorpholinyl or said 5- or 6-membered heterocyclic ring is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, OH, oxo, halogen, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF ₃ and CF ₃ ;

B is phenyl substituted with 1-4 substituents selected from alkyl^b, alkoxy, OH, halogen, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃And CF₃; or B is selected from benzothiophenyl, benzofuranyl and a 5 or 6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S; wherein said 5- or 6-membered heterocyclic ring may be aromatic or non-aromatic; and wherein said benzothiophenyl, said benzofuranyl or said 5- or 6-membered heterocyclic ring is substituted with 1-3 substituents selected from alkyl^b, alkoxy, OH, oxo, halogen, CN, heteroaryl, COOR8, NHCOR8, CONR8R9, OCF₃ and C.F.₃; where is the alkyl^b, alkoxy, R8 and R9 are as defined above.

B is selected from phenyl, pyridyl, pyrimidone, pyrimidine, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiophenyl, benzothiophenyl and furanyl, each of which is substituted, if possible, with 1-3 substituents selected from alkyl ^b , alkoxy, OH, oxo, halogen, CN, COOR8, CONR8R9, OCF ₃ and CF ₃ ; where alkyl ^b , alkoxy, R8 and R9 are as defined above.

B is selected from phenyl, pyridyl, pyrimidone, thiazolyl, pyrazolyl, isoxazolyl, thiophenyl, benzothiophenyl and furanyl, each of which is substituted, if possible, with 1-3 substituents selected from alkyl ^b , alkoxy, OH, oxo, halogen, CN, COOR8, CONR8R9, OCF ₃ and CF ₃ ; where alkyl ^b , alkoxy, R8 and R9 are as defined above.

B is selected from phenyl, thiophenyl, benzothiophenyl and pyridyl, each of which is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, halogen, CN, COOR8, CONR8R9, OCF ₃ and CF ₃ ; where alkyl ^b , alkoxy, R8 and R9 are as defined above.

B is selected from phenyl and pyridyl, each of which is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, CN, CF ₃ and halogen; where alkyl ^b and alkoxy are as defined above.

B is selected from phenyl and pyridyl, each of which is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, CF ₃ and halogen; where alkyl ^b and alkoxy are as defined above.

B is selected from phenyl and pyridyl, each of which is substituted with 1-3 substituents selected from methyl, ethyl, methoxy, ethoxy, CF ₃ , CN and F.

B is selected from phenyl and pyridyl, each of which is substituted with 1-3 substituents selected from methyl, ethyl, methoxy, ethoxy, CF ₃ , Cl, CHF ₂ and F.

B is selected from phenyl substituted with 1-3 substituents selected from methyl, ethyl, methoxy, ethoxy, CN, CF ₃ , Cl, CHF ₂ and F.

B is selected from phenyl substituted with 1-3 substituents selected from methyl, ethyl, methoxy, ethoxy, CF ₃ , Cl, CHF ₂ and F.

- W represents 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 five-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 represents 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 represents C.

X represents 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 independently selected from H, alkyl, cycloalkyl, alkoxy, halogen, OH, aryl, heteroaryl, N-linked pyrrolidinyl, N-linked piperidinyl, N-linked morpholinyl, N-linked piperazinyl, -NR8R9, CN, COOR8, CONR8R9, -NR8COR9 and CF ₃ ; where at least one of R5 and R6 is present and is not H; where 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 CF ₃ ; where at least one of R5 and R6 is present and is not H; where alkyl, cycloalkyl, R8 and R9 are as defined above.

R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cycloalkyl, CN, -NR8R9, -NR8COR9 and CF ₃ ; where at least one of R5 and R6 is present and is not H; where cycloalkyl, R8 and R9 are as defined above.

R5 and R6 are independently absent or independently selected from H, cycloalkyl, CN, -NR8R9, -NR8COR9 and CF ₃ ; where at least one of R5 and R6 is present and is not H; where cycloalkyl, R8 and R9 are as defined above.

R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cycloalkyl, CN, NR8R9 and CF ₃ ; where R8 and R9 represent H and cycloalkyl is as defined above; and where at least one of R5 and R6 is present and is not H.

R7 represents H.

R7 is H, and R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cyclopropyl, CN, NH ₂ and CF ₃ ; where at least one of R5 and R6 is present and is not H.

R7 is H, and R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cyclopropyl, NH ₂ , CN and CF ₃ ; where at least one of R5 and R6 is present and is not H.

R7 is H, and R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cyclopropyl, NH ₂ and CF ₃ ; where at least one of R5 and R6 is present and is not H.

R7 is H, R6 is absent, and R5 is selected from CH ₂ OCH ₃ , cyclopropyl, NH ₂ and CF ₃ .

R7 is H, R6 is absent, and R5 is CH ₂ OCH ₃ .

- W is C, X is N, Y and Z are selected from C and N, R7 is H, and R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cycloalkyl, NR8R9 and CF ₃ ; where 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 CH ₂ OCH ₃ , cyclopropyl, NH ₂ and CF ₃ .

- A is selected from aryl and heteroaryl, each of which is substituted as above.

A is phenyl, pyridyl, thiophenyl or quinolinyl, each of which is substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, halogen, CN, aryl ^b , -(CH ₂ ) _1-3 -aryl ^b , -( CH ₂ ) _1-3 -heteroaryl, -(CH ₂ ) _0-3 -NR10R11 and CF ₃ ; where alkyl, alkoxy, heteroaryl, aryl ^b , R10 and R11 are as defined above.

A is phenyl or pyridyl, each of which is substituted with 1, 2 or 3 substituents independently selected from alkyl, alkoxy, halogen, -(CH ₂ ) _1-3 -aryl ^b , -(CH ₂ ) _1-3 -heteroaryl, CF ₃ and -(CH ₂ ) _0-3 -NR10R11; where alkyl, alkoxy, heteroaryl, aryl ^b , R10 and R11 are as defined above.

A is pyridyl substituted with 1, 2 or 3 substituents independently selected from alkyl, halogen, heteroaryl ^b , CF ₃ and -NR10R11; where alkyl, heteroaryl ^b , R10 and R11 are as defined above.

A is pyridyl substituted with heteroaryl ^b or -NR10R11 and optionally with 1 or 2 additional substituents independently selected from alkyl, halogen and CF ₃ ; where alkyl, heteroaryl ^b , R10 and R11 are as defined above.

A is phenyl substituted with 1, 2 or 3 substituents independently selected from alkyl, halogen, -(CH ₂ ) _1-3 -heteroaryl, CF ₃ and -(CH ₂ ) _1-3 -NR10R11; where alkyl, heteroaryl, R10 and R11 are as defined above.

A is phenyl substituted with -(CH ₂ ) _1-3 -heteroaryl or -(CH ₂ ) _1-3 -NR10R11 and optionally with 1 or 2 additional substituents independently selected from alkyl, halogen and CF ₃ ; where alkyl, heteroaryl, R10 and R11 are as defined above.

A selected from:

A selected from:

A selected from:

A selected from:

A represents:

A represent:

- R8 and R9 are independently selected from H and alkyl; where alkyl is as defined above.

R8 and R9 are independently selected from H and methyl, ethyl, n-propyl and isopropyl.

R8 and R9 are independently selected from H and methyl.

- R10 and R11 are independently selected from H, alkyl, aryl ^b and heteroaryl ^b , or R10 and R11 together with the nitrogen atom to which they are bonded form a carbon-containing 4-, 5-, 6- or 7-membered heterocyclic ring, optionally containing an additional heteroatom selected from N, S and O, which may be saturated or unsaturated with 1 or 2 double bonds and which may optionally be mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, halogen and CF ₃ ; where alkyl, alkoxy, aryl ^b and heteroaryl ^b 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 bonded, form a carbon-containing 5- or 6-membered heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 1 or 2 double bonds and which may optionally be mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, Cl, F and CF ₃ ; where alkyl and alkoxy have the meanings 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 bonded, form a 5- or 6-membered carbon-containing heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 1 or 2 double bonds and optionally mono- or di-substituted with substituents selected from oxo, methyl, Cl and F; where alkyl is as defined above.

R10 and R11, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered carbon-containing heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 1 or 2 double bonds and optionally mono- or di-substituted substituents selected from oxo, methyl, Cl and F.

R10 and R11, together with the nitrogen atom to which they are bonded, form a 6-membered carbon-containing heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 1 or 2 double bonds and may optionally be oxo-substituted.

R10 and R11, together with the nitrogen atom to which they are bonded, form a carbon-containing 5- or 6-membered saturated heterocyclic ring.

R10 and R11 are independently selected from H and alkyl ^b ; where alkyl ^b is as defined above.

The present invention also 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)pyrazol-4-carboxamide; N-[(3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(3-ethoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; 1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(2,4-dimethoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(2,6-difluoro-4-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide ; N-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide; N-[(2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(2-chloro-6-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide; N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide ; N-[(4-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(3-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide ; N-[(3-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(5-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-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)pyrazol-4-carboxamide; N-{[5-chloro-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide; N-[(2,4-dimethylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(2,6-dimethylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; 1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)-N-[(2,4,6-trimethylphenyl)methyl]pyrazol-4-carboxamide; N-[(3-fluoro-2-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(2-fluoro-4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(3-fluoropyridin-2-yl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-[(4-chloropyridin-2-yl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrazol-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}pyrazol-4- carboxamide; 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrazol-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}pyrazol-4- carboxamide; N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazol-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)pyrazol-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)pyrazol-4 -carboxamide; 3-amino-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide; 6-cyano-2-fluoro-3-methoxy-benzylamide 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-pyrazol-4-carboxylic acid; 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; 6-cyano-2-fluoro-3-methoxy-benzylamide 3-methoxymethyl-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazol-4-carboxylic acid; 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

and their pharmaceutically acceptable salts and solvates.

The present invention also 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)pyrazol-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide; N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-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)pyrazol-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

and pharmaceutically acceptable salts and solvates thereof.

The present invention also 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

and pharmaceutically acceptable salts and solvates thereof.

Therapeutic Applications

As stated above, the compounds of the present invention are potent and selective inhibitors of plasma kallikrein. They are therefore useful in the treatment of disease states in which excessive plasma kallikrein activity is a causative factor.

Accordingly, the present invention provides a compound of formula (I) for use in medicine.

The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the treatment or prevention of a disease or condition that is directly related to the activity of plasma kallikrein.

The present invention also provides a compound of formula (I) for use in the treatment or prevention of a disease or condition that is directly related to plasma kallikrein activity.

The present invention also provides a method of treating a disease or condition that is directly related to plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

In one aspect, the disease or condition that is directly related to plasma kallikrein activity is selected from decreased visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, intracerebral hemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, surgery while on cardiopulmonary bypass, and bleeding after surgery.

In a preferred aspect, the disease or condition that is directly related to plasma kallikrein activity is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Combination therapy

The compounds of the present invention can be administered in combination with other therapeutic agents. Suitable combination therapies include a compound of formula (I) in combination with one or more agents selected from agents that inhibit platelet-derived growth factor (PDGF), endothelial growth factor (VEGF), alpha5beta1 integrin, steroids, other agents that inhibit plasma kallikrein, and other inflammation inhibitors. Specific examples of therapeutic agents that can be used in combination with the compounds of the present invention include those disclosed in EP2281885A and S. Patel in Retina , 2009 Jun;29(6 Suppl):S45-8.

When combination therapy is used, the compounds of the present invention and the agents used in combination therewith may be present in the same or different pharmaceutical compositions and may be administered separately, sequentially or simultaneously.

In another aspect, the compounds of the present invention can be administered in combination with laser treatment of the retina. The combination of laser therapy with intravitreal injection of a VEGF inhibitor for the treatment of 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. 27 April 2010).

Definitions

The term "alkyl" includes saturated hydrocarbon moieties including:

- linear groups containing up to 10 carbon atoms (C ₁ -C ₁₀ ) or up to 6 carbon atoms (C ₁ -C ₆ ) or up to 4 carbon atoms (C ₁ -C ₄ ). Examples of such alkyl groups include, but are not limited to, _C1 -methyl, _C2 -ethyl, _C3 -propyl and _C4 -n-butyl.

- branched groups containing from 3 to 10 carbon atoms (C ₃ -C ₁₀ ) or up to 7 carbon atoms (C ₃ -C ₇ ) or up to 4 carbon atoms (C ₃ -C ₄ ). Examples of such alkyl groups include, but are not limited to, _C3 isopropyl, _C4 sec-butyl, _C4 isobutyl, _C4 tert-butyl, and _C5 neopentyl.

each of these groups is optionally substituted as stated above.

Cycloalkyl is a monocyclic saturated hydrocarbon containing 3 to 7 carbon atoms, or 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Optionally, cycloalkyl may be substituted with 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 bonded form a 4-, 5-, 6- or 7-membered heterocyclic ring which may be saturated or unsaturated with 1 or 2 double bonds and which may optionally be mono- or di-substituted with substituents selected from oxo, alkyl, alkoxy, OH, F and CF ₃ . Cycloalkyl groups may contain from 3 to 7 carbon atoms, or from 3 to 6 carbon atoms, or from 3 to 5 carbon atoms, or from 3 to 4 carbon atoms. Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "alkoxy" includes O-linked hydrocarbon moieties including:

- linear groups containing from 1 to 6 carbon atoms (C ₁ -C ₆ ) or from 1 to 4 carbon atoms (C ₁ -C ₄ ). Examples of such alkoxy groups include, but are not limited to, C ₁ - methoxy, C ₂ - ethoxy, C ₃ - n-propoxy and C ₄ - n-butoxy;

- branched groups containing from 3 to 6 carbon atoms (C ₃ -C ₆ ) or from 3 to 4 carbon atoms (C ₃ -C ₄ ). Examples of such alkoxy groups include, but are not limited to, C ₃ isopropoxy and C ₄ sec-butoxy and tert-butoxy;

each of these groups is optionally substituted as stated above.

Unless otherwise specified, the halogen is selected from Cl, F, Br and I.

Aryl has the meaning as defined above. Typically, aryl is optionally substituted with 1, 2 or 3 substituents. Optional substituents are selected from those listed above. Examples of suitable aryl groups include phenyl and naphthyl (each of which is optionally substituted as above). Preferably, aryl is selected from phenyl, substituted phenyl (where the substituents are selected from those listed above) and naphthyl.

Heteroaryl has the same meaning as defined above. Typically, heteroaryl is optionally substituted with 1, 2 or 3 substituents. Optional substituents are selected from those listed 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, yl and isoquinolinyl (optional substituted as above).

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

The term “O-linked,” as in “O-linked hydrocarbon moiety,” means that the hydrocarbon moiety is attached to the rest of the molecule through an oxygen atom.

In groups such as -(CH ₂ ) _1-3 -aryl, "-" denotes the point of attachment of the substituent group to the rest of the molecule.

"Pharmaceutically acceptable salt" means a physiologically or toxicologically acceptable salt and includes, as appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. For example, (i) when a compound of the present invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts or organic amine salts such as diethylamine, N -methyl-glucamine, diethanolamine, or amino acids (eg lysine), etc.; (ii) when the compound of the present invention contains an alkaline group such as an amino group, pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates , phosphates, esylates, tosylates, benzenesulfonates, naphthalene disulfonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, p-acetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates, etc.

Hemisalts of acids and bases can also be formed, for example hemisulfate and hemicalcium salts.

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

“Prodrug” refers to a compound that can be converted in vivo by metabolism (eg, hydrolysis, reduction or oxidation) into a compound of the present invention. Suitable groups for the formation of prodrugs are described in 'The Practice of Medicinal Chemistry, 2 ^nd Ed. pp561-585 (2003) and in F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.

The compounds of the present invention may exist in either unsolvated or solvated form. The term 'solvate' is used herein to describe a molecular complex comprising a compound of the present invention and a stoichiometric amount of one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term 'hydrate' is used when the solvent is water.

The compounds of the present invention may exist in one or more geometric, optical, enantiomeric, diastereomeric and tautomeric forms, including, but not limited to, cis and trans forms, E and Z forms, R , S and meso forms, keto and enol forms. Unless otherwise indicated, reference to a specific compound includes all such isomeric forms, including racemic and other mixtures thereof. If necessary, such isomers can be isolated from mixtures thereof by the use or adaptation of known methods (eg chromatographic methods and recrystallization methods). If appropriate, such isomers can be prepared by using or adapting known methods (eg asymmetric synthesis).

Unless otherwise indicated, the compounds of the present invention include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds where hydrogen is replaced by deuterium or tritium, or where carbon is replaced by ¹³ C or ¹⁴ C are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

In the context of the present invention, references to “treatment” include references to therapeutic, palliative and prophylactic treatment.

General methods

The compounds of formula (I) need to be evaluated for their biopharmaceutical properties, such as solubility and stability in solution (at different pH values), permeability , etc. to select the most appropriate dosage form and route of administration to treat the intended indication. They can be administered alone or in combination with one or more other compounds of the present invention or in combination with one or more other drugs (or as any combination of the above). Typically, they can be administered as a composition in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient, other than the compound(s) of the present invention, that can impart functional (i.e. control of drug release rate) and/or non-functional (i.e. process additive or diluent) characteristics of the compositions. The choice of excipient depends largely on factors such as the specific route of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

The compounds of the present invention for pharmaceutical use can be administered in the form of a solid or liquid, for example, in the form of a tablet, capsule or solution. Pharmaceutical compositions suitable for delivering the compounds of the present invention, and methods for their preparation, will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.

For the treatment of conditions such as retinal vascular leakage associated with diabetic retinopathy and diabetic macular edema, the compounds of the present invention can be administered in a form suitable for injection into the eye of a patient, in particular in a form suitable for intravitreal injection. It is contemplated that compositions suitable for such use will take the form of sterile solutions of a compound of the present invention in a suitable aqueous vehicle. The compositions can be administered to a patient under the supervision of a physician.

The compounds of the present invention can also be administered directly into the bloodstream, into subcutaneous tissue, into muscle or into an internal organ. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous. Suitable devices for parenteral administration include needles (including microneedles), syringes, needleless injection devices, and infusion techniques.

Parenteral compositions are typically aqueous or oily solutions. In the case of an aqueous solution, excipients such as sugars (including but not limited to glucose, mannitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably for pH 3 to 9) are used, but for some More suitable applications are compositions formulated as a sterile non-aqueous solution or in a dried form for use with a suitable carrier such as sterile pyrogen-free water.

Parenteral compositions may include implants formed from degradable polymers such as polyesters (ie, polylactic acid, polylactide, polylactide-co-glycolide, polycaprolactone, polyhydroxybutyrate), polyorthoesters, and polyanhydrides. These compositions can be administered through a surgical incision into subcutaneous tissue, muscle tissue, or directly into specific organs.

Preparation of parenteral compositions under sterile conditions, for example by lyophilization, can be easily accomplished using standard pharmaceutical methods well known to those skilled in the art.

The solubility of the compounds of formula (I) used for the preparation of parenteral solutions can be increased using suitable formulation procedures, such as the inclusion of cosolvents and/or solubility enhancing agents such as surfactants, micellar structures and cyclodextrins.

In one embodiment, the compounds of the present invention can be administered orally. Oral administration may include ingestion, thereby passing the compound into the gastrointestinal tract, and/or buccal, lingual or sublingual administration, whereby the compound enters the bloodstream directly from the oral cavity.

Compositions suitable for oral administration include solid compresses, solid microparticles, semi-solids and liquids (including multiphase or dispersed systems), such as tablets; soft or hard capsules containing many discrete particles or nanoparticles, liquids, emulsions or powders; medicinal lozenges (including liquid-filled lozenges); chewable forms; gels; rapidly dispersing dosage forms; films; vaginal suppositories; sprays; and buccal/mucoadhesive patches.

Compositions suitable for oral administration may also be designed to deliver the compounds of the present invention in an immediate release or sustained release manner, where the release profile may be delayed, pulsed, controlled, sustained, or delayed and sustained, or may be modified so as to to optimize the therapeutic efficacy of these compounds. Agents for delivering compounds at a slow release rate are known in the art and include slow release polymers that can be formulated with the compounds to control their release.

Examples of rate-delaying polymers include degradable and non-degradable polymers that can be used to release the compounds by diffusion or a combination of diffusion and polymer degradation. Examples of rate-delaying polymers include hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, xanthan gum, polymethacrylates, polyethylene oxide and polyethylene glycol.

Liquid (including multiphase and dispersed systems) compositions include emulsions, solutions, syrups and elixirs. Such compositions may be presented as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropyl methylcellulose) and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and/or or suspending agents. Liquid compositions can also be prepared by restructuring a solid, for example from a sachet.

The compounds of the present invention can also be used in instant dosage forms, lozenge dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.

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

For administration to a patient, such as a human, the total daily dose of the compounds of the present invention is typically in the range of 0.01 mg to 1000 mg, or 0.1 mg to 250 mg, or 1 mg to 50 mg, depending, of course, on the method of administration.

The total dose may be administered in single or divided doses and may, at the discretion of the attending physician, be outside the typical range stated above. These doses are based on an average human subject having a body weight of approximately 60 kg to 70 kg. The healthcare provider will easily be able to determine doses for subjects with body weights outside this range, such as children and the elderly.

Synthesis methods

The compounds of the present invention can be prepared in accordance with the procedures shown in the following schemes and examples using suitable materials, and are illustrated in more detail by the specific examples presented herein below. In addition, by using the procedures described herein, those skilled in the art will readily be able to prepare additional compounds that fall within the scope of the invention claimed herein. The compounds illustrated in the examples, however, should not be considered to form the only genus that is considered to be an invention. The examples further illustrate details for preparing the compounds of the present invention. Those skilled in the art will appreciate that known variations in conditions and implementation of the following preparation procedures can be used to obtain these compounds.

The compounds of the present invention can be isolated in the form of their pharmaceutically acceptable salts, such as the salts described above.

It may be necessary to protect reactive functional groups (eg, hydroxy, amino, thio or carboxy) in the intermediates used in the preparation of the compounds of the present invention to avoid their undesirable participation in the reaction leading to the formation of the compounds. Traditional protecting groups may be used, such as those described in TW Greene and PGM Wuts, “Protective Groups in Organic chemistry,” John Wiley and Sons, ^4th Edition, 2006. For example, a traditional amino protecting group suitable for use in the present invention is 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 can be removed by hydrogenation using a palladium catalyst under hydrogen, or a 9-fluorenylmethyloxycarbonyl (Fmoc) group, which can be removed by dissolving secondary organic amines such as diethylamine or piperidine, in an organic solvent. Carboxyl groups are typically protected as esters such as methyl, ethyl, benzyl or tert-butyl, which can all be removed by hydrolysis in the presence of bases such as lithium or sodium hydroxide. Benzyl protecting groups can also be removed by hydrogenation using a palladium catalyst under hydrogen, while tert-butyl groups can also be removed using trifluoroacetic acid. Alternatively, the trichlorethyl ether protecting group is removed using zinc in acetic acid. A conventional hydroxy protecting group suitable for use in the present invention is methyl ether, deprotection conditions include boiling in 48% aqueous HBr for 1-24 hours, or by stirring with boron tribromide in dichloromethane for 1-24 hours . Alternatively, when the hydroxy group is protected as a benzyl ether, deprotection conditions include hydrogenation using a palladium catalyst under a hydrogen atmosphere.

Examples of synthetic methods that can be used to prepare 4-carboxyimidazoles are described in EP 1426364 A1 (Imidazole-derivatives as factor Xa inhibitors, p. 27-28).

Compounds of general Form I can be prepared using traditional synthetic routes, such as, but not limited to, the method shown in Scheme 1. Amine 2 is reacted with acid 1 to yield compound 3. This coupling is typically carried out using standard coupling conditions , such as hydroxybenzotriazole and carbodiimide, such as water-soluble carbodiimide, in the presence of an organic base. Other standard coupling methods include reactions of acids with amines 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-tris-pyrrolidino-phosphonium hexafluorophosphate, in the presence of organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine. Alternatively, amide formation can occur via an acid chloride in the presence of an organic base. Such acid chlorides can be prepared by methods well known in the literature, for example by reacting the acid with oxalyl chloride or thionyl chloride.

Scheme 1

Alternatively, compounds according to general formula I can be prepared using the method shown in Scheme 2a. Acid 4 can be reacted with amine 2 using suitable coupling methods as described above to give compound 5. In a typical second step, the nitrogen of the heterocyclic ring is alkylated with compound 6 to give compound 7. Alkylation can be carried out in the presence of a base such as a carbonate potassium, cesium carbonate, sodium carbonate or sodium hydride, in which case the leaving group is a halide or sulfonate. Alternatively, alkylation can be accomplished using an alcohol under Mitsunobu reaction conditions in the presence of triphenylphosphine.

Scheme 2a

In an embodiment of Scheme 2a, compounds according to general formula I can be prepared using the method shown in Scheme 2b. Scheme 2b differs from Scheme 2a in that the group is Y=N, so a protecting group strategy can be used and the synthesis steps are carried out in a different order. The pyrazole carboxylic acid protected as an ester (PG) as described above, compound 8, is alkylated using compound 6. The 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. Alternatively, alkylation can be carried out using an alcohol under Mitsunobu reaction conditions, in the presence of triphenylphosphine. In this case, there are two possible nitrogens for alkylation to occur and therefore there is the possibility of forming two regioisomers 9 and 10. Compounds 9 and 10 can be separated at this stage or at a subsequent stage of the synthesis using separation methods well known to those skilled in the art, e.g. , chromatography or fractionated crystallization. The protecting group of compound 9 is removed by hydrolysis to obtain the corresponding acid 11 using standard methods described above. Compound 11 can be reacted with amine 2 using suitable coupling methods as described above to produce compound 12.

Scheme 2b

Alternatively, compounds according to general formula I can be prepared using the method shown in Scheme 3. Pyrrole 17 can be formed in two steps, the first of which involves the reaction of the sodium salt of alkyl ketoacetate 13, typically protected with a protecting group (PG) as described above using chloroketone 14, in the presence of a base such as potassium carbonate, to obtain compound 15, which in a typical second step is reacted with amine 16 in the presence of an acid, such as, but not limited to, sulfonic acid derivatives, e.g. p-toluenesulfonic acid to give compound 17, which is then hydrolyzed in a typical third step to the corresponding acid 18 using standard methods as described above. In a typical fourth step, acid 18 can be reacted with amine 2 using suitable coupling methods as described above to produce compound 19.

Scheme 3

The amine, compound 2, can be prepared using traditional synthetic routes, such as, but not limited to, the routes shown in Scheme 4. The nitrile of compound 20 is reduced using standard reducing agents, including, but not limited to, lithium aluminum hydride, sodium borohydride, sodium borohydride and nickel chloride, sodium borohydride and 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 when catalytic hydrogenation is used, it is possible to protect the resulting amino group in situ, for example leading to carbamate 21, for example t- butoxycarbamate. This may be useful for performing, for example, chromatographic purification of intermediate 21. The protecting group is then removed using standard conditions as described above to obtain compound 2.

Scheme 4

Examples

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

aq. Water solution DCM Dichloromethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) hrs watch HOBt Hydroxybenzotriazole LCMS Liquid chromatography/mass spectrometry Me Methyl MeCN Acetonitrile MeOH Methanol min. minutes MS Mass spectrum NMR Nuclear Magnetic Resonance Spectrum - NMR spectra were recorded at 400 MHz unless otherwise stated. Pet.ether Petroleum ether fraction, boiling at 60-80°C Ph Phenyl SWFI Sterile water for injection rt Room temperature THF Tetrahydrofuran T.F.A. Trifluoroacetic acid

All reactions were carried out under nitrogen atmosphere unless otherwise stated.

¹H NMR spectra were recorded on a Bruker (400 MHz) spectrometer relative to deuterium solvent and at room temperature.

Molecular ions were obtained using LCMS, which was performed using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, using a linear gradient of 10% to 90% 0.1% HCO ₂ H/MeCN in 0.1% HCO ₂ H/H ₂ O for 13 min, flow rate 1.5 ml/min, or using Agilent, X-Select, acid conditions, 5-95% MeCN/water for 4 min. Data were collected using a Thermofinnigan Surveyor MSQ electrospray ionization mass spectrometer coupled with a Thermofinnigan Surveyor LC system.

When products were purified by flash chromatography, 'silica' means chromatography on silica gel, 0.035-0.070 mm (220-440 mesh) (e.g. Merck silica gel 60), and applied nitrogen pressure up to ¹⁰ psi (0.703 kg/ ^cm2 ) accelerated column elution. Reverse-phase preparative HPLC purifications were performed using a Waters 2525 binary gradient system at a typical flow rate of 20 mL/min using a Waters 2996 photodiode array detector.

All solvents and commercial reagents were used as received.

Chemical names were obtained using an automatic program such as the Autonom program provided as part of the ISIS Draw package of MDL Information Systems, or the Chemaxon program provided as a MarvinSketch component or as an IDBS E-WorkBook component.

A. 1-(4-Hydroxymethylbenzyl)-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 hours, after which the solvent was removed in vacuo and the residue absorbed into chloroform (100 ml). This solution was washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel) eluting with 3% MeOH/97% CHCl ₃ to give a white solid identified as 1-(4-hydroxymethylbenzyl)-1H-pyridin-2-one (5.30 g, 24. 62 mmol, yield 77%).

[M+Na] ⁺ =238

B1. 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one

1-(4-Hydroxymethylbenzyl)-1H-pyridin-2-one (8.45 g, 39.3 mmol), anhydrous DCM (80 mL) and triethylamine (7.66 mL, 55.0 mmol) were cooled at ice bath. Methanesulfonyl chloride (3.95 mL, 51.0 mmol) was added and stirred in an ice bath for 15 minutes. 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 NH ₄ Cl (100 ml). The aqueous layer was extracted with additional DCM (2 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give 1-(4-chloromethylbenzyl)-1H-pyridine-2 -one (8.65 g, 36.6 mmol, 93% yield) as a pale yellow solid.

[MH] ⁺ =234.1

B2. 1-(4-Bromomethylbenzyl)-1H-pyridin-2-one

1-(4-Hydroxymethylbenzyl)-1H-pyridin-2-one (2.30 g, 6.97 mmol) was dissolved in DCM (250 ml). Phosphorus tribromide (5.78 g, 21.37 mmol) was added to this solution. The reaction mixture was stirred at room temperature for 18 hours and diluted with CHCl ₃ (250 ml). The filtrate was washed with saturated NaHCO ₃ (aq) (30 ml), water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a white solid, which was identified as 1-(4-bromomethylbenzyl)-1H-pyridin-2-one (2.90 g, 10.43 mmol, 98%).

[M+H] ⁺ =277.7

C. Methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate

Potassium carbonate (519 mg, 3.76 mmol) was added to a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (320 mg, 1.88 mmol; CAS no. 318496-66-1 (synthesized according to with the method described in WO 2012/009009)) and 1-(4-(chloromethyl)benzyl)pyridin-2(1H)-one (527 mg, 2.26 mmol) in DMF (5 ml) and heated at 60° C overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with brine (2 x 100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (40 g column, 0-100% EtOAc in isohexane) to give two regioisomers. The second isomer exiting 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, yield 53.7%) as a colorless resin.

[MH] ⁺ =368.2

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) a solution of 2M NaOH (15.39 ml, 30.8 mmol) was added 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 concentrated 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

G. [4-(4-Methylpyrazol-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 hours and at 60°C for 30 hours, the solvent was then removed in vacuo and the residue was taken up in EtOAc (100 ml). This solution was washed with water (30 ml), brine (30 ml), dried (MgSO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel), eluting with a gradient of 10 to 80% EtOAc in isohexane, the fractions were combined and evaporated in vacuo to give a white solid identified as [4-(4-methylpyrazol-1-ylmethyl)phenyl]methanol (3.94 g, 18.90 mmol, 54% yield).

[MH] ⁺ =203

H. 1-(4-chloromethylbenzyl)-4-methyl-1H-pyrazole

[4-(4-Methylpyrazol-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 hours and diluted with CHCl ₃ (250 ml). The mixture was washed with saturated NH ₄ Cl solution (30 ml), water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuum. The residue was purified by flash chromatography (silica gel), eluting with a gradient of 0 to 60% EtOAc in isohexane, the fractions were combined and evaporated in vacuo to give a white solid identified as 1-(4-chloromethylbenzyl)-4-methyl-1H-pyrazole (1.49 g, 6.62 mmol, 60% yield).

[MH] ⁺ =221, 223

M. 3-Amino-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid ethyl ester

1-(4-Bromomethylbenzyl)-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 hours , after which the reaction mixture was diluted with EtOAc (100 ml). This solution was washed with water (30 ml), brine (30 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel), eluting with a gradient of 30% Petroleum ether/70% EtOAc to 100% EtOAc to give two regioisomers. The second isomer effluent 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, yield 45%) as a white solid.

[MH] ⁺ =353.1

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 hours, after which volatile substances were removed in vacuo and the aqueous residue was washed with CHCl₃ (150 ml). The aqueous layer was acidified with 1M HCl to pH7 and extracted with CHCl₃(3 x 50 ml). The combined extracts were washed with water (30 ml), brine (30 ml), dried (Na₂SO₄) and 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 yield, 84%).

[MH] ⁺ =325.2

P. tert-Butyl ester (2-fluoro-3-methoxybenzyl)-carbamic acid

2-Fluoro-3-methoxybenzonitrile (500 mg, 3.31 mmol) was dissolved in methanol (40 ml). This 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, followed by sodium borohydride (876 mg, 23.16 mmol) in portions . The reaction mixture was stirred, allowed to warm to room temperature and stirred for 3 days. MeOH was removed in vacuo. The residue was dissolved in CHCl ₃ (150 ml), washed with saturated NaHCO ₃ (aq) (50 ml), water (50 ml), brine (50 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by chromatography (silica gel) eluting with 20% EtOAc/80% petroleum ether to give a white solid identified as (2-fluoro-3-methoxybenzyl)carbamic acid tert-butyl ester (540 mg, 0.2 mmol, yield 64%).

[MH] ⁺ =255.8

Q. 2-Fluoro-3-methoxybenzylamine hydrochloride

(2-Fluoro-3-methoxybenzyl)carbamic acid tert-butyl ester (600 mg, 2.35 mmol) was dissolved in 4M HCl in dioxane (40 ml). After standing for 2 hours at room temperature, the solvent was removed in vacuo to yield a pale yellow solid identified as 2-fluoro-3-methoxybenzylamine hydrochloride (414 mg, 2.17 mmol, 92% yield).

[MH] ⁺ =155.9

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 mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, water was added, separated, washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. Flash chromatography gave 1-tert-butyl-4-ethyl-3-aminopyrazole-1,4-dicarboxylate as a white solid (122 mg, 30% yield).

[MH] ⁺ =256.2

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, then heated at reflux for 2 hours. Excess acetyl chloride was removed in vacuo. Water was added and the resulting mixture was stirred for 18 hours at room temperature. 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 x 15 ml) and the combined organic layers were dried (MgSO ₄ ), filtered and concentrated in vacuo to give another batch of ethyl 3-acetamido-1H-pyrazole-4-carboxylate (48 mg) ( total yield 94 mg, 99%).

[MH] ⁺ =197.8

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 filtrates were 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

Example 1

N-(3,5-Dimethoxybenzyl)-3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxamide

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) were added N,N-diisopropylethylamine (99 μl , 0.566 mmol) and the mixture was left to stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography loaded into DCM, eluting using a gradient of 1 to 10% MeOH (containing 0.3% NH ₃ )/DCM to obtain a resin. This substance was dissolved in acetonitrile (0.5 ml) and water (3 ml) was added, and a precipitate formed. This material 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, td, 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, dd, 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

Example 2

2-Fluoro-3-methoxy-benzylamide 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 (75 mg, 0.23 mmol) was dissolved in DCM (20 ml) and DMF (1 ml). This solution was cooled to 0°C. 2-Fluoro-3-methoxybenzylamine hydrochloride (53 mg, 0.28 mmol) was added, followed by HOBt (34 mg, 0.25 mmol) and triethylamine (70 mg, 0.69 mmol). Water-soluble carbodiimide (53 mg, 0.28 mmol) was then 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) and washed with NaHCO ₃ (aq) (50 ml), water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuum. The residue was purified by flash chromatography (silica gel) eluting with 4% MeOH/96% CHCl ₃ to give a white solid identified as 2-fluoro-3-methoxy-benzylamide 3-amino-1-[4-(2-oxo- 2H-pyridin-1-ylmethyl)benzyl]-1H-pyrazole-4-carboxylic acid (92 mg, 0.20 mmol, 86% yield).

[MH] ⁺ =462.2

^1H 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 ).

Example 3

2-Fluoro-3-methoxy-benzylamide 1-(7-chloroquinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid

(7-chloroquinolin-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. Triethylamine (1.0 mL, 7.23 mmol) and isobutyl chloroformate (0.38 mL, 2.9 mmol) were added to this solution. The reaction mixture was stirred at -20°C for 20 minutes 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 hours. 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 (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give a yellow solid. The solid was purified by chromatography on silica gel, 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

3-Bromomethyl-7-chloroquinoline

(7-chloroquinolin-3-yl)-methanol (134 mg, 0.692 mmol) was dissolved in DCM (5 ml). PBr was added₃ (65 μl, 0.692 mmol) and the reaction mixture was stirred for 3 hours at room temperature. After completion, the reaction mixture was quenched with dilute NaHCO₃ (aq) (10 ml). The layers were separated and the organic layer was washed with water (10 ml) and brine (10 ml). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo yielding a yellow solid identified as 3-bromomethyl-7-chloroquinoline (78 mg, 44% yield).

[MH] ⁺ =257.6

1-(7-Chloroquinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester

Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (51 mg, 0.304 mmol; CAS no. 318496-66-1 (synthesized according to the method described in WO 2012/009009)) was taken up in DMF (2 ml) and treated with potassium carbonate (84 mg, 0.608 mmol) and 3-bromomethyl-7-chloroquinoline (78 mg, 0.304 mmol). The reaction mixture was stirred overnight at room temperature. EtOAc (60 ml) and water (20 ml) were added and the layers were separated. The organic layer was washed with water (3 x 10 ml), brine (10 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was purified by chromatography, eluting with EtOAc/petroleum ether to give two isomeric products. The more rapidly released product was identified as an undesired regioisomer. The slower release 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

1-(7-Chloroquinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid

To 1-(7-chloroquinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (53 mg, 0.153 mmol) in ethanol (10 ml), sodium hydroxide (61 mg, 1.53 mmol) and the reaction mixture was heated at high reflux for 4.5 hours. The mixture was cooled and concentrated in vacuo. The residue was diluted with water (5 ml), adjusted to pH 3.6 with 2M HCl and extracted with 90% chloroform/10% isopropyl alcohol (6 x 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 1-(7-chloroquinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid as a pale yellow solid ( 50 mg, yield 98%).

[MH] ⁺ =332

2-Fluoro-3-methoxy-benzylamide 1-(7-chloroquinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid

1-(7-chloroquinolin-3-ylmethyl)-3-methoxymethyl-1H-pyrazole-4-carboxylic acid (25 mg, 0.075 mmol) was taken up in DCM (5 ml) at 0°C. Triethylamine (52 μL, 0.377 mmol), HOBt (12 mg, 0.09 mmol), and water-soluble carbodiimide (20 mg, 0.106 mmol) were added to the solution. After 15 minutes, 2-fluoro-3-methoxybenzylamine hydrochloride (14 mg, 0.075 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred over the weekend. The reaction mixture was diluted with CHCl ₃ (50 ml) and washed with saturated aqueous NaHCO ₃ (20 ml), then water (20 ml) and brine (20 ml). The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with 6% methanol/94% DCM to give a white solid (16 mg, 45% yield) identified as 2-fluoro-3-methoxybenzylamide 1-(7-chloroquinolin-3-ylmethyl)- 3-methoxymethyl-1H-pyrazole-4-carboxylic acid.

[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=2.2 Hz)

Example 41

3-Fluoro-4-methoxypyridine-2-carbonitrile

Copper cyanide (1.304 g, 14.56 mmol) was added to a large microwave vial to a solution of 2-bromo-3-fluoro-4-methoxypyridine (1 g, 4.85 mmol) in DMF (5 mL). The reaction vessel was sealed and heated to 100°C for 16 hours. The reaction mixture was diluted with water (20 ml) and EtOAc (20 ml). The viscous suspension was sonicated and additional water (40 mL) and EtOAc (2 x 50 mL) with sonication were required to break up the precipitated solid. The combined layers were filtered through a celite plug and the organic layer was isolated, washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to yield a pale green solid identified as the title compound 3-fluoro- 4-methoxypyridine-2-carbonitrile (100 mg, 0.578 mmol, 12% yield)

(3-Fluoro-4-methoxypyridin-2-ylmethyl)-carbamic acid tert-butyl ester

3-Fluoro-4-methoxypyridine-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 in an ice-salt bath to -5°C and then sodium borohydride (153 mg, 4.05 mmol) was added portionwise, maintaining the temperature of the reaction mixture at ~0°C. The dark brown solution was left to stir at 0°C and allowed to warm slowly to room temperature and then left to stir at room temperature for 3 hours. The reaction mixture was evaporated to dryness at 40°C to obtain a black residue, which was diluted with DCM (10 ml) and washed with sodium hydrogen carbonate (10 ml). An emulsion formed and the organic layers were separated through a phase separation cartridge and concentrated. The crude liquid was purified by chromatography, eluting with EtOAc/isohexane, to give the title compound, (3-fluoro-4-methoxypyridin-2-ylmethyl)carbamic acid tert-butyl ester, as a clear yellow oil (108 mg, 62% yield). )

[MH] ⁺⁼ 257

C-(3-Fluoro-4-methoxypyridin-2-yl)methylamine, hydrochloride salt

(3-Fluoro-4-methoxypyridin-2-ylmethyl)carbamic acid tert-butyl ester (108 mg, 0.358 mmol) was taken up in isopropyl alcohol (1 ml) and then HCl (6N in isopropyl alcohol) (1 ml, 0.578 mmol) was added ) at room temperature and left to stir at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure and then triturated with diethyl ether, sonicated and then decanted to give a cream-colored solid (75 mg, 55% yield), identified as C-(3-fluoro-4-methoxypyridinium-hydrochloride salt). 2-yl)-methylamine.

[MH] ⁺⁼ 157

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-( hydrochloride salt 3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine (49 mg, 0.212 mmol) and HATU (89 mg, 0.233 mmol) were suspended in anhydrous DCM (3 ml), triethylamine (177 µl, 1.270 mmol), sonicated and then left to stir 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). An off-white solid was obtained which was sonicated, filtered under reduced pressure, washed with water and then kept in a vacuum oven at 40°C overnight. The crude material was purified by chromatography, eluting with (1% ammonia-methanol)/DCM to give (3-fluoro-4-methoxy-pyridin-2-ylmethyl)amide 3-methoxymethyl-1-[4-(2-oxo-2H -pyridin-1-ylmethyl)benzyl]-1H-pyrazole-4-carboxylic acid 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, 8.9 Hz), 7.75 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J=5.4Hz)

Example 77

6-Bromo-2-fluoro-3-methoxybenzoic acid

Bromine (6.06 mL, 118 mmol) was added dropwise to a suspension of 2-fluoro-3-methoxybenzoic acid (10 g, 58.8 mmol) in acetic acid (50 mL) and water (50 mL) at room temperature. The reaction mixture was then heated to 60°C for 1 hour. The reaction mixture was cooled to room temperature and the white precipitate was filtered. The solid was washed with water (200 ml) and isohexane (50 ml) to give 6-bromo-2-fluoro-3-methoxybenzoic acid as a white solid, 12.098 g, 82% yield.

[MH] ⁺ =249/251

(6-Bromo-2-fluoro-3-methoxyphenyl)methanol

To a stirred solution of 6-bromo-2-fluoro-3-methoxybenzoic 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 hour, the reaction mixture was filtered to remove any salts formed, and the solid was washed with additional THF (10 ml). The filtrate and washes were combined and cooled to 0°C in an ice bath and then NaBH ₄ (0.659 g, 17.41 mmol) in cold water (10 ml) was added in one portion (gassing occurred), then allowed to warm to room temperature and stirred within 2 hours. The reaction mixture was quenched by carefully adding 1M 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 x 100 ml) to remove the starting carboxylic acid, then acidified by washing with 1M HCl (100 ml), then brine (100 ml), dried over magnesium sulfate, filtered and the solvent was removed in a vacuum. The crude product was purified by chromatography, eluting with 0-50% EtOAc/isohexane to give (6-bromo-2-fluoro-3-methoxyphenyl)methanol as a colorless oil, 1.37 g, 50% yield.

[MH] ⁺ =217/219

1-Bromo-2-chloromethyl-3-fluoro-4-methoxybenzene

A solution of (6-bromo-2-fluoro-3-methoxyphenyl)methanol (500 mg, 2.127 mmol) in anhydrous DCM (4 mL) was treated with triethylamine (415 μL, 2.98 mmol) then methanesulfonyl chloride (214 μL, 2.77 mmol). The mixture was left to stir at ambient temperature overnight. The reaction mixture was partitioned between DCM (50 ml) and saturated aqueous NH ₄ Cl (40 ml). The organic layer was collected and the aqueous layer was extracted with additional DCM (40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by chromatography, eluting with a 0 to 30% EtOAc/isohexane gradient to give 1-bromo-2-chloromethyl-3-fluoro-4-methoxybenzene (468 mg, 86% yield) as a white solid.

2-(6-Bromo-2-fluoro-3-methoxybenzyl)isoindole-1,3-dione

To a solution of 1-bromo-2-chloromethyl-3-fluoro-4-methoxybenzene (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 for nights. The mixture was diluted with EtOAc (75 ml) and washed with water (3 x 35 ml), brine (35 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give a yellow solid. The crude material was purified by flash chromatography, eluting using a 0 to 50% EtOAc/isohexane gradient. The target product 2-(6-bromo-2-fluoro-3-methoxybenzyl)isoindole-1,3-dione was isolated in the form of white needle crystals, 372 mg, yield 56%.

[MH] ⁺ =364.0/366.0

6-Bromo-2-fluoro-3-methoxybenzylamine

A suspension of 2-(6-bromo-2-fluoro-3-methoxybenzyl)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 heated at reflux for 5 hours. The crude mixture was loaded directly onto an SCX column (8 g), washed with MeOH and eluted with 1% NH ₃ /MeOH to give 6-bromo-2-fluoro-3-methoxybenzylamine (204 mg, 85% yield) as a yellow oil

[MH] ⁺⁼ 233.9/235.9

6-Bromo-2-fluoro-3-methoxy-benzylamide 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid

3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (130 mg, 0.368 mmol) was charged into a 25 mL flask. , (6-bromo-2-fluoro-3-methoxybenzylamine (86 mg, 0.368 mmol), HATU (154 mg, 0.405 mmol), anhydrous DCM (3 ml) and anhydrous DMF (0.5 ml). N,N was added -diisopropylethylamine (160 μl, 0.920 mmol) and the mixture was left to stir at ambient temperature overnight. The reaction mixture was concentrated under vacuum and redissolved in MeOH (4 ml), then purified by SCX, washing with MeOH, eluting. 1% NH ₃ /MeOH. The residue was purified again by chromatography, eluting with a gradient of 0 to 10% MeOH (containing 0.3% NH ₃ )/DCM to give 6-bromo-2-fluoro-3-methoxybenzylamide 3- methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)benzyl]-1H-pyrazole-4-carboxylic acid (191 mg, 89% yield) as a white foam.

[MH] ⁺⁼ 569.2/571.2

6-Cyano-2-fluoro-3-methoxy-benzylamide 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid

To a degassed solution of dicyanozinc (24.13 mg, 0.205 mmol) and 6-bromo-2-fluoro-3-methoxybenzylamide 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)benzyl]- 1H-pyrazole-4-carboxylic acid (90 mg, 0.158 mmol) in dimethylacetamide (1.2 ml), tetrakis(triphenylphosphine) palladium(0) (18.26 mg, 0.016 mmol) was added and the mixture was heated to 110°C for nights. The mixture was purified by chromatography, eluting using a 0 to 10% (0.3% NH ₃ /MeOH)/DCM gradient to give 6-cyano-2-fluoro-3-methoxy-benzylamide 3-methoxymethyl-1-[4- (2-oxo-2H-pyridin-1-ylmethyl)benzyl]-1H-pyrazole-4-carboxylic acid as a pale yellow foam, 21 mg, 25% yield.

[MH] ⁺⁼ 516.3

^1H NMR ( ^d6 -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, dd, 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)

Example 83

2-chloro-3-fluoro-6-methoxybenzaldehyde

Sodium hydride (1.318 g, 33.0 mmol) was slowly added to the ice-salt bath cooled flask containing methanol (8 mL, 198 mmol). Once the addition was complete, the cooling bath was removed and the mixture was then allowed to warm 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 heated to 60°C. While the temperature of the reaction mixture was 60°C, sodium methoxide solution was slowly added to the mixture. Once the addition was complete, the reaction mixture was left to warm at 60°C overnight. The solvent was removed under reduced pressure to obtain a bright yellow solid, which was quenched with water (100 ml), sonicated and then left to stir for 30 minutes. The resulting yellow solid was filtered, washed with water and then left to dry under reduced pressure before being transferred to a vacuum oven at 40°C overnight. The crude material was purified by chromatography, eluting with EtOAc/isohexane, to give the title compound, 2-chloro-3-fluoro-6-methoxybenzaldehyde, as an off-white solid, 3.19 g, 61% yield.

[MH] ⁺⁼ 189/191

2-Chloro-3-difluoromethyl-1-fluoro-4-methoxybenzene

2-Chloro-3-fluoro-6-methoxybenzaldehyde (2 g, 10.61 mmol) was dissolved in anhydrous DCM (30 mL, 466 mmol) under a nitrogen balloon and cooled in an ice-salt bath. Diethylaminosulfur trifluoride (4.20 mL, 31.8 mmol) was added dropwise to the solution to obtain a yellow solution. The reaction mixture was stirred at 0°C for 5 minutes and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was slowly quenched in saturated sodium hydrogen carbonate solution (100 ml), the organic layer was separated, washed with saturated saline (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/isohexane. 2-Chloro-3-difluoromethyl-1-fluoro-4-methoxybenzene (1.0 g, 43% yield) was isolated as a pale yellow oil which solidified on standing.

2-Difluoromethyl-6-fluoro-3-methoxybenzonitrile

2-Chloro-3-difluoromethyl-1-fluoro-4-methoxybenzene (1 g, 4.75 mmol) was dissolved in anhydrous dimethylacetamide (7 ml, 74.7 mmol), dicyanozinc (0.558 g, 4.75 mmol) was added to the resulting solution mmol). The reaction mixture was bubbled with nitrogen for 20 minutes, then tris(dibenzylideneacetone)dipalladium(0) (0.087 g, 0.095 mmol) and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.139 g, 0.190) were added mmol). The reaction mixture was heated at 150°C overnight under a nitrogen atmosphere. The reaction mixture was quenched in water (100 ml) and then extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with brine (3 x 200 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a dark brown oil. The crude product was purified by chromatography eluting with EtOAc/isohexane to give 2-difluoromethyl-6-fluoro-3-methoxybenzonitrile (182 mg, 17% yield) as a brown solid.

[MH] ⁺⁼ 202.1

(2-Difluoromethyl-6-fluoro-3-methoxybenzyl)carbamic acid tert-butyl ester

2-(Difluoromethyl)-6-fluoro-3-methoxybenzonitrile (182 mg, 0.778 mmol) was dissolved in anhydrous methanol (5 ml, 124 mmol), nickel chloride hexahydrate (19 mg, 0.078 mmol) was added to the resulting solution, followed by di-tert-butyl dicarbonate (343 mg, 1.556 mmol). The resulting pale green solution was cooled in an ice-salt bath to -5°C and then sodium borohydride (206 mg, 5.45 mmol) was added portionwise, maintaining the temperature of the reaction mixture at ~0°C. The dark brown solution was left to stir at 0°C and allowed to warm slowly to room temperature overnight. The solvent was removed under reduced pressure and then the mixture was partitioned between DCM (10 ml) and water (10 ml). The aqueous phase was again extracted with DCM (2 × 10 ml). The combined organic layers were washed with brine (10 ml), dried using a phase separator cartridge and concentrated in vacuo. The crude product was purified by chromatography, eluting with EtOAc/isohexane, to give (2-difluoromethyl-6-fluoro-3-methoxybenzyl)carbamic acid tert-butyl ester as a white waxy solid (158 mg, 63% yield).

[MNa] ⁺⁼ 328

2-Difluoromethyl-6-fluoro-3-methoxybenzylamine hydrochloride

(2-Difluoromethyl-6-fluoro-3-methoxybenzyl)carbamic acid tert-butyl ester (158 mg, 0.492 mmol) was taken up in isopropyl alcohol (1 ml) and then HCl (6N in isopropyl alcohol) (1 ml, 0.778 mmol) was added ) and stirred at 40°C for 1 hour. An off-white precipitate formed and was collected by vacuum filtration and washed with isopropyl alcohol (1 ml) to give the title product 2-difluoromethyl-6-fluoro-3-methoxybenzylamine hydrochloride as an off-white solid (43 mg, yield 22 %).

[MH] ⁺⁼ 206

2-Difluoromethyl-6-fluoro-3-methoxybenzylamide 3-methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)benzyl]-1H-pyrazole-4-carboxylic acid

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-methoxybenzylamine hydrochloride (40.2 mg, 0.163 mmol) and HATU (68.3 mg, 0.180 mmol) were suspended in anhydrous DCM (3 ml), triethylamine (91 μl, 0.653 mmol) was added to the mixture, sonicated and then left to stir at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was quenched with ammonium chloride solution (5 ml), resulting in the formation of a pale brown solid, which was left to stir at room temperature over the weekend. The solid was filtered under reduced pressure, washed with water, dried under reduced pressure and then placed in an oven at 50°C for 3 hours. Target product, 2-difluoromethyl-6-fluoro-3-methoxy-benzylamide 3-,ethoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (74 mg, 83% yield) was isolated as a free-flowing creamy 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)

Example 126

5-Bromomethyl-2-fluoropyridine

2-Fluoro-5-methylpyridine (5.0 g, 45 mmol) was dissolved in 1,2-dichloroethane (120 ml). N-bromosuccinimide (9.61 g, 54 mmol) and azobiisobutyronitrile (739 mg, 4.5 mmol) were added to this solution. The reaction mixture was stirred at reflux (95°C) for 5 hours, then the reaction mixture was cooled to room temperature. The reaction mixture was diluted with CHCl ₃ (50 ml) and washed with saturated NaHCO ₃ solution (1 x 20 ml), water (1 x 20 ml), then brine (1 x 20 ml), dried (Na ₂ SO ₄ ) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica gel), eluting with 10% EtOAc, 90% petroleum ether to give a colorless oil identified as 5-bromomethyl-2-fluoropyridine, 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)

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), 5-bromomethyl-2-fluoro-pyridine (1.3 g, 6. 84 mmol) and cesium carbonate (6.69 g, 20.53 mmol). The reaction mixture was stirred at 50°C for 18 hours, then the reaction mixture was diluted with EtOAc (100 ml), washed with water (1 x 30 ml), brine (1 x 30 ml), dried (Na ₂ SO ₄ ) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica gel), eluting with 85% petroleum ether, 15% EtOAc to give a white foamy solid (1.26 g, 58% yield), identified as 1-(6-fluoro-pyridine-3- ethyl ester). ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid.

[MMeCN] ⁺⁼ 358.75

1-(6-Fluoropyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid

1-(6-Fluoropyridin-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 hours, after which the solvent was concentrated in vacuo and the residue was taken up in EtOAc (50 ml). The aqueous layer was extracted and acidified with 1M HCl to pH2 and extracted with CHCl ₃ (3 x 50 ml). The combined extracts were washed with water (1 x 30 ml), then brine (1 x 30 ml), dried (Na ₂ SO ₄ ) and filtered through PS paper and evaporated in vacuo. The residue was purified by chromatography (silica gel), eluting with 3% MeOH, 97% CHCl ₃ to give a colorless oil identified as 1-(6-fluoropyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid, 946 mg, yield 82%.

[MH] ⁺ =289.82

1-(6-Pyrrolidin-1-ylpyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid

1-(6-Fluoropyridin-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. Once complete, the reaction mixture was diluted with EtOAc (100 ml), this solution was washed with water (1 x 30 ml), brine (1 x 30 ml), dried (Na ₂ SO ₄ ) and filtered through PS paper and evaporated in vacuum . The residue was purified by chromatography eluting with 1% AcOH, 9% MeOH, 90% CHCl ₃ to give a white foamy solid (267 mg, 76% yield) identified as 1-(6-pyrrolidin-1-ylpyridin-3-ylmethyl )-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid.

MH] ⁺ =340.72

1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 2-Fluoro-3-methoxybenzylamide

2-Fluoro-3-methoxybenzylamine hydrochloride (56 mg, 0.294 mmol) and 1-(6-pyrrolidin-1-ylpyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (100 mg, 0.294 mmol ) were combined and absorbed in DCM (10 ml) at 0°C. HOBt (48 mg, 0.353 mmol), triethylamine (205 μL, 1.469 mmol) and water-soluble carbodiimide (79 mg, 0.411 mmol) were added to the solution. The reaction mixture was allowed to warm to room temperature and the mixture was stirred for 3 days. The reaction mixture was diluted with CHCl ₃ (50 ml) and saturated aqueous NaHCO ₃ (20 ml) was added. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by chromatography, eluting with MeOH/DCM, to give the title product, 1-(6-pyrrolidin-1-ylpyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 2-fluoro-3-methoxybenzylamide acid, as a white solid, 95 mg, yield 68%.

[MH] ⁺⁼ 478.0

^1H 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)

Table 1 Example number R14 R15 R16 R17 18 Free base molecular weight [M+H] ⁺ 4 F Ome H H H 501.5 501.8 5 H OMe H H H 483.5 484.1 6 H OEt H H H 497.5 497.6 7 H OCF ₃ H H H 537.5 537.8 8 H H Me H H 467.5 468.1 9 H Ome H H F 501.5 501.9 10 Ome H OMe H H 513.5 513.8 eleven F H OMe H F 519.5 520.0 12 CF ₃ H Ome H H 551.5 551.8 13 F H H H F 489.4 490.0 14 F H H H Cl 505.9 506.0 15 F H H H CF ₃ 539.4 540.0 16 F H Cl H F 523.9 523.9 17 F H Cl H H 505.9 506.0 18 F Cl H H F 523.9 523.9 19 F Cl H H H 505.9 505.9 20 F H H Cl H 505.9 505.8 21 F Cl H H CF ₃ 573.9 573.8 22 Cl H H H Cl 522.4 593.9 23 H H Cl H CF ₃ 555.9 555.8 24 Me H Me H H 481.5 481.9 25 Me H H H Me 481.5 481.9 26 Me H Me H Me 495.5 496.1 27 Me F H H H 485.5 485.9 28 F H Me H H 485.5 486.1

table 2 Example number R14 R15 Free base
Mol. weight [M+H] ⁺ 29 F H 472.4 472.9 thirty H Cl 488.9 488.9

Table 3 Example number R14 R15 R16 R18 Free base
Mol. weight [M+H] ⁺ 31 CF ₃ H H H 511.5 512.0 32 H H Me H 457.5 458.3 33 F Ome H H 491.5 34 NHCOMe H H H 500.5 35 F H H CF ₃ 529.5 36 H H H CF ₃ 511.5 512.3 37 CF ₃ H H H 511.5 512.0 38 F H H H 461.5 39 H H Me H 457.5 458.3

Table 4 Example number R14 R15 R17 Free base
Mol. weight [M+H] ⁺ 40 H H Ome 473.5 474.0 41 F OMe H 491.5 492.0 42 F H OMe 491.5 492.3

Table 5 Example number R14 R16 Free base
Mol. weight 43 Cl H 483.0 44 Cl Me 497.0

Table 6 Example number A Free base
Mol. weight [M+H] ⁺ 45 533.0 533.0 46 496.0 495.9 47 520.0 520.0

Table 7 Example number R5 R14 R15 R16 R17 R18 Free base
Mol. weight [M+H] ⁺ 48 CONH ₂ H H H H 481.5 482.0 49 H CONH ₂ H H H 481.5 481.6 50 H H CONH ₂ H H 481.5 481.7 51 CF3 F H H H CF3 552.4 552.9 52 F Ome H H H 486.5 486.8 53 _CH2OMe F Ome H H H 490.5 491.0 54 _CH2OMe F Ome H H Ome 520.6 521.2 55 NHMe F Ome H H H 475.5 56 NHCH ₂ CH ₃ F Ome H H H 489.5 57 NHCH(M) ₂ F Ome H H H 503.6 58 NH ₂ H H OCF ₃ H H 497.5 497.6 59 NMe ₂ F Ome H H H 489.5 490.2 60 NH ₂ F Ome H H F 479.5 61 NHMe F Ome H H F 493.5 62 _CH2OMe F H H H H 460.5 461.2 63 _CH2OMe CF ₃ H H H H 510.5 511.3 64 _CH2OMe F H H Ome H 490.5 491.3 65 _CH2OMe F H Me H H 474.5 475.3 66 _CH2OMe F Ome H H F 508.5 509.0 67 _CH2OMe H Cl H OMe H 507.0 507.0 68 _CH2OMe CHF ₂ H H H H 492.5 493.0 69 _CH2OMe CHF ₂ Ome H H H 522.5 523.0 70 NH ₂ F H H H CF ₃ 499.5 500.0 71 NHCOMe F OMe H H H 503.5 504.0 72 NMeCOMe F Ome H H H 517.6 518.0 73 _CH2OMe F Cl H H F 512.9 513.2 74 _CH2OMe F Ome Me H H 504.6 75 _CH2OMe CN H H Ome H 497.5 76 _CH2OMe CN H H Cl H 502.0 502.2 77 _CH2OMe F Ome H H CN 515.5 516.3 78 _CH2OMe CF ₃ Ome H H H 540.5 541.1 79 _CH2OMe CF ₃ H H Ome H 540.5 541.1 80 _CH2OMe CHF ₂ H H H F 510.5 511.2 81 _CH2OMe CHF ₂ H H Ome H 522.5 523.1 82 _CH2OMe CHF ₂ H H Ome F 540.5 83 _CH2OMe CHF ₂ Ome H H F 540.5 541.2 84 _CH2OMe Cl H H OMe H 507.0 85 _CH2OMe CONH ₂ H H H F 503.5 504.3 86 _CH2OMe CONH ₂ H H OMe H 515.6 516.3 87 _CH2OMe COOH H H H H 486.5 487.1 88 _CH2OMe H H H F 528.5 89 _CH2OMe H H H F 528.5 90 _CH2OMe F OCHF ₂ H H H 526.5 527.2 91 _CH2OMe H OCHF ₂ H H H 508.5 509.2 92 _CH2OMe F H H H OCF ₂ 526.5 527.3 93 _CH2OMe F H Me H CH ₂ 524.5 94 _CH2OMe F H H F H 478.5 479.0 95 _CH2OMe H Ome H F H 490.5 491.3 96 _CH2OMe F OMe H F H 508.5 509.0 97 _CH2OMe F H H H Me 474.5 475.0 98 _CH2OMe F OMe H Cl H 525.0 99 _CH2OMe F OMe H H Cl 525.0 525.0 100 _CH2OMe F OMe H H CF3 558.5 101 _CH2OMe F H Me H CF3 542.5 102 _CH2OMe F H Cl H CF3 562.9 103 CN F Ome H H H 471.5 129 _CH2OMe F OH H H H 476.5 477.0 130 NH ₂ F OH H H H 447.5 447.9 131 _CH2OMe COOMe H H H H 500.6 501.1 132 _CH2OMe F CH ₂ Me H H H 488.6 489.3 133 CHOMe H OMe H H H 472.5 473.1

Table 8 Example number A R5 R18 Free base
Mol. weight [M+H] ⁺ 104 _CH2OMe H 491.5 492.0 105 _CH2OMe F 526.5 106 _CH2OMe F 522.5 523.0 107 _CH2OMe H 508.5 108 _CH2OMe F 526.5 527.0 109 _CH2OMe F 552.6 553.0 110 _CH2OMe H 507.6 111 _CH2OMe H 482.5 112 _CH2OMe H 496.6 113 NH ₂ H 448.5 134 _CH2OMe CN 502.5 135 _CH2OMe CN 479.5 136 CF ₃ CN 503.5 114 _CH2OMe H 508.5 115 _CH2OMe H 525.0 116 _CH2OMe F 444.5 117 _CH2OMe H 431.4 118 _CH2OMe H 465.4 119 _CH2OMe H 467.4

Table 9 Example number R5 Free base
Mol. weight [M+H] ⁺ 121 Me 460.5 461.0 122 NH ₂ 461.5 123 486.5 124 CF ₃ 514.5 515.0 125 _CH2OMe 490.5

Table 10 Example number R5 R18 Free base
Mol. weight [M+H] ⁺ 126 CF ₃ H 477.5 478.0 127 NH ₂ H 424.5 128 _CH2OMe H 453.5 137 _CH2OMe CN 478.5 138 CF ₃ CN 502.5

Table 11 Example number T Free base
Mol. weight [M+H] ⁺ 139 Me 519.0 519.1 140 H 505.0 505.1

Table 12
Connection names Example number Name 4 N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 5 N-[(3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 6 N-[(3-ethoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 7 1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-N-{[3-(trifluoromethoxy)phenyl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide 8 N-[(4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 9 N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 10 N-[(2,4-dimethoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide eleven N-[(2,6-difluoro-4-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 12 N-{[4-methoxy-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide 13 N-[(2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 14 N-[(2-chloro-6-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 15 N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide 16 N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 17 N-[(4-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 18 N-[(3-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 19 N-[(3-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 20 N-[(5-chloro-2-fluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 21 N-{[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl) pyrazole-4-carboxamide 22 N-[(2,6-dichlorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 23 N-{[5-chloro-2-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide 24 N-[(2,4-dimethylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 25 N-[(2,6-dimethylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 26 1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)-N-[(2,4,6-trimethylphenyl)methyl]pyrazol-4-carboxamide 27 N-[(3-fluoro-2-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 28 N-[(2-fluoro-4-methylphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 29 N-[(3-fluoropyridin-2-yl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide thirty N-[(4-chloropyridin-2-yl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide 31 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrazol-4- carboxamide 32 3-(methoxymethyl)-N-[(6-methylpyridin-3-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 33 N-[(4-fluoro-5-methoxypyridin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 34 N-[(4-acetamidopyridin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 35 N-{[4-fluoro-2-(trifluoromethyl)pyridin-3-yl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl) pyrazole-4-carboxamide 36 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(trifluoromethyl)pyridin-3-yl]methyl}pyrazol-4- carboxamide 37 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethyl)pyridin-3-yl]methyl}pyrazol-4- carboxamide 38 N-[(4-fluoropyridin-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 39 3-(methoxymethyl)-N-[(6-methylpyridin-3-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 40 3-(methoxymethyl)-N-[(6-methoxypyridin-2-yl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 41 N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 42 N-[(3-fluoro-6-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 43 N-[(3-chlorothiophen-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 44 N-[(3-chloro-5-methylthiophen-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 45 N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 46 N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazol-4- carboxamide 47 N-[(5-chloro-1-benzothiophen-3-yl)methyl]-3-(methoxymethyl)-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazol-4 -carboxamide 48 N-[(2-carbamoylphenyl)methyl]-3-cyclopropyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 49 N-[(3-carbamoylphenyl)methyl]-3-cyclopropyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 50 N-[(4-carbamoylphenyl)methyl]-3-cyclopropyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 51 N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazole-4- carboxamide 52 3-cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 53 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 54 N-[(2-fluoro-3,6-dimethoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 55 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 56 3-(ethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 57 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(isopropylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 58 3-amino-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[4-(trifluoromethoxy)phenyl]methyl}pyrazole-4-carboxamide 59 3-(dimethylamino)-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 60 3-amino-N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 61 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methylamino)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 62 N-[(2-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 63 3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-{[2-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxamide 64 N-[(2-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 65 N-[(2-fluoro-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 66 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 67 N-[(3-chloro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 68 N-{[2-(difluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 69 N-{[2-(difluoromethyl)-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 70 3-amino-N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 71 3-acetamido-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 72 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(N-methylacetamido)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 73 N-[(3-chloro-2,6-difluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 74 N-[(2-fluoro-3-methoxy-4-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 75 N-[(2-cyano-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 76 N-[(5-chloro-2-cyanophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 77 N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 78 N-{[3-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4- carboxamide 79 N-{[5-methoxy-2-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4- carboxamide 80 N-{[2-(difluoromethyl)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 81 N-{[2-(difluoromethyl)-5-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 82 N-{[6-(difluoromethyl)-2-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole -4-carboxamide 83 N-{[2-(difluoromethyl)-6-fluoro-3-methoxyphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole -4-carboxamide 84 N-[(2-chloro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 85 N-[(2-carbamoyl-6-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 86 N-[(2-carbamoyl-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 87 2-({[3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazol-4-yl]formamido}methyl)benzoic acid 88 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 89 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 90 N-{[3-(difluoromethoxy)-2-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 91 N-{[3-(difluoromethoxy)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 92 N-{[2-(difluoromethoxy)-6-fluorophenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 93 N-{[2-(difluoromethyl)-6-fluoro-4-methylphenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole -4-carboxamide 94 N-[(2,5-difluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 95 N-[(3-fluoro-5-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 96 N-[(2,5-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 97 N-[(2-fluoro-6-methylphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 98 N-[(5-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 99 N-[(6-chloro-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4 -carboxamide 100 N-{[2-fluoro-3-methoxy-6-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl) pyrazole-4-carboxamide 101 N-{[2-fluoro-4-methyl-6-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl) pyrazole-4-carboxamide 102 N-{[4-chloro-2-fluoro-6-(trifluoromethyl)phenyl]methyl}-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl) pyrazole-4-carboxamide 103 3-cyano-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 129 N-[(2-fluoro-3-hydroxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 130 3-amino-N-[(2-fluoro-3-hydroxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 131 methyl 2-({[3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazol-4-yl]formamido}methyl)benzoate 132 N-[(3-ethyl-2-fluorophenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 133 3-(methoxymethyl)-N-[(3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 104 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyrazin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 105 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(4-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole -4-carboxamide 106 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(4-methyl-2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole -4-carboxamide 107 1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)pyrazole-4 -carboxamide 108 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(5-fluoro-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole -4-carboxamide 109 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-1-({4-[(4-ethoxy-2-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole -4-carboxamide 110 N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(5-methoxy-4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazol-4 -carboxamide 111 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[5-(2-oxopyridin-1-yl)thiophen-3-yl]methyl}pyrazole-4-carboxamide 112 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({5-[(2-oxopyridin-1-yl)methyl]thiophen-3-yl}methyl)pyrazol-4 -carboxamide 113 3-amino-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide 134 6-cyano-2-fluoro-3-methoxy-benzylamide 3-methoxymethyl-1-[4-(4-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-pyrazol-4-carboxylic acid 135 6-cyano-2-fluoro-3-methoxy-benzylamide 3-methoxymethyl-1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-1H-pyrazol-4-carboxylic acid 136 1-(2-pyrrolidin-1-yl-pyrimidin-5-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide 114 N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-fluoro-6-oxopyridin-1-yl)methyl]phenyl}methyl)-3-(methoxymethyl)pyrazole-4 -carboxamide 115 1-({4-[(2-chloro-6-oxopyridin-1-yl)methyl]phenyl}methyl)-N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)pyrazole-4 -carboxamide 116 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({2-[(methylamino)methyl]phenyl}methyl)pyrazole-4-carboxamide 117 N-[(2,6-difluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(methylamino)pyridin-4-yl]methyl}pyrazole-4-carboxamide 118 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(2,2,2-trifluoroethyl)phenyl]methyl}pyrazole-4-carboxamide 119 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[2-(trifluoromethoxy)phenyl]methyl}pyrazole-4-carboxamide 121 N-[(2-fluoro-3-methoxyphenyl)methyl]-2-methyl-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide 122 2-amino-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide 123 2-cyclopropyl-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide 124 N-[(2-fluoro-3-methoxyphenyl)methyl]-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)-2-(trifluoromethyl)imidazole-4-carboxamide 125 N-[(2-fluoro-3-methoxyphenyl)methyl]-2-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)imidazole-4-carboxamide 126 N-[(2-fluoro-3-methoxyphenyl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}-3-(trifluoromethyl)pyrazole-4-carboxamide 127 3-amino-N-[(2-fluoro-3-methoxyphenyl)methyl]-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide 128 N-[(2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}pyrazole-4-carboxamide 137 6-cyano-2-fluoro-3-methoxy-benzylamide 3-methoxymethyl-1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-1H-pyrazol-4-carboxylic acid 138 1-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid 6-cyano-2-fluoro-3-methoxy-benzylamide 139 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 140 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

Table 13
NMR data examples (solvent d6 DMSO) Example number Chemical shift 4 1.98 (3H, s), 3.82 (3H, s), 4.39 (2H, d, J=5.7Hz), 5.22 (2H, s), 5.40 (2H, s) , 6.86-6.90 (1H, m), 7.04-7.10 (2H, m), 7.19-7.29 (5H, m), 7.53 (1H, s), 8 .43 (1H, s), 8.74 (1H, t, J=5.7Hz) 5 1.87 (3H, s), 3.72 (3H, s), 4.35 (2H, d, J =5.9Hz), 5.22 (2H, s), 5.41 (2H, s) , 6.80-6.86 (3H, m), 7.20 (2H, d, J =8.2Hz), 7.23-7.29 (4H, m), 7.53 (1H, s) , 8.42 (1H, s), 8.75 (1H, br.s) 6 1.30 (3H, t, J=6.9Hz), 1.98 (3H, s), 3.99 (2H, sq., J=7.0Hz), 4.34 (2H, d, J= 5.9Hz), 5.22 (2H, s), 5.41 (2H, s), 6.78-6.84 (3H, m), 7.19-7.27 (6H, m), 7 .53 (1H, s), 8.43 (1H, s), 8.75 (1H, t, J=5.8Hz) 7 1.98 (3H, s), 4.42 (2H, d, J=6.0Hz), 5.22 (2H, s), 5.41(2H, s), 7.19-7.33 ( 8H, m), 7.46 (1H, t, J=7.7Hz), 7.53 (1H, s), 8.43 (1H, s), 8.86 (1H, t, J=5, 9Hz) 8 1.98 (3H, s), 2.27 (3H, s), 4.32 (2H, d, J=5.8 Hz), 5.22 (2H, s), 5.40 (2H, s ), 7.11-7.23 (9H, m), 7.54 (1H, s), 8.42 (1H, s), 8.75 (1H, t, J=5.9 Hz) 9 1.98 (3H, s), 3.70 (3H, s), 4.37 (2H, d, J=5.7Hz), 5.23 (2H, s), 5.41 (2H, s) , 6.84-6.87 (2H, m), 7.09-7.13 (1H, m), 7.21-7.29 (5H, m), 7.54 (1H, s), 8 .44 (1H, s), 8.77 (1H, t, J=5.7Hz) 10 1.98 (3H, s), 3.74 (3H, s), 3.78 (3H, s), 4.25 (2H, d, J=5.6Hz), 5.23 (2H, s) , 5.40 (2H, s), 6.47 (1H, dd, J=8.4, 2.4Hz), 6.54 (1H, d, J=2.3Hz), 7.09 (1H, d, J=8.3Hz), 7.20 (2H, d, J=8.2Hz), 7.24 (1H, s), 7.28 (2H, d, J=8.1Hz), 7, 54 (1H, s), 8.44 (1H, d, J=0.6), 8.51 (1H, t, J =5.6Hz) eleven 1.98 (3H, s), 3.77 (3H, s), 4.33 (2H, d, J= 5.0Hz), 5.22 (2H, s), 5.38 (2H, s) , 6.74 (2H, d, J=9.7Hz), 7.19 (2H, d, J=8.1Hz), 7.24 (2H, d, J=3.7Hz), 7.26 ( 1H, s), 7.54 (1H, s), 8.37 (1H, s), 8.55 (1H, t, J=5.0Hz) 12 1.98 (3H, s), 3.81 (3H, s), 4.47 (2H, d, J=5.2Hz), 5.23 (2H, s), 5.42 (2H, s) , 7.20-7.24 (5H, m), 7.29 (2H, d, J=8.0Hz), 7.44 (1H, d, J=8.2Hz), 7.54 (1H, s), 8.46 (1H, s), 8.78 (1H, t, J=4.8Hz) 13 1.98 (3H, s), 4.42 (2H, d, J=5.1Hz), 5.22 (2H, s), 5.38 (2H, s), 7.06-7.09 ( 2H, m), 7.10-7.13 (2H, m), 7.18-7.26 (3H, m), 7.37-7.44 (1H, m), 7.54 (1H, s), 8.38 (1H, s), 8.65 (1H, t, J=5.1Hz) 14 1.98 (3H, s), 4.49-4.50 (2H, m), 5.21 (2H, s), 5.38 (2H, s), 7.18 (2H, d, J= 8.2Hz), 7.23-7.27 (4H, m), 7.34-7.43 (2H, m), 7.54 (1H, s), 8.38 (1H, s), 8 .55 (1H, t, J=4.8Hz) 15 1.98 (3H, s), 4.52 (2H, d, J=3.9Hz), 5.21 (2H, s), 5.38 (2H, s), 7.18 (2H, d, J=8.1Hz), 7.23-7.25 (3H, m), 7.53 (1H, s), 7.58-7.63 (3H, m), 8.35 (1H, s) , 8.51 (1H, t, J= 4.3Hz) 16 1.98 (3H, s), 4.38 (2H, d, J=5.1Hz), 5.22 (2H, s), 5.39 (2H, s), 7.18 (1H, s) , 7.20 (1H, s), 7.24 (2H, d, J=4.5Hz), 7.27 (1H, s), 7.38 (2H, d, J=7.4Hz), 7 .54 (1H, s), 8.36 (1H, s), 8.67 (1H, t, J=5.1Hz) 17 1.98 (3H, s), 4.38 (2H, d, J=5.6Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19 (1H, s) , 7.21 (1H, s), 7.24 (1H, s), 7.26-7.29 (3H, m), 7.37 (1H, t, J=8.2Hz), 7.43 (1H, dd, J=10.0, 2.0Hz), 7.55 (1H, s), 8.44 (1H, s), 8.82 (1H, t, J=5.8Hz) 18 1.98 (3H, s), 4.44 (2H, d, J=5.2 Hz), 5.22 (2H, s), 5.39 (2H, s), 7.18-7.27 (6H, m), 7.53 (1H, s), 7.58-7.62 (1H, m), 8.46 (1H, s), 8.71 (1H, t, J=5.2Hz ) 19 1.98 (3H, s), 4.44 (2H, d, J=5.6Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19-7.23 ( 4H, m), 7.27-7.32 (3H, m), 7.47-7.51 (1H, m), 7.53 (1H, s), 8.44 (1H,s), 8 .82 (1H, t, J= 5.6Hz) 20 1.98 (3H, s), 4.39 (2H, d, J=5.7Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19-7.30 ( 6H, m), 7.36-7.40 (2H, m), 7.54 (1H, s), 8.45 (1H, s), 8.80 (1H, t, J=5.7Hz) 21 1.98 (3H, s), 4.56 (2H, d, J=3.7 Hz), 5.21 (2H, s), 5.39 (2H, s), 7.19 (2H, d , J=8.1Hz), 7.24 (2H, d, J=2.8Hz), 7.26 (1H, s), 7.53 (1H, s), 7.65 (1H, d, J =8.6Hz), 7.82 (1H, t, J=7.8Hz), 8.35 (1H, s), 8.54 (1H, t, J=4.2Hz) 22 1.98 (3H, s), 4.61 (2H, d, J=4.4Hz), 5.21 (2H, s), 5.38 (2H, s), 7.18 (2H, d, J=8.2Hz), 7.22-7.26 (3H, m), 7.38-7.40 (1H, m), 7.49-7.53 (3H, m), 8.38 ( 1H, s), 8.45 (1H, t, J= 4.3Hz) 23 1.98 (3H, s), 4.54 (2H, d, J=5.6Hz), 5.23 (2H, s), 5.44 (2H, s), 7.20-7.24 ( 3H, m), 7.30 (2H, d, J=8.1Hz), 7.53 (2H, d, J=5.5Hz), 7.57 (1H, d, J=8.5Hz), 7.77 (1H, d, J=8.4Hz), 8.49 (1H, s), 8.90 (1H, t, J=5.8Hz) 24 1.98 (3H, s), 2.24 (6H, s), 4.31 (2H, d, J=5.6 Hz), 5.22 (2H, s), 5.40 (2H, s ), 6.95 (1H, d, J=7.7 Hz), 6.98 (1H, s), 7.10 (1H, d, J=7.6 Hz), 7.18-7.29 (5H, m), 7.54 (1H, s), 8.44 (1H, s), 8.60 (1H, t, J=5.6 Hz) 25 1.97 (3H, s), 2.31 (6H, s), 4.38 (2H, d, J=4.7 Hz), 5.21 (2H, s), 5.36 (2H, s ), 7.01 (1H, s), 7.03 (1H, s), 7.07-7.11 (1H, m), 7.16 (1H, s), 7.18 (1H, s) , 7.23 (2H, d, J=3.5 Hz), 7.25 (1H, s), 7.53 (1H, s), 8.26 (1H, t, J=5.0 Hz) , 8.38 (1H, s) 26 1.97 (3H, s), 2.20 (3H, s), 2.26 (6H, s), 4.34 (2H, d, J=4.8Hz), 5.21 (2H, s) , 5.36 (2H, s), 6.84 (2H, s), 7.17 (2H, d, J=8.1Hz), 7.23-7.25 (3H, m), 7.53 (1H, s), 8.20 (1H, t, J=4.7Hz), 8.38 (1H, s) 27 1.98 (3H, s), 2.19 (3H, d, J=1.7Hz), 4.38 (2H, d, J=5.6Hz), 5.22 (2H, s), 5, 40 (2H, s), 7.04-7.09 (2H, m), 7.16-7.29 (6H, m), 7.53 (1H, s), 8.44 (1H, s) , 8.68 (1H, t, J=5.2Hz) 28 1.98 (3H, s), 2.29 (3H, s), 4.35 (2H, d, J=5.7 Hz), 5.23 (2H, s), 5.40 (2H, s ), 6.98 (1H, d, J=8.1 Hz), 7.01 (1H, d, J=11.6 Hz), 7.19-7.22 (3H, m), 7.24 (1H, s), 7.27 (1H s), 7.29 (1H, s), 7.55 (1H, s), 8.44 (1H, s), 8.75 (1H, t, J =5.7 Hz) 29 1.99 (3H, s), 4.55 (2H, dd, J=5.5, 1.4Hz), 5.23 (2H, s), 5.41 (2H, s), 7.19- 7.24 (3H, m), 7.28 (2H, d, J= 8.2 Hz), 7.38-7.43 (1H, m), 7.54 (1H, s), 7.67- 7.72 (1H, m), 8.36-8.38 (1H, m), 8.44 (1H, s), 8.76 (1H, t, J=4.2Hz) thirty 1.99 (3H, s), 4.49 (2H, d, J=5.9Hz), 5.24 (2H, s), 5.43 (2H, s), 7.20-7.25 ( 3H, m), 7.30-7.31 (2H, m), 7.49-7.50 (2H, m), 7.55 (1H, s), 8.52 (2H, d, J= 5.8Hz), 8.97 (1H, d, J= 5.9Hz) 31 3.20 (3H, m), 4.53 (2H, d, J=2.9Hz), 4.59 (2H, d, J=5.2Hz), 5.06 (2H, s), 5, 30 (2H, s), 6.19-6.27 (1H, m), 6.40 (1H, d, J=9.2Hz), 7.18-7.34 (4H, m), 7, 36-7.47 (1H, m), 7.76 (2H, t, J=6.4Hz), 8.24-8.37 (1H, s), 8.54 (1H, s), 8, 74-8.86 (2H, m) 32 2.73 (3H, s), 3.22 (3H, s), 4.46-4.58 (4H, m), 5.08 (2H, s), 5.30 (2H, s), 6 ,20-6.27 (1H, m), 6.40 (1H, d, J=9.1Hz), 7.20-7.32 (4H, m), 7.42 (1H, ddd, J= 2.1, 6.6, 8.8Hz), 7.78 (1H, dd, J=1.5, 6.8Hz), 7.88 (1H, d, J=8.3Hz), 8.30 (1H, s), 8.39 (1H, dd, J=2.0, 8.3Hz), 8.64-8.76 (2H, m) 36 3.21 (3H, s), 4.54 (2H, s), 4.58 (2H, d, J=5.7Hz), 5.07 (2H, s), 5.30 (2H, s) , 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.2Hz), 7.20-7.31 (4H, m), 7, 41 (1H, dd, J=8.9, 6.6, 2.1Hz), 7.70 (1H, dd, J=7.9, 4.7Hz), 7.76 (1H, dd, J= 6.8, 2.1Hz), 7.97 (1H, d, J=7.8Hz), 8.28 (1H, s), 8.50 (1H, t, J=5.8Hz), 8, 62 (1H, d, J=4.9Hz) 37 3.20 (3H, m), 4.53 (2H, d, J=2.9Hz), 4.59 (2H, d, J=5.2Hz), 5.06 (2H, s), 5, 30 (2H, s), 6.19-6.27 (1H, m), 6.40 (1H, d, J=9.2Hz), 7.18-7.34 (4H, m), 7, 36-7.47 (1H, m), 7.76 (2H, t, J=6.4Hz), 8.24-8.37 (1H, s), 8.54 (1H, s), 8, 74-8.86 (2H, m) 39 2.73 (3H, s), 3.22 (3H, s), 4.46-4.58 (4H, m), 5.08 (2H, s), 5.30 (2H, s), 6 ,20-6.27 (1H, m), 6.40 (1H, d, J=9.1Hz), 7.20-7.32 (4H, m), 7.42 (1H, ddd, J= 2.1, 6.6, 8.8Hz), 7.78 (1H, dd, J=1.5, 6.8Hz), 7.88 (1H, d, J=8.3Hz), 8.30 (1H, s), 8.39 (1H, dd, J=2.0, 8.3Hz), 8.64-8.76 (2H, m) 40 3.21 (3H, s), 3.83 (3H, s), 4.40 (2H, d, J=5.8Hz), 4.55 (2H, s), 5.07 (2H, s) , 5.30 (2H, s), 6.22 (1H, dt, J=1.4, 6.6Hz), 6.40 (1H, ddd, J=0.7, 1.4, 9.1Hz ), 6.67 (1H, dd, J=0.8, 8.2Hz), 6.88 (1H, dd, J=0.8, 7.3Hz), 7.22-7.29 (4H, m), 7.41 (1H, dd, J=2.1, 6.6, 9.2Hz), 7.65 (1H, dd, J=7.3, 8.2Hz), 7.76 (1H , ddd, J=0.8, 2.1, 6.8Hz), 8.28 (1H, s), 8.42 (1H, t, J=5.8Hz) 41 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, 6.7 Hz), 6.39 (1H, ddd, J=0.7, 1.4, 9.2 Hz), 7.17-7.28 (5H, m), 7.41 (1H, ddd, J=2.1, 6.6, 8.9 Hz), 7.75 (1H, ddd, J=0.7, 2.1, 6, 8 Hz), 8.21-8.29 (2H, m), 8.42 (1H, t, J=5.4 Hz) 42 3.21 (3H, s), 3.79 (3H, s), 4.49 (2H, dd, J=2.0, 5.5Hz), 4.54 (2H, s), 5.07 ( 2H, s), 5.29 (2H, s), 6.23 (1H, td, J=1.4, 6.7Hz), 6.38-6.43 (1H, m), 6.77 ( 1H, dd, J=3.0, 8.9Hz), 7.20-7.25 (2H, m), 7.25-7.30 (2H, m), 7.41 (1H, ddd, J =2.1, 6.6, 8.9Hz), 7.65 (1H, t, J=8.9Hz), 7.76 (1H, dd, J=1.5, 6.8Hz), 8, 26 (1H, s), 8.31 (1H, t, J=5.5Hz) 45 3.17 (3H, s), 4.53 (2H, s), 4.61 (2H, d, J=5.7Hz), 5.06 (2H, s), 5.27 (2H, s) , 6.21 (1H, dt, J=6.8, 1.3Hz), 6.39 (1H, dt, J=9.3Hz), 7.22 (2H, dt, J=8.2Hz), 7.26 (2H, d, J=8.3Hz), 7.38-7.42 (2H, m), 7.69 (1H, s), 7.75 (1H, dd, J=6.8 , 1.8Hz), 7.99 (1H, d, J=2.0Hz), 8.02 (1H, d, J=8.6Hz), 8.22 (1H, s), 8.36-8 .43 (1H, m) 46 1.91-1.93 (4H, m), 3.19 (3H, s), 3.31-3.36 (4H, m), 4.54 (2H, s), 4.61 (2H, d, J=5.7Hz), 5.12 (2H, s), 6.40 (1H, d, J=8.7Hz), 7.40 (1H, dd, J=8.6, 2.0Hz ), 7.43 (1H, dd, J=8.7, 2.4Hz), 7.68 (1H, s), 7.98 (1H, d, J=2.0Hz), 8.01 (1H , s), 8.03 (1H, s), 8.08 (1H, d, J=2.2Hz), 8.14 (1H, s), 8.38 (1H, t, J=5.2Hz ) 47 1.98 (3H, s), 3.17 (3H, s), 4.53 (2H, s), 4.61 (2H, d, J=5.6Hz), 5.20 (2H, s) , 5.27 (2H, s), 7.17 (2H, d, J=8.2Hz), 7.21 (2H, d, J=8.2Hz), 7.22 (1H, s), 7 .41 (1H, dd, J=8.6, 2.0Hz), 7.52 (1H, s), 7.69 (1H, s), 7.99 (1H, d, J=2.0Hz) , 8.03 (1H, d, J=8.6Hz), 8.22 (1H, s), 8.40 (1H, t, J=5.7Hz) 48 0.72-0.75 (2H, m), 0.80-0.84 (2H, m), 2.50-2.55 (1H, m), 4.52 (2H, d, J=5 ,9Hz), 5.06 (2H, s), 5.19 (2H, s), 6.21-6.25 (1H, m), 6.39 (1H, d, J=9.0Hz), 7.18 (2H, d, J=8.2Hz), 7.25 (2H, d, J=8.2Hz), 7.27-7.30 (1H, m), 7.35-7.49 (4H, m), 7.77 (1H, dd, J=1.9, 6.8Hz), 7.80 (1H, s), 7.98 (1H, s), 8.14 (1H, s ), 8.31 (1H, t, J=6.0Hz) 49 0.72-0.76 (2H, m), 0.79-0.84 (2H, m), 2.52-2.64 (1H, m), 4.40 (2H, d, J=5 ,9Hz), 5.06 (2H, s), 5.19 (2H, s), 6.20-6.24 (1H, m), 6.39 (1H, d, J=8.8Hz), 7.18 (2H, d, J=8.2Hz), 7.25 (2H, d, J=8.1Hz), 7.38-7.44 (4H, m), 7.72-7.77 (2H, m), 7.80 (1H, s), 7.95 (1H, s), 8.11 (1H, s), 8.40 (1H, t, J=5.9Hz) 50 0.73-0.76 (2H, m), 0.79-0.84 (2H, m), 2.57-2.62 (1H, m), 4.41 (2H, d, J=5 ,9Hz), 5.07 (2H, s), 5.19 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, d, J=8.8Hz), 7.18 (2H, d, J=8.2Hz), 7.25 (2H, d, J=8.1Hz), 7.27-7.35 (4H, m), 7.39-7.43 (1H, m), 7.76 (1H, dd, J=1.9, 6.5Hz), 7.81 (1H, d, J=8.2Hz), 7.91 (1H, s), 8 .11 (1H, s), 8.20 (1H, t, J=6.0Hz) 51 4.52 (2H, d, J=3.9Hz), 5.06 (2H, s), 5.31 (2H, s), 6.20-6.24 (1H, m), 6.38 ( 1H, t, J=9.0Hz), 7.26 (4H, s), 7.39-7.45 (1H, m), 7.63 (3H, t, J=2.0Hz), 7, 76 (1H, dd J=4.8, 1.9Hz), 8.35 (1H, s), 8.51 (1H, t, J=4.5Hz) 52 0.72-0.75 (2H, m), 0.79-0.82 (2H, m), 2.56-2.62 (1H, m), 3.82 (3H, s), 4, 39 (2H, d, J=5.7Hz), 5.06 (2H, s), 5.18 (2H, s), 6.21-6.24 (1H, m), 6.39 (1H, d, J=8.9Hz), 6.86-6.90 (1H, m), 7.04-7.07 (2H, m), 7.18 (2H, d, J=8.1Hz), 7.25 (2H, d, J=8.1Hz), 7.39-7.43 (1H, m), 7.76 (1H, sq., J=5.1Hz), 8.12 (1H, s), 8.35 (1H, t, J=5.9Hz) 53 3.2 (3H, s), 3.82 (3H, s), 4.41 (2H, d, J=5.6Hz), 4.52 (2H, s), 5.07 (2H, s) , 5.28 (2H, s), 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.8Hz), 6.86-6, 90 (1H, m), 7.05-7.10 (2H, m), 7.22-7.27 (4H, m), 7.39-7.43 (1H, m), 7.76 ( 1H, dd, J=6.8, 1.9Hz), 8.24 (1H, s), 8.34 (1H, t, J=5.7Hz) 54 3.16 (3H, s), 3.77 (6H, d, J=1.8Hz), 4.39 (2H, dd, J=1.6, 5.2Hz), 4.45 (2H, s ), 5.05 (2H, s), 5.25 (2H, s), 6.21 (1H, td, J=1.4, 6.7Hz), 6.36-6.40 (1H, m ), 6.76 (1H, dd, J=1.7, 9.1 Hz), 7.05 (1H, t, J=9.4Hz), 7.17-7.27 (4H, m); 7.40 (1H, dd, J=2.1, 6.6, 8.9Hz), 7.74 (1H, dd, J=2.1, 6.8Hz), 7.95 (1H, t, J=5.1Hz), 8.21 (1H, s) 58 4.36 (2H, d, J=5.9Hz), 5.04 (2H, s), 5.07 (2H, s), 5.37 (2H, s), 6.21-6.24 ( 1H, m), 6.39 (1H, d, J=9.1Hz), 7.20 (2H, d, J=8.1Hz), 7.26 (2H, d, J=8.1Hz), 7.27-7.31 (2H, m), 7.38-7.43 (3H, m), 7.76 (1H, dd, J=2.0, 6.8Hz), 7.97 (1H , s), 8.35 (1H, t, J=5.9Hz) 59 2.72 (6H, s), 3.82 (3H, s), 4.41 (2H, d, J=5.6Hz), 5.07 (2H, s), 5.17 (2H, s) , 6.21-6.25 (1H, m), 6.40 (1H, d, J=8.8Hz), 6.86-6.89 (1H, m), 7.04-7.07 ( 2H, m), 7.21-7.25 (4H, m), 7.39-7.41 (1H, m), 7.76 (1H, dd, J=6.9, 1.6Hz), 8.07 (1H, s), 8.35 (1H, t, J=5.8Hz) 62 3.20 (3H, s), 4.42 (2H, J=5.7Hz), 4.53 (2H, s), 5.07 (2H, s), 5.28 (2H, s), 6 .22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.2Hz), 7.13-7.38 (8H, m), 7.41 ( 1H, dd, J=8.9, 6.6, 2.1Hz), 7.76 (1H, dd, J=6.8, 2.1Hz), 8.25 (1H, s), 8.35 (1H, t, J=5.8Hz) 63 3.20 (3H, s), 4.53 (2H, s), 4.57 (2H, d, J=5.7Hz), 5.07 (2H, s), 5.30 (2H, s) , 6.22 (1H, td, J=6.7, 1.4Hz), 6.40 (1H, d, J=9.1Hz), 7.22-7.31 (4H, m), 7, 41 (1H, ddd, J=8.9, 6.5, 2.1Hz), 7.47 (1H, t, J=7.6Hz), 7.54 (1H, d, J=7.7Hz) , 7.65 (1H, t, J=7.6Hz), 7.72 (1H, d, J=7.7Hz), 7.76 (1H, dd, J=6.8, 2.1Hz), 8.29 (1H, s), 8.43 (1H, t, J=5.8Hz) 64 3.20 (3H, s), 3.70 (3H, s), 4.38 (2H, d, J=5.7Hz), 4.52 (2H, s), 5.07 (2H, s) , 5.28 (2H, s), 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.1Hz), 6.80-6, 81 (2H, m), 7.10 (1H, dd, J=9.6, 8.9Hz), 7.20-7.30 (4H, m), 7.41 (1H, dd, J=9 ,2, 6.6, 2.1Hz), 7.76 (1H, dd, J=6.8, 2.1Hz), 8.25 (1H, s), 8.33 (1H, t, J= 5.7Hz) 65 2.28 (3H, s), 3.20 (3H, s), 4.37 (2H, d, J=5.7Hz), 4.52 (2H, s), 5.06 (2H, s) , 5.28 (2H, s), 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.1Hz), 6.93-7, 04 (2H, m), 7.18-7.30 (5H, m), 7.41 (1H, ddd, J=9.2, 6.6, 2.1Hz), 7.75 (1H, ddd , J=6.8, 2.1Hz), 8.24 (1H, s), 8.30 (1H, t, J=5.7Hz), 66 3.20 (3H, s), 3.81 (3H, s), 4.43 (2H, d, J=5.3Hz), 4.49 (2H, s), 5.06 (2H, s) , 5.26 (2H, s), 6.21 (1H, dt, J=1.4, 6.7Hz), 6.39 (1H, ddd, J=0.7, 1.4, 9.1Hz ), 7.02 (1H, dt, J=1.9, 9.2Hz), 7.12 (1H, dt, J=5.3, 9.3Hz), 7.18-7.27 (4H, m), 7.40 (1H, ddd, J=2.1, 6.6, 9.2Hz), 7.75 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8 .21 (1H, s), 8.24 (1H, t, J=5.3Hz) 67 3.21 (3H, s), 3.75 (3H, s), 4.35 (2H, d, J=5.9Hz), 4.54 (2H, s), 5.07 (2H, s) , 5.29 (2H, s), 6.22 (1H, dt, J=1.4, 6.7Hz), 6.40 (1H, ddd, J=0.7, 1.4, 9.2Hz ), 6.82 (1H, dd, J=1.4, 2.4Hz), 6.87-6.93 (2H, m), 7.21-7.31 (4H, m), 7.41 (1H, ddd, J=2.1, 6.6, 9.2Hz), 7.76 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.24 (1H, s ), 8.39 (1H, t, J=5.9Hz) 68 3.18 (3H, d, J=0.7Hz), 4.53 (4H, d, J=8.8Hz), 5.07 (2H, s), 5.29 (2H, s), 6, 22 (1H, tt, J=1.0, 6.7Hz), 6.39 (1H, d, J=9.2Hz), 7.13-7.45 (8H, m), 7.51 (1H , t, J=7.5Hz), 7.58 (1H, d, J=7.7Hz), 7.76 (1H, dd, J=2.0, 6.8Hz), 8.25 (1H, s), 8.39 (1H, t, J=5.9Hz) 69 3.19 (3H, s), 3.83 (3H, s), 4.52 (2H, s), 4.59 (2H, d, J=5.8 Hz), 5.07 (2H, s ), 5.29 (2H, s), 6.22 (1H, td, J=1.4, 6.7Hz), 6.39 (1H, dt, J=1.0, 9.1Hz), 7 .01 (1H, d, J=7.8Hz), 7.06 (1H, d, J=8.4Hz), 7.14-7.48 (7H, m), 7.76 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.27 (1H, s), 8.34 (1H, t, J=5.9Hz) 70 4.14 (2H, d, J=6.2Hz), 4.55 (2H, brs), 5.04 (2H, s), 6.20 (1H, td, J=6.7, 1 ,3Hz), 6.38 (1H, d, J=9.2Hz), 7.20-7.29 (4H, m), 7.37-7.42 (1H, m), 7.57 (1H , d, J=3.8Hz), 7.60 (3H, br.s), 7.74 (2H, dd, J=6.7, 1.9Hz), 8.40 (1H, br.s) , 12.01 -12.19 (1H, m) 71 1.98 (3H, s), 3.83 (3H, s), 4.41 (2H, d, J=5.8Hz), 5.04 (2H, s), 5.59 (2H, s) , 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, dd, J=9.1, 0.5Hz), 6.79-6.83 (1H, m ), 7.03-7.05 (2H, m), 7.08-7.10 (2H, m), 7.19 (1H, s), 7.21 (1H, s), 7.22 ( 1H, s), 7.39-7.43 (1H, m), 7.74 (1H, dd, J=6.7, 1.9Hz), 9.13 (1H, t, J=5.9Hz ), 10.53 (1H, s) 72 1.93 (3H, s), 3.10 (3H, s), 3.83 (3H, s), 4.42 (2H, d, J=4.8Hz), 5.05 (2H, s) , 5.64 (2H, s), 6.22 (1H, td, J=6.7, 1.3Hz), 6.40 (1H, d, J=9.5Hz), 6.79-6, 81 (1H, m), 6.87 (1H, brs), 7.03-7.06 (2H, m), 7.07-7.11 (2H, m), 7.18-7, 21 (2H, m), 7.39-7.44 (1H, m), 7.75 (1H, dd, J=6.8, 1.9Hz), 9.08 (1H, br.s) 73 3.22 (3H, s), 4.46 (2H, d, J=5.3Hz), 4.51 (2H, s), 5.07 (2H, s), 5.27 (2H, s) , 6.22 (1H, td, J=1.4, 6.7Hz), 6.40 (1H, d, J=8.5Hz), 7.15-7.29 (5H, m), 7, 38-7.46 (1H, m), 7.54-7.64 (1H, m), 7.76 (1H, dd, J=1.5, 6.8Hz), 8.20 (1H, s ), 8.34 (1H, t, J=5.4Hz) 76 3.22 (3H, s), 4.54 (4H, m), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H, td, J=1.4, 6.7Hz), 6.40 (1H, ddd, J=0.7, 1.4, 9.1Hz), 7.20-7.30 (4H, m), 7.41 (1H, ddd, J =2.1, 6.6, 9.2Hz), 7.52-7.59 (2H, m), 7.76 (1H, ddd, J=0.7, 2.1, 6.8Hz), 7.84-7.91 (1H, m), 8.26 (1H, s), 8.58 (1H, t, J=5.7Hz) 77 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, dd, 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) 78 3.20 (3H, s), 3.86 (3H, s), 4.49-4.56 (4H, m), 5.07 (2H, s), 5.29 (2H, s), 6 .22 (1H, td, J=1.4, 6.7Hz), 6.39 (1H, ddd, J=0.7, 1.4, 9.2Hz), 7.07 (1H, d, J =7.8Hz), 7.18 (1H, d, J=8.4Hz), 7.22-7.29 (4H, m), 7.39-7.44 (1H, m), 7.55 (1H, t, J=8.1Hz), 7.76 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.27 (1H, s), 8.34 (1H, t, J=5.8Hz) 79 3.20 (3H, s), 3.79 (3H, s), 4.53 (4H, m), 5.07 (2H, s), 5.30 (2H, s), 6.22 (1H , td, J=1.4, 6.7Hz), 6.40 (1H, dt, J=1.0, 9.1Hz), 6.96-7.05 (2H, m), 7.22- 7.31 (4H, m), 7.41 (1H, ddd, J=2.1, 6.6, 8.9Hz), 7.66 (1H, d, J=8.6Hz), 7.76 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.29 (1H, s), 8.40 (1H, t, J=5.8Hz) 80 3.16 (3H, s), 4.43-4.52 (4H, m), 5.05 (2H, s), 5.26 (2H, s), 6.21 (1H, td, J= 1.4, 6.7Hz), 6.39 (1H, dt, J=1.0, 9.2Hz), 7.23 (4H, sq., J=8.3Hz), 7.31-7, 62 (5H, m), 7.75 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.22 (1H, s), 8.33 (1H, t, J=5 ,4Hz) 81 3.18 (3H, s), 3.76 (3H, s), 4.51 (4H, m), 5.07 (2H, s), 5.29 (2H, s), 6.22 (1H , td, J=1.4, 6.7Hz), 6.40 (1H, dt, J=1.2, 9.0Hz), 6.88-6.98 (2H, m), 7.03- 7.33 (5H, m), 7.41 (1H, ddd, J=2.1, 6.6, 8.9Hz), 7.51 (1H, d, J=9.1Hz), 7.76 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.26 (1H, s), 8.38 (1H, t, J=5.8Hz) 83 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) 85 3.17 (3H, s), 4.44 (2H, s), 4.54 (2H, d, J=5.2 Hz), 5.05 (2H, s), 5.25 (2H, s ), 6.21 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.2Hz), 7.14-7.32 (6H, m), 7 .34-7.44 (2H, m), 7.60 (1H, s), 7.75 (1H, dd, J=6.8, 2.1Hz), 8.07-8.18 (2H, m), 8.21 (1H, s) 86 3.21 (3H, s), 3.74 (3H, s), 4.50 (2H, s), 4.55 (2H, d, J=5.9Hz), 5.06 (2H, s) , 5.28 (2H, s), 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.1Hz), 6.82-6, 91 (2H, m), 7.18-7.33 (5H, m), 7.41 (1H, ddd, J=8.9, 6.6, 2.1Hz), 7.49 (1H, d , J=8.4Hz), 7.76 (1H, d, J=6.8, 2.1Hz), 7.81 (1H, br.s), 8.25 (1H, s), 8.30 (1H, t, J=6.0Hz) 87 3.21 (3H, s), 4.50 (2H, s), 4.70 (2H, d, J=5.9Hz), 5.06 (2H, s), 5.28 (2H, s) , 6.22 (1H, td, J=1.4, 6.7 Hz), 6.39 (1H, dd, J=1.3, 9.1 Hz), 7.21-7.28 (4H, m), 7.32-7.44 (3H, m), 7.51 (1H, td, J=1.5, 7.5 Hz), 7.76 (1H, dd, J=2.1, 6.8 Hz), 7.86 (1H, dd, J=1.4, 7.8 Hz), 8.26 (1H, s), 8.34 (1H, t, J=5.9 Hz) , 13.08 (1H, br.s) 90 3.21 (3H, s), 4.45 (2H, d, J=5.8Hz), 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H, s) , 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.2Hz), 7.16-7.31 (7H, m), 7, 24 (1H, t, J=72Hz), 7.38-7.44 (1H, m), 7.77 (1H, dd, J=6.8, 2.1Hz), 8.26 (1H, s ), 8.45 (1H, t, J=5.8Hz) 91 3.20 (3H, s), 4.40 (2H, d, J=5.9Hz), 4.54 (2H, s), 5.07 (2H, s), 5.29 (2H, s) , 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.1Hz), 7.02-7.10 (2H, m), 7, 16 (1H, d, J=7.7Hz), 7.20 (1H, t, J=72Hz), 7.21-7.29 (4H, m), 7.35-7.43 (2H, m ), 7.76 (1H, dd, J=6.8, 2.1 Hz), 8.24 (1H, s), 8.41 (1H, t, J=5.9Hz) 92 3.18 (3H, s), 4.43 (2H, d, J=5.3Hz), 4.47 (2H, s), 5.05 (2H, s), 5.25 (2H, s) , 6.21 (1H, td, J=6.6, 1.4Hz), 6.39 (1H, d, J=9.2Hz), 7.07 (1H, d, J=8.3Hz), 7.14 (1H, t, J=8.5Hz), 7.20 (2H, d, J=8.2Hz), 7.24 (1H, t, J=72Hz), 7.25 (2H, d , J=8.3Hz), 7.36-7.47 (2H, m), 7.75 (1H, dd, J=6.8, 2.1Hz), 8.11 (1H, t, J= 5.1Hz), 8.20 (1H, s) 94 3.21 (3H, s), 4.40 (2H, d, J=5.8Hz), 4.53 (2H, s), 5.07 (2H, s), 5.29 (2H, s) , 6.22 (1H, td, J=1.4, 6.7Hz), 6.39 (1H, dt, J=1.0, 9.1Hz), 7.15 (2H, dd, J=4 ,9, 8.4Hz), 7.20-7.30 (5H, m), 7.41 (1H, ddd, J=2.1, 6.6, 8.9Hz), 7.76 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.25 (1H, s), 8.40 (1H, t, J=5.8Hz) 95 3.21 (3H, s), 3.75 (3H, s), 4.36 (2H, d, J=5.9Hz), 4.55 (2H, s), 5.08 (2H, s) , 5.30 (2H, s), 6.19-6.27 (1H, m), 6.40 (1H, dd, J=0.6, 9.2Hz), 6.65-6.75 ( 3H, m), 7.22-7.31 (4H, m), 7.41 (1H, ddd, J=2.1, 6.6, 9.0Hz), 7.73-7.81 (1H , m), 8.25 (1H, s), 8.39 (1H, t, J=5.9Hz) 96 3.21 (3H, s), 3.84 (3H, s), 4.39 (2H, d, J=5.7Hz), 4.53 (2H, s), 5.07 (2H, s) , 5.28 (2H, s), 6.22 (1H, td, J=6.7, 1.4Hz), 6.39 (1H, d, J=9.1Hz), 6.68 (1H, ddd, J=9.0, 4.9, 3.1Hz), 7.02 (1H, ddd, J=10.1, 6.8, 3.1Hz), 7.19-7.30 (4H, m), 7.41 (1H, dd, J=8.9, 6.6, 2.1Hz), 7.76 (1H, dd, J=6.8, 2.1Hz), 8.25 (1H , s), 8.39 (1H, t, J=5.8 Hz) 97 2.37 (3H, s), 3.15 (3H, s), 4.42 (2H, dd, J=1.7, 5.1Hz), 4.48 (2H, s), 5.05 ( 2H, s), 5.25 (2H, s), 6.21 (1H, td, J=1.4, 6.7Hz), 6.39 (1H, dt, J=0.9, 9.2Hz ), 7.02 (2H, dd, J=8.0, 11.8Hz), 7.16-7.29 (5H, m), 7.40 (1H, dd, J=2.1, 6, 6, 8.9Hz), 7.74 (1H, ddd, J=0.7, 2.1, 6.8Hz), 8.04 (1H, t, J=5.2Hz), 8.22 (1H , With) 99 3.18 (3H, s), 3.84 (3H, s), 4.49 (4H, d, J=4.9Hz), 5.06 (2H, s), 5.26 (2H, s) , 6.21 (1H, dt, J=1.4, 6.7Hz), 6.39 (1H, ddd, J=0.7, 1.4, 9.1Hz), 7.12-7.28 (6H, m), 7.40 (1H, ddd, J=2.1, 6.6, 8.9Hz), 7.75 (1H, ddd, J=0.7, 2.1, 6.7Hz ), 8.14 (1H, t, J=5.1Hz), 8.21 (1H, s) 129 3.20 (3H, s), 4.38 (2H, d, J=5.6Hz), 4.52 (2H, s), 5.07 (2H, s), 5.28 (2H, s) , 6.21 (1H, dt, J=6.6, 1.2Hz), 6.39 (1H, dt, J=9.1Hz), 6.73 (1H, dt, J=6.4, 1 ,4Hz), 6.83 (1H, dt, J=8.2, 1.7Hz), 6.91 (1H, t, J=7.9Hz), 7.23 (2H, dt, J=8, 3Hz), 7.26 (2H, d, J=8.2Hz), 7.38-7.43 (1H, m), 7.75 (1H, dd, J=6.8, 1.7Hz), 8.24 (1H, s), 8.28 (1H, t, J=5.1Hz), 9.73 (1H, br.s) 130 4.35 (2H, d, J=5.7Hz), 5.03 (2H, s), 5.07 (2H, s), 5.36 (2H, brs), 6.22 (1H, dt, J=6.6, 1.2 Hz), 6.39 (1H, d, J=8.8Hz), 6.70 (1H, dt, J=7.6, 1.4Hz), 6, 82 (1H, dt, J=8.3, 1.6Hz), 6.90 (1H, t, J=7.8Hz), 7.20 (2H, dt, J=8.1Hz), 7.26 (2H, d, J=8.1Hz), 7.38-7.43 (1H, m), 7.75 (1H, dd, J=7.0, 1.8Hz), 7.99 (1H, s), 8.20 (1H, t, J=5.6Hz), 9.70 (1H, br.s) 131 3.20 (3H, s), 3.84 (3H, s), 4.50 (2H, s), 4.68 (2H, d, J=5.8Hz), 5.06 (2H, s) , 5.28 (2H, s), 6.22 (1H, dt, J=1.4, 6.7Hz), 6.39 (1H, ddd, J=0.6, 1.3, 9.1Hz ), 7.22-7.28 (4H, m), 7.36-7.43 (2H, m), 7.45 (1H, dd, J=1.2, 7.9Hz), 7.56 (1H, dt, J=1.5, 7.5Hz), 7.77 (1H, ddd, J=0.7, 2.1, 6.8Hz), 7.86 (1H, dd, J=1 ,4, 7.8Hz), 8.26 (1H, s), 8.32 (1H, t, J=5.9Hz) 132 1.16 (3H, t, J=7.5Hz), 2.62 (2H, sq., J=7.6Hz), 3.20 (3H, s), 4.41 (2H, d, J= 5.7Hz), 4.52 (2H, s), 5.06 (2H, s), 5.28 (2H, s), 6.22 (1H, td, J=6.7, 1.4Hz) , 6.39 (1H, d, J=9.2Hz), 7.07 (1H, t, J=7.5Hz), 7.13-7.30 (6H, m), 7.41 (1H, ddd, J=8.9, 6.6, 2.1Hz), 7.77 (1H, dd, J=6.8, 2.1Hz), 8.26 (1H, s), 8.35 (1H , t, J=5.8Hz) 133 3.19 (3H, s), 3.72 (3H, s), 4.35 (2H, d, J=5.8Hz), 4.53 (2H, s), 5.06 (2H, s) , 5.28 (2H, s), 6.22 (1H, dt, J=1.4, 6.7Hz), 6.39 (1H, dt, J=1.0, 9.1Hz), 6, 78-6.83 (1H, m), 6.83-6.88 (2H, m), 7.18-7.30 (5H, m), 7.41 (1H, ddd, J=2.1 , 6.6, 8.9Hz), 7.77 (1H, ddd, J=0.7, 2.1, 6.7Hz), 8.25 (1H, s), 8.36 (1H, t, J=5.9Hz) 104 3.20 (3H, s), 3.82 (3H, s), 4.41(2H, d, J=5.7Hz), 4.52 (2H, s), 5.05 (2H, s) , 5.29 (2H, s), 6.87-6.90 (1H, m), 7.04-7.10 (2H, m), 7.25 (2H, d, J=8.1Hz) , 7.30-7.35 (3H, m), 7.76 (1H, dd, J=4.3, 1.0Hz), 8.02 (1H, d, J=1.2Hz), 8, 26 (1H, s), 8.36 (1H, t, J=5.7Hz) 106 2.10 (3H, d, J=0.6Hz), 3.20 (3H, s), 3.81 (3H, s), 4.43 (2H, d, J=5.3Hz), 4, 49 (2H, s), 5.01 (2H, s), 5.25 (2H, s), 6.07 (1H, dd, J=6.9, 1.9Hz), 6.20 (1H, s), 7.01 (1H, td, J=9.2, 1.7Hz), 7.09-7.15 (1H, m), 7.18-7.24 (4H, m), 7, 61 (1H, d, J=6.9Hz), 8.20 (1H, s), 8.23 (1H, t, J=5.0Hz) 108 3.20 (3H, s), 3.81 (3H, s), 2.50 (2H, d, J=3.6Hz), 4.49 (2H, s), 5.00 (2H, s) , 5.26 (2H, s), 6.43 (1H, dd, J=10.0, 5.4Hz), 7.01 (1H, td, J=9.2, 1.7Hz), 7, 09-7.15 (1H, m), 7.21 (2H, d, J=8.2Hz), 7.27 (2H, d, J=8.2Hz), 7.53-7.58 (1H , m), 8.01 (1H, dd, J=4.6, 3.4Hz), 8.21 (1H, s), 8.23 (1H, t, J=5.2Hz) 109 2.50 (3H, t, J=1.8Hz), 3.20 (3H, s), 3.81 (3H, s), 3.98 (2H, sq., J=7.0Hz), 4 .43 (2H, d, J=5.1Hz), 4.49 (2H, s), 4.98 (2H, s), 5.25 (2H, s), 5.77 (1H, d, J =2.7Hz), 5.92 (1H, dd, J=7.6, 2.9Hz), 7.01 (1H, td, J=9.2, 1.7Hz), 7.09-7, 15 (1H, m), 7.18-7.23 (4H, m), 7.61 (1H, d, J=7.6Hz), 8.20 (1H, s), 8.23 (1H, t, J=5.1Hz) 121 2.26 (3H, s), 3.81 (3H, s), 4.41 (2H, d, J=6.3Hz), 5.07 (2H, s), 5.16 (2H, s) , 6.22 (1H, ddd, J=6.6, 6.6, 1.4Hz), 6.40 (1H, d, J=8.8Hz), 6.81-6.85 (1H, m ), 7.00-7.07 (2H, m), 7.17 (2H, d, J=8.2Hz), 7.27 (2H, d, J=8.1Hz), 7.41 (1H , ddd, J=8.9, 6.5, 2.0Hz), 7.64 (1H, s), 7.76 (1H, dd, J=6.7, 2.0Hz), 8.31 ( 1H, t, J=6.0Hz) 124 3.82 (3H, s), 4.44 (2H, d, J=6.2Hz), 5.08 (2H, s), 5.40 (2H, s), 6.22 (1H, dt, J=6.6, 1.4Hz), 6.40 (1H, d, J=8.9Hz), 6.85 (1H, dt, J=6.6, 1.8Hz), 7.01-7 .08 (2H, s), 7.19 (2H, d, J=8.1Hz), 7.28 (2H, d, J=8.1Hz), 7.41 (1H, ddd, J=8, 8. 6.6, 2.1Hz), 7.75 (1H, dd, J=6.6, 1.7Hz), 8.09 (1H, s), 8.68 (1H, br.s) 126 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) 139 2.81 (3H, s), 2.98 (1H, dd, J=12.0, 7.3Hz), 3.26 (1H, dd, J=12.0, 2.6Hz), 3.35 -3.45 (2H, m), 4.26-4.28 (1H, m), 5.04 (2H, s), 5.07 (2H, s), 5.37 (2H, br.s ), 6.22 (1H, td, J=6.6, 1.3Hz), 6.40 (1H, d, J=8.8Hz), 6.68 (1H, d, J=8.7Hz) , 6.73 (1H, d, J=2.4Hz), 6.80 (1H, dd, J=8.6, 2.4Hz), 7.21 (2H, d, J=8.2Hz), 7.27 (2H, d, J=8.1Hz), 7.39-7.43 (1H, m), 7.76 (1H, dd, J=7.0, 1.9Hz), 7.99 (1H, s), 8.00 (1H, t, J=5.7Hz) 140 2.96-3.02 (1H, m), 3.29-3.34 (1H, m), 3.34-3.43 (2H, m), 4.07-4.12 (1H, m ), 5.04 (2H, s), 5.07 (2H, s), 5.36 (2H, brs), 5.93 (1H, brs), 6.22 (1H, td, J=6.7, 1.4Hz), 6.40 (1H, d, J=9.9Hz), 6.55-6.58 (1H, m), 6.68-6.71 (2H, m ), 7.21 (2H, d, J=8.1Hz), 7.27 (2H, d, J=8.2Hz), 7.39-7.43 (1H, m), 7.76 (1H , dd, J=7.0, 2.0Hz), 7.98 (1H, t, J=5.8Hz), 7.99 (1H, s)

Biological methods

The ability of the compounds of formula (I) to inhibit plasma kallikrein can be determined using the following biological assays:

Determination of IC ₅₀ for plasma kallikrein

Plasma kallikrein inhibitory activity in vitro was determined using standard published methods (see, for example, Johansen et al. , Int. J. Tiss. Reac. 1986, 8, 185; Shori et al. , Biochem. Pharmacol., 1992 , 43, 1209; Stürzebecher et al. , Biol. Chem., 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 compound. Residual enzymatic activity (initial reaction rate) was determined by measuring the change in optical absorbance at 410 nm and the IC ₅₀ value for the test compound was determined.

Data from these analyzes are shown in Table 14.

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

Determination of IC ₅₀ for KLK1

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

Data from this analysis are shown in Table 14.

Selected compounds were then 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:

Determination of % inhibition for FXIa

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

Data from this analysis are shown in Table 14.

Table 14 Example number IC ₅₀ (human PKal) nM IC50 (human KLK1) nM % Inhibition @ 40µM (human FXIa) 1 698 >10000 0 2 8.7 >10000 8 3 2580 >10000 3 4 136 >10000 5 364 >10000 6 2360 >10000 0 7 >10000 >10000 8 539 >10000 9 239 >10000 10 1270 >10000 eleven 456 >10000 12 746 >10000 13 439 >10000 14 514 >10000 15 219 >10000 16 263 >10000 17 865 >10000 18 373 >10000 19 1130 >10000 20 740 >10000 21 257 >10000 22 1350 >10000 23 1060 >10000 24 717 >10000 25 1840 >10000 26 1340 >10000 27 >10000 >10000 28 280 >10000 29 2190 >10000 thirty 915 >10000 31 392 >10000 32 7870 >10000 36 4170 >10000 0 37 392 >10000 0 39 7870 >10000 0 40 3700 >10000 1 41 3.3 >40000 0 42 831 >10000 1 45 144 >10000 46 2400 >10000 47 753 >10000 48 647 >10000 2 49 5450 >10000 0 50 1800 >10000 51 48.9 >40000 52 23.3 >40000 1 53 20.2 >10000 54 2.1 >40000 17 58 5780 >10000 0 59 73.4 >10000 0 62 572 >10000 0 63 342 >10000 0 64 35.2 >10000 0 65 43.3 >10000 0 66 4.6 >10000 4 67 393 >10000 0 68 81.1 >10000 6 69 16.8 >40000 0 70 26.7 >10000 6 71 300 >10000 0 72 6610 >10000 1 73 120 >10000 8 76 28.3 >40000 5 77 0.6 >40000 28 78 612 >10000 0 79 14.7 >40000 2 80 20.4 >40000 81 2.3 >40000 1 83 6.8 >40000 14 85 79.2 >40000 46 86 8.7 >40000 87 >10000 >10000 2 90 154 >40000 2 91 523 >10000 0 92 16.0 >10000 4 94 780 >10000 0 95 308 >40000 1 96 75.0 >40000 0 97 153 >10000 0 99 6.4 >10000 4 129 437 >40000 0 130 174 >40000 0 131 1510 >10000 0 132 135 >40000 0 133 90.2 >10000 1 104 691 >10000 0 106 140 >10000 2 108 5.5 >10000 109 2980 >10000 2 121 43.9 >10000 0 124 191 >10000 0 126 742 >10000 10 139 64.7 >40000 33 140 10.6 >40000 9

Pharmacokinetics

Pharmacokinetic studies of the compounds presented in Table 15 were performed to evaluate the pharmacokinetics after a single oral dose of male Sprague-Dawley rats. Two rats were administered a single oral dose of 5 ml/kg of a nominal 2 mg/ml (10 mg/kg) formulation of the test compound in vehicle. After administration, blood samples were collected over a 24-hour period. Sampling times were 5, 15 and 30 minutes, then 1, 2, 4, 6, 8 and 12 hours. After collection, blood samples were centrifuged and the plasma fraction was analyzed for the concentration of the test compound by LCMS. Oral plasma drug content data obtained from these studies are shown below:

Table 15
Data on the content of the drug substance in plasma after oral administration Example number Carrier Dose po (mg/kg) Cmax
(ng/ml) Tmax (min) 2 10% DMSO/10% Cremophor/80% SWFI 9.5 351 60 41 10% DMSO/10% Cremophor/80% SWFI 10.5 1534 180 51 5% Cremophor/5% ethanol/90% phosphate buffered saline 13.7 101 15 52 10% DMSO/10% Cremophor/80% SWFI 17.9 1472 45 53 10% DMSO/10% Cremophor/80% SWFI 8.6 1031 15 66 10% DMSO/10% Cremophor/80% SWFI 11.3 2892 60 77 10% DMSO/10% Cremophor/80% SWFI 5.5 397 thirty

Claims (93)

1. A pharmaceutical composition intended for the treatment of a disease or condition that is associated with the activity of plasma kallikrein, containing: (i) a pharmaceutically acceptable carrier, diluent or excipient and (ii) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound formula (I) is Where B is phenyl substituted with 1-3 substituents selected from alkyl^b, alkoxy, OH, halogen, CN, tetrazolyl, COOR8, CONH₂,OCF₃And CF₃; or B is selected from benzothiophenyl, benzomorpholinyl, a 5-membered heterocyclic ring containing two heteroatoms that are N, wherein said 5-membered heterocyclic ring is aromatic, and a 6-membered heterocyclic ring containing one or two heteroatoms selected from N, wherein said 6-membered heterocyclic ring is aromatic; and wherein said benzothiophenyl is substituted with 1 substituent which is halogen, said benzomorpholinyl is substituted with 1-2 substituents selected from alkyl ^b and halogen, said 5-membered heterocyclic ring is substituted with 1-2 substituents selected from alkyl ^b and halogen, or said The 6-membered heterocyclic ring is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, halogen, CN and CF ₃ ; 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 pyrazole or imidazole; R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, NR8R9, -NR8COR9 and CF ₃ ; where at least one of R5 and R6 is present and is not H; R7 represents H; A is selected from aryl and heteroaryl; where aryl is substituted with 1 substituent independently selected from -(CH ₂ ) ₁ -heteroaryl and -(CH ₂ ) ₁ -NR10R11; and the heteroaryl is substituted with 1 substituent independently selected from halogen and -(CH ₂ ) _0-1 -NR10R11; R8 and R9 are independently selected from H and alkyl; alkyl is a linear saturated hydrocarbon containing up to 2 carbon atoms, optionally substituted with 1 substituent, which is (C ₁ )alkoxy; alkyl ^b is a linear saturated hydrocarbon containing up to 2 carbon atoms; alkyl ^b may optionally be substituted with 1 or 2 substituents that represent fluorine; cycloalkyl is a monocyclic saturated hydrocarbon containing 3 carbon atoms; alkoxy is a linear O-linked hydrocarbon containing 1 to 2 carbon atoms (C ₁ -C ₂ ); alkoxy may optionally be substituted with 1 or 2 substituents which are fluorine; aryl is phenyl; heteroaryl is a 5, 6 or 10 membered mono- or bicyclic aromatic ring containing, where possible, 1 or 2 ring members which are N; heteroaryl may optionally be substituted with 1 or 2 substituents independently selected from alkyl, halogen and -(CH ₂ ) _0-1 -NR10R11; R10 and R11, together with the nitrogen atom to which they are bonded, form a carbon-containing 5-membered heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 2 double bonds and which may optionally be mono- or disubstituted with substituents, selected from alkyl or halogen, or R10 and R11 together with the nitrogen atom to which they are bonded form a carbon-containing 6-membered heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 2 double bonds and which may optionally be mono- or disubstituted with substituents selected from oxo, alkyl, alkoxy and halogen. 2. The use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in a method of treating a disease or condition that is associated with plasma kallikrein activity; where the compounds of formula (I) are as defined in claim 1. 3. A method of treating a disease or condition that is associated with plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; where the compounds of formula (I) are as defined in claim 1. 4. Use according to claim 2, or the method according to claim 3, where the disease or condition that is associated with the activity of plasma kallikrein is selected from decreased visual acuity, diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, intracerebral hemorrhage , nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, surgery on cardiopulmonary bypass, and bleeding after surgery. 5. The use of claim 2, or the method of claim 3, wherein the disease or condition that is associated with plasma kallikrein activity is retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema. 6. Use according to claim 2, or the method according to claim 3, wherein the disease or condition that is associated with the activity of plasma kallikrein is hereditary angioedema. 7. Use according to claim 2, or the method according to claim 3, wherein the disease or condition that is associated with the activity of plasma kallikrein is diabetic macular edema. 8. Compound of formula (I), Where B is phenyl substituted with 1-3 substituents selected from alkyl^b, alkoxy, OH, halogen, CN, tetrazolyl, COOR8, CONH₂,OCF₃And CF₃; or B is selected from benzothiophenyl, benzomorpholinyl, a 5-membered heterocyclic ring containing two heteroatoms that are N, wherein said 5-membered heterocyclic ring is aromatic, and a 6-membered heterocyclic ring containing one or two heteroatoms selected from N, wherein said 6-membered heterocyclic ring is aromatic; and wherein said benzothiophenyl is substituted with 1 substituent which is halogen, said benzomorpholinyl is substituted with 1-2 substituents selected from alkyl ^b and halogen, said 5-membered heterocyclic ring is substituted with 1-2 substituents selected from alkyl ^b and halogen, or said The 6-membered heterocyclic ring is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, halogen, CN and CF ₃ ; 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 pyrazole or imidazole; R5 and R6 are independently absent or independently selected from H, alkyl, cycloalkyl, -NR8R9, -NR8COR9 and CF ₃ ; where at least one of R5 and R6 is present and is not H; R7 represents H; A is selected from aryl and heteroaryl; where aryl is substituted with 1 substituent independently selected from -(CH ₂ ) ₁ -heteroaryl and -(CH ₂ ) ₁ -NR10R11; and the heteroaryl is substituted with 1 substituent independently selected from halogen and -(CH ₂ ) _0-1 -NR10R11; R8 and R9 are independently selected from H and alkyl; alkyl is a linear saturated hydrocarbon containing up to 2 carbon atoms, optionally substituted with 1 substituent, which is (C ₁ )alkoxy; alkyl ^b is a linear saturated hydrocarbon containing up to 2 carbon atoms; alkyl ^b may optionally be substituted with 1 or 2 substituents that represent fluorine; cycloalkyl is a monocyclic saturated hydrocarbon containing 3 carbon atoms; alkoxy is a linear O-linked hydrocarbon containing 1 to 2 carbon atoms (C ₁ -C ₂ ); alkoxy may optionally be substituted with 1 or 2 substituents which are fluorine; aryl is phenyl; heteroaryl is a 5, 6 or 10 membered mono- or bicyclic aromatic ring containing, where possible, 1 or 2 ring members which are N; heteroaryl may optionally be substituted with 1 or 2 substituents independently selected from alkyl, halogen and -(CH ₂ ) _0-1 -NR10R11; R10 and R11, together with the nitrogen atom to which they are bonded, form a carbon-containing 5-membered heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 2 double bonds and which may optionally be mono- or disubstituted with substituents, selected from alkyl or halogen, or R10 and R11 together with the nitrogen atom to which they are bonded form a carbon-containing 6-membered heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 2 double bonds and which may optionally be mono- or disubstituted with substituents selected from oxo, alkyl, alkoxy and halogen; and its pharmaceutically acceptable salts and solvates, wherein said connection cannot be one of the following: 3-[[[[1-[(3-chlorophenyl)methyl]-3-methyl-1H-pyrazol-4-yl]carbonyl]amino]methyl]-benzoic acid; 4-[[([1-[(3-chlorophenyl)methyl]-3-methyl-1H-pyrazol-4-yl]carbonyl]amino]methyl]-benzoic acid; 5-[[[[1-[(3-chlorophenyl)methyl]-3-methyl-1H-pyrazol-4-yl)carbonyl]amino]methyl]-2-furancarboxylic acid; 5-[[[[1-[(3-chlorophenyl)methyl]-3-methyl-1H-pyrazol-4-yl]carbonyl]amino]methyl]-2-methoxybenzoic acid; 5-[[[[1-[(3-chlorophenyl)methyl]-3-methyl-1H-pyrazol-4-yl]carbonyl]amino]methyl]-2-methyl-3-furancarboxylic acid, and 4-[[[[1-[(3-chlorophenyl)methyl]-3-methyl-1H-pyrazol-4-yl]carbonyl]amino]methyl]-2-methoxybenzoic acid. 9. Pharmaceutical composition according to claim 1, use according to any of claims 2 or 4-7, method according to any of claims 3-7, or a compound according to claim 8, where B is phenyl substituted with 1-3 substituents selected from alkyl^b, alkoxy, OH, halogen, CN, tetrazolyl, COO(alkyl), CONH₂,OCF₃And CF₃; or wherein B is selected from benzothiophenyl, benzomorpholinyl, a 5-membered heterocyclic ring containing two heteroatoms that are N, wherein said 5-membered heterocyclic ring is aromatic, and a 6-membered heterocyclic ring containing one or two heteroatoms selected from N, wherein said 6-membered heterocyclic ring is aromatic; and wherein said benzothiophenyl is substituted with 1 substituent which is halogen, said benzomorpholinyl is substituted with 1-2 substituents selected from alkyl ^b and halogen, said 5-membered heterocyclic ring is substituted with 1-2 substituents selected from alkyl ^b and halogen, or said The 6-membered heterocyclic ring is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, halogen, CN and CF ₃ ; or a pharmaceutically acceptable salt or solvate thereof. 10. Pharmaceutical composition according to claim 1, use according to any of claims 2 or 4-7, method according to any of claims 3-7, or a compound according to claim 8, where B is selected from phenyl substituted with 1-3 substituents, selected from alkyl^b, alkoxy, OH, halogen, CN, tetrazolyl, COOR8, CONH₂,OCF₃And CF₃; or B is selected from benzothiophenyl, a 5-membered heterocyclic ring containing two heteroatoms that are N, wherein said 5-membered heterocyclic ring is aromatic, and a 6-membered heterocyclic ring containing one or two heteroatoms selected from N, wherein said 6 -membered heterocyclic ring is aromatic; and wherein said benzothiophenyl is substituted with 1 substituent which is halogen, said 5-membered heterocyclic ring is substituted with 1-2 substituents selected from alkyl ^b and halogen, or said 6-membered heterocyclic ring is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, halogen, CN and CF ₃ ; where alkyl ^b , alkoxy, R8 and R9 have the meanings defined in paragraph 1; or a pharmaceutically acceptable salt or solvate thereof. 11. Pharmaceutical composition according to claim 1 or 10, use according to any of claims 2 or 4-7 or 10, method according to any of claims 3-7 or 10, or a compound according to claim 8 or 10, where B is selected from phenyl, benzothiophenyl and pyridyl, wherein phenyl is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, halogen, CN, COOR8, CONH ₂ , OCF ₃ and CF ₃ , benzothiophenyl is substituted with 1 substituent which is halogen, and pyridyl is substituted with 1 -3 substituents selected from alkyl ^b , alkoxy, halogen, CN and CF ₃ ; where alkyl ^b , alkoxy, R8 and R9 have the meanings defined in paragraph 1; or a pharmaceutically acceptable salt or solvate thereof. 12. Pharmaceutical composition according to any of paragraphs 1 or 10, 11, use according to any of paragraphs 2, 4-7 or 10, 11, method according to any of paragraphs 3-7 or 10, 11, or a compound according to any of claims 8-11, wherein B is selected from phenyl and pyridyl, wherein phenyl is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, CF ₃ and halogen, and pyridyl is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, CF ₃ and halogen; where alkyl ^b and alkoxy have the meanings defined in paragraph 1; or a pharmaceutically acceptable salt or solvate thereof. 13. The pharmaceutical composition according to claim 12, the use according to claim 12, the method according to claim 12, or the compound according to claim 12, where B is pyridyl, which is substituted with 1-3 substituents selected from alkyl ^b , alkoxy, CF ₃ and halogen; where alkyl ^b and alkoxy have the meanings defined in paragraph 1; or a pharmaceutically acceptable salt or solvate thereof. 14. Pharmaceutical composition according to any of claims 1 or 10-13, use according to any of claims 2, 4-7 or 10-13, method according to any of claims 3-7 or 10-13, or a compound according to any of claims 8 to 13, wherein W is C, X is N, and Y and Z are selected from C and N, such that the ring containing W, X, Y and Z is a pyrazole or an imidazole. or a pharmaceutically acceptable salt or solvate thereof. 15. Pharmaceutical composition according to any of claims 1 or 10-14, use according to any of claims 2, 4-7 or 10-14, method according to any of claims 3-7 or 10-14, or a compound according to any of claims 8-14, wherein R5 and R6 are independently absent or independently selected from H, CH ₂ OCH ₃ , cycloalkyl, -NR8R9, -NR8COR9 and CF ₃ ; where cycloalkyl, R8 and R9 have the meanings defined in paragraph 1; and where at least one of R5 and R6 is present and is not H. or a pharmaceutically acceptable salt or solvate thereof. 16. Pharmaceutical composition according to any of claims 1 or 10-15, use according to any of claims 2, 4-7 or 10-15, method according to any of claims 3-7 or 10-15, or a compound according to any of 8-15, where R5 means CH ₂ OCH ₃ ; or a pharmaceutically acceptable salt or solvate thereof. 17. Pharmaceutical composition according to any of claims 1 or 10-16, use according to any of claims 2, 4-7 or 10-16, method according to any of claims 3-7 or 10-16, or a compound according to any of claims 8-16, where A is phenyl substituted with -(CH ₂ ) ₁ -heteroaryl or -(CH ₂ ) ₁ -NR10R11; where heteroaryl, R10 and R11 have the meanings defined in paragraph 1; or a pharmaceutically acceptable salt or solvate thereof. 18. Pharmaceutical composition according to any of claims 1 or 10-16, use according to any of claims 2, 4-7 or 10-16, method according to any of claims 3-7 or 10-16, or a compound according to any of claims 8-16, where A is pyridyl substituted with -NR10R11; where R10 and R11 have the meanings defined in paragraph 1; or a pharmaceutically acceptable salt or solvate thereof. 19. Pharmaceutical composition according to claim 17 or 18, use according to claim 17 or 18, method according to claim 17 or 18, or compound according to claim 17 or 18, where R10 and R11, together with the nitrogen atom to which they are attached, form a 5-membered carbon-containing heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 2 double bonds and which may optionally be mono- or disubstituted methyl , Cl or F, or R10 and R11, together with the nitrogen atom to which they are attached, form a 6-membered carbon-containing heterocyclic ring, optionally containing an additional N atom, which may be saturated or unsaturated with 2 double bonds, and optionally mono- or disubstituted with substituents selected from oxo, methyl, Cl and F; or a pharmaceutically acceptable salt or solvate thereof. 20. Pharmaceutical composition according to any of claims 1 or 10-16, use according to any of claims 2, 4-7 or 10-16, method according to any of claims 3-7 or 10-16, or a compound according to any of pp.8-16, where A is selected from: And or a pharmaceutically acceptable salt or solvate thereof. 21. Pharmaceutical composition according to claim 20, use according to claim 20, method according to claim 20, or compound according to claim 20, where A is selected from: ; or a pharmaceutically acceptable salt or solvate thereof. 22. Pharmaceutical composition according to claim 20, use according to claim 20, method according to claim 20, or compound according to claim 20, where A is selected from: ; or a pharmaceutically acceptable salt or solvate thereof. 23. Pharmaceutical composition according to claim 1, use according to any of claims 2, 4-7, method according to any of claims 3-7, or a compound according to claim 8, where the compound is selected from: 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)pyrazol-4-carboxamide; N-[(2-fluoro-5-methoxyphenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4-carboxamide; N-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-4- carboxamide; N-[(4-chloro-2,6-difluorophenyl)methyl]-1-({4-[(4-methylpyrazol-1-yl)methyl]phenyl}methyl)-3-(trifluoromethyl)pyrazol-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)pyrazol-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 and their pharmaceutically acceptable salts and solvates. 24. A pharmaceutical composition having the ability to inhibit the activity of plasma kallikrein, containing (i) a compound or a pharmaceutically acceptable salt or solvate thereof according to claim 8 and (ii) a pharmaceutically acceptable carrier, diluent or excipient.